Mitral Valve Disease and the
Cavalier King Charles Spaniel

Page 3 -- Veterinary Resources

Veterinary Resources

This is a list of citations and summaries of veterinary research journal articles which are applicable to mitral valve disease and cavalier King Charles spaniels.

This list is in chronological order, from 1964 to the current date, with the most recent additions added at the bottom of this page. Hyper-linked titles are linked to the actual articles which are available on-line.

1960s & 1970s

Endocardial splitting of the left atrium in the dog with hemorrhage and hemopericardium. James W. Buchanan, Alan M. Kelly. Vet. Rad. January 1964; doi: 10.1111/j.1740-8261.1964.tb01302.x. Quote: In a series of 22 dogs with mitral insufficiency, endocardial splitting of the left atrium was found at necropsy. In 7 of these dogs, hemorrhage through the left atrial wall into the pericardial sac had occurred and caused hemopericardium. The purpose of this communication is to describe the clinical and radiographic appearance of hemopericardium due to left atrial hemorrhage and to contrast these with the clinical and radiographic appearance of pericardial effusion due to other causes. ... The etiology of endocardial splitting is not certain, although trauma and dilatation of the left atrium due to chronic mitral insufficiency must be considered major factors in the development of this lesion. Apparently endocardial splitting is not necessarily a fatal event occurring with left atrial dilatation since several dogs had healed splits. The largest splits were located in the caudal wall of the left atrium where jet lesions of chronic mitral insufficiency are most frequently observed. However, the occurrence of endocardial splitting in the left auricular appendage makes it necessary to consider etiologic factors in addition to the direction of the regurgitant jet of blood in mitral insufficiency.

Selective Angiography and Angiocardiography in Dogs with Acquired Cardiovascular Disease. James W. Buchanan. Vet. Rad. & Ultra. January 1965;6(1):5-20. Quote: Angiocardiograms are radiographs made while a radiopaque medium is circulating through the heart (and closely associated vessels). In selective angiocardiography, the contrast medium is injected through a catheter, the tip of which has been positioned into a specific vessel or cardiac chamber to visualize best a suspected abnormality based upon the clinical findings. The principles in selecting the chamber or vessel for the injection are based primarily upon the knowledge that cardiac valves are normally unidirectional and blood pressures in the left atrium, left ventricle, and aorta normally exceed the pressures in corresponding right heart structures. ... In dogs with suspected valvular insufficiencies, injections are made into the vessel or cardiac chamber from which the contrast medium would regurgitate (i.e., immediately “down stream” from the affected valve).

Epidemiologic and Genetic Studies of Congenital Heart Disease in the Dog. D. F. Patterson. Circulation Research. August 1968;23:171-202. Quote: "The prevalence rate for cardiovascular malformations in dogs presented to a large university veterinary clinic was 6.8 per 1000. Patent ductus arteriosus, as in man, was found predominantly in females. Breed-specific prevalence rates were significantly greater in purebred dogs than in mongrels, and the breed distributions of patent ductus arteriosus, pulmonic stenosis, subaortic stenosis, persistent right aortic arch, and tetralogy of Fallot were significantly different than would be expected if all breeds were equally susceptible to each type of malformation. On the basis of these observations, two hypotheses were made: (1) Genetic factors are determinants of certain types of congenital heart disease in the dog. (2) These genetic factors have specific effects on cardiac morphogenesis, resulting in specific types of cardiovascular malformations. Preliminary genetic studies confirmed the specific hereditary transmission of valvular pulmonic stenosis in beagles, persistent right aortic arch in German shepherds, and conal septal defects (including ventricular septal defects and tetralogy of Fallot) in keeshonden. The pattern of inheritance of these defects was not consistent with any simple genetic hypothesis. Patent ductus arteriosus in dogs of poodle ancestry and fibrous subaortic stenosis in Newfoundlands were shown provisionally to be transmitted in a manner consistent with autosomal dominant inheritance. The significance of these findings is considered in relation to present and future understanding of the etiology and pathogenesis of congenital heart disease."

Assessment of Cardiac Contractility: The Relation Between the Rate of Pressure Rise and Ventricular Pressure During Isovolumic Systole. Dean T. Mason, Eugene Braunwald, James W. Covell, Edmund H. Sonnenblick, John Ross, Jr. Circulation. July 1971; 44:47-58. Quote: It was considered that the relationship between dp/dt and simultaneously developed pressure during the course of isovolumic contraction might afford a more accurate measure of contractility than the maximum rate of intraventricular pressure rise (peak dp/dt). ... In conclusion, the determination of dp/dt and intraventricular pressure throughout isovolumic contraction in the presence of variable arterial pressure and small changes of preload provides a useful, simple, and experimentally verified approach to the assessment of alterations of the contractile state of the heart in intact man.

Observations on the effect of age on the severity of heart valve lesions in the dog. J. G. Whitney. J. Sm. Anim. Pract. August 1974; doi: 10.1111/j.1748-5827.1974.tb06529.x. Quote: Chronic valvular disease (valvular endocardiosis) is the most common cardiac abnormality of the dog. This paper demonstrates how this condition increases in frequency and severity with advancing age by means of a visual impression method for the gross examination of the heart valves. These lesions occur in descending order of frequency and severity in the left atrioventricular valve, the septal cusp of the right atrioventricular valve, the mural cusp of the same valve, the aortic valve and the pulmonary valve. The histopathological features of these lesions are outlined. ... There is considerable variation in the size of the normal heart valve in different breeds of dogs, therefore direct measurement of valve lesions offers little assistance as a gauge of the degree of valve damage. These difficulties have been overcome by the use of a visual impression method which classifies the valve lesions inot one of four grades. this means has proved most useful in practice; the principal criteria for this classification system are as follows: Type I lesion: A few small oedematous nodules are seen in the apposition, opposite the origins of the chordae tenineae. the chordae tendineae themselves are un-changed. There is no valvular incompetence. Type II lesion: Here the oedematouse nodules are larger and more numerous and some are greyish-white in colour. These lesions are confined to the area of apposition . The chordae tendineae are unaffected and there is no evidence of valvular incompetence. Type III lesion: Here there are larger greyish-white nodules and plaque-like elevations located in the area of apposition and associated with thickening and irregularity c--- proximal portion of the chordae tendineae, where they join the inflow surface of the valve cusp. There is evidence of valvular incompetence in some of these lesions. Type IV lesion: Here there are large greyish-white nodules and plaque-like elevations situated in the area of apposition and an associated thickening and irregularity of re... the chordae tendineae. These chordae may be stretched and ruptured in some cases. There is evidence of valvular incompetence in the majority of these cases. Areas of haemorrhage into the valve leaflet may be seen at any stage of the disease. The assessment of valvular competency is based on the clinical and pathological examination of the heart.

The renin-angiotensin-aldosterone system in congestive failure in conscious dogs. L Watkins, Jr, J A Burton, E Haber, J R Cant, F W Smith, A C Barger. J Clin Invest. June 1976;57(6):1606–1617. Quote: "The role of the renin-angiotensin-aldosterone system in the development of congestive failure has been assessed in the conscious dog by use of the nonapeptide converting enzyme inhibitor. Constriction of the pulmonary artery or thoracic inferior vena cava was maintained for 2 wk while daily measurements were made of plasma renin activity, plasma aldosterone, plasma volume, hematocrit, serum sodium and potassium concentrations, sodium and water balance, body weight, and arterial, caval, and atrial pressures. The initial response to constriction was a reduction in blood pressure, a rise in plasma renin activity, plasma aldosterone, and water intake, and nearly complete sodium retention. In the days after moderate constriction plasma volume and body weight increased (with development of ascites and edema); blood pressure, sodium excretion, plasma renin acvitity, and plasma aldosterone returned to normal. In animals in which blood pressure was not restored, plasma renin activity and plasma aldosterone remained elevated throughout the period of constriction. Single injections of converting enzyme inhibitor reduced blood pressure when plasma renin activity was elevated. Chronic infusion of the inhibitor in dogs with thoracic inferior vena caval constriction prevented the restoration of blood pressure and suppressed the rise in plasma aldosterone; sodium retention and volume expansion were less than in control experiments. Thus the renin-angiotensin-aldosterone system plays an essential role in the maintenance of blood pressure during the genesis of congestive failure. Initially, the restoration of blood pressure is dependent upon circulating angiotensin II; in the later stages, blood pressure is dependent upon the increase in plasma volume."

 Instantaneous Pressure-Volume Relationship of the Canine Right Ventricle. W. Lowell Maughan, Artin A. Shoukas, Kiichi Sagawa, Myron L. Weisfeldt. Circ. Res. March 1979;44(3):309-315. Quote: The instantaneous isovolumic and ejecting pressure-volume relationship of the right ventricle was studied in 11 cross-circulated, isolated canine hearts to characterize the right ventricular contractile state. Accurate measurement of volume was achieved by the use of a water-filled, thin latex balloon in the right ventricle connected to a special volume loading and transducing chamber. Pressure was measured with a miniature pressure transducer mounted within the balloon. Wide variations in loading conditions were achieved by changing the volume of air above the volumetric chamber. The pressure and volume data were collected from multiple beats under a constant contractile state in the same mode of contraction while the left ventricle was vented to air. Linear regression analysis applied to each of the isochronal pressure-volume data sets at 20-msec intervals from the onset of contraction showed a highly linear correlation between the pressure and the volume. Both the slope and the volume intercept of the regression lines changed with time throughout the cardiac cycle. The maximal slope of the regression line (E,,,,) averaged 2.50 ± 0.49 mm Hg/ml (mean ± SD) for ejecting beats and 2.68 ± 0.55 mm Hg/ml for isovolumic beats. Epinephrine infusions of 12.5 fig/min and 25.0 /ig/min increased E^u by 31% and 82%, respectively (P < 0.005). We conclude that: (1) The instantaneous pressure-volume relationships of the right ventricle in the isovolumic and ejecting modes can be regarded as linear, at least within the physiological range; however, these two modes of contraction did not yield an identical relationship. (2) The slope of these pressure-volume relationship curves changes with a change in the contractile state.

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1980s

Bradykinin stimulates afferent vagal C-fibres in intrapulmonary airways of dogs. Kaufman MP, Coleridge HM, Coleridge JCG, Baker DG. J Appl Physiol 1980;48:511-7.

Rapid shallow breathing evoked by selective stimulation of airway C fibres in dogs. H. M. Coleridge, J. C. G. Coleridge, A. M. Roberts. J Physiol 1983 Vol 340 pp 415-433.

Myocardial function in small dogs with chronic mitral regurgitation and severe congestive heart failure. Kittleson MD, Eyster GE, Knowlen GG, Bari Olivier N, Anderson LK. JAVMA. February 1984;184(4):455-459. Quote: “Systolic myocardial function was assessed in 16 dogs with severe congestive heart failure due to chronic mitral valve fibrosis. End-systolic diameters were measured on echocardiograms and end-systolic volume indices were calculated. Thirteen of the 16 dogs (81%) had normal or only mildly abnormal myocardial function. These data suggested that myocardial failure is not a prominent factor contributing to signs of heart failure in dogs with mitral regurgitation. Because of these data, the routine use of digitalis glycosides to increase cardiac contractility is seriously questioned in dogs with heart failure secondary to chronic mitral regurgitation. ... This study suggests that the contractile performance of the left ventricle in most dogs with chronic mitral valve fibrosis and clinical evidence of severe congestive heart failure is either normal or mildly depressed. This suggests that congestive heart failure in these patients is due to severe regurgitation and subsequent volume overload of the left ventricle and atrium. Heart failure secondary to mitral regurgitation can be due not only to myocardial failure, but also to severe regurgitation by itself or in combination with myocardial failure.”

Quantitative cross-sectional echocardiography in the normal dog. O’Grady MR, Bonagura JD, Powers JD, Herring DS. Vet Radiol March 1986;27(2):34–49. Quote: Two-dimensional echocardiography was performed on 18 unanesthetized, normal dogs (4.5 to 30 kg). Measurements of wall thickness, intracavitary dimensions, and cross-sectional area of the left atrium, left ventricle, and aorta were made. Satisfactory data were obtained from 17 dogs, and were used to determine normal values. Normal data were tested for significant correlation to body weight (kg) by linear regression. Repeatability was studied in six dogs examined, on three separate occasions, during a 5-day period. Differences between values obtained on different days were evaluated by analysis of variance. Satisfactory qualitative echocardiograms were repeatedly obtained by using consistent sites of transducer placement and by identifying internal cardiac structures. These tomographic planes were highly reproducible, with only ventricular length, and some views of the ventricular septum, showing statistically significant (P < 0.05) differences. Almost all linear and area measurements were significantly correlated to body size, while most indices of left ventricular function were independent of body weight. Dimensions obtained from the left and right parasternal position were nearly identical. Cross-sectional echocardiography allows repeatable assessment of cardiac anatomy, and it should prove useful for identification and quantitation of heart disease in the dog. ... LA:Aorta (RP) mean: 2.37.

The pharmacology of ketanserin, the first selective serotonin S2-antagonist. Frans Awouters. Drug Development Research. 1985;6(4):263. Quote: "The quinazolinedione derivative ketanserin was studied in many known and newly introduced tests to obtain its detailed pharmacological profile. Ketanserin was a potent, orally very effective antagonist of endogenous serotonin (5-HT): 0.15 mg/kg (ED50 s.c. and p.o.) protected rats from the gastric lesions induced by the mast cell activator compound 48/80. Many other in vivo observations, such as antagonism of tryptamine-induced cyanosis in rats (ED50 s.c., 0.056 mg/kg), inhibition of mescaline-induced head twitches in rats (ED50 s.c., 0.097 mg/kg), and inhibition of 5-HT-induced effects in various species, revealed the potent antagonist activity of ketanserin on vasoconstrictor and bronchoconstrictor actions of serotonin. When compared to other compounds with 5-HT-antagonist activity, the pharmacological profile of ketanserin corresponds to that of a potent, peripherally acting serotonin antagonist with weak associated α-adrenergic blocking and antihistamine activity. In addition, binding experiments and studies on isolated tissues and platelets disclosed the high selectivity of ketanserin's serotonin antagonism. Serotonin S2-receptors of the rat frontal cortex were labeled by low concentrations of ketanserin (Ki = 0.39 nM), and affinity of drugs for S2-receptors highly correlated with their activity against serotonin-induced contractions of blood vessel preparations (e.g., of the rat caudal artery, A2-value of ketanserin: 0.83 nM) and serotonin-induced platelet aggregation. In these experiments, ketanserin was devoid of serotonin! -binding, of agonist activity on vascular smooth muscle, of inhibition of 5-HT uptake into platelets, and of 5-HT antagonism on gastrointestinal smooth muscle. The absence of all these secondary activities is pharmacologically characteristic for ketanserin when compared to known serotonin-antagonists. On the basis of this profile of pure and selective serotonin S2-antagonism, ketanserin was studied in experimental hypertension and in many spontaneous and induced circulatory dysfunctions. A prolonged antihypertensive effect can be obtained with ketanserin in the absence of distinct compensatory mechanisms. Vascular dysfunction can start at low, sensitizing concentrations of serotonin and be almost completely corrected by ketanserin, despite the involvement of other mediators. Ketanserin is a very effective antagonist of the mixture of vasoactive substances released by aggregating platelets. In experimental thrombosis, sustained ketanserin treatment prevents the impairment of blood flow and the associated organ deficiency. When deviations from normal hemorrheology are long-standing, as in aged spontaneously hypertensive dogs, acute ketanserin administration is distinctly antihypertensive and reduces hemorrheological abnormalities. At the conclusion of these extensive studies, serotonin appears to act at peripheral S2-receptors as the primary pathological mediator of vascular congestion."

Valvular incompetence in cavalier King Charles spaniels. Darke, PG. Vet Rec., Apr 1987(15); 120: 365 - 366. Paraprase: 50% of Cavalier King Charles (CKC) spaniels have a murmur due to MR by the age of 5–6 years and at 10 years of age, the prevalence of murmurs approaches 100%.

Enhanced recovery of diastolic function after global myocardial ischemia in the intact animal. Kevin Tveter, John St.Cyr, Joseph Schneider, Richard Bianco, John Foker. Pediatr. Res. 1988; 23:226A. Quote: "The relationship of myocardial ATP levels and postischemic dysfunction remains controversial. In an intact animal model of global ischemia (Isc) and recovery, we have found ribose (R) or adenine (A) and R accelerated the return of ATP levels (84% and 80% recovery by 24 hrs). The purpose of this study was to determine the effects of enhancing ATP recovery on postlsc function. Following 20 min of Isc on cardiopulmonary bypass, dogs received either R (80mM) (n=S), A (20mM) and R (80mM)(n=5) or saline (NS)(n=6) for 24 hrs. The end-systolic pressure-volume ratio CEmax• mmHg/ml), dP/dt (mmHg/sec) and diastolic circumferential stress (cr, dynes x 103/cm2)-strain (e:) relationships were determined from sonomicrometry and micromanometry data during transient vena caval occlusions. ... We conclude: (1) recovery of systolic function is essentially complete by 4 hrs. (2) Return of diastolic function is enhanced similarly to ATP recovery by R or A/R. (3) Because A did not further enhance ATP recovery, R appears to be the rate limiting ATP precursor."

Enhanced high energy phosphate recovery with ribose infusion after global myocardial ischemia in a canine model. John A. St. Cyr, Richard W. Bianco, Joseph R. Schneider, John R. Mahoney, Jr., Kevin Tveter, Stanley Einzig, John E. Foker. J. Surgical Res. February 1989;46:157-162. Quote: High energy phosphate levels are depressed following global ischemia and require several days to completely recover. Short-term methods to enhance ATP recovery have included infusion of ATP precursors, inhibition of enzymes that catabolize AMP, and membrane transport stabilization. Several precursors have been used to augment adenine nucleotide synthesis including adenosine, inosine, adenine, and ribose. Because of the short-term nature of previous experiments, recovery had been incomplete and the effects in the intact animal unknown. The purpose of this study was to determine the effects of ribose infusion in a long-term model of global ischemia and attempt to identify the precursor which limits myocardial ATP regeneration in the intact animal. Global myocardial ischemia (20 min, 37°C) was produced in dogs on cardiopulmonary bypass. With reperfusion either ribose (80 mM) in normal saline or normal saline alone was infused at 1 ml/min into the right atrium and the animals were followed for 24 hr. Ventricular biopsies were obtained through an indwelling ventricular cannula prior to ischemia, at the end of ischemia, and 4 and 24 hr postischemia and analyzed for adenine nucleotides and creatine phosphate levels. Radiolabeled microspheres were used to measure myocardial and renal blood flows and no significant difference was found between ribose-treated control groups. In both groups, myocardial ATP levels fell by at least 50% at the end of ischemia. No significant ATP recovery occurred after 24 hr in the control dogs, but in the ribose-treated animals, ATP levels rebounded to 85% of control by 24 hr. Total myocardial adenine nucleotide content and energy charge also recovered in the ribose group but not in the control animals. The ribose infusion, therefore, significantly enhanced the recovery of energy levels in the postischemic myocardium in the intact animals.

Effects of the positive inotropic agents milrinone and pimobendan on the development of lethal ischemic arrhythmias in conscious dogs with recent myocardial infarction. Lynch JJ Jr, Uprichard AC, Frye JW, Driscoll EM, Kitzen JM, Lucchesi BR. J Cardiovasc Pharmacol. October 1989;14(4):585-97. Quote: The effects of milrinone and pimobendan upon the initiation of programmed ventricular stimulation-induced ventricular tachycardia (VT) and the incidence of lethal ischemic ventricular arrhythmias were assessed in conscious dogs with recent anterior myocardial infarctions. Based upon the results of previous studies, the animals which were entered into this investigation were nonresponsive to baseline programmed stimulation and, therefore, considered to be at "low risk" toward the development of subsequent lethal ischemic arrhythmias. Milrinone (200 micrograms/kg/h continuous i.v. infusion) and pimobendan (300 micrograms/kg i.v.) were administered in dosing regimens shown to produce equivalent and sustained increases in left ventricular (LV) + dP/dt. At the time of repeat electrophysiologic testing, 9 of 9 pimobendan-, 9 of 10 milrinone-, and 12 of 12 concurrent vehicle-treated animals remained nonresponsive to programmed ventricular stimulation. Compared to a total control population of 39 "low risk" postinfarction dogs; however, both milrinone and pimobendan administration increased the incidence of sudden ventricular fibrillation occurring in response to the development of acute posterolateral ischemia (milrinone 4 of 10 [40%] and pimobendan 4 of 10 [40%] versus "low risk" control population 4 of 39 [10.3%]; p = 0.038). The incidence of ischemic mortality at 24 h after the development of posterolateral myocardial ischemia was increased in the milrinone-treated group (6 of 10 [60%]) compared to the "low risk" control population (6 of 39 [15.2%]; p = 0.007), whereas the incidence of 24-h ischemic mortality in the pimobendan-treated group (4 of 10 [40%]) was only of borderline statistical significance when compared to that of the "low risk" control population (p = 0.083). Milrinone, but not pimobendan, delayed the onset of acute posterolateral myocardial ischemia in the postinfarction dogs. The predominant electrophysiologic effects of both milrinone and pimobendan were decreases in ventricular refractoriness in both non-infarct (NZ) and in infarct zones (IZ), as well as reductions in electrocardiographic QTc or QT intervals. These findings suggest that with both positive inotropic agents, including milrinone which may possess protective antithrombotic action, sudden death may be increased via a reduction in ventricular refractoriness in the ischemically injured heart. ... In this investigation, both pimobendan and milrinone administration resulted in a significant increase in the incidence of sudden ischemic ventricular fibrillation (40.0% pimobendan and 40.0% milrinone versus 10.3% total "low risk" population, p = 0.038 for each comparison). ... In the present investigation, both milrinone and pimobendan, administered in equivalently inotropic dosing regimens to "low risk" postinfarction dogs, increased the incidence of sudden primary ventricular fibrillation and of total 24-h mortality occurring in response to the development of posterolateral myocardial ischemia and previous anterior myocardial infarction. ... The enhanced susceptibility toward the development of ischemic ventricular arrhythmias in the presence of the inotropic interventions is not predicted by programmed ventricular stimulation testing prior to the ischemic event. ... The present data, even when subjected to adjustments for multigroup comparisons, indicate strong trends toward increasing incidences of sudden ischemic ventricular fibrillation in the presence of both pimobendan and milrinone (p = 0.076 compared to control), as well as a significant increase in the incidence of 24-h ischemic postinfarction mortality with milrinone (p = 0.014 compared to control). Hence, these findings suggest that with both positive inotropic agents, including milrinone which may possess protective antithrombotic action, sudden death may be increased via a reduction in ventricular refractoriness in the ischemically injured heart. It is possible that such a deleterious electrophysiologic action might occur at lower dosages in the setting of more severe myocardial ischemic injury.

Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. D M Mancini, E Coyle, A Coggan, J Beltz, N Ferraro, S Montain, J R Wilson. Circulation. November 1989;80(5):1338-1346. Quote: Patients with heart failure frequently exhibit abnormal skeletal muscle metabolic responses to exercise, as assessed with 31P NMR. To investigate whether these metabolic abnormalities are due to intrinsic skeletal muscle changes, we performed gastrocnemius muscle biopsies on 22 patients with heart failure and on eight normal subjects. Biopsies were analyzed for fiber type and area, capillarity, citrate synthase, phospho-fructokinase, lactate dehydrogenase, and beta-hydroxyacyl CoA dehydrogenase activity. All patients with heart failure also underwent 31P NMR studies of their calf muscle during plantarflexion at three workloads. Muscle pH responses and the relation of the ratio of inorganic phosphate to phosphocreatine (Pi/PCr) to systemic VO2 were then evaluated. Compared with normal subjects, patients with heart failure exhibited a shift in fiber distribution with increased percentage of the fast twitch, glycolytic, easily fatigable type IIb fibers, atrophy of type IIa and type IIb fibers, and decreased activity of beta-hydroxyacyl CoA dehydrogenase. ... Type IIb fibers represent fibers that are fast twitch, have a low aerobic potential, and are easily fatigued. ... No significant linear correlation could be identified between the slope of the Pi/PCr to VO2 relation and muscle histochemistry or enzyme activities. Similarly, no linear relation was found between intracellular pH at peak exercise and any muscle variable. These data suggest that patients with heart failure develop intrinsic skeletal muscle changes but that these intrinsic muscle changes do not contribute significantly to the abnormal skeletal muscle 31P NMR metabolic responses observed in such patients.

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1990 to 1994

Depressed contractile function due to canine mitral regurgitation improves after correction of the volume overload. K Nakano, M M Swindle, F Spinale, K Ishihara, S Kanazawa, A Smith, R W Biederman, L Clamp, Y Hamada, M R Zile, et al. Journal of Clinical Investigation 1991 June; 87(6): 2077–2086. It is known that long-standing volume overload on the left ventricle due to mitral regurgitation eventually leads to contractile dysfunction. However, it is unknown whether or not correction of the volume overload can lead to recovery of contractility. In this study we tested the hypothesis that depressed contractile function due to volume overload in mitral regurgitation could return toward normal after mitral valve replacement. Using a canine model of mitral regurgitation which is known to produce contractile dysfunction, we examined contractile function longitudinally in seven dogs at baseline, after 3 mo of mitral regurgitation, 1 mo after mitral valve replacement, and 3 mo after mitral valve replacement. After 3 mo of mitral regurgitation (regurgitant fraction 0.62 +/- 0.04), end-diastolic volume had nearly doubled from 68 +/- 6.8 to 123 +/- 12.1 ml (P less than 0.05). All five indices of contractile function which we examined were depressed. For instance, maximum fiber elastance (EmaxF) obtained by assessment of time-varying elastance decreased from 5.95 +/- 0.71 to 2.25 +/- 0.18 (P less than 0.05). The end-systolic stiffness constant (k) was also depressed from 4.2 +/- 0.4 to 2.1 +/- 0.3. 3 mo after mitral valve replacement all indexes of contractile function had returned to or toward normal (e.g., EmaxF 3.65 +/- 0.21 and k 4.2 +/- 0.3). We conclude that previously depressed contractile function due to volume overload can improve after correction of the overload.

The Effect of Pimobendan on Myocardial Mechanical Function and Metabolism in Dogs: Comparison with Dobutamine. Kazuo Ichihara, Yashusi Abikio. J. Pharm. Pharmacol. August 1991;43:583-588. Quote: The effect of pimobendan, a newly developed cardiotonic agent, on myocardial mechanical function and energy metabolism has been examined in the dog heart, and compared with that of dobutamine. Either saline, vehicle for pimobendan, dobutamine (0·3 and 1 μg kg−1), or pimobendan (0·3 and 1 mg kg−1) was injected intravenously. Dobutamine and pimobendan both increased the first derivative of left ventricular pressure and percent segment shortening, indicating their positive inotropic action. After 2 min of dobutamine injection, or after 20 min of pimobendan injection, the myocardium was removed, and used for determination of the tissue levels of metabolites of energy and carbohydrate metabolism. In genera), all metabolic parameters measured were not changed by either dobutamine or pimobendan injection. In animals with aortic constriction for 10 months, dobutamine and pimobendan injections did not alter the myocardial energy and carbohydrate metabolism. Although dobutamine and pimobendan increased the cardiac mechanical function, they did not disturb the myocardial energy and carbohydrate metabolism. ... Pimobendan did not alter the levels of ATP, ADP or AMP.

Understanding Mitral Valve Problems in Cavaliers. Buchanan J, Beardow A. Cavaliers of the Northeast News & Views; Nov 1991.

Mitral valve replacement in dilated canine hearts with chronic mitral regurgitation. Importance of the mitral subvalvular apparatus. Yun KL, Rayhill SC, Niczyporuk MA, Fann JI, Zipkin RE, Derby GC, Handen CE, Daughters GT, Ingels NB, Bolger AF Circulation. 1991 Nov.; 84: 5 Suppl: III112-24.

Prevalence of mitral valve insufficiency in cavalier King Charles spaniels. Malik R, Hunt GB, Allan GS. Vet Rec., Apr 1992; 130: 302 - 303.

Alterations of skeletal muscle in chronic heart failure. H Drexler, U Riede, T Münzel, H König, E Funke, H Just. Circulation. May 1992;85(5):1751-1759. Quote: BACKGROUND: The present study was designed to define the prevalence and characteristics of skeletal muscle alterations in patients with chronic heart failure (CHF) and their relation to exercise capacity. METHODS AND RESULTS: The ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry in 57 patients with CHF and 18 healthy controls. The volume density of mitochondria (Vvm) and the surface density (Svmc) of mitochondrial cristae were evaluated as a structural correlate of oxidative capacity of skeletal muscle. Vvm and Svmc were reduced by approximately 20% in patients with severe CHF irrespective of age and etiology. The cytochrome oxidase activity in mitochondria as determined by cytochemistry and subsequent morphometry in a subset of patients (n = 10) was significantly decreased in heart failure (p less than 0.01). The capillary length density of skeletal muscle was reduced in CHF (n = 12, p less than 0.05), and the fiber type distribution was shifted to type II fibers (n = 15, p less than 0.05). Vvm and Svmc were significantly related to peak exercise VO2 (r = 0.56, p less than 0.001, n = 60) and to VO2 at anaerobic threshold (r = 0.535, p less than 0.0001, n = 60). In 16 patients with severe heart failure, Vvm was inversely related to the duration of heart failure (r = 0.545, p less than 0.03). In 11 patients who underwent repeat biopsies after 4 months, a correlation was observed between the change in Vvm and the change in peak exercise VO2 (r = 0.89, p less than 0.001). ... The present study provides evidence that the volume density, cristae surface density, and cytochrome oxidase activity of skeletal muscle mitochondria are substantially reduced in patients with severe chronic heart failure, indicating a decreased oxidative capacity of working muscle. ... This suggests that the functional aerobic and anaerobic capacity of patients with severe heart failure is limited not only by the capacity of the oxygen transport system but also by the oxidative capacity of mitochondria in the skeletal muscles. ... The fiber type distribution was shifted to type II fibers in patients with chronic heart failure, consistent with two recent studies that reported a shift to type IIB fibers. Because type IIB fibers possess less oxidative capacity than type IIA or even type I fibers, the reduced overall oxidative capacity of skeletal muscle in our patient population could be attributed to this shift of oxidative capacity in all fiber type distribution. Conversely, a reduction of oxidative capacity in all fiber types may result in a shift in fiber type distribution, e.g., by reducing the concentration of oxidative enzymes within type I and IIA fibers and thereby missing the critical level required to be classified as type I or type IIA fiber. ... The decrease in mitochondrial mass was accompanied by a similar reduction in capillary length density in a subset of our patients with chronic heart failure, suggesting inadequate capillary blood per unit volume of skeletal muscle. Similarly, the capillary length density has been shown to decrease with immobilization, whereas the capillary supply is substantially increased in accordance with the oxidative capacity of skeletal muscle during exercise training. It is conceivable, therefore, that the same mechanisms control mitochondrial content and capillary supply of skeletal muscle. ... Importantly, the evaluation of a large cohort of patients with a wide range of functional impairment revealed that skeletal muscle alterations emerge late in the course of this disorder, being present only in patients with severe heart failure and related to the duration of heart failure. ... CONCLUSIONS: The present study demonstrates that patients with severe chronic heart failure develop a reduction in oxidative capacity of skeletal muscle, which, in turn, may play an important role in the clinical syndrome of heart failure by adversely affecting exercise capacity in this condition. Thus, the functional capacity of patients with heart failure is limited not only by the capacity of the oxygen transport system but also by the oxidative capacity of mitochondria in working muscle. The alterations of skeletal muscle are similar to those observed with prolonged deconditioning or immobilization and are related to the duration of heart failure. Thus, our data would support the notion that chronic deconditioning is involved in the development of these potentially reversible skeletal muscle alterations.

Chronic valvular disease in the cavalier King Charles spaniel in Sweden. Häggström J, Hansson K, Kvart C, L Swenson L. Vet Rec., Dec 1992; 131: 549 - 553. Quote: "The prevalence of chronic valvular disease was studied in 494 cavalier King Charles spaniels with a mean (+/- sd) age of 3.0 +/- 2.7 years. Cardiac murmurs were detected in 65 (13.2 per cent) of the dogs. Among 61 cavalier King Charles spaniels with a mean age of 6.4 +/- 2.8 years, cardiac murmurs were detected in 32 (52 per cent). In both groups of dogs the prevalence of cardiac murmurs was low among dogs younger than three years (1.9 per cent) but increased with age (P < 0.001). The estimated ages at which 50 per cent of the dogs had developed murmurs were 7.5 and 6.2 years, respectively. When 39 of the 61 dogs were re-examined three years later, cardiac murmurs were detected in 28 (72 per cent), and the intensities of the murmurs had generally increased (P < 0.05). Nine (28 per cent) of the dogs which had previously had murmurs had been euthanased for signs of congestive heart failure whereas none of the dogs which had been free of murmurs had died from congestive heart failure. Animal insurance statistics from 1982 to 1990 (1983 excluded) for dogs less than 10 years old showed that claims for veterinary care or death or euthanasia were five times more common in the cavalier King Charles spaniel than in dachshunds (P < 0.001) and eight times more common than the mean for all other insured breeds (P < 0.001)."

Chronic Mitral Valve Disease in Cavalier King Charles Spaniels: 95 Cases (1987-1991). Beardow A, Buchanan J. JAVMA 1993, Jan; 203(7): 1023-1029. Quote: "Systolic heart murmurs caused by chronic mitral valve disease are particularly common in Cavalier King Charles Spaniels (CKCS) in Great Britain. To determine if American-bred CKCS have a similar high prevalence of chronic valve disease, results of stethoscopic examinations on 394 CKCS were analyzed. Left apical systolic heart murmurs were found in 22% of the dogs. The prevalence ranged from 9% in dogs < 1 year old to 100% in those > or = 10 years old; prevalence was 56% in dogs > or = 4 years old. Differences were not found in prevalence between sexes and among various coat colors. Reexamination of 79 dogs after 1 year revealed an incidence of new murmurs of 21%. Comparison of ages at initial examination in 128 referral hospital cases with chronic mitral valve disease revealed a mean age of 6.25 years in 17 CKCS, in contrast to a mean age of 12 years in other breeds. Echocardiographic and necropsy findings indicated that ruptured chordae tendineae and mitral valve prolapse are major components in the chronic valve disease process in CKCS."

Effects of dietary sodium intake on blood pressure measurements in partially nephrectomized dogs. Greco DS, Lees GE, Dzendzel G, Carter AB. Amer. J. Vet. Res. January 1994;55(1):160-165. Quote: "Systolic, diastolic, and mean arterial blood pressure were measured by femoral artery puncture every other day in 2 groups (n = 4) of partially nephrectomized (approx 75%) dogs fed 2 concentrations of dietary sodium beginning 9 weeks after partial nephrectomy was completed. In a double crossover design, dogs were fed a low-sodium (0.18% sodium on a dry-weight basis) or high-sodium (1.3% sodium on a dry-weight basis) diet in 2 sequences (L/H/L or H/L/H) for 3 consecutive 4-week observation periods. Significant effect of sequence was found in dogs fed the L/H/L sequence, compared with those fed the H/L/H sequence. Systolic blood pressure was significantly (P < 0.05) increased in dogs fed the L/H/L sequence (175 +/- 16 mm of Hg), compared with dogs fed the H/L/H sequence (156 +/- 14 mm of Hg). Mean arterial blood pressure was higher, but not significantly different, for the L/H/L sequence (116 +/- 8 mm of Hg) vs the H/L/H sequence (109 +/- 6 mm of Hg). Significant difference in diastolic pressure was not observed between the L/H/L (86 +/- 10 mm of Hg) and H/L/H (86 +/- 10 mm of Hg) sequences. Restricted sodium intake (0.18% sodium on a dry-weight basis) was associated with moderate systolic hypertension in dogs with experimentally induced chronic renal disease. Acute fluctuations in dietary sodium intake had no apparent immediate effect on blood pressure in dogs with this mild to moderate degree of renal dysfunction."

Plasma concentration of atrial natriuretic peptide in relation to severity of mitral regurgitation in Cavalier King Charles Spaniels. Häggström J, Hansson K, Karlberg BE, Kvart C, Olsson K. Am J Vet Res. 1994 May;55(5):698-703. Quote: "Plasma concentration of immunoreactive atrial natriuretic peptide (ir-ANP) was investigated in 83 Cavalier King Charles Spaniels with variable severity of mitral regurgitation caused by chronic valvular disease (CVD). Severity of mitral incompetence was assessed by echocardiography. Significant differences in plasma concentrations of ir-ANP were not found between clinically normal dogs (New York Heart Association functional class O), dogs with only cardiac murmur (class I), and dogs with echocardiographic evidence of slight to moderate left atrial and ventricular dilatation (class II). Dogs with severe left atrial and ventricular dilatation and clinical signs of congestion (classes III and IV) were found to have significantly (P < 0.001) increased plasma concentration of ir-ANP. Overall, moderate degree of association was found between plasma concentration of ir-ANP and left atrial and left ventricular diameters (Pearson's r = 0.65, 0.60, respectively, P < 0.001), as well as heart rate (r = 0.47, P < 0.01). However, left atrial enlargement was found to have the predominant effect on plasma ir-ANP concentration. It is concluded that the plasma concentration of ir-ANP did not become markedly increased before decompensation of chronic mitral regurgitation associated with severe enlargement of the left atrium and ventricle in Cavalier King Charles Spaniels.

Tricuspid and mitral valvular disease: valve replacement. Breznock EM. Seminars in Vety Med & Surg (Small Anim). 1994 Nov;9(4):234-9.

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1995

Mitral Valve Disease in Cavalier King Charles Spaniels. Darke PG. In Kirks Current Veterinary Therapy, XII, Small Animal Practice. Bonagura (Editor). 1995:837-841.

Vertebral Scale System to Measure Canine Heart Size in Radiographs. James Buchanan and Jörg Bücheler. JAVMA January 1995; 206(2): 194-199. Quote: "A method for measuring canine heart size in radiographs was developed on the basis that there is a good correlation between heart size and body length regardless of the conformation of the thorax. The lengths of the long and short axes of the heart of 100 clinically normal dogs were determined with calipers, and the dimensions were scaled against the length of vertebrae dorsal to the heart beginning with T4. The sum of the long and short axes of the heart expressed as vertebral heart size was 9.7 +/- 0.5 vertebrae. The differences between dogs with a wide or deep thorax, males and females, and right or left lateral recumbency were not significant. The caudal vena cava was 0.75 vertebrae +/- 0.13 in comparison to the length of the vertebra over the tracheal bifurcation. ... The major uses of the VHS method are in helping determine whether cardiomegaly exists in dogs with minimal radiographic changes and quantification of the progression of cardiomegaly over time in a glven dog." 

Heart sounds and murmurs: changes related to severity of chronic valvular disease in the Cavalier King Charles spaniel. Häggström J, Kvart C, Hansson K. J Vet Intern Med. 1995 Mar-Apr;9(2):75-85.  Quote: "Auscultatory, phono-cardiographic (PCG), radiographic, and echocardiographic evidence of chronic valvular disease (CVD) were studied in 79 Cavalier King Charles Spaniels with a mean age of 7.6 years (SD 2.6). Cardiac murmurs were present in 59 of the dogs and the intensity of the systolic cardiac murmur, assessed by auscultation (grade 1-6), was correlated (P < .001) to the severity of CVD (heart failure class) and to the echocardiographic dimensions of the heart (left atrial ratio, La/Ao-d, and left ventricular end diastolic diameter, LVEDD) (both P < .001). ...The relationship between cardiac dimensions (LVEDD and La/Ao-d) and S1a/S2a ratio was described by quadratic regression and found to be significant for both parameters (LVEDD; P < .001, R2 = .54 and La/Ao-d; P < .001, R2 = .63). The presence of a third heart sound (S3) was detected, using PCG, in 21 of the 68 dogs. The proportion of dogs exhibiting S3 increased with heart failure class (and increasing cardiac dimensions) (P < .001). These findings were confirmed by observations in 13 Cavalier King Charles Spaniels with cardiac failure progressing from heart failure class I to class II (Mean LVEDD from 30.2 to 35.2 mm and mean La/Ao-d from 1.09 to 1.43). An increase in intensity of the heart murmur, assessed by auscultation, increase in the ratio of the amplitudes of S1 and S2, as well as a shortening in Q-S2 and S1-S2 intervals (all P < .01) were found in these dogs. ... This study shows that the heart sounds and murmurs can provide the clinician with valuable information when evaluating dogs with mitral regurgitation. The intensity of the murmur is correlated to the severity of the CVD (heart failure class) and almost always seems to increase in intensity over a 3-year period in the Cavalier King Charles Spaniel. An increase in intensity of the first heart sound together with a decrease in intensity of the second heart sound and the presence of an S3 (on PCG recordings) are further signs of moderate to severe CVD. Therefore, a rough estimation of the severity of mitral regurgitation is possible by auscultation and phonocardiography of the typical small dog affected by CVD."

Acute and Short-Term Hemodynamic, Echocardiography, and Clinical Effects of Enalapril Maleate in Dogs With Naturally Acquired Heart Failure: Results of the Invasive Multicenter PROspective Veterinary Evaluation of Enalapril Study: The IMPROVE Study Group. D. David Sisson. J. Vet. Intern. Med.  July 1995;9(4):234-242. Quote: The efficacy of enalapril maleate in dogs with naturally acquired class III or class IV heart failure was evaluated in a multicenter study. Fifty-eight dogs with dilated cardiomyopathy (35 dogs), mitral regurgitation (22 dogs), or aortic regurgitation (1 dog) receiving conventional therapy for heart failure (furosemide with or without digoxin) were included in a randomized double-blind study. Thirty-one dogs received enalapril tablets PO at approximately 0.5 mg/kg body weight bid, and 27 dogs received placebo tablets PO bid. Physical, electrocardiographic, hemodynamic, echocardiographic, radiographic, and clinical examinations were performed on each dog before treatment and at the end of the approximately 21-day study. After treatment on day 0, the enalapril-treated dogs had significantly (P < .05) lower heart rate, mean systemic arterial blood pressure, and mean pulmonary arterial blood pressure than the placebo-treated dogs. Pulmonary capillary wedge pressure was marginally decreased (P= .0567) in the enalapril-treated dogs. When compared with those in the placebo-treated dogs, scores for pulmonary edema were significantly (P= .05) decreased on day 2 in the enalapril-treated dogs. At the end of the study, enalapril-treated dogs had significantly (P= .05) greater decreases in class of heart failure, pulmonary edema score, and mobility score relative to baseline, and had significantly (P= .05) better overall evaluation scores when compared with the placebo-treated dogs. This study shows the beneficial hemodynamic and clinical effects of adding enalapril to conventional therapy for dogs with heart failure.

Controlled Clinical Evaluation of Enalapril in Dogs With Heart Failure: Results of the Cooperative Veterinary Enalapril Study Group The COVE Study Group. Jerry A. Woodfield. J. Vet. Intern. Med. July 1995;9(4):243-252. Quote: The clinical efficacy and safety of enalapril were evaluated in dogs with moderate or severe heart failure. This study was conducted at 19 centers and included 211 clientowned dogs with heart failure caused by mitral regurgitation (MR) due to acquired valvular disease or dilated cardiomyopathy (DCM). Dogs of various breeds, ages, and weights were included in the study. Replicates of 2 dogs each were formed, using separate allocation schedules for dogs with MR or DCM. One dog within each replicate received placebo tablets (vehicle tablets without enalapril) PO sid or bid, and the other dog received enalapril tablets at approximately 0.5 mg/kg sid or bid, based on individual need. In addition to the experimental drug, all dogs, except 1 in the placebo group, received furosemide; 73.3% of the dogs in the placebo group and 78.3% of those in the enala pril group received digoxin. Doses of enalapril or placebo were administered for approximately 28 days. In the placebo group, 68.6% of the dogs completed the study compared with 84.9% in the enalapril group; the difference between groups was significant (P= .01). Significantly (P= .01) more dogs in the placebo group compared with the enalapril group died or were removed from the study because of progression of heart failure. On day 28, all 14 clinical variables measured improved significantly (P= .01) in the enalapril group compared with the placebo group. Five dogs (3 from the placebo group and 2 from the enalapril group) had to be removed from the study as a result of azotemia.

Plasma Taurine Concentrations in Normal Dogs and in Dogs With Heart Disease. George A. Kramer, Mark D. Kittleson, Philip R. Fox, Julia Lewis, Paul D. Pion. J.Vet.Int.Med. July 1995;9(4):253-258. Quote: "Plasma taurine concentrations were determined in 76 dogs with dilated cardiomyopathy (DCM), 28 dogs with acquired valvular disease (AVD), and 47 normal (control) dogs. ... [P]lasma taurine concentrations were highest in dogs with AVD [e.g., MVD]. ... The importance of high plasma taurine concentrations in dogs with acquired valvular disease is unknown. One possible explanation is that the high plasma taurine concentrations may be part of a mechanism to provide the stressed myocardium a larger pool of taurine for active transport across the sarcolemma. The liver is a major source of taurine synthesis for export into the One might therefore expect a higher Lcystine-sulfinate carboxylase (EC 4. I. 1.29) activity in dogs with AVD compared with control dogs if this hypothesis is valid. Alternatively, the higher plasma taurine concentrations in dogs with AVD may be a direct result of feeding behavior of owners of dogs with AVD (generally small breeds) versus owners of dogs with DCM (generally large breeds), or it may be an artifact secondary to enhanced release of taurine from platelets or other blood elements during more difficult venipuncture in small dogs with AVD. ... We conclude that plasma taurine concentrations may be increased in dogs with AVD and that most dogs with DCM do not have taurine deficiency. However, there may be certain breeds or individual dogs that have low plasma taurine concentrations in association with DCM. Whether this is a consistent finding in certain breeds, whether or not the association is causal, and whether or not DCM in dogs with low plasma taurine concentrations respond to taurine supplementation remains to be determined."

Mitral valve replacement for the treatment of congenital mitral dysplasia in a bull terrier. White R.N., Stepien R.L., Hammond R.A., Holden D.J., Milner H.R., Cobb M.A., Hellens S.H. The Journal of Small Animal Practice 1995: 36, 407–410.

Activation of the renin-angiotensin system in dogs with asymptomatic and mildly symptomatic mitral valvular insufficiency. Henrik D. Pedersen, Jørgen Koch, Knud Poulsen, Asger L. Jensen, Annette Flagstad. J. Vet. Intern. Med. September 1995;9(5):328-331. Quote: The renin-angiotensin system has important pathophysiologic implications in the development of congestive heart failure. The activity of the renin-angiotensin system early in the course of heart disease and heart failure in dogs was evaluated by measuring the plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in 18 Cavalier King Charles Spaniels with asymptomatic or mildly symptomatic mitral valvular insufficiency, and in 18 healthy Cavalier King Charles Spaniels. All dogs were unmedicated and had no other diseases. The PRA was high in the dogs with mitral valvular insufficiency (median 3.44 ng/mL/h, interquartile interval 2.59 to 8.66 ng/mL/h) compared with the controls (median 2.51 ng/mL/h, interquartile interval 1.44 to 3.58 ng/mL/h). The PAC was also higher in the dogs with mitral insufficiency (median 53 pg/mL, interquartile interval 33 to 138 pg/mL) than in the control group (median 27 pg/mL, interquartile interval 11.5 to 54 pg/mL). However, there was considerable overlap between the 2 groups in both PRA and PAC. It was concluded from these data that there is early activation of the renin-angiotensin system in some Cavalier King Charles Spaniels with mitral valvular insufficiency. Further prospective studies are needed to determine if early intervention with angiotensin-converting enzyme inhibitors will be valuable in this group of patients. ... In conclusion, this study demonstrates an early activation of the RAS in Cavalier King Charles Spaniels with asymptomatic or mildly symptomatic MVI. This indicates a need to determine if. beneficial effects might be obtained by initiating the treatment of dogs with MVI with ACE inhibitors early in the course of the disease. Final evidence of this statement must await a thoroughly conducted clinical trial.

Mitral valve prolapse in 3-year-old healthy Cavalier King Charles Spaniels. An echocardiographic study. H D Pedersen, B O Kristensen, K A Lorentzen, J Koch, A L Jensen, and A Flagstad. Can J Vet Res. 1995 October; 59(4): 294–298.  Quote: "Clinical studies have shown that Cavalier King Charles Spaniels (CKCS) have a high prevalence of mitral valvular insufficiency (MVI). Echocardiography has the potential to disclose early valvular changes, and the present prospective study was designed to investigate the occurrence of mitral valve prolapse (MVP) in young CKCS without heart murmurs, and to correlate the degree of MVP with the clinical status of the dogs by including CKCS with MVI as well. The study was based on blinded evaluations of echocardiographic recordings of mitral valves from 34 CKCS and 30 control dogs. Thirteen (87%) of 15 three-year-old CKCS without heart murmurs had MVP (2 total and 11 partial), as compared with 1 (7%) of 15 three-year-old normal Beagle dogs (P < 0.0001), and none of 15 three-year-old normal Medium Size Poodles (P < 0.0001). Of 19 CKCS with MVI, MVP was found in 84% of the entire group and in 100% of dogs with pulmonary congestion or edema. The occurrence of total MVP tended to be higher in the group with MVI (47%, 9/19), when compared with the younger CKCS without heart murmurs (13%, 2/15, P = 0.06). MVP was positively associated with excessive heart rate variability (P = 0.003). The radius of curvature of the anterior mitral valve leaflet in systole was significantly reduced in dogs with MVP when compared with those without (P < 0.0001). In conclusion, this study shows that CKCS at an early age have a high occurrence of MVP. This suggests: 1) A genetic predisposition of CKCS to MVP; and 2) That MVP is a pathogenetic factor in the development of mitral valvular insufficiency. Follow up studies may add further support to these proposals, and clarify whether echocardiography may be an aid in selecting CKCS for future breeding."

Increased ACE and chymase-like activity in cardiac tissue of dogs with chronic mitral regurgitation. L. J. Dell'Italia , Q. C. Meng, E. Balcells , I. M. Straeter-Knowlen , G. H. Hankes , R. Dillon , R. E. Cartee , R. Orr , S. P. Bishop , S. Oparil. Amer. J. Physiology. Dec. 1995;269(6):H2065-H2073. Quote: "The current study was designed to test the hypothesis that intracardiac angiotensin-converting enzyme (ACE) activity, chymase-like activity, and angiotensin (ANG) peptide levels are increased and are positively related to wall stress estimates in response to the chronic low pressure volume overload of mitral regurgitation produced by percutaneous chordal rupture in the dog. Chronic mitral regurgitation (MR) resulted in an increase in left ventricular (LV) end-diastolic volume [59 +/- 11 (SD) to 103 +/- 32 ml, P < 0.001], LV mass (96 +/- 17 to 114 +/- 23 g, P < 0.001), and a decrease in the LV mass-to-end-diastolic volume ratio (1.64 +/- 0.22 to 1.16 +/- 0.23 g/ml, P < 0.001) measured by magnetic resonance imaging. In vitro studies of heart tissue extracts demonstrated that the majority of ANG II-forming activity was from chymase-like activity rather than from ACE activity in five normal (83.5 +/- 7.5 vs. 6.04 +/- 5.2%) and seven MR hearts (86 +/- 3.9 vs. 2.6 +/- 1.7%). ACE activity (1.22 +/- 0.22 vs. 3.55 +/- 0.62 mU/g, P < 0.05) and chymase-like activity (9.42 +/- 4.64 vs. 20.60 +/- 8.41 nmol.g-1.min-1, P < 0.05) were increased in MR compared with normal hearts. ACE activity correlated with the LV mass-to-volume ratio (r = -0.93, P < 0.001) and LV diastolic wall stress ( r = 0.71, P < 0.05); however, chymase-like activity did not correlate with any hemodynamic parameter. ANG II levels were significantly higher in the midwall of the left ventricle in MR hearts than in normal controls (85 +/- 39 vs. 27 +/- 16 pg/g, P < 0.01). Our results demonstrate a positive correlation between LV diastolic wall stress and increased ACE activity with increased ANG II stores, suggesting that mechanical wall stress activated intracardiac ACE. Although chymase accounted for most ANG II formation in vitro in extracts of both normal and MR dog hearts, the significance of this enzyme in vivo remains unclear."

New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function--a study in normals and dilated cardiomyopathy. Tei C., Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, Tajik AJ, Seward JB. J. Cardiology. December 1995;26(6):357-366. Quote: "Background: Because systolic and diastolic dysfunction frequently coexist, it is hypothesized that a combined measure of left ventricular chamber performance may be more reflective of overall cardiac dysfunction than systolic or diastolic measures alone. Methods: Study patients consisted of 170 subjects: 70 normals, 47 patients with severe dilated cardiomyopathy in NYHA class III-IV awaiting cardiac transplantation and 53 patients with idiopathic dilated cardiomyopathy of intermediate severity [NYHA class II, ejection fractions (EF) 30-50%]. EF, stroke volume and cardiac indexes were measured using conventional echo-Doppler methods. Pre-ejection period/ejection time (PEP/ET), isovolumetric relaxation time (IRT), isovolumetric contraction time/ET (ICT/ET) were also measured. A new derived index of myocardial performance: (ICT+IRT)/ET, was obtained by subtracting ET from the interval between cessation and onset of the mitral inflow velocity to give the sum of ICT and IRT. Results: The index was easily measured, reproducible, and had a narrow range in normals. The mean value of the index was significantly different between normal, intermediate and pre-transplant subjects (0.39 +/- 0.05, 0.59 +/- 0.10 and 1.06 +/- 0.24, respectively, p < 0.001 for all comparisons). The degree of inter-group overlap was smaller for the index compared to PEP/ET, ICT/ET and other parameters. Within functional groups, the value of the index did not appear to be related to heart rate, mean arterial pressure and the degree of mitral regurgitation. Conclusion: (ICT+IRT)/ET is a conceptually new, simple and reproducible Doppler index of combined systolic and diastolic myocardial performance in patients with primary myocardial systolic dysfunction."

Mechanisms of Action of Calcium-Sensitizing Drugs. Haikala, Heimo; Lindén, Inge-Britt. J. Cardiovascular Pharmaology. 1995;26(Suppl. 1). Quote: This review compares the mechanisms of action of the calcium-sensitizing agents levosimendan, pimobendan, MCI-154. and EMD 53998. By using purified human recombinant troponin-C (cTnC). the role of cTnC as a target protein for these compounds was investigated. Accordingly, the calcium-dependent binding to cTnC in a cTnC-high-performance liquid affinity chromatography (HPLAC) column and the stabilizing effects of the compounds on the calcium-induced conformation of dansylated cTnC were studied. Only levosimendan showed calcium-dependent action on cTnC. Of the studied compounds, levosimendan was the most potent calcium sensitizer in skinned fiber experiments. Furthermore, EMD 53998 and MCI-154, but not levosimendan and pimobendan, increased myosin ATPase activity, indicating that they may enhance the cycling rate of myosin-actin crossbridges. ... Pimobendan does not increase myosin ATPase activity. although the compound has been reported to increase calcium binding to skinned fihers IX) and suhsequently the force developed by the fibers. Therefore. it is suggested that pimobendan slows the crosshridge cycling, yielding more tension without an increase in energy consumption. Levosimendan did not increase myosin ATPase activity even at 30-fold higher concentrations than needed for the maximal positive inotropic effect. Levosimendan appears to increase the number of attached cross bridges per time unit (skinned fiber study). but the presumed slowing of the rate of crossbridge cycling eliminated the effect on A TP consumption. ... By analyzing the velocity (dT/dt) of isometric tension development in paced papillary muscles, it was shown that levosimendan probably enhances the association rate but decreases the dissociation rate of myosin-actin crossbridges. These effects occurred before the peak twitch tension was achieved. Therefore, levosimendan does not seem to affect the actual relaxation phase. The other calcium sensitizers. however, appear to act mainly by decreasing the dissociation rate of crossbridges. The weak calcium-sensitizing effect of pimobendan may be based on indirectly mediated increase in affinity of cTnC for calcium. MCI-154 might act in a similar way but, like EMD 53998. MCI-154 also acts on myosinactin crossbridges. We suggest that levosimendan binds in a calcium-dependent manner to the N-terminal domain of cTnC. which magnifies the extent of the contraction produced by cTnC when it is calcium-activated.

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1996

Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial. J. Lubsen, H. Just, A. C. Hjalmarsson, D. La Framboise, W. J. Remme, J. Heinrich-Nols, J. M. Dumont, P. Seed. Heart. September 1996;76:223-231. Quote: "Primary Objective: To determine the effects of pimobendan 2.5 and 5 mg daily on exercise capacity in patients with chronic heart failure. Design: A randomised, double blind, placebo controlled trial of the addition of pimobendan to conventional treatment with a minimum follow up of 24 weeks. Setting: Outpatient cardiology clinics in six European countries. Patients: 317 patients with stable symptomatic heart failure, objectively impaired exercise capacity, and an ejection fraction of 45% or lower who were treated with at least an angiotensin converting enzyme inhibitor and a diuretic and who tolerated a test dose of pimobendan. Results: Compared with placebo, both pimobendan 2.5 and 5 mg daily improved exercise duration (bicycle ergometry) by 6% (P = 0.03 and 0.05) after 24 weeks of treatment. At that time 63% of patients allocated to pimobendan and 59% of those allocated to placebo were alive and able to exercise to at least the same level as at entry (P = 0.5). No significant effects on oxygen consumption (assessed in a subgroup of patients) and on quality of life (assessed by questionnaire) were observed. Pimobendan was well tolerated. Proarrhythmic effects (24-hour electrocardiography) were not observed. In both pimobendan groups combined the hazard of death was 1.8 (95% confidence interval 0.9 to 3.5) times higher than in the placebo group. Conclusions: Pimobendan improves exercise capacity in patients with chronic heart failure who are also on conventional treatment. The balance between benefit and risk of treatment with this compound remains to be established however."

Relationship Between Parental Cardiac Status in Cavalier King Charles Spaniels and Prevalence and Severity of Chronic Valvular Disease in Offspring. Swenson L, Häggström J, Kvart C, Juneja RK. JAVMA 1996, Jan; 208(12): 2009-2012.  Quote: "Objective: To study the relationship between parental cardiac status in Cavalier King Charles Spaniels and development of chronic valvular disease (CVD) in offspring. Design: Historical cohort. Animals: 54 female and 53 male Cavalier King Charles Spaniel offspring. Procedure: 7 sires, selected on the basis of their liability to develop CVD, were screened for clinical signs of CVD and assigned to 1 of 3 groups (late, intermediate, and early onset of CVD). The mates of these sires (30 dams) were selected and classified likewise, and 107 offspring produced in 1988 from matings between these parents were screened for clinical signs of CVD at a mean age of 5.3 +/- 0.3 years. Results: 55% of the offspring were free from clinical signs of CVD, whereas 45% had cardiac murmurs of low or moderate intensity. The proportion of offspring with heart murmurs and the intensity of murmurs were significantly greater with increased parental classification. More males than females had developed murmurs, and murmurs of moderate intensity also were more prevalent in males. Results of multiple-regression analysis indicated that mean parental classification and sex had significant effects on proportion of offspring with murmurs and their intensity. Additionally, age affected disease prevalence and severity, despite the narrow range in age of offspring examined. Clinical Implications: Parental CVD status is an important factor influencing the probability of heart murmurs and their intensity in offspring. The results of this study indicate that CVD development is a polygenic threshold trait and that sex of the offspring influences threshold levels."

Heart rate variability in relation to severity of mitral regurgitation in Cavalier King Charles spaniels. Häggström J, Hamlin RL, Hansson K, Kvart C. J Small Anim Pract. 1996 Feb;37(2):69-75.  Quote: "Heart rate variability was measured in 81 Cavalier King Charles spaniels to investigate if it could be used to evaluate the severity of mitral regurgitation and to predict decompensation. Heart rate variability was assessed by the natural logarithm of the variance of the R-R intervals for 20 consecutive beats obtained from electrocardiographic recordings. Twenty-two of the dogs were clinically normal and 59 had mitral regurgitation caused by chronic valvular disease. The severity of mitral regurgitation was evaluated by echocardiography and thoracic radiography. Heart rate variability was found to be reduced (P < 0.001) among dogs with severe left atrial and ventricular dilatation and clinical signs of congestion. No significant differences in heart rate variability were found among normal dogs, dogs with only cardiac murmur, and dogs with echoradiographic evidence of slight to moderate left atrial and ventricular dilatation. Overall, an association was found between heart rate variability and left atrial to aortic root ratio and left ventricular end diastolic diameters (r = 0.72 and 0.64, respectively, P < 0.001), as well as heart and respiratory rate (r = 0.80 and 0.69, respectively, P < 0.001). Multiregression analysis showed that, in order of importance, heart rate, left atrial diameter and respiratory rate had significant effects on heart rate variability. Among these parameters, heart rate variability and left atrial diameter were found to be most efficient in separating decompensated dogs from compensated. It is concluded that heart rate variability may provide the clinician with valuable information when assessing the severity of mitral regurgitation caused by chronic valvular disease."

Epidemiological study of blood pressure in domestic dogs. Bodey AR, Michell AR. J Small Anim Pract. March 1996; 37:116–125. Quote: "Previous experience has shown that a noninvasive (indirect) technique using an oscillomet-ric monitor in conjunction with a tail cuff makes routine clinical blood pressure measurement practicable in dogs. The relationship between indirect and direct readings has been evaluated in both anaesthetised and conscious dogs (Bodey and others 1994, 1996). In this study, more than 2000 pressure measurements were taken from 1903 dogs. It was found that systolic is the most variable pressure parameter and that it depends on age, breed, sex, temperament, disease state, exercise regime and, to a minor extent, diet. Diet was not a significant determinant of diastolic and mean arterial pressure. Age and breed were the major predictors for all parameters. Heart rate was primarily affected by the temperament of the animal, though other factors also play a part in prediction. The distribution of systolic, diastolic, mean arterial pressure and heart rate across the dog population approximates to a log normal distribution. On the basis of these results it is possible to describe normal ranges for canine blood pressure; definition of hypertension, though, demands attention to age and breed normal values. The existence of statistically defined hypertension in an individual or breed does not imply adverse effects justifying therapy. Among the secondary causes of hypertension, such as diabetes, obesity and hyperadrenocorticism, hepatic disease was a new addition also undocumented in humans. The hypothesis that dogs, though classic model animals for hypertension, are resistant to its development found support from the modest increase in mean pressure values observed among dogs with renal disease, notably those with substantial reduction of glomerular filtration rate. The existence of breeds such as deerhounds with average pressures in the borderline range for hypertension in humans (and many individuals, therefore, well above) suggests that dogs may also be resistant to some of the adverse effects of high blood pressure."

Cavalier About Cavalier Heart Disease? Minors S. CKCSCC Newsletter. 1996.

Chronic Valvular Disease in Cavalier King Charles Spaniels: Epidemilogy, inheritance, and pathophysiology. Jens Häggström. Thesis, Swedish Univ. Ag. Sci., Uppsala, 1996.

The problem of inherited diseases. 5: Valvular disease in Cavalier King Charles spaniels. Swift, S.,  J. Small Animal Prac. 1996;37:505-506.

Comparison of the effects of levosimendan, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency. Pagel PS, Hettrick DA, Warltier DC. Basic.Res.Cardiology. July 1996;91(4):296-307. Quote: "We examined and compared the effects of levosimendan, a new myofilament calcium sensitizer with phosphodiesterase inhibiting activity, pimobendan, and milrinone on left ventricular-arterial coupling and mechanical efficiency in 21 experiments performed in open-chest, barbiturate-anesthetized dogs instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), +dP/dt, and LV volume (conductance catheter). ... Pimobendan and milrinone caused dose-related increases in Ees/Ea, SW/PVA, and SW/PWI. The results indicate that levosimendan, pimobendan, and milrinone augment myocardial contractility, produce venous and arteriolar vasodilation, and enhance LV-arterial coupling and mechanical efficiency in open-chest, barbiturate-anesthetized dogs."

Port-access mitral valve replacement in dogs. Pompili MF, Stevens JH, Burdon TA, Siegel LC, Peters WS, Ribakove GH, et al. J Thorac Cardiovasc Surg 1996; 112: 1268–1274.

Effects of enalapril on exercise tolerance and longevity in dogs with heart failure produced by iatrogenic mitral regurgitation. Hamlin, RL, Benitz, AM, Ericsson, GF, et al. J Vet Intern Med 1996; 10:85-87.

Mitral Valve Disease in Cavalier King Charles Spaniels. Darke, P., Fuentes VL, Kvart C, Häggström J. Swenson L.  Proceedings, Seminar by Intervet UK Ltd and The Cavalier King Charles Spaniel Club UK. November 1996.

Effects of long-term treatment with enalapril or hydralazine on the reninangiotensin-aldosterone system and fluid balance in dogs with naturally acquired mitral valve regurgitation. Häggström, J, Hansson, K, Karlberg BE, Kvart C, Madej A, Olsson K. .  Amer J Vet Res. November 1996; 57:1645-1652. Quote: Objective: To study long-term effects of enalapril, an angiotensin-converting enzyme inhibitor, and hydralazine, an arteriodilator, on renin-angiotensin-aldosterone system and fluid balance before and after administration of furosemide. Animals: 22 dogs with clinical signs of congestive heart failure (CHF) attributable to mitral regurgitation. Procedure: After initial examination, 12 dogs received enalapril and 10 received hydralazine. Dogs were re-examined 3 weeks and 6 months after initial examination. Furosemide was added after the 3-week examination, and at 6 months, dogs had received furosemide for at least 4 months. Results: Angiotensin II and aldosterone plasma concentrations were low before treatment, and only aldosterone became significantly decreased after enalapril monotherapy. Concentrations of both hormones and heart rate increased in dogs receiving hydralazine monotherapy, and fluid retention was evident. After long-term treatment with either of the 2 drugs together with furosemide, angiotensin II and aldosterone values increased in both groups. Natriuresis and kaliuresis developed in all dogs, with greatest effect in those receiving enalapril and furosemide. These dogs had decreased plasma sodium concentration, whereas potassium concentration was equally decreased in both groups. After 6 months, the enalapril group, but not the hydralazine group, had increased cardiac size. All dogs had moderate reduction of weight and were azotemic, although changes were more pronounced in those of the hydralazine group. Conclusion: The 2 drugs have different effects on the renin-angiotensin-aldosterone system and fluid balance in dogs with CHF.

Doppler echocardiographic index for assessment of global right ventricular function. Chuwa Tei, Karl S. Dujardin, David O. Hodge, Kent R. Bailey, Michael D. McGoon, A.Jamil Tajik, James B. Seward. J. Amer. Soc. of Echocardiography. November 1996;9(6):838-847. Quote: "The purpose of this study was to assess the clinical value of a Doppler-derived index, combining systolic and diastolic intervals of the right cycle, in assessing global right ventricular function in patients with primary pulmonary hypertension. ... It is well known that right ventricular systolic and diastolic dysfunction coexist in patients with primary pulmonary hypertension. This article reports the use of an easily obtainable Doppler-derived index that combines elements of systolic and diastolic function. This index appears to be a useful noninvasive means that correlates with symptoms and survival in patients with primary pulmonary hypertension."

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1997

Effects of naturally acquired decompensated mitral valve regurgitation on the renin-angiotensin-aldosterone system and atrial natriuretic peptide concentration in dogs. Häggström J, Hansson K, Kvart C, Karlberg BE, Vuolteenaho O, Olsson K. Am J Vet Res. January 1997;58(1):77-182. Quote: Objective: To investigate activity of the renin-angiotensin-aldosterone system and N-terminal pro-atrial natriuretic peptide (NT-proANP) during development of clinical signs of decompensated mitral valve regurgitation (MR). Animals: 11 Cavalier King Charles Spaniels with advanced MR attributable to chronic valvular disease. Procedure: Dogs were subjected to repeated examinations at 6-month intervals until signs of decompensation had developed (end point). Data acquired at end point were compared with data obtained from examinations 1 year and 1 to 6 months before decompensation. Each examination included physical examination, collection of venous blood, thoracic radiography, and echocardiography. Results: Echocardiographic measurements of left atrial-to-aortic root ratio and left ventricular end diastolic diameter increased considerably during the study, whereas left ventricular end systolic diameter remained unchanged. The increase in cardiac size was associated with increased plasma concentration of NT-proANP. In contrast, plasma concentrations of aldosterone and angiotensin II were reduced at decompensation (aldosterone compared with the 2 earlier examinations and angiotensin II compared with values obtained 1 to 6 months before), despite decreased plasma protein concentration and hematocrit, suggesting fluid retention. The urine-to-plasma creatinine ratio was reduced at end point. Conclusion & Clinical Implications: Early decompensated MR in dogs was not associated with increased circulating renin-angiotensin-aldosterone system activity, which may be caused by increased activity of ANP, and may be important for future therapeutic strategies of MR.

Update on Mitral Valve Disease. Kvart C, Häggström J. Proceedings, 15th ACVIM Forum, 1997.

Chronic Valvular Disease in Cavalier King Charles Spaniels. Jacobs G. Outline of Lecture to CKCSC,USA 1997.

Results of the multicenter spaniel trial (MUST): taurine- and carnitine-responsive dilated cardiomyopathy in American cocker spaniels with decreased plasma taurine concentration. Kittleson MD, Keene B, Pion PD, Loyer CG. J Vet Intern Med;July 1997;11(4):204-211. Quote: "Fourteen American Cocker Spaniels (ACS) with dilated cardiomyopathy (DCM) were studied to determine if individuals of this breed with DCM are systemically taurine- or carnitine-deficient and to determine if they are responsive to taurine and carnitine supplementation. American Cocker Spaniels with DCM were identified using echocardiography, and plasma was analyzed for taurine and carnitine concentrations. Each dog was randomly assigned to receive either taurine and carnitine supplementation or placebos. ... We conclude that ACS with DCM are taurine-deficient and are responsive to taurine and carnitine supplementation. Whereas myocardial function did not return to normal in most dogs, it did improve enough to allow discontinuation of cardiovascular drug therapy and to maintain a normal quality of life for months to years."

Efficacy of Monotherapy with Benazepril, an Angiotensin Converting Enzyme Inhibitor, in Dogs with Naturally Acquired Chronic Mitral Insufficiency. Hitoshi Kitagawa, Hiromasa Wakamiya, Katsuya Kitoh, Yasuhito Kuwahara, Yasunori Ohba, Motomi Isaji, Toshiroh Iwasaki, Masakazu Nakano, Yoshihide Sasaki. J. Vet. Med. Sci. July 1997;59(7):513-520. Quote: Benazepril (BP), an angiotensin convertive enzyme inhibitor, was administered orally once daily for 4 weeks to 31 dogs with mild to moderate (NYHA functional classes II and III) congestive heart failure caused from mitral insufficiency (MI). There were no significant changes in clinical signs, electrocardiogram findings, radiographical observations and plasma biochemical results in 11 dogs treated with placebo for 4 weeks. In 31 dogs treated with BP, appetite increased, and mean scores of heart failure signs, such as activity, exercise tolerance, cough and respiratory effort, were significantly improved. No dog displays signs suggesting systemic hypotension. One dog died suddenly on the 26th day of treatment with BP. This dog had good vigor and appetite till the evening before the death, and cough and exercise tolerance had been gradually improving. The heart rate and ECG parameters of BP treated dogs did not change significantly, but length of long axis of the heart decreased. In plasma biochemical tests, plasma urea nitrogen (UN) levels did not change significantly, and plasma creatinine (CRE) levels increased slightly within the normal ranges during BP trial. Two dogs had higher plasma UN levels with slightly higher plasma CRE levels, but had normal general condition and other biochemical results. Plasma ACE activity decreased to 57.3% of pre-treatment level at 4 weeks after BP treatment. It is concluded that BP monotherapy was efficacious at least in dogs with relatively low grade congestive heart failure caused by MI.

The cardiac effects of pimobendan (but not amrinone) are preserved at rest and during exercise in conscious dogs with pacing-induced heart failure. Ohte N, Cheng CP, Suzuki M, Little WC. J. Pharmacol. Exp. Ther. July 1997;282(1):23-31.

Mechanoenergetic effect of pimobendan in failing dog hearts. Y Goto, K Hata. Heart Vessels. 1997;Suppl 12(0):103-5. Quote: The effect of cardiotonic drugs with a calcium-sensitizing effect (Ca2+ sensitizers) on cardiac mechanoenergetics in the failing heart is not fully understood. Accordingly, we measured left ventricular (LV) contractility (Emax) and the relation between myocardial oxygen consumption (VO2) and pressure-volume area (PVA; a measure of LV total mechanical energy) before and during enhancement of contractility by infusion of dobutamine (DOB) or pimobendan (PIMO) in six cross-circulated hearts isolated from pacing-induced heart failure (FL) dogs, and compared the results with those reported in normal hearts (NL, n = 12). Although the baseline Emax was much lower in FL dogs than in NL dogs (P < 0.01), DOB and PIMO comparably enhanced Emax in the FL dogs. The O2 cost of contractility, defined as the increase in unloaded VO2 at zero PVA divided by the increase in Emax, obtained during an enhancement of contractility with DOB, was significantly higher in FL dogs than in NL dogs, suggesting that a larger amount of O2 is consumed during Ca2+ cycling with DOB in FL dogs. In contrast, the O2 cost of contractility with PIMO was similar between FL and NL dogs. Furthermore, the VO2 per minute was significantly higher with DOB (P < 0.05) than with PIMO partly because of an excessive positive chronotropic effect of DOB. We concluded that (1) PIMO exerts a positive inotropic effect comparable to that of DOB in both NL and FL dogs; (2) the O2 cost of contractility with DOB is higher in FL dogs than in NL dogs; and (3) PIMO has a relative O2-saving effect compared with DOB in FL dogs.

Comparative cardiac toxicity of the i.v. administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs. Schneider P, Güttner J, Eckenfels A, Heinzel G, von Nicolai H, Trieb G, Lehmann H. Exp Toxicol Pathol. August 1997;49(3-4):217-24. Quote: "The new positive-inotropic and vasodilatating drug Pimobendan (racemate), 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3 (2-H)-pyridazinone, and its enantiomers were investigated with regard to their cardiotoxicity in young adult female Chbb: Beagle dogs. The racemate and the (-)-isomer (eutomer) were intravenously injected once daily for 4 consecutive weeks at doses of 0.25, 0.75 and 2.25 mg/kg, and the (+)-isomer (distomer) at doses of 0.75, 2.25 and 6.75 mg/kg, respectively. Clinical signs, hematological, clinico-chemical, ophthalmologic and electrophysiological parameters were monitored. Plasma concentration-time profiles of the parent compound and the major metabolite UD-CG 212 were established on day 1 and in week 4 using an HPLC assay. Partial areas under the curves from 0.08 h to 1 h (AUC0.08-1 h) as well as the plasma concentration at time point 0.5 h/C0.5 h) were used for statistical calculations. Necropsy and histopathologic examination were performed after completion of the treatment period. Reduction of the blood pressure occurred already at low dosages of the racemate and the eutomer, but only in high dose distomer-treated animals. A tendency to tachycardia developed only in high dose females receiving the racemate. Consequently, with respect to the pharmacological effects and the adverse events, the racemate is equivalent to the eutomer. Plasma concentrations of parent compound and metabolite were dose-linear for racemate, eutomer and distomer within the dose range 0.25-2.25 mg/kg.d at both time points. There were no significant effects of form or repeated administration. A moderate increase of AUC0.08 1 h and C0.5 h could be seen on day 23 for the distomer indicating a stereoselektive metabolism of the latter. Histologic changes of the valvular and parietal endocardium being termed jet lesion were observed after administration of the racemate (> or = 0.75 mg/kg.d) and the eutomer (> or = 0.25 mg/kg.d) at distinctly lower doses than after the distomer (> or = 2.25 mg/kg.d). Furthermore, extent and severity of the morphologic lesions were found to be higher in dogs exposed to the racemate or the eutomer than in those receiving the distomer. The results gave evidence that the so-called cardiotoxicity by Pimobendan in dogs resulted from the exaggerated pharmacodynamic effect but not from the chemical nature of the compound per se. They corroborate also the previously raised assumption that the exaggerated pharmacodynamic activity of cardiotonic compounds in the broadest sense accounts for their morphologic adverse effects in experimental animals."

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1998

International Symposium on Chronic Cardiac Valve Disease in the Cavalier King Charles Spaniel. Beardow A, Buchanan J, Fuentes VL, Keene B, Swenson L. Transcript of Private Recording of Proceedings, CKCSC,USA. May 1998.

Effects of enalapril on survival in dogs with naturally acquired heart disease: Results of the long-term investigation of veterinary enalapril (LIVE) study group. LIVE Study Group. J Am Vet Med Assoc 1998;213:1573–1577.  Quote: Objective: To test the long-term effect of enalapril maleate treatment on progression of clinical signs of heart disease in dogs with moderate or severe naturally acquired heart failure associated with chronic degenerative mitral valvular disease (mitral regurgitation [MR]) or dilated cardiomyopathy (DCM). Design: Prospective multicenter study. Animals: 110 dogs enrolled at 15 locations in the United States. Procedure: All dogs enrolled in this study were maintained on their randomly allocated treatment regimen until death, treatment failure (deterioration of condition requiring additional medication), or termination of the study. All dogs entered in the study received standard heart failure treatment (furosemide with or without digoxin). Statistical analysis (log-rank test) was performed to compare the distribution of number of days in the study between dogs that received placebo tablets and dogs that received enalapril tablets. Results: When dogs with MR and DCM were grouped together, mean number of days until treatment failure was significantly different between those receiving enalapril and those given placebo tablets (157.5 and 77.0 days, respectively). For dogs with MR, mean number of days until treatment failure was significantly different between those receiving enalapril and placebo tablets (159.5 and 86.6 days, respectively). Mean number of days until treatment failure among dogs with DCM receiving enalapril and placebo tablets was 142.8 and 56.5, respectively. Clinical Implications: Use of enalapril in combination with standard treatment (diuretics with or without digoxin) appears to be beneficial over an extended period, compared with standard treatment alone.

Nutritional alterations and the effects of fish oil supplementation in dogs with heart failure. Lisa M. Freeman, John E. Rush, Joseph J. Kehayias, James N. Ross, Jr., Simin N. Meydani, Don J. Brown, Gregory G. Dolnikowski, Bonnie N. Marmor, Michael E. White, Charles A. Dinarello, Ronenn Roubenoff. J. Vet. lntern. Med. October 1998:12(11):440-448. Quote: "Alterations in body composition and nutritional status are common in humans with heart failure and are related, in part. to increases in cytokine concentrations. Cytokines have not been studied previously in dogs with naturally occurring cardiac disease nor has fish oil administration been used in this population to decrease cytokine production. The purposes of this study were to characterize nutritional and cytokine alterations in dogs with heart failure and to test the ability of fish oil to reduce cytokines and improve clinical outcome. Body composition. insulinlike growth factor- I , fatty acids, and cytokines were measured in 28 dogs with heart failure and in 5 healthy controls. Dogs with heart failure then were randomized to receive either fish oil or placebo for 8 weeks. All parameters were measured again at the end of the study period. At baseline. 54% of dogs with heart failure were cachectic and the seventy of cachexia correlated with circulating tumor necrosis factor-cx concentrations (P = .05). Cytokine concentrations at baseline, however, were not significantly increased in dogs with heart failure compared to controls. Baseline plasma arachidonic acid (P = .02), eicosapentaenoic acid (P = .03). and docosahexaenoic acid (P = ,004) concentrations were lower in dogs with heart failure than in controls. Fish oil supplementation decreased interleukin-1P (IL-I) concentrations ( P = .02) and improved cachexia ( P = .01) compared to the placebo group. The mean caloric intake of the heart failure dogs as a group was below the maintenance energy requirement (P < .001), but no difference was found in food intake between the fish oil and placebo groups. Insulinlike growth factor- I concentrations (P = .01) and reductions in circulating IL-1 concentrations over the study period ( P = .02) correlated with survival. These data demonstrate that canine heart failure is associated with cachexia. alterations in fatty acids, and reduced caloric intake. Fish oil supplementation decreased IL- 1 concentrations and improved cachexia. In addition, reductions in IL- 1 predicted survival, suggesting that anticytokine strategies may benefit patients with heart failure."

Hypomagnesemia and mitral valve prolapse in Cavalier King Charles Spaniels.  Pedersen HD, Mow T.; Zentralbl Veterinarmed A. December 1998; doi:10.1111/j.1439-0442.1998.tb00865.x . Quote: There is a high incidence of mitral valve prolapse (MVP), an abnormal displacement of one or both mitral valve leaflets during systole, in Cavalier King Charles Spaniels (CKCS). In humans, MVP is known to be associated with a low magnesium status. In this study, the plasma magnesium concentration was measured in 30 CKCS without heart failure. It was also investigated whether MVP-severity and degree of regurgitation correlated with plasma magnesium and a number of parameters of the renin-angiotensin system, and whether 4 weeks magnesium supplementation affected plasma magnesium or the high renin/low aldosterone profile associated with MVP. A high prevalence of hypomagnesemia was observed: plasma concentrations < 0.70 mmol/l were found in 15 dogs (50%) before and in 12 dogs (40%) after 4 weeks magnesium supplementation. The mean plasma level was 0.69 ± 0.07 mmol/l before and 0.71 + 0.07 mmol/l after magnesium (P = 0.22). Plasma magnesium concentrations did not correlate with MVP-severity and degree of regurgitation. Plasma aldosterone levels correlated negatively with MVP-severity and positively with the degree of regurgitation, and serum angiotensin-converting enzyme activities correlated negatively with the degree of regurgitation. Magnesium supplementation had no effects on renin and aldosterone nor on the ratio between the two. In conclusion, many CKCS without heart failure have hypomagnesemia whether they are fed supplementary magnesium or not - a finding which may be associated with the high prevalence of MVP in this breed. Further studies, however, are needed to clarify the role of a low magnesium status in canine MVP.

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1999

Effects of renal impairment on the disposition of orally administered enalapril, benazepril, and their metabolites. Lefebvre, HP, Laroute, V, Concordet, D, Toutain, P. J Vet Intern Med. Jan-Feb 1999;13(1):21-27.

Auscultation in Mild Mitral Regurgitation in Dogs: Observer Variation, Effects of Physical Maneuvers, and Agreement with Color Doppler Echocardiography and Phonocardiography. Pedersen HD, Häggström J, Falk T, Mow T, Olsen LH, Iversen L, Jensen AL. J Vet Intern Med. 1999 Jan-Feb;13(1):56-64.

Echocardiographic mitral valve prolapse in cavalier King Charles spaniels: epidemiology and prognostic significance for regurgitation. D. Pedersen, K. A. Lorentzen, B. Ø. Kristensen. Vet.Rec. March 1999;144:315-320. Quote: This study investigated the epidemiology and prognostic significance of mitral valve prolapse, detected by ultrasonography, in 153 cavalier King Charles spaniels which were screened consecutively during a period of one year. Seventy-five of the dogs, which had either no murmur or a grade I murmur on screening, were reexamined three years later. The screening revealed that 82 per cent of the dogs aged one to three years and 97 per cent of the dogs over three years had various degrees of mitral valve prolapse. The presence and severity of the condition were independent of gender but correlated positively with age and negatively with bodyweight. The degree of mitral valve prolapse at screening correlated with the regurgitation status (murmur intensity and size of the regurgitant jets) at re-examination and with the percentage increase in the left ventricular end diastolic diameter over the three-year period. The presence of a grade I murmur was not a useful prognostic indicator. ... In addition, the significant correlation found between jet size and murmur intensity adds to previously published data showing that murmur intensity is a reasonable way of monitoring the degree of mitral regurgitation.

Textbook Of Canine And Feline Cardiology: Principles And Clinical Practice.  Fox P., Sisson D. D., Moise N. S., Saunders (Elsevier) 1999.

Renal safety of chronic enalapril therapy in dogs with compensated mitral regurgitation. VETPROOF Study Group. J Vet Intern Med 1999; 13:246. Quote: "The objective of this study was to determine the effect of chronic ACE-inhibition with enalapril on renal function in dogs with compensated mitral regurgitation (MR). Blood samples from 116 dogs involved in a study of the efficacy of enalapril in delaying the onset of heart failure in naturally-occuring MR in client-owned dogs were evaluated. Serum creatinine concentrations (Cr) were determined at the outset of the study, and at 2 weeks and 3, 6, 9, and 12 months after institution of either enalapril or placebo in a randomized, double-blinded fashion. Without breaking the code, Cr were compared between groups 1 (enalapril or placebo) and 2 (opposite of group 1) at each time point. In addition, the percentage of dogs in which Cr rose more than 35% from baseline values and the change in Cr from baseline to 6 and 12 months’ therapy were compared between groups 1 and 2. There were no differences between groups 1 and 2 in any of the parameters evaluated. No dogs from either group became azotemic during the study and none dropped out of the study due to worsening azotemia. We conclude that chronic enalapril therapy of up to 12 months’ duration does not appear to have a deleterious effect on renal function, based on Cr in dogs with MR, prior to the onset of heart failure."

The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: results of a multi center, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial. The BENCH Study Group. J Vet Cardiol 1999;1(1):5–18. Quote: "Objective: To test the efficacy and tolerability of long-term administration of the angiotensin converting enzyme inhibitor, benazepril, in dogs with heart failure. Methods: The study was a prospective, randomized, double-blind, placebo-controlled clinical trial involving 16 centers in France, Italy, Switzerland and UK. A total of 162 dogs with class II and III (ISACHC classification) heart failure caused by chronic valvular disease (CVD) or dilated cardiomyopathy (DCM) were enrolled. Benazepril (minimum dosage, 0.25 mg/kg) or placebo were administered orally once daily for up to 34 months, either alone or as add-on therapy to "standard therapy" i.e. diuretics and/or digoxin and/or anti-arrhythmic drugs. Results: The mean survival time (to death or withdrawal from the study due to worsening of heart failure) was 2.7 times longer in the benazepril treated group (428 days) as compared with the placebo group (158 days). Differences reached statistical significance (p<0.05 Cox proportional hazards model, 44% reduction in risk). The survival rate after one year was 49% with benazepril and 20% with placebo. Benazepril produced a statistically significant (p<0.05) reduction (by 46%) in the risk of worsening of heart failure (to ISACHC class III) when therapy was initiated early (in ISACHC class II). In sub-group analyses, a statistically significant (p<0.05) benefit of benazepril was reached for both survival and worsening endpoints for dogs with CVD (n=125), but not for the small sample of dogs with DCM (37). Benazepril also improved the exercise tolerance and global clinical condition at day 28 (p<0.05). As compared to the placebo group, dogs treated with benazepril presented with the same frequency of undesirable clinical events and fewer biochemical disturbances (less frequent increases in plasma urea or creatinine and decreases in plasma potassium). Cconclusions: Benazepril extended the useful life-span of dogs with ISACHC class II and III heart failure (due to CVD) and was well tolerated."

No Expression of Angiotensin II Receptors and Angiotensin-Converting Enzyme in Myxomatous Canine Mitral Valve Leaflets. An Autoradiographic Study. Mow T., Pedersen H.D. J. Vet. Med. Series A; Oct 1999; 46(8):465-472.

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2000

Effects of long-term therapy with bosentan on the progression of left ventricular dysfunction and remodeling in dogs with heart failure. Takayuki Mishima, Mitsuhiro Tanimura, George Suzuki, Anastassia Todor, Victor G Sharov, Sidney Goldstein, Hani N Sabbah. J. Am. Coll. of Cardiology. January 2000;35(1):222-229. Quote: "Objectives: In this study, we examined the effects of long-term therapy with bosentan on the progression of LV dysfunction and remodeling in dogs with moderate HF. Background: Acute intravenous administration of bosentan, a mixed endothelin-1 type A and type B receptor antagonist, was shown to improve left ventricular (LV) function in patients and dogs with heart failure (HF). Methods: Left ventricular dysfunction was induced by multiple, sequential intracoronary microembolizations in 14 dogs. Embolizations were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to three months of therapy with bosentan (30 mg/kg twice daily, n = 7) or no therapy at all (control, n = 7). Results: In untreated dogs, EF decreased from 35 ± 1% before initiating therapy to 29 ± 1% at the end of three months of therapy (p = 0.001), and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 71 ± 3 vs. 84 ± 8 ml, p = 0.08; ESV: 46 ± 2 vs. 60 ± 6 ml, p = 0.03). By contrast, in dogs treated with bosentan, EF tended to increase from 34 ± 2% before initiating therapy to 39 ± 1% at the end of three months of therapy (p = 0.06), and EDV and ESV decreased (EDV: 75 ± 3 vs. 71 ± 4 ml, p = 0.05; ESV: 48 ± 2 vs. 43 ± 3 ml, p = 0.01). Furthermore, compared with untreated dogs, dogs treated with bosentan showed significantly less LV cardiomyocyte hypertrophy and LV volume fraction of interstitial fibrosis. Conclusions: In dogs with moderate HF, long-term therapy with bosentan prevents the progression of LV dysfunction and attenuates LV chamber remodeling. The findings support the use of mixed endothelin-1 receptor antagonists as adjuncts to the long-term treatment of HF."

Vertebral scale system to measure heart size in radiographs. Buchanan, JW. Vet Clin North Am Small Anim Pract 2000; 30:379–393. Quote: This article describes a method for measuring heart size relative to vertebral length in radiographs. The lengths of the long and short axes of the heart are scaled against the length of vertebrae dorsal to the heart beginning with the fourth thoracic vertebra (v). The sum of the long and short axes of the heart is the vertebral heart size (VHS). In 100 normal dogs, VHS was 9.7 v +/- 0.5 SD. The differences between wide- and deep-chested dogs, males and females, and right or left lateral recumbency were not significant. In 100 normal cats, the average VHS was 7.5 v +/- 0.3. The short-axis dimension of the heart in ventrodorsal radiographs of cats was 3.4 v +/- 0.25. ... In addition to initial assessment of heart size, the VHS method is also useful in monitoring the progression of heart enlargement over time. 1' 5 Recording the heart size using a vertebral scale encourages objectivity and is a convenient way of recording changes in heart size in response to treatment or progression of cardiomegaly.

Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. H. Kim, G.L. Yung, J.J. Marsh, R.G. Konopka, C.A. Pedersen, P.G. Chiles, T.A. Morris, R.N. Channick. Eur. Respiratory J. 2000;15:640-648. Quote: "It is well known that endothelin (ET)-1 mediates vascular remodelling in various kinds of clinical and experimental pulmonary hypertension. The aim of this study was to investigate whether ET-1 is associated with the development of pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor antagonist, was administered throughout the study. Haemodynamic measurements and plasma ET-1 assays were performed every 2 months. Eight months after initial embolization, computer-assisted morphometry and immunohistochemistry were performed on the lung tissue including that from three control dogs. Pulmonary arterial pressure and pulmonary vascular resistance were increased in all embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1 concentration and pulmonary arterial wall thickness were increased compared to control animals, and ET-1 immunoreactivity was detected in thickened pulmonary arteries. In bosentan treated dogs, pulmonary arterial walls were not significantly thickened. Pulmonary vascular remodelling, associated with elevated plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung tissue is attenuated by the endothelin receptor antagonist, bosentan. These findings suggest that endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension."

 "Acquired valvular heart disease." (Kvart C, Häggström J.) in: Textbook of Veterinary Internal Medicine. 5th ed., Ettinger SJ, Feldman EC, eds.;WB Saunders, 2000:787-800.

New Insights on Effect of Kidney Insufficiency on Disposition of Angiotensin-Converting Enzyme Inhibitors: Case of Enalapril and Benazepril in Dogs. Pierre-Louis Toutain, Hervé P. Lefebvre and Valérie Laroute. J. Pharmacology & Experimental Therapeutics; March 2000; 292(3):1094-1103. Quote: "The influence of a renal injury on the disposition of benazeprilat, the active moiety of benazepril, and of enalaprilat, the active moiety of enalapril, two angiotensin-converting enzyme (ACE) inhibitors (ACEI), having different routes of elimination in dog was investigated during a mild renal insufficiency obtained by a nephrectomy-electrocoagulation method reducing glomerular filtration rate by ∼50%. Plasma concentrations of the active moieties were analyzed with a physiologically based model taking into account the binding to ACE (high affinity, low capacity). An influence of renal insufficiency on enalapril disposition was shown with an increase in its plasma concentration, which was correlated to the reduction of the glomerular filtration rate. No such effect was evidenced for benazepril. With the physiologically based model analysis, it was shown that renal impairment led to an increase of the apparent benazeprilat clearance (260%), whereas that of enalaprilat was reduced to 40 to 55%. Renal insufficiency had no significant effect either on the apparent volume of distribution of each drug or on the binding parameters [i.e., maximal binding capacity (Bmax) and affinity (Kd)]. Enalaprilat and benazeprilat inhibitory action on ACE also was evaluated ex vivo. Similar patterns of inhibition were observed for both drugs. Renal injury had no significant influence on the overall effect of benazeprilat, whereas the inhibition effect of enalaprilat was significantly increased. It was concluded that renal insufficiency may have effects on the ACEI disposition but that the measurable active moiety plasma concentration is not the most appropriate endpoint to describe and interpret the consequence of a renal injury on ACEI."

Evaluation of Four 2-Dimensional Echocardiographic Methods of Assessing Left Atrial Size in Dogs. Mark Rishniw, Hollis N. Erb. J. Vet. Intern. Med. July 2000;14(4):429–435. Quote: Two-dimensional (2D) echocardiography is the cornerstone of noninvasive evaluation of the cardiac patient, and often involves estimating left atrial (LA) size. However, 2D echocardiographic methods of estimating LA size have been inadequately described, and most reference intervals are based on M-mode echocardiographic measurements. We determined reference intervals for 4 different 2D echocardiographic methods of estimating LA size in adult ( 9-month-old) dogs without cardiovascular disease. Thirty-six dogs, placed in right lateral recumbency, were examined by 2D echocardiography. The left atrium was measured at specific time points in the cardiac cycle. Measurement methods were LA diameter in short axis, LA diameter in long axis, LA circumference in short axis, and LA cross-sectional area in short axis. Comparisons of these LA dimensions to appropriate aortic dimensions provided body weight–independent estimates of LA size. We found strong associations of LA dimensions with body weight (r2 = .76–.88). Comparable body weight–independent 2D echocardiographic estimates of LA size in short axis exceeded historical M-mode reference intervals. These data provide echocardiographers with reference intervals for 2D echocardiographic estimates of LA size in adult dogs. ... In our study, 100% of the dogs [36 dogs of 22 breeds-- none were CKCSs] had LASAX:Ao  <1.6 (Table 2), and the median (and mean) LASAX :Ao was 1.3. ... Finally, we have not examined dogs with left-heart disease. However, even in dogs with left-heart disease, atria that measure within the limits we have described would be considered normal sized. Further studies in dogs with left-heart disease are needed to qualify degrees of LA enlargement.

Pulmonary artery lesions in Cavalier King Charles Spaniels. Karlstam E, Häggström J, Kvart C, Jönsson L. Michaelsson, M. Vet. Rec. August 2000;147:166–167. Quote: Abstract Postmortem samples from 7 Cavalier King Charles Spaniels (aged 8-9 years) that died or been killed because of problems associated with chronic valvular disease (CVD) were examined. The findings included mitral CVD and dilation of the left atrium and ventricle in all dogs, and left atrial rupture in two and severe pulmonary artery thrombosis in one. all dogs also showed wrinkling and irregularity of the endothelial surface of the main pulmonary artery and its branches. The pulmonary artery wall showed sever intimal thickening due to subendothelial fibrosis and abundant vacuolated, Alcian blue-PAS-positive intercellular substances compatible with glycosaminoglycans (GAGS). GAGS were also found in the tunica media. In more sever cases the internal elastic lamina, separating the tunica intima from the tunica media was fragmented and poorly discernible. It is suggested that CVD is part of a more generalised connective tissue diseases. ... In cavalier King Charles spaniels, intimal thickening and breaks in the internal elastic lamina of the femoral artery have been reported (Buchanan and others 1997), and these lesions were associated with thrombosis and vascular occlusion. ... The cases presented here were seven consecutive, nonselected spaniels that underwent postmortem examination over a comparably short period of time. The observations reported indicate that pulmonary vascular lesions are common in middle-aged to old cavalier King Charles spaniels. However, the study does not allow a conclusion as to the true prevalence.

Mitral valve prolapse in the dog: a model of mitral valve prolapse in man. Henrik D. Pedersen, Jens Häggström. Cardiovascular Res. August 2000;47:234–243. Quote: "50% of Cavalier King Charles (CKC) spaniels have a murmur due to MR by the age of 5–6 years and at 10 years of age, the prevalence of murmurs approaches 100%. Echocardiographically, the majority of CKC spaniels have MVP."

The role of coenzyme Q10 in the pathophysiology and therapy of experimental congestive heart failure in the dog. Amy K. Harker-Murray, A. Jamil Tajik, Fumiobu Ishikura, Donna Meyer,John C. Burnett, Margaret M. Redfield. J. Cardiac Failure. September 2000;6(3):230-242. Quote: Background: Coenzyme Q10 (CoQ10) is essential for ATP generation and has antioxidant properties. Decreased CoQ10 levels have been reported in human heart failure (CHF), but it remains unclear if this is a conserved feature of CHF. The objective of the study was to determine if tachycardia-induced CHF in the dog is associated with reduced CoQ10 levels. Furthermore, it was hypothesized that CoQ10 supplementation may improve CHF severity by preventing CoQ10 deficiency (if present) or via antioxidant effects. Methods and Results: Serum and myocardial levels of CoQ10 were examined in normal dogs (n = 6), dogs with CHF (control, n = 5), and dogs with CHF treated with CoQ10 (CoQ10; 10 mg/kg/day, n = 5). Serum CoQ10 levels did not change with CHF in control dogs, and myocardial levels were similar to those of normal dogs. CoQ10 therapy increased serum but not myocardial levels of CoQ10. In early CHF, CoQ10-treated dogs had lower filling pressures, and, in severe CHF, CoQ10-treated dogs had less hypertrophy as compared with untreated dogs. Other indices of CHF severity were similar in control and CoQ10-treated dogs. Conclusion: These data indicate that CoQ10 deficiency is not present in this model of CHF. Although dramatic effects on hemodynamics were not observed, CoQ10 supplementation did appear to attenuate the hypertrophic response associated with CHF.

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2001

Nutritional Therapy in the Treatment of Heart Disease in Dogs. Robert S. Dove. Alternative Medicine Review; 6 Supp.: S/38-S/45; 2001.

Ribose improves myocardial function and quality of life in congestive heart failure patients. Illien S, Omran H, Mac Carter D, J.A. St.Cyr. J Mol Cell Cardiol. 2001;33:A173. Quote:  Alterations in myocardial energy levels may play a role in heart failure. Ribose (R), a naturally occurring sugar, has shown to enhance myocardial energy levels following ischemia. Might R aid in patients with congestive heart failure (CHF)? Fifteen CHF patients, NYHA II-III, were randomized in a cross-over study, R (15 gms/day) vs.placebo (dextrose, 15 gms/day). Patients received oral supplement for 3 weeks,1 week washout, and an additional 3 weeks of the alternative supplement. Echocardiographic and quality of life (QOL-SF36) assessments were performed (pre-and post) during each 3 weeks of supplementation. There were no adverse events. R demonstrated significance in E-wave deceleration rate (p&.002), both % atrial contribution to left ventricular filling and left atrial volume (pcO.O2), QOL (pcO.004); and phylical functionine score (n<O.O2).With the known difficultv in clinically >anagigg m&y CHF patients, R sh&ld strongly be. considered as a therapeutic option in this heart disease state.

Increased platelet aggregation response in Cavalier King Charles spaniels with mitral valve prolapse.  Olsen,L.H., Kristensen, A.T., Häggström, J., Jensen, A.L., Klitgaard, B., Hansson, H., Pedersen, H.D. J.Vet. Internal Med. 2001, 15:209-216.

Use of breed-specific ranges for the vertebral heart scale as an aid to the radiographic diagnosis of cardiac disease in dogs. Lamb CR, Wikeley H, Boswood A, Pfeiffer DU. Vet Rec. 2001 Jun 9;148(23):707-11. Quote: "The vertebral heart scale was measured on right lateral recumbent thoracic radiographs of 320 dogs of six popular breeds, including for each breed at least 20 dogs with no clinical signs of cardiovascular or respiratory disease and at least 19 dogs with cardiac or respiratory disease. There were significant differences between the mean values of the scale for the different breeds; the normal boxer dogs had a significantly higher mean value than the normal dogs of all the other breeds, and the labrador retrievers had a significantly higher mean value than all the other breeds except the boxer and the cavalier King Charles spaniel. ... Cavalier King Charles spaniel [50 dogs]: Normal: 10-6 (0-5); Cardiac: 10-6 (0-7) 12.4 (1-5); Normal ranges: 9.9-11-7. ... For all the breeds except the boxer, there was a trend for dogs with cardiac disease (but not respiratory disease) to have higher mean values on the scale than normal dogs of the same breed; however, at the optimal value of the scale for distinguishing between dogs of each breed with and without cardiac disease, the sensitivity and specificity were relatively low, in the range 58 to 83 per cent. The scale was most accurate for the diagnosis of cardiac disease in the Yorkshire terrier and the cavalier King Charles spaniel, breeds affected by predominantly dilative forms of cardiac disease. ... On the basis of this study, it appears that values of the vertebral heart scale greater than 10-4 for the Yorkshire terrier and 11 1 for the cavalier King Charles spaniel should provide about 80 per cent accuracy for the diagnosis of cardiac disease. A threshold value of 10-7 (calculated from the data of Buchanan and Bucheler 1995) would result in similar accuracy for the Yorkshire terrier (a slight decrease in sensitivity being almost balanced by an increase in specificity) and a slightly reduced accuracy for the cavalier King Charles spaniel (the slight increase in sensitivity being outweighed by the loss of specificity). ... In contrast, it was very inaccurate in the boxer, a breed that has a higher incidence of cardiac diseases associated with concentric hypertrophy."

Vertebral scale system to measure heart size in growing puppies. Margaret M. Sleeper and James W. Buchanan. J Am Vet Med Assoc July 2001;219(1):57–59. Quote: "Objective: To determine relative heart size in clinically normal puppies and assess whether relative heart size changes with growth. Design: Prospective radiographic study. Animals: 11 puppies without evidence of disease (Eleven 3-month-old puppies (6 mixed-breeds, 2 Golden Retrievers, 1 Labrador Retriever, 1 Beagle, and 1 German Shepherd Dog) were selected for the study. Seven were females, and 4 were males.) Procedure: Standardized measurements of the long and short axes of the heart, midthoracic vertebrae, and other structures were made at 3, 6, 12, and 36 months of age. Measurements were recorded in millimeters and number of thoracic vertebral lengths spanned by each dimension, measured caudally from T4 on lateral radiographic views. The long and short axis measurements of the heart, expressed in vertebral lengths, were added to yield vertebral heart size. Results—Mean ± SD vertebral heart sizes on lateral radiographic views at 3, 6, 12, and 36 months of age were 10.0 ± 0.5, 9.8 ± 0.4, 9.9 ± 0.6, and 10.3 ± 0.6 vertebrae, respectively. Significant differences were not detected. Conclusions and Clinical Relevance: Vertebral heart size measurements in puppies are within the reference range for adult dogs (9.7 ± 0.5 vertebrae) and do not change significantly with growth to 3 years of age. Standards for determining cardiac enlargement are similar in puppies and adult dogs."

Ultrastructural morphologic evaluation of the phenotype of valvular interstitial cells in dogs with myxomatous degeneration of the mitral valve. Black A., French A.T., Dukes-McEwan J., Corcoran B.M. AmJ.Vet.Res., 2001 Nov; 66(8):1408-1414.

Effect of age and body weight on neurohumoral variables in healthy Cavalier King Charles Spaniels. Eriksson A.S., Järvinen A.-K., Eklund K.K., Vuolteenaho O.J., Toivari M.H., Nieminen M.S. Am.J.Vet.Res. 2001 Nov,62(11):1818-1824.  Quote: "Objective: To evaluate the effect of age and body weight on several neurohumoral variables that are commonly altered in heart failure in Cavalier King Charles Spaniels. Animals: 17 healthy privately owned Cavalier King Charles Spaniels, 10 males and 7 females, ranging in age from 0.4 to 9.7 years, and ranging in body weight from 6.6 to 12.2 kg. Procedure: The clinical condition of the dogs was evaluated by physical examination, thoracic radiography, and echocardiography. Plasma nitrate and nitrite (P-NN), N-terminal atrial natriuretic and brain natriuretic peptides (NT-ANP and BNP, respectively), endothelin (ET-1), urine cyclic guanosine monophosphate (UcGMP), and urine nitrate and nitrite (U-NN) concentrations were analyzed. Results: Plasma concentrations of NT-ANP and P-NN increased significantly with age, but plasma NT-ANP and P-NN also correlated significantly, irrespective of age. A modest increase of left atrial size did not explain the increase of NT-ANP and P-NN with age. Concentration of ET-1 correlated positively with heart rate; heart rate did not change with age. Weight had a negative impact on NT-ANP, P-NN, and U-cGMP concentrations and left atrial relative size. Conclusions and Clinical Relevance: Age-matched controls are essential for evaluation of NT-ANP and PNN concentrations and left atrial size. Weight may alter reference values of plasma NT-ANP, P-NN, and urine cGMP concentrations. Natriuretic peptides can be used as further evidence that heart failure exists. The increased plasma concentrations of NT-ANP (but not BNP) and P-NN with aging reflect neurohumoral physiologic changes that must be distinguished from pathologic changes in patients with heart failure."

Assessment of survey radiography as a method for diagnosis of congenital cardiac disease in dogs. C. R. Lamb, A. Boswood, A. Volkman, D. J. Connolly. J. Sm. Anim. Pract. November 2001;42(11):541-545. Quote: In order to assess the diagnostic accuracy of survey radiography for canine congenital cardiac anomalies, thoracic radiographs of 57 dogs with congenital cardiac anomalies, 31 normal dogs and 27 dogs with acquired cardiac disease were mixed, and reviewed by two independent observers, who were blinded to any patient information. The congenital anomalies were aortic stenosis (n=25), pulmonic stenosis (n=10), patent ductus arteriosus (n=Q), ventricular septa1 defect (n=8), tricuspid dysplasia (n=3) and mitral dysplasia (n=2). Both observers were moderately accurate at identifying dogs with cardiac disease. Their ability to distinguish dogs with congenital versus acquired cardiac disease was poorer and this assessment was probably influenced by the recognition of patients that were skeletally immature, which biased observers towards a diagnosis of congenital cardiac anomaly. The diagnosis rate for specific congenital anomalies was also poor (the differential list included a correct diagnosis in only 40 and 37 per cent of cases). Radiographic signs of specific cardiac chamber enlargement or pulmonary vascular abnormalities were recognised by both observers in only 20 per cent of Instances in which they might be expected. They were, however, recognised more frequently in dogs with anomalies that imposed a volume load on the heart than in dogs with anomalies that induced a pressure load on the organ. Conclusions: Even in the hands of experienced clinicians, survey radiography is an inaccurate method for diagnosing canine congenital cardiac anomalies because of the difficulty in recognising the classic radiographic signs, which are not present in every case. ... The results of radiography should be considered as only one part of the clinical assessment and an attempt should be made routinely to reconcile the clinical signs with radiographic findings in order to avoid placing unwarranted emphasis on the perceived size or shape of the cardiac silhouette alone. ... Clinicians should be very cautious about diagnosing congenital cardiac disease based on survey radiographs and it is not recommended that owners are given advice about the potential for treatment or the prognosis for suspected congenital cardiac anomalies on the basis of survey radiographs alone.

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2002

Efficacy of Enalapril for Prevention of Congestive Heart Failure in Dogs with Myxomatous Valve Disease and Asymptomatic Mitral Regurgitation. ("Scandinavian Veterinary Enalapril Prevention [SVEP] Trial").  Kvart C, Häggström J, Pedersen HD, Hansson K, Eriksson A, Jarvinen AK, Tidholm A, Bsenko K, Ahlgren E, Ilves M, Ablad B, Falk T, Bjerkfas E, Gundler S, Lord P, Wegeland G, Adolfsson E, Corfitzen J. J Vet Intern Med. 2002 Jan-Feb;16(1):80-88.  Quote: "We evaluated the long-term effect of early angiotensin-converting enzyme (ACE) inhibition (enalapril maleate) as monotherapy to postpone or prevent congestive heart failure (CHF) in asymptomatic dogs with mitral regurgitation (MR) attributable to myxomatous valvular disease (MVD) in a prospective, randomized, double-blinded, placebo-controlled multicenter trial involving 14 centers in Scandinavia. Two hundred twenty-nine Cavalier King Charles (CKC) Spaniels with MR attributable to MVD but no signs of CHF were randomly allocated to treatment with enalapril 0.25–0.5 mg daily (n = 116) or to placebo groups (n = 113). Each dog was evaluated by physical examination, electrocardiography, and thoracic radiography at entry and every 12 months (±30 days). The number of dogs developing heart failure was similar in the treatment and placebo groups (n = 50 [43%] and n = 48 [42%], respectively; P= .99). The estimated means, adjusted for censored observations, for the period from initiation of therapy to heart failure were 1,150 ± 50 days for dogs in the treatment group and 1,130 ± 50 days for dogs in the placebo group (P= .85). When absence or presence of cardiomegaly at the entrance of the trial was considered, there were still no differences between the treatment and placebo groups (P= .98 and .51, respectively). Multivariate analysis showed that enalapril had no significant effect on the time from initiation of therapy to heart failure (P= .86). Long-term treatment with enalapril in asymptomatic dogs with MVD and MR did not delay the onset of heart failure regardless of whether or not cardiomegaly was present at initiation of the study."

A Double-Blind, Randomized, Placebo-Controlled Study of Pimobendan in Dogs with Dilated Cardiomyopathy. Fuentes V. L.,Corcoran C., French A., Schober K. E., Kleemann R. , Justus C.; J Vet Intern Med. 2002 May;16(3):255–261.

Left atrial to aortic root indices using two-dimensional and M-mode echocardiography in cavalier King Charles spaniels with and without left atrial enlargement. Hansson, K., Häggström, J., Kvart, C. & Lord, P. Vet. Rad. & Ultra. November 2002;43(6):568–575. Quote: Two-dimensional (2-D) echocardiographic measurement of the left atrium (LA) has the potential to be more accurate than the standard M-mode method, because the LA body can be measured. We evaluated a 2-D method for measuring LA and aorta (AO) in a right parasternal short-axis view and compared it to the M-mode method. An index for LA size (LA/AO) was calculated in 166 cavalier King Charles spaniels, 56 normal and 110 dogs with mitral regurgitation (MR) of varying degrees secondary to chronic valvular disease. In normal dogs, the AO-2-D and LA/AO-2-D did not correlate to body weight (BW) or BW2; whereas, all M-mode values and the LA-2-D were significantly (p < .05) related to both BW parameters. In normal dogs, there was no difference between M-mode and 2-D indices. For all dogs (normal and dogs with MR) there was an 11% bias between the M-mode and 2-D index with the LA/AO-2-D being higher than the LA/AO-M. The association between the mean and the difference of the indices demonstrated a quadratic relationship. Dogs with a mean LA/AO of 2.0–2.5 showed the largest difference between the two indices. Small values for the 2-D coefficients of variation for respiration and stage of diastole were found; 3.4 and 3.1%, respectively. The 2-D index is more sensitive to LA enlargement than the M-mode index. ... The 2-D method can be used for any breed, but direct extrapolation of our normal values should not be made to other breeds, because the heart has a slightly different appearance in various breeds reflecting variability in size, shape, and position within the thorax. ... In this study, we have deliberately refrained from introducing index ranges for mild, moderate, and severe enlargement, because the grading would be arbitrary and was not included in the study design.

Understanding The Importance Of Carnitine, Taurine, And Other Neutraceuticals In The Cardiology Patient. Bruce W. Keene. WSAVA 2002. Quote: "Taurine is an amino acid that is important in both calcium transport and handling as well as energy metabolism in the heart muscle cells. Taurine supplementation is indicated whenever plasma or whole blood taurine concentrations are found to be low. These concentrations should be measured in all cases of dilated cardiomyopathy in cats, and should probably be measured in dilated cardiomyopathy of American or other cocker spaniels, or other breeds where the owner is willing to search for an underlying (and potentially reversible) cause of dilated cardiomyopathy. ... Few Doberman pinschers, Boxers, or other usual giant breed dogs have been shown to be taurine deficient associated with dilated cardiomyopathy, so supplementation in such cases is generally only recommended after discovery of deficiency."

Chronic valvular heart disease in dogs. Rush J.E.. In: Proceedings of the 26th Annual Waltham Diets; OSU Symposium for the Treatment of Small Animal Cardiology, pp. 1-7, 2002.

Enalapril monotherapy in asymptomatic mitral regurgitation: results of VETPROOF (Veterinary Enalapril Trial to Prove Reduction in Onset Of Failure). Atkins CE. ACVIM Forum Presentation, 75-76, 2002.

Effects of long-term administration of enalapril on clinical indicators of renal function in dogs with compensated mitral regurgitation. Atkins CE, Brown WA., Coats JR, et al.; JAVMA 2002 Sept; 221(5):654-658.

Clinical and Echo Doppler Follow-Up of a Mitral Valve Stenosis Corrected by Open Heart Surgery in a Dog. Carlos C, Daniel P, Borenstein N.; Proceedings, 37th World Small Animal Vet. Assn., Oct 2002.

A Clinical Trial about the Efficacy of Pimobendan in Comparison to Enalapril in Dogs with Mitral Valve Endocardiosis.  Deinert M, Ripken A; Proceedings, 37th World Small Animal Vet. Assn., Oct 2002. Quote: Objectives: The echocardiographic examination was performed to compare the effects of the two drugs on heart chamber size and wall motion. Of special interest was the development or the increase of a hyperkinetic wall motion pattern in the Pimobendan group compared to the Enalapril group. Please refer also to Part 1. Materials: The echocardiographic parameters measured on day 0, 7 and 28 of the study consisted of left atrial to aortic ratio, left ventricular wall thickness and diameters (LVID) and calculations from these values i.e., FS (fractional shortening) and ESVI (end systolic volume index). Please refer also to Part 1. Results: Within the Pimobendan group no significant difference in the echocardiography parameters were seen. On the other hand we found significant enlargements (p < 0,05) of LVIDd, LVIDs and ESVI within the Enalapril group after 28 days. The comparison between the groups showed significantly larger (p < 0,05) LVIDd and ESVI on day 7 and significantly larger (p < 0,05) LVIDd and LVIDs on day 28 in the Enalapril group. The FS calculations showed no significant changes within or between the groups (Enalapril group: Day 0: 44,4 %, day 28: 40,9 %; Pimobendan group: Day 0: 47,1 %, day 28: 46,7 %; ns). Conclusion: According to our echocardiographic data treatment with Enalapril lead to a significant increase of the left ventricular diameters. This effect did not occur in the Pimobendan group. Treatment with Pimobendan on the other hand did not lead to an increase of the fractional shortening nor occurred a hyperkinetic wall motion pattern, the related parameters showed no significant changes. Also from this echocardiographic data, it can be concluded, that Pimobendan is a safe and efficacy drug for the treatment of patients with mitral valve endocardiosis.

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2003

Effects of rolipram, pimobendan and zaprinast on ischaemia-induced dysrhythmias and on ventricular cyclic nucleotide content in the anaesthetized rat. M.D. Carcelest, F. Aleixandret, T. Fuente~,]. L6pez-Vidalt, M. L. Laorden. Euro. J. Anaesthesiology. 2003;20:205-211. Quote: This study was designed to compare the haemodynamic, electrophysiological and pharmacodynamic effects of three selective inhibitors of the different isoenzyme forms of phosphodiesterase (PDE) on ischaemia-induced dysrhythmias in the anaesthetized rat. The drugs used were pimobendan, a selective PDE III inhibitor, rolipram, a selective PDE IV inhibitor, and zaprinast, a selective PDE V inhibitor. The coronary artery was occluded 15 min after commencing drug administration, and myocardial ischaemia was maintained for 30 min during which the heart rate and mean arterial pressure were recorded. cAMP and cGMP were determined by radioimmunoassay. Pretreatment with rolipram decreased the duration of ventricular tachycardia without any change in the incidences of dysrhythmias or the mortality rate. This drug did not modify ventricular content of adenosine 3',5'-cyclic monophosphate (cAMP) or guanosine 3',5'-cyclic monophosphate (cGMP). Pimobendan (1 mg kg(-1) + 0.1 mg kg(-1) min) decreased the duration of ventricular tachycardia. This dose of pimobendan and zaprinast (1 mg kg(-1) + 0.1 mg kg(-1) min(-1)) increased the incidence rate of ventricular fibrillation following coronary artery ligation and the mortality rate. Moreover, both drugs increased cGMP in the ventricle. The results demonstrated that pimobendan and zaprinast increased the incidence of dysrhythmias and the mortality rate, which was accompanied by an increase in the ventricular content of cGMP. Rolipram decreased the duration of ventricular tachycardia without a change in the cyclic nucleotide content or in the mortality rate. ... In conclusion, our results suggest that the administration of the Class III PDE inhibitor pimobendan and the Class V PDE zaprinast are associated with raised myocardial cGMP content in the anaesthetized rat ischaemic left ventricle animal model, whereas the Class IV PDE inhibitor rolipram produces no corresponding rise in cGMP. Both pimobendan and zaprinast administration were associated with an increased mortality from dysrhythmias, an effect not shown with rolipram. We provide evidence that a rise in intracellular cGMP may be important in the aetiology of ischaemia-induced dysrhythmias. However, it is possible that other mechanisms in addition to cyclic nucleotides have been implicated in ischaemiainduced dysrhythmias.

Regurgitant Fraction Measured by Using the Proximal Isovelocity Surface Area Method in Dogs with Chronic Myxomatous Mitral Valve Disease.  Kittleson M. D., Brown, W. A.; J Vet Intern Med. 2003 Jan;17(1):84-88. Quote: Previous studies have demonstrated that regurgitant fraction can be measured by using the proximal isovelocity surface area (PISA) method. For this study, we utilized this Doppler echocardiographic method to estimate the magnitude of mitral regurgitation in dogs with myxomatous mitral valve disease. Seventeen older, small dogs with chronic mitral regurgitation and no to mild myocardial failure were studied. A blinded observer judged the clinical severity of mitral regurgitation to be mild, moderate, or severe by using echocardiographic assessment of left heart size. The regurgitant fraction was calculated by using the PISA method and spectral Doppler echocardiography. The regurgitant fraction was compared to the clinical assessment of severity for each dog and to calculations of left atrial size. Five dogs had clinically mild mitral regurgitation. Four of these dogs had a regurgitant fraction between 22 and 41%, whereas 1 had a regurgitant fraction of 73%. The 3 dogs with clinical evidence of moderate mitral regurgitation had a regurgitant fraction of 46–65%. All 9 dogs with clinically severe mitral regurgitation had a regurgitant fraction greater than 75% (78–88%). The regurgitant fraction was statistically different between each group (P < .001). A good but curvilinear relationship was found between left atrial size and regurgitant fraction (r2= 0.72). In this study, dogs with clinically severe mitral regurgitation consistently had hemodynamically severe regurgitation (regurgitant fraction > 75%), whereas dogs with clinically mild to moderate disease had lesser degrees of regurgitation. Good correlation was found between regurgitant fraction and left atrial size. We conclude that the major determinant of left atrial size and disease severity in dogs with mitrial regurgitation is the degree of mitral regurgitation.

Spectral analysis of heart rate variability in dogs with mild mitral regurgitation. Fujii Y., Wakao Y. AmJ.Vet.Res. 2003 Feb; 64(2):145-148.

Brain Natriuretic Peptide Concentration in Dogs with Heart Disease and Congestive Heart Failure. Kristin A. MacDonald, Mark D. Kittleson, Coralie Munro, and Philip Kass. J Vet Intern Med. 2003 Mar;17(2):172–177. Quote: Plasma brain natriuretic peptide concentration ([BNP]) is high in humans with cardiac disease and is further increased with congestive heart failure (CHF). The hypotheses of this study were that dogs with moderate to severe mitral regurgitation due to myxomatous mitral valve disease (MVD) would have increased plasma [BNP] compared to normal dogs, that plasma [BNP] would be higher in dogs with CHF, and that plasma [BNP] would predict premature death from cardiovascular disease. The study population consisted of 34 dogs: 9 normal dogs and 25 dogs with MVD. Patients were divided into 4 groups: group I—10 dogs with moderate to severe MVD and no radiographic evidence of CHF; group II—6 dogs with severe MVD and mild CHF; group III—7 dogs with severe MVD and moderate CHF; and group IV—2 dogs with severe MVD and severe CHF. Diagnostic tests included thoracic radiographs, an echocardiogram, a serum chemistry profile, and the measurement of plasma [BNP] by a caninespecific radioimmunoassay. There was a significant positive correlation between the plasma [BNP] and heart disease/failure groups. Plasma [BNP] increased with progressively increasing severity of MVD and CHF. Group I dogs had higher plasma [BNP] than did control dogs, and plasma [BNP] was higher in dogs with CHF (groups II–IV versus group I). Plasma [BNP] was also weakly positively correlated with left atrial size. For every 10-pg/mL increase in plasma [BNP], the mortality rate over 4 months’ time increased approximately 44%.

Decreased Plasma Concentration of Nitric Oxide Metabolites in Dogs with Untreated Mitral Regurgitation. Henrik D. Pedersen, Trine Schutt, Rikke Søndergaard. Karen Qvortrup, Lisbeth H. Olsen, Annemarie T. Kristensen. J.Vet.Int.Med. March 2003;17(2):178-184. Quote: "Endothelium-dependent (nitric oxide [NO]-mediated) vasodilation is impaired in humans with heart failure. This dysfunction is an important therapeutic target. The plasma concentration of the NO metabolites nitrate and nitrite (collectively referred to as NOx) is a measure of whole-body NO production, provided that the dietary intake of the ions is low. Fifty clinically healthy dogs older than 1 year (median 5.0 years; interquartile interval 2.6–8.2 years) were studied, including 9 controls of various breeds, 23 Cavalier King Charles Spaniels (CKCSs) with no or minimal mitral regurgitation (MR), 9 CKCSs with mild MR (regurgitant jet occupying 15–50% of the left atrial area), and 9 CKCS with moderate to severe MR (jet ± 50%) due to myxomatous valve disease. None of the dogs received medication. The dogs were given NOx-free water and a diet with a low concentration of NOx for 96 hours before blood sampling. Multiple linear regression analysis revealed that dog group, but not gender, age, serum creatinine concentration, and platelet count, was associated with NOx concentrations. Control dogs had the same NOx concentration (median 20.0 μM; interquartile interval 15.1–25.5 μM) as CKCSs without MR (median 18.7 μM; interquartile interval 15.5–25.9 μM). Compared to CKCSs without MR, the NOx concentration was lower in CKCSs with mild (median 12.9 μM; interquartile interval 11.0–13.5 μM; P= .04) and moderate to severe (median 11.2 μM; interquartile interval 6.9–17.1 μM; P= .02) MR. In conclusion, CKCSs with mild to severe, clinically silent MR have decreased plasma NOx concentrations, suggesting that endothelial dysfunction develops early in the course of developing MR in dogs."

Effect of amlodipine on severity of mitral regurgitation in dogs with chronic mitral valve disease. Oyama MA, Prosek R, DD Sisson. J. Vet. Intern. Med. (ACVIM Forum). June 2003;17(4):399-400. Quote: Amlodipine is a vasoactive calcium-channel blocker capable of inducing arterial vasodilation and reducing afterload. We sought to evaluate the effects of amlodipine on mitral regurgitant stroke volume (RSV) and regurgitant orifice area (ROA) in dogs with naturally occurring chronic mitral valve disease. Dogs with moderate to severe mitral valve regurgitation were administered oral amlodipine therapy in addition to stable doses of conventional background therapy. RSV and ROA at baseline and after amlodipine treatment were calculated using a modified proximal isovelocity surface area method previously validated by the investigators. Left ventricular, aortic annulus, and left atrial dimensions were measured using M-Mode and 2D echocardiography. Systolic blood pressure was measured via Doppler or oscillometric techniques. The study population consisted of 16 dogs described by the following signalment data: sex: 9 male and 7 female; breed: 6 mixed breed and 8 purebred; age (ave 6 SD): 11.3 6 2.7 years; weight: 8.1 6 4.3 kg. The average administered dose of amlodipine was 0.25 mg/kg PO q24h (range = 0.13–0.53). Concurrent background therapy included ACE-inhibitor in 9 dogs (56%), Lasix in 8 dogs (50%), digoxin in 4 dogs (25%), and spironolactone in 1 dog (6%). Six dogs (38%) were receiving no other cardiac medications other than amlodipine. No dog had radiographic or clinical evidence of congestive heart failure at time of entry. Follow-up averaged 20 days (range = 7–49). Treatment with amlodipine was associated with a 9.6% decrease in systolic blood pressure versus baseline (149 versus 134 mm Hg; P = .001), a 21.4% decrease in RSV (16.9 versus 13.7 ml; P = .004), a 17.7% decrease in ROA (0.225 versus 0.183 cm2; P = .016), a 15.1% decrease in regurgitant fraction (74 versus 62.6%; P< .02), and a 3.5% decrease in LV end-diastolic dimension (3.9 versus 3.7 cm; P 5 .04). No change in LA:Ao was found (P = .31). The average heart rate of the patient population was the same at baseline and at recheck (138 versus 141 bpm; P = .60), and a patient’s change in heart rate did not correlate with any echocardiographic measurements (P > .05 in all instances). No adverse side effects were reported in any of the patients during treatment with amlodipine. Treatment with amlodipine reduced systolic blood pressure and severity of mitral regurgitation in dogs with moderate to severe mitral valve disease, and can be used simultaneously with standard cardiac therapy.

Spectral analysis of heart rate variability in dogs with mild mitral regurgitation. Fujii Y, Wakao Y. Am J Vet Res 2003;64:145–148.

M-mode echocardiographic ratio indices in normal dogs, cats, and horses: a novel quantitative method. Donald J. Brown, John E. Rush, John MacGregor, James N. Ross Jr, Barbara Brewer, William M. Rand. J. Vet. Intern. Med. September 2003;17(5):653-662. Quote: A novel method for quantitative echocardiographic interpretations is introduced based on the calculation of ratio indices in which each raw M-mode measurement is divided by the aortic root dimension (Ao). “Aorta-based” indices were calculated with the animal's measured aortic root dimension (Aom) as the length standard. Conversely, “weight-based” indices employed an idealized estimate of aortic dimension (Aow) with a weighted least squares linear regression against the cube root of body weight (Aow=kW1/3). Use of these indices circumvented undesirable statistical characteristics inherent in linear regression of echocardiographic dimensions against body weight and, to a lesser extent, body surface area. Compared with the regressions, ratio indices resulted in substantial refinement of the predictive range for each M-mode measurement in dogs, particularly with decreasing body size. Weight-based indices outperformed aorta-based indices in this regard. To refine the predictive range, neither type of index was clearly advantageous in cats compared with the simple average method typically employed for that species. Several of the raw M-mode measurements, however, were correlated with body weight in cats and horses, indicating the need for an appropriate correction for body size in these species. The ratio index method was suitable for this purpose. Summary statistics derived from normal dogs (n = 53), cats (n = 32), and horses (n = 17) are presented for each index, including novel clinical indices calculated from area ratios. The latter were designed to represent body size-adjusted left ventricular stroke area (ie, volume overload) and myocardial wall area (ie, hypertrophy). ... Our study was limited in that there were insufficient numbers within individual breed or age groups to permit comparisons among such groups or determination of group-specific indices. Ratio indices are, however, ideally suited to studying breed differences, and somatotype (ie, shape) is defined logically in terms of these ratios. ... Our study population, however, was limited, and a comprehensive determination of normal values and ranges for these indices must await further study.

Decreased Platelet Function in Cavalier King Charles Spaniels with Mitral Valve Regurgitation.  Tarnow I., Kristensen A. T., Texel H., Olsen L. H., Pedersen H. D. J Vet Intern Med. September 2003;17(5):680-686. Quote: With aggregometry, increased platelet activity has been reported in Cavalier King Charles Spaniels (CKCS) without mitral regurgitation (MR). In contrast, dogs with MR have been found to have decreased platelet activity. The purpose of this study was to test an easy bedside test of platelet function (the Platelet Function Analyzer [PFA-100t]) to see if it could detect an increase in platelet activity in CKCS without MR and a decrease in platelet activity in CKCS with MR. This study included 101 clinically healthy dogs .1 year of age: 15 control dogs of different breeds and 86 CKCS. None of the dogs received medication or had a history of bleeding. The PFA-100 evaluates platelet function in anticoagulated whole blood under high shear stress. Results are given as closure times (CT): the time it takes before a platelet plug occludes a hole in a membrane coated by agonists. The CT with collagen and adenosine-diphosphate as agonists was similar in control dogs (median 62 seconds; interquartile interval 55–66 seconds) and CKCS with no or minimal MR (55; 52–64 seconds). The CT was higher in CKCS with mild MR (regurgitant jet occupying 15–50% of the left atrial area) (75; 60–84 seconds; P 5 .0007) and in CKCS with moderate to severe MR (jet .50%) (87; 66–102 seconds; P , .0001). CKCS with mild, moderate, and severe, clinically inapparent MR have decreased platelet function. The previous finding of increased platelet reactivity in nonthrombocytopenic CKCS without MR could not be reproduced with the PFA-100 device.

Investigation of pimobendan versus benazepril in canine myxomatous valvular disease. Boswood A, McEwan JD, French A, Little C, Swift S, Smith S, Patteson M. Vet Rec. 2003 Oct 4;153(14):439-40.

D-Ribose improves diastolic function and quality of life in congestive heart failure patients: a prospective feasibility study. Omran Heyder, Illien Stefan, MacCarter Dean, St. Cyr John, Lüderitz Berndt. European J. of Heart Failure. Oct. 2003;5(5):615-619. Quote: "Patients with chronic coronary heart disease often suffer from congestive heart failure (CHF) despite multiple drug therapies. D-Ribose has been shown in animal models to improve cardiac energy metabolism and function following ischaemia. This was a prospective, double blind, randomized, crossover design study, to assess the effect of oral D-ribose supplementation on cardiac hemodynamics and quality of life in 15 patients with chronic coronary artery disease and CHF. The study consisted of two treatment periods of 3 weeks, during which either oral D-ribose or placebo was administered followed by a 1-week wash out period, and then administration of the other supplement. Assessment of myocardial functional parameters by echocardiography, quality of life using the SF-36 questionnaire and functional capacity using cycle ergometer testing was performed. The administration of D-ribose resulted in an enhancement of atrial contribution to left ventricular filling (40±11 vs. 45±9%, P=0.02), a smaller left atrial dimension (54±20 vs. 47±18 ml, P=0.02) and a shortened E wave deceleration (235±64 vs. 196±42, P=0.002) by echocardiography. Further, D-ribose also demonstrated a significant improvement of the patient's quality of life (417±118 vs. 467±128, P≤0.01). In comparison, placebo did not result in any significant echocardiographic changes or in quality of life. This feasibility study in patients with coronary artery disease in CHF revealed the beneficial effects of D-ribose by improving diastolic functional parameters and enhancing quality of life."

Clinical investigation of Ramipril(VASOTOP) on canine chronic heart failure. Okusa Kiyoshi, Inoue Midori, Kurita Tooru, Takehara Kazutaka, Sasagawa Kazuyasu, Nameki Yoshikazu, Yonezawa Satoru, Kanno Shigeyuki. Jap.J.Sm.An.Prac. 2003; 22(2):93-103 Quote: "The efficacy of ramipril(Vasotop) was confirmed in a clinical investigation conducted in 26 small-animal hospitals using 89 dogs with chronic heart failure. 74 dogs were received ramipril and the other 15 dogs were received placebo tablets. Two of 74 dogs didn't visit the hospital for the last evaluation, other two dogs died of morbid pulmonary edema and one dog was terminated administration at 7th day due to vomit, polydipsia & polyuria, anorexia and decrease of activity. Ramipril was administered orally once a day for 28 consecutive days to achieve a minimum dosage of 0.125mg/kg. The daily dosage in the ramipril group(69 dogs) ranged from 0.125 to 0.313mg/kg. The clinical effectiveness of ramipril was evaluated using the five parameters as activity, exercise tolerance, breathing difficulties, cough and NYHA class. As a result, 1) Significant improvement was observed in ramipril group at 7th day after treatment. 2) Effective rate of ramipril treatment was 87.0%. And even a plain administration of ramipril(without concomitant drug) indicated curative properties as equal as 85.9%. 3) The improvement of the symptoms was observed in all 7 dogs, which showed high BUN value before administration(>35mg/dl). As for BUN values of these dogs, they showed decline or no change except one uremia dog. Accordingly, the clinical efficacy of ramipril orally given at 0.125-0.25mg/kg once daily on canine chronic heart failure was confirmed significantly. In the context of safety, no adverse drug reactions potentially inhibiting clinical applications were observed."

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2004

Identification of surface morphologic changes in the mitral valve leaflets and chordae tendineae of dogs with myxomatous degeneration. Corcoran BM, Black A, Anderson H, Dukes-McEwan J, French A, Smith P, Devine C. Am. J. Vet. Res. February 2004;65:198–206. Quote: "To describe structural changes in the left atrioventricular (mitral) valve complex of dogs with endocardiosis by use of scanning electron microscopy. 5 clinically normal dogs and 4 dogs with mitral valve endocardiosis [3 Cavalier King Charles Spaniels and 1 mixed-breed dog]. The mitral valve complex from each dog was fixed and prepared for examination via scanning electron microscopy. Findings in valves from clinically normal and affected dogs were compared to identify surface changes associated with endocardiosis. Compared with findings in valves from clinically normal dogs, endocardiosis-affected mitral valve complexes had several morphologic abnormalities. Tissue swelling on the edge of valve leaflets, chordae tendineae, and the chordal-papillary muscle junction was evident. Damage to the valve complex endothelium was unevenly distributed; in some areas, denudation of endothelial cells had exposed the basement membrane or subendothelial valve collagen matrix. This damage was most noticeable on the leaflet edges and extended more to the ventricular aspect of the valve than the atrial side. Cell loss also extended to the chordae tendineae but was less apparent at the chordal-papillary muscle junction. The remaining endothelial cells on affected valves were arranged in less-ordered rows and had more plasmalemmal microappendages, compared with cells on unaffected valves. Morphologic changes associated with mitral valve endocardiosis in dogs were similar to those observed in humans with mitral valve prolapse. In dogs with mitral valve endocardiosis, gross changes in the valve complex may affect hemodynamics in the heart; alterations in the leaflet and chordal endothelium may contribute to pathogenesis of this disease."

Brain Natriuretic Peptide Enhances Renal Actions of Furosemide and Suppresses Furosemide-Induced Aldosterone Activation in Experimental Heart Failure. Alessandro Cataliotti, Guido Boerrigter, Lisa C. Costello-Boerrigter, John A. Schirger, Toshihiro Tsuruda, Denise M. Heublein, Horng H. Chen, Lorenzo S. Malatino and John C. Burnett, Jr. Circulation. March 2004;109:1680-1685. Quote: "Background: The renal actions of brain natriuretic peptide (BNP) in congestive heart failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF. Methods and Results—CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg · kg 1 · h 1). A second group (Fs BNP) received 45-minute intravenous coinfusion of Fs (1 mg · kg 1 · h 1) and low-dose (2 pmol · kg 1 · min 1) BNP followed by 45-minute coinfusion of Fs (1 mg · kg 1 · h 1) and high-dose (10 pmol · kg 1 · min 1) BNP. Fs increased urinary flow, but the effect of Fs BNP was greater. Similarly, urinary sodium excretion was higher in the Fs BNP group. Although GFR tended to decrease in the Fs group, it increased in the Fs BNP group (35 3 to 56 4*) (* indicates P 0.05 versus baseline) (P 0.0001 between groups). Plasma aldosterone increased with Fs (41 10 to 100 11* ng/dL) but was attenuated in the Fs BNP group (44 11 to 54 9 ng/dL low-dose and to 47 7 ng/dL high-dose) (P 0.0007 between groups). Conclusions—Fs BNP has more profound diuretic and natriuretic responses than Fs alone and also increases GFR without activation of aldosterone. Coadministration of BNP and loop diuretic is effective in maximizing natriuresis and diuresis while preserving renal function and inhibiting activation of aldosterone."

Determinants of weak femoral artery pulse in dogs with mitral valve prolapse. I. Tarnow, L. H. Olsen, M. B. Jensen, K. M. Pedersen, H. D. Pedersen. Res, Vet, Sci. April 2004; doi: 10.1016/j.rvsc.2003.10.001. Quote: In three substudies encompassing 247 dogs from two breeds predisposed to myxomatous mitral valve disease (MMVD), femoral artery pulse strength was palpated and related to potential explanatory factors, including quantitative echocardiographic measures of MMVD, aortic and femoral artery diameter and wall thickness and blood pressure. In addition, in 109 Cavalier King Charles Spaniels (of which 61 were included in the three substudies mentioned above), the relation between femoral artery pulse strength and presence of thrombocytopenia was investigated. ... A weak femoral artery pulse is a common finding in CKCS. ... No relation, however, was found between presence of thrombocytopenia and femoral artery pulse strength in this study. ... In conclusion, this study demonstrated that a weak femoral artery pulse is a common finding in CKCS and Dachshunds, and that the pulse strength in any one dog is reasonably reproducible. Pulse strength was found to be inversely related to heart rate, degree of obesity and MVP severity. In addition, femoral artery pulse strength decreased with age. The weak femoral artery pulses appear to reflect a decrease in diastolic artery diameter and/or systolic distension associated with a local decrease in blood flow, not artery occlusion or changes in pulse pressure and stroke volume.  ... In 26% of the dogs, a pulse ⩽50% of normal strength was detected; six dogs (2.0%) had an absent pulse unilaterally or bilaterally. Mitral valve prolapse severity, degree of obesity, heart rate and age all influenced femoral artery pulse strength negatively. Weak femoral artery pulses were not related to clinical signs or to decreased pulse pressure or stroke volume. A weak femoral artery pulse reflected reduced artery diameter and/or distension rather than occlusion. In conclusion, weak femoral artery pulses in dogs with MMVD seem to be associated with regional/local reductions in blood flow and not arteriosclerosis or platelet count.

Allometric Scaling of M-Mode Cardiac Measurements in Normal Adult Dogs.  Craig C. Cornell, Mark D. Kittleson, Paul Della Torre, Jens Häggström, Christophe W. Lombard, Henrik D. Pedersen, Andrea Vollmar, Aaron Wey. J. Vet. Intern. Med. May 2004;18:311–321. Quote: Indices for M-mode measurements in dogs usually have been based on the assumption that a linear relationship exists between these measurements and body weight (BW) or body surface area (BSA). The relationships between the geometry of 3-dimensional objects do not support this assumption.The purposes of this study were to retrospectively examine M-mode data from a large number [494] of dogs of varying sizes and [8 purebreds and mixed] breeds [including 57 cavalier King Charles spaniels] that were examined by a large number of ultrasonographers, to use the allometric equation to determine the appropriate BW exponent required to predict these cardiac dimensions, and to determine normal mean values and prediction intervals for common M-mode variables. Linear regression analyses of data from 494 dogs (2.2–95 kg) revealed a good correlation between M-mode measurements and BW after logarithmic transformation of the data (r2= .55-.88). Most variables were most closely related to an index of body length, BW1/3, although the exponent that best predicted diastolic and systolic left ventricular wall thicknesses was closer to 0.25. No variable indexed well to BW or BSA. With these data, appropriate mean values and prediction intervals were calculated for normal dogs, allowing veterinarians to correctly and appropriately index M-mode values. ... If the [LVIDd] result is between 1.27 and 1.85, the value is within the normal [95%] prediction interval for this study. ... The equations developed from this study appear to be applicable to adult dogs of most breeds. ... The effect of breed on the echocardiogram is controversial. Athletic ability and susceptibility to heart disease are undoubtedly influenced by dog breed, and it would be surprising if breed of dog did not also affect the size and function of the heart.

Assessment of the Ability of Pimobendan to Increase the Frequency of Ventricular Ectopy in Dogs with CHF Due to DCM and Chronic Mitral Valve Insufficiency. MR O’Grady, SL Minors, ML O'Sullivan, R Horne. J Vet Intern Med; May/June 2004;18(3) (ACVIM 22st Ann. Vet. Med. Forum Abstract Program: Abstract 258).

Evaluation of techniques and outcomes of mitral valve repair in dogs. Griffiths LG, Orton EC, Boon JA. J Am Vet Med Assoc. 2004 Jun 15;224(12):1941-5.

Differences between breeds of dog in a measure of heart rate variability. Doxey S, Boswood A. Vet Rec. 2004 Jun 5;154(23):713-7. Quote: The vasovagal tonus index (VVTI), a time-domain indicator of heart rate variability, was measured in 92 dogs of six breeds (German shepherd dogs, labrador retrievers, cocker spaniels, boxers, bulldogs and [12] cavalier King Charles spaniels). There was a significant difference in VVTI between the six breeds (P=0-003). Brachycephalic dogs had a higher VVTI than other types of dog (P<0-005), and when comparing individual breeds brachycephalic breeds tended to have a higher vvri than non-brachycephalic breeds, although the difference was not always significant. The VYTI was negatively correlated with heart rate (P<OO1) and dogs suffering from congestive heart failure had a lower VVTI than other dogs, whether compared within or between breeds (P<O-OO1). ... Six of the 92 dogs were suffering from congestive heart failure and their mean (sd) VVTI was 5-51 (1-02), significantly lower than that of the other 86 dogs (8-10 [1-5]) (P<0.001). Two of the six were German shepherd dogs ... . The other four were cavalier King Charles spaniels and their mean VVTI was 5-94 (3.87), significantly lower than that of the other eight cavalier King Charles spaniels (8.71 [1-07]) (P<0.001).

Caractéristiques épidémiologiques, cliniques, écho-doppler de l’endocardiose mitrale chez le Cavalier King Charles en France: étude rétrospective de 451 cas (1995 à 2003). Valérie Chetboul, Renaud Tissier, Florence Villaret, Audrey Nicolle, Eric Déan, Thierry Benalloul, Jean-Louis Pouchelon. Can Vet J 2004;45:1012–1015. Quote: "A study performed on 451 Cavalier King Charles showed that 40.6% of dogs had a left apical systolic heart murmur, whose prevalence increased with age (. 11-year-old, 100%), but was not different between males and females. Mitral valve endocardiosis represented 93.3% of the ultrasonographic abnormalities."

Breed Predispositions to Disease in Dogs & Cats.  Alex Gough, Alison Thomas. 2004; Blackwell Publ. 44-45.

Echocardiographic Estimation of Mean Left Atrial Pressure in a Canine Model of Acute Mitral Valve Insufficiency. Mark A. Oyama, D. David Sisson, Barret J. Bulmer, Peter D. Constable. J. Vet. Intern. Med. September 2004;18(5):667-672. Quote: High mean left atrial pressure (MLAP) due to canine degenerative mitral valve disease is associated with clinically relevant morbidity and mortality. The ability to noninvasively measure MLAP would assist in the diagnosis and treatment of disease. Doppler echocardiography allows measurement of early transmitral blood flow (E) and the velocity of the mitral valve annulus (Ea). The ratio of early mitral inflow velocity to early mitral annular velocity (E: Ea) correlates well with MLAP in human subjects. We sought to determine the ability of E: Ea to predict MLAP in dogs with experimentally induced mitral regurgitation. Nine anesthetized purpose-bred dogs underwent placement of a Swan-Ganz catheter into the left atrium and recording of MLAP. Simultaneous transthoracic echocardiographic and hemodynamic studies were performed after acute chordae tendineae rupture and during IV infusion with nitroprusside (2.5-5.0 μg?kg-1?min-1) or hydralazine (1-1.5 mg/kg). Mitral regurgitant fraction, measured by single-plane angiography and thermodilution, ranged from 17% to 81%. MLAP increased from 5.4 ± 2.5 mm Hg to 17.4 ± 9.4 mm Hg after creation of mitral valve regurgitation (MR; P= .018). Forty sets of echocardiographic measurements were obtained from 7 dogs, and E, as well as E: Ea, were linearly related to MLAP. The R2 value for the linear regression equation containing E: Ea as the dependent variable (0.83) was greater than that for E (0.73). The 95% confidence intervals were calculated for predicting MLAP = 20 mm Hg from E:Ea, and E:Ea > 9.1 or < 6.0 indicated a 95% probability that MLAP was ≥ 20 mm Hg or ≤20 mm Hg, respectively. Echocardiography can be used to predict MLAP in isoflurane-anesthetized dogs with experimentally induced acute mitral valve insufficiency.

Ischemic Heart Disease: Metabolic Approaches to Management. Daniel F. Pauly, Carl J. Pepine. Clin. Cardiol. 2004;27:439-441. Quote: "The number of patients with coronary artery disease and its risk factors is increasing in Western nations. New treatments for these patients may soon include a class of agents known as the metabolic modulators. This group of agents consists of the partial fatty acid oxidation inhibitors trimetazidine and ranolazine, as well as dichloroacetate, which promotes carbohydrate utilization. Metabolic modulators also include the nutriceuticals L-carnitine and D-ribose. The available evidence regarding the benefits of each of these five agents is reviewed."

Use of pimobendan in the management of heart failure. Fuentes VL. Vet Clin North Am Small Anim Pract. 2004 Sep;34(5):1145-55.

New insights into degenerative mitral valve disease in dogs. Jens Häggström, Henrik Duelund Pedersen, and Clarence Kvart. Vet. Clinics of No. Amer.: Small Anim.Pract.2004 Sep;34(5):1209-26.

Experimental models and mechanisms of enhanced coughing. Donald C. Bolser. Pulmonary Pharmacology & Therapeutics 17 (2004) 383–388. Quote: "Enhanced coughing can be produced in a variety of animal models, including the guinea pig, cat, dog and pig. Typically, airway inflammation has been produced by sensitization, exposure to cigarette smoke, sulphur dioxide or angiotensin-converting enzyme inhibitors. In some of these models, inflammatory mediators such as bradykinin and tachykinins have been shown to contribute to the enhanced coughing."

Comparison of the effects of imidapril and enalapril in a prospective, multicentric randomized trial in dogs with naturally acquired heart failure. Amberger C, Chetboul V, Bomassi E, et al. J Vet Cardiol 2004;6:9-16.

D-ribose aids congestive heart failure patients. Heyder Omran, Dean McCarter, John St Cyr, Berndt Lüderitz. Exp Clin Cardiol Summer 2004;9(2):117-118. Quote: "Patients with congestive heart failure often experience fatigue despite intensive pharmacological therapy. Ribose can aid the recovery of ATP levels and, hence, diastolic function. Clinical trials have shown that ribose supplementation improves ischemic threshold and enhances diastolic function in congestive heart failure."

Angiotensin-converting enzyme inhibitors in the therapy of renal diseases. Lefebvre, H. P. & Toutain, P. L. J. Vet. Pharm. & Therap., Oct.2004; 27(5):265-281.

Why Is Cardiac Radiology So Difficult? Christoper R. Lamb. WSAVA Congress 2004. Quote: In a recent study two experienced observers examined the radiographs of 57 dogs with common congenital cardiac anomalies without access to any clinical information in order to avoid biasing their interpretations. Under these conditions, the observers reached the correct diagnosis in less than 40% cases. This poor result reflects the difficulty observers had identifying shape changes that can occur in radiographs of dogs with enlarged cardiac chambers. Radiographic signs of specific cardiac chamber enlargement (or pulmonary vascular abnormalities) were recognised by both observers in only 20% instances in which they might be expected

Assessment of changes in hemostatic markers in Cavalier King Charles Spaniels with myxomatous mitral valve disease. Tarrow I, Kristensen AT, Olsen LH, Pedersen HD. Am J Vet Res 2004 Dec.;65(12):1644–1652. Quote: Objective: To evaluate markers of hemostasis and their relationship to the degree of mitral regurgitation (MR) and platelet function in Cavalier King Charles Spaniels (CKCSs) with myxomatous mitral valve disease. Animals: 76 clinically healthy CKCSs and 24 control dogs. Procedure: All dogs underwent echocardiographic examination; various hemostatic, hematologic, and biochemical variables were evaluated in blood. The CKCSs were allocated to 1 of 3 groups on the basis of MR severity. In 8 control dogs and 8 CKCSs, plasma von Willebrand factor (vWF) multimer analysis was performed. Results: Compared with control dogs, plasma fibrinogen concentration was higher in all CKCSs and related to left ventricular end diastolic diameter and left atrial-to-aortic root ratio among all CKCSs. The activated partial thromboplastin times and plasma Ddimer concentration were similar among the 4 groups. Plasma vWF concentration was lower in CKCSs with moderate to severe MR, compared with that of CKCSs with no MR and control dogs. There was a relationship between plasma vWF concentration and platelet function in CKCSs but not in control dogs. In 4 CKCSs with moderate to severe MR and low plasma vWF concentration, amounts of vWF high-molecular-weight multimers (HMWMs) were low. Conclusions and Clinical Relevance: In CKCSs, MR appeared to be associated with a low plasma vWF concentration and likely a loss of vWF HMWMs (possibly through their destruction via shear stress to the blood). The importance of the changes in plasma fibrinogen concentration and the thromboembolic risk in dogs with MR remain to be investigated.

Epidemiological, clinical, echo-Doppler characteristics of mitral valve endocardiosis in Cavalier King Charles in France: a retrospective study of 451 cases (1995 to 2003). Chetboul V, Tissier R, Villaret F, Nicolle A, Déan E, Benalloul T, Pouchelon JL. Canadian Vet. J. Dec.2004;45(12):1012-1015. Quote: "A study performed on 451 Cavalier King Charles showed that 40.6% of dogs had a left apical systolic heart murmur, whose prevalence increased with age (> 11-year-old, 100%), but was not different between males and females. Mitral valve endocardiosis represented 93.3% of the ultrasonographic abnormalities."

Assessment of left ventricular function using pulsed tissue Doppler imaging in healthy dogs and dogs with spontaneous mitral regurgitation. Teshima K., Asano K., Sasaki Y., Kato Y., Kutara K., Edamura K., Hasegawa A., Tanaka S. J. Vet. Med. Sci. December 2005;67:1207–1215. Quote: "Pulsed tissue Doppler imaging (pulsed TDI) has been demonstrated to be useful for the estimation of left ventricular (LV) systolic and diastolic functions in various human cardiac diseases. The objectives of this study were to investigate the relationship between pulsed TDI and LV function by using cardiac catheterization in healthy dogs and to evaluate the clinical usefulness of pulsed TDI in dogs with spontaneous mitral regurgitation (MR). The peak early diastolic velocity (E'), peak atrial systolic velocity (A'), and peak systolic velocity (S') were detectable in the velocity profiles of the mitral annulus in all the dogs. In the healthy dogs, S' and E' were correlated with LV peak +dP/dt and -dP/dt, respectively. E' was lower in dogs with MR than in dogs without cardiac diseases. E/E' in the MR dogs with decompensated heart failure was significantly increased in comparison with those with compensated heart failure. The sensitivity and specificity of the E/E' cutoff value of 13.0 for identifying decompensated heart failure were 80% and 83%, respectively. In addition, E/E' was significantly correlated with the ratio of left atrial to aortic diameter. These findings suggest that canine pulsed TDI can be applied clinically for estimation of cardiac function and detection of cardiac decompensation and left atrial volume overload in dogs with MR."

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2005

Non-invasive real-time measurements of cardiac vagal tone in dogs with cardiac disease. Little C,J,, Julu P.O., Hansen S., and Reid S.W. Vet Rec., Jan 2005; 156: 101 - 105.

Canine Heart Failure - Current Concepts: Strengths and Weaknesses. Atkins C. Proceedings, 19th No. Am. Vet. Conf., Jan. 2005: 111-113.

Carvedilol and the Heart - A Promising Therapy. Miller M. Proceedings, 19th No. Am. Vet. Conf., Jan. 2005: 125, 130.

Future Directions for Diagnosis Treatment and Management Strategies. Miller M. Proceedings, 19th No. Am. Vet. Conf., Jan. 2005: 131-133.

Pimobendan A New Drug for Heart Failure Management. Miller M. Proceedings, 19th No. Am. Vet. Conf., Jan. 2005: 129.

The Tei Index of Myocardial Performance: Applications in Cardiology. John A. Lakoumentas, Fotis K. Panou, Vasiliki K. Kotseroglou, Konstantina I. Aggeli, Panagiotis K. Harbis. Hellenic J. Cardiology. January 2005;46:52-58. Quote: "There are many limitations to the use of classical echocardiographic indexes for the estimation of systolic and diastolic left ventricular (LV) function. The ejection fraction (EF, an index of systolic function) and LV volumes are subject to large errors when the ellipsoid shape of the heart becomes spherical. Age, rhythm and conduction disturbances, and changes in loading all affect the Doppler signal of transmitral flow, which is the most commonly used method for studying diastolic function. Tei Chuwa devised and published in 1995 an index of myocardial performance (the Tei index) that evaluates the LV systolic and diastolic function in combination. The Tei index has proved to be a reliable method for the evaluation of LV systolic and diastolic performance, with clear advantages over older established indexes and prognostic value in many kinds of heart disease. Calculation of the Tei index The Tei index is a pure number and is calculated from the ratio of time intervals (a-b/b) derived with the aid of pulsed Doppler echocardiography."

Mortality in over 350,000 Insured Swedish dogs from 1995–2000: I. Breed-, Gender-, Age- and Cause-specific Rates. BN Bonnett, A Egenvall, Å Hedhammar, P Olson. Acta Vet Scand. 2005; 46(3): 105–120. Quote: "As an example, in Cavalier King Charles spaniels ... deaths ... in the diagnostic category heart ... account for 52% of all deaths in that breed."

Increased Mitral Valve Regurgitation and Myocardial Hypertrophy in Two Dogs With Long-Term Pimobendan Therapy. R. Tissier; V. Chetboul; R. Moraillon; A. Nicolle; C. Carlos; B. Enriquez; J-L. Pouchelon. Cardiovascular Toxicology; March 2005; 5(1):43-52(10). Quote: "The aim of this article is to describe original adverse effects in two dogs chronically treated with the inodilator pimobendan. We report a German shepherd (i.e., dog 1) and a poodle (i.e., dog 2) that were referred to our cardiology unit after receiving pimobendan for 10 and 5 mo, respectively. In both dogs, conventional echo-Doppler examination demonstrated mitral valve regurgitation and myocardial hypertrophy. Tissue Doppler imaging (TDI) was performed in the first case and revealed an abnormal relaxation phase. Our reports demonstrate original adverse effects associated with chronic treatment with pimobendan in two dogs. In both cases, mitral valve regurgitation strongly decreased when pimobendan therapy was stopped. Ventricular hypertrophy was also demonstrated and appeared to be at least partially reversible in one dog after pimobendan treatment was replaced with the angiotensin-converting enzyme inhibitor benazepril. ... Importantly, both dogs were treated with dosages (0.33 and 0.29 mg/kg PO q12h, respectively) close to those recommended in canine systolic heart failure (0.3–0.6 mg/kg/d) (4). The described potential adverse effects could not therefore be related to high dosage and might be observed at the therapeutic level. ... In our study, the first important finding is pimobendan-induced increase in mitral valve regurgitation. The imputability of this phenomenon to pimobendan is highly probable because regurgitation was strongly reduced after stopping this therapy. Obviously, increased valve regurgitation might be explained by ventricular hypercontractility, which was characterized by greater shortening fraction during pimobendan therapy (Table 1). ... However, we observed a total disappearance of systolic left apical murmur after stopping pimobendan therapy in dog 1. It also supports a strong decrease in mitral regurgitation because murmur intensity and Doppler-assessed jet size were demonstrated to be well-correlated (21). Finally, it should be noted that exercise tolerance was rapidly better in both dogs (several days) after stopping administration of pimobendan, even though this parameter was assessed subjectively. The second major finding of this short article is the observation of myocardial hypertrophy in these two pimobendan-treated dogs.  After the first examination, pimobendan administration was stopped in both cases and dogs were re-examined 3 and 1 mo later, respectively. Mitral valve regurgitation assessed by echocardiography decreased in both dogs, and the systolic heart murmur disappeared in dog 1. Importantly, most echocardiographic and TDI parameters tended to normalize in dog 1, suggesting, at least partial reversal of both myocardial hypertrophy and relaxation abnormality produced during inodilator therapy. This is the first report to describe an increase in mitral regurgitation under clinical conditions in dogs treated with pimobendan. We also suggest that pimobendan may induce ventricular hypertrophy. However, prospective studies are needed to confirm this observation."

Degenerative Mitral Valve Disease Prevalence in King Charles Spaniels. Odhelius A. Master thesis 2005:1, Swedish Univ. of Agricultural Sciences. An Approach to Asymptomatic Acquired Heart Disease in Dogs and Cats. Clarke E. Atkins. World Small Animal Veterinary Association, 30th World Small Animal Vet. Assn., May 2005.

Efficacy and safety of pimobendan in canine heart failure caused by myxomatous mitral valve disease. Smith P J.; French A T.; Van Israël N; Smith S G.W.; Swift S T.; Lee A J.; Corcoran B M.; Dukes-McEwan J. J Small Animal Practice, 31 March 2005, 46(3):121-130(10). Quote: "Treatment with pimobendan was well tolerated compared with treatment with ramipril. Pimobendan dogs were 25 per cent as likely as ramipril dogs to have an adverse heart failure outcome ... These results should be interpreted cautiously ... [and] warrants further investigation."

Hemodynamic effects of orally administered carvedilol in healthy conscious dogs. Abbott JA, Broadstone RV, Ward DL, Pyle RL. Am J Vet Res 2005;66:637–641.

Interobserver Variability of Vertebral Heart Size Measurements in Dogs with Normal and Enlarged Hearts. Hansson K, Häggström J, Kvart C, Lord P, Veterinary Rad. & Ultrasound, Mar. 2005, 46(2): 122. Quote: The vertebral heart size (VHS) method by Buchanan is based on anatomic landmarks. A potential source of variation among observers is differences in the selection of measurement points. The objective was to test variability between observers with different levels of training in thoracic radiology and small animal clinical practice. Fifty sets of thoracic radiographs of cavalier King Charles spaniels, were divided into five groups; (Normal) normal cardiopulmonary structures, (I) slight cardiomegaly, (II) moderate cardiomegaly, (II+) moderate cardiomegaly with congestive heart failure, and (III+) severe cardiomegaly with congestive heart failure. Cardiomegaly was confirmed by echocardiography to be caused by mitral regurgitation because of myxomatous mitral valve disease. Sixteen observers representing four levels of experience (four observers/level) evaluated the radiographs; (1) European Diplomates in Veterinary Diagnostic Imaging, (2) Experienced small animal clinicians, (3) Trainees in small animal clinical practice (4) Veterinary students. Almost identical mean VHS values were found among the four experience levels for each of the five groups of radiographs with a low coefficient of variation, range 1.5–3.2%. Mean difference among the 16 observers was 1.05±0.32 vertebrae (v). Mean difference among individuals in each observer group was approximately 0.5 v for all but the groups of trainees were the difference was 0.6–0.9 v. ... The mean VHS for normal cavalier King Charles spaniels was 10.8 ± 0.49 v (10.0–11.4) with a CV of 2.7% (Table 2). The long axis was 5.6 0.37 v and short axis was 5.1 ± 0.28 v. The long axis CV was 4.0% and the short axis CV was 2.2%. ... The mean VHS value in the normal dogs was 10.8 ± 0.5 v, which is slightly above the suggested upper limit for normal heart size in most breeds. It is also approximately one vertebral unit higher than the suggested mean value 9.7 0.5 v. However, in the study by Lamb the normal value for cavalier King Charles spaniels was 10.6 ± 0.5 v,11 128 which is consistent with our value. ... The use of breed-specific VHS values is needed for the VHS method to have a high specificity for normal heart size. ... The conclusion is that VHS method for heart size is independent of observer experience but dependent of individual observers selection of reference points and transformation of long and short axis dimensions into VHS units. ... The VHS values for heart size can be affected by several factors. Individual variations in actual heart size and vertebral length between dogs need to be considered as well as narrowed disc spaces.

Surgical Correction of a Partial Atrioventricular Septal Defect With a Ventricular Septal Defect in a Dog. Midori Akiyama, DVM, Ryou Tanaka, DVM, PhD, Kohji Maruo, DVM, PhD and Yoshihisa Yamane, DVM, PhD. J.Amer. Animal Hosp. Assn.41:137-143 (2005). (A 6-month-old, 15.6 lb., male Shiba Inu with a cardiac murmur "due to an ostium primum septal defect, a ventricular septal defect, and mitral valve malformation with regurgitation. The mitral valve and tricuspid valve were separated and displaced at the same level as the ventricular septum. The mitral valve had a cleft in the septal cusp. ... An incision was made in the right atrium, and an ASD (25 x 15 mm in diameter) was identified in the lower portion of the atrial septum immediately above the ventricular septum. The mitral valve was seen through the ASD, and there was a cleft in the septal cusp. The cleft separated the septal cusps into two portions, both of which had thick edges. The cleft was repaired with mattress sutures of 5-0 polypropylenes. The ASD was then closed with sutures of 5-0 polypropylene using pledgets. A small VSD (5 mm in diameter) was observed behind the septal cusp of the tricuspid valve. The VSD was closed with simple mattress sutures of 5-0 polypropylene. The right atrium was sutured closed with a simple continuous pattern of 5-0 polypropylene.")

Mitral valve prolapse in Cavalier King Charles Spaniel: A review and case study. Hyun C. J. Vet. Sci. 2005 Mar;6(1):67-73.  Quote: "A 5 year-old spayed female Cavalier King Charles Spaniel was presented after a 3- to 5-day onset of severe respiratory distress. The dog also had a history of several episodes of syncope prior to presentation. A comprehensive diagnostic investigation revealed a midsystolic click sound on cardiac auscultation, signs of left sided cardiac enlargement in ECG and thoracic radiography, mitral valvular leaflet protrusion into left the atrium, decreased E-point-to septal separation (EPSS) and mitral regurgitated flow in echocardiography, all of which are characteristic signs of mitral valvular prolapse. After intensive care with antidiuretics and a vasodilator with oxygen supplement, the condition of the dog was stabilized. The dog was then released and is being medicated with angiotensin converting enzyme (ACE) inhibitor with regular followup."

Technique and outcome of mitral valve replacement in dogs. Orton EC, Hackett TB, Mama K, Boon JA. J Am Vet Med Assoc. May 2005;226(9):1508-11, 1500. Quote: The purpose of the study reported here was to describe a technique for and assess outcome of mitral valve replacement with a mechanical prosthesis in dogs with naturally occurring severe MR. ... Dogs were considered candidates for mitral valve replacement if they had severe mitral regurgitation, were in CHF, and had an apparent absence of serious noncardiac disease. Severe MR was defined as turbulent flow in >50% of the area of the left atrium as revealed by colorflow Doppler echocardiography (either right parasternal long axis or left apical 4-chamber views). Congestive heart failure was defined as a requirement for long-term treatment with furosemide to control or prevent recurrence of cardiogenic pulmonary edema. ... In this study, the basic protocols for anesthesia and cardiopulmonary bypass used were those performed previously by this group. ... Eight dogs underwent mitral valve replacement between July 1998 and November 1999. The cause of mitral regurgitation was DMD in 7 dogs and DCM in 1 dog. Median age at the time of surgery was 10 years (range, 8 to 12 years). Median weight of dogs was 10.1 kg (22.2 lb). Range of weights was 4.3 to 32.2 kg (9.5 to 70.8 lb), respectively. ... All dogs underwent mitral valve replacement with a bileaflet, tilting-disk, mechanical prosthesisd; size ranged from 19 to 26 mm. One dog died during surgery after several failed attempts to wean from cardiopulmonary bypass. Obstruction of left ventricular outflow by an oversized valve prosthesis (19-mm valve in a 4.5-kg [9.9-lb]dog) was the suspected cause of an inability to wean from cardiopulmonary bypass. Seven dogs survived surgery and were discharged from the hospital. Surviving dogs with DMD had resolution of CHF and did not require furosemide administration after surgery. The dog with DCM still required diuretic administration to control CHF after surgery. Echocardiography performed 5 to 7 days after surgery revealed a significant decrease in LVDVI but no difference in LVSVI, compared with indices obtained before surgery (Figure 4). Mean LA:Ao ratio decreased (P = 0.046) to 1.73 ± 0.65 after surgery. Mean fractional shortening decreased (P = 0.018) to 26.7 ± 9.2% after surgery. Median survival after surgery was 4.5 months (range, 0.75 months to 5.25 years). Six dogs died from acute severe medically refractory pulmonary edema. Three of these dogs had thrombosis of the valve prosthesis as confirmed by histologic examination. In each dog, thrombosis involved the prosthetic hinge mechanism and caused loss of motion of 1 or both prosthetic valve leaflets. Valve prosthesis thrombosis was considered the suspected cause of fatal pulmonary edema in the other 3 dogs. ... The only surgery-related death was likely the result of the smallest available valve prosthesis (19 mm) being too large for the smallest dog (4.3 kg) in this series. The dramatic decrease in left atrial and ventricular dimensions within days of surgery reflected the immediate hemodynamic benefit that dogs in this study gained from complete correction of severe MR. These results suggest that dogs with severe MR tolerate mitral valve replacement surprisingly well, even relatively late in the course of CHF, and defy predictions that dogs need surgery early in the course of their disease to survive the surgery. Although the number of dogs in each series was small, the immediate outcome (ie, surgery survival and acute resolution of CHF) was better in dogs that underwent mitral valve replacement than in dogs that underwent mitral valve repair.14 Perfect correction of MR, which was seldom achieved in dogs that underwent valve repair, was the most likely reason for a more favorable immediate outcome in dogs that underwent valve replacement. Fractional shortening decreased significantly after mitral valve replacement. However, this was primarily the result of decreased left ventricular diastolic dimension rather than increased systolic dimension; thus, worsened systolic function was not the cause of decreased fractional shortening after surgery. Fractional shortening decreased because of a profound decrease in preload caused by sudden correction of MR-induced volume overload. Mitral valve repair preserves systolic function better than mitral valve replacement in humans patients.18 Such a benefit was not apparent in dogs because systolic function after surgery was similar in dogs in this study, compared with dogs that underwent mitral valve repair.14 One of the reasons cited for improved systolic function after mitral valve repair is that chordal-papillary muscle continuity is maintained during mitral repair, and this in turn retains diastolic and systolic support to the left ventricular wall.15,18,19 For many years, the standard technique for mitral valve replacement included excision of both valve leaflets; consequently support of the left ventricular wall by the mitral valve apparatus was lost. It is now standard practice to preserve either 1 or both mitral leaflets to maintain chordal-papillary muscle continuity and preserve ventricular function after surgery.15,19 In the dogs in our study, the mural leaflet was retained and reefed into the mattress sutures securing the valve prosthesis. This was done to maintain chordal-papillary muscle continuity and may account, in part, for relatively well-preserved systolic function after surgery. ... Despite a favorable immediate outcome, long-term outcome after mitral valve replacement with a mechanical prosthesis was disappointing. Although 1 dog lived longer than 5 years, most dogs in this series survived <1 year after surgery. The cause of death was thrombosis of the valve prosthesis, either confirmed or suspected, in all but 1 dog that survived surgery. ... In the absence of an established recommendation for anticoagulation in dogs, the guideline for humans was chosen for dogs in this study. Unfortunately, valve thrombosis occurred despite the best efforts of attending veterinarians to maintain anticoagulation with warfarin. Whether this failure was caused by comparative inexperience with warfarin treatment in dogs, a greater propensity of dogs to undergo prosthetic valve thrombosis, or both is a matter of speculation. Results of interviews with attending veterinarians suggested that most dogs in this study had either inadequate anticoagulation or a disruption in warfarin administration within a 72-hour period proceeding valve thrombosis. A common reason for the disruption in warfarin administration was concern that the dog might be either hemorrhaging internally or at risk for eminent hemorrhage. In retrospect, it is perhaps worth noting that none of the dogs in this study had major hemorrhage while receiving warfarin. It is unclear whether increased experience and a greater appreciation of the importance of warfarin administration could improve the late-term outcome in dogs that undergo mitral valve replacement with a mechanical prosthesis in the future. Given the favorable immediate outcome of dogs in this study and the certainty of an unfavorable outcome without surgery, mitral valve replacement is likely worth further exploration as a treatment option for dogs with severe MR. Improving late-term outcome will depend on finding strategies to prevent prosthetic valve thrombosis or to explore valve prostheses that do not require lifetime anticoagulation therapy (eg, glutaraldehyde-fixed tissue valves).

Development and evaluation of a questionnaire for assessing health-related quality of life in dogs with cardiac disease. Lisa M. Freeman, John E. Rush, Andrew E. Farabaugh​‌. June 2005. J Am Vet Med Assoc;226(11):1864–1868. Quote: "Objective — To develop and evaluate a questionnaire (functional evaluation of cardiac health [FETCH] questionnaire) for assessing health-related quality of life in dogs with cardiac disease. Animals — 360 dogs with cardiac disease. Procedure — The questionnaire was developed on the basis of widely accepted clinical signs of cardiac disease in dogs. A FETCH score was calculated by summing responses to questionnaire items; possible scores ranged from 0 to 85. For questionnaire validation, owners of 60 dogs were asked to complete the questionnaire and provide an overall assessment of their dogs' quality of life (16 owners completed the questionnaire twice). Disease severity was assessed with the International Small Animal Cardiac Health Council (ISACHC) classification for cardiac disease. Following validation, the final questionnaire was administered to owners of the remaining 300 dogs. Results — Internal consistency of the questionnaire was good, and the FETCH score was significantly correlated with the owner-reported quality-of-life score and with ISACHC classification. For owners that completed the questionnaire twice, scores were significantly correlated. During the second phase of the study, the FETCH score ranged from 0 to 70 (median, 7) and was significantly correlated with ISACHC classification, but did not vary significantly with underlying disease. For dogs examined twice, the change in FETCH score was significantly greater for dogs in which ISACHC classification improved than for dogs in which ISACHC classification was unchanged. Conclusions and Clinical Relevance — Results suggest that the FETCH questionnaire is a valid and reliable method for assessing health-related quality of life in dogs with cardiac disease.

Evaluation of a New Brain Natriuretic Peptide Assay in Dogs. William E. Herndon, Justine A. Lee, Kenneth J. Drobatz, Matthew J. Ryan. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 68).

Short-term Hemodynamic Effects of Chronic Oral Carvedilol in Cavalier King Charles Spaniels with Asymptomatic Chronic Degenerative Valve Disease. S.G. Gordon, A. Bahr, M.W. Miller, D.M. Boothe, & K. Glaze. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 69).

Biomarkers of Platelet Activation in Cavalier King Charles Spaniels. D.F. Hogan, D.J. Weiss, C.A. Thompson, M.P. Ward. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 175).

Use of quantitative two-dimensional color tissue Doppler imaging for assessment of left ventricular radial and longitudinal myocardial velocities in dogs. Valerie Chetboul, Carolina Carlos Sampedrano, Didier Concordet, Renaud Tissier, Thierry Lamour, Jacques Ginesta, Vassiliki Gouni, Audrey P. Nicolle, Jean-Louis Pouchelon, Hervé P. Lefebvre. Am J. Vet. Res. June 2005; doi: 10.2460/ajvr.2005.66.953. Quote: Objective: To determine left ventricular free wall (LVFW) radial and longitudinal myocardial contraction velocities in healthy dogs via quantitative 2-dimensional color tissue Doppler imaging (TDI). Animals: 100 dogs [15 breeds plus mixed breeds, including 2 cavalier King Charles spaniels]. Procedure: TDI was used by a single trained observer to measure radial and longitudinal myocardial movement in the LVFW. Radial myocardial velocities were recorded in segments in the endocardial and epicardial layers of the LVFW, and longitudinal velocities were recorded in segments at 3 levels (basal, middle, apical) of the LVFW. Results: LVFW velocities were higher in the endocardial layers than in the epicardial layers. Left ventricular free wall velocities were higher in the basal segments than in the middle and apical segments. Radial myocardial velocity gradients, defined as the difference between endocardial and epicardial velocities, were (mean ± SD) 2.5 ± 0.8 cm/s, 3.8 ± 1.5 cm/s, and 2.3 ± 0.9 cm/s in systole, early diastole, and late diastole, respectively. Longitudinal myocardial velocity gradients, defined as the difference between basal and apical velocities, were 5.9 ± 2.2 cm/s, 6.9 ± 2.5 cm/s, and 4.9 ± 1.7 cm/s in systole, early diastole, and late diastole, respectively. [Peak mitral early diastolic velocity (E; m/s) Mean ± SD: 0.87 ± 0.13; Median: 0.85; Range: 0.58 - 1.17.] A breed effect was detected for several systolic and diastolic TDI variables. In all segments, systolic velocities were independent of fractional shortening. Conclusions and Clinical Relevance: LVFW myocardial velocities decreased from the endocardium to the epicardium and from base to apex, thus revealing intramyocardial radial and longitudinal velocity gradients. These indices could enhance conventional echocardiographic analysis of left ventricular function in dogs. Breed-specific reference intervals should be defined.

Long-term Effects of Pimobendan and Benazepril On Several Echocardiographic and Tissue Doppler Imaging Variables in Dogs with Asymptomatic Myxomatous Mitral Valve Disease. V. Chetboul, H.P. Lefebvre, C. Carlos Sampedrano, A.P. Nicolle, V. Saporano, V. Gouni, D. Concordet, J.-L. Pouchelon. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 199).  Quote: "Long-term administration of benazepril (BNZ), an angiotens in converting enzyme inhibitor, has already been shown to improve quality of life, increase exercise tolerance and extend life expectancy in dogs with naturally acquired NYHA class II-IV heart failure due to myxomatous mitral valve disease (MVD) or dilated cardiomyopathy (DCM). Pimobendan (PIMO), an oral inodilator compound, has been demonstrated to result in significant improvement in heart failure class when added to standard therapy in dogs with DCM and is also registered in many countries for use in canine congestive heart failure due to MVD. The cardiac effects of both BNZ and PIMO on dogs with asymptomatic (class I) MVD are however unknown. The aim of this study was to compare the cardiac effects of long-term monotherapy with PIMO or BNZ in dogs with asymptomatic MVD and mild mitral valve regurgitation. The study was a blinded, randomized and parallel-group design. Twelve female Beagle dogs (age 6.8 ± 2.1 years) with class I MVD and a grade 1 or 2 left apical systolic heart murmur were selected. They were randomized into two groups of six animals (BNZ and PIMO groups). BNZ and PIMO were administered orally for 206 days at the recommended dosages (0.25 mg/kg sid and 0.25 mg/kg bid for the BNZ and PIMO groups, respectively). All dogs were examined before the start of treatment and then at 15, 49, 124 and 206 days following initiation of therapy (cardiovascular examination, ECG, blood pressure, standard echo-Doppler examination and analysis of the left ventricular myocardial motion via 2D color tissue Doppler imaging). Some differences between the PIMO and BNZ groups were already detected at day 15. The amplitudes of the differences increased throughout the experimental period and were maximal at day 206. The most striking differences were observed for the following parameters at day 206 for the PIMO and BNZ groups, respectively: heart murmur (increased in average by two grades in the PIMO group), fractional shortening (45.0% vs 34.7%, p<0.001), systolic endocardial (7.5 vs 5.2 cm.s-1, p=0.001) and basal velocities (9.4 vs 7.0 cm.s-1, p<0.001), maximum mitral regurgitant jet area/left atrium area (37.7% vs 14.8%, p<0.001) and peak velocity of mitral regurgitant jet (6.5 vs 2.6 m.s-1, p<0.001). In conclusion, these preliminary results should encourage investigators to perform long-term studies in well-controlled conditions to clearly identify the benefit to risk ratio of the currently recommended treatments for naturally occurring canine MVD.

VETMEDIN Target Animal Safety Study in Dogs, Study BIVI 6150-0990-01C-074. Michael A. Schnell. Quote: "Study Design: Laboratory safety study, randomized and masked. This 6-month oral safety study was conducted in accordance with the Good Laboratory Practice Regulations (GLPs). Study Animals: 24 healthy Beagles, 12 to 18 months of age and 8.7 to 15.3 kg body weight, 6 dogs per group (3 males and 3 females). ... Conclusions: VETMEDIN administered to healthy Beagles at three and five times the recommended dose caused severe left ventricular hypertrophy with multifocal subendocardial ischemic lesions, myxomatous thickening of the mitral valves, mitral valve insufficiency murmurs, left atrial jet lesions, endocardial thickening of the left ventricular outflow tract, a granulomatous lesion within the right atrial myocardium, decreased blood pressure, increased heart rate, and a subtle increase in ventricular premature contractions. These effects are typical of positive inotropic and vasodilator drug toxicity in normal dogs. None of the dogs had clinical signs associated with their cardiac pathology. Infrequent and self-limiting diarrhea and vomiting, mild changes in blood glucose, mild increases in alkaline phosphatase and potassium, and a mild decrease in platelet count were associated with VETMEDIN administration but the effects were not dose dependent."

Circulating Concentrations of Insulin-Like Growth Factor-1 in Dogs with Naturally Occurring Mitral Regurgitation.  Pedersen H. D., Falk T., Häggström J., Tarnow I., Olsen L. H., Kvart C., Nielsena M. O.; J Vet Intern Med. 2005 Jul;19(4):528-532.

Dogs with Heart Diseases Causing Turbulent High-Velocity Blood Flow Have Changes in Platelet Function and von Willebrand Factor Multimer Distribution.  Tarnow I., Kristensen A. T., Olsen L. H., Falk T., Haubro L., Pedersen L. G.,Pedersen H. G.; J Vet Intern Med. 2005 Jul-Aug;19(4):515-521. Quote: "The purpose of this prospective study was to investigate platelet function using in vitro tests based on both high and low shear rates and von Willebrand factor (vWf) multimeric composition in dogs with cardiac disease and turbulent high-velocity blood flow. Client-owned asymptomatic, untreated dogs were divided into 4 groups: 14 Cavalier King Charles Spaniels (Cavaliers) with mitral valve prolapse (MVP) and no or minimal mitral regurgitation (MR), 17 Cavaliers with MVP and moderate to severe MR, 14 control dogs, and 10 dogs with subaortic stenosis (SAS). Clinical examinations and echocardiography were performed in all dogs. PFA100 closure times (the ability of platelets to occlude a hole in a membrane at high shear rates), platelet activation markers (plasma thromboxane B2 concentration, platelet surface P-selectin expression), platelet aggregation (in whole blood and platelet-rich plasma with 3 different agonists), and vWf multimers were analyzed. Cavaliers with moderate to severe MR and dogs with SAS had longer closure times and a lower percentage of the largest vWf multimers than did controls. Maximal aggregation responses were unchanged in dogs with SAS but enhanced in Cavaliers with MVP (regardless of MR status) compared with control dogs. No significant difference in platelet activation markers was found among groups. The data suggest that a form of platelet dysfunction detected at high shear rates was present in dogs with MR and SAS, possibly associated with a qualitative vWf defect. Aggregation results suggest increased platelet reactivity in Cavaliers, but the platelets did not appear to circulate in a preactivated state in either disease."

Quantitative Echocardiographic Evaluation of Mitral Endocardiosis in Dogs Using Ratio Indices. Brown D.J., Rush J.E., MacGregor J., Ross J.N.Jr., BrewerB., and Rand W.M. J Vet Intern Med 2005 Jul-Aug;19 (4):542–552.

Why Most Published Research Findings Are False. John P. A. Ioannidis, PLOS Medicine. August 2005. Quote: There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

Neurohormonal and Circulatory Effects of Short-Term Treatment with Enalapril and Quinapril in Dogs with Asymptomatic Mitral Regurgitation. Moesgaard S.G., Pedersen L.G., Teerlink T., Häggström J., Pedersen H.D. J. Vet. Intern. Med. 2005 Sep-Oct; 19(5): 712-719.

Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs. Arsenault, W.G., Boothe, D.M., Gordon, S.G., Miller, M.W., Chalkley J.R., Petrikovics, I. Am J Vet Res 2005;66:2172–2176. 

Mortality in over 350,000 Insured Swedish dogs from 1995–2000: I. Breed-, Gender-, Age- and Cause-specific Rates. BN Bonnett, A Egenvall, Å Hedhammar, P Olson. Acta Vet. Scand. September 2005;46(3):105-120. Quote: This study presents data on over 350,000 insured Swedish dogs up to 10 years of age contributing to over one million dog-years at risk (DYAR) during 1995–2000. A total of 43,172 dogs died or were euthanised and of these 72% had a claim with a diagnosis for the cause of death. The overall total mortality was 393 deaths per 10,000 DYAR. Mortality rates are calculated for the 10 most common breeds, 10 breeds with high mortality and a group including all other breeds, crudely and for general causes of death. Proportional mortality is presented for several classifications. Five general causes accounted for 62% of the deaths with a diagnosis (i.e. tumour (18%), trauma (17%), locomotor (13%), heart (8%) and neurological (6%)). Mortality rates for the five most common diagnoses within the general causes of death are presented. ... As an example, in Cavalier King Charles spaniels there were 246 deaths per 10,000 DYAR in the diagnostic category heart that account for 52% of all deaths in that breed. In addition, heart deaths in the Cavalier King Charles spaniel represent 28% of all deaths due to a heart diagnosis in the insured population. ... Heart disease in the Cavalier King Charles spaniel accounts for over 50% of deaths in that breed (in dogs under 10 years of age) and for over one-quarter of the heart deaths in the insured population. Although heart disease in Cavalier King Charles spaniels is well recognized, these statistics give further insight into the impact of this cause of death in this breed. By comparison, in Irish wolfhounds, although the actual rate of mortality due to heart disease is higher than in the Cavalier King Charles spaniel, that diagnostic category accounts for only 25% of deaths in Irish wolfhounds as they also have other frequent causes of death. Irish wolfhounds represent only 2.7% of all heart deaths in the population, as they as are a less common breed (data not shown). How should these statistics be most effectively used? Mortality rates can be monitored over time to see if there is an increase or decrease in the actual incidence due to, for example, breeding practices. The perception of the commonness of disease occurrence by veterinarians will be a reflection of the population level proportional mortalities, which are also of interest to the insurance company. Proportional mortalities within a breed should inform health strategies among dog breeders, helping them to focus on those diseases causing the most deaths at "too early an age" in their breed. ... Further details on survival and relative risk by breed and age are presented in the companion paper.

Mortality in over 350,000 Insured Swedish Dogs from 1995–2000: II. Breed-Specific Age and Survival Patterns and Relative Risk for Causes of Death. A Egenvall, BN Bonnett, Å Hedhammar, P Olson. Acta Vet. Scand. September 2005;46(3):121-136. Quote: This study continues analysis from a companion paper on over 350,000 insured Swedish dogs up to 10 years of age contributing to more than one million dog-years at risk during 1995–2000. The age patterns for total and diagnostic mortality and for general causes of death (trauma, tumour, locomotor, heart and neurological) are presented for numerous breeds. Survival estimates at five, eight and 10 years of age are calculated. ... The age patterns are reflected in the survival statistics and highlight differences across breeds. For Cavalier King Charles spaniels there is a very low early mortality with a sharp rise after five years of age. Only 7% of Cavalier King Charles spaniels are dead by five years of age, [23% by 8 years] but 48% are dead by 10 years. ... Multivariable analysis was used to estimate the relative risk for general and more specific causes of death between breeds accounting for gender and age effects, including two-way interactions. Older females had tumour as a designated cause of death more often than males in most breeds, but not in the Bernese mountain dog. ... Dachshunds (both breed groups) and poodles were at decreased risk of death due to tumours, as were Cavalier King Charles spaniels. ... Information presented in this and the companion paper inform our understanding of the population level burden of disease, and support decision-making at the population and individual level about health promotion efforts and treatment and prognosis of disease events. (See this compapanion paper.)

Nutritional and Herbal Therapies in the Treatment of Heart Disease in Cats and Dogs. Rebecca E. Gompf. J.Am.Anim. Hosp.Assn. Nov. 2005;41:355-367. Quote: "Role of Taurine in Dogs: Because dogs readily make taurine from free sulfur amino acids, only lose a small amount in their bile acids, and can maintain normal blood levels of taurine despite their diets, they do not tend to develop taurine-deficient DCM. ... More scientific studies are needed to further define the role of taurine and carnitine in normal and diseased hearts. Prospective, randomized, double-blind studies in different breeds of dogs and cats are also needed to evaluate the effectiveness of taurine and carnitine in diseased hearts. ... Carnitine and taurine are the two nutritional supplements that have been investigated more than other supplements or herbs in dogs and cats, and they have been found to be beneficial in treating certain cardiac diseases. The exact mechanism of action and benefits of these two supplements are not fully understood and require further investigation."

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2006

Body size, but neither age nor asymptomatic mitral regurgitation, influences plasma concentrations of dimethylarginines in dogs. L.G. Pedersen, I. Tarnow, L.H. Olsen, T. Teerlink, H.D. Pedersen. Research in Vet. Sci. 2006;80:336-342. Quote: Asymmetric dimethylarginine (ADMA) is a marker of various cardiovascular diseases in man. The aim of the present study was to test if Cavalier King Charles Spaniels (CKCS) with varying degrees of mitral regurgitation (MR) had increased plasma concentration of ADMA and furthermore, characterize the plasma level of ADMA and symmetric dimethylarginine (SDMA) in normal dogs. Seventy-six dogs were included (44 CKCS and 32 dogs of other breeds). The CKCS had various degrees of MR, whereas the remaining dogs had either no or minimal MR. Apart from cardiac murmurs, no dogs showed signs of cardiac or systematic disease. The degree of MR had no significant influence on ADMA (P = 0.33). Body weight was directly associated with ADMA (P = 0.0004) and creatinine was directly associated with SDMA (P < 0.0001). Furthermore, the plasma concentration of ADMA was three to four times higher than found in healthy humans.

Mechanisms and Use of Calcium-Sensitizing Agents in the Failing Heart. David A. Kass, R. John Solaro. Circulation. January 2006;113:305-315. Quote: "Depressed cardiac contractility is central to many forms of cardiac disease and reflects the heart’s inability to generate adequate force despite being provided physiological activator calcium and chamber load. Yet, successful methods to enhance cardiac contractility have remained elusive. Agents such as dobutamine or milrinone that work through the β-receptor-cAMP-protein kinase A pathway are used to manage acute hemodynamic decompensation, but short-term and, particularly, long-term use can increase risks of arrhythmia and worsen outcome. These and other data have led to the conclusion that successful heart failure management should probably avoid the targeting of contractility improvement. ... Pimobendan: Pimobendan is a combination calcium sensitizer and PDE3 inhibitor. It was tested in heart failure patients in the late 1990s but remains clinically approved in Japan only. Pimobendan lowers the Ca2+ level required for actin sliding in an in vitro motility assay using reconstituted thin filaments. Clinical data showed benefits on exercise capacity but also a trend toward increased mortality, and further clinical development has not been reported. ... Conclusions: The search for novel approaches to improve cardiac function in heart failure is presently receiving a long-needed boost with the development of agents that can enhance contraction without requiring greater activator Ca2+. Although few existing agents have made it to successful clinical trials, levosimendan maybe poised for this. Others, such as the myosin enhancers, are just entering clinical investigation. Whether pure myofilament activation mechanisms are ideal, or whether having some off-target effects such as KATP channel agonism or even some PDE3 inhibition is ultimately optimal, remains to be clarified. Nonetheless, this class of drugs offers promise and hopefully will provide a useful therapeutic approach for both acute and chronic management of heart failure in the relatively near future."

Updates on the Diagnosis and Treatment of Canine Heart Disease. Gordon, Sonya G. Proceedings, 20th No. Am. Vet. Conf., Jan. 2006: 216-218.

Role of Positive Inotropic Agents for Managing Dogs with Mitral Valve Disease. Häggström, Jens. Proceedings, No. Am. Vet. Conf., Vol. 20, Jan. 2006: 221.

Value of Measuring Cardiac Troponins in Your Practice. Häggström, Jens. Proceedings, No. Am. Vet. Conf., Vol. 20, Jan. 2006: 222.

Diagnostic and Prognostic Variables in Mitral Valve Disease in Dogs. Häggström, Jens. Proceedings, No. Am. Vet. Conf., Vol. 20, Jan. 2006: 226-227.

How I Treat Heart Failure Due to Mitral Regurgitation. Häggström, Jens. Proceedings, No. Am. Vet. Conf., Vol. 20, Jan. 2006: 228.

UK Kennel Club 2004 Cavalier Breed Health Survey Results. UK Kennel Club. February 2006. Summary: Forms were received representing 1,253 living dogs & 682 deceased dogs. The most commonly reported disease condition in live dogs was heart (cardiac) murmur. The most commonly reported cause of death was cardiac (heart) failure. The median longevity for the cavalier King Charles spaniel was 11 years, 5 months. Cause of death: cardiac related: 42.8%.

Pimobendan in Heart Failure Therapy – A Silver Bullet? Gordon S.G., Miller M.W., and Saunders A.B. J. Am. Animal Hosp. Assn. March/April 2006; 42:90-93. Quote: "Pimobendan is a novel agent with properties that are highly desirable in the clinical management of congestive heart failure (CHF) secondary to both dilated cardiomyopathy (DCM) and chronic degenerative valvular disease in dogs. Review of available data suggests that pimobendan is safe, well tolerated, and leads to enhanced quality of life in dogs with CHF secondary to DCM or chronic valvular disease when used in combination with furosemide or other conventional therapies (e.g., angiotensin-converting enzyme inhibitors, digoxin). Pimobendan leads to a reduction in mortality from CHF associated with DCM, and ongoing studies are evaluating its effects on mortality associated with chronic valvular disease."

Pharmacodynamics of Carvedilol in Conscious, Healthy Dogs. Sonya G. Gordon, Wendy G. Arsenault, Mike Longnecker, Dawn M. Boothe, Matthew W. Miller, and Jeff Chalkley. J Vet Intern Med March/April 2006;20:297–304. Quote: "These data suggest that carvedilol (1.5 mg/kg PO q12h) in healthy, conscious dogs confers nonselective beta blockade for 12 hours, with minimal effects on resting HR, BP, and echocardiographic variables. Additionally, the magnitude of beta blockade correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful."

Efficacy of oral tadalafil, a new long-acting phosphodiesterase-5 inhibitor, for the short-term treatment of pulmonary arterial hypertension in a dog. Serres F, Nicolle AP, Tissier R, Gouni V, Pouchelon JL, Chetboul V. J Vet Med A Physiol Pathol Clin Med. 2006 Apr;53(3):129-33.

Retrospective study of 942 small-sized dogs: Prevalence of left apical systolic heart murmur and left-sided heart failure, critical effects of breed and sex. Pierre Serfass, Valérie Chetboul, Carolina Carlos Sampedrano, Audrey Nicolle, Thierry Benalloul, Hervé Laforge, Christophe Gau, Carole Hébert, Jean-Louis Pouchelon, Renaud Tissier. J. Vet. Cardiology. May 2006;8(1):11-18. Quote: "Objectives: The main goals of this study were (1) to carry out a retrospective study of the prevalence of left apical systolic heart murmurs, which are considered to clinically reflect the presence of MVD, in the 6 small canine breeds most popular in France, i.e., Yorkshire Terrier, Bichon Maltese, Dachshund, Poodle, Lhassa Apso and Shi Tzu and (2) to compare the results with those obtained in a recent report published by our group on MVD in 451 CKC. Background: Mitral valvular disease (MVD) has been extensively studied in Cavalier King Charles spaniels (CKC) but seldom studied and compared in other small-breed dogs. The first clinical sign of MVD is the early appearance of a left apical systolic heart murmur. Animals: Nine hundred and forty-two adult dogs were included in the present study (mean ± SD, age = 6.5 ± 4.4 years, weight = 6.2 ± 2.6 kg). Results: The average total prevalence of left apical systolic heart murmur was 14.4% compared with 40.6% in CKC. It was significantly more prevalent in males (18.5%) than in females (9.8%). Shi Tzu and Dachshunds were the most affected breeds investigated. Most (81%) of the dogs with left apical systolic murmur were classified in ISACHC heart failure class I. Conclusion: This large retrospective study suggests that the prevalence of MVD is higher in CKC than in the 6 small breeds investigated. Moreover, most of the dogs do not develop congestive heart failure."

C-Reactive Protein Concentration in Dogs with Chronic Valvular Disease. John E. Rush, Nathan D. Lee, Lisa M. Freeman, and Barbara Brewer. J Vet Intern Med; May/June 2006;20:635–639. Quote: "The purpose of the study reported here was to determine whether dogs with chronic valvular disease have increased plasma Creactive protein concentration, compared with that in clinically normal dogs. ... In veterinary medicine, CRP concentration has been documented to increase in inflammatory states, such as pancreatitis.  To our knowledge, studies that investigate the role of CRP in CVD have not been reported. Therefore, the study reported here was designed to determine CRP concentration in dogs with CVD, compared with that in healthy controls. ... Blood was collected from 47 dogs with physical and echocardiographic evidence of chronic valvular disease [Cavalier King Charles Spaniel (n = 8)] and from 20 healthy controls [Cavalier King Charles Spaniel (n = 3)] . C-reactive protein concentration was determined with a commercial canine C-reactive protein enzyme immunoassay. Compared with controls, dogs with chronic valvular disease had higher plasma concentration of C-reactive protein (median 2.17 mg/mL [range, 0.86–33.8 mg/mL]) versus 1.43 mg/mL [range, 0.84–4.99 mg/mL]; P , .001). C-reactive protein concentration was not related to the presence of congestive heart failure or murmur grade. The results of this study suggest that increased concentration of C-reactive protein is found in dogs with chronic valvular disease."

Acute Cardiovascular Effects of Pimobendan in Dogs with Stable Congestive Heart Failure Due To Chronic Degenerative Atrioventricular Valve Disease. RM Roland, SG Gordon, A Bahr , MW Miller, AB Saunders. J Vet Intern Med; May/June 2006;20(3) (ACVIM 24th Ann. Vet. Med. Forum Abstract Program: Abstract 75).

Physiological Flow Murmurs in Cavalier King Charles Spaniels.  LH Olsen, R Hjarbaek, HD Pedersen. J Vet Intern Med; May/June 2006;20(3) (ACVIM 24th Ann. Vet. Med. Forum Abstract Program: Abstract 136).

Cardiovascular effects of a phosphodiesterase III inhibitor in the presence of carvedilol in dogs. Uechi M, Hori Y, Fujimoto K, Ebisawa T, Yamano S, Maekawa S. J Vet Med Sci. 2006 Jun;68(6):549-53.

Clinical Efficacy of Pimobendan Versus Benazepril for the Treatment of Acquired Atrioventricular Valvular Disease in Dogs. [VetSCOPE (Veterinary Study for the Confirmation of Pimobendan in Canine Endocardiosis) study] Christophe W. Lombard, Olaf Jöns, and Claudio M. Bussadori. J. Am. Anim. Hosp. Assoc., July/August 2006; 42: 249 - 261. Quote: "Seventy-six dogs with clinical acquired atrioventricular valvular disease were evaluated to determine the efficacy of pimobendan (n=41) versus benazepril hydrochloride (n=35) in a randomized, positive-controlled, multicenter study. The study was divided into 56-day and long-term evaluation periods. In a subgroup of dogs with concurrent furosemide treatment (pimobendan [n=31], benazepril [n=25]), the Heart Insufficiency Score improved in favor of pimobendan (P=0.0011), equating to a superior overall efficacy rating (P<0.0001) at day 56. Long-term median survival (i.e., death or treatment failure) for dogs receiving pimobendan was 415 days versus 128 days for dogs not on pimobendan (P=0.0022)."

Heart Disease as a Cause of Death in Insured Swedish Dogs Younger Than 10 Years of Age. Agneta Egenvall, Brenda N. Bonnett, and Jens Häggström. J Vet Intern Med July/August 2006;20:894–903.  Background: Population-based information on disease occurrence is paramount in clinical decision making and in designing preventative measures, but such information is scarce. Hypothesis: The risk of cardiac death is higher in certain breeds and mortality varies by age and sex. Dogs: Dogs that were life insured by an animal insurance company between 1995 and 2002. Methods: The mortality pattern for heart disease in insured dogs up to 10 years of age was studied. The influences of sex, age, breed, month, and geographic location were investigated by means of incidence rates, proportions, and survival proportions. Cox proportional hazards regression was used to model time to heart disease. Results: 405,376 dogs contributed to a denominator of 1,431,933 dog-years at risk (DYAR) and 3,049 dogs had been assigned a cardiac-related diagnosis as cause of death. The cardiac-related mortality for dogs < 10 years of age, was 21.3 deaths per 10,000 DYAR. This mortality in males and females was 27.3 deaths and 15.4 deaths per 10,000 DYAR, respectively. Twelve of 54 breeds had a point estimate above the overall rate. The 3 breeds with the highest point estimates were: Irish Wolfhounds, Cavalier King Charles Spaniels, and Great Danes (rates of 356, 247, and 179 deaths per 10,000 DYAR, respectively). ... Indeed, the number of claims for Cavalier King Charles Spaniels was higher than that of the other 9 most affected breeds combined. ... It could further be argued that, for high-risk breeds for which previous evidence shows that the breed is prone to 1 specific type of heart disease, the rate for this type of disease is probably close to the total burden of cardiac mortality. For example, in the Irish Wolfhound or Cavalier King Charles Spaniel, such could be the case. ... In the actual number of claims, the Cavalier King Charles Spaniel stands out, with 840 claims. We suspect that the majority of claims in this breed were a result of MMVD, but 32 (4%) of the claims were classified as CMP. These 32 cases may represent DCM, but some of them may have been cases of widespread myocardial infarction secondary to arteriosclerotic changes of the coronary arteries, secondary to thromboembolism,18 or simply the result of misclassification. Previous studies have shown that the incidence of other types of cardiac disease (congenital or acquired) is low in this breed. ... Conclusions and Clinical Importance: Breed, age, and sex affect cardiac mortality in certain breeds of dogs, but no effects of month and geographic location were identified. These findings can assist clinicians in establishing diagnoses, and can assist breeders in defining priorities for preventative measures."

Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease. Mark A. Oyama, and Sridar V. Chittur. Am. J.Vet. Research; Aug. 2006, 67(8):1307-1318. Quote: Objective: To evaluate global genome expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease (DMVD). ... We hypothesize that platelet attraction to damaged valvular endothelium through increased cytokine and adhesion molecule expression, followed by subsequent heightened local serotonin signaling, may contribute to DMVD in Cavalier King Charles Spaniels. The interaction between platelets, serotonin, and TGF-β is complex as serotonin enhances, whereas TGF-β inhibits megakaryocytopoiesis. ... Sample Population: Anterior mitral valve leaflets of 4 dogs with severe DMVD and 4 healthy control dogs. [None were CKCSs.] Procedures: Transcriptional activities of 23,851 canine DNA sequences were determined by use of an oligonucleotide microarray. Genome expression patterns of tissue from dogs with DMVD were evaluated by measuring the relative amount of complementary RNA hybridization to the microarray probes and by comparing it with gene expression from healthy control dogs. Results: 229 transcripts were differentially expressed (≥ 2-fold change). In dogs with DMVD, expression of 159 transcripts was upregulated and expression of 70 transcripts was downregulated. Of the 229 transcripts, 152 genes could be specifically identified. These genes were grouped into 1 of 9 categories on the basis of their primary physiologic function. Grouping revealed that pathways involving cell signaling, inflammation, extracellular matrix, immune function, cell defense, and metabolism were generally upregulated. Inflammatory cytokines and the serotonin-transforming growth factor-β pathway were identified as contributory to the pathophysiologic aspects of DMVD. Conclusions and Clinical Relevance: Evaluation of global expression patterns provides a molecular portrait of mitral valve disease, yields insight into the pathophysiologic aspects of DMVD, and identifies intriguing genes and pathways for further study.

Effects of Dietary Modification in Dogs with Early Chronic Valvular Disease. Lisa M. Freeman, John E. Rush, and Peter J. Markwell. J Vet Intern Med, Sep 2006;20:(5)1116–1126.  Quote: "The potential benefits of nutritional modification in early canine cardiac disease are not known. We hypothesized that echocardiographic, neuroendocrine, and nutritional variables will differ between dogs with asymptomatic chronic valvular disease (CVD) and healthy controls, and that a moderately reduced sodium diet enriched with antioxidants, n-3 fatty acids, taurine, carnitine, and arginine will alter these variables in dogs with CVD. Echocardiography was performed and blood was collected. After baseline comparison with healthy controls, all dogs with CVD were fed a low-sodium run-in diet for 4 weeks, reevaluated, and then randomized to receive either the cardiac diet or a placebo diet for 4 weeks. RESULTS: At baseline, dogs with CVD (n = 29) had significantly lower circulating sodium, chloride, arginine, and methionine concentrations and higher plasma concentrations of atrial natriuretic peptide compared to healthy controls. In dogs with CVD, plasma aldosterone concentration and heart rate increased significantly after 4 weeks of eating the run-in diet. The cardiac diet group (n = 14) had larger increases in levels of cholesterol (P = .001), triglycerides (P = .02), eicosapentaenoic acid (P < .001), docosahexaenoic acid (P < .001), total omega-3 fatty acids (P < .001), vitamin C (P = 0.04), alpha-tocopherol (P < .001), and gamma-tocopherol (P < .001) compared to the placebo diet group (n = 15). The cardiac diet group also had larger reductions in maximal left-atrial dimension (P = .003), left-ventricular internal dimension in diastole (P = .03), and weight-based maximal left-atrial dimension (P = .03). CONCLUSIONS AND CLINICAL IMPORTANCE: Observed changes in both blood variables and echocardiographic measurements warrant additional studies on dietary modifications in dogs with early CVD."

Retrospective Evaluation of Sildenafil Citrate as a Therapy for Pulmonary Hypertension in Dogs. Jonathan F. Bach, Elizabeth A. Rozanski, John MacGregor, Jean M. Betkowski, and John E. Rush. J.Vet.Intern.Med. Sept. 2006; 20(5):1132-1135. Quote: "Pulmonary arterial hypertension (PH) is a pathologic condition in dogs characterized by abnormally high pressures in the pulmonary circulation and has been associated with a poor outcome. Sildenafil is a type V phosphodiesterase inhibitor that produces nitric oxide-mediated vasodilatation. Sildenafil treatment decreases pulmonary arterial pressure and pulmonary vascular resistance in people with PH. The purpose of this study was to describe the clinical characteristics and outcome of dogs with PH treated with sildenafil. The cardiology database was searched for dogs with PH treated with sildenafil. PH was defined as systolic pulmonary arterial pressure (PAPS) 25 mmHg at rest. Medical records were reviewed for the following information: signalment, duration and type of clinical signs before treatment, underlying disease, estimated or measured PAPS, dosage and dosing interval of sildenafil, and the effect of treatment on clinical signs and pulmonary arterial pressure and survival time. Thirteen affected dogs were identified. Clinical signs included collapse, syncope, respiratory distress, and cough. Duration of clinical signs before presentation ranged from 3 days to 5 months. An underlying cause was identified in 8 dogs. The median sildenafil dosage was 1.9 mg/kg. Ten dogs received concurrent medications. Median PAPS was 90 mmHg; 8 dogs were reevaluated after therapy, and the median decrease in PAPS was 16.5 mmHg. The median survival time of all dogs was 91 days. Sildenafil appeared to be well tolerated in dogs with PH and was associated with decreased PAPS and amelioration of clinical signs in most. Sildenafil represents a reasonable treatment option for dogs with pulmonary hypertension."

Echocardiographic estimation of systemic systolic blood pressure in dogs with mild mitral regurgitation. SP Tou, DB Adin, AH Estrada. J Vet Intern Med, Sep 2006;20:1127-1131.

Comparison of Canine Cardiac Troponin I Concentrations as Determined by 3 Analyzers. Darcy B. Adin, Mark A. Oyama, Margaret M. Sleeper, and Rowan J. Milner. J. Vet Intern Med, Sep 2006;20:1136–1142.

Recurrent syncope: only the heart was considered. Peter Stiefelhagen. MMW Fortschr Med. 2006 Sep 28;148 (39):21.

Pimobendan: Understanding its cardiac effects in dogs with myocardial disease. Justin D. Thomason, Tiffany K. Fallaw, and Clay Calvert. Vet. Med. Oct. 2006.

Finding cardiovascular disease genes in the dog. Heidi G. Parker, Kathryn M. Meurs, Elaine A. Ostrander. J. Vet. Cardiol. November 2006 ;8(2):115–127. Quote: Recent advances in canine genomics are changing the landscape of veterinary biology, and by default, veterinary medicine. No longer are clinicians locked into traditional methods of diagnoses and therapy. Rather major advances in canine genetics and genomics from the past five years are now changing the way the veterinarian of the 21st century practices medicine. First, the availability of a dense genome map gives canine genetics a much needed foothold in comparative medicine, allowing advances made in human and mouse genetics to be applied to companion animals. Second, the recently released 7.5x whole genome sequence of the dog is facilitating the identification of hereditary disease genes. Finally, development of genetic tools for rapid screening of families and populations at risk for inherited disease means that the cost of identifying and testing for disease loci will significantly decrease in coming years. Out of these advances will come major changes in companion animal diagnostics and therapy. Clinicians will be able to offer their clients genetic testing and counseling for a myriad of disorders. Such advances are certain to generate healthier and more long lived dogs, improving quality of life for owner and pet alike. The clinician of the 21st century, therefore, faces incredible opportunities as well as challenges in the management of genetic disease. In this review we summarize recent findings in canine genomics and discuss their application to the study of canine cardiac health. ... Canine cardiac diseases are common, complex, and devastating to owners. They are often silent killers, leaving owners and breeders wondering what could have been done to prevent the loss of their treasured pet. The advances of the past three years by the canine genomics community offer hope to dog owners and breeders alike, as the tools and resources are now available to understand the genetic susceptibility for many cardiac diseases. Key to the success of such endeavors will be the partnership between the owner, veterinarian, and research scientist. Every genetic study must start with a sampling of individuals affected with the disease under scrutiny. In order to achieve success, owners must be willing to provide accurate medical histories for their dogs as well as blood and, where appropriate, tissue samples. Even with unlimited samples, a genetic study is only as good as the pathology and clinical data that it is built upon. Veterinarians must be willing to abstract important information from owners regarding disease presentation, family history, and past treatment responses, and to encourage the completion of tests needed to provide unambiguous diagnosis. Finally, the geneticist must communicate clearly what samples and information are required in order for the study to take place and should facilitate the collection of both by sharing experimental plans and information with clinicians and owners alike.

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2007

Effects of treatment type on Vertebral Heart Score in dogs with MMVD. Woolley, R., Smith, P., Munro, E., Smith, S., Swift, S., Devine, C., Corcoran, B., and French, A. Int'l J. Applied Research in Vet. Med. January 2007;5(1):43-48. Quote: The effect of treatment protocols including either pimobendan or ramipril on vertebral heart size (VHS) in dogs with class II-III (Scandinavian-modified NYHA system) congestive heart failure (CHF) ue to myxomatous mitral valve disease (MMVD) was assessed. Radiographs from 42 dogs [58% were cavalier King Charles spaniels] were analysed with 21 randomized to pimobendan and 21 to ramipril. VHS was measured prior to treatment at inclusion (Month 0) and at Months 1, 3, and 6. The least square means for the individual treatment groups showed that, for the pimobendan group, a reduction of VHS at Months 1 and 3 of treatment was observed with an increase at Month 6. In the ramipril group, an increase in VHS occurred at Months 1, 3, and 6. A difference in the treatment group least square means was demonstrable after 1 month of treatment and persisted for the remainder of the study period. Treatment with pimobendan led to lower VHS than treatment with ramipril. The clinical relevance of the changes observed in this study is as yet unclear and needs further investigation. However, it can be speculated that a reduction in VHS is a positive outcome and pimobendan would appear to be more beneficial than ramipril in this respect.

Distinguishing Cardiac and Noncardiac Dyspnea in 48 Dogs Using Plasma Atrial Natriuretic Factor, B-Type Natriuretic Factor, Endothelin, and Cardiac Troponin-I. Robert Prosek, D. David Sisson, Mark A. Oyama, and Philip F. Solter. J Vet Intern Med 2007;21:238–242.

Prospective Clinical Evaluation of an ELISA B-Type Natriuretic Peptide Assay in the Diagnosis of Congestive Heart Failure in Dogs Presenting with Cough or Dyspnea. Teresa C. DeFrancesco, John E. Rush, Elizabeth A. Rozanski, Bernard D. Hansen, Bruce W. Keene, Dominic T. Moore, and Clarke E. Atkins. J Vet Intern Med 2007;21:243–250.

Chordae tendineae Rupture in Dogs with Degenerative Mitral Valve Disease: Prevalence, Survival, and Prognostic Factors (114 Cases, 2001–2006). Francois Serres, Valerie Chetboul, Renaud Tissier, Carolina Carlos Sampedrano, Vassiliki Gouni, Audrey P. Nicolle, and Jean-Louis Pouchelon. J.Vet.Intern.Med. March 2007;21(2):254-264. Quote: "Background: Degenerative mitral valve disease (MVD) is the most common heart disease in small breed dogs, and chordae tendineae rupture (CTR) is a potential complication of this disease. The survival time and prognostic factors predictive of survival in dogs with CTR remain unknown. Hypothesis: The prevalence and prognosis of CTR in dogs with MVD increases and decreases, respectively, with heart failure class. Animals: This study used 706 dogs with MVD. Methods: The diagnosis of CTR was based on a flail mitral leaflet with the tip pointing into the left atrium during systole, which was confirmed in several 2-dimension imaging planes using the left and right parasternal 4-chamber views. Results: CTR was diagnosed in 114 [including 11 cavalier King Charles spaniels] of the 706 dogs with MVD (16.1%) and most of these (106/114, 93%) had severe mitral valve regurgitation as assessed by color Doppler mode. CTR prevalence increased with International Small Animal Cardiac Health Council (ISACHC) clinical class (i.e., 1.9, 20.8, 35.5, and 69.6% for ISACHC classes Ia, Ib, II, and III, respectively [P, .05]). Long-term follow-up was available for 57 treated dogs (angiotensin-converting enzyme inhibitors and diuretics) and 58% of these (33/57) survived 1 year after initial CTR diagnosis (median survival time, 425 days). Clinical class, the presence of ascites or acute dyspnea at the time of diagnosis, heart rate, plasma urea concentration, and left atrial size were predictors of survival. Conclusions and Clinical Relevance: CTR is associated with a higher overall survival time than previously supposed. Its prognosis mostly depends on a combination of clinical and biochemical factors."

Beating Heart Mitral Valve Replacement with a Bovine Pericardial Bioprosthesis for Treatment of Mitral Valve Dysplasia in a Bull Terrier. Luc Behr, Valérie Chetboul, Carolina Carlos Sampedrano, Gouni Vassiliki, Jean-louis Pouchelon, François Laborde, and Nicolas Borenstein. Veterinary Surgery, Volume 36, Issue 3: 190-198, 2007.

Healing of wound sutures on the mitral valve: an experimental study. Koichi Tamura, Mayumi Murakami, and Makoto Washizu. J. Gen. Thoracic and Card. Surg.; 55(3): pp. 98-104; March, 2007. Quote: "Objective: The aim of this study was to examine the histopathological changes that occur during the heading process of a sutured wound on the mitral valve. Methods In 12 mongrel dogs, an incision was made at a right angle to the annulus at the center of the free edge of the anterior mitral leaflet and then sutured. Animals were killed 2–16 weeks later and the wounds were examined histologically. Results: Two weeks after the operation, fibrin thrombi were found on the atrial surfaces of the wound, and organized thrombi became part of the neointima thereafter. There were capillaries in the thrombi, but only a few extended from the valvular ring. On the ventricular surfaces, fibrous neointima extending from adjacent intima without capillary proliferation covered the wound at 2 weeks. These heading processes started from the valvular ring side of the wound. Processes were delayed near the free edge area, and myxomatous granulation tissue extended from the adjacent spongiosa. There were abundant collagen fibers obscuring the suture line at 4 weeks in the basal region and at 12–16 weeks near the free edge. Calcified deposits with cartilage were found in a thick scar in the basal region at 4 weeks and extended to the central area thereafter. Conclusion: The healing of mitral valvular wounds is slow, especially near the free edge area. The wound is covered by organized thrombi at the atrial surface and by fibrous sheaths at the ventricular surface. These processes should be taken into consideration during the patients’ care after valvoplasty, especially during the first several months after surgery."

Effects of Pimobendan for Mitral Valve Regurgitation in Dogs. Nobuyuki Kanno, Hiroshi Kuse, Masaya Kawasaki, Akashi Hara, Rui Kano, Yoshihide Sasaki. J. Vet. Med. Sci. April 2007;69(4):373-377. Quote: "Pimobendan has a dual mechanism of action: it increases myocardial contractility by increasing calcium sensitization to troponin C and it promotes vasodilation by inhibiting PDEIII. This study examined the effects of pimobendan on cardiac function, hemodynamics, and neurohormonal factors in dogs with mild mitral regurgitation (MR). The dogs were given 0.25 mg/kg of pimobendan orally every 12 hr for 4 weeks. With pimobendan, the heart rate and stroke volume did not change, but the systolic blood pressure gradually decreased and the degree of mitral valve regurgitation tended to decrease. Renal blood flow was significantly increased and the glomerular filtration rate was slightly increased at 2 and 4 weeks. Furthermore, over the 4-week period, the plasma norepinephrine concentration decreased significantly, the systolic index increased slightly, the left atrial diameter and the left ventricular diameters decreased significantly, and the heart size improved. Given these results, pimobendan appears to be useful for treating MR in dogs. However, further long-term studies of pimobendan involving a larger number of dogs with mild and moderate MR are needed to establish the safety of pimobendan and document improvements in quality of life."

Clinical evaluation of imidapril in congestive heart failure in dogs: results of the EFFIC study. B. Besche, V. Chetboul, M.-P. Lachaud Lefay, E. Grandemange. J. Small An. Prac. May 2007;48 (5):265–270. Quote: The success rate in the imidapril group was 66 compared with 68 per cent in the benazepril group. Regarding safety, 35 dogs in each group experienced at least one adverse event. Nine dogs in each group experienced at least one serious adverse event. The difference between these results was not statistically significant. ... Imidapril is as efficacious and safe as the reference product, benazepril.

Guidelines for the identification, evaluation and management of systemic hypertension in dogs and cats. 2007 ACVIM Forum Consensus Statement. S. Brown, C. Atkins, R. Bagley, A. Carr, L. Cowgill, M. Davidson, B. Egner, J. Elliott, R. Henik, M. Labato, M. Littman, D. Polzin, L. Ross, P. Snyder, R. Stepien J. Vet. Intern. Med. May 2007;21(3):542–558.

Effects of breed, gender, exercise and white-coat effect on markers of endothelial function in dogs. S.G. Moesgaard, A.V. Holte, T. Mogensen, J. Mølbak, A.T. Kristensen, A.L. Jensen, T. Teerlink, A.J. Reynolds, L.H. Olsen. Rees. Vet. Sci. June 2007; doi: 10.1016/j.rvsc.2006.09.003. Quote: This study examines how systemic biomarkers of endothelial function and nitric oxide metabolism are affected by exercise in dogs. Furthermore, breed variation and white-coat effect have been tested by sampling three different dog breeds both in their home and in a clinical setting. Short-term exercise increased plasma nitrate and nitrite (NOx) and von Willebrand factor (vWf). There was significant difference between Pointers and the small dog breeds Cairn Terriers and Cavalier King Charles Spaniels in the general plasma levels of vWf and asymmetric dimethylarginine (ADMA). NOx and vWf were significantly higher when the sample was taken in the laboratory cf. at home, whereas ADMA and l-arginine were significantly lower. In conclusion, both short-term exercise and white-coat effect influence several plasma markers of endothelial function depending also on the breed and gender of the dogs. These findings should be considered in future studies concerning endothelial function in dogs.

Hemostatic Biomarkers in Dogs with Chronic Congestive Heart Failure. Inge Tarnow, Torkel Falk, Anna Tidholm, Torben Martinussen, Asger L. Jensen, Lisbeth H. Olsen, Henrik D. Pedersen, Annemarie T. Kristensen. J. Vet. Int. Med. June 2007;21(3):451-457. Quote: Background: Chronic congestive heart failure (CHF) in humans is associated with abnormal hemostasis, and abnormalities in hemostatic biomarkers carry a poor prognosis. Alterations in hemostatic pathways can be involved in the pathogenesis of CHF in dogs, and microthrombosis in the myocardium could contribute to increased mortality. Hypothesis: That plasma concentration or activity of hemostatic biomarkers is altered in dogs with CHF and that these factors predict mortality. Animals: Thirty-four dogs with CHF caused by either dilated cardiomyopathy (DCM, n = 14) or degenerative valvular disease (CDVD, n = 20 [CKCSs: 13]) compared with 23 healthy age-matched control dogs were included in this study. Dogs with CHF were recruited from 2 referral cardiology clinics, and control dogs were owned by friends or colleagues of the investigators. Methods: Clinical examination and echocardiography were performed in all dogs. Plasma fibrinogen and D-dimer concentrations, antithrombin and protein C activity, and thrombin-antithrombin complex (TAT) were measured in all dogs. Results: Dogs with CHF had significantly higher fibrinogen (P= .04), D-dimer (P= .002), and TAT concentration (P < .0001), lower antithrombin (P < .0001) and protein C activity (P < .001) compared with control dogs. None of the hemostatic biomarkers were associated with risk of death. Conclusions and Clinical Importance: There is evidence of a procoagulant state in dogs with CHF. The lack of predictive value for survival might be due to the small number of dogs examined. Further studies are necessary to investigate the presence and importance of microthrombosis in dogs with CHF.

Natriuretic Peptides Are Elevated in Cavalier King Charles Spaniels with Congestive Heart Failure but Not in Dogs with Clinically Inapparent Mitral Valve Disease. I. Tarnow, H.D. Pedersen, C. Kvart, K. Hoglund, T.S. Kamstrup, L.H. Olsen, J. Häggström. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 54). Quote: "These data confirm previous findings of elevated plasma ANP and BNP in dogs with CHF. However, the data do not support the relevance of NT-proBNP and proANP assays in blood-based detection of clinically inapparent MVD."

Frequency of Ventricular Ectopy in Dogs with Chronic Mitral Valve Disease and Congestive Heart Failure Treated with Pimobendan or Benazepril. M.L. O’Sullivan, M.R. O’Grady, C. Walker. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 55). Quote: "Pimobendan did not result in an increase in frequency of ventricular arrhythmias in comparison to benazepril."

Brain Naturetic Peptide for Discrimination of Respiratory Distress Due to Congestive Heart Failure or Primary Pulmonary Disease. D.M. Fine, .E. Declue, C.R. Reinero. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 56).

The Utility of NT-proBNP to Differentiate Cardiac And Respiratory Causes of Coughing or Dyspnea In Dogs. G. Wess, N. Timper, J. Hirschberger. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 131).

Acute Hemodynamic Effects of Oral Tadalafil in Dogs with Severe Mitral Valve Disease and Pulmonary Hypertension. JS Orvalho, WP Thomas, PH Kass. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 137). Quote: "These data suggest that oral tadalafil, when added to conventional heart failure therapy, decreases the pulmonary artery pressure in this group of dogs."

Evaluation of Pimobendan in the Treatment of Early Mitral Valve Disease. Ouellet M, Difruscia R, Bélanger MC. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 138). Quote: "... data suggest a possible non-sustained positive inotropic effect and a reduction of the (mitral regurgitation fraction) at 90 days with the administration of pimobendan in early chronic MVD."

Pharmacokinetics of Bisoprolol Versus Carvedilol in Dogs. G Beddies, PR Fox, M Papich, V-R Kanikanti, R Krebber, BW Keene. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 139). Quote: "These dramatic differences suggest that bisoprolol has less inter-individual pharmacokinetic variability than carvedilol in the dog. The pharmacokinetic advantages of bisoprolol versus carvedilol should be considered when contemplating clinical application of these agents."

The Effect of Pimobendan on the Renin-Angiotensin-Aldosterone System and Arrhythmogensis in the Dog. M.A. Booth, C.E. Atkins, Y. Fujii, A.K. Adams, T.C. DeFrancesco, B.W. Keene. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 140). Quote: "We conclude that there is no significant increase in ventricular ectopy in healthy dogs given a combination of furosemide and pimobendan and, as postulated, that pimobendan does not activate the RAAS. However, pimobendan given concurrently with furosemide does not prevent RAAS activation."

D-Ribose--fantastic in congestive heart failure and other cardiac problems. Teitelbaum, Jacob. Townsend Letter: The Examiner of Alternative Medicine, July 2007, p. 146+. Quote: Energy Utilization and Depletion in Ischemic Failing Hearts Ischemic heart disease and congestive heart failure (CHF) remain the major causes of death in the US today. Other than systemic hypertension, ischemia is the most common etiology of congestive heart failure, and improving long-term prognosis is a major goal in its management. It is widely held that an imbalance of energy supply and demand in the progressively failing myocardium is a major factor in the pathophysiology of the disease. In addition, the work of Dr. Paul Cheney has shown that diastolic CHF has even been shown to play a significant role in Chronic Fatigue Syndrome (CFS)/Fibromyalgia Syndrome (FMS) as well. In this month's column, I will discuss how to dramatically improve cardiac function naturally, focusing on a powerful new nutrient: ribose. In looking at energy production, it helps to look at the "energy molecules" like adenosine 5'-triphosphate (ATP), the reduced form of nicotinamide adenine dinucleotide (NADH), and the reduced form of flavin adenine dinucleotide FADH). These represent the energy currency in your body and are like the paper on which money is printed. You can have all the fuel you want, but if it cannot be converted to these molecules, it is useless! For years, I talked about the importance of B vitamins, which are a key component of these molecules. These helped to a degree, but it was clear that a key component was missing. In looking at the biochemistry of these energy molecules, they are also made of two other key components: adenine and ribose. Adenine is plentiful in the body, and supplementing with adenine did not help CFS. We then turned our attention to ribose. Ribose is made in your body in a slow, laborious process and cannot be found in food. We knew that CFS/FMS causes your body to dump other key energy molecules like acetyl-l-carnitine. We then found that the body did the same with ribose, making it hard to get mitochondria working again even after the other problems were treated. This was like one of those "Eureka!" moments where things came together. Not having ribose would be like trying to build a fire without kindling--nothing would happen. We wondered if giving ribose to people with CFS would jump-start their energy furnaces. The answer was a resounding yes! Our recently published study showed an average 44.7% increase in energy after only three weeks (improvement began at 12 days) and an average overall improvement in quality of life of 30%. Two-thirds of the CFS/FMS patients felt they had improved. (1) Usually a ten percent improvement for a single nutrient is considered excellent. A 44.7% increase left us amazed, and I am now recommending ribose for CFS/FMS patients, heart problem patients, athletes, and anyone with pain or fatigue. In fact, one patient in our study had atrial fibrillation that resolved with ribose, and most practitioners using it are finding it to be simply outstanding for their cardiac patients in general.

Quantification of mitral valve regurgitation in dogs with degenerative mitral valve disease by use of the proximal isovelocity surface area method. Vassiliki Gouni, François J. Serres, Jean-Louis Pouchelon, Renaud Tissier, Hervé P. Lefebvre, Audrey P. Nicolle, Carolina Carlos Sampedrano, Valérie Chetboul. J Am Vet Med Assn Aug 2007;231(3): 399-406. Quote: Objective: To determine the within-day and between-day variability of regurgitant fraction (RF) assessed by use of the proximal isovelocity surface area (PISA) method in awake dogs with degenerative mitral valve disease (MVD), measure RF in dogs with MVD, and assess the correlation between RF and several clinical and Doppler echocardiographic variables. Design: Prospective study. Animals: 6 MVD-affected dogs with no clinical signs and 67 dogs with MVD of differing severity (International Small Animal Cardiac Health Council [ISACHC] classification). Procedures: The 6 dogs were used to determine the repeatability and reproducibility of the PISA method, and RF was then assessed in 67 dogs [16 cavalier King Charles spaniels] of various ISACHC classes. Mitral valve regurgitation was also assessed from the maximum area of regurgitant jet signal-to-left atrium area (ARJ/LAA) ratio determined via color Doppler echocardiographic mapping. Results: Within- and between-day coefficients of variation of RF were 8% and 11%, respectively. Regurgitation fraction was significantly correlated with ISACHC classification and heart murmur grade and was higher in ISACHC class III dogs (mean ± SD, 72.8 ± 9.5%) than class II (57.9 ± 20.1%) or I (40.7 ± 19.2%) dogs. Regurgitation fraction and left atriumto-aorta ratio, fractional shortening, systolic pulmonary arterial pressure, and ARJ/LAA ratio were significantly correlated. Conclusions and Clinical Relevance: Results suggested that RF is a repeatable and reproducible variable for noninvasive quantitative evaluation of mitral valve regurgitation in awake dogs. Regurgitation fraction also correlated well with disease severity. It appears that this Doppler echocardiographic index may be useful in longitudinal studies of MVD in dogs.  

Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study. Valérie Chetboul, Hervé P Lefebvre, Carolina Carlos Sampedrano, Vassiliki Gouni, Vittorio Saponaro, François Serres, Didier Concordet, Audrey P Nicolle, Jean-Louis Pouchelon. J Vet Intern Med. July 2007; 21 (4):742-53. Quote: "This study demonstrates that long-term administration of PIMO in dogs with asymptomatic MVD is associated with an increase in systolic function and, concomitantly, a progressive worsening of MVD with development of specific mitral valve lesions. Conversely, long-term treatment with BNZ does not lead to adverse cardiac effects and is not associated with worsening of the valvular disease. ... A significant treatment effect was observed as soon as day 15 with increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening (P < .0001) and tissue Doppler variables (P = .001). Concurrently, the maximum area and peak velocity of the regurgitant jet signal increased (P < .001), whereas these variables remained stable in the BNZ group. Histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group. Moreover, acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans were observed in the mitral valves of dogs from the PIMO group but not in those of the BNZ group. ... PIMO has adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD. Additional investigation in dogs with symptomatic MVD is now warranted."

Collagen Organization in Canine Myxomatous Mitral Valve Disease: An X-Ray Diffraction Study. Mojtaba Hadian, Brendan M. Corcoran, Richard I. Han, J. Gunter Grossmann, and Jeremy P. Bradshaw. Biophysical J. Oct. 2007; 93:2472–2476. Quote: "Collagen fibrils, a major component of mitral valve leaflets, play an important role in defining shape and providing mechanical strength and flexibility. Histopathological studies show that collagen fibrils undergo dramatic changes in the course of myxomatous mitral valve disease in both dogs and humans. However, little is known about the detailed organization of collagen in this disease. This study was designed to analyze and compare collagen fibril organization in healthy and lesional areas of myxomatous mitral valves of dogs, using synchrotron small-angle x-ray diffraction. The orientation, density, and alignment of collagen fibrils were mapped across six different valves. The findings reveal a preferred collagen alignment in the main body of the leaflets between two commissures. Qualitative and quantitative analysis of the data showed significant differences between affected and lesion-free areas in terms of collagen content, fibril alignment, and total tissue volume. Regression analysis of the amount of collagen compared to the total tissue content at each point revealed a significant relationship between these two parameters in lesion-free but not in affected areas. This is the first time this technique has been used to map collagen fibrils in cardiac tissue; the findings have important applications to human cardiology."

The effect of amlodipine and the combination of amlodipine and enalapril on the renin-angiotensin-aldosterone system in the dog. C. E. Atkins, W. P. Rausch, S. Y. Gardner, T. C. Defrancesco, B. W. Keene, J. F. Levine. J. Vet. Pharmacol. Ther. October 2007;30(5):394–400. Quote: Excessive aldosterone secretion is detrimental to the heart, vessels and kidneys, contributing to hypertension and the signs and progression of heart failure. Aldosterone secretion, abnormally elevated in heart failure and hypertension, can be blunted with angiotensin-converting enzyme inhibitors. Amlodipine, used to treat hypertension and heart failure, was hypothesized to activate the renin-angiotensin-aldosterone system (RAAS). A study was conducted with six normal adult male beagle dogs. Each dog received amlodipine (0.57 mg/kg b.i.d.) for 6 days, followed by amlodipine (0.57 mg/kg b.i.d.) and enalapril (0.57 mg/kg b.i.d.) for 4 days. Blood pressure, heart rate, serum chemistries and urinary aldosterone excretion, as a measure of RAAS activation, were compared with baseline values. Blood pressure fell by approximately 7% with amlodipine (P = 0.05) and a further 7% with the combination of amlodipine and enalapril (P < 0.01). Blood urea nitrogen increased with the combination (P < 0.05) but only one dog became mildly azotemic. Renin-angiotensin-aldosterone system activation, based on 24 h urinary aldosterone excretion and by aldosterone:creatinine ratio was increased by approximately threefold (P < 0.05) with amlodipine administration. This effect was blunted by enalapril, such that aldosterone excretion was no longer different from that observed under control conditions, although values for 24-h aldosterone excretion did not return to pretreament levels.

Modulation of the tissue renin-angiotensin-aldosterone system in dogs with chronic mild regurgitation through the mitral valve. Yoko Fujii, Kensuke Orito, Makoto Muto, Yoshito Wakao. Am J Vet Research Oct 2007;68(10): 1045-1050. Quote: "The tissue renin-angiotensin-aldosterone system (RAAS) was modulated without changes in the plasma RAAS in dogs with mild mitral valve regurgitation during the chronic stage of the condition. An ACE-dependent pathway may be a major route for production of angiotensin II during this stage of the condition."

Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. Clarke E. Atkins, Bruce W. Keene, William A. Brown, Julie R. Coats, Mary Ann Crawford, Teresa C. DeFrancesco, N. Joel Edwards, Phillip R. Fox, Linda B. Lehmkuhl, Michael W. Luethy, Kathryn M. Meurs, Jean-Paul Petrie, Frank S. Pipers, Steven L. Rosenthal, Jennifer A. Sidley, Justin H. Straus. J Amer Vet Med Assn. October 2007;231(7): 1061-1069. Quote: Objective: To determine the efficacy of long-term enalapril administration in delaying the onset of congestive heart failure (CHF). Design: Placebo-controlled, double-blind, multicenter, randomized trial. Animals: 124 dogs [10 cavalier King Charles spaniels] with compensated mitral valve regurgitation (MR). Procedures: Dogs randomly assigned to receive enalapril or placebo were monitored for the primary endpoint of onset of CHF for ≤ 58 months. Secondary endpoints included time from study entry to the combined endpoint of CHF-all-cause death; number of dogs free of CHF at 500, 1,000, and 1,500 days; and mean number of CHF-free days. Results: Kaplan-Meier estimates of the effect of enalapril on the primary endpoint did not reveal a significant treatment benefit. Chronic enalapril administration did have a significant benefit on the combined endpoint of CHF-all-cause death (benefit was 317 days [10.6 months]). Dogs receiving enalapril remained free of CHF for a significantly longer time than those receiving placebo and were significantly more likely to be free of CHF at day 500 and at study end. Conclusions and Clinical Relevance: Chronic enalapril treatment of dogs with naturally occurring, moderate to severe MR significantly delayed onset of CHF, compared with placebo, on the basis of number of CHF-free days, number of dogs free of CHF at days 500 and study end, and increased time to a combined secondary endpoint of CHF-all-cause death. Improvement in the primary endpoint, CHF-free survival, was not significant. Results suggest that enalapril modestly delays the onset of CHF in dogs with moderate to severe MR.

Pimobendan treatment in dogs with congestive heart failure. Justin D. Thomason, Clay A. Calvert, Tiffany L. Fallaw. Vet. Med. November 2007. Quote: "Pimobendan, a benzimidazole-pyridazinone drug, is classified as an inodilator because of its nonsympathomimetic, nonglycoside positive inotropic (through myocardial calcium sensitization) and vasodilator properties.1-4 As such, pimobendan increases ventricular contractility and reduces preload and afterload in patients with advanced cardiac insufficiency. Pimobendan (Vetmedin—Boehringer Ingelheim Vetmedica) is now approved in the United States for use in dogs to manage signs of mild, moderate, or severe congestive heart failure originating from atrioventricular valvular insufficiency or dilated cardiomyopathy. ... Pimobendan's principal inotropic mechanism is troponin-C calcium sensitization, and this positive inotropic effect is accomplished with only a small increase in myocardial energy consumption. Pimobendan also causes peripheral arteriolar dilation, coronary artery dilation, pulmonary artery dilation, and peripheral venodilation by inhibiting phosphodiesterases III and V in vascular smooth muscle. ... Patients with degenerative mitral valve disease have good contractility as assessed by echocardiography, even when the left heart is severely dilated. Thus, the inotropic action of pimobendan would seem to be of little value. However, the vasodilator action may contribute to preload and afterload reduction. ... According to owners, most dogs with overt signs of advanced heart disease feel better and have improved activity tolerance within a few days of adding pimobendan to existing treatment. The clinical improvement may not correlate with hemodynamic improvement. In these cases, pimobendan may have a central nervous system effect that promotes a feeling of physical and mental well-being in dogs as demonstrated by other phosphodiesterase inhibitors (i.e. propentofylline). ... Clinical findings or adverse effects reported during a field study included polyuria, polydipsia, vomiting, azotemia, inappetence, lethargy, diarrhea, dyspnea, pleural effusion, cough, ascites, heart murmur, weakness and ataxia, and syncope. Sudden death may also occur. A dose-related sinus tachycardia can result, and as with any strong inotropic agent, ventricular tachyarrhythmias may develop or worsen while pimobendan is administered. Ventricular tachyarrhythmias are of particular concern in Doberman pinschers and boxers but could occur in any dog with advanced dilated cardiomyopathy. Pimobendan's effect on myocytes—conserved energy demand with small increases in intracellular calcium concentration—may reduce the likelihood of a proarrhythmic effect, but additional studies are warranted."

Sildenafil Citrate Therapy in 22 Dogs with Pulmonary Hypertension. Heidi B. Kellum, Rebecca L. Stepien. J.Vet.Intern. Med. Nov. 2007; 21(6):1258-1264. Quote: "Background: Pulmonary hypertension (PH) is a disease condition characterized by abnormally increased pulmonary artery pressures and often is associated with a poor prognosis. Sildenafil is a phosphodiesterase inhibitor that causes pulmonary arterial vasodilation and reduction in pulmonary artery pressures. Hypothesis: Treatment with sildenafil will improve echocardiographic determinants of PH in dogs, while also improving quality of life and survival. Animals: Twenty-two dogs [including a cavalier King Charles spaniel] with clinical and echocardiographic evidence of pulmonary hypertension. Methods: A retrospective study evaluating the effects of sildenafil on physical examination, ECG and radiographic findings, blood pressure and echocardiographic findings of PH, clinical score, and outcome was completed. PH was defined as a peak tricuspid regurgitation flow velocity ?2.8 m/s or a peak pulmonic insufficiency flow velocity ?2.2 m/s. Results: Sixteen of 22 dogs with PH were elderly females of small body size. Their clinical score was significantly improved (P= .0003) with sildenafil treatment, but physical examination findings remained unchanged. Heart rate, respiratory rate, vertebral heart size, ECG heart rate, and systolic blood pressure did not change significantly with sildenafil treatment (P > .05). Peak tricuspid regurgitation flow velocities did not change significantly with the treatment of sildenafil, but selected systolic time intervals were significantly improved. Survival times for all dogs ranged from 8 to >734 days. Conclusions and Clinical Importance: Sildenafil did not significantly lower the degree of measurable PH in dogs. Clinical improvement and increased quality of life was seen with sildenafil treatment, despite lack of significant change in other variables."

Blood pressure in the Cavalier King Charles Spaniel. Anna Franzén. Thesis, Swedish Univ. Ag. Sci., Uppsala, 2007.  study of the utility of NT-proBNP in distinguishing animals with heart disease and heart failure from animals with respiratory disease and normal animals. Adrian Boswood. To be published in 2007(?).

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2008

Guidelines for the Identification, Evaluation, and Management of Systemic Hypertension in Dogs and Cats. S. Brown, C. Atkins, R. Bagley, A. Carr, L. Cowgill, M. Davidson, B. Egner, J. Elliott, R. Henik, M. Labato, M. Littman, D. Polzin, L. Ross, P. Snyder, and R. Stepien. J. Vet. Int. Med. February 2008;21(3):542-558.  Quote: "Although frequently recommended as an initial step in the pharmacological management of high BP, dietary salt restriction is controversial, and the available evidence suggests that substantial sodium restriction alone generally does not reduce BP. In fact, sodium restriction activates the renin-angiotensin-aldosterone axis and may actually increase BP in certain settings. These effects may lead to progression of undesirable vascular, renal, and cardiac changes and necessitate utilization of antihypertensive agents that interfere with this hormonal system (eg, angiotensin-converting enzyme inhibitors [ACEI], angiotensin receptor blockers [ARB], and aldosterone receptor blockers). However, this approach is controversial, as high salt intake may produce adverse consequences in some settings, particularly in animals with CKD. Currently, there is no clear rationale for this approach and the panel recommends avoiding high dietary sodium chloride intake in hypertensive animals but does not recommend that a specific effort be made solely to restrict dietary sodium chloride intake. Until more data are available, the selection of appropriate diet should be based on other patient-specific factors, such as underlying or concurrent diseases and palatability."

Survival Characteristics and Prognostic Variables of Dogs with Mitral Regurgitation Attributable to Myxomatous Valve Disease. M. Borgarelli, P. Savarino, S. Crosara, R. A. Santilli, D. Chiavegato, M. Poggi, C. Bellino, G. La Rosa, R. Zanatta, J. Haggstrom, A. Tarducci. J. Vet. Intern. Med. January 2008;22(1):120-128. Quote: Background: There are few studies evaluating the natural history and prognostic variables in chronic mitral valve disease (CMVI) in a heterogeneous population of dogs. Objectives: To estimate survival and prognostic value of clinical and echocardiographic variables in dogs with CMVI of varying severity. Five hundred and fifty-eight dogs belonging to 36 breeds were studied. ... The majority of dogs included in the study were small (< 20 kg) mixed breed dogs (n=176; 31%) followed by Yorkshire Terrier (n=58; 10.4%) and Miniature Poodle (n=50; 9.0%).  [The remaining 274 dogs comprised 33 unidentified breeds -- 8.3 dogs per breed average.] ... Methods: Dogs were included after clinical examination and echocardiography. Long-term outcome was assessed by telephone interview with the owner. Results: The mean follow-up time was 22.7 ± 13.6 months, and the median survival time was 19.5 ± 13.2 months. In univariate analysis, age>8 years, syncope, HR>140 bpm, dyspnea, arrhythmias, class of heart failure (International Small Animal Cardiac Health Council), furosemide therapy, end-systolic volume-index (ESV-I)>30 mL/m2, left atrial to aortic root ratio (LA/Ao)>1.7, E wave transmitral peak velocity (Emax)>1.2 m/s, and bilateral mitral valve leaflet engagement were associated with survival time when all causes of death were included. For the cardiac-related deaths, all the previous variables except dyspnea and EDV-I>100 mL/m2 were significantly associated with survival time. Significant variables in multivariate analysis (all causes of death) were syncope, LA/Ao>1.7 m/s, and Emax>1.2 m/s. For cardiac-related death, the only significant variable was LA/Ao>1.7. Conclusions and Clinical Importance: Mild CMVI is a relatively benign condition in dogs. However, some clinical variables can identify dogs at a higher risk of death; these variables might be useful to identify individuals that need more frequent monitoring or therapeutic intervention. ... The most significant clinical and echocardiographic independent predictors in our study for survival when all causes of deaths were included were syncope, LA/Ao ratio, and Emax. However, when only cardiac-related deaths were included only the LA/Ao ratio maintained statistical significance. Left atrial enlargement reflects the degree of severity and chronic nature of mitral valve regurgitation, whereas peak velocity of early transmitral filling is dependent on atrial volume and pressure. Consequently, increased LA/Ao ratio and Emax can be considered as indicators of left atrium volume overload and increased left atrial pressure. ... ... In this large study, 384 of 558 dogs survived or died for causes unrelated to CMVI during the observation period. This finding may indicate that CMVI is a comparably benign condition as previously reported in both humans and dogs. This is particularly apparent for dogs in ISACHC class 1 HF. More than 60% of the dogs in this group were still alive after 70 months after initial diagnosis. This finding is in agreement with previous reports. The mean interval time to develop HF in 113 asymptomatic Cavalier King Charles Spaniels without any medical treatment was reported to be 27.2 ± 13.5 months. ... Fig. 2: more than 70% of dogs with class ISACHC 1 survived during the [80 month] observation period.

The Cough Reflex in Animals: Relevance to Human Cough Research. Brendan J. Canning. Lung; Feb 2008; Vol 186:Supp 1: pp. 23-28. Quote: "All mammalian species studied cough or display some similar respiratory reflex upon aerosol challenge with tussigenic stimuli such as citric acid or capsaicin. Animals cough to the same stimuli that evoke coughing in humans, and therapeutic agents that display antitussive effects in human studies also prevent coughing in animals."

Pimobendan – What You Need to Know. Amara Estrada. FVMA convention Apr 2008.  Quote: "... There is evidence that treatment with a positive inotropic agent such as pimobendan prior to the development of systolic myocardial failure can have deleterious effects. Experimental data have shown that valvular and parietal endocardial jet lesions could be induced within 4 weeks in healthy dogs even in the absence of previous valvular disease. Additionally, clinical reports of dogs chronically treated with pimobendan have described adverse cardiac effects, such as increased regurgitant fraction and left atrial enlargement, which were in part reversed following cessation of pimobendan therapy. Moreover, a recent prospective study in dogs with naturally occurring mild, asymptomatic mitral valve disease treated with pimobendan demonstrated increased regurgitant fraction and induction of mitral valve lesions including acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinea with glycosaminoglycans. These reports raise an important issue: is pimobendan indicated in dogs without systolic myocardial dysfunction? While the answer is not entirely clear at this point in time, careful case selection when deciding when and how to use pimobendan is advised and at present, it should be reserved for use when systolic myocardial failure is detected or suspected."

Association of body weight and body condition with survival in dogs with heart failure. Slupe JL, Freeman LM, Rush JE.
J Vet Intern Med. May 2008; doi: 10.1111/j.1939-1676.2008.0071.x. Quote: "Background: Obesity is a risk factor for Fig 2cardiovascular disease in people, but overweight and obese human heart failure patients have improved survival compared with normal- or underweight controls—the obesity paradox. The purpose of this study was to determine if there is an association of body weight and body condition with survival in dogs with heart failure. Hypothesis: That body condition and changes in body weight are predictors of survival in dogs with heart failure. Animals: One hundred and eight [108] dogs with heart failure (International Small Animal Cardiac Health Council stages 2, 3a, or 3b) secondary to dilated cardiomyopathy or chronic valvular disease. Methods: Medical records were reviewed, and data regarding initial body weight and body condition score (BCS), subsequent changes in body weight, and treatment were collected. Survival times were determined for dogs that were discharged from the hospital and lived >24 hours. Results: Survival was significantly different between dogs that gained, lost, or maintained body weight over the course of their disease, with dogs that gained weight surviving the longest [Fig 2]. BCS and medications were not significantly associated with survival time; however, n-3 fatty acid intake was associated with longer survival time (P= .009). Conclusions and Clinical Importance: These results suggest that changes in body weight might be an important consideration in the survival of dogs with heart failure."

Comparison of 3 ultrasound methods for quantifying left ventricular systolic function: correlation with disease severity and prognostic value in dogs with mitral valve disease. F. Serres, V. Chetboul, R. Tissier, L. Poujol, V. Gouni, C. Carlos Sampedrano, J.-L. Pouchelon. J. Vet. Intern. Med. May 2008; doi: 10.1111/j.1939-1676.2008.0097.x. Quote: Background: End‐systolic volume index (ESVI) is a marker of systolic function, which can be assessed by the geometric (GM, based on Teichholz formula) or 2 planimetric methods (PM, Simpson's derived and length area methods). Hypothesis: Systolic dysfunction (SyD) may be observed in dogs with mitral valve disease (MVD) and is better assessed by PM than GM, which does not take into account the longitudinal left ventricular systolic shortening. Animals: Six healthy dogs were used to determine the variability of the tested variables (Study 1). These variables were then prospectively assessed (Study 2) in 101 small breed dogs: 77 dogs with MVD [including 21 cavalier King Charles spaniels] and 24 healthy controls [including 7 (29%) CKCSs (CD). Methods: ESVI was measured by GM and PM in awake dogs. Results: All within- and between-day coefficients of variation were <11% (Study 1). For Study 2, a nonlinear overestimation of ESVI was observed by GM compared with PM. PM-derived ESVI was significantly increased in ISACHC class 3 dogs compared with ISACHC class 1 dogs and exerted a significant influence on cardiac events at 5 months in dogs with MVD from ISACHC classes 2 and 3. Conclusions and Clinical Importance: ESVI can be calculated by GM and PM with good repeatability and reproducibility. However, GM overestimates ESVI in a nonlinear way. Therefore, PM-derived ESVI should be preferred for the detection of SyD that is present at the late stages of the disease. ... Further studies should, therefore, be carried out to establish breed-specific reference ranges of PM variables. Until such studies are completed, the detection of SyD using PM-ESVI should rely on longitudinal follow-up on the same animal.

Vetmedin (Pimobendan). George A. Kramer. atlanticcoastvet.com/news/vetmedin May 2008. Quote: "Pimobendan should be used only in dogs that are symptomatic for heart failure (modified NYHA class II-IV). ... It may have more value in dogs with DCM due to the positive inotropic effect since all dogs with DCM have decreased myocardial contractility. Most dogs with chronic valvular heart disease do not have decreased contractility and do not need positive inotropic support. ... According to Boehringer-Ingelheim, "treatment should be initiated only in symptomatic cases which will benefit from increased myocardial contractility (positive inotropy). ... ... There is a report out of Europe that documents negative effects on the heart and worsening of the mitral regurgitation in dogs chronically treated with pimobendan for valvular disease. The changes were reversed when the drug was discontinued. There is also a concern that the drug could predispose the heart to tachyarrhythmias and lead to an increased incidence of sudden death. Although pimobendan has been shown to cause a dose-dependent tachycardia, no studies to date have documented an increased risk of sudden death. One study comparing pimobendan to enalapril showed an increase in ventricular ectopy after 14 days of treatment."

Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity. Mark A. Oyama, Philip R. Fox, John E. Rush, Elizabeth A. Rozanski, Mike Lesser. J. Amer. Vet. Med. Assn. May 15, 2008; 232(10): pp. 1496-1503. Quote: "Objective—To determine whether serum N-terminal pro-B-type natriuretic (NT-proBNP) concentration could be used to identify cardiac disease in dogs and to assess disease severity in affected dogs. ... 119 dogs with mitral valve disease, 18 dogs with dilated cardiomyopathy, and 40 healthy control dogs. ... Results—Serum NT-proBNP concentration was significantly higher in dogs with cardiac disease than in control dogs, and a serum NT-proBNP concentration > 445 pmol/L could be used to discriminate dogs with cardiac disease from control dogs with a sensitivity of 83.2% and specificity of 90.0%. In dogs with cardiac disease, serum NT-proBNP concentration was correlated with heart rate, respiratory rate, echocardiographic heart size, and renal function. For dogs with cardiac disease, serum NT-proBNP concentration could be used to discriminate dogs with and without radiographic evidence of cardiomegaly and dogs with and without congestive heart failure. Conclusions and Clinical Relevance—Results suggested that serum NT-proBNP concentration may be a useful adjunct clinical test for diagnosing cardiac disease in dogs and assessing the severity of disease in dogs with cardiac disease."

Mutation in β1-Tubulin Correlates with Macrothrombocytopenia in Cavalier King Charles Spaniels. B. Davis, M. Toivio-Kinnucan, S. Schuller, M.K. Boudreaux. J.Vet.Int.Med. May-June 2008;22(3): 540-545. Quote: "Background: Cavalier King Charles Spaniels (CKCS) have a high prevalence of inherited macrothrombocytopenia. The purpose of this study was to determine if a mutation in β1-tubulin correlated with presumptive inherited macrothrombocytopenia. Hypothesis: A mutation in β1-tubulin results in synthesis of an altered β1-tubulin monomer. α-β tubulin dimers within microtubule protofilaments are unstable, resulting in altered megakaryocyte proplatelet formation. ... Methods: DNA was used in polymerase chain reaction (PCR) assays to evaluate β1-tubulin. Platelet numbers and mean platelet volume (MPV) were evaluated for a correlation with the presence or absence of a mutation identified in β1-tubulin. Platelets obtained from homozygous, heterozygous, and clear CKCS were further evaluated using electron microscopy and immunofluorescence. Results: A mutation in the gene encoding β1-tubulin correlated with macrothrombocytopenia in CKCS. Electron microscopy and immunofluorescence studies suggest that platelet microtubules are present but most likely are unstable and decreased in number. Conclusions and Clinical Importance: The macrothrombocytopenia of CKCS correlated with a mutation in β1-tubulin. α–β tubulin dimers within protofilaments most likely are unstable, leading to altered proplatelet formation by megakaryocytes. This information will aid in distinguishing inherited from acquired thrombocytopenia. It also provides insight into the mechanism of platelet production by megakaryocytes, and also may prove useful in understanding heart-related changes in macrothrombocytopenic CKCS with concurrent mitral valve regurgitation."

Mitral regurgitation in chronic canine valvular disease: conventional 2D, M-mode, and Doppler echocardiography. John D. Bonagura. Int'l Canine Valvular Disease Symposium; Stockholm, Sweden. May 2008;38-43. Quote: Heart Size – Dilation of the left atrium and the left ventricle develop in association with hemodynamically important mitral valve disease. These changes are probably related to the combined effects of regurgitant volume, elevated LA pressure, LV dysfunction, and plasma volume retention. In the author’s experience, initial left heart dilation is somewhat “symmetrical” inasmuch as the LV and LA dilate and maintain an approximate 1:1 ratio of LVd to LAs using the long axis 2D method described below. Subjectively, mild volume overload is readily overlooked in this setting. As MR progresses, the LA appears to dilate disproportionately to the LV. There is also rightward bowing of the dorsal atrial septum on the parasternal long axis plane and progressive dilation of the pulmonary venous entries, heralding moderate to severe MR. LV dilation is often easier to appreciate subjectively from the short axis tomographic image (at the high papillary muscle level), where a “squashed mushroom” appearance is observed. Moderate to severe LA dilation can be called subjectively from the 4-chamber long axis images or from short axis planes that include the auricle. ... The optimal method of measuring LA size in MR has not been determined but there are a number of reasonable approaches. Unfortunately, the M-mode measurement in dogs markedly underestimates maximum atrial dimensions when compared to 2D studies (unless an anatomic M-mode approach is used). The author uses three general 2D echo approaches for measuring internal left atrial diameters.

Meta-analysis of normal canine echocardiographic dimensional data using ratio indices. Hall DJ, Cornell CC, Crawford S, Brown DJ. J. Vet. Cardiol. June 2008;10(1):11-23. Quote: Objectives: To investigate the dependence of echocardiographic ratio indices (ERIs) on age, body weight (BW) and breed/study group using individually contributed and published summarized data in dogs. Background: ERIs allow for narrow prediction intervals of M-mode echocardiographic measurements in generic adult dogs. Breed and age-specific differences have not been examined systematically using ERI methods. Animals, materials and methods: Individual M-mode measurements were contributed by 15 published investigators from 661 dogs [including 57 cavalier King Charles spaniels], allowing direct calculation of ERIs and summary statistics for each of these breed/study groups. M-mode ERI summary statistics were estimated from published summaries of 22 additional groups that included 527 adult and 36 growing dogs. Individual two-dimensional (2DE) left atrial (LA) and aortic root (Ao) measurements were contributed from 36 dogs. ERIs were analyzed for dependence on BW, breed/study group and age. Results: The majority of variation among ERIs was due to differences in the breed or study technique with comparatively little dependence on BW. Age dependence of ERIs was seen in the early growth phases of young dogs, but expected values for each ERI became static long before maturity, roughly at 10–12 weeks of age. ERIs derived from individual 2DE LA and Ao measurements showed no significant dependence on BW. Conclusions: ERIs are well normalized for body size and may be useful for clinical evaluation of individuals, prediction of expected M-mode and 2DE cardiac dimensions, and investigation of age or breed-specific cardiac shape changes.

Effect of Benazepril on Survival and Cardiac Events in Dogs with Asymptomatic Mitral Valve Disease: A Retrospective Study of 141 Cases. J.-L. Pouchelon, N. Jamet, V. Gouni, R. Tissier, F. Serres, C. Carlos Sampedrano, M. Castaignet, H. P. Lefebvre, V. Chetboul. J.Vet.Int.Med. July-Aug 2008;22(4): 905-914. Quote: Background: Angiotensin-converting enzyme inhibitors (ACEIs) improve quality of life and extend the life span of dogs with naturally acquired ISACHC class II-III congestive heart failure (CHF). However, their effects on asymptomatic heart disease remain controversial. Hypothesis: Benazepril (BNZ), an ACEI, could have beneficial effects at the asymptomatic stage of degenerative mitral valve disease (MVD). Animals: Dogs with ISACHC class Ia MVD and moderate-to-severe mitral regurgitation (MR) assessed by the color Doppler mapping technique at entry (Day 0) were retrospectively included. Methods: Dogs were assigned to the treated group (BNZ group) if they received BNZ (and no other cardiac medication) from Day 0 or to the untreated group (UT group) if they did not receive any cardioactive treatment until occurrence of CHF. Results: A total of 141 dogs were included in the study, 66 in the BNZ group (dosage: 0.30 ± 0.13 mg/kg) and 75 in the UT group. In the population (n = 93) including all breeds except Cavalier (CKC) and King Charles Spaniels (KC), median survival time to all causes of death in the BNZ group (n = 34, 3.3 years) was significantly longer than in the UT group (n = 59, 1.9 years) as was time to cardiac event (P < .05). Conversely, no effect of the BNZ treatment was observed in the CKC and KC population. ... No differences in the time to onset of CHF were found between the BNZ and UT groups in the whole study population or in the OB and CKC populations. ... Conclusions and Clinical Relevance: BNZ had beneficial effects in asymptomatic dogs other than CKC and KC affected by MVD with moderate-to-severe MR. Breed distribution should be taken into account for interpretation of clinical trials performed in dogs with cardiac disease.

Serum Serotonin Concentration Is Elevated in Dogs with Degenerative Mitral Valve Disease. JW Arndt, MA Oyama, JM Connolly, CA Reynolds, RJ Levy. J Vet Intern Med. 2008; 22(3) (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract 58). Quote: "Little is known concerning the molecular mechanisms involved in degenerative mitral valve disease (DMVD). In humans, elevated serotonin (5-HT) is associated with development of valvular lesions. Canine mitral valve cells demonstrate dose-dependent 5-HT-mediated ERK1/2 signaling, suggesting a possible link with canine DMVD. We sought to measure serum 5-HT concentration in dogs with DMVD, dogs predisposed to DMVD (small breed dogs weighing < 10 kg and without a murmur), and healthy large breed control dogs. ... Seventy-nine dogs were enrolled (27 affected, 24 predisposed, and 28 controls), with 17/27 affected and 15/24 predisposed dogs being Cavalier King Charles Spaniels (CKCS). ... Subgroup analysis revealed that predisposed CKCS had greater mean serum 5-HT than predisposed non-CKCS (CKCS, 903.9 [321.5] ng/ml vs. non-CKCS, 536.0 [153.7]; P50.004). We conclude that dogs with clinically apparent DMVD as well as CKCS that are predisposed to DMVD have elevated serum 5-HT. Our results suggest that 5-HT may play a role in the development of DMVD in small breed dogs, and in particular in the CKCS. Further studies involving the relationship between 5-HT, DMVD, breed, and platelet number, morphology, and function are warranted."

NT-pro-BNP Concentration in Preclinical (ISACHC 1A & 1B) Chronic Degenerative Atrioventricular Valve Disease. LT Drourr, SG Gordon, RM Roland, AB Saunders, SE Achen and MW Miller. J Vet Intern Med. 2008; 22(3) (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract 192). Quote: "This study reports the NT-proBNP median and range in dogs with various degrees of cardiac remodeling due to preclinical CVD and the correlation between NT-proBNP and various echocardiographic and radiographic indices of cardiac remodeling and Doppler derived E:Ea as an index of cardiac filling pressures. ... Eighteen dogs with preclinical CVD were evaluated a total of 24 times; 15 of the 18 dogs were CKCS, mean age was 8.2 ± 2.8 years, and 60% were male. NT-proBNP concentrations were not normally distributed. The median NT-proBNP was 508 with an interquartile range of 323–793, a minimum of 200, and maximum of 2255. Dogs with an increased LVIDd and/or LVIDs (7/24) had significantly elevated NT-proBNP when compared to those whose LVIDd and LVIDs were normal, with a median NT-proBNP of 1247 (interquartile range 503–1861) and 371 (interquartile range 279–626) respectively. There was a significant correlation between NT-pro-BNP and 2D derived La:Ao ratio. There was no significant correlation between NT-pro BNP and VHS, M-mode derived La:Ao ratio, LVIDd and LVIDs (indexed to body surface area), or Doppler derived E:Ea ratio. NT-proBNP is elevated to various degrees in preclincal CVD and is not correlated to many common indices of cardiac remodeling. Its true utility may lie in its correlation to important clinical endpoints such as onset of congestive heart failure. Larger prospective studies are warranted to further evaluate the clinical utility of this novel test."

Plasma and Urinary Levels of 6-keto-Prostaglandinf1a in Dogs with Myxomatous Mitral Valve Disease. CE Rasmussen, AV Sundqvist, CT Kjempff, I Tarnow, M jelgaard-Hansen, TS Kamstrup, A Sterup, TM Soerensen and LH Olsen. J Vet Intern Med. 2008; 22(3) (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract 195). Quote: "Endothelial dysfunction might be involved in the pathogenesis of myxomatous mitral valve disease (MMVD) in dogs. A decreased plasma concentration of the nitric oxide metabolites nitrate and nitrite have been found in Cavalier King Charles Spaniels (CKCS) with mitral regurgitation, suggesting an endothelial dysfunction in dogs with MMVD. It is speculated that the vasodilator prostacyclin also plays a role in the pathogenesis of MMVD. The aims of this study were to validate an enzyme immunoassay for a metabolite of canine prostacyclin (6-keto-prostaglandin(PG)F1a) and to compare plasma and urinary 6-keto-PGF1a in dogs with different degrees of MMVD. The study included 76 privately owned dogs: 34 CKCS, 32 Dachshunds and 10 control dogs of different breeds not predisposed to MMVD. All dogs went through clinical and echocardiographic examination. ... In conclusion, the enzyme immunoassay seemed valid for measuring canine 6-keto-PGF1a in plasma and urine. Plasma or urinary 6-keto-PGF1a does not appear to be influenced by the degree of MMVD in CKCS or Dachshunds. However, the cause of lower creatinine standardized urinary 6-keto-PGF1a in control dogs compared to CKCS and Dachshunds remains to be established."

Stem Cell Treatments of Mitral Valve Disease in Cavalier King Charles Spaniels. Jane Mercer, Medlink 2008. Quote: "As Mitral Valve Disease in Cavalier King Charles Spaniels is a degenerative disease, it could be possible to use stem cells to regenerate the affected mitral valve in the heart. From the research previously conducted, it is shown that bone marrow stromal cells can be differentiated and specialised under specific conditions into different types of cell, and can therefore be developed into cardiac muscle. These cells have been induced by external factors, such as introduction to hormones, and will become cells with the specific function of beating cells in the heart. The stem cells will divide and multiply to produce more cardiac muscle and therefore regenerate and repair the mitral valve. As the muscle is repairing, it is suggested in other reports that more stem cells from the bone marrow will naturally migrate to the heart to aid the process of reparation. In spite of this, Mitral Valve Disease is polygenetic, hence stem cells will not be able to prevent the disease from affecting the dogs, as only DNA modification can stop the passing on of the alleles which cause the disease. Stem cells will, however, enable the treatment of the disorder and therefore prevent any further suffering and discomfort to the Cavalier King Charles Spaniels. Hypothetically, it is potentially possible to take stem cells from any body tissue and, under suitable conditions, induce them to become specialised cells which can repair and regenerate damaged muscle. New data suggests that stem cells may exist in the heart and can repair damage, preventing scar tissue from permanently replacing the functioning heart muscle. By injecting bone marrow stromal cells into the diseased heart, there is hope in the future that the stem cells, with the right stimulus, could potentially regenerate the heart muscle."

Expression of Transforming Growth Factor-β1, -β2 and -β3 in Normal and Diseased Canine Mitral Valves. H. Aupperle, I. März, J. Thielebein, H.-A. Schoon. J. Compar. Pathol. August 2008;139(2):97-107. Quote: The pathogenesis of chronic valvular disease (CVD) in dogs remains unclear, but activation and proliferation of valvular stromal cells (VSC) and their transdifferentiation into myofibroblast-like cells has been described. These alterations may be influenced by transforming growth factor-β (TGF-β), a cytokine involved in extracellular matrix (ECM) regulation and mesenchymal cell differentiation. The present study investigates immunohistochemically the expression of TGF-β1, -β2, -β3 and smooth muscle alpha actin (α-SMA) in normal canine mitral valves (MVs) (n = 10) and in the valves of dogs with mild (n = 7), moderate (n = 14) and severe (n = 9) CVD. [No cavalier King Charles spaniels.] In normal mitral valves there was no expression of α-SMA but VSC displayed variable expression of TGF-β1 (10% of VSC labelled), TGF-β2 (1–5% labelled) and TGF-β3 (50% labelled). In mild CVD the affected atrialis contain activated and proliferating α-SMA-positive VSC, which strongly expressed TGF-β1 and -β3, but only 10% of these cells expressed TGF-β2. In unaffected areas of the leaflet there was selective increase in expression of TGF-β1 and -β3. In advanced CVD the activated subendothelial VSC strongly expressed α-SMA, TGF-β1 and -β3. Inactive VSC within the centre of the nodules had much less labelling for TGF-β1 and -β3. TGF-β1 labelling was strong within the ECM. These data suggest that TGF-β plays a role in the pathogenesis of CVD by inducing myofibroblast-like differentiation of VSC and ECM secretion. Changed haemodynamic forces and expression of matrix metalloproteinases (MMPs) may in turn regulate TGF-β expression.

A QUEST begins. Mark A. Oyama. J.Vet.Int.Med. Aug. 2008;22:1076–1078.

Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study. Häggström J, Boswood A, O'Grady M, Jöns O, Smith S, Swift S, Borgarelli M, Gavaghan B, Kresken JG, Patteson M, Ablad B, Bussadori CM, Glaus T, Kovačević A, Rapp M, Santilli RA, Tidholm A, Eriksson A, Belanger MC, Deinert M, Little CJ, Kvart C, French A, Rønn-Landbo M, Wess G, Eggertsdottir AV, O'Sullivan ML, Schneider M, Lombard CW, Dukes-McEwan J, Willis R, Louvet A, Difruscia R. J Vet Intern Med. Sept-Oct 2008; 22(5). Quote: "Two hundred and sixty client-owned dogs in CHF caused by Myxomatous mitral valve disease (MMVD) [including 82 cavalier King Charles spaniels] were recruited from 28 centers in Europe, Canada, and Australia. ... A prospective single-blinded study with dogs randomized to PO receive pimobendan (0.4–0.6 mg/kg/d) or benazepril hydrochloride (0.25–1.0 mg/kg/d). The primary endpoint was a composite of cardiac death, euthanized for heart failure, or treatment failure. Results: ... One hundred and twenty-four dogs were randomized to pimobendan and 128 to benazepril. One hundred and ninety dogs reached the primary endpoint; the median time was 188 days (267 days for pimobendan, 140 days for benazepril hazard ratio = 0.688, 95% confidence limits [CL] = 0.516–0.916, P= .0099). The benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a Cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration. Increases in several indicators of cardiac enlargement (left atrial to aortic root ratio, vertebral heart scale, and percentage increase in left ventricular internal diameter in systole) were associated with a shorter time to endpoint, as was a worse tolerance for exercise. Conclusions and Clinical Importance: Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy."

Feasibility of Myxomatous Mitral Valve Repair Using Direct Leaflet and Chordal Radiofrequency Ablation. Jeffrey L. Williams, Yoshiya Toyoda, Takeyoshi Ota, Dmitry Gutkin, William Katz, Marco Zenati, and David Schwartzman. J Interv Cardiol. 2008 December ; 21(6): 547–554. Quote: "Objective: Minimally invasive repair of mitral valve prolapse (MVP) causing severe mitral regurgitation (MR) should reduce mitral regurgitation and have chronic durability. Our ex-vivo, acute in-vivo, and chronic in-vivo studies suggest that direct application of radiofrequency ablation (RFA) to mitral leaflets and chordae can effect these repair goals to decrease MR. Methods: A total of seven canines were studied to assess the effects of RFA on mitral valve structure and function. RFA was applied ex-vivo (n=1), acutely in-vivo using a right lateral thoracotomy and cardiopulmonary bypass (n=3), and chronically in-vivo using percutaneous access to the heart (n=3). RFA was applied to the mitral valve and its associated chordae. Mitral valve structure and function (in-vivo preparations) were then assessed. Results: Ex-vivo application of RFA resulted qualitative reduction in mitral leaflet surface area and chordal length. Acute in-vivo application of RFA to canines found to have MVP causing severe MR demonstrated a 43.7–60.7% statistically significant (p=0.039) reduction in post-ablation MR. Chronic, in-vivo, percutaneous application of RFA was found to be feasible and the engendered alterations durable. Conclusion: These data suggest that myxomatous mitral valve repair using radiofrequency energy delivered via catheter is feasible."

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2009

Gingival Hyperplasia Associated with the Administration of Amlodipine to Dogs with Degenerative Valvular Disease (2004–2008). J.D. Thomason, T.L. Fallaw, K.P. Carmichael, M.A. Radlinsky, C.A. Calvert. J. Vet. Intern. Med. January 2009; doi: 10.1111/j.1939-1676.2008.0212.x. Quote: Background: Calcium channel blocking drugs, usually nifedipine and less often amlodipine, have been reported to cause gingival hyperplasia (GH) in humans. Hypothesis: Amlodipine, a dihydropyridine calcium channel blocking drug, can cause GH when administered chronically to older small dogs with degenerative valvular disease. Animals Studied: From January 2004 to May 2008, 82 client-owned dogs with degenerative valvular disease and left atrial dilatation were treated with amlodipine in combination with spironolactone and enalapril and followed for >6 months. Methods: Retrospective study. A chronological observation of GH in 2 dogs treated with amlodipine in 2004 and 2006 prompted the study. Patient histories and medical records of each dog treated with amlodipine for degenerative valvular disease from January 2004 to May 2008 were reviewed. Results: GH was observed by clients and the authors in 7 of 82 (8.5%) dogs. Histologic confirmation of the diagnosis was made in 2 dogs. The minimum duration of treatment before diagnosis of GH was 5 months. GH began to resolve within 2 weeks of discontinuing amlodipine and resolution was complete within 6 months. Amlodipine administration was reinstituted in 1 dog in which GH had resolved, and GH reoccurred within 4 months. Conclusion and Clinical Importance: Long-term administration of amlodipine to dogs with degenerative valvular disease may cause GH in a small percentage of patients. GH resolves quickly after withdrawal of amlodipine treatment.

Autocrine Serotonin and Transforming Growth Factor β1 Signaling Mediates Spontaneous Myxomatous Mitral Valve Disease. Sirilak Disatian, E. Christopher Orton. J Heart Valve Dis 18:44-51, Jan. 2009. Quote: "Background and aim of the study: Although serotonin and serotoninergic drugs are known to cause myxomatous-like valvulopathy, the role of serotonin in spontaneous myxomatous valve disease (MVD) remains unclear. Tryptophan hydroxylase 1 (TPH1) is the limiting enzyme for peripheral serotonin synthesis, and its expression in myxomatous valves could implicate an autocrine serotonin signaling mechanism. Studies in cultured cells demonstrate a close coupling between serotonin and transforming growth factor β1 (TGFβ1) signaling. The study aim was to investigate serotonin and TGFβ1 signaling in spontaneous MVD. Methods: In canine normal and myxomatous mitral valves, target signaling proteins including TPH1, serotonin 2B receptor (5HT2BR), serotonin transmembrane transporter (SERT), total and phosphorylated extracellular signaling-regulated kinase (ERK) 1/2, latent TGFβ1 and TGFβ1 receptors I and II, were studied using immunohistochemistry and immunoblot analysis. In human myxomatous valves, TPH1 was determined using immunofluorescence and immunoblot analysis. Results: In canine mitral valves, both 5HT2BR and TPH1 were increased in myxomatous valves, whereas SERT, a key protein in serotonin metabolism, was decreased in myxomatous valves. Phosphorylated, but not total, ERK 1/2 was increased in myxomatous valves, consistent with an enhanced active serotonin signaling. The expression of TGFβ1 receptors I and II, and of latent TGFβ1, was increased in myxomatous valves. Human myxomatous mitral valves expressed TPH1. Conclusion: The expression of TPH1 by canine and human myxomatous valves demonstrates a capacity for local serotonin production. Key signaling protein expression patterns support active serotonin and TGFβ1 signaling in canine myxomatous valves. These findings implicate an autocrine serotonin and TGFβ1 mechanism in the pathogenesis of spontaneous MVD."

Use of the vertebral heart score in coughing dogs with chronic degenerative mitral valve disease. Guglielmini C, Diana A, Pietra M, Di Tommaso M, Cipone M. J. Vet. Med. Sci. January 2009;71(1):9-13. Quote: The objective of the present study was to evaluate the usefulness of the vertebral heart score (VHS) in coughing dogs with chronic degenerative mitral valve disease (MVD). Survey thoracic radiographs of 90 dogs with a history of cough and clinical and echocardiographic evidence of MVD were evaluated by 2 independent observers. The observers were asked to first determine the origin of the cough as cardiac, non-cardiac or mixed and then to measure the VHS. Agreement regarding diagnosis of the origin of cough was obtained (kappa=0.64) in 69 dogs. Of these 69 dogs, 28 (41%), 32 (46%) and 9 (13%) had a cough of cardiac, non-cardiac and mixed origin, respectively. The dogs with a cough of non-cardiac origin had a significantly lower VHS (mean ± SD, 11 ± 0.9) compared with those of dogs with a cough of cardiac or mixed origin (12.8 ± 1 and 12.9 ± 0.9, respectively). Receiver operating characteristic curve analysis showed that a VHS ≤ 11.4 is fairly accurate for exclusion of a cough of cardiac origin in dogs with MVD. The results indicate that the VHS may be an additional tool for differentiating the origin of cough in dogs with MVD.

Cardiac cachexia: a systematic overview. von Haehling S, Lainscak M, Springer J, Anker SD. Pharmacol Ther. March 2009;121(3):227-52. Quote: "Cardiac cachexia as a terminal stage of chronic heart failure carries a poor prognosis. The definition of this clinical syndrome has been a matter of debate in recent years. This review describes the ongoing discussion about this issue and the complex pathophysiology of cardiac cachexia and chronic heart failure with particular focus on immunological, metabolic, and hormonal aspects at the intracellular and extracellular level. These include regulators such as neuropeptide Y, leptin, melanocortins, ghrelin, growth hormone, and insulin. The regulation of feeding is discussed as are nutritional aspects in the treatment of the disease. The mechanisms of wasting in different body compartments are described. Moreover, we discuss several therapeutic approaches. These include appetite stimulants like megestrol acetate, medroxyprogesterone acetate, and cannabinoids. Other drug classes of interest comprise angiotensin-converting enzyme inhibitors, beta-blockers, anabolic steroids, beta-adrenergic agonists, anti-inflammatory substances, statins, thalidomide, proteasome inhibitors, and pentoxifylline."

Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease. M. Ouellet, M.C. Bélanger, R. DiFruscia, G. Beauchamp. J Vet Int Med March/April 2009; 23(2):258-263. Quote: "Background: Pimobendan (PIMO) is a novel inodilator that has shown promising results in the treatment of advanced mitral valve disease (MVD), but little is known about its hemodynamic effects, especially regarding the mitral regurgitant volume in naturally occurring MVD. Hypothesis: The addition of pimobendan to treatment decreases the regurgitant fraction (RF) in dogs with asymptomatic MVD. Animals: Twenty-four client-owned dogs affected by International Small Animal Cardiac Health Council class Ib MVD. Methods: Prospective, blinded, and controlled clinical trial. Dogs were assigned to a PIMO treatment group (n = 19) (0.2–0.3 mg/kg q12h) or a control group (n = 5). Echocardiographic evaluations were performed over a 6-month period. Results: The addition of PIMO to treatment did not decrease the RF of dogs affected by asymptomatic class 1b MVD over the study period (P= .85). There was a significant increase in the ejection fraction of the PIMO treated dogs at 30 days (80.8 ± 1.42 versus 69.0 ± 2.76, corrected P= .0064), and a decrease in systolic left ventricular diameter (corrected P= .011) within the PIMO group compared with baseline. However, this improvement in systolic function was not sustained over the 6-month trial period. Conclusion and Clinical Importance: This study did not identify beneficial long-term changes in the severity of mitral regurgitation after addition of PIMO to angiotensin converting enzyme inhibitor treatment of dogs with asymptomatic MVD."

Pimobendan– A Silver Bullet? CVCA - Cardiac Care for Pets Newsletter. May 2009. Quote: "CVCA’s Experience with Pimobendan: CVCA’s therapeutic stance is a result of collaborative discussions and thoughtful consideration of the most appropriate use of Pimobendan given the best available evidence and collective clinical experience. There is currently no evidence that instituting Pimobendan early in the course of disease offers benefit over standard therapy nor has it been shown to slow the progression of disease. On the contrary, there is published evidence of significant worsening of histopathologic changes of valves and degree of regurgitation in dogs with naturally occurring valve disease when receiving chronic administration of Pimobendan in comparison to Benazepril. In a small study performed by CVCA, it was determined that after two to three weeks of Pimobendan therapy about 75% of dogs had an increased frequency of ventricular arrhythmias documented on 24 hour ambulatory ECG monitoring. There is also published evidence that there is no positive change in hemodynamic or echocardiographic parameters in dogs with asymptomatic heart disease."

Predictive value of natriuretic peptides in dogs with mitral valve disease. Tarnow I, Olsen LH, Kvart C, Hoglund K, Moesgaard SG, Kamstrup TS, Pedersen HD, Häggström J. Vet J. May 2009;180(2):195-201. Quote: "Natriuretic peptides are useful in diagnosing heart failure in dogs. However, their usefulness in detecting early stages of myxomatous mitral valve disease (MMVD) has been debated. This study evaluated N-terminal (NT) fragment pro-atrial natriuretic peptide (NT-proANP) and NT-pro-brain natriuretic peptide (NT-proBNP) in 39 Cavalier King Charles Spaniels (CKCS) with pre-clinical mitral valve regurgitation (MR), sixteen dogs with clinical signs of heart failure (HF) and thirteen healthy control dogs. Twenty seven CKCS and ten control dogs were re-examined 4 years after the initial examination and the status of the dogs 5 years after the initial examination was determined by telephone calls to the owner. All dogs were evaluated by clinical examination and echocardiography. CKCS with severe MR had higher NT-proANP and NT-proBNP compared to controls and CKCS with less severe MR. Dogs with clinical signs of HF had markedly elevated NT-proANP and NT-proBNP. Plasma concentrations of the natriuretic peptides measured at re-examination could predict progression in regurgitant jet size."

Expression of Genes Encoding Matrix Metalloproteinases (MMPs) and their Tissue Inhibitors (TIMPs) in Normal and Diseased Canine Mitral Valves. H. Aupperle, J. Thielebein, B. Kiefer, I. März, G. Dinges, H.-A. Schoon, A. Schubert. J. of Comparative Pathology; May 2009; 140(4):271-277. Quote: "The pathogenesis of canine chronic valvular disease (CVD) is not fully characterized. The present study investigates the expression of genes encoding matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in normal and diseased mitral valves (MVs). Samples from normal (n = 15) or diseased (n = 10) canine MVs were subject to real-time polymerase chain reaction (PCR) for quantification of mRNA encoding MMP-1, -2, -9 and -14 and TIMP-2, -3 and -4. In normal valves there was low expression of mRNA encoding MMP-2, -9 and -14 and TIMP-3. In the valves from dogs with CVD there was significantly increased transcription of mRNA encoding MMP-1 and -14 and TIMP-2, -3 and -4, but no elevation in mRNA encoding MMP-2 and -9. MMPs and TIMPs are therefore likely to be involved in extracellular matrix metabolism in normal canine MVs and there are significant alterations in the expression of genes encoding these molecules during CVD."

Serial evaluation of NTproBNP in dogs with CHF predicts clinical score and the presence or absence of radiographic pulmonary edema. Achen SE, Gordon SG, Roland RM. J Vet Intern Med. May 2009;23(3):687(#8). Quote: Human studies have found NT-proBNP useful in clinical decision making in CHF. The objective of this prospective study was to evaluate serial NT-proBNP in dogs with CHF due to chronic valve disease (CVD). Evaluations included thoracic radiographs, blood work, BP, echocardiogram, NT-proBNP, and therapy changes. Statistical analysis evaluated the predictive value of the change in NT-proBNP (∆NT-proBNP) against clinical score (CS; -1= ↓ furosemide ± ↑ pimobendan ± fluid therapy, 0= no therapy change, 1 = ↑ furosemide ± ↑ pimobendan ± parenteral furosemide) and radiographic cardiogenic infiltrate score (RIS; 0 = none, 1 = cardiogenic infiltrate). Eighteen dogs had 58 total serial evaluations. NT-proBNP between successive visits was calculated, giving 38 observations on 14 dogs. Median NT-proBNP was -170 pmol/L (range -2,000–3,700 pmol/L). Using logistic and multinomial logistic models, with Huber-White standard errors to account for correlation of observations on the same dog, NT-proBNP is significantly predictive of both CS and RIS (p<0.05). For a ↓ in NT-proBNP 2,000 pmol/L, a CS of -1 was likely, with an 80% probability. For NT-proBNP between -1,000 and 2,000 pmol/L, a CS of 0 was likely, with a probability >70%. For NT-proBNP >2,000 pmol/L, a CS of 1 was likely, with a 60% probability. A NT-proBNP >2,000 pmol/L, predicted an RIS=1 while a ↓ in NTproBNP, or an ↑ <2,000 pmol/L, predicted an RIS=0. These results suggest serial evaluation of NTproBNP may facilitate management of CHF due to CVD.

Metabolic Cardiology: An Integrative Strategy in the Treatment of Congestive Heart Failure Part 2. Stephen T. Sinatra. Alt. Ther. Health Med. May 2009;15(3):44-52. Quote: The purpose of this article is to introduce metabolic cardiology as a vital therapeutic strategy using nutritional biochemical interventions that preserve and promote adenosine triphosphate (ATP) production. Treatment options that incorporate metabolic interventions targeted to preserve energy substrates (D-ribose) or accelerate ATP turnover (L-carnitine and coenzyme Q10) are indicated for at-risk populations or patients at any stage of CHF. The integration of these metabolic supports provides the missing link in CHF treatment that has been eluding physicians for decades. ... The preservation of ATP is vital in the heart as a reduction in ATP level corresponds to a loss of diastolic function. The administration of ribose supports purine synthesis and salvage pathways promoting diastolic function. ... Cardiovascular function depends on the operational capacity of myocardial cells to generate the energy to expand and contract. Insufficient myocardial energy contributes significantly to CHF. Literally, heart failure is an “energy-starved heart.” ... In simple terms, sick hearts leak out and lose vital ATP, and the endogenous restoration of ATP cannot keep pace with this insidious deficit and relentless depletion. When ATP levels drop, diastolic function — the most important precursor of congestive heart failure — deteriorates. D-ribose, L-carnitine, and CoQ10 act to promote cardiac energy metabolism and help normalize myocardial adenine nucleotide concentrations. These naturally occurring compounds exert a physiological benefit that directly affects heart function. As the rate-limiting compound, supplemental ribose supports ATP quantity in the synthesis of new ATP. CoQ10 and carnitine enhance the turnover of ATP in the inner mitochondrial chain. All are recommended as adjunctive metabolic therapies in the treatment of heart failure and cardiomyopathy.

The Effect of Furosemide and Pimobendan on the Renin-Angiotensin-Aldosterone System (RAAS) in Dogs. AC Lantis, CE Atkins, TC DeFrancesco, BW Keene.  J Vet Intern Med June 2009;23; (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract #2). Quote: "We have shown that pimobendan, at the labeled dosage, does not accentuate furosemide- induced RAAS activation. We observed a three-fold increase in RAAS activity with furosemide alone and in combination with pimobendan. Therefore, furosemide, with or without pimobendan, is not recommended for chronic use in the absence of concurrent therapy to blunt RAAS activity, such as ACEI, aldosterone receptor blockers, or angiotensin II type I receptor blockers."

The effect of high dose pimobendan on the furosemide-induced renin-angiotensin-aldosterone-system (RAAS). MK Ames, CE Atkins, AC Lantis. J Vet Intern Med June 2009;23; (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract C-20). Quote: Pimobendan confers positive inotropic and vasodilatory effects, the latter known to activate the RAAS, which is harmful in heart failure. Evaluation of 118 dogs (from 4/2007- 8/2011) receiving pimobendan >TID for refractory heart failure revealed 30.5% to be receiving >1.2mg/kg/day (mean 2.20mg/kg/day; range 1.22-3.90mg/kg/day; recommended dosage 0.5-0.6mg/kg/day), indicating the potential negative clinical impact of a stimulatory RAAS effect of ‘high-dose’ pimobendan. The purpose of this study was to determine if high-dose pimobendan (0.6mg/kg PO q12h) potentiates furosemide-induced RAAS activation. We hypothesized, based on a previous study, that high-dose pimobendan, when used concurrently with moderate-dose furosemide, would activate the RAAS more than furosemide alone at the same dose. Twelve healthy dogs, randomized into groups of six, received furosemide (2mg/kg PO q12h) for 10 days (Group 1) or furosemide (2mg/kg PO q12h) and pimobendan (0.6mg/kg PO q12h) for 10 days (Group 2). Heart rate, body weight, blood pressure, and urine aldosterone:creatinine (UA:C, a measure of circulatory RAAS activation) were measured on days -2,-1,1,5 and 10. Serum chemistry and CBC were measured on days -2,5 and 10. Although there was a statistically significant rise in UA:C in Group 2 over the study period (p=0.0015), the increase differed significantly only on day 1 (p=0.044). ‘High-dose’ pimobendan, therefore, neither suppresses nor potentiates, to a clinically-significant degree, furosemide-induced RAAS in healthy dogs.

Long-term Survival of Two Dogs after Mitral Valve Plasty Using Expanded Polytetrafluoroethylene Chords: Pathological Study. Mnishida, M Uechi, T Mizukoshi, T Ebisawa, M Mizuno, T Mizuno, K Harada, M Fujiwara, N Nakayama. J Vet Intern Med June 2009;23:749 (ACVIM 27th Ann. Vet. Med. Forum Abstract Program: Abstract 219). Quote: "Mitral valve plasty is one of the treatment options for mitral regurgitation (MR). Expanded polytetrafluoroethylene (e-PTFE) is a polymer, which has been widely used to make artificial chords. In this study, we report autopsy and histological findings in two dogs that underwent cardiopulmonary bypass for mitral annuloplasty using e-PTFE sheets and chordoplasty using e-PTFE sutures. Case 1 was a neutered, 7-year-and-5-month-old male Cavalier King Charles Spaniel with severe MR. Postoperative progress was favorable until 10 months later when the dog showed severe diastolic dysfunction with significantly decreased fractional shortening by echocardiography. The dog died unexpectedly at 23 months after surgery. Case 2 was a 10-year-and-3-month-old female Maltese with severe MR. Postoperative progress was also satisfactory, but the dog died at 26 months after surgery from respiratory failure caused by intrathoracic fibrosarcoma. By histopathological examination, the structural integrity of both atrial and ventricular muscle fibers was maintained in Case 1, with no evidence of degeneration, fibrosis or fiber disarray. In Case 2, mild fibrosis was noted at the base of the left ventricular papillary muscle, indicating an old myocardial infarct. In both cases, e-PTFE sheets and sutures were not damaged and well integrated in the surrounding, highly differentiated connective tissues. There was no evidence of reactive changes around e-PTFE. These results suggest that e-PTFE is excellent in tissue compatibility and durability and useful for canine mitral valve plasty."

Mitral Valve Plasty in 11 Cavalier King Charles Spaniels. M Nishida, M Uechi, T Mizukoshi, T Ebisawa, M Mizuno, T Mizuno, K Harada, M Fujiwara. J Vet Intern Med June 2009;23:749 (ACVIM 27th Ann. Vet. Med. Forum Abstract Program: Abstract 220). Quote: "This study aimed at retrospectively assessing the effectiveness of mitral valve plasty in Cavalier King Charles Spaniel (CKCS), a breed predisposed to mitral valve disease (MVD). Eleven CKCS (5 males and 6 females; bodyweight, 8.8 1.4 kg; age, 110 26.7 months) underwent cardiopulmonary bypass for mitral valve plasty ... Postoperative complications included 1 case of tricuspid valve insufficiency and 3 cases of left atrial thrombosis (one had a preexisting thrombus at the time of surgery). In 3 cases, neurological symptoms became evident after surgery due to preexisting syringomyelia. The mean survival time was 10.4 6.8 months. One dog died from a suspected cardiac cause at 22 months after surgery, and another from possible thromboembolism at 4 months after surgery. Nine dogs were still alive at the time of the report. At 1 and 3 months after surgery, the left atrial to aortic root diameter ratio (1.76 0.36 and 1.68 0.33, respectively; n57) and the plasma atrial natriuretic peptide level (117.9 54.8 and 85.8 38.2 pg/mL, respectively; n54) were lower than those before surgery (2.60 0.61 and 198.0 109.9 pg/mL). There were also significant improvements in the number of prescribed cardiovascular drugs 1 month after surgery (1.6 1.3 vs. 4.5 1.6 preoperatively, po0.05; n511) and in the cardiac murmur grade (2.5 0.8 vs. 5.1 0.6 preoperatively, po0.05; n59). These results suggest that mitral valve plasty is beneficial in CKCS with MVD."

Intra- and Post-operative Complications in 47 Dogs That Underwent Mitral Valve Plasty. T Mizuno, M Uechi, T Ebisawa, M Mizuno, T Mizukoshi, K Harada, M Nishida, M Fujiwara, T Nakayama. J Vet Intern Med June 2009;23:749 (ACVIM 27th Ann. Vet. Med. Forum Abstract Program: Abstract 221). Quote: "To assess the incidence of intra- and post-operative complications, we retrospectively reviewed 47 cases that underwent MVP with CPB at the Nihon University Animal Medical Center between August 2006 and September 2008. The subjects were 47 dogs [22 males and 25 females, age: 62–175 (123 25) months, bodyweight: 1.8–13.5 (5.7 3.0) kg]. The mean age of the 10 dogs that died within 4 months after surgery was 140 21 (range: 115–175) months, which was significantly higher compared to those that survived beyond 4 months postsurgery [119 25 (range: 62–157) months]. The 4-month postoperative mortality was 29% for dogs aged 10 years or older and 11% for those younger than 10 years. The causes of death were surgical technical problems (2 cases), thrombosis (4 cases), pancreatitis (2 cases), pulmonary hypertension (1 case) and unknown (1 case). Of the 37 cases that survived for 4 months or longer, 4 cases had postoperative complications (thrombotic cerebral infarction, pulmonary infarction, cerebellar infarction and aspiration pneumonitis; 1 case each). Thrombus formation (including those in the left atrium) was observed in 12 cases and was the most frequent causes of postoperative complication and/or death. These results suggest that prevention of thrombosis is an important strategy for improving the surgical outcome of MVP. For dogs over 10 years old, in addition, preoperative stabilization and postoperative management are critical, and earlier surgery is recommended."

Association of Plasma N-Terminal Pro-B-Type Natriuretic Peptide Concentration with Mitral Regurgitation Severity and Outcome in Dogs with Asymptomatic Degenerative Mitral Valve Disease. V. Chetboul, F. Serres, R. Tissier, H.P. Lefebvre, C. Carlos Sampedrano, V. Gouni, L. Poujol, G. Hawa, and J.L. Pouchelon. J Vet Intern Med June 2009;23(5):984-994. Quote: "Background: The clinical outcome of dogs affected by degenerative mitral valve disease (MVD) without overt clinical signs is still poorly defined, and criteria for identification of animals that are at a higher risk of early decompensation have not yet been determined. Hypothesis: N-terminal pro-B-type natriuretic peptide plasma concentration (NT-proBNP) is correlated with mitral regurgitation (MR) severity and can predict disease progression in dogs with asymptomatic MVD. Animals: Seventy-two dogs with asymptomatic MVD, with or without heart enlargement (International Small Animal Cardiac Health Council: ISACHC classes 1a and 1b), and a control group of 22 dogs were prospectively recruited. ... Results: ... Among the 55 dogs available for statistical analysis, MVD remained stable in 45 (82%) dogs (S group), whereas the other 10 dogs (18%) either died from acute pulmonary edema (n 5 3) or developed clinical signs of CHF (n 5 7) confirmed by examination at our unit. ... NT-proBNP was higher in dogs with MVD (ISACHC classes 1a and 1b) compared with the control group (P= .025 and < .001, respectively). The difference was not significant when only dogs from ISACHC class 1a with RF < 30% were considered. Lastly, NT-proBNP was higher in dogs that underwent MVD decompensation at 12 months (P < .05). Conclusions and Clinical Importance: NT-proBNP is correlated with MVD severity and prognosis in dogs with asymptomatic MVD."

Aldosterone receptor antagonists – how cardiovascular actions may explain their beneficial effects in heart failure. P. Ovaert, J. Elliott, F. Bernay, E. Guillot, & T. Bardon. J. Vet. Pharmacol. Therap. 2009; 33:109–117. Quote: "Historically, aldosterone receptor antagonists (ARA) have been classified as ‘potassium sparing diuretics’. However, the positive effect of spironolactone, the most extensively studied ARA, on morbidity and mortality observed in humans suffering cardiac insufficiency could not be explained by the renal effect of the drug alone, and a pivotal clinical study has led to extensive research. Many experimental studies have demonstrated that ARA have previously unexpected beneficial effects on the cardiovascular system including reduction in remodelling of the vascular smooth muscle cells and myocytes and improvement of endothelial cell dysfunction in heart failure. These effects improve vascular compliance and slow down the progression of left ventricular dysfunction and end-organ damage. Furthermore, aldosterone receptor blockade also restores the baroreceptor reflex, improving heart rate variability in heart failure in humans. Some of these effects have been demonstrated in dog models of cardiac disease and so justified further investigation of the potential benefit of ARA in dogs with congestive heart failure (CHF). Positive effects of spironolactone on morbidity and mortality appear to have been seen in studies conducted in dogs suffering from naturally occurring CHF. In addition, eplerenone has been shown to have benefits in canine models of heart failure. The precise mechanisms by which ARA produce these beneficial effects in dogs remain to be determined but this group of drugs clearly provide therapeutic actions out-with their diuretic effects."

Effects of Short-term Treatment with Pimobendan in Dogs with Myxomatous Valve Disease. A. Caro, E. Ynaraja, J.A. Montoya. J. Appl. Anim. Res. June 2009;35:113-117. Quote: The aim of the study was to evaluate the short-term effects of pimobendan, a novel drug, in dogs with naturally occurring mitral valve myxomatous disease. The study involved twenty dogs with no previous treatment. The results show that pimobendan is well tolerated and can be administered effectively and safely in the treatment of congestive heart failure myxomatous mitral valve disease of the dog.

Acute Effect of Pimobendan and Furosemide on the Circulating Renin-Angiotensin-Aldosterone System in Healthy Dogs. M.B. Sayer, C.E. Atkins, Y. Fujii, A.K. Adams, T.C. DeFrancesco, and B.W. Keene. J Vet Intern Med 2009;23(5):1003-1006. Quote: "Background: The renin-angiotensin-aldosterone system (RAAS) is activated in states of decreased cardiac output and by certain cardiovascular therapeutic agents, such as loop diuretics and vasodilators. Hypothesis: Short-term treatment with the inodilator, pimobendan, will not activate the circulating RAAS because its vasodilatory action will be offset by its positive inotropic property, thereby ameliorating RAAS stimulation at the juxtaglomerular apparatus. Furthermore, pimobendan will suppress RAAS activation produced by furosemide. Animals: Nine healthy laboratory dogs were used in this study. Methods: Experimental, cross-over study. Dogs were administered pimobendan (0.5 mg/kg q12h) for 4 days followed by furosemide (2  mg/kg q12h) and then, after a wash-out period, a combination of the drugs. Aldosterone : creatinine (A : Cr) was measured at the end of each treatment cycle. Results: There was no significant increase in the average urinary A : Cr with the administration of pimobendan (control urinary A : Cr = 0.46, standard deviation (SD) 0.33; pimobendan A : Cr = 0.48, SD 0.28). There was a significant increase in the average urinary A : Cr after administration of furosemide (urinary A : Cr = 1.3, SD 0.70) and with the combination of furosemide and pimobendan (urinary A : Cr = 2.9, SD 1.6). Conclusions and Clinical Relevance: Short-term administration of high-dose pimobendan, does not activate the RAAS in healthy dogs. Pimobendan did not prevent RAAS activation associated with furosemide therapy. These results in healthy dogs suggest that furosemide therapy, with or without pimobendan, should be accompanied by RAAS suppressive therapy."

Echocardiographic assessment of 537 dogs with mitral valve prolapse and leaflet involvement. Eloisa Terzo, Marco Di Marcello, Hester Mcallister, Brendan Glazier, Daniele Lo Coco, Chiara Locatelli, Valentina Palermo, Paola Giuseppina Brambilla. Vet. Radiology & Ultrasound. July 2009;50(4):416-422. Quote: "In this work we investigated which mitral valve leaflet was most often involved in mitral valve prolapse with degenerative mitral valve disease and whether there was an association with breed, age, gender, or weight. Five hundred and thirty-seven dogs with mitral valve prolapse-degenerative mitral valve disease were assessed; the cross-breed dog was the most represented breed (248 dogs, 46.2%). Mitral valve prolapse was more common in male dogs, and the average age was 11.3±2.8 years. Prolapse of the anterior leaflet was present in 48.4% of dogs, prolapse of the the posterior leaflet in 7.1%, and bileaflet prolapse was present in 44.5%; this distribution is different than that typically found in humans. There was a significant correlation between severity of mitral regurgitation and severity of mitral valve prolapse or ISACHC class, and between severity of mitral valve prolapse and ISACHC class. There was no relationship between the particular affected leaflet(s) and severity of mitral regurgitation, severity of mitral valve prolapse, or ISACHC class. Our findings suggest that the susceptibility to the mitral valve prolapse-degenerative mitral valve disease is not confined to a specific breeds and that the specific leaflet prolapsing is different in dogs compared with humans."

Evaluation of Plasma N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Concentrations in Dogs with Mitral Valve Insufficiency. Naoyuki Takemura, Noriko Toda, Yuichi Miyagawa, Kazuyuki Asano, Kenji Tejima, Nobuyuki Kanno, Kohji Arisawa, Tohru Kurita, Kohji Nunokawa, Atsushi Hirakawa, Shigeo Tanaka, Hisashi Hirose. J. Vet. Med. Sci. August 2009;71(7):925-929. Quote: "The diagnostic significance of the plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) was evaluated in 72 dogs with mitral valve insufficiency [including 6 cavalier King Charles spaniels] and 36 control dogs. In the controls, the plasma NT-proBNP concentration was 163.9 ± 114.7 (SD) pmol/l. The values in those with International Small Animal Cardiac Health Council (ISACHC) functional classification of heart failure class Ia, Ib, II and IIIa mitral valve insufficiency were 302.8 ± 257.1 (n=21), 634.2 ± 642.5 (n=23), 1,277.9 ± 756.2 (n=18) and 1,908.9 ± 538.8 (n=10) pmol/l, respectively; those in the class Ib or severer groups were significantly higher than that in the controls. In dogs in which the intensity of cardiac murmurs was Levine 3, 4, 5 and 6, plasma NT-proBNP concentrations were 647.6 ± 577.3 (n=27), 1,184.7 ± 841.0 (n=18), 1,532.4 ± 784.2 (n=10) and 1,461.8 ± 932.2 (n=4) pmol/l, respectively, and were significantly higher than that in the controls. The plasma NT-proBNP concentration was significantly correlated with the cardiac size (VHS) and LA/Ao (r=0.611, n=89, p<0.01; and r=0.705, n=91, p<0.01, respectively). When dogs with ISACHC class II or IIIa were regarded as heart failure, the cut-off value was 713.5 pmol/l, and the sensitivity and specificity were 0.913 and 0.857, respectively. These findings could indicate that plasma NT-proBNP concentration was significantly associated with the severity of heart failure due to mitral valve insufficiency in dogs. Further investigation is required to determine factors other than heart failure affecting plasma NT-proBNP concentration."

D-ribose aids advanced ischemic heart failure patients. MacCarter D, Vijay N, Washam M, Shecterle L, Sierminski H, St Cyr JA. Int J Cardiol. September 2009;137(1):79-80. Quote: "Patients with advanced heart failure are exercise intolerant. Low cellular energy levels in the failing heart have been proposed. Energy enhancing substrates have revealed mixed results. Ribose, a pentose monosaccharide, has shown to replenish low myocardial energy levels, improving cardiac dysfunction following ischemia, and improving ventilation efficiency in patients with heart failure. As current pharmaceuticals do not address cellular energy levels, this study was designed to investigate the role of ribose on ventilation at anaerobic threshold in congestive heart failure patients. d-ribose (5 gms/dose, tid) was assessed in 16 NYHA class III-IV, heart failure patients with VO(2), tidal volume/VCO(2), heart rate/tidal volume evaluated at 8 weeks. All patients had a significant improvement in ventilatory parameters at anaerobic threshold, along with a 44% Weber class improvement. Ribose improved the ventilatory exercise status in advanced heart failure patients."

Fenfluramine Disrupts the Mitral Valve Interstitial Cell Response to Serotonin. Jeanne M. Connolly, Marina A. Bakay, James T. Fulmer, Robert C. Gorman, Joseph H. Gorman, III, Mark A. Oyama, and Robert J. Levy. Am J Pathol. September 2009; 175(3): 988–997. Quote: "Serotonin (5HT) receptor signaling and 5HT-related agents, such as the anorexogen fenfluramine (Fen), have been associated with heart valve disease. We investigated the hypothesis that Fen may disrupt mitral valve interstitial cell (MVIC) homeostasis through its effects on mitogenesis and extracellular matrix biosynthesis. Normal and myxomatous mitral valves, both human and canine, were harvested, and primary MVIC cultures were established. 5HT caused increased phosphorylation of extracellular signal-related kinase in MVIC; Fen alone did not. However, Fen combined with 5HT increased the level of MVIC extracellular signal-related kinase, when compared with 5HT alone. In addition, MVIC mitogenesis per 3H-thymidine (3HTdR) demonstrated a 5HT dose-dependent increase, with no effect of Fen alone. In contrast, Fen combined with 5HT inhibited the MVIC 3HTdR response when compared with 5HT alone. Furthermore, fluoxetine, a 5HT transporter inhibitor, while having no effect alone, suppressed Fen-5HT 3HTdR inhibition when administered with Fen plus 5HT. Finally, MVIC incorporations of 3H-proline and 3H-glucosamine, measures of extracellular matrix collagen and glycosaminoglycan respectively, were increased with 5HT alone; however, Fen did not affect MVIC glycosaminoglycan or collagen either alone or in combination with 5HT. Taken together, the ratios of 3H-proline or 3H-glycosaminoglycan to 3HTdR in MVIC, normalized to 5HT alone, demonstrated a significant imbalance of extracellular matrix production versus proliferation in MVIC cultures with Fen plus 5HT exposure. This imbalance may explain in part the pathophysiology of Fen-related mitral valve disease. ... Interestingly, ketanserin, a 5HTR-2A receptor inhibitor, significantly reduced 3HTdR in canine MVIC (Figure 3C) as did GR55562, a type 1B inhibitor. Both ketanserin and GR55562 inhibited pERK1/2 in canine MVIC (see Figure 3B), thus indicating that in canine MVIC 5HT receptor types 1B and 2A may be involved in receptor signaling related to 5HT-induced mitogenesis."

Chronic Vagus Nerve Stimulation Improves Autonomic Control and Attenuates Systemic Inflammation and Heart Failure Progression in a Canine High-Rate Pacing Model. Youhua Zhang, Zoran B. Popović, Steve Bibevski, Itaf Fakhry, Domenic A. Sica, David R. Van Wagoner, Todor N. Mazgalev. Circulation: Heart Failure. September 2009;2:692-699. Quote: "Background: Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). Although the therapeutic benefits of sympathetic inhibition with β-blockers in HF are clear, the role of increased vagal tone in this setting has been less studied. We have investigated the impact of enhancing vagal tone (achieved through chronic cervical vagus nerve stimulation, [VNS]) on HF development in a canine high-rate ventricular pacing model. Methods and Results: Fifteen dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 bpm for the first 4 weeks to develop HF and another 4 weeks at 180 bpm to maintain HF). Concomitant VNS, at an intensity reducing sinus rate ≈20 bpm, was delivered together with the ventricular pacing in the VNS group. At 4 and 8 weeks of ventricular pacing, both left ventricular end-diastolic and -systolic volumes were lower and left ventricular ejection fraction was higher in the VNS group than in the control group. Heart rate variability and baroreflex sensitivity improved in the VNS dogs. Rises in plasma norepinephrine, angiotensin II, and C-reactive protein levels, ordinarily expected in this model, were markedly attenuated with VNS treatment. Conclusions: Chronic VNS improves cardiac autonomic control and significantly attenuates HF development in the canine high-rate ventricular pacing model. The therapeutic benefit of VNS is associated with pronounced anti-inflammatory effects. VNS is a novel and potentially useful therapy for treating HF."

Cardiac Drugs for Treatment of Canine Heart Failure. Mark A.Oyama. NAVC Clinician's Brief. October 2009;56-59. Quote: "Degenerative mitral valve disease (DMVD) and dilated cardiomyopathy (DCM) are common cardiac diseases in adult dogs.Both diseases can lead to heart failure and loss of quality and quantity of life. Various cardiac drugs prolong survival and many others help alleviate clinical signs. ... Diuretics ... ACE Inhibitors: ... Considerations: In dogs with DMVD, the use of ACE inhibitors in those without clinical signs remains controversial. Two well-designed studies offer slightly different perspectives: One study in Cavalier King Charles spaniels with mild–moderate DMVD clearly indicated that enalapril did not delay onset of CHF. Another study involving dogs of many different breeds and more advanced DMVD also failed to show benefit with respect to the study’s primary endpoint; however, analysis of several secondary endpoints suggested that dogs that received enalapril avoided heart failure longer than dogs that did not. In my opinion, if ACE inhibitors delay heart failure in dogs with DMVD that show no clinical signs, the effect is inconsistent from individual to individual, relatively small, and unlikely to dramatically change progression of disease. In dogs with severe heart enlargement and at high risk for CHF, I prefer to use an ACE inhibitor in tandem with low-dose diuretic therapy (furosemide, 1 mg/kg Q 24 H), as this more likely reduces plasma volume, intracardiac pressure, and risk of CHF than using an ACE inhibitor alone. ... Pimobendan: Indications: Both DMVD and DCM are associated with progressive loss of myocardial contractility. Poor contractility is much easier to detect in dogs with DCM as opposed to DMVD, where the presence of a large degree of mitral regurgitation often confounds routine echocardiographic evaluation of contractility. Pimobendan is a positive inotrope and increases contractility through a mechanism different from that of traditional inotropes such as digoxin—the advantage of which is increased contractility without significant increases in myocardial oxygen demand. Pimobendan also relaxes vascular smooth muscle and elicits modest arterial vasodilation; this dual 'inodilating' action is unique. Pimobendan improves survival and quality of life in dogs with DMVD, and very likely does the same in dogs with DCM. ... Considerations: The benefits of pimobendan have been substantiated in dogs showing clinical signs associated with heart disease due to DMVD and DCM; treatment with this agent is recommended only if clinical signs are evident. Thus, in the majority of instances, pimobendan is prescribed only if and when dogs experience congestive heart failure and its attendant clinical manifestations (eg, cough, dyspnea, tachypnea). Less commonly, dogs with exercise intolerance or syncope are also candidates for treatment. Currently, no evidence exists for the use of pimobendan in dogs with DMVD or DCM prior to the onset of clinical signs. ... Spironolactone ... Beta-Blockers."

Radiographic features of cardiogenic pulmonary edema in dogs with mitral regurgitation: 61 cases (1998-2007). Diana A, Guglielmini C, Pivetta M, Sanacore A, Di Tommaso M, Lord PF, Cipone M. JAVMA. November 2009;235(9):1058-1063. Quote: Objective: To evaluate radiographic distribution of pulmonary edema (PE) in dogs with mitral regurgitation (MR) and investigate the association between location of radiographic findings and direction of the mitral regurgitant jet (MRJ). Design: Retrospective case series. Animals: 61 dogs with cardiogenic PE and MR resulting from mitral valve disease (MVD; 51 dogs), dilated cardiomyopathy (9), and hypertrophic cardiomyopathy (1). Procedures: Thoracic radiographs of dogs with Doppler echocardiographic evidence of MR were reviewed for location (diffuse, perihilar, or focal) of PE. Also, direction (central or eccentric) of the MRJ, as evaluated by Doppler color flow mapping (DCFM), and distribution (symmetric or asymmetric) of radiographic findings were evaluated. Results: Diffuse, perihilar, and focal increases in pulmonary opacity were observed in 11 (18.0%), 7 (11.5%), and 43 (70.5%) of 61 dogs, respectively. Radiographic evidence of asymmetric PE in a single lung lobe or 2 ipsilateral lobes was found in 21 dogs, with involvement of only the right caudal lung lobe in 17 dogs. Doppler color flow mapping of the MRJ was available for 46 dogs. Of 31 dogs with a central MRJ, 28 had radiographic findings indicative of symmetric PE. Of 15 dogs with eccentric MRJ, 11 had radiographic evidence of asymmetric PE, and all of these dogs had MVD. Conclusions and Clinical Relevance: In dogs with cardiogenic PE, a symmetric radiographic distribution of increased pulmonary opacity was predominantly associated with a central MRJ, whereas an asymmetric radiographic distribution was usually associated with eccentric MRJ, especially in dogs with MVD.

ACVIM Consensus Statement: Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease. C. Atkins, J. Bonagura, S. Ettinger, P. Fox, S. Gordon, J. Häggström, R. Hamlin, B. Keene (Chair), V. Luis-Fuentes, and R. Stepien. J Vet Intern Med. Nov/Dec 2009;23(6):1142–1150. Quote: "Cavalier King Charles Spaniels are predisposed to developing CVHD at a relatively young age, but the time course of their disease progression to heart failure does not appear to be markedly different from that of other small breed dogs except for the early age of onset. ... The classification system presented below and used in these guidelines is meant to complement, not replace, functional classification systems. The new system describes 4 basic stages of heart disease and failure: (a) Stage A identifies patients at high risk for developing heart disease but that currently have no identifiable structural disorder of the heart (e.g., every Cavalier King Charles Spaniel without a heart murmur); (b) Stage B identifies patients with structural heart disease (e.g., the typical murmur of mitral valve regurgitation is present), but that have never developed clinical signs caused by heart failure. Because of important clinical implications for prognosis and treatment, the panel further subdivided Stage B into Stage B1 and B2; (i) Stage B1 refers to asymptomatic patients that have no radiographic or echocardiographic evidence of cardiac remodeling in response to CVHD; (ii) Stage B2 refers to asymptomatic patients that have hemodynamically significant valve regurgitation, as evidenced by radiographic or echocardiographic findings of left-sided heart enlargement; (c) Stage C denotes patients with past or current clinical signs of heart failure associated with structural heart disease. Because of important treatment differences between dogs with acute heart failure requiring hospital care and those with heart failure that can be treated on an outpatient basis, these issues have been addressed separately by the panel. Some animals presenting with heart failure for the 1st time may have severe clinical signs requiring aggressive therapy (eg, with additional afterload reducers or temporary ventilatory assistance) that more typically would be reserved for those with refractory disease (see Stage D); (d) Stage D refers to patients with end-stage disease with clinical signs of heart failure caused by CVHD that are refractory to ‘‘standard therapy’’ (defined later in this document). Such patients require advanced or specialized treatment strategies in order to remain clinically comfortable with their disease. As with Stage C, the panel has distinguished between animals in Stage D that require acute, hospital-based therapy and those that can be managed as outpatients. ... Diagnosis for Stage A -- Consensus recommendations: (a) Small breed dogs, including breeds with known predisposition to develop CVHD (e.g., Cavalier King Charles Spaniels, Dachshunds, Miniature and Toy Poodles) should undergo regular evaluations (yearly auscultation by the family veterinarian) as part of routine health care. (b) Owners of breeding dogs or those at especially high risk, such as Cavalier King Charles Spaniels, may choose to participate in yearly screening events at dog shows or other events sponsored by their breed association or kennel club and conducted by board-certified cardiologists participating in an ACVIM-approved disease registry."

Evaluation of pimobendan and N-terminal probrain natriuretic peptide in the treatment of pulmonary hypertension secondary to degenerative mitral valve disease in dogs. Atkinson, K. J.; Fine, D. M.; Thombs, L. A.; Gorelick, J. J.; Durham, H. E. J Vet Intern Med Nov/Dec 2009; 23(6):1190-1196.  Quote: "Background: Pimobendan is a positive inotrope and vasodilator that may be useful in the treatment of pulmonary hypertension (PHT) secondary to degenerative mitral valve disease. Hypothesis: Pimobendan decreases the severity of PHT measured echocardiographically and improves quality-of-life scores. Changes in N-terminal probrain natriuretic peptide (NT-proBNP) concentrations will reflect improvement in severity of PHT. Animals: Ten client-owned dogs with peak tricuspid regurgitant flow velocity (TRFV) ≥3.5 m/s. Methods: Prospective short-term, double-blinded, crossover design, with a long-term, open-label component. Short term, dogs were randomly allocated to receive either placebo or pimobendan (0.18-0.3 mg/kg PO q12 h) for 14 days. After a 1-week washout, they received the alternative treatment for 14 days, followed by pimobendan open-label for 8 weeks. Results: Short-term comparison: peak TRFV decreased in all dogs on pimobendan compared with placebo from a median of 4.40 (range, 3.2-5.6) to 3.75 (range, 2.4-4.8) m/s (P<.0001). NT-proBNP concentration decreased after treatment with pimobendan from a median of 2,143 (range, 450-3,981) to 1,329 (range, 123-2,411) pmol/L (P=.0009). All dogs improved their quality-of-life score (P=.006). In the long-term comparisons, peak TRFV decreased in all dogs from a median of 4.28 (range, 3.5-5.7) to 3.52 (range, 2.4-5.0) m/s (P<.0001). No significant changes in NT-proBNP or quality-of-life scores were detected. Conclusions and Clinical Importance: Pimobendan lowered severity of measurable PHT, improved quality-of-life scores, and decreased NT-proBNP concentrations short-term. Long term, only the reduction in TRFV was maintained."

Serum Serotonin Concentrations in Dogs with Degenerative Mitral Valve Disease. Arndt JW, Reynolds CA, Singletary GE, Connolly JM, Levy RJ, Oyama MA. J Vet Intern Med. Nov/Dec 2009;23(6) 1208-1213. Quote: "Background: Increased serotonin (5HT) signaling has been implicated in valvular disease of humans and animals, including canine degenerative mitral valve disease (DMVD). High circulating 5HT concentration is a potential source of increased signaling, and serum 5HT concentrations have not been previously reported in dogs with DMVD. Hypothesis: Dogs with DMVD and small breed dogs predisposed to DMVD have higher serum 5HT concentrations than large breed controls. Animals: Fifty dogs affected with DMVD, 34 dogs predisposed to DMVD but without cardiac murmur or echocardiographic evidence of DMVD, and 36 healthy large breed control dogs. Methods: Prospective analysis. Serum 5HT concentration was measured by an ELISA test. Results: Median serum 5HT concentration was significantly higher in dogs with DMVD and in dogs predisposed to DMVD as compared with controls (DMVD, 765.5 ng/mL [interquartile range, 561.3-944.4]; predisposed, 774.9 ng/mL [528.3-1,026]; control, 509.8 ng/mL [320.8-708.8]; P= .0001). Subgroup analysis of predisposed dogs indicated significantly higher serum 5HT concentrations in Cavalier King Charles Spaniel (CKCS) dogs than in other breeds (CKCS, 855.0 ng/mL [635.8-1,088]; non-CKCS, 554.2 ng/mL [380.6-648.4]; P= .0023). Age, platelet count, and platelet morphology were not correlated with 5HT concentration in any group. Conclusions and Clinical Importance: Dogs with DMVD had significantly higher serum 5HT concentrations when compared with large breed control dogs. Healthy CKCS dogs had significantly higher serum 5HT concentrations than other healthy dogs predisposed to DMVD. Additional investigation into a possible role of 5HT in the pathogenesis of DMVD is warranted."

Study of collagen structure in canine myxomatous mitral valve disease. Mojtaba Hadian. Thesis 2009, Div. Vet. Biomed. Sci., Med. & Vet. Sci. College, Univ. Edinburgh.  Quote: "Myxomatous mitral valve disease (MMVD) is the single most common acquired cardiac disease of dogs, and is a disease of significant veterinary importance. It also bears close similarities to mitral valve prolapse in humans and therefore is a disease of emerging comparative interest. Realising the importance of collagen fibres in mitral heart valves and considering the paramount significance of myxomatous mitral valve disease, a better understanding of the pathogenesis of MMVD is essential. Thus, this study was designed to investigate the changes in collagen molecules, including fibril structure, fibril orientation, d-spacing, collagen density, collagen content, thermal stability, and the status of mature and immature crosslinks. A combination of biophysical and biochemical tools such as x-ray diffraction, neutron diffraction, HPLC were utilised in order to fulfil the objectives. Biochemical assay of hydroxyproline revealed a 10% depletion of collagen in mildly affacted (grade I and II) leaflets, while a 20% depletion of fibrillar collagen was revealed by mapping the collagen fibrils onto the anatomy of cardiac leaflets using x-ray data. Differential scanning calorimetry showed that there were no significant differences in the onset temperature of denaturation of collagen between the healthy and affected leaflets. However, in affected areas of leaflets, the enthalpy of denaturation significantly dropped by 20%. In the affected regions, neutron diffraction results showed an increase in the immature reducible cross-links though the low number of the samples can be considered a limiting factor in this regard. However, the HPLC results showed a 25% decrease in the number of mature cross-links. Additionally, the recently introduced imaging technologies to biology and medicine such as differential enhancing imaging (DEI) and coherent anti-Stokes Raman scattering spectroscopy (CARS) were, to the author’s best knowledge, applied for the first time to this disease. In doing so, this thesis furthers our understanding of the pathogenesis of MMVD, especially in relation to the collagen. The thesis provides new findings about MMVD and demonstrates the potential of biophysical tools for studying similar conditions."

VP Client Information Sheets: Pimobendan (Vetmedin). Mark Rishniw. Vet. Info. Network. Quote: "Pimobendan is not currently recommended for use in dogs with heart disease prior to the onset of congestive heart failure. One study in dogs with early mitral valve disease suggested an increase in valve damage in the dogs given pimobendan."

Circumferential mid-ventricular intramyocardial injections of alginate hydrogel improve left ventricular
function and prevent progressive remodeling in dogs with chronic heart failure. Sabbah H.N.; Wang M.; Jiang A.; Ilsar I.; Sabbah M.S.; Helgerson S.; Peterson R.; Tarazona N.; Lee R. Circulation. 2009;120: S912. Quote: "Background: Progressive LV enlargement and increased chamber sphericity are characteristics of heart failure (HF) and are associated with increased mortality and morbidity. We tested the hypothesis that direct mid-ventricular intramyocardial injections of Alginate hydrogel implants (Algisyl-LVR, Symphony Medical, Inc.) into the free wall of the failing LV reduce LV size, restore LV shape, lower LV wall stress and improve LV function. Methods: A total of 14 dogs with coronary microembolization-induced HF (LV ejection fraction, EF<30%) were studied. Eight dogs received 7 injections of 0.25– 0.35 ml of Alginate during an open-chest procedure and 6 received saline and served as controls. The Alginate or saline injections were made ~1 to 1.5 cm apart along the circumference of the LV free wall halfway between the apex and base starting at the antero-septal groove and ending at the postero-septal groove. LV end-diastolic (ED) volume (EDV), end-systolic (ES) volume (ESV), EF, ES sphericity index (ESSI), ED wall stress (EDWS), deceleration time of early mitral inflow velocity (DT), severity of functional mitral regurgitation (MR) and slope of the ES pressure-volume (P-V) relationship (ESPVR) quantified from P-V loops recorded from conductance catheters during inferior vena caval occlusion were measured before therapy (Pre) and at 17 weeks after therapy (Post). The treatment effect ({Delta}) was calculated as the difference between Pre and Post. Results: Compared to saline control, Alginate implants significantly reduced LV EDV, ESV, EDWS and severity of MR. Alginate implants significantly increased LV EF and slope of the ESPVR indicating improved LV systolic performance. Treatment with Alginate implants also showed a safe and non-arrhythmogenic chronic profile. Conclusion: LV reconstruction using a circumferential pattern of intramyocardial Alginate hydrogel implants represents a novel approach for the treatment of chronic HF."

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2010

Cardiac troponin I as a marker for severity and prognosis of cardiac disease in dogs. S. Fonfara, J. Loureiro, S. Swift, R. James, P. Crippse and J. Dukes-McEwan. The Veterinary Journal. doi:10.1016/j.tvjl.2009.04.004. Quote: "The use of cardiac troponin I (cTnI) to assess the severity of disease and prognosis in 120 dogs presented for cardiac evaluation was analysed. cTnI concentrations were measured using a commercially available assay. Dogs were placed into three groups: group 1, cTnI 0.15 ng/mL; group 2, cTnI 0.151–1.0 ng/mL; group 3, cTnI>1.01 ng/mL. Dogs in group 1 were significantly younger (P < 0.0001) and had no or stable cardiac diseases and longest survival times, whereas those in groups 2 and 3 had severe cardiac diseases and significantly reduced survival times (P < 0.0001). Thirty dogs with initially increased cTnI concentrations had a repeat assay less than 2 months later with significant reductions in cTnI concentrations (P = 0.005). Initial cTnI concentrations could not differentiate dogs that survived in group 3 from those that did not. However, dogs that survived showed significant cTnI reductions (P = 0.015) in the repeated assay in contrast to the dogs that died (P = 0.22). It was concluded that cTnI is useful in assessing the prognosis and severity of cardiac diseases in dogs, and progression and response to treatment can be assessed by repeat sampling. cTnI concentrations >1.0 ng/mL and persistent increases in cTnI concentrations are indicators of a poor prognosis in dogs with cardiac disease."

Structural and Cellular Changes in Canine Myxomatous Mitral Valve Disease: An Image Analysis Study. Richard I. Han, Alexander Black, Geoff J. Culshaw, Anne T. French, Brendan M Corcoran. J. Heart Valve Disease. January 2010; 19(1):60-70. Quote: Myxomatous mitral valve disease (MMVD) is the single most common cardiac disease of the dog, and bears close similarities to chronic degenerative mitral valve disease in humans. However, limited quantitative data are available on cellular and morphological changes in both species. The study aim was to use an image analysis system to examine various morphological changes associated with MMVD, and in particular to measure changes in cell numbers in overtly myxomatous areas of the distal portion of the valve. Mitral valve complexes were collected from normal dogs and dogs with varying severity of myxomatous mitral valve disease (veterinary Whitney grades 1-4; a measure of disease severity and age-related disease progression in the dog). An image analysis technique (ImageJ; National Institutes of Health, USA) was used to measure valve leaflet length, thickness, connective tissue content and density, glycosaminoglycan (GAG) content, cell number and shape in normal and myxomatous areas of diseased valves. There was a change in the valve leaflet anterior/posterior length ratio in the diseased valves, suggestive of valve lengthening. Distinct and statistically significant changes occurred in the valve thickness ratio for both anterior and posterior leaflets as the disease progressed, and the posterior leaflet thickness ratios were consistently higher than for the anterior leaflets. There was a statistically significant decrease in cell numbers in overtly myxomatous areas of the distal portion of affected valves compared to similar locations in normal valves, but there was no difference between the different grades of disease. The majority of cells in both diseased and normal valves had a circularity score typical of a spindle (elongated) shape. Connective tissue derangement was clearly seen in the myxomatous areas, and this was associated with a significant reduction in connective tissue density. The reduction in connective tissue density was associated with advancing disease severity (age). There was an increase in GAG expression with disease severity, as shown by the level of Alcian blue staining, but this could not be quantified with ImageJ. Mitral valve myxomatous degeneration in the dog is associated with lengthening and thickening of valve leaflets, a loss of connective tissue, and a decrease in cell numbers in selected myxomatous areas, but no change in cell circularity. Some of these changes were age- (disease severity-) related.

Acute Feasibility Study of a Novel Device for the Treatment of Mitral Regurgitation in a Normal Canine Model. Takaseya, Tohru, Fumoto, Hideyuki, Saraiva, Roberto M., Shiose, Akira MD, Arakawa, Yoko, Park, Margaret, Rao, Santosh, Dessoffy, Raymond, Kramer, Larry D. Jr., Juravic, Mark, Lombardi, Pierluca, Fukamachi, Kiyotaka. Innovations: Technology & Techniques in Cardiothoracic & Vascular Surgery. January 2010;5(1):28-32. Quote: "Objective: The purpose of this study was to evaluate the implantability of a novel epicardial mitral annuloplasty device and its ability to reduce the septal-lateral (S-L) dimension of the mitral annulus. Methods: The devices were implanted on the beating heart in 2 healthy dogs (the 24-mm long device in dog A and the 27-mm and 24-mm standard devices in dog B) by sliding the anterior arm onto the floor of the transverse sinus and positioning the posterior arm just apical to the atrioventricular groove on the left ventricular posterolateral wall. The devices were secured with titanium helical tacks driven through the device into the ventricular wall. Two-dimensional epicardial echocardiograms were performed before and after device implantation to evaluate the degree of mitral regurgitation (MR) and the S-L dimension. Results: Device implantation was uneventful, taking only ∼30 seconds to deploy. MR (1+) in both dogs at baseline was reduced to zero after implant. The reductions in S-L dimension in systole for the 24-mm device were 7.5% in dog A and 30.5% in dog B. For the 27-mm device in dog B, S-L reduction in systole was 29.9%. The leaflet coaptation length was increased in both cases. Conclusions: The new device was effective in reducing S-L dimension and 1+ MR without requiring the use of cardiopulmonary bypass. We are currently evaluating this device for the treatment of MR in a rapid-pacing canine heart failure model."

Insights into Serotonin Signaling Mechanisms Associated with Canine Degenerative Mitral Valve Disease. M.A. Oyama and R.J. Levy. J Vet Intern Med Jan/Feb 2010;24(1):27–36. Quote: "In Cavalier King Charles Spaniels, the time from onset of a heart murmur to death because of congestive heart failure can be quite accelerated, highlighting the rapid nature of disease progression in this particular breed. ... Little is known about the molecular abnormalities associated with canine degenerative mitral valve disease (DMVD). The pathology of DMVD involves the differentiation and activation of the normally quiescent mitral valvular interstitial cell (VIC) into a more active myofibroblast phenotype, which mediates many of the histological and molecular changes in affected the valve tissue. In both humans and experimental animal models, increased serotonin (5-hydroxytryptamine, 5HT) signaling can induce VIC differentiation and myxomatous valve damage. In canine DMVD, numerous lines of evidence suggest that 5HT and related molecules such as transforming growth factor-b play a critical role in the pathogenesis of this disease. A variety of investigative techniques, including gene expression, immuno-histo-chemistry, protein blotting, and cell culture, shed light on the potential role of 5HT in the differentiation of VIC, elaboration of myxomatous extracellular matrix components, and activation of mitogen-activated protein kinase pathways. These studies help support a hypothesis that 5HT and its related pathways serve as an important stimulus in canine DMVD. This review describes the pathological characteristics of canine DMVD, the organization and role of the 5HT pathway in valve tissue, involvement of 5HT in human and experimental models of valve disease, avenues of evidence that suggest a role for 5HT in naturally occurring DMVD, and finally, a overarching hypothesis describing a potential role for 5HT in canine DMVD. ... Interestingly, activation of canine VIC could be inhibited by coincubation with either ketanserin, a 5HT-R2A receptor blocker, or GR55562, a 5HT-R1B receptor blocker, indicating that these 2 receptor types are potentially involved in 5HT-induced changes. ... Interestingly, Cavalier King Charles Spaniels, which are highly predisposed to DMVD as well as macrothrombocytosis, had significantly higher serum 5HT concentrations than did other breeds of dogs."

Cardiac Troponin I Is Associated with Severity of Myxomatous Mitral Valve Disease, Age, and C-Reactive Protein in Dogs. I. Ljungvall, K. Höglund, A. Tidholm, L.H. Olsen, M. Borgarelli, P. Venge, and J. Häggström. J Vet Intern Med, Jan/Feb 2010;24(1):153–159. Quote: "Background: Concentrations of cardiac troponin I (cTnI) and C-reactive protein (CRP) might be associated with cardiac remodeling in dogs with myxomatous mitral valve disease (MMVD). Age- and sex-dependent variations in cTnI concentration have been described. Objective: To investigate whether plasma concentrations of cTnI and CRP are associated with severity of MMVD, and investigate potential associations of dog characteristics on cTnI and CRP concentrations. Animals: Eighty-one client-owned dogs with MMVD of varying severity [including 67 Cavalier King Charles spaniels]. Methods: Dogs were prospectively recruited for the study. Dogs were classified according to severity of MMVD. Plasma cTnI was analyzed by a high sensitivity cTnI assay with a lower limit of detection of 0.001 ng/mL, and plasma CRP was analyzed by a canine-specific CRP ELISA. Results: Higher cTnI concentrations were detected in dogs with moderate (0.014 [interquartile range 0.008–0.029] ng/mL, P 5 .0011) and severe (0.043 [0.031–0.087] ng/mL, Po.0001) MMVD, compared with healthy dogs (0.001 [0.001–0.004] ng/mL). Dogs with severe MMVD also had higher cTnI concentrations than dogs with mild (0.003 [0.001–0.024] ng/mL, P o .0001) and moderate (P 5 .0019) MMVD. There were significant associations of age, CRP, heart rate, and left ventricular end-diastolic diameter, on cTnI concentration C-reactive protein did not differ among severity groups, butwas significantly associated with cTnI, breed, and systolic blood pressure on CRP concentration. Conclusions and Clinical Importance: Analysis of cTnI concentration has potential to increase knowledge of overall cardiac remodeling in dogs with MMVD. However, effect of age on cTnI needs consideration when assessing cTnI."

The potential role of MRI in veterinary clinical cardiology. Stephen H. Gilbert, Fraser J. McConnell, Arun V. Holden, Mohan U. Sivananthan, Joanna Dukes-McEwan. Vet. J. February 2010;183(2):124-134. Quote: "Over the last decade, magnetic resonance imaging (MRI) has become established as a useful referral diagnostic method in veterinary medicine that is widely used in small animal brain and spinal diseases, aural, nasal and orbital disorders, planning soft tissue surgery, oncology and small animal and equine orthopaedics. The use of MRI in these disciplines has grown due to its unparalleled capability to image soft tissue structures. This has been exploited in human cardiology where, despite the inherent difficulties in imaging a moving, contractile structure, cardiac MRI (CMRI) has become the optimal technique for the morphological assessment and quantification of ventricular function. Both CMRI hardware and software systems have developed rapidly in the last 10 years but although several preliminary veterinary CMRI studies have been reported, the technique’s growth has been limited and is currently used primarily in clinical research. A review of published studies is presented with a description of CMRI technology and the potential of CMRI is discussed along with some of the reasons for its limited usage."

Efficacy of Spironolactone on Survival in Dogs with Naturally Occurring Mitral Regurgitation Caused by Myxomatous Mitral Valve Disease. F. Bernay, J.M. Bland, J. Häggström, L. Baduel, B. Combes, A. Lopez, and V. Kaltsatos. J Vet Intern Med, Mar/Apr 2010;24(2):331-341.Quote: "Hypothesis: Spironolactone in addition to conventional therapy increases survival compared with conventional therapy in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Animals: ... 212 dogs with moderate to severe mitral regurgitation (MR) caused by MMVD (International Small Animal Cardiac Health Council classification classes II [n = 190] and III [n = 21]). Methods: Double-blinded, field study conducted with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin converting enzyme inhibitor, plus furosemide and digoxin if needed). Primary endpoint was a composite of cardiac-related death, euthanasia, or severe worsening of MR. Results: Primary endpoint reached by 11/102 dogs (10.8%) in the spironolactone group (6 deaths, 5 worsening) versus 28/110 (25.5%) in control group (14 deaths, 8 euthanasia, 6 worsening). Risk of reaching the composite endpoint significantly decreased by 55% (hazard ratio [HR] = 0.45; 95% confidence limits [CL], 0.22–0.90; log rank test, P= .017). Risk of cardiac- related death or euthanasia significantly reduced by 69% (HR = 0.31; 95% CL, 0.13–0.76; P= .0071). Number of dogs not completing the study for cardiac and other miscellaneous reasons similar in spironolactone (67/102) and control groups (66/110). Conclusion and Clinical Importance: Spironolactone added to conventional cardiac therapy decreases the risk of reaching the primary endpoint (ie, cardiac-related death, euthanasia, or severe worsening) in dogs with moderate to severe MR caused by MMVD."

Rate of change of heart size before congestive heart failure in dogs with mitral regurgitation. P. Lord, K. Hansson, C. Kvart, and J. Häggström. J Small An Prac; Apr 2010; 51(4):210-218. Quote: "Objectives: The objective of the study was to examine the changes in vertebral heart scale, and left atrial and ventricular dimensions before and at onset of congestive heart failure in cavalier King Charles spaniels with mitral regurgitation. Methods: Records and radiographs from 24 cavalier King Charles spaniels with mitral regurgitation were used. Vertebral heart scale (24 dogs), and left atrial dimension and left ventricular end diastolic and end systolic diameters (18 dogs) and their rate of increase were measured at intervals over years to the onset of congestive heart failure. They were plotted against time to onset of congestive heart failure. Results: Dimensions and rates of change of all parameters were highest at onset of congestive heart failure, the difference between observed and chance outcome being highly significant using a two-tailed chi-square test (P<0·001). Clinical significance: The left heart chambers increase in size rapidly only in the last year before the onset of congestive heart failure. Increasing left ventricular end systolic dimension is suggestive of myocardial failure before the onset of congestive heart failure. Rate of increase of heart dimensions may be a useful indicator of impending congestive heart failure."

Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual-Acting Angiotensin Receptor−Neprilysin Inhibitor (ARNi). Jessie Gu, Adele Noe, Priya Chandra, Suliman Al-Fayoumi, Monica Ligueros-Saylan, Ramesh Sarangapani, Suzanne Maahs, Gary Ksander, PhD, Dean F. Rigel, Arco Y. Jeng, Tsu-Han Lin, Weiyi Zheng, William P. Dole. J. Clinical. Pharmacology. April 2010;50(4):401-414. Quote: "Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). ... Oral administration of LCZ696 to beagle dogs (n = 3) led to a rapid increase in plasma concentrations of valsartan. The tmax for valsartan following LCZ696 dosing was 1.3 hours, whereas combined administration of valsartan (free acid) and AHU377 (calcium salt) tablets yielded a tmax for valsartan of 4.0 hours (Table I). Systemic exposure (AUC and Cmax) to valsartan following LCZ696 administration was about 3-fold higher than that observed following administration of approximately equimolar doses of valsartan and AHU377. LCZ696 or valsartan plus AHU377 delivered similar exposure to LBQ657 (Table I). All pharmacokinetic parameters were derived from 3 beagle dogs per treatment group, with the exception of valsartan AUC0-∞ in the valsartan + AHU377 group, which was determined in 2 dogs. ... Pharmacokinetic studies in beagle dogs and a dose escalation study in human participants showed a rapid rise in plasma concentrations of valsartan and AHU377 following oral administration of LCZ696. ... LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor—NEP inhibitor (ARNi) for hypertension and heart failure."

Optimisation of breeding strategies to reduce the prevalence of inherited disease in pedigree dogs. Lewis, T.W.; Woolliams, J.A.; Blott, S.C. Animal Welfare 19(Supp 1):93-98(6), May 2010. Quote: "One option for improving the welfare of purebred dog breeds is to implement health breeding programmes, which allow selection to be directed against known diseases while controlling the rate of inbreeding to a minimal level in order to maintain the long-term health of the breed. The aim of this study is to evaluate the predicted impact of selection against disease in two breeds: the Cavalier King Charles spaniel (CKCS) .... Heritabilities for mitral valve disease, syringomyelia in the CKCS ... were estimated to be 0.64 (± 0.07), 0.32 (± 0.125) ... respectively, which suggest encouraging selection responses are feasible based upon the estimation of breeding values (EBVs) if monitoring schemes are maintained for these breeds. Although using data from disease databases can introduce problems due to bias, as a result of individuals and families with disease usually being over-represented, the data presented is a step forward in providing information on risk. EBVs will allow breeders to distinguish between potential parents of high and low risk, after removing the influence of life history events. Analysis of current population structure, including numbers of dogs used for breeding, average kinship and average inbreeding provides a basis from which to compare breeding strategies. Predictions can then be made about the number of generations it will take to eradicate disease, the number of affected individuals that will be born during the course of selective breeding and the benefits that can be obtained by using optimisation to constrain inbreeding to a pre-defined sustainable rate."

Evaluation of plasma and urinary levels of 6-keto-prostaglandin F1α as a marker for asymptomatic myxomatous mitral valve disease in dogs. Rasmussen, C.E., Sundqvist, A.V., Kjempff, C.T., Tarnow, I., Kjelgaard-Hansen, M., Kamstrup, T.S., Sterup, A.L., Soerensen, T.M., Olsen, L.H. Vet. J. May 2010; 184(2):241–246. Quote: "Endothelial dysfunction might be involved in the pathogenesis of myxomatous mitral valve disease (MMVD). The aims of this study were (1) to validate an enzyme immunoassay (EIA) for canine 6-keto-prostaglandin (PG)F1α (prostacyclin metabolite and marker for endothelial function) and (2) to compare plasma and urinary 6-keto-PGF1α in dogs with asymptomatic MMVD. The study included two breeds predisposed to MMVD and two control groups (Cairn terriers and dogs of different breeds). Echocardiography was used to estimate the severity of MMVD. The intra- and inter-assay coefficients of variation were between 3.1% and 24.5% in the assay range. No echocardiographic parameter was correlated with plasma or urinary 6-keto-PGF1α (P > 0.05), but all control dogs had lower urinary 6-keto-PGF1α (P < 0.02) and the Cairn terriers had higher plasma 6-keto-PGF1α (P < 0.02). The EIA appeared valid for measuring canine 6-keto-PGF1α in plasma and urine. It is suggested that 6-keto-PGF1α levels are related to breed and not MMVD in asymptomatic stages."

Cardiac troponin I as a marker for severity and prognosis of cardiac disease in dogs. S. Fonfaraa, J. Loureiroa, S. Swifta,R. Jamesa, P. Crippse and J. Dukes-McEwan. Vet.J. June 2010; 184(3): 334-339. Quote: "The use of cardiac troponin I (cTnI) to assess the severity of disease and prognosis in 120 dogs presented for cardiac evaluation was analysed. cTnI concentrations were measured using a commercially available assay. Dogs were placed into three groups: group 1, cTnI 0.15 ng/mL; group 2, cTnI 0.151–1.0 ng/mL; group 3, cTnI>1.01 ng/mL. Dogs in group 1 were significantly younger (P < 0.0001) and had no or stable cardiac diseases and longest survival times, whereas those in groups 2 and 3 had severe cardiac diseases and significantly reduced survival times (P < 0.0001). Thirty dogs with initially increased cTnI concentrations had a repeat assay less than 2 months later with significant reductions in cTnI concentrations (P = 0.005). Initial cTnI concentrations could not differentiate dogs that survived in group 3 from those that did not. However, dogs that survived showed significant cTnI reductions (P = 0.015) in the repeated assay in contrast to the dogs that died (P = 0.22). It was concluded that cTnI is useful in assessing the prognosis and severity of cardiac diseases in dogs, and progression and response to treatment can be assessed by repeat sampling. cTnI concentrations >1.0 ng/mL and persistent increases in cTnI concentrations are indicators of a poor prognosis in dogs with cardiac disease."

Thromboelastography in Dogs with Asymptomaticmyxomatous Mitral Valve Disease. I Tarnow, LH Olsen, SG Moesgaard, AU Martinsen, AC Birkegaard, AT Kristensen, B Wiinberg. J Vet Intern Med 2010;24:--- (ACVIM 28th Ann. Vet. Med. Forum Abstract Program: Abstract 11). Quote: "Changes in platelet aggregation responses and von Willebrand factor multimer levels have been reported in dogs with asymptomatic heart disease. Alterations in hemostatic pathways may be involved in the progression of canine mitral valve disease by causing microthrombosis and vessel changes in the myocardium, and it is being debated whether dogs with heart disease could benefit from antithrombotic therapy. We hypothesized that a global hypercoagulability is present in dogs with asymptomatic mitral valve disease. The study investigated Kaolin and Tissue Factor activated thromboelastographic (TEG) tracings in 3 groups of dogs: 11 Cavalier King Charles Spaniels (CKCS) with no or minimal mitral regurgitation (MR) (age 5.0 1.8 years), 14 CKCS with severe MR (regurgitant jet size by echocardio-graphy 50%) (age 7.1 1.6 years), and 8 healthy Beagles with no or minimal MR (age 7.7 2.3 years). ... These data do not support the hypothesis that a global hypercoagulability is present in CKCS with asymptomatic myxomatous mitral valve disease. Moreover, prospective longitudinal trials are needed to demonstrate a benefit of anti-thrombotic therapy in dogs with asymptomatic heart disease. The data supports previous findings that CKCS with macrothrombocytopenia have a normal coagulation response despite low platelet counts."

To Give or Not to Give... Ace Inhibitors. Hervé P. Lefebvre 2010 WSAVA Congress.   Quote: "Adverse effects of ACE inhibitors are rare. Renal safety of ACE inhibitors was an early concern, but their impact on renal function in adult normohydrated animals is minimal. The risk of hyperkalemia is very limited. ACE inhibitors are contraindicated in pregnant animals and neonates, as renal RAAS indeed plays a pivotal role in nephrogenesis and renal development. Although ACE inhibitors are mildly hypotensive agents in dogs and cats, they are contraindicated in animals with pre-existing hypotension, hypovolemia, hyponatremia and acute renal failure. Drug interactions mentioned in the literature include potential adverse effects of dual therapy with NSAIDs and ACEI. This interaction is clinically relevant as osteoarthritis and CKD can occur concomitantly in the same patient. COX inhibition induces a vasoconstriction of the afferent arteriole while ACE inhibitors, by blocking angiotensin II synthesis, induce vasodilation of the efferent arteriole. The drop in glomerular capillary pressure may lead to a decrease in GFR, and consequently to acute renal failure. Nevertheless, the contraindication for use of NSAIDs in a patient treated with ACE inhibitor is only relative in IRIS stage II and III, but a very careful monitoring of renal function is recommended when such a dual therapy is initiated."

Proposal For a New Simple Echo Index Predicting Congestive Heart Failure (CHF) in Mitral Valve Disease (MVD). Gerard Le Bobinnec. 2010 WSAVA Congress.   Quote: "MVD has a very variable progression, and there is a question still unsolved: when must we start the treatment? For it's now well demonstrated that if ACE inhibitors improve clinical status and prolong longevity in dogs with symptomatic MVD, unfortunately they have no preventive effect in asymptomatic stages; 3 successive publications demonstrated it now unquestionably: Kvart, SVEP trial 2002; Atkins, VETPROOF, 2007; Pouchelon, JVIM, 2008. Therefore, we evidently need a 'key' to predict the risk and time to onset of CHF, just to permit a precocious intervention and then to really improve outcome. Many attempts were published, not really convincing, except one of the latest (Reynolds, ACVIM, 2008) using Left Atrium and Aorta ratio ( LA/Ao) and serum NT-proBNP: 45% probability of CHF when LA/Ao = 1,8 & NT-proBNP = 1086 ; 100% probability of CHF when LA/ Ao = 2,8 & NT-proBNP = 2192. Two shortcomings in this statistical model: 1) It provides a probability, but not a threshold. 2) Serum NT-proBNP dosage is not yet a routine one, immediately accessible to all practitioners. A few years ago (ICVS, Paris, 2004), we underlined the interest of the Left Ventricular Internal Diameter in diastole (LVd) calculated on a standard transventricular M-mode as an interesting measurement correlated with many other parameters: murmur, class of CHF, LA/Ao (Häggström, JVIM, 1995), prognosis and mortality prediction (Moonarmat, JSAP, 2010). But because raw measurement are not available between dogs, we were very interested with the M-mode echographic ratio indices published by Brown et al (JVIM, 2003), and particularly with the LVd/Ao ratio: in normal dog, LVd/Ao = 1,6 +/- 0,2 , that means LV dilation starts over 1,8 (and then NT-proBNP secretion too). Because La/Ao and LVd/Ao separately failed to discriminate asymptomatic and symptomatic MVD (classes 1a-1b from classes 2-3a), despite a good linear correlation of these 2 indexes with CHF classes, our idea was to add the 2 indexes: we realised it on 397 dogs with MVD, and the results seem to be promising: Left Chambers on Aorta ratio (LC/Ao) = LA/Ao + LVd/Ao = in Class 1a: 3,12; Class1b: 4,01; Class 2: 4,59; Class 3a: 5,04 (see tables for details). It means that if you have an asymptomatic MVD with a LC/Ao > 4,5, you may immediately start treatment with ACE inhibitors, Pimobendan, or even Spironolactone more usefully than with a blind approach."

Beneficial effects of Omega 3 fatty acids in cardiovascular disease. Freeman LM. J Small Anim Pract July 2010;51(9):462-470. Quote: There is a large body of evidence supporting beneficial effects of omega-3 fatty acids for both primary and secondary prevention of cardiac disease in people. However, evidence is increasing for the use of omega-3 fatty acids in dogs with cardiac disease as well. Omega-3 fatty acids’ anti-inflammatory and anti-arrhythmic effects may be beneficial in managing the loss of lean body mass and arrhythmias that are common in heart failure. However, omega-3 fatty acids also may have positive effects on myocardial energy metabolism, endothelial function, heart rate and blood pressure, and immune function. Additional research is needed to determine optimal indications, doses and formulations for dogs and cats with cardiac disease.

Clinical Efficacy of Sildenafil in Treatment of Pulmonary Arterial Hypertension in Dogs. A.J. Brown, E. Davison, M.M. Sleeper. J.Vet.Intern.Med. July 2010; 24(4):850-854. Quote: "Background: Pulmonary arterial hypertension (PAH) in dogs carries a poor prognosis. Sildenafil increases exercise capacity and improves hemodynamics in people with PAH. Hypothesis/Objectives: Dogs receiving sildenafil will have lower pulmonary arterial pressure, increased exercise capacity, and better quality of life (QOL) than dogs receiving placebo. Animals: Thirteen dogs with echocardiographic evidence of PAH. Methods: Prospective short-term, randomized, placebo controlled, double-blind, crossover study. Dogs with PAH were randomly allocated to receive sildenafil or placebo for 4 weeks, followed by the alternative treatment for 4 weeks. Results: Dogs receiving sildenafil had a significantly lower estimated pulmonary arterial pressure (median, 56 mmHg; range, 34–83 mmHg) than at baseline (median, 72 mmHg; range, 61–86 mmHg; P= .018), but not significantly lower than those receiving placebo (median, 62 mmHg; range, 49–197 mmHg). Exercise capacity was significantly greater in dogs receiving sildenafil than those receiving placebo (mean activity count per minute: 101 ± 47 versus 74 ± 32; P= .05). QOL scores were significantly higher in dogs receiving sildenafil than dogs receiving placebo. Conclusions and Clinical Importance: Sildenafil decreases systolic pulmonary arterial pressure from baseline in dogs with PAH and is associated with increased exercise capacity and QOL when compared to treatment with placebo."

Canine Degenerative Myxomatous Mitral Valve Disease: Natural History, Clinical Presentation and Therapy. Michele Borgarelli, Jens Häggström. Vet. Clinics of No. America: Sm. An. Prac.; July 2010; 40(4)651-663. Quote: "Myxomatous mitral valve disease is a common condition in geriatric dogs. ... The prevalence of the disease has been correlated with the age and the breed. In some breeds, such as the cavalier King Charles spaniel, the prevalence of the disease in animals older than 10 years is greater than 90%. Males are also reported to develop the disease at a younger age than females, which means that the prevalence at a given age is higher in males than in females. ... Most dogs affected are clinically asymptomatic for a long time. However, about 30% of these animals present a progression to heart failure and eventually die as a consequence of the disease. Left atrial enlargement, and particularly a change in left atrial size, seems to be the most reliable predictor of progression in some studies, however further studies are needed to clarify how to recognize asymptomatic patients at higher risk of developing heart failure. According to the published data on the natural history of the disease and the results of published studies evaluating the effect of early therapy on delaying the progression of the disease, it seems that no currently available treatment delays the onset of clinical signs of congestive heart failure (CHF). Although the ideal treatment of more severely affected dogs is probably surgical mitral valve repair or mitral valve replacement, this is not a currently available option. The results of several clinical trials together with clinical experience suggest that dogs with overt CHF can be managed with acceptable quality of life for a relatively long time period with medical treatment including furosemide, an angiotensin-converting enzyme inhibitor, pimobendan, and spironolactone."

Genetics of Cardiac Disease in the Small Animal Patient. Kathryn M. Meurs. Vet. Clinics of No. America: Sm. An. Prac.; July 2010; 40(4)701-715. Quote: "There is increasing evidence that many forms of congenital and acquired cardiovascular disease in small animal patients are of familial origin. The large number of familial diseases in domestic purebred animals is thought to be associated with the desire to breed related animals to maintain a specific appearance and the selection of animals from a small group of popular founders (founder effect). Clinicians can use knowledge that a particular trait or disease may be inherited to provide guidance to owners and animal breeders to reduce the frequency of the trait. Even if the molecular cause is not known, identification of a pattern of inheritance and information on clinical screening can be useful for a breeder trying to make breeding decisions. Common forms of inheritance for veterinary diseases include autosomal recessive, autosomal dominant, X-linked recessive, and polygenic. These genetic traits and their possible involvement in cardiac disease in small animals are discussed in this article."

Associations between cardiac pathology and clinical, echocardiographic and electrocardiographic findings in dogs with chronic congestive heart failure. Torkel Falk, Lennart Jönsson, Lisbeth H. Olsen, Inge Tarnow, and Henrik D. Pedersen. Vet. J. July 2010; 185(1)68-74. Quote: "The objective of this study was to correlate defined pathological features with clinical findings in dogs with naturally occurring congestive heart failure (CHF). Fifty-eight dogs with CHF were examined clinically and using echocardiography and electrocardiography. Detailed cardiac post-mortem examination was used to assess intra-myocardial arterial narrowing, myocardial fibrosis and atrophy and myxomatous mitral valve degeneration (MMVD). Arterial narrowing significantly correlated with fibrosis (P < 0.0001) and with fractional shortening, an indicator of systolic function (P = 0.002). The grade of fibrosis was associated with shorter survival time (P = 0.002), and the papillary muscle fibrosis score tended to correlate with proximal isovelocity surface area radius (P = 0.03). Data from this study lend support to the hypothesis that naturally occurring canine CHF is affected by several factors such as MMVD, myocardial atrophy and fibrosis, and by arteriosclerosis. Further, more extensive research will be required to establish cause–effect relationships between these cardiac lesions and the pathophysiology of CHF in dogs."

Acquired atrial septal defects secondary to rupture of the atrial septum in dogs with degenerative mitral valve disease. Gordon D. Peddle, James W. Buchanan. J. Vet. Cardiol. August 2010;12(2):129-134. Quote: Acquired atrial septal defects (ASDs) secondary to atrial septal rupture are uncommon in dogs with degenerative mitral valve disease. Echocardiographic diagnosis of these defects has not previously been described. The echocardiographic features in two cases identified antemortem are presented in this report. ... Dog 1: A 5.3 kg, 11.5-year-old spayed female CavalierKing Charles Spaniel was referred to our hospitalfor acute abdominal distension. The dog had presented to the local veterinarian for coughing two months prior and had a 1 year history of a leftapical systolic heart murmur. Cardiovascular examination findings included tachycardia (HR:150 bpm), grade V/VI left apical systolic murmur, jugular vein pulsation, split second heart sound, abdominal fluid wave, and cachexia. Thoracic radiographs indicated enlargement of the left ventricle, left atrium, right ventricle [vertebral heart size (vertebra = v): 15.6v (reference range: 8.7 - 10.7v)], caudal vena cava and pulmonaryveins, compression of mainstem bronchi, hepatomegaly,and decreased abdominal detail. A heartworm antigen test was negative. ... ASDs can be difficult to identify on two-dimensional echocardiogram when relatively small in size and may be under-reported. ... The etiology of spontaneous endocardial splitting in dogs remains unclear but is likely multifactorial, related to increased left atrial volume and pressure and mechanical trauma to the endocardium induced by the regurgitant jet. Endocardial splitting may be preceded by rupture of mitral valve chordae tendinae and genetically influenced variations in endocardial tissue may predispose certain dog breeds to endocardial degeneration and splitting. ... Acquired ASDs may alter the physiology, treatment plan and prognostic implications for the dogs in which they occur, and their presence should be considered in all cases of degenerative mitral valve disease that develop signs of right-sided heart failure.

Acute left ventricular reconstruction with circumferential mid-ventricular intramyocardial injections of alginate hydrogel in dogs with chronic heart failure. Ilsar I.; Wang M.; Sabbah M.S.; Gupta R.C.; Rastogi S.; Helgerson S.; Tarazona N.; Lee R.J.; Sabbah H.N. J. Cardiac Failure. August 2010;16(8):S42-43. Quote: "Background: LV chamber dilation and sphericity are features of heart failure (HF) associated with increased mortality and morbidity. Surgical LV reconstruction and passive LV containment are approaches that address this maladaptive geometry. We examined the acute effects of a novel approach for improving LV function and geometry in dogs with HF, namely injections of Alginate hydrogel implants (AHIs) (Algisyl-LVR) into the LV free wall. Methods: 12 microembolization-induced HF dogs (LV ejection fraction, EF<30%) were studied; 6 received 7 injections of 0.25-0.35 ml of AHI during open-chest procedure and 6 received saline (Sham Controls). Injections were made 1 to 1.5 cm apart along an LV wall circumference from the anteroseptal to the posteroseptal groove halfway between the apex and base. LV end-diastolic (ED) volume (EDV), end-systolic (ES) volume (ESV), EF, ES sphericity index (ESSI), ES thicknesses of the anterior (AWT) and posterior (PWT) LV wall, and slopes of the ES and ED pressure-volume relationships (PVR) quantified from pressure-volume loops, were measured before (Pre) and 3 hours after therapy. Results:  Compared to controls, AHI reduced both EDV and ESV and increased EF, ESSI, mid-ventricular AWT and PWT."

Molecular changes in fibrillar collagen in myxomatous mitral valve disease. Mojtaba Hadian, Brendan M. Corcoran, and Jeremy P. Bradshaw. Cardiovascular Pathology, Sep. 2010; 19(5):e141-e148. Quote: "Introduction: Myxomatous mitral valve disease (MMVD) is the single most common acquired cardiac disease of dogs and is a disease of significant veterinary importance. It also bears close similarities to mitral valve prolapse in humans and therefore is a disease of emerging comparative interest. We have previously mapped the structure of collagen fibrils in valve leaflets using synchrotron X-rays and have demonstrated changes in collagen structure associated with the regions of disease. Methods: Differential scanning calorimetry (DSC), biochemical assay of collagen content, high-performance liquid chromatography (HPLC), and neutron diffraction were combined with further analysis of our previous X-ray data to elucidate molecular changes in fibrillar collagen in mild to moderately affected MMVD dogs. Results: Comparing diseases and adjacent grossly uninvolved areas in the same leaflets, there was a 20% reduction in collagen fibrils, but only a 10% depletion of collagen content. The enthalpy of collagen denaturation was reduced in affected areas. Chromatography showed a 25% decrease in mature nonreducible covalent cross-links in the affected samples, and neutron diffraction data showed fewer reducible immature covalent cross-links in grossly uninvolved tissue samples. Conclusions: Mild to moderate MMVD in the dog is associated with a marginal decline in collagen content in overtly diseased areas of valves, but more importantly is associated with an increase in immature collagen content. These changes will contribute to the mechanical dysfunction of the leaflet, and this study provides important information on the structure–mechanical alterations associated with this disease. The data suggests MMVD involves a dyscollagenesis process in the development of valve pathology."

Evaluation of the Swedish breeding program for cavalier King Charles spaniels. Tobias Lundin, Clarence Kvart. Acta Veterinaria Scandinavica, Sept. 2010, 52:54. Quote: "The Swedish Kennel club and the Special club for cavalier King Charles spaniels (SCKCS) started a breeding program in 2001 with the aim of reducing MMVD in the Swedish population of CKCS. In this program, dogs are not allowed to breed until four years of age and need a heart auscultation without murmurs within eight months before mating. However, dogs are allowed to breed at an age of 24 months, if the dog and its parents are examined and no murmurs are detected. Male dogs that have a heart auscultation at seven years of age without murmurs are allowed to breed without further heart evaluation. Breeding animals whose parents have heart murmurs before four years of age are not allowed to breed. The aim of this investigation was to study the prevalence of heart murmurs in the Swedish population of six-year-old CKCS born 2001 and 2003, and to estimate if prevalence has decreased since the breeding program was introduced 2001. ... In this investigation 353 CKCS were selected as a sample of the population and 150 were examined by auscultation for heart murmurs when they reached the age of six years in 2007 and 2009. ... The effect of the breeding program was evaluated by comparing the prevalence of heart murmurs in the two groups. In 2007, the prevalence of heart murmurs was 52% (50% for females and 54% for males) and in 2009, the prevalence was 55% (44% for females and 67% for males). No significant difference was found in the prevalence of heart murmurs between 2007 and 2009 (P=0.8). For all six-year-old CKCS, the prevalence of heart murmur was 53% (females 46% and males 61%), which is higher than previous Swedish investigations. ... The result from this investigation indicates that the prevalence of MMVD in six-year-old cavalier King Charles spaniels, born 2001 and 2003, is at least 50% and lacks signs of decrease despite the current breeding program introduced in Sweden 2001."

Open Heart Surgery with Deep Hypothermia and Cardiopulmonary Bypass in Small and Toy Dogs. Isamu Kanemoto, Daisuke Taguchi, Satoko Yokoyama, Masashi Mizuno, Hiromi Suzuki, and Tougaku Kanamoto. Vet. Surgery 2010; 39:674–679. Quote: "Objective: To evaluate open heart surgery with deep surface-induced hypothermia (sHT) and low-flow cardiopulmonary bypass (CPB) in small and toybreed dogs. Animals: Small breed dogs (n=8) weighing o5.5 kg with naturally occurring cardiac disease. [None were Cavaliers.] ... Conclusion: Deep sHT with low-flow rate CPB may be used for open heart surgery in small dogs weighing o5.5 kg. Clinical Relevance: Open heart surgery for selected congenital defects and acquired defects in small and toy-breed dogs may be successfully performed using deep sHT and CPB."

Lack of efficacy of low-dose spironolactone as adjunct treatment to conventional congestive heart failure treatment in dogs. Schuller, S., Van Israël, N., Vanbelle, S., Clercx, C., McEntee, K. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2010.01235.x.

Breed Predispositions to Disease in Dogs & Cats (2d Ed.). Alex Gough, Alison Thomas. 2010; Wiley-Blackwell Publ. 51.

Myxomatous Degenerative Mitral Valve Disease: An Update. Sirilak Disatian. Thai J. Vet. Med. 2010 40(2): 151-157. Quote: "This article was written to summarize an update of canine MVD concerning clinical approach, etiology, and treatment. ... canine MVD is the number one acquired heart disease in dogs. Although MVD is a common disease easily found in veterinary hospitals, its etiology is still unknown. To date, treatments goals have been to correct circulatory disturbances secondary to mitral valve regurgitation, improve quality of life and prolong survival time. A better understanding in the pathogenesis of valve degeneration will guide a treatment protocol to treat the actual lesions as well as to prevent the degenerative progression rather than to control resultant circulatory disturbances which may help MVD dogs to have a better quality of life with a longer time before developing heart failure or death."

Letter to Editor Re: Efficacy of Spironolactone on Survival in Dogs with Naturally Occurring Mitral Regurgitation Caused by Myxomatous Mitral Valve Disease. M.D. Kittleson, J.D. Bonagura. J. Vet. Intern. Med. November 2010;24(6):1245-1246. Quote: "Thus, we respectfully dispute that a survival benefit of spironolactone in canine MR is proven. Our arguments are centered on (1) patient categorization, (2) definition of HF, (3) heterogeneity of MR severity and HF within groups, and (4) the low event rates relative to the high number of case withdrawals. We are uncertain which dogs if any did benefit from spironolactone. Thus, regardless of the current EU regulatory approval, we consider use of spironolactone in MR empirical. We also plead for better collaboration between pharmaceutical companies and independent investigators at every stage of clinical trials. We believe this should be a focus for regulatory agencies and our scientific journals. While we would be happy to be corrected—that spironolactone greatly improves outcomes in dogs with HF due to MR—we believe that conclusion would require a different study."

Detection of Congestive Heart Failure in Dogs by Doppler Echocardiography. K.E. Schober, T.M. Hart, J.A. Stern, X. Li, V.F. Samii, L.J. Zekas, B.A. Scansen, and J.D. Bonagura. J Vet Intern Med. November 2010;24(6):1358–1368. Quote: "Background: Echocardiographic prediction of congestive heart failure (CHF) in dogs has not been prospectively evaluated. Hypothesis: CHF can be predicted by Doppler echocardiographic (DE) variables of left ventricular (LV) filling in dogs with degenerative mitral valve disease (MVD) and dilated cardiomyopathy (DCM). Animals: Sixty-three client-owned dogs. Methods: Prospective clinical cohort study. Physical examination, thoracic radiography, analysis of natriuretic peptides, and transthoracic echocardiography were performed. Diagnosis of CHF was based upon clinical and radiographic findings. Presence or absence of CHF was predicted using receiver-operating characteristic (ROC) curve, multivariate logistic and stepwise regression, and best subsets analyses. Results: Presence of CHF secondary to MVD or DCM could best be predicted by E: isovolumic relaxation time (IVRT) (area under the ROC curve [AUC]50.97, P o .001), respiration rate (AUC50.94, P o .001), Diastolic Functional Class (AUC50.93, P o .001), and a combination of Diastolic Functional Class, IVRT, and respiration rate (R250.80, P o .001) or Diastolic Functional Class (AUC51.00, P o .001), respiration rate (AUC51.00, P o .001), and E: IVRT (AUC50.99, P o .001), and a combination of Diastolic Functional Class and E: IVRT (R250.94, P o .001), respectively, whereas other variables including N-terminal pro-brain natriuretic peptide, E: Ea, and E: Vp were less useful. Conclusion and Clinical Importance: Various DE variables can be used to predict CHF in dogs with MVD and DCM. Determination of the clinical benefit of such variables in initiating, modulating, and assessing success of treatments for CHF needs further study."

The Cardiac Biomarker Sodium-Calcium Exchanger (NCX-1) Can Differentiate between Heart Failure and Renal Failure: A Comparative Study of NCX-1 Expression in Dogs with Chronic Mitral Valvular Insufficiency and Azotemia. S.-J. Nam, S.-H. Han, H.-W. Kim, C. Hyun. J.Vet.Int.Med. Nov/Dec 2010;24(6):1383-1387. Quote: "The sodium-calcium exchanger (NCX-1), an established cardiac biomarker, was postulated previously as differentiating between heart failure (HF) and renal failure (RF) in dogs. The effect of azotemia on NCX-1 expression has not been studied. In contrast to other cardiac biomarkers (eg, N-terminal-proBNP), we hypothesized that the expression level of NCX-1 is not influenced by either azotemia or decreased renal clearance. Fifteen client-owned healthy control dogs, 14 dogs with chronic mitral valvular insufficiency (CMVI), classified based on severity of the disease by the established International Small Animal Cardiac Health Council classification system, and 15 dogs with RF, grouped according to the International Renal Interest Society stage classification. A comparative study of the expression levels of NCX-1, evaluated in peripheral blood samples from dogs with HF, RF, and healthy controls by quantitative PCR. NCX-1 expression was significantly increased in moderate (2.99 ± 0.61 [fold changes relative to normal group]) to severe (4.35 ± 1.44) CMVI dogs (P < .01). In contrast, NCX-1 expression was not increased in the azotemic dogs. Furthermore, there was also no correlation between increased concentrations of creatinine and urea nitrogen in serum and NCX-1 expression in the RF group. Azotemia likely does not affect NCX-1 expression."

Pulmonary Blood Volume in Mitral Regurgitation in Cavalier King Charles Spaniels. A. Eriksson, K. Hansson, J. Häggström, A.-K. Järvinen, P. Lord. J.Vet.Int.Med. Nov/Dec 2010;24(6):1393-1399. Quote: "Pulmonary edema and venous congestion are well-recognized signs of congestive heart failure (CHF) in advanced canine chronic mitral regurgitation (MR). However, little is known about pulmonary blood volume (PBV), blood pulmonary transit time (PTT), and the regulation of these. Objectives: To measure and evaluate the relationships of PBV, forward stroke volume (FSV), and heart rate normalized blood pulmonary transit time (nPTT) in healthy dogs and dogs with MR. ... 33 Cavalier King Charles Spaniels; 11 healthy, 4 in modified New York Heart Association (NYHA) class I, 11 in class II, and 7 in CHF were studied. ... Increased PBV, not decreased FSV, is the main cause of increased nPTT in MR. Increased nPTT can be used as an indicator of abnormal cardiopulmonary function in dogs with MR."

Serotonin transmembrane transporter is down-regulated in late-stage canine degenerative mitral valve disease. Sarah M. Scruggs, Sirilak Disatian, E. Christopher Orton. J. Vet. Cardiology. Dec. 2010;12(3):163-169. Quote: "Objective: To compare expression of the serotonin transmembrane transporter (SERT) in normal, early-stage degenerative, and late-stage degenerative canine mitral valve disease. Animals: 24 post-mortem canine mitral valves. Methods: SERT expression was determined in canine normal (n = 8), early-stage degenerative (n = 8), and late-stage degenerative (n = 8) mitral valves by immunohistochemistry (IHC) and immunoblot (IB) analyses. Results: SERT was expressed in valve interstitial cells of all layers of normal and early-stage degenerative mitral valves based on IHC. SERT was markedly down-regulated in valve interstitial cells, but not valve endothelial cells, of late-stage degenerative mitral valves. SERT expression was significantly decreased in late-stage compared to normal and early-stage degenerative mitral valves based on IB analysis (P < 0.05). Conclusions: Down-regulation of SERT expression occurs in valve interstitial cells of late-stage, but not early-stage, canine degenerative mitral valves. Down-regulation of SERT could enhance the recently speculated role of serotonin in canine DMVD by decreasing serotonin metabolism and increasing interaction with its receptor. Down-regulation of SERT likely does not play an initiating role in canine DMVD since it does not occur in early-stage disease."

 Novel epicardial off-pump device for mitral regurgitation: acute evaluation. Takaseya T, Shiose A, Saraiva RM, Fumoto H, Arakawa Y, Juravic M, Lombardi P, Fukamachi K. Eur. J. Cardiothorac Surgery. December 2010;37(6):1291-1296. Quote: "Objective: This study evaluates the ability of a novel epicardial annuloplasty device Mitral Touch (MAQUET Cardiovascular LLC, San Jose, CA, USA) to reduce functional mitral regurgitation (MR) in a rapid ventricular pacing-induced dilated cardiomyopathy model in dogs. Methods: A median sternotomy was performed in 13 dogs after MR induction by rapid ventricular pacing (230 beats/min for an average of 35.6 + or - 12.8 days). Two-dimensional epicardial echocardiographic and haemodynamic measurements were performed to evaluate the baseline MR grade, the septal-lateral (S-L) dimension of the mitral annulus, mitral valve (MV) geometry and left ventricular function. The Mitral Touch was implanted by sliding the anterior arm onto the floor of the transverse sinus and positioning the posterior arm just apical to the atrioventricular groove on the left ventricular posterolateral wall. The 24-mm-long device was implanted in eight dogs, the 27-mm-long device in four and the 30-mm standard length device in one. MR grade, S-L dimension and haemodynamics data acquisition were immediately rechecked after device implantation. Results: All implantations, which took only approximately 30s to deploy, were performed on beating hearts without cardiopulmonary bypass. In one early case, after extended manipulation with undersized devices, an atrial laceration was created and bleeding occurred. Design changes were made to eliminate this complication. The MR grade was significantly (p=0.003) reduced from 3.1 + or - 1.1 at baseline to 1.4 + or - 0.8 after device implantation. The S-L dimension at end of systole was also significantly (p=0.001) reduced from 2.7 + or - 0.4 cm at baseline to 2.3 + or - 0.3 cm after device implantation (% reduction: 15.1 + or - 10.6%). The mitral valve coaptation length was significantly (p=0.0001) increased from 0.36 + or - 0.11 cm to 0.50 + or - 0.08 cm, and the mitral valve tethering area was significantly (p=0.0003) decreased from 1.36 + or - 0.38 cm(2) to 0.81 + or - 0.29 cm(2) after Mitral Touch implantation. Conclusions: This new epicardial device was effective in significantly reducing MR and S-L dimensions acutely on the beating heart without requiring the use of cardiopulmonary bypass. Further studies are necessary to confirm the long-term maintenance of MR and S-L reductions."

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2011

Pharmacokinetics of nicorandil in dogs with mild mitral regurgitation. K. Fukunaga, Y. Fujii, N. Chiba, A. Ueshima, Y. Wakao, K. Mishima, M. Fujiwara, K. Orito. Research in Vet. Sci. January 2011;90:95-98. Quote: The aim of this study was to examine the pharmacokinetics of nicorandil, a hybrid of an adenosine triphosphate-sensitive potassium channel opener and a nitrate, and to estimate its clinical doses in dogs with mild mitral valve regurgitation (MR). Nicorandil (0.1, 0.3, and 1.0 mg/kg) was administered orally to normal dogs and those with experimentally-induced MR, and its plasma concentrations were analyzed using high-performance liquid chromatography. Plasma concentrations increased dose-dependently after the administration of nicorandil, and were not different between normal dogs and those with MR. Similar to the effective plasma values obtained in cardiac disease in humans, the findings of this pharmacokinetic study may indicate that a dose of 0.3–1.0 mg/kg has the same effectiveness in dogs with cardiac dysfunction.

Feverfew (Tanacetum parthenium L.): A systematic review. Anil Pareek, Manish Suthar, Garvendra S. Rathore, Vijay Bansal. Pharmacognosy Rev. January 2011;5(9):103-110. Quote: "Feverfew (Tanacetum parthenium L.) (Asteraceae) is a medicinal plant traditionally used for the treatment of fevers, migraine headaches, rheumatoid arthritis, stomach aches, toothaches, insect bites, infertility, and problems with menstruation and labor during childbirth. The feverfew herb has a long history of use in traditional and folk medicine, especially among Greek and early European herbalists. Feverfew has also been used for psoriasis, allergies, asthma, tinnitus, dizziness, nausea, and vomiting. The plant contains a large number of natural products, but the active principles probably include one or more of the sesquiterpene lactones known to be present, including parthenolide. Other potentially active constituents include flavonoid glycosides and pinenes. It has multiple pharmacologic properties, such as anticancer, anti-inflammatory, cardiotonic, antispasmodic, an emmenagogue, and as an enema for worms. In this review, we have explored the various dimensions of the feverfew plant and compiled its vast pharmacologic applications to comprehend and synthesize the subject of its potential image of multipurpose medicinal agent. The plant is widely cultivated to large regions of the world and its importance as a medicinal plant is growing substantially with increasing and stronger reports in support of its multifarious therapeutic uses. ... Researchers have demonstrated that parthenolide noncompetitively inhibited serotonin (5-HT)-mediated spasmogenic response of indirect-acting 5-HT agonists in isolated rat stomach fundus preparation. Parthenolide noncompetitively antagonized the contractions elicited by the serotonergic drugs fenfluramine and dextroamphetamine on the fundal tissue. The mechanism of action associated with parthenolide does not involve the inhibition of 5-HT2 receptors directly, but rather occurs at the level of 5-HT stored in vesicles of the intramural neurons of fundal tissue. Effects on platelets: Extracts of feverfew inhibit platelet 5-HT secretion via neutralization of sulfhydryl groups inside or outside the cell. The sesquiterpenes in feverfew contain the alpha-methylenebutyrolactone unit capable of reacting with sulfhydryl groups. Feverfew extracts are not only potent inhibitors of serotonin release from platelets but also of polymorphonuclear leukocyte granules, providing a possible connection between the claimed benefit of feverfew in migraines and arthritis. ... Ten patients who had taken extracts of the plant for up to 8 years to control migraine headaches were evaluated for physiologic changes that may have been related to the plant. The platelets of all the treated patients aggregated characteristically to ADP and thrombin similarly to those of control patients. However, aggregation in response to serotonin was greatly attenuated in the feverfew users."

A sugar for congestive heart failure patients. Linda M. Shecterle, Susan Wagner, John A. St Cyr. Ther. Adv. Cardiovasc. Dis. February 2011; doi: 10.1177/1753944711398266. Quote: D-ribose, a natural occurring pentose carbohydrate has shown great promise. D-ribose is important in many cellular processes, a key component in the energy molecule, ATP, and plays an important role genetically in both RNA and DNA synthesis. More recently, there has been interest in further delineating the cellular role of poly(ADP-ribose) in cardiovascular diseases, such as myocardial infarction and ischemic reperfusion injury. Multiple preclinical animal studies have demonstrated that supplementation of D-ribose following myocardial ischemia enhanced the regeneration of ATP, and unlike the lengthy energy recovery time previously reported, D-ribose substantially shortened this interval. Biochemically, supplemental D-ribose bypasses rate-limiting enzymatic steps in the pentose phosphate pathway and enhances the production of ATP molecules. Clinically, similar benefits have been observed. Pliml and colleagues found benefits with oral supplementation of D-ribose in patients with stable ischemic coronary artery disease by exercising longer without developing angina or developing significant electrocardiographic changes. Omran and colleagues reported in a randomized controlled study that the daily use of D-ribose in CHF improved diastolic function, as well as quality of life and physical function parameters. Vijay and colleagues found improvements in ventilatory efficiency parameters in CHF patients with D-ribose. Furthermore, Sinatra has advocated metabolic support with D-ribose, L-carnitine and coenzyme Q10 as a therapeutic strategy in CHF treatments. D-ribose, a natural sugar, can enhance the repletion of cellular energy and aid in functional recovery for patients with ischemic cardiovascular diseases, including CHF [congestive heart failure]. Important to this discussion, Baliga and Young emphasized the relationship between a metabolic deficiency and resultant diastolic dysfunction, stating that “modulating myocardial energetics could emerge as an important strategy to improve outcomes in diastolic heart failure; the future could very well be in ‘revving-up’ diastole” [Baliga and Young, 2008]. The altered energy state in CHF should direct future therapeutic efforts at replenishing this energy deficiency. Previous published studies have reported the enhancing energy benefits of D-ribose; however, future multicenter studies with D-ribose should be performed to substantiate these initial findings.

Evaluation of pimobendan in dogs with cardiomegaly caused by preclinical mitral valve disease. Adrian Boswood, Sarah Smith, Mark Patteson. Vet Rec; Feb. 2011;168:222. Quote: "We wish to announce the launch of a new study called EPIC (Evaluation of Pimobendan In dogs with Cardiomegaly caused by preclinical mitral valve disease [MVD]). EPIC is a global, randomised, double-blinded, parallel group, placebo-controlled study conducted within Good Clinical Practice guidelines. The study has been designed to assess whether using pimobendan in the preclinical phase of MVD extends the time to the onset of clinical signs of congestive heart failure. Colleagues will be aware that pimobendan is already licensed, and widely used, for the treatment of congestive heart failure attributable to both valvular insufficiency and dilated cardiomyopathy."

The Effect of Furosemide on Left Atrial Pressure in Dogs with Mitral Valve Regurgitation. S. Suzuki, T. Ishikawa, L. Hamabe, D. Aytemiz, H. Huai-Che, R. Fukushima, N. Machida, R. Tanaka. JVIM; Mar/Apr 2011;25(2):244–250. The effects of furosemide on left atrial pressure (LAP) in dogs with mitral regurgitation (MR) have not been documented in a quantitative manner and between different routes of administration. Objective: To document LAP and echocardiographic parameters in MR dogs administered furosemide IV or PO, in order to document changes in LAP after furosemide treatment. Animals: Five healthy Beagle dogs (3 males and 2 females; aged 2 years) were used. Methods: Experimental, cross-over, and interventional study. LAP was measured before the administration of furosemide, and 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours after administration. Furosemide 1, 2, or 4 mg/kg IV, PO or placebo was administered. Results: LAP was significantly decreased with all administrations of furosemide but not after placebo. The max reduction was observed 1 hour (1 mg/kg IV, 15.04 ± 7.02 mmHg), 3 hours (2, 4 mg/kg IV, 13.28 ± 8.01, 9.23 ± 4.92 mmHg), 4 hours (1 mg/kg PO, 14.68 ± 11.51 mmHg), and 5 hours (2, 4 mg/kg PO, 13.19 ± 10.52, 10.70 ± 7.69 mmHg). E wave and E/Ea were significantly decreased corresponding to the reduction of LAP after administration of 2 and 4 mg/kg  Conclusions: LAP was decreased in proportion to the dosage of furosemide, which did not significantly differ between IV and PO of the same dosages. E wave and E/Ea might be useful for the treatment evaluation of furosemide.

Heritability of premature mitral valve disease in Cavalier King Charles spaniels. Tom Lewis, Simon Swift, John A. Woolliams, and Sarah Blott. Vet J, April 2011, 188(1):73-76. Quote: "Mixed model analysis of 1252 records of cardiac auscultation of ≥4- to <5-year-old Cavalier King Charles spaniels (CKCS) from 1991 to 2008 in conjunction with the Kennel Club pedigree records of all dogs registered from the mid 1980s to September 2007 was used to estimate variance parameters of premature mitral valve disease (MVD). Data were limited to dogs 4 and <5 years of age to ensure diagnostic distinction between early and late onset MVD. Cardiac murmurs were detected in 108/1252 (8.6%) dogs. Heritability estimates of 0.67 (standard error, SE 0.071) for the grade of murmur and 0.33 (SE 0.072) for the presence/absence of murmur were calculated. The variance due to clinician was 0.02 (SE 0.012) for grade and 0.03 (SE 0.017) for presence/absence of murmur. These results indicate that the presence and severity of MVD, as assessed by cardiac auscultation, in 4- to 5-year-old CKCS is highly heritable and that selection against the disease should be successful."

Oxidative Stress in Dog with Heart Failure: The Role of Dietary Fatty Acids and Antioxidants. Emmanuelle Sagols and Nathalie Priymenko. Vet.Med.Int'l. Apr. 2011;2011:180206. Quote: "In dogs with heart failure, cell oxygenation and cellular metabolism do not work properly, leading to the production of a large amount of free radicals. In the organism, these free radicals are responsible of major cellular damages: this is oxidative stress. However, a suitable food intake plays an important role in limiting this phenomenon: on the one hand, the presence of essential fatty acids in the composition of membranes decreases sensitivity of cells to free radicals and constitutes a first protection against the oxidative stress; on the other hand, coenzyme Q10, vitamin E, and polyphenols are antioxidant molecules which can help cells to neutralize these free radicals."

Canine Heart Failure - Early Diagnosis, Prompt Treatment. Mark A. Oyama. Univ. of Penna. Departmental Papers (Vet). May 2011. Quote: "In dogs, mitral valve disease (MVD) and dilated cardiomyopathy (DCM) are the most common causes of heart failure, with prevalence being very high in certain breeds (90% for MVD in older Cavalier King Charles spaniels, 33%-50% for DCM in Doberman pinschers). Heart failure typically manifests in signs of either congestion (“backward heart failure”) or low cardiac output (“forward heart failure”). Diagnosis of heart failure involves careful history taking, physical examination, and in cases of left-sided failure, thoracic radiography (see Radiographic Signs of Left-Sided Heart Failure). Echocardiography, electrocardiography, and blood pressure measurement add to the diagnostic database but often are not required to achieve a working diagnosis and to formulate an initial treatment plan."

Holter Monitoring in Clinically Healthy Cavalier King Charles Spaniels, Wire-Haired Dachshunds, and Cairn Terriers. C.E. Rasmussen, S. Vesterholm, T.P. Ludvigsen, J. Häggström, H.D. Pedersen, S.G. Moesgaard, L.H. Olsen. J.Vet.Int.Med. May 2011; 25(3):460–468. "Objectives: To investigate influence of breed, age, sex, body weight, degree of recording artifact, and mitral valve prolapse (MVP) on Holter recordings of 3 breeds of small dogs that have differing predispositions for myxomatous mitral valve disease. The study also assessed if heart rate (HR) at clinical examination (HRex) was associated with HR during Holter monitoring and evaluated the reproducibility of Holter variables. Animals: This study included 54 privately owned dogs: 23 Cavalier King Charles Spaniels (CKCS) (at high risk to develop MMVD), 18 wirehaired Dachshunds (wD) (at moderate risk to develop MMVD) and 13 Cairn Terriers (CT) (at low risk to develop MMVD). All dogs were between two and nine years old and clinical healthy based on history, clinical examination, echocardiography, serum biochemistry and complete blood count. ... Results: Fifteen out of 27 Holter derived variables were significantly associated with breed (P < .03), but not with age (P > .7), sex (P > .2), body weight (P > .7), degree of recording artifact (P > .4), or MVP (P > .6). CKCS had a significantly higher HRex (mean 121 ± SD 12 bpm) compared to wD (94 ± 18 bpm) (P > 0.0001) and CT (102 ± 16 bpm) (P = 0.0009). The minimum HR (HRmin) measured during Holter recording was significantly higher in CKCS (51 ± 10 bpm) compared to wD (42 ± 7 bpm) (P = 0.001) and CT (45 ± 7 bpm) (P 5 0.05). In addition, CKCS had a higher mean HR (HRmean) during Holter recording (83 ± 13 bpm) compared to would (68 ± 8 bpm) (P > 0.0001) and CT (75 ± 10 bpm) (P = 0.04). Both HRmean (P > 0.0001) and HRmin (P = 0.001) were positively correlated with HRex. Second-degree atrioventricular-block (AV) and single, sporadic, uniform ventricular premature complexes (VPC) occurred in 63.0% and 40.7% of the dogs, respectively. The occurrence of second-degree AV-block and VPC showed no breed difference. In conclusion, HR parameters were higher in CKCS compared to wD and CT. HRmean and HRmin were correlated with Hrex. However, further studies are required to clarify the possible influence of high HR in the development of MMVD in CKCS. Second degree AV-block and single, sporadic, uniformed VPC, were common in CKCS, wD and CT but not related to breed."

ACE-Inhibitors, Emerging & Established Roles in the Treament of Heart Failure. Clarke E. Atkins. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 048). Quote: "... Future uses of ACE-I include the use of other drugs concurrently in the advent of aldosterone escape. Reciprocally speaking, the use of ACE-I to suppress the activation of RAAS as is seen with amlodipine and furosemide will become more important as it is better understood. The discovery and better understanding of tissue RAAS activators will help us to suppress the tissue RAAS which makes up 90-99% of the body’s RAAS. Electronic remodeling during arrhythmias can be blocked in part with ACE-I, so this drug group will play a role in management of arrhythmias in the future. Lastly, ACE-I will likely find greater use in combination with pimobendan (which have to date only been studied in designs comparing their efficacy, without concern for additive benefit) and beta-blockers which show promise in treatment of heart failure and slowing the progression of asymptomatic heart disease."

Beta Blockers: Emerging & Established Roles in the Treatment of Heart Failure. Jonathan A. Abbott. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 049). Quote: "... The efficacy of BAA (beta-adrenergic antagonists) in heart failure has been unequivocally demonstrated in people with HF and experimental evidence favors the use of BAAs in dogs with systolic dysfunction. Based on this, the cautious use of BAA in veterinary patients can be justified. However, beta-blockade in canine patients with systolic dysfunction is currently an unproven therapy. Furthermore, BAA can have catastrophic effects in patients with severe myocardial dysfunction who may be critically dependent on a limited inotropic reserve in order to maintain adequate cardiac output.The author considers the use of BAA, generally metoprolol or carvedilol, in patients with echocardiographic evidence of myocardial dysfunction who have not developed congestive signs or in those in which congestive signs have resolved with therapy. Unwillingness on the part of the pet-owner to contend with frequent dosage adjustments or accept the potential for adverse effects is a relative contraindication."

Inodilators: Emerging & Established Roles in the Treatment of Heart Disease. Sonya Gordon.  J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 050). Quote: "... Currently, pimobendan is available as an oral formulation and milrinone and levosimendan are available as intravenous (IV) preparations. ... The clinical veterinary indication for milrinone is for acute cardiovascular support in dogs with HF, however in most cases dobutamine is the preferred agent for this indication. No clinical studies of the effects of intravenous milrinone administration for acute myocardial failure in dogs or cats have been performed. Clinical studies of the effects of chronic oral administration have been performed but this form of the drug has not been approved for veterinary use and is not available for human use. ... Milrinone is chemically incompatible with furosemide and thus should not be administered in the same intravenous line without flushing adequately in between. ... Overall, pimobendan enhances systolic function by improving the efficiency of contraction, limiting the arrhythmogenic side effects of positive inotropes whose sole mechanism of action is to increase myocardial intracellular calcium. Pimobendan inhibits PDE-III in vascular smooth muscle resulting in dilation of both arteries and veins leading to a reduction of both cardiac preload and afterload. Pimobendan has also been demonstrated to have additional vasodilatory properties that are reportedly endothelium mediated (nitric oxide) and may involve inhibition of PDE-V. ... This product [pimobendan] in not currently available as an IV preparation however the oral preparation is rapidly absorbed with peak effects in 2-4 hours. The recommended canine dose is 0.25-0.3 mg/kg twice daily. In later stages of heart failure or when clinical signs become refractory the dose (0.25-0.3 mg/kg) is frequently increased to three times daily. ... Levosimendan exerts its positive inotropy predominantly through calcium sensitization. It appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependant manner. ... It is used for the acute/short-term support of decompensated heart failure. An oral formulation of levosimendan was recently developed for evaluation in the treatment of canine congestive heart failure but to date no clinical trial results have been reported. ... Pimobendan has been proven to prolong survival and reduce clinical signs in dogs with congestive heart failure secondary to both CVD and DCM.8-10 According to the ACVIM consensus statement guidelines for the diagnosis and treatment of CVD pimobendan should be considered a cornerstone of multimodal therapy in dogs with Stage C and D heart failure due to CVD. ... Pimobendan is currently used off label for the treatment of both right and left heart failure due to a variety of underlying etiologies. It is used as a rescue agent on a case by case basis in patients with symptomatic heart failure when conventional heart failure therapy is failing and/or when the underlying cardiac disease (based on echocardiogram) is characterized by ventricular systolic dysfunction or myocardial failure. ... Pimobendan has recognized use in the emergency treatment of congestive heart failure but this indication could be better evaluated for this indication if an IV formulation were available. The availability of an IV formulation would likely lead to its evaluation for short-term support of the cardiovascular system in dogs with recognized heart disease (e.g. Stage B2 CVD and DCM) that require general anesthesia. ... "

Regulation of Cardiac β-1, β-2, and β-3 Adrenergic Receptors in Canine Valvular Heart Disease. OL Nelson, J Häggström, K Höglund, I Ljungvall, C Kvart. Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 155B). Quote: "... Use of β- receptor blocking drugs in dogs with heart failure has been disappointing as compared to results in people. Dogs with overt congestive failure do not tolerate the hemodynamic drug effects, and clinical trials in subclinical heart disease have not shown clear benefit in survival or disease progression. It is therefore logical to hypothesize that the canine species may express β- adrenergic receptors in different proportions than humans, and these receptor proportions may regulate differently in canine heart disease. We also hypothesized that dogs with CHF would have upregulation of β1 & 3 adrenergic receptors compared to healthy dogs. We quantified mRNA expression of β1, 2, and 3 adrenergic receptors in atrial and ventricular myocardium of 13 dogs that were euthanized at various stages of degenerative mitral valvular disease (DMVD) and congestive heart failure (CHF). The mean age of DMVD dogs was 10.1 (6 males, 7 females). Breeds of dogs with DMVD were 1 border collie, 1 beagle, 1 miniature poodle and 10 Cavalier King Charles Spaniels (CKCS). Six healthy mix breed dogs (mean age, 5.5years; mean weight, 15.9kg; 3 males, 3 females) without cardiac disease were used as controls. Normal canine LV myocardium expressed similar proportions of β1 and β2 adrenergic receptors, whereas β3 receptors were slightly less. Δ Ct values did not differ in LV myocardium between healthy dogs and CHF dogs for RPS5 (housekeeping gene), β1 or β3 adrenergic receptors. β2 adrenergic receptor was significantly upregulated in LV myocardium of CHF dogs. The LA myocardium results were very similar to the LV myocardium. Six CKCS did not register β1 receptor signal for LA or LV myocardium. These results may suggest that upregulation of β2 adrenergic receptors are a predominant finding in the dog, which could explain the differences in tolerance of beta-blocking drugs in dogs compared to humans (which predominately upregulate β1). We also postulate that some CKCS may have polymorphisms of their β1 adrenergic receptor to account for lack of amplification. These results could be further investigated by quantifying β adrenergic receptor protein in myocardium and sequencing the β1 receptor in the CKCS. Understanding regulation of β- adrenergic receptors in various stages of canine heart disease will elucidate answers to these common questions regarding the use of β -receptor blocking drugs for heart failure therapy in canine patients."

Identification of Two Deletion Polymorphisms Within the Canine Beta-1 Adrenoceptor Gene. BA Maran, KM Meurs, SL Lahmers, OL Nelson.  J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum: Abstract C-08).  Quote: "... The field of pharmacogenomics, which is the influence of genetics on drug response, is very new in the dog and very little is known about breed specific or family variation in the genes that impact cardiac drug function. The hypothesis of this study is that polymorphisms are present in the canine ß1-AR gene, which could result in an altered pharmacologic response to beta-blocker therapy. The objective of the study was to sequence the canine ß1-AR gene in unrelated dogs of several different breeds to evaluate for the presence of polymorphisms. The canine ß1-AR gene was amplified with specifically designed and optimized primers using the canine ß1-AR sequence, standard PCR techniques, and PCR-based genomic sequencing. DNA samples from 40 dogs of five breeds were evaluated. Computer modeling (POLYVIEW3D) was performed to evaluate the structural impact of any observed polymorphisms. We identified two polymorphisms within the canine ß1-AR gene that may alter responsiveness to commonly administered beta-blockers. We sequenced 40 DNA samples from five breeds (Newfoundland, Boxer Dog, Doberman Pinscher, King Charles Cavalier (CKCS), Great Dane) of dogs and identified two separate deletion polymorphisms, with some individuals displaying both deletions. One polymorphism, a six to nine base pair deletion, was identified in five Boxer dogs, six Newfoundlands, seven Great Danes, seven Doberman Pinschers, and one CKCS. This deletion correlates to a loss of two to three aspartic acids. A second polymorphism was identified in four Newfoundlands, four Great Danes, and two CKCS and consists of a 24 base pair deletion. This deletion correlates to a loss of eight amino acids, a repeating strand of glycine and alanine. Computer modeling (POLYVIEW3D) of these deletions determined substantial tertiary structural change within the intracellular domain that has the potential to alter receptor function. Although the clinical significance of these deletions are unknown, additional investigation into the pharmacogenomics of beta-blockers in dogs is warranted as these polymorphisms may alter the commonly accepted therapeutic strategies for various cardiac diseases in dogs."

Bronchomalacia in Dogs with Myxomatous Mitral Valve Degeneration. MK Singh, LR Johnson, MD Kittleson, RE Pollard. William R. Pritchard. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-12). Quote: "Coughing in the small breed dog may be related to cardiac causes associated with myxomatous mitral valve degeneration (MMVD) including pulmonary edema and compression of the mainstem bronchus by a severely enlarged left atrium, or due to respiratory causes such as tracheal and/or bronchial collapse or chronic bronchitis. The purpose of this study was to evaluate the association between left atrial enlargement and large airway collapse in dogs with MMVD and chronic cough. We hypothesized that airway collapse was independent of degree of left atrial enlargement. ... Preliminary results failed to identify an association between left atrial enlargement and airway collapse in dogs with MMVD but did suggest that airway inflammation is common in affected dogs. Further studies are needed to identify factors contributing to airway collapse in dogs with and without MMVD."

Reverse Remodeling after Mitral Valve Repair under Cardiopumonary Bypass in Dogs. Masami Uechi. . J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 157A). Quote: "We evaluated cardiac reverse remodeling after mitral valve repair under cardiopulmonary bypass (CPB) for mitral regurgitation in small breed dogs. Fifty dogs (body weight 1.8–9.3 kg, age 5–14 years) with mitral regurgitation were treated between August 2006 and November 2009. The cardiac murmur was grade 4/6–6/6. The preoperative chest X-rays showed cardiac enlargement (vertebral heart scale (VHS) 11.0–13.1). Echocardiography showed severe mitral regurgitation and left atrium enlargement (LA/Ao 2.0–4.2). After inducing anesthesia, a thoracotomy was performed in the fifth intercostal space. CPB was started by using a CPB circuit connected to carotid artery and jugular vein catheters. After inducing cardiac arrest, the left atrium was sectioned and chordae tendineae rupture confirmed. The chordae tendineae were replaced with expanded polytetrafluoroethylene. A mitral annulus plasty was also done, and the left atrium was closed. After de-clamping for restarting the heart, the chest was closed. Heart rate decreased from 118–164 bpm to 75–138 bpm. The grade of cardiac murmur was reduced to 0/6–3/6 three months postoperatively, and the heart shadow was reduced (VHS 9.8–11.5) in the chest x-rays. Echocardiography confirmed the marked reduction in mitral regurgitation and the left atrial dimensions (LA/Ao 1.2–2.2). Mitral valve repair reduced enlarged cardiac size by reduction of regurgitant rate."

Associations Between N-terminal Procollagen Type III (PIIINP) and Ventricular Remodelling in Dogs with Mitral Valve Disease.  MJ Hezzell, A Boswood, J Elliott. . J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-17). Quote: "PIIINP is a serum biomarker of collagen biosynthesis and is described as a marker of myocardial fibrosis in human patients. We hypothesised that PIIINP concentrations would vary according to the degree of remodelling demonstrable in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Serum PIIINP concentrations (mg/ml) were measured in dogs with MMVD and healthy controls using a validated commercially available radioimmunoassay. Results are reported as (Mean ± SD). Non-normally distributed variables were logarithmically transformed. Comparisons of continuous variables were made between groups using t-tests and one-way ANOVAs with Tukey’s post-hoc comparisons. Univariable analyses were used to evaluate associations between PIIINP and clinical characteristics (age, breed [cavalier King Charles spaniel (CKCS) yes/ no], sex, weight, heart rate [measured from ECG], treatment with ACEi [yes/ no], treatment with diuretics [yes/ no] and echocardiographic measurements [LA/Ao, LVEDD/ LVFWd, LVEDDN, LVESDN]). Multivariable analysis was initially performed with all dogs included and then repeated excluding all dogs receiving therapy. Dogs with MMVD were divided into those with no cardiomegaly (NC) (LA/Ao < 1.5 and LVEDDN < 1.8), those with cardiomegaly (LA/Ao 1.5 and/ or LVEDDN 1.8) but no clinical signs (C) and those dogs with cardiomegaly requiring treatment for congestive heart failure (CHF). One hundred and fifty-four dogs with MMVD and 23 control dogs were studied. There was no difference in age (P = 0.870) or weight (P = 0.606) between the MMVD and control groups. There was a significant difference in serum PIIINP (P 5 0.034) between normal (11.2 ± 3.66), NC (11.6 ± 4.57), C (10.1 ± 3.44) and CHF (9.4 ± 3.06) groups. Post-hoc comparisons demonstrated a difference between NC and CHF groups (P = 0.038). There was no difference in serum PIIINP between genders (P = 0.228). In the univariable analysis CKCS (yes/ no) (P = 0.016) was positively associated with serum PIIINP. Age (P < 0.0001), Log (LA/Ao) (P = 0.002) and LVEDDN (P = 0.002) were negatively associated with serum PIIINP. In the multivariable model including all dogs, LVEDDN (P o 0.0001, B =-4.04 (95%CI = -6.11 to -1.97)), age (P = 0.006, B = -0.28 (95%CI = -0.47 to -0.08)) and CKCS (yes/ no) (P = 0.003, B 5 2.01 (95%CI = 0.67 to 3.34)) were independently associated with serum PIIINP. In the multivariable model including only dogs not receiving therapy (n 5 141), LVEDDN(P50.006, B= -4.30 (95%CI = -7.32 to-1.29)), age (P = 0.011, B = -0.31 (95%CI = -0.55 to -0.07)) and CKCS (yes/ no) (P = 0.034, B = 1.75 (95%CI = 0.13 to 3.37)) were independently associated with serum PIIINP. In conclusion, serum PIIINP decreases with age and with increasing LVEDDN. CKCS have higher serum PIIINP measurements independent of age and LVEDDN, which may reflect a difference in collagen turnover in this breed."

Advanced Electrocardiography Can Predict Mitral Regurgitation in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease. M Spiljak, AD Petric, LH Olsen, A Stepancic, T Falk, CE Rasmussen, V Starc. . J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-32). Quote: "Recently, multiple advanced resting electrocardiographic (ECG) techniques have been applied in humans for detection of cardiac autonomic and repolarisation function. This has improved the diagnostic and/or prognostic value of short-time ECG in detection of common human cardiac diseases even before onset of symptoms or changes in the standard ECG. Therefore, this study investigates, if advanced ECG can predict the severity of mitral regurgitation (MR) in dogs with myxomatous mitral valve disease (MMVD) and thereby improve the diagnostic value of ECG. The study included 77 privately owned Cavalier King Charles Spaniels (CKCSs) (age 6.0 ± 2.7 years; 30 males and 47 females). All dogs were examined by echocardiography and a short-time (3–5 min) high-fidelity 12-lead ECG, with the dog in a resting position and in sinus rhythm. Dogs were divided into 5 groups according to the degree of MR estimated as the percentage of the left atrium area using color Doppler mapping (0%; 0% < jet 15%; 15% < jet 50%; jet > 50%; jet = 100% and with clinical signs of congestive heart failure). ECG recordings were evaluated via custom software programs to calculate 76 different parameters, including heart rate variability (HRV), QT variability (QTV), T-wave complexity, wave morphology and 3-D ECG. One-way ANOVA determined 21 ECG parameters, which were significantly different (P < 0.05) between the 5 dog groups. Principal component factor analysis identified a 5- factor model with 83.2% explained variability. QRS dipolar voltage and two repolarization indices of QTV increased significantly with MR severity, whereas total power of the frequency spectrum of RR interval and the standard deviation of QTV decreased significantly with MR severity. For the 5 selected parameters the prediction of MR jet value was tested by multiple linear regression. A correlation coefficient (R) of 0.65 indicated that the prediction value was significant (P < 0.01). If age was included in the multiple linear regression the prediction value was further increased (R = 0.80). Our results indicate that for a cut-off criteria of MR 50% jet the five selected ECG parameters could predict the severity of MR caused by MMVD in CKCSs with sinus rhythm with sensitivity 65% (78% with age inclusion) and specificity 98% (92% with age inclusion) (P < 0.05)."

Heart Rate and Heart Rate Variability in Dogs with Different Degrees of Myxomatous Mitral Valve Disease. CE Rasmussen, T Falk, NE Zois, SG Moesgaard, HD Pedersen, J Häggström, and LH Olsen. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-42). Quote: "Heart rate variability (HRV) is an indirect measurement of the autonomic modulation of heart rate (HR). Reduced HRV measured from short-time electrocardiography is seen in dogs with heart failure (HF) secondary to myxomatous mitral valve disease (MMVD). However, HRV is suggested to increase with disease severity at early stages of MMVD. The aims of this study were 1) to associate HR and HRV with severity of MMVD in Cavalier King Charles Spaniels (CKCS) and 2) to compare HR and HRV between CKCS and other dog breeds in a group of dogs in HF secondary to MMVD. One-hundred dogs were examined by echocardiography and 24-hour electrocardiography. The dogs were divided into five groups: 1) CKCS with no/minimal mitral regurgitation (MR) (MR jet 15% of the left atrial area using color Doppler mapping) and no murmur, 2) CKCS with mild MR (20% < jet 50%), 3) CKCS with moderate/severe MR (jet > 50%) and no clinical signs of HF, 4) CKCS in HF (HF defined as left atrium to aortic root ratio (LA/Ao) > 1.5, clinical signs of HF and furosemide responsiveness) and 5) non-CKCS in HF. Dogs in HF were allowed HF therapy. Both HR and HRV were analyzed over a 24-hour period, while HRV were also analysed over a 6-hour nightly period. Analyses of variance were performed with HR or HRV as response variables and the explanatory variables dog group and echocardiographic indices of MMVD were included separately. All P-values were Bonferroni corrected. Minimum- and mean HR were significantly higher in CKCS with moderate/severe MR and in HF compared to CKCS with no/minimal and mild MR (all P < 0.001). Seven out of 26 HRV variables were significantly decreased in CKCS with moderate/severe MR and in HF compared to CKCS with no/minimal and mild MR (all P < 0.02). Another 10 HRV variables showed the same groupwise differences (all P < 0.02), except that the difference between CKCS with mild MR and CKCS with moderate/severe MR did not reach statistical significance. M minimum HR, mean HR and the HRV variables (7 and 10) differing between dog groups, also consistently decreased with increasing MR, LA/Ao and the proximal isovelocity surface area in CKCS. Non-CKCS in HF had a lower minimum HR compared to CKCS in HF (P = 0.03) and a higher triangular index measured in both periods (all P < 0.04). In conclusion, HR increased and most HRV variables decreased with increasing severity of MMVD in CKCS, even prior to the development of HF. Other breeds in HF secondary to MMVD had lower minimum HR, but higher triangular index compared to CKCS in HF."

Dynamics of the Renin-angiotensin-aldosterone System (RAAS) after Oral Administration of Benazepril in Dogs. J Mochel, G Strehlau, R Mohamed, M Peyrou . J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract P-1). Quote: "In dogs, RAAS activation is a major feature of congestive heart failure (CHF). Benazepril (Fortekor) is a potent ACE inhibitor with well-documented effectiveness in canine CHF. Although ACE activity (ACE[A]) has been used in preclinical studies as a surrogate marker of efficacy, some authors have reported a poor correlation between plasma ACE[A] and changes in angiotensin II (AII) or aldosterone (AL). The purpose of this study was to investigate the effect of benazepril on canine plasma renin activity/concentration (PRA/PRC), angiotensin I (AI), AII, AL, and fractional excretion of potassium (UfeK), sodium (UfeNa) and aldosterone (UfeAL). Sixteen beagle dogs were fed a low-sodium diet and dosed with placebo or benazepril tablets (10 mg PO, q24h) for 5 days. Blood and urine samples were collected on day 1 (D1) and day 5 (D5) over 24-hour periods. Data were analyzed by repeated measures ANOVA of baseline corrected values, and ANOVA of AUC[24hours]. Compared with placebo, benazepril induced a significant increase in PRA and AI at D1 (p-value [PRA]:0.001, p-value [AI]:0.002) and D5 (p-value [PRA]:0.001, p-value [AI] < 0.001). No differences in PRC were noticed. Based on AUC[24hours], AII levels were 34% lower in the benazepril group at D5 (p-value [AII]:0.01). UfeAL and AL decreased by up to 27% and 24% at D1 and D5, respectively, though differences did not reach statistical significance. Benazepril markedly influences RAAS dynamics in dogs. Decreased exposure to AII and AL are likely to be the key events required to counteract pathological remodeling of the heart in CHF."

Serum Serotonin Concentration in Relation to Severity of Spontaneous Degenerative Mitral Valve Disease in Dogs. S.J. Lim, S.H. Lee, H.J Park, D.W. Jung, H.J. Choi, H.Y Youn, H.M. Park, D.H. Kim, K.H. Song. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-37). Quote: "... Serotonin and serotonin-related mechanisms have been implicated as a cause of valvular disease in human and animals, including spontaneous DMVD in dogs. Increased circulating 5HT concentration as a potential source of heightened 5HT signaling is demonstrated in small dogs with DMVD. The aim of this study was to investigate whether serum 5HT concentrations were associated with severity of naturally occurring DMVD in small dogs and to investigate potential associations of dog characteristics on serum 5HT concentrations in our study population. Forty-eight dogs were included in this study and were classified into control and DMVD groups according to the results of physical and echocardiographic examinations. ... Significantly higher 5HT concentrations were observed in dogs with moderate (P < .05) and severe (P < .05) DMVD, compared with concentration in control group. Additionally, 5HT concentration in dogs with moderate DMVD were significantly higher (P < .05) than concentration in dogs with mild DMVD. Also, dogs with severe DMVD had significantly higher 5HT concentration than dogs with mild (P < .05) and moderate (P < .05) DMVD. There was no significant association of age, platelet, and LVIDd, on serum 5HT concentration, however, weak correlation between serum 5HT increased significantly and LA:Ao ratio (R² = .211, P < .05) was observed. The results of this study indicate that serum 5HT concentrations were higher with increasing severity of spontaneous DMVD, which may be the potential cause to advance the progression of DMVD. Further studies should be performed to reveal the role of 5HT in inducing and accelerating spontaneous DMVD and to investigate if lowering serum 5HT concentration could alter the progression of DMVD."

Circulating cytokine concentrations in dogs with different degrees of myxomatous mitral valve disease. Nora E. Zois, Sophia G. Moesgaard, Mads Kjelgaard-Hansen, Caroline E. Rasmussen, Torkel Falk, Christine Fossing, Jens Häggström, Henrik D. Pedersen, and Lisbeth H. Olsen. Vet.J. June 2011. Quote: "Cytokines have been associated with the progression of congestive heart failure (CHF) in humans and may be implicated in the pathophysiology of myxomatous mitral valve disease (MMVD) in dogs. The aim of this study was to determine the serum concentrations of cytokines in dogs with MMVD. The study included 16 Cairn terriers with no or minimal mitral regurgitation (MR), 41 Cavalier King Charles Spaniels (CKCS) with different degrees of MR and 11 dogs of different breeds with CHF due to MMVD. Granulocyte–macrophage colony-stimulating factor, interferon-ã, interleukin (IL)-2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, keratinocyte-derived chemokine, interferon-ã-induced protein and monocyte chemoattractant protein-1 (MCP-1) were measured using a canine-specific multiplex immunoassay. CHF dogs had significantly higher MCP-1 concentrations than dogs with no or minimal MR. Among the CKCS, IL-2 and IL-7 decreased with increasing left atrial size and IL-7 also decreased with increasing MR. IL-8 decreased with increasing left ventricular end-systolic internal dimensions. MCP-1 was increased in CHF dogs compared to healthy control dogs and IL-2, IL-7 and IL-8 decreased with increasing indices of disease severity. The results suggest a role for these cytokines in canine MMVD and CHF."

Bioprosthesis valve replacement in dogs with congenital tricuspid valve dysplasia: Technique and outcome. Shiori Arai, Leigh G. Griffiths, Khursheed Mama, Timothy B. Hackett, Eric Monnet, June A. Boon, Leslie Carter, E. Christopher Orton. J. Vet. Cardiol. June 2011;13(2):91-99. Quote: Objective: To describe the surgical technique and report outcome of dogs undergoing bioprosthesis valve replacement for severe tricuspid regurgitation (TR) secondary to congenital tricuspid valve dysplasia (TVD). Animals, materials and methods: Twelve client-owned dogs (19–43 kg) with TVD underwent tricuspid valve replacement with a bovine pericardial or porcine aortic bioprosthesis with the aid of cardiopulmonary bypass. Anticoagulation with warfarin was maintained for 3 months after surgery and then discontinued. Results: Ten of 12 (83.3%) dogs survived surgery and were discharged from the hospital. Seven dogs were alive with complete resolution of TR for a median period of 48 months (range 1–66 months) after surgery. Two dogs underwent euthanasia because of bioprosthesis failure due to inflammatory pannus at 10 and 13 months after surgery. Two dogs experienced valve thrombosis that was resolved by tissue plasminogen activator. One dog developed suspected endocarditis after surgery that was resolved with antibiotics. Serious cardiac complications included atrial fibrillation and flutter, right-to-left shunt through an uncorrected patent foramen ovale, complete atrioventricular block, and sudden cardiac arrest. Postoperative atrial fibrillation or flutter did not occur in 7 dogs treated prophylactically with oral amiodarone before surgery. Conclusions: Curative intermediate-term outcomes are possible in dogs undergoing open tricuspid valve replacement with a bioprosthesis. Prosthesis-related complications include inflammatory pannus, thrombosis, and endocarditis. Postoperative atrial fibrillation or flutter can be reduced or prevented by prophylactic preoperative treatment with amiodarone. Several identified complications are avoidable or can be reduced with increased awareness and experience with these techniques.

Lack of efficacy of low-dose spironolactone as adjunct treatment to conventional congestive heart failure treatment in dogs. Schuller, S., Van Israël, N., Vanbelle, S., Clercx, C., McEntee, K. J. Vet. Pharmacol. Therap. Aug 2011; 34(4):322–331. Quote "Aldosterone plays an important role in the pathophysiology of heart failure. Aldosterone receptor blockade has been shown to reduce morbidity and mortality in human patients with advanced congestive left ventricular heart failure. This study was designed to assess the efficacy and tolerance of long-term low-dose spironolactone when added to conventional heart failure treatment in dogs with advanced heart failure. Eighteen client-owned dogs with advanced congestive heart failure due to either degenerative valve disease (n = 11) or dilated cardiomyopathy (n = 7) were included in this prospective, placebo-controlled, double-blinded, randomized clinical study. After initial stabilization including furosemide, angiotensin-converting enzyme inhibitors, pimobendan and digoxin, spironolactone at a median dose of 0.52 mg/kg (range 0.49–0.8 mg/kg) once daily (n = 9) or placebo (n = 9) was added to the treatment, and the dogs were reassessed 3 and 6 months later. Clinical scoring, echocardiography, electrocardiogram, systolic blood pressure measurement, thoracic radiography, sodium, potassium, urea, creatinine, alanine aminotransferase, aldosterone and aminoterminal atrial natriuretic propeptide were assessed at baseline, 3 and 6 months. Survival times were not significantly different between the two treatment groups. Spironolactone was well tolerated when combined with conventional heart failure treatment."

Effects of treatment on respiratory rate, serum natriuretic peptide concentration, and Doppler echocardiographic indices of left ventricular filling pressure in dogs with congestive heart failure secondary to degenerative mitral valve disease and dilated cardiomyopathy. Karsten E. Schober, Taye M. Hart, Joshua A. Stern, Xiaobai Li, Valerie F. Samii, Lisa J. Zekas, Brian A. Scansen, John D. Bonagura. JAVMA Aug 2011;239(4):468-479. Quote: "Objective: To evaluate the effects of treatment on respiratory rate, serum natriuretic peptide concentrations, and Doppler echocardiographic indices of left ventricular filling pressure in dogs with congestive heart failure (CHF) secondary to degenerative mitral valve disease (MVD) and dilated cardiomyopathy (DCM). Design: Prospective cohort study. Animals: 63 client-owned dogs [45 with MVD of which 13 were cavalier King Charles spaniels]. Procedures: Physical examination, thoracic radiography, analysis of natriuretic peptide concentrations, and Doppler echocardiography were performed twice, at baseline (examination 1) and 5 to 14 days later (examination 2). Home monitoring of respiratory rate was performed by the owners between examinations. Results: In dogs with MVD, resolution of CHF was associated with a decrease in respiratory rate, serum N-terminal probrain natriuretic peptide (NT-proBNP) concentration, and diastolic functional class and an increase of the ratio of peak velocity of early diastolic transmitral flow to peak velocity of early diastolic lateral mitral annulus motion (E:Ea Lat). ... Only respiratory rate predicted the presence of CHF at examination 2 with high accuracy. Conclusions and Clinical Relevance: Resolution of CHF was associated with predictable changes in respiratory rate [In the present study, all dogs with CHF had high respiratory rate and resolution of heart failure was accompanied by a predictable decrease of respiratory rate to values equivalent to or below the respiratory rate of dogs without clinical signs of CHF. ... The clinical relevance of this is that in addition to predicting successful short-term treatment of CHF, the respiratory rate measured at home may allow both clinicians and owners to more accurately tailor home treatment to a target respiratory rate and to avoid excessive or insufficient diuresis. This study suggests that veterinarians should instruct owners to monitor respiratory rate and that respiratory rate is useful for both diagnosis and management of dogs with CHF.], serum NT-proBNP concentration, and selected Doppler echocardiographic variables in dogs with DCM and MVD. ... Home monitoring of respiratory rate is simple and very useful in the assessment of CHF in dogs with either DCM or MVD. The use of respiratory rate, analysis of serum NT-proBNP concentration, and transthoracic Doppler echocardiography for clinical guidance in the treatment of CHF merits further study."

NT-proBNP, NT-proANP and cTnI concentrations in dogs with pre-capillary pulmonary hypertension. Heidi B. Kellihan, Brian A. MacKie, Rebecca L. Stepien. J Vet Cardio. September 2011;13(3):171-182. Quote: Objectives: To compare [NT-proBNP], [NT-proANP] and [cTnI] between control dogs with respiratory disease without pulmonary hypertension (PH) and dogs with pre-capillary PH, and to assess the accuracy of [NT-proBNP], [NT-proANP], [cTnI] to predict Doppler-derived peak tricuspid regurgitation (TR) gradient. Animals: 20 dogs. 8 control dogs with respiratory disease with no PH and 12 with pre-capillary PH. Methods: [NT-proBNP], [NT-proANP] and [cTnI] were compared between the 2 groups and simple linear regression analysis was used to predict peak TR gradients from various blood biomarkers. Results: Median [NT-proBNP] was higher in the dogs with PH (2011 pmol/L, 274–7713 pmol/L) compared to control dogs (744 pmol/L; 531–2710 pmol/L) (p = 0.0339). [NT-proBNP] was associated with peak TR gradient (R2 = 0.7851, p = 0.0001). Median [NT-proANP] did not differ between dogs with PH (1747 fmol/L; 894–2884 fmol/L) and control dogs (1209 fmol/L; 976–1389 fmol/L (p = 0.058). [NT-proANP] was not associated with peak TR gradient (R2 = 0.2780, p = 0.0781). Median [cTnI] did not differ between dogs with PH (0.2850 ng/mL; 0.19–1.13 ng/mL) and control dogs (0.2 ng/mL; 0.19–0.82 ng/mL, p = 0.3051). Median [TnI] was not associated with peak TR gradient (R2 = 0.024, p = 0.6307). Conclusions: [NT-proBNP] concentration is significantly higher in dogs with pre-capillary PH when compared to dogs with respiratory disease without PH, and [NT-proBNP] may be useful to predict the severity of estimated PH. Elevations in [NT-proBNP] due to pre-capillary PH may complicate the interpretation of [NT-proBNP] elevations in patients presenting with cardiorespiratory abnormalities. [NT-proANP] and [cTnI] were not elevated in dogs with pre-capillary PH.

Identification of 2 Loci associated with development of myxomatous mitral valve disease in cavalier king charles spaniels. Madsen MB, Olsen LH, Häggström J, Höglund K, Ljungvall I, Falk T, Wess G, Stephenson H, Dukes-McEwan J, Chetboul V, Gouni V, Proschowsky HF, Cirera S, Karlskov-Mortensen P, Fredholm M. J Hered. 2011 Sep-Oct;102 Suppl 1:S62-7. Quote: "Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. It is characterized by chronic progressive degenerative lesions of the mitral valve. The valve leaflets become thickened and prolapse into the left atrium resulting in mitral regurgitation (MR). MMVD is most prevalent in small to medium sized dog breeds, Cavalier King Charles Spaniels (CKCS) in particular. The onset of MMVD is highly age dependent, and at the age of 10 years, nearly all CKCS are affected. The incidence of a similar disease in humans-mitral valve prolapse-is 1-5%. By defining CKCSs with an early onset of MMVD as cases [139 CKCSs] and old dogs with no or mild signs of MMVD as controls [102 CKCSs], we conducted a genome-wide association study (GWAS) to identify loci associated with development of MMVD. We have identified a 1.58 Mb region on CFA13 (P(genome) = 4.0× 10(-5)) [CFA 13q2.2.3] and a 1.68 Mb region on CFA14 (P(genome) = 7.9× 10(-4)) [CFA 14q1.3] associated with development of MMVD. ... Twenty protein-coding genes have been annotated in the candidate region of CFA 13 (1.68 Mb) and in the homologous region of HSA 4, whereas 11 protein-coding genes have been annotated in the CFA 14 region (1.58 Mb) and in the homlogous HSA 7 region. ...This confirms the power of using the dog as a model to uncover potential candidate regions involved in the molecular mechanisms behind complex traits. ... We will initiate studies of the most promising candidate genes in the 2 candidate regions which hopefully will lead us to the mutations affecting the development of mitral valve disease."

Leptin Expression in Dogs with Cardiac Disease and Congestive Heart Failure. Fonfara, S., Hetzel, U., Tew, S., Dukes-Mcewan, J., Cripps, P. and Clegg, P. J Vet Int Med Sept 2011; 25(5):1017–1024.  Quote: "Leptin belongs to the group of adipokines and has recently attracted attention because of its effects on the cardiovascular system. Increased leptin concentrations are reported in obese dogs but its role in cardiac disease (CD) is not known. Therefore, we investigated leptin expression in blood samples from dogs with congestive heart failure (CHF), and from myocardial samples of dogs with CDs. Leptin mRNA was analyzed from blood samples of 8 dogs presented for cardiac screening in which no abnormalities were detected and 8 dogs in CHF. In addition, myocardial samples (interventricular septum, right and left atria, and ventricles) of 10 dogs with no cardiac abnormalities (controls), 7 dogs with acquired and 3 dogs with congenital CDs were investigated using real-time polymerase chain reaction (PCR). Results: Dogs with CHF had significantly higher blood concentrations of leptin mRNA than dogs without CD (P = .013). Myocardial leptin expression was significantly increased in acquired (P = .035) and decreased in congenital CD (P = .016) in comparison to controls. Dogs in heart failure stage D showed higher myocardial leptin concentrations than dogs in stage C3 and B (P = .031). Differences according to myocardial region (P < .05) were detected and higher leptin concentrations were present in the atria in comparison to the ventricles in dogs with CD (P = .005). Comparing male and female dogs with CD revealed higher leptin concentrations in female dogs (P = .001). Conclusions: These results indicate leptin mRNA concentrations vary with CD, severity of CD, myocardial region, and possibly sex. Therefore, leptin might play a role in canine CD."

Assessment of Global and Regional Left Ventricular Volume and Shape by Real-Time 3-Dimensional Echocardiography in Dogs with Myxomatous Mitral Valve Disease. I. Ljungvall, K. Höglund, C. Carnabuci, A. Tidholm, J. Häggström. September 2011;25(5):1036-1043. Figure 2Quote: Background: Left ventricular (LV) remodeling occurs in response to chronic volume overload. Real-time 3-dimensional (RT3D) echocardiography offers new modalities for LV assessment. Objective: To investigate LV changes in shape and volume in response to different severities of naturally acquired myxomatous mitral valve disease (MMVD) in dogs by RT3D echocardiography. Animals: Sixty-five client-owned dogs [including 47 cavalier King Charles spaniels] . Methods: Prospectively recruited dogs were classified by standard echocardiography into healthy, mild, moderate, and severe MMVD groups. Endocardial border tracking of LV RT3D dataset was performed, from which global and regional (automatically acquired basal, mid, and apical segments based on LV long-axis length) end-diastolic (EDV) and end-systolic volumes (ESV), LV long-axis length, and sphericity index were obtained. Results: Global and regional EDV and ESV (indexed to body weight) were most prominently increased in dogs with severe MMVD. All 3 regional LV segments contributed to increased global EDV and ESV with increasing MMVD severity, but mid-EDV contributed the most to the global EDV increase. Furthermore, LV long-axis length and LV sphericity index increased with increasing MMVD severity. Basal and apical EDV segments displayed the strongest association with sphericity index (P < .0001). Conclusions and Clinical Importance: The present RT3D echocardiographic study showed prominent LV volume expansion only in dogs with more severe MMVD. ... All 3 regional LV segments contributed to the increase in global EDV and ESV with increasing MMVD severity, but mid-EDV contributed the most to the global EDV increase. The increase in LV sphericity index with increasing disease severity indicates that the LV shape changes from elliptical to more globular in response to chronic volume overload. The apical and basal segments contributed the most to the increased sphericity. [See Figure 2 above.] ... Assessment of LV volume and shape potentially could allow early detection of dogs at risk for rapid progression into congestive heart failure.

Radiographic Heart Size and Its Rate of Increase as Tests for Onset of Congestive Heart Failure in Cavalier King Charles Spaniels with Mitral Valve Regurgitation. P.F. Lord, K. Hansson, C. Carnabuci, C. Kvart, J Häggström. J Vet Int Med Sept 2011; 25(6):1312-1319.  Quote: "Background: In canine mitral regurgitation (MR) the rate of heart enlargement increases in the last year before congestive heart failure (CHF). Measurement of heart size and its rate of increase may be useful tests for CHF in MR. Objectives: To determine the value of vertebral heart scale (VHS) and its rate of increase (∆VHS units/month) for diagnosing the presence and predicting the onset of CHF. Animals: Longitudinal study of 94 Cavalier King Charles Spaniels (CKCS). Methods: VHS was measured at intervals before CHF. ∆VHS/month was calculated from sequential pairs of VHS measurements and the interval between them. Diagnostic accuracy and utility were determined by the areas under receiver operating characteristic plots (AUROC), and likelihood ratios (LR). Results: AUROC for VHS at the onset of CHF was 0.93 (95% CI, 0.96–0.90), to predict CHF 1–12 months before CHF was 0.74 (95% CI, 0.81–0.66), and for ∆VHS/month at CHF was 0.98 (95% CI, 0.99–0.96). Interval LRs and their cutoff values for CHF were for VHS: 13 (95% CI, 20–7.3) at ≥12.7; 1.2 (95% CI, 2.0–0.68) between 12.7 and 12.0; 0.04 (95% CI, 0.18–0.01) at ≤12.0, and for ∆VHS/month: 15 (95% CI, 30–7.7) at ≥0.08; 0.72 (95% CI, 2.0–0.25) between 0.08 and 0.06; and 0.05 (95% CI, 0.13–0.02) at ≤0.06. Conclusions and Clinical Importance: Under the conditions of this study, VHS and particularly ∆VHS/month are useful measurements for detecting onset of CHF in CKCS with MR."  [See, Letter to the Editor from Dr. Mark Oyama, commenting on this study, and Letter to the Editor from the study's authors, replying to Dr. Oyama.]

The Effect of Pimobendan on Left Atrial Pressure in Dogs with Mitral Valve Regurgitation. S. Suzuki, R. Fukushima, T. Ishikawa, L. Hamabe, D. Aytemiz, H. Huai-Che, S. Nakao, N. Machida, R. Tanaka. J. Vet. Internal Med.; 2011;25(6):1328-1333. Quote: "Background: The effects of pimobendan on left atrial pressure (LAP) in dogs with mitral valve disease (MR) have not been documented in a quantitative manner. Objective: The objective was to document and study the short-term effects of pimobendan on LAP and echocardiographic parameters in MR dogs. Animals: Eight healthy Beagle dogs weighing 10.0–14.7 kg (3 males and 5 females; aged 2 years) were used. Methods: Experimental, cross-over, and interventional study. Dogs with surgically induced MR received pimobendan at either 0.25 mg/kg or 0.50 mg/kg PO q12h for 7 days and then, after a 7-day wash-out period, the other dosage. LAP was measured for 30 minutes at baseline and again on days 1, 2, 4, and 7 of pimobendan administration. Results: Mean LAP was significantly decreased after the administration of 0.25 mg/kg (15.81 ± 5.44 mmHg to 12.67 ± 5.71 mmHg, P < .001) and 0.50 mg/kg (15.76 ± 5.45 mmHg to 10.77 ± 5.23 mmHg, P < .001). Also, the 0.50 mg/kg group led to a significantly lower LAP (P < .01) compared with the 0.25 mg/kg group. Significant reduction was seen for the first time 4 days after the administration of 0.25 mg/kg and a day after the administration of 0.50 mg/kg. Conclusions and Clinical Importance: Pimobendan decreased LAP in a dose-dependent manner in dogs with acute MR caused by experimental chordal rupture. This study did not evaluate adverse effects of high-dose pimobendan, and additional studies in clinical patients are warranted."

Relationship between aldosterone and clinical parameters in dogs with mitral valve disease. Adrian Boswood, Melanie Hezzell. CEVA CardioSymposium, October 2011. Quote: "The aims of this stuy were to measure the urine aldosterone to creatinine ratio (UAC) in a large population of dogs with naturally occurring degenerative mitral valve disease (DMVD) and to investigate the relationship between UAC and clinical variables including echocardiographic measurements. ... CKCS was chosen as the comparator breed since this was the most frequently represented breed, and this breed is particularly prone to MMVD and previous studies have suggested differences in the natural history of the disease in this breed. ... UAC appears to be higher in CKCS by comparison to other breeds and this effect seems independent of the influence of age and stage of disease. UAC also seems to be higher at times of active ventricular remodeling; showing a significant relationship with prior change in ventricular diastolic diameter and subsequent change in ventricular systolic diameter. Our findings suggest that aldosterone production, as indicated by the UAC, is increased at times of active ventricular remodeling in dogs with MMVD."

The DELAY Study (DELay of Appearance of sYmptoms of canine degenerative mitral valve disease treated with Spironolactone and Benazepril). CEVA CardioSymposium, October 2011. Quote: "The DELAY study will include 240 dogs with advanced pre-clinical CDVD ISACHC class 1b or ACVIM consensus stage B2. The primary aims for this study are to evaluate the efficacy of spironolactone in combination with benazepril on delaying time of onset of overt heart failure and to evaluate if NT-proBNP and Tnl are clinically relevant biomarkers to predict time of onset of heart failure. The study has started on November 2010 and enrollment will terminate on December 2012. End of the study is December 2015."

Cardio-Renal Syndrome, what is behind it? A rock and a hard place: cardiorenal syndrome in clinical canine veterinary patients. Rebecca L. Stepien. CEVA CardioSymposium, October 2011. Quote: "Cardio-renal syndrome has been variously defined. In clinical medicine, it may be viewed as 'a state In which therapy to relieve heart failure symptoms is limited by worsening renal function', but this arguably is a clinical view reflecting a cardiologist's concern; a nephrologist may be more likely to define CRS as ' ... a normal kldney that is dysfunctional because of a diseased heart ...'. An expansive, multisystem view is required In order to understand the complex bidirectional interactions of these two critical body systems, in which '... each dysfunctional organ has the ability to initiate and perpetuate disease in the other organ through common hemodynamic, neurohormonal, and immunological/ biochemical feedback pathways'. ... Cardio-renal syndrome may be divided into 5 types. Type 2 CRS appears to be of significant clinical concern in cardiac patients. ... The prevalence of azotemia and decreased renal function in canine CHF patients is similarly high. In a report in 2010, 24.1% of 223 dogs with heart disease were azotemic, although the prevalence of CHF in this cohort of heart patients was not specified. In an eartler study, Nicolle and colleagues reported that 50% of small dogs (<13 kg) with degenerative valve disease were azotemic either by Blood Urea Nitrogen (BUN) or Creat or both. This study included dogs in all stages of heart failure (NYHA grades I-IV) and some were treated at the time of the study. As their NYHA class increased, a greater percentage of patients were azotemic and were also more likely to have already been treated with some combination of angiotensin-converting enzyme inhibitors, furosemide, spironolactone and digoxin. Older dogs were also more likely to be azotemic. The severity of CHF was also linked to renal function; Class III-IV dogs had 45% decrease in GFR compared with class I-II dogs, and 7/9 grade III-IV dogs had abnormally decreased GFR. In human and canine patients, the presence and severity of RAAS activation and azotemia is affected by therapy, especially furosemide and vasodilators. ... In some cases, inadequate therapy of venous congestion may contribute to renal dysfunction, resulting in 'congestive kidney failure'. Human and veterinary literature supports the use of ACEI and aldosterone receptor antagonists such as spironolactone to limit the RAAS activation that has beer documented with CHF therapy, and use of these modalities has prolonged survival times in affected patients. The topic of cardiorenal syndrome is becoming an increasingly important concern in clinical veterinary medicine. Avoidance of WRF in dogs before and during CHF therapy is crucial to maintain quality of life as survival in dogs with this common disease increases."

Mitral Valve Disease - Alternative Therapies Such as Beta Blockers, Amlodipine and Pimobendan. Christophe W. Lombard. WSAVA 2011 Congress.

Use of the loop diuretic torsemide in three dogs with advanced heart failure. Mark A. Oyama, Gordon D. Peddle , Caryn A. Reynolds, and Gretchen E. Singletary. J Vet Cardio; Oct 2011; doi:10.1016/j.jvc.2011.10.001. Quote: "Diuretics are a mainstay of therapy in dogs with heart failure. In dogs with advanced heart failure, moderate to high doses of loop diuretics such as furosemide are used with diminishing effects as profound activation of neuroendocrine systems promote signs of congestive heart failure. The loop diuretic torsemide has several characteristics that make it suitable for treatment of advanced heart failure including longer half-life, increased potency of diuretic action, and anti-aldosterone effects. ... This case series describes 3 dogs [including a 12 year-old cavalier King Charles spaniel] with advanced heart disease that despite treatment with multiple cardiac medications and moderate to high doses of furosemide experienced frequently recurring episodes of CHF. ... In each dog, replacement of furosemide with a torsemide dose, in terms of mg/kg, at one-tenth to one-thirteenth of the daily furosemide dose were associated with apparent resolution of CHF for relatively long durations of time. We speculate that when switching to torsemide, restoration of diuretic response was the most likely cause of this observation. In these and other cases managed by the authors, pet owners report notable increases in their dog’s diuresis and water consumption following institution of torsemide. In a small prospective blinded cross-over study,13 dogs with heart failure experienced significantly higher serum albumin and significantly lower urine specific gravity when receiving torsemide as compared to furosemide, suggesting that torsemide is associated with a relatively greater diuretic response. ... Torsemide’s safety and superior efficacy have previously been established in human patients with CHF. ... The restoration of diuretic responsiveness and the accompanying volume depletion that follows torsemide administration might increase risk for renal insufficiency, and care should be taken to limit or reduce administration of concurrent diuretics such as hydrochlorothiazide and to closely monitor renal function when administering torsemide. The authors also recommend that owners of dogs receiving torsemide closely monitor their dog’s urine production, water consumption, and appetite. ... Torsemide has several attractive pharmacologic properties that might aid in the long-term treatment of canine heart disease. Clinical guidelines or recommendations involving torsemide should follow from prospective clinical trials demonstrating the long-term safety and potential superiority of torsemide over furosemide and other commonly used diuretics. "

Pimobendan and Its Use in Treating Canine Congestive Heart Failure. Danielle Bowles and Darren Fry. Compendium; Nov 2011; 33(11). Quote: "Pimobendan sensitizes cardiomyocytes to calcium rather than causing absolute increases in myocardium calcium concentration in systole, thereby reducing the risk of calcium-mediated proarrhythmic effects. The labeled pimobendan dose is 0.1 to 0.3 mg/kg PO bid. Pimobendan is an inodilator: it is a calcium sensitizer and phosphodiesterase inhibitor. Pimobendan is approved for use in dogs with CHF secondary to DCM and MVD. It has been shown to improve quality of life, heart insufficiency scores, and overall mortality rates in canine patients with naturally occurring CHF. Pimobendan has been shown to induce valvular lesions in patients with asymptomatic MVD, raising the question as to its use in asymptomatic MVD patients. Further studies are under way to fully evaluate pimobendan use in dogs with naturally occurring heart disease secondary to MVD and DCM."

Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: A retrospective study of 21 cases. Eric de Madron, Jonathan N. King, Günther Strehlau, Regina Valle White. Can Vet J. Nov 2011; 52(11): 1219–1225. Quote: "This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m2 for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate."

Cardiology: Validating an echocardiographic scoring system for mitral valve disease. Julia Sargent, Virginia Luis Fuentes and Holger Volk. Vet Rec Nov 2011;169(22):590. Quote: "We are currently enrolling cases for a cardiac MRI (cMRI) clinical study in order to validate a new echocardiographic scoring system for assessing the severity of degenerative mitral valve disease in asymptomatic dogs." Contact: vluisfuentes@rvc.ac.uk 

The effect of pimobendan on left atrial pressure in dogs with mitral valve regurgitation. S Suzuki, R Fukushima, T Ishikawa, L Hamabe, D Aytemiz, H Huai-Che, S Nakao, N Machida, R Tanaka. J Vet Intern Med. November 2011;25(6):1328-33. Quote: Background: The effects of pimobendan on left atrial pressure (LAP) in dogs with mitral valve disease (MR) have not been documented in a quantitative manner. Objective: The objective was to document and study the short-term effects of pimobendan on LAP and echocardiographic parameters in MR dogs. Animals: Eight healthy Beagle dogs weighing 10.0-14.7 kg (3 males and 5 females; aged 2 years) were used. Methods: Experimental, cross-over, and interventional study. Dogs with surgically induced MR received pimobendan at either 0.25 mg/kg or 0.50 mg/kg p.o. q12h for 7 days and then, after a 7-day wash-out period, the other dosage. LAP was measured for 30 minutes at baseline and again on days 1, 2, 4, and 7 of pimobendan administration. Results: RESULTS: Mean LAP was significantly decreased after the administration of 0.25 mg/kg (15.81 ± 5.44 mmHg to 12.67 ± 5.71 mmHg, P < .001) and 0.50 mg/kg (15.76 ± 5.45 mmHg to 10.77 ± 5.23 mmHg, P < .001). Also, the 0.50 mg/kg group led to a significantly lower LAP (P < .01) compared with the 0.25 mg/kg group. Significant reduction was seen for the first time 4 days after the administration of 0.25 mg/kg and a day after the administration of 0.50 mg/kg. Conclusions & Clinical Importance: Pimobendan decreased LAP in a dose-dependent manner in dogs with acute MR caused by experimental chordal rupture. This study did not evaluate adverse effects of high-dose pimobendan, and additional studies in clinical patients are warranted. ... This study was not designed to evaluate potential adverse effects of long-term administration of pimobendan at a dosage of 0.50 mg/kg q12h. Toxic effects may occur with long-term administration of pimobendan at high dosages in asymptomatic dogs.

Self-Reported Two-dimensional Echocardiographic Estimates Of Left Atrial Size By Cardiologists: Comparison With Measured Variables. R. Georgiev, M. Rishniw, D. Ohad. J. Vet. Intern. Med. November 2011;25(6):1482. Quote: Two dimensional measurements of left atrial (LA) size are routinely obtained in echocardiographic evaluations, and often normalized to the aortic (AO) dimensions but clinicians provide subjective assessments of LA size in clinical reports. How these assessments compare to objective measurements is not known. We obtained LA and AO linear and area dimensions for 98 dogs and 20 cats with heart diseases that can result in LA enlargement from 21 cardiologists along with their subjective assessments of LA size (none, mild, moderate, severe). We compared the LA:AO and LAarea:AOarea with the self-reported subjective assessments. Additionally, we examined inter-operator variability in obtaining LA:AO and LAarea:AOarea from a single series of echocardiographic images. LA:AO differed between subjectively classified groups, except for mild and moderate classifications, which were not different from each other. Overlap existed across all but the most extreme groups. LAarea:AOarea did not differ between normal and mild classifications or moderate and severe classifications. Overlap existed across all groups. LA:AO in cats separated better than in dogs. Interobserver comparison of measurement of LA:AO and LAarea:AOarea showed that 95% of the LA:AO estimates fell within ±0.3 and 95% of the LAarea:AOarea estimates fell within ±1.2, with no evidence of bias. Our data show that objective measures of LA:AO and LAarea:AOarea differ between subjective classifications of LA size, but considerable overlap exists. Trained echocardiographers measure the LA and AO similarly from identical images.

Effects of tolvaptan on systemic and renal hemodynamic function in dogs with congestive heart failure. Toshiyuki Onogawa, Yuki Sakamoto, Shigeki Nakamura, Sunao Nakayama, Hiroyuki Fujiki, Yoshitaka Yamamura. Cardiovasc. Drugs Ther. November 2011; doi: 10.1007/s10557-011-6350-4. Quote: Purpose: We investigated the effects of tolvaptan, a vasopressin V2-receptor antagonist, on diuretic response and systemic and renal hemodynamic characteristics in conscious dogs with congestive heart failure (CHF). We also compared these effects with those of furosemide, a loop diuretic. Methods: CHF was induced by rapid right-ventricular pacing at 260 beats/min for at least 3 weeks, and maintained with a pacing rate of 220–240 beats/min. CHF dogs were orally given tolvaptan (10 mg/kg), furosemide (10 mg/kg) and vehicle in random order during the stable CHF state. Urine excretion, systemic and renal hemodynamic parameters, and plasma hormone levels were measured over 6-hour periods after drug administration. Results: Tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Tolvaptan also decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate or renal blood flow. Tolvaptan tended to increase plasma arginine vasopressin concentrations but did not affect plasma renin activity. In contrast, furosemide induced clear saluresis with increased electrolyte excretion, resulting in decreased pulmonary capillary wedge pressure. However, furosemide also decreased serum potassium concentration and increased plasma arginine vasopressin concentrations and plasma renin activity. Conclusion: Tolvaptan elicited a potent aquaretic response and reduced the cardiac preload without unfavorable effects on systemic or renal hemodynamics, the renin–angiotensin–aldosterone system, or the sympathetic nervous system in CHF dogs. Thus, tolvaptan may offer a novel approach to remove excess water congestion from patients with CHF.

Therapeutic use of fish oils in companion animals. John E. Bauer. JAVMA. December 2011;239(11):1441-1451. Quote: "Cardiovascular disorders — Dogs with heart failure have low plasma concentrations of EPA, regardless of the underlying disease. Thus, administration of omega-3 LC PUFAs may help mitigate this condition."

Effects of furosemide and the combination of furosemide and the labeled dosage of pimobendan on the circulating renin-angiotensin-aldosterone system in clinically normal dogs. Andrea C. Lantis, Clarke E. Atkins, Teresa C. DeFrancesco, Bruce W. Keene, Stephen R. Werre. Amer.J.Vet.Research. Dec. 2011;72(12):1646-1651, Quote: "Objective: To evaluate the effect of administration of the labeled dosage of pimobendan to dogs with furosemide-induced activation of the renin-angiotensin-aldosterone system (RAAS). Animals: 12 healthy hound-type dogs. Procedures: Dogs were allocated into 2 groups (6 dogs/group). One group received furosemide (2 mg/kg, PO, q 12 h) for 10 days (days 1 to 10). The second group received a combination of furosemide (2 mg/kg, PO, q 12 h) and pimobendan (0.25 mg/kg, PO, q 12 h) for 10 days (days 1 to 10). To determine the effect of the medications on the RAAS, 2 urine samples/d were obtained for determination of the urinary aldosterone-to-creatinine ratio (A:C) on days 0 (baseline), 5, and 10. Results: Mean ± SD urinary A:C increased significantly after administration of furosemide (baseline, 0.37 ± 0.14 μg/g; day 5, 0.89 ± 0.23 μg/g) or the combination of furosemide and pimobendan (baseline, 0.36 ± 0.22 μg/g; day 5, 0.88 ± 0.55 μg/g). Mean urinary A:C on day 10 was 0.95 ± 0.63 μg/g for furosemide alone and 0.85 ± 0.21 μg/g for the combination of furosemide and pimobendan. Conclusions and Clinical Relevance: Furosemide-induced RAAS activation appeared to plateau by day 5. Administration of pimobendan at a standard dosage did not enhance or suppress furosemide-induced RAAS activation. These results in clinically normal dogs suggested that furosemide, administered with or without pimobendan, should be accompanied by RAAS-suppressive treatment."

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2012

Nutritional Management of Cardiovascular Diseases, Chapter 18 in Applied Veterinary Clinical Nutrition. Lisa M. Freeman, John E. Rush. January 2012; doi: 10.1002/9781119375241.ch18. Quote: Cardiac disease is one of the most common disorders in both dogs and cats, affecting 11% of all dogs and up to 20% of some feline populations. The goal of nutritional management for animals with cardiac disease was purely symptomatic and focused only on sodiumrestriction. Hypertrophic cardiomyopathy currently is the most common form of cardiac disease in cats, but other forms of cardiomyopathy and other diseases also can occur. Dilated cardiomyopathy (DCM) once was one of the most common heart diseases in cats, until the publication of a paper associating feline DCM and taurine deficiency, with reversal of cardiomyopathy following taurine supplementation. Cardiac disease is one of the most common health problems seen in dogs, with approximately 95% of affected dogs having adult-onset. In dogs, small- to mediumsized breeds are predisposed to MMVD, while DCM is the most common cause of congestive heart failure in large-breed dogs.

Flow-Mediated Vasodilation Measurements in Cavalier King Charles Spaniels with Increasing Severity of Myxomatous Mitral Valve Disease. S.G. Moesgaard, C. Klostergaard, N.E. Zois, T. Teerlink, M. Molin, T. Falk, C.E. Rasmussen, V. Luis Fuentes, I.D. Jones, L.H. Olsen. J. Vet. Intern. Med. January 2012;26(1):61-68. Quote: Background: Cardiovascular disease is associated with endothelial dysfunction in humans and studies of plasma biomarkers suggest that dogs with myxomatous mitral valve disease (MMVD) might also have endothelial dysfunction. Hypothesis: That progression of mitral regurgitation (MR) is associated with development of endothelial dysfunction. Animals: Forty-three Cavalier King Charles Spaniels (CKCS) with MR of varying severity. Methods: Privately owned CKCS were prospectively recruited and divided in 4 groups: (1) 12 CKCS with minimal MR; (2) 9 CKCS with mild MR; (3) 11 CKCS with moderate‐severe MR; and (4) 11 CKCS with moderate-severe MR and clinical signs compatible with heart failure. Dogs underwent blood sampling, echocardiography, blood pressure (BP) recordings, and flow-mediated vasodilation (FMD) measurements. The effect of progressive MR on FMD was determined by multivariate analyses. Results: Flow-mediated vasodilation decreased with progression of MR. Group 4 (4.79 ± 3.22%) had significantly lower FMD than groups 1 (10.40 ± 4.58%) and 2 (10.14 ± 3.67%) and group 3 (6.79 ± 3.98%) had a significantly lower FMD than group 1. Increasing left ventricular end-diastolic diameter and the combination of age (P = .01) and body weight were significantly associated with reduced FMD. FMD did not correlate with sex, BP, or plasma markers. Conclusions and Clinical Importance: Reduced FMD indicates that increased disease severity in CKCS with MMVD is associated with development of endothelial dysfunction which might be a future therapeutic and/or diagnostic target.

Survival Characteristics and Prognostic Variables of Dogs with Preclinical Chronic Degenerative Mitral Valve Disease Attributable to Myxomatous Degeneration. M. Borgarelli, S. Crosara, K. Lamb, P. Savarino, G. La Rosa, A. Tarducci, J. Häggström. J. Vet. Intern. Med. January 2012;26:69–75 Quote: "Background: Preclinical myxomatous mitral valve degeneration (MMVD) includes a heterogeneous group of dogs. Therefore, identifying risk factors for progression of the disease is of clinical importance. Objectives: To investigate survival time and risk factors for clinical and echocardiographic variables taken at initial examination for clinical progression in preclinical MMVD dogs. Animals: A total of 256 dogs with stage B1 or B2 MMVD. Materials and Methods: Medical records of 256 dogs with preclinical MMVD were reviewed retrospectively. Long-term outcome was assessed by telephone interview. Dogs alive at the time of phone interview were asked to return to the hospital for re-evaluation of their cardiac status. Results: Seventy of 256 (27.3%) dogs died during the observation period. The median survival time, regardless of cause of death, was 588 (range 75–1,668) days. The presence of a murmur was associated with an increased risk of death (AHR 2.14; 95% CI 1.12, 4.11; P = 0.022). Thirty (12%) deaths were considered cardiac related. LA/Ao > 1.4 was the only negative predictor (AHR 2.64; 1.13, 6.13; P = 0.024) for cardiac-related deaths. Eighty-three dogs were re-examined, of which 34 progressed to a more advanced stage of MMVD. The presence of Emax > 1.2 (AHR 2.75; 95% CI 1.01, 7.48; P = 0.047) and cough (AHR 7.89; 95% CI 3.18, 20.07; P < 0.001) were significant in the multivariate analysis. Conclusions and Clinical Importance: Preclinical MMVD represents a relatively benign condition in dogs. Clinicians might find stratification of this dog population according to risk factors based on clinical and echocardiographic findings helpful in determining treatment."

Flow-mediated vasodilation measurements in Cavalier King Charles Spaniels with increasing severity of myxomatous mitral valve disease. S. .G. Moesgaard, C. Klostergaard, N.E. Zois, T. Teerlink, M. Molin, T. Falk, C.E. Rasmussen, V. Luis Fuentes, I.D. Jones, L.H. Olsen. J. Vet. Int. Med. January 2012;26(1):61-68. Quote: "Background: Cardiovascular disease is associated with endothelial dysfunction in humans and studies of plasma biomarkers suggest that dogs with myxomatous mitral valve disease (MMVD) might also have endothelial dysfunction. Hypothesis: That progression of mitral regurgitation (MR) is associated with development of endothelial dysfunction. Animals: Forty-three Cavalier King Charles Spaniels (CKCS) with MR of varying severity. Methods: Privately owned CKCS were prospectively recruited and divided in 4 groups: (1) 12 CKCS with minimal MR; (2) 9 CKCS with mild MR; (3) 11 CKCS with moderate-severe MR; and (4) 11 CKCS with moderate-severe MR and clinical signs compatible with heart failure. Dogs underwent blood sampling, echocardiography, blood pressure (BP) recordings, and flow-mediated vasodilation (FMD) measurements. The effect of progressive MR on FMD was determined by multivariate analyses. Results: Flow-mediated vasodilation decreased with progression of MR. Group 4 (4.79 ± 3.22%) had significantly lower FMD than groups 1 (10.40 ± 4.58%) and 2 (10.14 ± 3.67%) (P < .005) and group 3 (6.79 ± 3.98%) had a significantly lower FMD than group 1 (P = .03). Increasing left ventricular end-diastolic diameter (P = .0004, R2 = 0.27) and the combination of age (P = .01) and body weight (P = .002) (R2 = 0.31) were significantly associated with reduced FMD. FMD did not correlate with sex, BP, or plasma markers. Conclusions and Clinical Importance: Reduced FMD indicates that increased disease severity in CKCS with MMVD is associated with development of endothelial dysfunction which might be a future therapeutic and/or diagnostic target."

Heart Rate, Heart Rate Variability, and Arrhythmias in Dogs with Myxomatous Mitral Valve Disease. C.E. Rasmussen, T. Falk, N.E. Zois, S.G. Moesgaard, J. Häggström, H.D. Pedersen, B. Åblad, H.Y. Nilsen, L.H. Olsen. J.Vet.Int.Med. Jan/Feb 2012;26(1):76-84. Quote: "Background: Autonomic modulation of heart rhythm is thought to influence the pathophysiology of myxomatous mitral valve disease (MMVD). Hypotheses: (1) Holter-derived variables reflecting autonomic modulation of heart rhythm change with MMVD severity in Cavalier King Charles Spaniels (CKCS); (2) Holter-derived variables can identify MMVD severity in CKCS; and (3) Holter-derived variables in CKCS in congestive heart failure (CHF) secondary to MMVD differ from those in dogs of other breeds in CHF. Animals: Ninety privately owned dogs: 70 CKCS with variable MMVD severity and 20 non-CKCS in CHF secondary to MMVD. Methods: Dogs were prospectively recruited and divided into 5 MMVD severity groups based on history, breed, and physical and echocardiographic examination findings. Holter-derived variables included heart rate variability (HRV), heart rate (HR), and arrhythmia evaluated from 24-hour Holter recordings. Results: In CKCS, 18 of 26 HRV (all P < .0002) and 3 of 9 arrhythmia (all P < .0004) variables decreased with increasing MMVD, whereas minimum and mean HR (all P < .0001) increased with increasing MMVD severity. An arrhythmia variable representing sinus arrhythmia (“premature normals”) (P < .0001) and the HRV variable triangular index (TI) (P < .0001) could distinguish CKCS with moderate or severe mitral regurgitation from CKCS in CHF in specific intervals. Among dogs in CHF, Holter-derived variables did not differ among breeds. Conclusions and Clinical Importance: In CKCS, Holter-derived variables changed with MMVD severity. “Premature normals” and TI showed diagnostic potential. Breed differences were not seen among dogs in CHF secondary to MMVD."

Cachexia and Sarcopenia: Emerging Syndromes of Importance in Dogs and Cats. L.M. Freeman. J. Vet. Int. Med. January 2012;26(1):3-17. Quote: "Cachexia is the loss of lean body mass (LBM) that affects a large proportion of dogs and cats with congestive heart failure (CHF), chronic kidney disease (CKD), cancer, and a variety of other chronic diseases. ... Cardiac Cachexia: Cardiac cachexia is the form of cachexia that has been longest recognized and best studied. ... In 1 study of dogs, over 50% of dogs with dilated cardiomyopathy (DCM) and CHF had some degree of cachexia. The presence of cardiac cachexia, even using the relatively insensitive measure of weight loss, confers an increased risk for death in people. In addition, cachexia increases morbidity and adversely affects quality of life. Thus, it is a syndrome of substantial clinical and economic importance. An excellent systematic review of cardiac cachexia recently was published. The deleterious effects of cardiac cachexia have been emerging, and recent studies have emphasized the role of body weight and body composition in heart failure. Whereas obesity is a risk factor for development of heart disease in people, obesity actually may be associated with a protective effect once heart failure is present—this is known as the obesity paradox. ... Dogs with CHF that gained body weight had longer survival times compared with those that lost or maintained weight. ... These data emphasize the importance of avoiding weight (and muscle) loss in dogs or cats with CHF by careful attention to both the medical and nutritional aspects of their care. Cardiac cachexia typically is recognized only after CHF has developed. Loss of LBM is most readily evident in the epaxial, gluteal, scapular, or temporal muscles. Typically, the epaxial muscles over the thoracic and lumbar region are the sites in which muscle loss can be identified in its earliest stages. Anecdotally, dogs appear to be quite variable in the degree to which they show temporal muscle wasting. In some dogs, temporal muscle wasting is apparent at an early stage of CHF, whereas in other dogs, moderate to severe muscle wasting is present elsewhere before substantial temporal muscle wasting is apparent. It is also the author's clinical impression that dogs often have more substantial muscle wasting compared with cats with a similar stage of CHF. Dogs with right-sided CHF have more advanced muscle loss compared with dogs with left-sided CHF."

Renal Resistive Index in 55 Dogs with Degenerative Mitral Valve Disease. V. Chetboul, T. Daste, V. Gouni, D. Concordet, E. Trehiou-Sechi, F. Serres, J.L. Pouchelon, C.A. Germain, C. Layssol-Lamour, H.P. Lefebvre. J.Vet.Int.Med. Jan-Feb 2012; 26(1):101-108. Quote: "Background: Azotemia occurs frequently in dogs with degenerative mitral valve disease (DMVD). It could indicate changes in renal hemodynamics. Hypothesis/Objectives: To assess the renal resistive index (RI) in dogs with DMVD, and the statistical link between heart failure class, azotemia, echo-Doppler parameters, several plasma variables, and RI. Animals: Fifty-five dogs [including 15 cavaliers] with naturally occurring DVMD were used (ISACHC class 1 [n = 28], 2 [n = 19], and 3 [n = 8]). Methods: Observational, blinded study, performed under standardized conditions. Physical examination, renal ultrasonography, and echo-Doppler examinations were performed in awake dogs. The RI of the renal, interlobar, and arcuate arteries were measured. Plasma creatinine, urea, and N-terminal pro-B-type natriuretic peptide concentrations (NT-proBNP) were determined. Statistical links between variables and RI were tested by means of a general linear model. Results: Although the RI of renal and arcuate arteries were unaffected by ISACHC class, the left interlobar RI increased (P < .001) from 0.62 ± 0.05 (mean ± SD) in class 1 to 0.76 ± 0.08 in class 3. It was also higher (P < .001) in azotemic (0.74 ± 0.08) than in non-azotemic (0.62 ± 0.05) dogs. Similar findings were observed for right interlobar RI. Univariate analysis showed a positive statistical link between NT-proBNP (P = .002), urea (P < .001), creatinine (P = .002), urea-to-creatinine ratio (P < .001), left atrium-to-aorta ratio (P < .001), regurgitation fraction (P < .001), systolic pulmonary arterial pressure (P < .001), shortening fraction (P = .035), and RI. Conclusion and Clinical Importance: In dogs with DMVD, interlobar RI increases with heart failure severity and azotemia but a cause and effect relationship remains to be established."

Advanced Electrocardiographic Parameters Change with Severity of Mitral Regurgitation in Cavalier King Charles Spaniels in Sinus Rhythm. M. Sˇ piljak Pakkanen, A. Domanjko Petricˇ , L.H. Olsen, A. Stepancˇ icˇ , T.T. Schlegel, T. Falk, C.E. Rasmussen, and V. Starc. J.Vet.Int.Med.; Jan 2012;26(1):93-100. Quote: "Background: Multiple advanced resting ECG (A-ECG) techniques have improved the diagnostic or prognostic value of ECG in detecting human cardiac diseases even before onset of clinical signs or changes in conventional ECG. Objective: To determine which A-ECG parameters, derived from 12-lead A-ECG recordings, change with severity of mitral regurgitation (MR) caused by myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCSs) in sinus rhythm. Animals: 76 privately owned CKCSs. Methods: Dogs were prospectively divided into 5 groups according to the degree of MR (estimated by color Doppler mapping as the percentage of the left atrial area affected by the MR jet) and presence of clinical signs. High fidelity approximately 5-minute 12-lead ECG recordings were evaluated using custom software to calculate multiple conventional and A-ECG parameters. Results: Nineteen of 76 ECG parameters were significantly different (P < .05) across the 5 dog groups. A 4-parameter model that incorporated results from 1 parameter of heart rate variability, 2 parameters of QT variability, and 1 parameter of QRS amplitude was identified that explained 82.4% of the variance with a correlation coefficient (R) of 0.60 (P < .01). When age or murmur grade was included in the statistical model the prediction value further increased the R to 0.74 and 0.85 (P < .01), respectively. Conclusion: In CKCSs with sinus rhythm, 4 selected A-ECG parameters further improve prediction of MR jet severity beyond age and murmur grade, although the predictive increment in this study probably is not sufficient to warrant utilization in clinical veterinary practice."

Evaluation of plasma N-terminal pro-B-type natriuretic peptide concentrations in dogs with and without cardiac disease. Stephen J. Ettinger, Giosi Farace, Scott D. Forney, Michelle Frye, Andrew Beardow. JAVMA Jan 2012; 240(2):171-180. Quote: "Objective—To evaluate plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in a large, diverse population of dogs with and without cardiac disease and to define the upper reference limit for the biomarker in this species. Design—Cross-sectional single center study. Animals—1,134 dogs [including 37 cavalier King Charles spaniels]. Procedures—Dogs underwent blood sample collection, physical examination, ECG, and echocardiographic and thoracic radiographic evaluations. Cardiac status was graded by use of a 9-grade cardiac disease classification system and a simplified 4-stage cardiac scoring system. Vertebral heart score (VHS) was assessed in 280 dogs. Associations of plasma NT-proBNP concentrations with multiple variables were evaluated via univariate and multivariate linear regression analysis. Sensitivity and specificity of NT-proBNP concentrations and of VHS to discriminate between dogs with and without clinical signs of cardiac disease were evaluated via receiver-operating characteristic curve analysis. Results—974 dogs had cardiac disease, 37 had noncardiac-related disease, and 123 were healthy. Plasma NT-proBNP concentrations correlated with cardiac grade and stage; VHS was also associated with cardiac grade. At a cutoff of 874 pmol/L, sensitivity and specificity of NT-proBNP concentration to detect clinical signs of cardiac disease were 70% and 83%, respectively; for VHS, sensitivity and specificity were 56% and 85%, respectively, at a cutoff of 11.5. Mean NT-proBNP concentration was significantly increased in dogs with cardiac-related dyspnea or coughing, compared with dogs in which these signs were noncardiac related. Conclusions and Clinical Relevance—Results suggested that 900 pmol/L is the upper reference limit of plasma NT-proBNP concentration in dogs. This biomarker may be a useful tool for staging of cardiac disease and identifying cardiac-related coughing or dyspnea in this species."

The rapidly evolving field of biomarkers of cardiac function and injury in dogs: Challenges and next steps. Wayne R. Buck, Bruce E. LeRoy, Eric A.G. Blomme. Vet.J. Jan 2012;191(1):13-14. Quote: "[B]iomarkers have received a similar level of attention, in particular the two natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). While ANP can be measured directly, BNP release is most often evaluated indirectly through the measurement of the inactive amino terminal of the prohormone ProBNP (NT-proBNP), which has a longer circulating half-life, higher concentration in the circulation and higher stability than BNP. ... The value of any biomarker is not only based on its biological nature, but also on the assay used to measure it. Hence, it is critical for authors to thoroughly describe or document the nature and analytical performance of assays used and, when appropriate, their associated reference values."

Differentiating the aging of the mitral valve from human and canine myxomatous degeneration. Patrick S. Connell, Richard I. Han, K. Jane Grande-Allen. J. Vet. Cardiol. January 2012;14:31–45. Quote: "During the course of both canine and human aging, the mitral valve remodels in generally predictable ways. The connection between these aging changes and the morbidity and mortality that accompany pathologic conditions has not been made clear. By exploring work that has investigated the specific valvular changes in both age and disease, with respect to the cells and the extracellular matrix found within the mitral valve, heretofore unexplored connections between age and myxomatous valve disease can be found. This review addresses several studies that have been conducted to explore such age and disease related changes in extracellular matrix, valvular endothelial and interstitial cells, and valve innervation, and also reviews attempts to correlate aging and myxomatous disease. Such connections can highlight avenues for future research and help provide insight as to when an individual diverts from an aging pattern into a diseased pathway. Recognizing these patterns and opportunities could result in earlier intervention and the hope of reduced morbidity and mortality for patients."

Compounded Pimobendan for Canine Chronic Degenerative Mitral Valve Disease and Pulmonary Hypertension. Helms Scott R, Fox Samantha, Mixon William, Vail Jane. Int'l J. Pharmaceutical Compounding. Jan. 2012;16(1):34-41. Quote: "Pimobendan (Vetmedin) is an effective treatment for canine chronic degenerative mitral valve disease and dilated cardiomyopathy. In an off-label use, it may also be of benefit for the treatment of pulmonary hypertension in dogs. In this report, we describe the effects of a palatable customized oral form of pimobendan used with both compounded and commercially manufactured conventional drug therapy to treat degenerative mitral valve disease and pulmonary hypertension in two small dogs. For those patients, who resisted many types of oral medication, the standard manufactured dose of pimobendan was inappropriate. Formulations of the preparations used to treat the patients described in this report are provided for easy reference. It should be noted that at the time of this writing, Boehringer Ingelheim GmbH (Ingelheim am Rhein, Germany), the manufacturer of pimobendan, has expressed concern about the stability of that agent in aqueous compounded form. To our knowledge, no current data confirming the stability or bioequivalence of compounded pimobendan exist."

How I treat hypertension. Clarke Atkins. Vet.Focus. 2012;22(1):17-23.

Mitral valve degeneration: Still more questions than answers. E. Christopher Orton. J.Vet.Card. March 2012;14(1):3-5. Quote: "While many questions remain, it is apparent that DMVD is receiving ever-increasing and well-deserved attention as a canine and human health problem. Future progress depends on continued collaboration between research scientists and clinician scientists from multiple disciplines. Ths special issue is testament that the prospect for continued progress looks bright."

Characterisation and cardiac directed differentiation of canine adult cardiac stem cells. Hannah M. Hodgkiss-Geere, David J. Argyle, Brendan M. Corcoran, Bruce Whitelaw, Elspeth Milne, David Bennett, Sally A. Argyle. Vet.J. February 2012;191(2):176-182. Quote: This study describes the isolation and characterisation of adult canine cardiac stem cells, and explores their ability to differentiate into cardiac myocytes. Direct comparisons are also made with available human data. Atrial cardiac explants were taken from dogs post-mortem and cultured to isolate adult stem cells. Cells were able to survive successive passages in serum-free media, were able to form cardiospheres, and under controlled culture conditions were capable of clonal expansion, demonstrating their ability for self-renewal. Characterisation of these cells demonstrated the following marker profile: c-kit, GATA 4 and flk-1 positive; cardiac troponin T and NKx2.5 low. Cardiac lineage directed differentiation was performed based on the published literature. Gene expression studies demonstrated that cardiac directed differentiation was partially achieved, with up-regulation of cardiac troponin T and NKx2.5, and down-regulation of c-kit and endothelial lineage markers. However the cells did not express the ryanodine receptor or β1-adrenergic receptors and did not contract spontaneously.

Myxomatous mitral valve disease in dogs: Does size matter? Heidi G. Parker and Paul Kilroy-Glynn. J.Vet.Card. March 2012; 14(1): 19–29.  Quote: "Myxomatous mitral valve disease (MMVD) is the most commonly diagnosed cardiovascular disease in the dog accounting for more than 70% of all cardiovascular disease in dogs. ... The incidence is particularly high in some breeds such as the Cavalier King Charles Spaniel (CKCS) with as many as 90% developing MMVD by the age of 10 years. Evidence from highly susceptible breeds such as the CKCS and dachshund shows a strong inherited component to the disease and suggests a polygenic mode of inheritance. In fact, two loci [chromosomes CFA13 and CFA14] have been recently associated with MMVD in the CKCS. ... As are most canine diseases with genetic underpinnings, risk of MMVD is greatly increased in a subset of breeds. What is uncommon is that the vast majority of the breeds at elevated risk for MMVD are small or toy breeds with average adult weights under 9 kg. These breeds appear to have little in common other than their diminutive size. ... [T]hey found that nearly 75% of breeds with average body weight of less than 9 kg report cardiovascular issues as a major cause of death compared to only 25% of breeds with average weights over 9 kg. Can there be a link between being small and developing heart disease? ... This study revealed two important facts about dogs: one, genes that affect major morphologic traits will be shared across multiple breeds, and two, all small dog breeds share at least one common ancestor that contributed the IGF1 allele. This finding is particularly intriguing when we consider that the IGF1 gene has been implicated in cardiac development as well as body size. ... Since it has been shown that IGF1 is a major contributor to reduction in body size in dogs, if the heart is not shrinking at the same scale in small dogs, this mutation alone could be responsible for over-crowding leading to the valve malformations. In addition, IGF1 has a direct effect on heart growth which could lead to malformations if regulated improperly as would be expected under selection for small size. ... We have considered a variety of mechanisms to explain the over-representation of small and toy breeds in the list of those most at risk for MMVD. One possibility is that smaller dogs have a larger heart to body size ratio than do larger dogs. ... Many genes that affect skeletal growth and development also affect cardiac development. In addition, genes can be found near the growth loci that are required for normal cardiac valve formation. Because all small breeds carry many of the same mutations that create small size they will also carry linked genes that could increase susceptibility to MMVD. ... Many of the at-risk breeds share common ancestry from an early small dog that has transmitted susceptibility genes to its descendants. As the source of MMVD risk, this transmission could be identified through admixture mapping of the atrisk breeds with a dense set of markers and a large dataset of breed haplotypes. It is formally possible that each breed has developed a unique mutation that has become prevalent due to restrictive breeding practices. However, given the high incidence of the disease combined with similarity among susceptible breeds, it is more likely that shared loci contribute to the disease. ... A final trait that is shared between small dogs that might contribute to the development of MMVD is extended lifespan. It is often noted that small dogs live longer, on average, than large dogs. MMVD is reported to be a disease of the aging heart, as described in detail by Connell et al. in this issue. This has led to the speculation that small dogs are diagnosed more often merely because they live long enough for the disease to progress. While age is doubtless a contributor, lifespan is unlikely to be the sole reason for the increased appearance of MMVD in small dogs. ... Though we have proposed many possibilities within this review, only time and experimental evidence will reveal the means by which MMVD has arisen in small breeds."

Post-mortem evaluation of expanded polytetrafluoroethylene (ePTFE) used in mitral valve repair in dogs. Miki Nishida, Yumiko Kagawa, Takahiro Mizukoshi, Masashi Mizuno, Takeshi Mizuno, Kayoko Harada, Masami Uechi. J.Vet.Card. March 2012;14(1):307-312. Quote: "Mitral valve repair is one of the treatment options for mitral regurgitation. Expanded polytetrafluoroethylene (ePTFE) is a polymer that has been widely used in cardiovascular surgery. In this case series, we report the autopsy and histological findings in 6 dogs that underwent cardiopulmonary bypass for mitral annuloplasty using ePTFE sheets and chordoplasty using ePTFE sutures. From May 2005 to October 2009, 3 female and 3 male dogs with severe mitral regurgitation underwent mitral valve repair. This case series included 3 Cavalier King Charles spaniels, 2 Maltese, and 1 Shih Tzu. The survival period after surgery was 19–72 (35 ± 19) months. In all the cases, autopsy revealed that the ePTFE sheets and sutures were not damaged and well integrated into the surrounding highly differentiated, connective tissues. Low-power microscopy revealed that in all cases, the tissues surrounding the ePTFE sheet in the mitral valve annulus had almost completely been covered by granulation tissue. No inflammatory infiltrate or thrombogenesis was observed around the ePTFE in any of the cases. There was no evidence of reactive changes in the region surrounding the ePTFE. These results suggest that ePTFE has excellent tissue compatibility and durability and can be effectively used for canine mitral valve repair."

Left ventricular function quantified by myocardial strain imaging in small-breed dogs with chronic mitral regurgitation. Danielle N. Smith, John D. Bonagura, Nicole M. Culwell, Karsten E. Schober. J. Vet. Cardiol. March 2012; doi: j.jvc.2011.11.002. Quote: Background: The presence of left ventricular (LV) systolic dysfunction may influence prognosis or therapy in dogs with chronic mitral regurgitation (MR). Assessment of LV function in MR by conventional echocardiography is confounded by altered ventricular loading. Myocardial deformation (strain) imaging might offer more sensitive estimates of LV function in this disease. Objective: Prospectively measure myocardial strain in dogs with asymptomatic MR compared to a control group. Animals, materials and methods: Forty healthy dogs (3.5–11.5 kg): 20 Controls; 20 dogs [including 9 (45%) cavalier King Charles spaniels] with MR and LV remodeling (Stage B2), were evaluated in this study. LV size and function were assessed in a short-axis plane. Segmental radial strain and strain rate and global circumferential strain were measured using a 2D echocardiographic speckle-tracking algorithm (GE EchoPAC). Groups were compared using Bonferroni t-tests. Influences of heart rate and body weight were explored with linear regression. ... Owing to the over-representation of one breed in the MR group, the key global systolic and diastolic strain variables were assessed in two sub-groups, Cavalier King Charles spaniel versus “other breed”. ... Results: The MR group had significantly greater mean values for heart rate, LV size, and LV systolic function. Specifically, LV diastolic diameter, diastole area, shortening fraction, averaged peak systolic and early diastolic radial strain, global circumferential strain, and averaged radial strain rate were significantly greater in the MR group (p < 0.015 to p < 0.001). Strain was unrelated to weight, but weakly correlated with heart rate. ... In the secondary analyses of dogs in the MR group based on breed (Cavalier King Charles Spaniels vs. other breeds) or treatment (enalapril or not), there were no significant differences identified between the two sub-groups for any of the strain indices. While not analyzed statistically, the mean and 95% confidence intervals for the means of the six individual segments in the MR dogs were similar. ... While the two study groups were very close in terms of age and weight, the groups were unbalanced in terms of breed with the Cavalier King Charles Spaniel over-represented in the MR group. ... Conclusions: Similar to conventional indices, Stage B2 dogs with MR demonstrate hyperdynamic deformation in the short-axis plane. Short-axis strain variables measured by 2D speckle tracking are greater than for controls of similar age and weight. These results imply either preserved LV systolic function or that LV dysfunction is masked by altered ventricular loading.

Retrospective review of carvedilol administration in 38 dogs with preclinical chronic valvular heart disease. Sonya G. Gordon, Ashley B. Saunders, Crystal D. Hariu, May M. Boggess, Matthew W. Miller. J.Vet.Card. March 2012;14(1):243-252. Quote: "Objectives: Report the effect of carvedilol administration on clinical and echocardiographic parameters and outcome in dogs with preclinical (ACVIM Stage B) chronic valvular heart disease (CVD). Animals: Retrospective case series of 38 client-owned dogs. Results: Baseline data and follow-up were evaluated. Median and interquartile range (IQR) for age and weight were 8.6 (7.2–10.8) years and 8.5 (7.6–9.6) kg. 14/38 were male; 33/38 were Cavalier King Charles Spaniels; 33/38 had Stage B2 CVD. The initial dose of carvedilol was 0.31 (0.26–0.35) mg/kg PO twice daily. The carvedilol dose achieved following up titration was 1.11 (0.81–1.32) mg/kg twice daily. No adverse effects were recorded during up titration. Median survival for all dogs was 48.5 months with a 95% CI of 38.3–58.6. Conclusions: This study suggests that carvedilol at the dose reported herein is well tolerated in small breed dogs with preclinical CVD. Prospective studies to evaluate efficacy are warranted."

Effect of torsemide and furosemide on clinical, laboratory, radiographic and quality of life variables in dogs with mitral valve disease. Gordon D. Peddle, Gretchen E. Singletary, Caryn A. Reynolds, Dennis J. Trafny, Maggie C. Machen, Mark A. Oyama. J.Vet.Card. March 2012;14(1):253-259. Quote: "Objectives: Diuretic therapy reduces preload and relieves congestion secondary to cardiac dysfunction. Torsemide (torasemide) is a loop diuretic with longer duration of action, decreased susceptibility to diuretic resistance, and adjunctive aldosterone antagonist properties compared with furosemide. We hypothesized that torsemide would be well tolerated and no less effective than furosemide at diuresis, control of clinical signs, and maintenance of quality of life (QOL) in dogs with congestive heart failure (CHF). Animals, materials and methods: Seven client-owned dogs with stable CHF receiving twice daily oral furosemide and adjunctive medications. Utilizing a double-blinded, randomized, crossover design, dogs were administered either oral furosemide at their current dose or an equivalent oral dose of torsemide (1/10 of the daily furosemide dose divided into twice daily dosing) on day 0. Crossover occurred at day 7 and the study ended on day 14. Clinical, laboratory, radiographic, and QOL variables were evaluated on days 0, 7 and 14. Results: No dogs developed recurrent CHF during the study. Mean furosemide dose on day 0 was 5.13 mg/kg/day (range 2.8–9.6). Following torsemide treatment, creatinine (P = 0.020), urea nitrogen (P = 0.013), phosphorus (P = 0.032), albumin (P = 0.019), carbon dioxide (P = 0.015) and anion gap (P = 0.005) were significantly increased, and urine specific gravity (P = 0.004) and chloride (P = 0.021) were significantly decreased compared with furosemide dosing. No differences in QOL were found. Conclusions: Results indicate that torsemide is equivalent to furosemide at controlling clinical signs of CHF in dogs and is likely to achieve greater diuresis vs. furosemide. Larger clinical trials evaluating torsemide as a first or second-line loop diuretic for congestive heart failure in dogs are warranted."

Selected echocardiographic variables change more rapidly in dogs that die from myxomatous mitral valve disease. Melanie J. Hezzell, Adrian Boswood, Walasinee Moonarmart, Jonathan Elliott. J.Vet.Card. March 2012;14(1):269-279. Quote: "Objectives: To determine if echocardiographic measurements change at a greater rate in dogs with myxomatous mitral valve disease (MMVD) that die of cardiac mortality. Animals: Client-owned dogs (n = 242) with MMVD of varying severity were recruited from first opinion private practice . Only dogs which died during the study period (n = 102) were included in statistical analyses. ... Cavalier King Charles spaniels (CKCS) were most frequently represented (n = 26) [25.5%] ...  Methods: Prospective cohort study comparing the rate of change of echocardiographic variables between dogs that experienced cardiac mortality and those that experienced non-cardiac mortality. ... There were significantly more CKCS in the cardiac death group than in the non-cardiac death group.  ... Measurements were repeated approximately every 6 months and repeated measures linear models were constructed to estimate the rate of change of each variable over time. Results: Left ventricular (LV) end-diastolic diameter, normalized for body weight (LVEDDN) increased over time in both mortality groups. LV end-systolic diameter, normalized for body weight (LVESDN), LV end-diastolic diameter to LV free wall thickness in diastole (LVEDD/LVFWd) ratio, E wave velocity, E- to A-wave velocity ratio and left atrial to aortic root diameter ratio all increased over time in the cardiac mortality group, but did not change in the non-cardiac mortality group. MR velocity decreased over time in the cardiac mortality group but did not change in the non-cardiac mortality group. Tricuspid regurgitation jet velocity increased over time in both mortality groups. A wave velocity and fractional shortening did not change over time in either mortality group. Conclusions: Serial echocardiographic examination every 6–12 months is useful to identify dogs with progressive MMVD that are at increased risk of cardiac mortality."

Echocardiographic assessment of canine degenerative mitral valve disease. Valérie Chetboul, Renaud Tissier. J.Vet.Card. March 2012;14(1):127-148. Quote: "Degenerative mitral valve disease (MVD), the most common acquired heart disease in small-sized dogs, is characterized by valvular degeneration resulting in systolic mitral valve regurgitation (MR). Worsening of MR leads to several combined complications including cardiac remodeling, increased left ventricular filling pressure, pulmonary arterial hypertension, and myocardial dysfunction. Conventional two-dimensional, M-mode, and Doppler examination plays a critical role in the initial and longitudinal assessment of dogs affected by MVD, providing information on mitral valve anatomy, MR severity, left ventricular (LV) size and function, as well as cardiac and vascular pressures. Several standard echocardiographic variables have been shown to be related to clinical outcome. Some of these markers (e.g., left atrium to aorta ratio, regurgitation fraction, pulmonary arterial pressure) may also help in identifying asymptomatic MVD dogs at higher risk of early decompensation, which remains a major issue in practice. However, both afterload and preload are altered during the disease course. This represents a limitation of conventional techniques to accurately assess myocardial function, as most corresponding variables are load-dependent. Recent ultrasound techniques including tissue Doppler imaging, strain and strain rate imaging, and speckle tracking echocardiography, provide new parameters to assess regional and global myocardial performance (e.g., myocardial velocities and gradients, deformation and rate of deformation, and mechanical synchrony). As illustration, the authors present new data obtained from a population of 91 dogs (74 MVD dogs, 17 age-matched controls) using strain imaging, and showing a significant longitudinal systolic alteration at the latest MVD heart failure stage."

Prediction of first onset of congestive heart failure in dogs with degenerative mitral valve disease: The PREDICT cohort study. Caryn A. Reynolds, Dorothy Cimino Brown, John E. Rush, Philip R. Fox, Thaibihn P. Nguyenba, Linda B. Lehmkuhl, Sonya G. Gordon, Heidi B. Kellihan, Rebecca L. Stepien, Bonnie K. Lefbom, C. Kate Meier, Mark A. Oyama. J.Vet.Card. March 2012;14(1):193-202. Quote: "Objective: To identify risk factors for first-onset congestive heart failure (CHF) in dogs with degenerative mitral valve disease (DMVD). Animals: Eighty-two dogs with and without CHF secondary to DMVD were retrospectively assigned to a derivation cohort. Sixty-five dogs with asymptomatic DMVD were recruited into a prospective validation cohort. Methods: Variables associated with risk of CHF in dogs were identified in a derivation cohort and used to construct a predictive model, which was then prospectively tested through longitudinal examination of a validation cohort. Results: Logistic regression analysis of the derivation cohort yielded a predictive model that included the left atrial to aortic root dimension ratio (LA:Ao) and plasma concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP). When this model was prospectively applied to the validation cohort, it correctly predicted first-onset of CHF in 72.5% of cases. Analysis of the validation cohort revealed that plasma NT-proBNP concentration and indexed left ventricular end-diastolic diameter (LVIDd:Ao) were independent risk factors for development of first-onset CHF in dogs with DMVD (NT-proBNP ≥1500 pmol/L, odds ratio (OR), 5.76, 95% confidence interval (CI), 1.37–24.28, P = 0.017; LVIDd:Ao ≥3, OR, 6.11, 95% CI, 1.09–34.05, P = 0.039). Conclusions: Measures of left heart size and plasma NT-proBNP concentration independently estimate risk of first-onset of CHF in dogs with DMVD. These parameters can contribute to the management of dogs with DMVD."

Ultrasonographic measurement of flow-mediated vasodilation in dogs with chronic valvular disease. Ian D. Jones, Virginia Luis Fuentes, Adrian Boswood, Melanie J. Hezzell, David Wrigglesworth, Ana Mateus, Walasinee Moonarmart, Jonathan Elliott. J.Vet.Card. March 2012;14(1):203-210. Quote: "Objectives: To measure flow-mediated vasodilation (FMD) in healthy dogs and in client-owned dogs with chronic valvular disease (CVD) and to investigate possible correlations between markers of CVD severity and FMD. Animals: Twelve dogs with CVD and 11 healthy weight-matched dogs. Methods: Brachial artery FMD following 5 min inflation of a cuff around the antebrachium was measured in 12 dogs with CVD and 11 healthy weight-matched dogs. Measurements were also obtained in the healthy dogs 5 min after cuff placement but without inflation (‘sham cuff placement’). Dogs with CVD underwent echocardiography to confirm and characterize their disease. Results: In healthy dogs (median age 4 [2–6] years), median FMD was 7.7% versus 3.4% with sham cuff placement (P = 0.003). In dogs with CVD (median age 8 [4–16] years) median FMD was 5.5% versus 7.7% in healthy dogs (P = 0.131). FMD showed an inverse correlation with left ventricular end-diastolic diameter normalized for body weight (r = −0.76, P = 0.0043). Conclusions: Brachial FMD in dogs with early CVD inversely correlates with severity of left ventricular remodelling."

The Combined Prognostic Potential of Serum High-Sensitivity Cardiac Troponin I and N-Terminal pro-B-Type Natriuretic Peptide Concentrations in Dogs with Degenerative Mitral Valve Disease. M.J. Hezzell, A. Boswood, Y.-M. Chang, W. Moonarmart, K. Souttar, J. Elliott. J.Vet.Int.Med. March 2012;26(2):302-311. Quote: Background: Identification of factors associated with decreased survival in dogs with degenerative mitral valve disease (DMVD) will allow more accurate prognosis. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is negatively associated with survival in dogs with DMVD. In human patients, multimarker strategies provide superior risk stratification compared with single markers. Hypothesis: High-sensitivity cardiac troponin I (hscTnI) and other clinical variables will be associated with survival time in dogs with DMVD. Measuring hscTnI and NT-proBNP in combination will be prognostically superior to measurement of either marker alone. The rate of change of these markers will vary according to cause of death. Animals: Client-owned dogs (n = 202) [77 were cavalier King Charles spaniels] with DMVD of varying severity and age-matched healthy control dogs (n = 30) [7 were CKCSs] recruited from first opinion private practice. Methods: Prospective cohort study relating clinical variables at enrollment in dogs with DMVD to survival time (all-cause, cardiac, and noncardiac mortality). Multivariable Cox regression analysis was used to identify factors associated with survival. Measurements were obtained approximately every 6 months. Repeated measures models were constructed to assess changes over time. Results: hscTnI, LVEDDN, heart rate, and age were independently associated with decreased survival time (all-cause mortality). Survival times were shortest in dogs in which both serum hscTnI and NT-proBNP were increased. hscTnI and NT-proBNP increased more rapidly in dogs that died of cardiac disease. Conclusions and Clinical Importance: Serum hscTnI has prognostic value in dogs with DMVD. Measurement of NT-proBNP and hscTnI is prognostically superior to measuring either alone. Serial measurement strategies provide additional prognostic information.

Pharmacologic management of myxomatous mitral valve disease in dogs. Clarke E. Atkins, Jens Häggström. J.Vet.Card. March 2012;14(1):165-184. Quote: "Myxomatous mitral valve disease (MMVD) causing mitral regurgitation is the most important disease of the heart in small animal cardiovascular medicine. Because MMVD is an example of a chronic disease that progresses from mild to severe over years, treatment strategies change with the stage of the disease. In this review the treatment options are compared and contrasted as they are discussed relative to the recently published ACVIM consensus statement regarding the treatment of MMVD. Results from clinical trials and evidence-based medicine promises to provide significant improvements in the management of MMVD in the coming decades." ... Authors concur on these points: "[C]linical efficacy (effect on time to onset of signs of congestive heart failure) and safety of inodilator therapy [e.g., pimobenan] in Class B dogs are not completely understood." "There are presently no clinical trial data supporting a prophylactic effect of BARA [beta blockers] in asymptomatic MMVD (or any other cardiac condition in animals)." "Whether spironolactone indeed counteracts intramyocardial arterial changes and replacement fibrosis in dogs with MMVD, and if this is associated with a better long-term prognosis, remains to be proven. A clinical trial is currently ongoing evaluating the effects of spironolactone in Class B2 MMVD dogs." "The most recent study, the QUEST trial offers the most compelling evidence of beneficial actions of pimobendan in dogs with CHF caused by MMVD. This, the largest clinical trial yet performed in veterinary cardiovascular medicine, was designed as single-blind study in which the effects of pimobendan, with conventional therapy, extended survival (267 vs 140 days, a 4 month benefit), when compared to conventional therapy plus benazepril. The beneficial effect on survival times was maintained after correcting for all baseline variables, compensating for any imbalance between treatment groups. These results established pimobendan as an effective therapeutic agent in the treatment of dogs with MMVD and CHF. ... While the QUEST trial clearly shows that pimobendan therapy is indicated in Class C2 dogs with MMVD, it does not provide any information concerning the impact of combining pimobendan and an ACE-I in these patients." Author Atkins' positions: "[I]t is my opinion that ACE-I are indicated in treatment of asymptomatic MMVD and MR and likely will remain part of any proven protocol in the future." Author Häggström's positions: "[I]t is my opinion that, even if the ACE-I have been shown to be comparably safe, the available data indicate that they are ineffective in preventing disease progression, but it is ultimately the decision of the practitioner to recommend ACE-I for chronic use in the class B2 MMVD dogs and the informed decision of the owner to put the effort and financial investment into medicating the pet chronically."

Signaling pathways in mitral valve degeneration. E. Christopher Orton, Carla M.R. Lacerda, Holly B. MacLea. J.Vet.Card. March 2012;14(1):7-17. Quote: "Heart valves exhibit a highly-conserved stratified structure exquisitely designed to counter biomechanical forces delivered over a lifetime. Heart valve structure and competence is maintained by heart valve cells through a process of continuous turnover extracellular matrix (ECM). Degenerative (myxomatous) mitral valve disease (DMVD) is an important disease associated with aging in both dogs and humans. DMVD is increasingly regarded as a disease with identifiable signaling mechanisms that control key genes associated with regulation and dysregulation of ECM homeostasis. Initiating stimuli for these signaling pathways have not been fully elucidated but likely include both mechanical and chemical stimuli. Signaling pathways implicated in DMVD include serotonin, transforming growth factor β (TGFβ), and heart valve developmental pathways. High circulating serotonin (carcinoid syndrome) and serotoninergic drugs are known to cause valvulopathy that shares pathologic features with DMVD. Recent evidence supports a local serotonin signaling mechanism, possibly triggered by high tensile loading on heart valves. Serotonin initiates TGFβ signaling, which in turn has been strongly implicated in canine DMVD. Recent evidence suggests that degenerative aortic and mitral valve disease may involve pathologic processes that mimic osteogenesis and chondrogenesis, respectively. These processes may be mediated by developmental pathways shared by heart valves, bone, and cartilage. These pathways include bone morphogenic protein (BMP) and Wnt signaling. Other signaling pathways implicated in heart valve disease include Notch, nitric oxide, and angiotensin II. Ultimately, increased understanding of signaling mechanisms could point to therapeutic strategies aimed at slowing or halting disease progression."

Historical review, epidemiology and natural history of degenerative mitral valve disease. Michele Borgarelli, James W. Figure 1Buchanan. J.Vet.Card. March 2012; 14:93-101. Quote: Chronic mitral valve disease due to myxomatous degeneration (MMVD) is the most common cardiovascular disease in dogs and has been known to cause congestive heart failure for more than 100 years. This article presents an historical perspective of the disease and reviews the most updated data on epidemiology and natural history of MMVD in dogs. ... The mitral valve is probably the most abused and stressed tissue in the body because it is intermittently bent, slammed, tensed, shear stressed and stretched, 50-200 times a minute, 24 h a day, 365 days a year for 10-15 years. The wonder is not that it degenerates but rather how it survives so well. ... An inverse relationship was found between the degree of MVP and body weight in Cavaliers. ... Conclusions: MMVD has been recognized in dogs for over a century but pathologic and clinical studies have not revealed its cause or why it occurs 10 times more frequently in dogs than in man. It is hoped that the development of new techniques of molecular biology, microscopy or histochemistry and biomarkers will finally provide insight and answers that can lead to ways of preventing or stopping the progression of the disease in dogs as well as humans.

Pathology of myxomatous mitral valve disease in the dog. Philip R. Fox. J.Vet.Card. March 2012;14(1):103-126. Quote: "Mitral valve competence requires complex interplay between structures that comprise the mitral apparatus – the mitral annulus, mitral valve leaflets, chordae tendineae, papillary muscles, and left atrial and left ventricular myocardium. Myxomatous mitral valve degeneration is prevalent in the canine, and most adult dogs develop some degree of mitral valve disease as they age, highlighting the apparent vulnerability of canine heart valves to injury. ... Younger animals can also be affected, particularly the Cavalier King Charles spaniel  ... Myxomatous valvular remodeling is associated with characteristic histopathologic features. Changes include expansion of extracellular matrix with glycosaminoglycans and proteoglycans; valvular interstitial cell alteration; and attenuation or loss of the collagen-laden fibrosa layer. These lead to malformation of the mitral apparatus, biomechanical dysfunction, and mitral incompetence. Mitral regurgitation is the most common manifestation of mxyomatous valve disease and in advanced stages, associated volume overload promotes progressive valvular regurgitation, left atrial and left ventricular remodeling, atrial tears, chordal rupture, and congestive heart failure. Future studies are necessary to identify clinical-pathologic correlates that track disease severity and progression, detect valve dysfunction, and facilitate risk stratification. It remains unresolved whether, or to what extent, the pathobiology of mxyomatous mitral valve degeneration is the same between breeds of dogs, between canines and humans, and how these features are related to aging and genetics."

Pulmonary hypertension in canine degenerative mitral valve disease. Heidi B. Kellihan, Rebecca L. Stepien. J.Vety.Cardio. March 2012;14(1):149-164. Quote: "Pulmonary hypertension secondary to degenerative mitral valve disease has been recognized clinically for many years in veterinary medicine, and clinical diagnosis of this syndrome in dogs has been enhanced greatly by widespread use of echocardiography and Doppler echocardiography. Medical therapy is now available to treat this clinical complication of mitral valve disease, making timely diagnosis even more important to patient longevity and quality of life. ... [including the use of diuretics (e.g. furosemide or torsemide), balanced vasodilators (e.g. angiotensin-coverrting-enzyme [ACE] inhibitors, pimobendan), neurohormonal blockers (e.g. ACE inhibitors, aldosterone antagonists) and positive intropes (e.g. pimobendan). In addition to the standard therapies used to treat MV disease in dogs, medications that directly affect abnormalities in the PA [pulmonary artery] endothelin pathway, prostanoid pathway and NO [nitric oxide] pathway have been described as possible PH [pulmonary hypertension] therapies. ... bosentan ... epoprostenol ... At present, calcium-sensitizinf PDE-3 inhibitors (e..g. pimobendan) and PDE-5 inhibitors (e.g. sildenafil) represent the most often used pulmonary vasodilators in dogs. ... In studies of dogs with PH of many causes including left-heart disease, sildenafil administration has been found to decrease PH severity, increase exercise capacity, and improve quality of life. ... Tadalafil (Cialis) and varenafil (Levitra) are long-acting, once daily, orally administered PDE-5 inhibitors. ... Further studies are required to delineate the clinical effects and potential clinical value of these medications."

Mitral valve dysplasia characterized by isolated cleft of the anterior leaflet resulting in fixed left ventricular outflow tract obstruction. Cristiane Otoni, Jonathan A.Abbott. J. Vet. Cardiol. March 2012;14(1):301-305. Quote: A 7-month-old, sexually intact male English toy spaniel weighing 4 kg was referred for evaluation of a subclinical cardiac murmur. Echocardiography disclosed fixed left ventricular outflow tract obstruction that was caused by attachment of a cleft anterior mitral valve leaflet to the interventricular septum. Neither atrial nor ventricular septal defects were detected. Fixed obstruction of the left ventricular outflow tract by a malformed mitral valve is rare in human beings and has not been previously reported in the dog. ... [A]t the age of 8.5 years, the patient was presented for evaluation and management of anemia. A diagnosis of lymphoid leukemia was confirmed antemortem and the petowner elected euthanasia. Regrettably, postmortem examination was not performed.

 Bronchomalacia in Dogs with Myxomatous Mitral Valve Degeneration. M.K. Singh, L.R. Johnson, M.D. Kittleson, R.E. Pollard. J. Vet. Intern. Med. March 2012;26(2):312-319. Quote: Background: Cough in the geriatric small breed dog with myxomatous mitral valve degeneration (MMVD), a large left atrium, and absence of heart failure often is attributed to compression of the left mainstem bronchus by the left atrium. Studies investigating this syndrome are lacking in dogs. Hypothesis: Airway collapse is independent of left atrial enlargement. Animals: A total of 16 dogs presenting with chronic cough in the absence of congestive heart failure. Group 1 dogs (n = 10) had moderate-to-severe left atrial enlargement based on an echocardiographically calculated left atrial:aortic surface area [LA:Ao(a)] > 6. Group 2 dogs (n = 6) had no to mild left atrial enlargement [LA:Ao(a) ≤ 6]. Methods: Dogs were prospectively evaluated. CBC, biochemistry, urinalysis, cervical and thoracic radiographs, fluoroscopy, echocardiography, and bronchoscopy were performed. Bronchoscopic abnormalities were compared between groups using Fisher's Exact Test. P < .05 was considered significant. Results: Fluoroscopy identified airway collapse in both groups. Bronchoscopic evidence of airway collapse >50% was observed in multiple bronchi with no difference between groups. All dogs had inflammation on airway cytology with respiratory infection in 1 dog in group 2. Left atrial size was interpreted radiographically as enlarged in 9 of 10 group 1 dog and in 2 of 6 group 2 dogs. VHS was above normal in both groups of dogs regardless of echocardiographic evidence of cardiomegaly. Conclusions: Results failed to identify an association between left atrial enlargement and airway collapse in dogs with MMVD, but did suggest that airway inflammation is common in dogs with airway collapse.

Comparison of multi-detector row computed tomography with echocardiography for assessment of left ventricular function in healthy dogs. Christiane R. Henjes, Stephan Hungerbühler, Iwona B. Bojarski, Ingo Nolte, Patrick Wefstaedt. Am. J. Vet. Res. March 2012;73:393–403. Quote: Objective: To evaluate the use of retrospectively ECG-gated, contrast-enhanced, multi-detector row computed tomography (MDCT) for assessment of left ventricular function in dogs and to compare the results with those obtained by use of 2-D and M-mode echocardiographc techniques. Animals: 10 healthy Beagles. Procedures: Dogs underwent MDCT (performed by use of a 64-detector row CT system) and echocardiography under general anesthesia. Left ventricular end-systolic volume (ESV), end-diastolic volume (EDV), and ejection fraction (EF) were determined in MDCT-generated multiplanar reformatted images by use of Simpson and biplane area-length calculation methods. Results were compared with left ventricular ESV, EDV, and EF determined in echocardiographc images by use of Teichholz and bullet method calculations. Results were evaluated via Deming regression analysis and Pearson correlation tests. Bland-Altman analysis was used to assess limits of agreement and systematic errors between the 2 methods. Results: Mean values for EDV and ESV determined by use of MDCT were highly correlated with those determined by use of echocardiography, regardless of the calculation methods compared (r = 0.91 to 0.96); volumes determined by use of MDCT appeared to be higher than those determined by use of echocardiography, although most differences were nonsignificant. Mean EF determined by use of MDCT with the Simpson calculation method was highly correlated with that determined by use of echocardiography with bullet method calculations (r = 0.90). Conclusions & Clinical Relevance: Results suggested that assessment of left ventricular volume and function in dogs is feasible with MDCT. To estimate left ventricular EF with MDCT. use of the Simpson calculation method is advised.

Mitral valve repair in dogs. Masami Uechi. J.Vet.Cardiology. March 2012;14(1):185-192. Quote: "Prognosis for dogs with severe mitral regurgitation is poor with medical therapy alone. Open surgical mitral valve repair consisting of circumferential mitral annuloplasty and artificial chordal replacement confers durability and improved long-term clinical outcome without a need for long-term antithrombotic therapies. This approach has been successfully used in canine patients, including small-breed dogs. Methods for mitral valve repair applicable to small dogs are described."

Systemic Inflammation and Endothelial Dysfunction in Dogs with Congestive Heart Failure. S.M. Cunningham, J.E. Rush, L.M. Freeman. J.Vet.Int.Med. April 2012. Quote: "Background: Congestive heart failure (CHF) is associated with endothelial dysfunction in people and in dogs with experimentally induced CHF, but this is not well characterized in dogs with naturally occurring CHF. Hypothesis/Objectives: To evaluate endothelial function via assessment of reactive hyperemia (RH) in healthy dogs and dogs with CHF, and to assess for relationships with plasma biomarkers of vascular function and clinical markers of disease severity. Animals: Twenty client-owned animals [including three cavalier King Charles spaniels] with CHF due to myxomatous mitral valve disease (n = 15) or dilated cardiomyopathy (n = 5) and 17 healthy control dogs. Methods: Prospective case-controlled observational study. Dogs underwent blood sampling, echocardiography, and Doppler assessment of brachial artery velocity (VTI) at baseline and during reactive hyperemia (RH-VTI). RH-VTIs between control dogs and dogs with CHF were compared, and the relationships between RH-VTI, clinical parameters, and plasma biomarkers were assessed. Results: Dogs with CHF (96.5 ± 51.7%) had an attenuated % increase in VTI during RH compared to healthy controls (134.8 ± 58.7%; P = .04). Increasing ISACHC class (R2 = 0.24; P = .004), plasma NT-proBNP (R2 = 0.15; P = .03) and CRP (R2 = 0.2; P = .02) were associated with reduced RH-VTI. Increased plasma CRP, NOx, and NT-proBNP concentrations were found in dogs with CHF (P < .02 for all). No differences were detected in other plasma markers. Conclusions and Clinical Importance: Dogs with CHF have an attenuated RH response, and increased plasma CRP and NOx concentrations. Doppler assessment of RH velocity could represent a novel noninvasive method of evaluating endothelial function in the dog."

Diagnostic performance of P wave duration in the identification of left atrial enlargement in dogs. P. Savarino, M. Borgarelli, A. Tarducci, S. Crosara, N. M. Bello, M. L. Margiocco. J.Sm.Anim.Prac. May 2012; 53:267-272. Quote: "Objectives: To determine sensitivity and specificity of P wave duration in the identification of left atrial enlargement in dogs. Methods: Electrocardiograms from normal dogs and dogs with various cardiovascular diseases were evaluated. Inclusion criteria were the availability of an electrocardiogram showing a stable isoelectric line, easily recognizable P waves and good quality two-dimensional echocardiographic estimate of left atrial dimensions using the left atrial to aortic root ratio. Using a metal caliper system, P wave duration was measured to the nearest 10 milliseconds for six consecutive heart beats; data were then averaged for each dog. The accuracy of P wave duration in predicting left atrial enlargement was determined using a receiver operating characteristic analysis. Results: One hundred and fifty-six dogs [including one cavalier King Charles spaniel] were included in the study. Average P wave durations of 20, 30, 40 and 50 milliseconds yielded sensitivities of 100, 85, 68 and 40% and specificities of 0, 16, 64 and 93%, respectively, for the diagnosis of Left Atrial Enlargement by echocardiography. The estimated area under curve of the receiver operating characteristic curve was 0·70 (95% confidence interval: 0·60 to 0·80). Clinical Significance: The diagnostic performance of P wave duration for identification of left atrial enlargement in dogs presents considerable limitations."

Letter to the Editor. M.A. Oyama. J.Vet.Int.Med. Mar-Apr 2012; 26(2):227. Quote: "I read with interest the report entitled “Radiographic heart size and its rate of increase as tests for the onset of congestive heart failure in Cavalier King Charles Spaniels with mitral valve regurgitation” (Lord et al. JVIM 2011;25:1312-1319). This well-performed study demonstrates that radiographic vertebral heart size (VHS) changes most rapidly in the period of time immediately preceding development of congestive heart failure (CHF). Specifically, in the 8.6 months preceding CHF, the VHS changed by an average of 0.17 vertebra/month as compared to 0.03 vertebra per month during earlier intervals. This finding raises several questions regarding practicality and timing. Based on the reported likelihood ratios, a rate of change of VHS > 0.08 vertebra/month was the best predictor of onset of CHF, and superior to measures of absolute VHS at any time point prior to CHF. Thus, in the 6 to 9 months preceding CHF, an absolute change in VHS of 0.48 to 0.72 vertebrae would signal risk of CHF; however, this change can be less than the reported intraobserver variability (0.6–0.7 vertebrae) of the VHS method.  Furthermore, the study raises the question of when to initiate more frequent radiographic vigilance. Without additional examinations within time frame interval 1 (ie, the 8.6 months preceding development of CHF), detection of an increased rate of change would not occur prior to the onset of CHF (Fig 1B). Indeed, if one were to rely on change in CHF alone, there is nothing in the 12 months prior to time 1 that would alert a clinician to recheck heart size more frequently in the subsequent months. In other words, the increased rate of change is identified one interval too late. CHF has already occurred at the end of the interval of interest, precluding the ability to intervene and potentially change the outcome. In contrast, the data regarding absolute VHS (Fig 1A) indicates an increase in VHS in the second time interval preceding CHF (ie, between times 2 and 1), suggesting that this data could be acted upon prior to the onset of CHF at time 1. This data raises the question of whether a risk model combining absolute VHS and rate of change of VHS would be superior to a model using either parameter alone. One might suspect that the two variables are sufficiently interrelated such that this would not be the case, but the data presented in Figure 1 of the original article suggests otherwise."

Letter to the Editor. Peter Lord, Kerstin Hansson, Cristina Carnabuci, Clarence Kvart, Jens Häggström. J.Vet.Int.Med. Mar-Apr 2012; 26(2):228-229. Quote: "We thank Dr. Oyama for his comments and questions, which have prompted us to examine the changes in VHS [vertebral heart size] more closely than was possible in the paper, which was strictly an evaluation of heart size and its rate of increase as diagnostic tests using the recommended monitoring intervals of dogs with mitral valve regurgitation. ... The longer the interval, the greater the true or instantaneous velocity at CHF is underestimated, because ∆VHS is then averaged over more months. The true velocity can only be measured with a relatively short time interval. The shorter the interval, the higher the measured ∆VHS/month and the closer it is to the true velocity. This explanation assumes that the heart size does not accelerate and then plateau for a while before CHF, an unlikely scenario. True velocities within a few months of CHF are probably close to, or even greater than, the higher values in Figure 2, but it would require frequent (monthly?) monitoring to measure them.  ... To summarize: measurement variation had little effect on the accuracy of ∆VHS/month [VHS velocity = change in VHS per month] to diagnose onset of CHF; true ∆VHS/month was underestimated by averaging the change in VHS during the interval before CHF and the true velocity is likely to be much higher than the cutoff value (0.08 VHS units/month) used to derive the likelihood ratio to diagnose CHF; measured rate of change was affected by the time interval; VHS was of little use to predict time to onset of CHF; a rise of ∆VHS/month above a selected percentile of the values at the interval preceding the last one might be a useful sign of impending CHF; combining interval likelihood ratios for VHS and ∆VHS/month greatly improved the accuracy of diagnosis of CHF. The study shows the value of incorporating the element of time dependency from serial measurements as rate of change, a summary of the response over time of each subject."

Comparative effects of amlodipine and benazepril on Left Atrial Pressure in Dogs with experimentally-induced Mitral Valve Regurgitation. Shuji Suzuki, Ryuji Fukushima, Taisuke Ishikawa, Yuta Yamamoto, Lina Hamabe, Soomin Kim, Rieko Yoshiyuki, Noboru Machida, Ryou Tanaka. BMC Veterinary Research 2012, 8:166. Quote: "Background: One of the purposes of treatment for dogs with mitral regurgitation (MR) is lowering left atrial pressure (LAP). There has been few study of the amlodipine in dogs with MR and amlodipine’s effect on LAP has not been fully evaluated in a quantitative manner because of difficulties in directly measuring LAP. The objective of our study was to compare the short-term effects of amlodipine (0.2 mg/kg PO q12h) vs benazepril (0.5 mg/kg PO q12h), on LAP and echocardiographic parameters in five beagle dogs with experimentally-induced MR. LAP of eight dogs that has own control were measured using radiotelemetry system at baseline and again on days 1, 2, 3, 4, 5, 6, 7 of the drug administration. Results: Mean LAP decreased significantly after amlodipine (11.20 ± 4.19 mmHg vs 14.61 ± 3.81 mmHg at baseline, p < .01) but not after benazepril treatment (13.19 ± 3.47 mmHg, p > .05). LAP was lower after 7 days of amlodipine treatment than after 7 days of benazepril treatment. Significant reduction was seen for the first time 4 days after the administration amlodipine. The rate of the maximal area of the regurgitant jet signals to the left atrium area (ARJ/LAA) of the amlodipine treatment was significantly lower (p < .05) after 7 days compared to baseline. Other echocardiographic parameters did not change significantly. Conclusions: LAP was significantly decreased after amlodipine treatment in dogs with surgically-induced MR but not after benazepril treatment. Although this study did not focus on adverse effects, amlodipine may be an effective drug for helping the patients with acute onset of severe MR, such as rupture of chordae tendinae or end stage patients where the LAP is likely to be elevated. Additional studies in clinical patients with degenerative mitral valve disease and acute chordal rupture are warranted because the blood-pressure lowering effects of amlodipine can decrease renal perfusion and this can further activate the RAAS."

Mitral valve repair under cardiopulmonary bypass in small-breed dogs: 48 cases (2006–2009). Masami Uechi, Takahiro Mizukoshi, Takeshi Mizuno, Masashi Mizuno, Kayoko Harada, Takashi Ebisawa, Junichirou Takeuchi, Tamotsu Sawada, Shuhei Uchida, Asako Shinoda, Arane Kasuya, Masaaki Endo, Miki Nishida, Shota Kono, Megumi Fujiwara, Takashi Nakamura. J.Am.Vet.Med.Assn.; May 2012; 240(10):1194-1201. Quote: "Objective: To determine whether mitral valve repair (MVR) under cardiopulmonary bypass would be an effective treatment for mitral regurgitation in small-breed dogs. Design: Retrospective case series. Animals: 48 small-breed dogs [including cavalier King Charles spaniels] (body weight, 1.88 to 4.65 kg [4.11 to 10.25 lb]; age, 5 to 15 years) with mitral regurgitation that underwent surgery between August 2006 and August 2009. Procedures: Cardiopulmonary bypass was performed with a cardiopulmonary bypass circuit. After induction of cardiac arrest, a mitral annuloplasty was performed, and the chordae tendineae were replaced with expanded polytetrafluoroethylene chordal prostheses. After closure of the left atrium and declamping to restart the heart, the thorax was closed. Results: Preoperatively, cardiac murmur was grade 3 of 6 to 6 of 6, thoracic radiography showed cardiac enlargement (median vertebral heart size, 12.0 vertebrae; range, 9.5 to 14.5 vertebrae), and echocardiography showed severe mitral regurgitation and left atrial enlargement (median left atrium-to-aortic root ratio, 2.6; range, 1.7 to 4.0). 45 of 48 dogs survived to discharge. Three months after surgery, cardiac murmur grade was reduced to 0/6 to 3/6, and the heart shadow was reduced (median vertebral heart size, 11.1 vertebrae, range, 9.2 to 13.0 vertebrae) on thoracic radiographs. Echocardiography confirmed a marked reduction in mitral regurgitation and left atrium-to-aortic root ratio (median, 1.7; range, 1.0 to 3.0). Conclusions and Clinical Relevance: We successfully performed MVR under cardiopulmonary bypass in small-breed dogs, suggesting this may be an effective surgical treatment for dogs with mitral regurgitation. Mitral valve repair with cardiopulmonary bypass can be beneficial for the treatment of mitral regurgitation in small-breed dogs."

Systemic Inflammation and Endothelial Dysfunction in Dogs with Congestive Heart Failure. S.M. Cunningham, J.E. Rush, L.M. Freeman. J.Vet.Inter.Med.; May 2012; 26(3):547-557. Quote: "Background: Congestive heart failure (CHF) is associated with endothelial dysfunction in people and in dogs with experimentally induced CHF, but this is not well characterized in dogs with naturally occurring CHF. ... A recent study by Ljungvall et al found that circulating CRP concentration was not associated with severity of MMVD; however, unlike the study reported herein, that study population was comprised predominantly of CKCS and CRP levels were found to be higher in non-CKCS dogs. ... Hypothesis/Objectives: To evaluate endothelial function via assessment of reactive hyperemia (RH) in healthy dogs and dogs with CHF, and to assess for relationships with plasma biomarkers of vascular function and clinical markers of disease severity. Animals: Twenty client-owned animals with CHF due to myxomatous mitral valve disease (n = 15) [including 3 cavalier King Charles spaniels] or dilated cardiomyopathy (n = 5) and 17 healthy control dogs. Methods: Prospective case-controlled observational study. Dogs underwent blood sampling, echocardiography, and Doppler assessment of brachial artery velocity (VTI) at baseline and during reactive hyperemia (RH-VTI). RH-VTIs between control dogs and dogs with CHF were compared, and the relationships between RH-VTI, clinical parameters, and plasma biomarkers were assessed. Results: Dogs with CHF (96.5 ± 51.7%) had an attenuated % increase in VTI during RH compared to healthy controls (134.8 ± 58.7%; P = .04). Increasing ISACHC class (R2 = 0.24; P = .004), plasma NT-proBNP (R2 = 0.15; P = .03) and CRP (R2 = 0.2; P = .02) were associated with reduced RH-VTI. Increased plasma CRP, NOx, and NT-proBNP concentrations were found in dogs with CHF (P < .02 for all). No differences were detected in other plasma markers. ... In conclusion, the results of this study provide evidence of systemic inflammation and microvascular endothelial dysfunction in this heterogeneous population of dogs with CHF. Both increased CRP concentration and impaired RH response were associated with markers of increasing heart failure severity and RH-VTI may prove valuable as a novel, relatively simple marker of endothelial function in the dog. Additional research is warranted to further characterize brachial artery flow profiles and to examine the relationship among inflammatory mediators, impaired endothelial function, and progression of cardiac disease in the dog. "

Myxomatous mitral valve disease in Cavalier King Charles Spaniels. MB Madsen, LH Olsen, J Haggstrom. Advances in Sm. Anim. Med. & Surg. May 2012;25(5):4. Quote: "Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. It is characterized by chronic progressive degenerative lesions of the mitral valve. The valve leaflets become thickened and incompetent, resulting in mitral regurgitation. MMVD is most prevalent in small- to medium-sized dogs, particularly the Cavalier King Charles Spaniel, and the onset of MMVD is age dependent. By the age of 10 years, nearly all CKCS are affected. The incidence of a similar disease in humans, mitral valve prolapse (MVP), is 1 to 5%."

Heart rate variability parameters of myxomatous mitral valve disease in dogs with and without heart failure obtained using 24-hour Holter electrocardiography. M. S. Oliveira, R. A. L. Muzzi, R. B. Araújo, L. A. L. Muzzi, D. F. Ferreira, R. Nogueira, and E. F. Silva. Vet. Rec. June 2012;170:622. Quote: "Time-domain heart rate variability (HRV) parameters and the correlation between echocardiography and Holter examinations in dogs with myxomatous mitral valve disease (MMVD) were determined. Holter examination was also performed at different time frames: an entire 24-hour period, a four-hour period during sleep, and a four-hour period while awake. Ten healthy (control group) and 28 MMVD dogs, 15 with and 13 without heart failure, were evaluated. The SDANN (sd of the mean normal RR intervals for all five-minute segments during 24-hour Holter) and pNN50 (percentage of differences between adjacent normal RR intervals that are >50 ms computed over 24-hour Holter) variables were significantly lower in the dogs with MMVD heart failure. The differences in HRV between the groups were only detected during the 24-hour evaluation period (P < 0.05). There were high correlations (canonical analysis) between Holter and echocardiography examinations when considering pNN50, SDANN, and LA/AO (left atrial to aortic root ratio) (r = 0.92; P < 0.05), indicating that both are important in evaluating MMVD dogs. SDANN and pNN50 are measures of parasympathetic control of the heart, and thus, it is possible to infer that the MMVD dogs exhibit parasympathetic withdrawal during the development of heart failure."

Genome-wide analysis of mitral valve disease in Cavalier King Charles Spaniels. Anne T. French, Rob Ogden, Cathlene Eland, Gibran Hemani, Ricardo Pong-Wong, Brendan Corcoran, Kim M. Summers. Vet J; July 2012;193(1):283-286.  Quote: "The Cavalier King Charles Spaniel (CKCS) is prone to severe early onset mitral valve disease. In this study, 36 purebred CKCS dogs were evaluated for mitral valve murmur and divided into early and late onset groups. A genome-wide genetic approach was used to assess whether the condition is determined by a small number of genetic factors. There were no regions of highly discrepant homo/heterozygosity in the two groups. Similarly, there was no evidence for loci associated with mitral valve murmur in a genome-wide association study. This analysis suggests that familial occurrence of mitral valve murmur in the CKCS breed is not due to a single major gene effect, indicating that breeding strategies to eliminate the disease cannot be based on genotype information at this time."

Clinical signs of cardiovascular effects secondary to suspected pimobendan toxicosis in five dogs. L. Noelani Reinker, Justine A. Lee, Lynn R. Hovda, Mark Rishniw. J. Amer. Animal Hosp. Assn. July 2012;48(4):250-255. Quote: "The purpose of this study was to review the medical records of dogs that were either suspected or known to have ingested large doses of pimobendan and to describe the clinical signs associated with pimobendan toxicosis. The database of Pet Poison Helpline, an animal poison control center located in Minneapolis, MN, was searched for cases involving pimobendan toxicosis from Nov 2004 to Apr 2010. In total, 98 cases were identified. Of those, seven dogs that ingested between 2.6 mg/kg and 21.3 mg/kg were selected for further evaluation. Clinical signs consisted of cardiovascular abnormalities, including severe tachycardia (4/7), hypotension (2/7), and hypertension (2/7). In two dogs, no clinical signs were seen. Despite a wide safety profile, large overdoses of pimobendan may present risks for individual pets. Prompt decontamination, including emesis induction and the administration of activated charcoal, is advised in the asymptomatic patient. Symptomatic and supportive care should include the use of IV fluid therapy to treat hypotension and address hydration requirements and blood pressure and electrocardiogram monitoring with high-dose toxicosis. Practitioners should be aware of the clinical signs associated with high-dose pimobendan toxicosis. Of the dogs reported herein, all were hospitalized, responded to supportive care, and survived to discharge within 24 hr of exposure."

Increased blood mRNA expression of inflammatory and anti-fibrotic markers in dogs with congestive heart failure. S. Fonfara, S.R. Tew, P. Cripps, J. Dukes-McEwan, P.D. Clegg. Research in Vet.Sci. Oct 2012; 93(2):879-885, Quote: "Inflammation and extracellular matrix (ECM) remodeling contribute to the development of congestive heart failure (CHF), but the pathogenesis is still incompletely understood. Therefore, whole blood samples from eight dogs without cardiac disease and eight dogs with CHF ... (Dogs with cardiac diseases included ... one cavalier King Charles spaniel ...) ... were investigated for mRNA expression of IL1β, IL2, IL4, IL6, IL8, IL10, TNFα, IFNγ, TGFβ1–3, MMP1, -2, -3, -9 and TIMP1–4 using quantitative PCR. Dogs with CHF had significantly higher IL1β (P = 0.015), IL2 (P = 0.043), MMP1 (P = 0.031), TIMP3 (P = 0.012) and lower TNFα (P < 0.001), TGFβ3 (P = 0.006), TIMP1 (P = 0.015) and TIMP2 (P = 0.011) mRNA levels. Increased pro-inflammatory IL1β and anti-fibrotic MMP1 and reduced pro-fibrotic TGFβ and TIMP1 and TIMP2 in dogs with CHF suggest progressive left ventricular remodeling. The reduction of TNFα and increase of immunomodulatory IL2 and TIMP3 might suggest control of the inflammatory response. A better understanding of inflammation and ECM remodeling in cardiac diseases may lead to novel treatment approaches."

Sleeping respiratory rates in apparently healthy adult dogs. M. Rishniw, I. Ljungvall, F. Porciello, J. Häggström, D.G. Ohad. Research in Vet.Sci. October 2012;93(2):965-969. Quote: "Respiratory rate monitoring of cardiac patients is recommended by many cardiologists. However, little objective data exist about respiratory rates in apparently healthy dogs when collected in the home environment. We measured sleeping respiratory rates (SRR) in apparently healthy dogs and compared sleeping and resting respiratory rates (RRR) with a cross-sectional prospective study. Participants collected 12–14 one-minute SRR over a period ranging from 1 week to 2 months on 114 privately owned adult dogs [including 14 cavalier King Charles spaniels]. Selected participants simultaneously collected RRR. Mean within-dog average SRR (SRRmean) was 13 breaths per minute (breaths/min). No dog had SRRmean >23 breaths/min; three dogs had instantaneous SRR measurements >30 breaths/min. Dogs had higher RRRmean (19 breaths/min) than SRRmean (15 breaths/min) (P < 0.05). Canine SRRmean was unaffected by age, bodyweight or geographic location. Data acquisition was considered relatively simple by most participants. This study shows that apparently healthy adult dogs generally have SRRmean <30 breaths/min and rarely exceed this rate at any time."

Lowered N-terminal pro-B-type natriuretic peptide levels in response to treatment predict survival in dogs with symptomatic mitral valve disease. Johanna Wolf, Nicola Gerlach, Karin Weber, André Klima, Gerhard Wess. J.Vet.Cardiology; Sept 2012; 14(3):399–408. Quote: "Objectives: In humans with congestive heart failure (CHF), better outcome is correlated with lower natriuretic peptide (NP) levels after starting treatment and greater percentage reduction of NP levels. Therefore, the aim of this study was to determine the relationship between absolute and relative changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and pro-atrial natriuretic peptide 31–67 (proANP 31–67) and overall cardiac survival in patients with symptomatic myxomatous mitral valve disease (MMVD). Furthermore, we sought to compare clinical and echocardiographic status of 12-month survivors and non-survivors. Animals, materials and methods: 26 dogs with CHF due to MMVD. Initial NP levels, as well as absolute and percentage changes of follow-up NP levels (between 7 and 30 days after treatment start) and heart failure (HF) class were tested as potential predictors of overall cardiac survivorship. Additionally, various echocardiographic parameters, creatinine concentrations and furosemide doses were compared between 12-month survivors and non-survivors. Results: Dogs with follow-up NT-proBNP level <965 pmol/l had a significantly longer overall cardiac survival than patients with NT-proBNP level >965 pmol/l (P = 0.03). Dogs in a higher HF class had a significantly (P = 0.03) higher probability of shorter survival independent of their NP levels. When dogs were grouped by 12-month survival, only follow-up NT-proBNP levels were significantly different between groups. Conclusions: HF class at presentation and NT-proBNP levels after initiating treatment are predictive of mortality in patients with symptomatic MMVD. ProANP 31–67 levels, percentage reduction in NPs levels, creatinine or urea concentration, echocardiographic parameters and furosemide dose did not predict outcome."

Evaluation of homocysteine levels in dogs with chronic mitral valve insufficiency. S-G. Lee, C. Hyun. Vet.Rec. 2012; 171:220. Quote: "Homocysteine is a nonessential amino acid that is biosynthesised through a multistep process from methionine, and can also be converted into cysteine (Chandler and Payne-James 2006, Rossi and others 2008). Many studies (including veterinary), have shown that a high concentration of homocysteine is a sensitive marker for folate and vitamin B deficiency, and also an independent risk factor for cardiovascular disease (McMichael and others 2000, Finch and Joseph 2010). Accordingly, homocysteine is considered a biomarker for increased risk of cardiovascular diseases and impaired clinical outcomes, regardless of the unknown relationship between homocysteine and cardiac dysfunction. Similarly, there have been very few veterinary studies that have showed a relationship between homocysteine and the severity of heart failure in dogs (Suematsu and others 2007, Rossi and others 2008, Trisolini and others 2008). This study focused on evaluating the baseline plasma levels of homocysteine in dogs at different stages of chronic mitral valve insufficiency (CMVI), in order to assess and delineate the relationship of plasma levels of homocysteine, to the severity of heart failure. The study population consisted of 101 dogs (median age: 11.2±2.4 years; range: 7–17 years) with CMVI [including cavalier King Charles spaniels]."

Blood Pressure, Heart Rate, and Urinary Catecholamines in Healthy Dogs Subjected to Different Clinical Settings. K. Höglund, S. Hanås, C. Carnabuci, I. Ljungvall, A. Tidholm, J. Häggström. J.Vet.Intern.Med. Nov. 2012; 26(6):1300–1308. "Background: Correct interpretation of blood pressure (BP) and heart rate (HR) recordings is important in a clinical environment, but little is known about effects of stress on BP and HR responses of dogs to different clinical settings. Objective: To investigate BP and HR responses in different clinical settings in dogs of 3 breeds, and to relate findings to urinary catecholamine concentrations measured by ELISA assays previously validated for use in human plasma and urine, after validation for use in dogs. Animals: Client-owned healthy dogs; 41 Labrador Retrievers, 33 Cavalier King Charles Spaniels (CKCS), and 15 Dachshunds. Methods: Prospective observational study. BP and HR were measured in 4 clinical settings with or without veterinarian and owner present. Urine samples were taken before and after examination. ELISA assays were validated for canine urine, and epinephrine/creatinine and norepinephrine/creatinine ratios were analyzed. Results: BP and HR were higher when measured by veterinarian alone than when owner was present (P < .020). Urinary catecholamine/creatinine ratios were higher after examination, compared with before, in all dogs (P < .0001). Labrador Retrievers had lower diastolic BP than Dachshunds in 2 settings (P ≤ .041), lower HR than CKCSs in 3 settings (all P < .0001), and lower catecholamine/creatinine ratios after examination than both other breeds (P ≤ .035). [The CKCSs had higher HR than Labrador Retrievers in all settings except the squeaky toy, while Dachshunds did not differ from the other breeds.] The in-house validation showed mean spiked recovery of 96.5% for epinephrine and 83.8% for norepinephrine. Conclusions and Clinical Importance: BP and HR responses were related to breed as well as clinical setting. [ BP and HR were higher when recordings were made by veterinarian alone. We therefore recommend owners be present when performing BP recordings. The potential stress or excitement induced by travel and examinations at the veterinary clinic was confirmed by significantly higher catecholamine/creatinine ratios in urine samples taken after the examination compared with samples taken before the examination. A notable observation was very high SBP and DBP readings in a few individual dogs. Several breed differences were found, with Labrador Retrievers having low DBP, HR, and catecholamine concentrations, possibly caused by less mobilization of the sympathetic nervous system in this breed.] Breed differences were detected in urinary catecholamine/creatinine ratios. Further studies on breed differences are warranted."

A new method of computing the vertebral heart scale by means of direct standardisation. X. Sánchez, D. Prandi, L. Badiella, A. Vázquez, F. Llabrés-Díaz, C. Bussadori and O. Domènech. J.Sm.Anim.Prac. Nov. 2012; 53(11):641-645. Quote: "Objectives: The aim of this study was to describe and compare a simplified vertebral heart scale computation method (Objective VHS) with the original Buchanan method (Buchanan VHS). Methods: The Objective VHS was compared to the Buchanan VHS method in 42 dogs including 14 healthy dogs [including ten mixed breeds and one cavalier King Charles spaniel] and 28 dogs [all mixed breeds; no CKCSs] with mitral insufficiency. For the Objective VHS, the sum of the length of the long and short axes of the cardiac silhouette obtained in centimetres using a metric ruler was subsequently converted into units of vertebral length by means of a direct standardization method. (The objective (direct standardisation) method to calculate the VHS was performed as follows: Measurements were obtained using a ruler (Screen Calipers 4.0, Iconico, NY, USA). A five-vertebrae-long index of vertebral body length was obtained by measuring in centimetres the distance from the cranial aspect of T4 to the caudal aspect of T8, running parallel to the vertebral column. L and S obtained as previously described were then measured in Figure 2, Objective VHS Methodcentimetres and translated onto VHS units (to the decimal point) by the statistician by means of unit conversion (Fig. 2 right) using the following equation: A/B = C/X, where the variable to be evaluated is in the right-hand denominator. The unit conversion states that X = BC/A, where A is the T4-T8 distance (cm); B is the sum of L and S (cm); and C is the T4-T8 distance expressed as v, equivalent to the computation of the Buchanan method when transferring the L and S measurements to the vertebral column. The distance between T4 and T8 in units of vertebral length measures 5 and is considered a statistical constant in this equation; and X the sum of L and S (VHS) expressed as v.) The Buchanan VHS was obtained as previously described. Results: No significant differences in vertebral heart scale values were found between the two methods in all dogs. There was a strong positive correlation (0·99) between Objective VHS and Buchanan VHS. Clinical Significance: The use of a direct standardization method based on a unit conversion allows -computation of vertebral heart scale values without transposing long and short axes to the cranial edge of T4."

Fossa ovalis tear causing right to left shunting in a Cavalier King Charles Spaniel. Geri A. Lake-Bakaar, Mai Yee Mok, Mark D. Kittleson. J.Vety.Cardio. December 2012; 14(4):541-545. Quote: Left atrial tear is an infrequent sequela of severe mitral regurgitation due to myxomatous mitral valve degeneration. Interatrial septal tear due to mitral regurgitation causing a left-to-right shunt is uncommon. Right to left shunting secondary to acute interatrial septal tear is very rarely reported in the human literature, and has not been reported in the veterinary literature in a dog. This case describes the clinical, radiographic, echocardiographic, gross pathologic, and histopathologic features of a dog presented in acute respiratory distress secondary to acute onset right to left shunting through the interatrial septum. [The dog was a 13 year old spayed female cavalier King Charles spaniel.] This was later documented to be due to a tear in the septum secondary to tricuspid regurgitation and pulmonary hypertension. The presence of an acquired right to left shunting atrial septal defect is of clinical and prognostic significance, and should be considered in cases of acute respiratory distress.

Associations among serum N-terminal procollagen type III concentration, urinary aldosterone-to-creatinine ratio, and ventricular remodeling in dogs with myxomatous mitral valve disease. Melanie J. Hezzell, Adrian Boswood, Yu-Mei Chang, Walasinee Moonarmart, Jonathan Elliott. Amer.J.Vety.Res. Nov. 2012; 73(11):1765-1774. Quote: "Objective: To assess relationships among serum N-terminal procollagen type III concentration, urinary aldosterone-to-creatinine concentration ratio (UAC), and clinical variables in dogs with myxomatous mitral valve disease (MMVD) and healthy dogs. Animals: 162 dogs with MMVD [including cavalier King Charles spaniels] and 24 healthy control dogs of comparable age and body weight. Procedures: Blood and urine samples were collected from each dog. Dogs with MMVD underwent echocardiography and ECG. Ventricular diameter measurements were normalized for body weight. Serum N-terminal procollagen type III and urinary aldosterone concentrations were measured via radioimmunoassay. Each dog was examined on 1 to 3 occasions. Examinations were repeated at approximately 6-month intervals. Results: Serum N-terminal procollagen type III concentration decreased with increasing severity of MMVD and was negatively associated with age and left ventricular end-diastolic and end-systolic diameters. The UAC increased with prior percentage change in left ventricular end-diastolic diameter per month, subsequent percentage change in left ventricular end-systolic diameter per month, and treatment with diuretics and was negatively associated with age. Both UAC and serum N-terminal procollagen type III concentration were higher in Cavalier King Charles Spaniels than in other breeds when other measured variables were controlled for. Conclusions and Clinical Relevance: In dogs with MMVD, echocardiographic indicators of left ventricular remodeling appeared to be associated with a decrease in serum concentration of a marker of collagen type III turnover and an increase in urinary aldosterone concentration."

Radial and Longitudinal Strain and Strain Rate Assessed by Speckle-Tracking Echocardiography in Dogs with Myxomatous Mitral Valve Disease. N.E. Zois, A. Tidholm, K.M. Nägga, S.G. Moesgaard, C.E. Rasmussen, T. Falk, J. Häggström, H.D. Pedersen, B. Åblad, H.Y. Nilsen and L.H. Olsen. J.Vet.Intern.Med. Nov. 2012. Quote: "Background: Assessment of left ventricular (LV) function using conventional echocardiographic methods is difficult in mitral regurgitation (MR) owing to altered hemodynamic loading conditions. Newer methods such as speckle-tracking echocardiography (STE) provide assessment of LV strain (St) and strain rates (SR). Hypotheses: Global St and SR are 1) decreased in dogs with clinical signs of congestive heart failure (CHF) due to myxomatous mitral valve disease (MMVD) compared with clinically healthy dogs, and are 2) associated with conventional echocardiographic indices of MMVD severity. ... Because the likelihood of developing MMVD differs among breeds, both clinically healthy Cavalier King Charles Spaniels (CKCS), being highly predisposed, and Beagles, having a lower predisposition, were included in the study. Specifically, the aims were: (1) to compare global St and SR in dogs with clinical signs of CHF due to MR caused by MMVD to dogs with no or minimal and compensated MR, (2) to examine whether global St and SR differed between dog groups with no or minimal MR, but with a different predisposition to MMVD or differed between CKCS and dogs of other breeds with clinical signs of CHF, and finally (3) to examine possible associations between global St and SR and conventional echocardiographic indices of MR severity and LV remodeling. ... Animals: The study subjects were 93 [including 65 cavalier King Charles spaniels] privately owned dogs with different MMVD severities. ...  Methods: Prospectively recruited dogs were grouped according to MMVD severity based on echocardiographic evaluation of MR and presence of clinical signs. Global radial and longitudinal St, SR, and indices of LV dyssynchrony were assessed. Results: On group-wise comparisons, dogs with CHF had increased global longitudinal St, global longitudinal and radial SR in systole (SRs), and early diastole (SRe) compared with dogs with no or minimal MR (all P < .04). On multiple regression analyses, these global STE variables increased with degree of MR, but associations with left atrial-to-aortic root ratio (LA/Ao) were best described by second-order polynomial equations. Thus, curvilinear relationships were found for LA/Ao and longitudinal St, SRs, and SRe (all P < .002) and radial St and SRe (all P < .001). Conclusions and Clinical Importance: Assessed by STE, LV function appeared to be augmented in moderate-to-severe disease. However, at CHF stages with greatly enlarged atria, a decrease to levels comparable to dogs with no or minimal MR was observed."

Evaluation of C-reactive Protein Before and after Mitral Valve Repair in Dogs with Mitral Regurgitation. M. Funayama, T. Mizuno, M. Mizuno, T. Mizukoshi, K. Harada, T. Sawada, M. Endo, J. Takeuchi, A. Shinoda, A. Takahashi, S. Uchida, M. Uechi. 22nd ECVIM-CA Congress. J.Vet.Intern.Med. Nov. 2012; 26(6):1505–1538. Quote: "Mitral regurgitation (MR) is the most common heart disease in dogs.Dogs with a more advanced stage of this disease are likely to develop pulmonary edema of heart failure. The aim of this study was to evaluate the plasma C-reactive protein (CRP) concentration in dogs that underwent mitral valve repair for MR.All dogs were operated between October 2006 and October 2010. The dogs were categorized according to the International Small Animal Cardiac Health Council (ISACHC) classification, and physical examination, thoracic radiography, and 2D color flow Doppler echocardiography were performed before and after surgery. The plasma CRP concentration and white blood cell counts were also determined before and after surgery. Cardiogenic pulmonary edema was diagnosed on the basis of clinical examination and thoracic radiography.Overall, 44 dogs (mean body weight, 5.6 ± 3.1 kg and mean age, 9.3 ± 2.2 years) were enrolled; 11 of these dogs had cardiogenic pulmonary edema. The dogs breeds were Chihuahua (n = 10), Cavalier King Charles Spaniel (n = 10), Maltese (n = 7), Yorkshire Terrier (n = 3), Shih Tzu (n = 2), Miniature Dachshund (n = 2), and others (n = 10). No significant difference was found for age and body weight. The vertebral heart size and LA/Ao ratio significantly decreased after surgery compared with the preoperative values. Before the operation, CRP concentration and white blood cell counts in ISACHC class IIIb dogs (2.5 ± 2.3 mg/dL and 21288 ± 7656 /μL, respectively) were higher than those in class Ib (0.2 ± 0.3 mg/dL and 11500 ± 1320 /μL, respectively), class II (0.1 ± 0.1 mg/dL and 8822 ± 2243/μL, respectively), and class IIIa (0.7 ± 1.8 mg/dL and 11731 ± 4620/μL, respectively) dogs. Additionally, CRP concentration and white blood cell counts in class IIIb dogs significantly decreased after surgery compared with preoperative values. CRP concentration and white blood cell counts in the dogs with cardiogenic pulmonary edema significantly increased compared with those with non-pulmonary edema. Furthermore, cardiogenic pulmonary edema disappeared within 3 months after surgery, and the CRP concentrations and white blood cell counts became normal.In conclusion, CRP concentration increases in dogs with MR and cardiogenic pulmonary edema. It is widely recognized that inflammatory reaction plays a key role in the development of heart failure. Consequently, these data indicate the importance of strict management for pulmonary edema and inflammation."

Serum Serotonin Concentration Is Associated with Severity of Myxomatous Mitral Valve Disease in Dogs. I. Ljungvall, K. Höglund, M.A. Oyama, A. Tidholm, J. Häggström. 22nd ECVIM-CA Congress. J.Vet.Intern.Med. Nov. 2012; 26(6):1505–1538. Quote: "The neurotransmitter serotonin (5-hydroxytryptamine, 5HT) has recently been suggested to have a role in development of myxomatous mitral valve disease (MMVD) in dogs. The aim of this study was to investigate whether serum 5HT concentration was associated with MMVD severity in dogs, and to assess potential associations between serum 5HT concentrations and dog characteristics, echocardiographic variables, heart rate, systolic blood pressure, and platelet size (mean platelet volume) in the study population.120 client-owned dogs with naturally acquired MMVD of varying severity were prospectively recruited for the study. Dogs were classified according to MMVD severity (breeds predisposed to early onset of MMVD, but without echocardiographic evidence of the disease, or mild, moderate or severe disease). Serum 5HT concentrations were analyzed using an ELISA assay. Lower serum 5HT concentrations were shown in dogs with severe MMVD, compared with dogs predisposed to MMVD (P = 0.0025) and dogs with mild MMVD (P = 0.0011). Unilinear and multiple regression analyses showed that serum 5HT concentrations decreased with increasing left atrial to aortic root ratio (LA/Ao), were higher in Cavalier King Charles Spaniel (CKCS) dogs compared to dogs of other breeds, and were higher in female dogs than in male dogs. The LA/Ao was the variable most strongly associated with serum 5HT concentration. In conclusion, the finding of higher serum 5HT concentrations in dogs predisposed to MMVD (CKCS) and dogs with mild MMVD suggests that alterations in 5HT signaling might play a role in progression of early stages of MMVD."

Anaesthesia in dogs and cats with cardiac disease – An impossible endeavour or a challenge with manageable risk? R. Steinbacher, R. Dörfelt. Wiener Tierärztliche Monatsschrift – Veterinary Medicine Austria. 2012. Quote: "Anaesthesia in patients with mitral valve insufficiency: Heart rate and blood pressure should be assessed already during preanaesthetic examination, in order to obtain reference values for intraoperative monitoring of these parameters. During anaesthesia, an increase of regurgitation must be avoided. Therefore, no centrally effective α2-agonists or massive infusion therapy should be given to avoid any increase in afterload. In these patients, a significant decrease in heart rate also leads to increased regurgitation as the increased ventricular filling enhances contractility. Any drugs, which induce an increase in vascular tone and, consequently, in afterload, like dopamine (in vasoconstrictive doses) and ephedrine, should also be avoided. Reducing the systemic vascular resistance by administering very small doses of acepromazine as a premedication in order to reduce the afterload is beneficial, as it reduces regurgitation and increases cardiac output despite reduced contractility. Excessive vasodilation, however, causes a drop in blood pressure, which in most cases can hardly be compensated for by the patient. Opioids like methadone or butorphanol, in combination with acepromazine, produce adequate sedation and, in addition, analgesia. As opioids, above all µ-agonists (e.g. methadone), can reduce the heart rate if administered at higher doses, an anticholinergic drug (like atropine or glycopyrrolate) should always be at hand when µ-agonists are used, in order to be prepared in case a drop in heart rate should occur. Whenever possible, induction of anaesthesia should be performed under complete monitoring and good preoxygenation. In severe cases, etomidate is a good choice as it has minimum cardiovascular side effects. In stable patients, low doses of ketamine can be used as an alternative, together with benzodiazepines or low doses of propofol. Negative inotropic drugs like propofol at high doses and thiopental can increase the regurgitation fraction in patients with severe valvular disease due to reduced forward propulsion of the blood and should therefore be used with caution. To maintain anaesthesia, inhalation anaesthetics can be used at concentrations that should be as low as possible. Another possibility is a partial or total intravenous anaesthesia using propofol, fentanyl or ketamine combinations (subanaesthetic doses). In case hypotension and bradycardia should occur, these can be treated by administration of anticholinergics. In doing so, the target heart rate should lie within the preanaesthetic range or slightly above. Should hypotension not be accompanied by bradycardia and not return to normal levels after reducing the concentration of the inhalant, positive inotropic drugs like dobutamine should preferably be administered."

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2013

Vertebral Heart Scores in Eight Dog Breeds. K. Jepsen-Grant, R.E. Pollard, L.R. Johnson. Veterinary Rad. & Ultrasound. January 2013'54(1):3-8. Quote: The vertebral heart score (VHS) measurement is commonly used to provide a more objective measurement of cardiomegaly in canines. However, several studies have shown significant breed variations from the value previously established by Buchanan and B¨ucheler (9.7 ± 0.5). This study describes VHS measurements in Pug, Pomeranian, Yorkshire Terrier, Dachshund, Bulldog, Shih Tzu, Lhasa Apso, and Boston Terrier dog breeds. Dogs with two or three view thoracic radiographs, no subjective radiographic evidence of cardiomegaly, and no physical examination findings of heart murmurs or gallop rhythms were included in the study. The Pug, Pomeranian, Bulldog, and Boston Terrier groups were found to have a VHS significantly greater than 9.7 ± 0.5 (P < 0.00001, P = 0.0014, P < 0.0001, P < 0.00001, respectively). Body condition score was found to have a significant effect on the VHS of Lhasa Apso group. Anomalous vertebrae in the thoracic column were associated with a significant increase in VHS of the Bulldog (P = 0.028) and Boston Terrier (P = 0.0004) groups. Thoracic depth to width ratio did not have a significant effect on VHS. ... Table 1. Mean VHS ± SD: Pug 10.7 ± 0.9; Pomeranian 10.5 ± 0.9; Yorkshire terrier 9.9 ± 0.6; Dachshund 9.7 ± 0.5; bulldog 12.7 ± 1.7; Shih Tzu 9.5 ± 0.6; Lhasa Apso 9.6 ± 0.8; Boston terrier 11.7 ± 1.4.  ... Findings from our study indicate that application of a single, generic VHS measurement to small breed dogs, especially dogs with thoracic vertebral anomalies, could yield a false positive identification of cardiomegaly. A high body condition score could also yield a false positive diagnosis of cardiomegaly, however overall correlations between VHS and BCS were weak in our dogs. Findings support the use of breed-specific VHS reference ranges for objective measurements of cardiac size, however comparisons to subjective radiographic assessments of cardiac size and echocardiographic data are still recommended.

Potential Adverse Effects of Omega-3 Fatty Acids in Dogs and Cats. C.E. Lenox, J.E. Bauer. J.Vety.Int.Med. Jan. 2013. Quote: "Fish oil omega-3 fatty acids, mainly eicosapentaenoic acid and docosahexaenoic acid, are used in the management of several diseases in companion animal medicine, many of which are inflammatory in nature. This review describes metabolic differences among omega-3 fatty acids and outlines potential adverse effects that may occur with their supplementation in dogs and cats with a special focus on omega-3 fatty acids from fish oil. Important potential adverse effects of omega-3 fatty acid supplementation include altered platelet function, gastrointestinal adverse effects, detrimental effects on wound healing, lipid peroxidation, potential for nutrient excess and toxin exposure, weight gain, altered immune function, effects on glycemic control and insulin sensitivity, and nutrient-drug interactions."

Modified Loop Technique in Three Dogs with Mitral Regurgitation. Takuma Aoki, Yoko Fujii, Hiroshi Sunahara, Hiroshi Takano, Yoshito Wakao. J. Vet. Med. Sci. January 2013; doi: 10.1292/jvms.11-0486. Quote: Mitral valvuloplasty (MVP) is used in dogs with refractory mitral regurgitation (MR); however, it is difficult to tie the artificial chord, i.e., the expanded polytetrafluoroethylene suture, at the planned height of the mitral valve, because of the slippery nature of the knot. The loop technique has resolved these difficulties in humans. ... In our modified loop technique, loops of various sizes were premanufactured prior to surgery and then selected during surgery for use in the chordae that required repair. The original loop technique, in which the loops were fabricated using a single ePTFE suture during surgery, is not preferable in veterinary medicine, because a shorter cardiac arrest time is required in animals due to the small blood volume and the later surgical timing, which results in a more injured myocardium. In addition, our modified method, in which loops of various sizes can be selected during surgery, might be effective for chordal reconstruction even when the valve cusp is not uniformly affected, although loops of the same length were used in the original method. ... However, in our study, an accurate mural leaflet height could not be easily measured in dogs without cardiomegaly due to our inexperience. Conversely, the strut chordae could be easily identified in the small surgical area, because the septal leaflet was larger than the mural leaflet and the strut chordae was the thickest of the chordae. Thus, the size of the artificial loops in the present study was determined on the basis of the length of the strut chordae that was adjacent to the elongated chordae since the strut chordae was wider than the marginal chordae [18], and therefore, seemed to be less elongated and more resistant to prolapse due to its wide width. ... In the current modified loop technique, the loops were fashioned using CV-6 ePTFE sutures (Gore-Tex CV-6 ePTFE suture; Japan Gore-Tex Co. Ltd., Tokyo, Japan) and sterilized by ethylene oxide gas prior to surgery. Each loop was tied using 1 surgical knot and 5 square knots on the apparatus that was fixed at a length of 8.0–15.0 mm at 1.0-mm increments. ... Premanufactured loops (length, 8.0–15.0 mm with 1.0-mm increments) were used in the new modified loop technique. In the current study, cardiac murmurs disappeared, and the MR markedly improved or completely disappeared approximately 3 months after surgery in 3 dogs. Therefore, this new technique might be effective in dogs.

Risk Factors for Coughing in Dogs with Naturally Acquired Myxomatous Mitral Valve Disease. L. Ferasin, L. Crews, D.S. Biller, K.E. Lamb, M. Borgarelli. J.Vety.Inter.Med. Feb. 2013. Background: Cough often is reported as the primary clinical sign of congestive heart failure (CHF) in dogs with chronic degenerative myxomatous mitral valve disease (MMVD). Concurrent airway disease and compression of the left mainstem bronchus by a large left atrium also have been proposed as potential causes of coughing in these patients. Objectives: To investigate the association between the presence of coughing and different potential causes of cough, including CHF, abnormal radiographic airway pattern, and cardiomegaly in dogs affected by naturally acquired MMVD. Animals: Two hundred six client-owned dogs. Methods: Retrospective analysis performed on medical records of dogs affected by MMVD that underwent full cardiac evaluation, including echocardiographic examination and thoracic radiography. Results: Univariate analyses showed that CHF is not a predictor of coughing (OR = 1.369; 0.723, 2.594), whereas abnormal radiographic airway pattern (OR = 3.650; 2.051, 6.496) and increased left atrial size observed radiographically (OR = 3.637; 1.904, 6.950) or echocardiographically (OR = 2.553; 1.436, 4.539) were significantly associated with coughing in dogs with MMVD. The same risk factors were significant in multivariate analyses. Conclusions and Clinical Importance: Coughing is not associated with CHF attributable to cardiogenic pulmonary edema in dogs with naturally acquired MMVD, whereas abnormal radiographic airway patterns and increased left atrial size showed a significant association with coughing in these dogs. The study also demonstrates that patients with radiographic evidence of pulmonary edema typically are tachypneic or dyspneic, indicating that cough, in the absence of dyspnea or tachypnea, rarely should be considered as a sole clinical indication of CHF in dogs.

Clinical assessment of systolic myocardial deformations in dogs with chronic mitral valve insufficiency using two-dimensional speckle-tracking echocardiography. Ryohei Suzuki, Hirotaka Matsumoto, Takahiro Teshima, Hidekazu Koyama. J. Vety. Cardiology. Feb. 2013. Quote: "Objective: The objective of this study was to clinically assess myocardial deformations in dogs with chronic mitral valve insufficiency (CMVI) using two-dimensional speckle-tracking echocardiography (2D-STE). Animals: 87 dogs with CMVI. Methods: Dogs were placed into 1 of 3 classes, based on the International Small Animal Cardiac Health Council classification. In addition, 20 weight- and age-matched healthy dogs were enrolled as controls. The dogs were examined for myocardial deformations using 2D-STE, and strain and strain rate in the longitudinal, circumferential, and radial directions were evaluated. Results: Class II and III dogs had higher circumferential strain than class I dogs (P = 0.002 and P = 0.001, respectively) and controls (P < 0.001 and P < 0.001, respectively). Class III dogs had higher radial strain than class I dogs (P = 0.001) and controls (P < 0.001). Class III dogs had higher radial strain rate than class I dogs (P = 0.006) and controls (P = 0.001). Other deformations, including longitudinal deformations, were not significantly different between classes of CMVI or between CMVI dogs and controls. Conclusions: In the clinical progression of CMVI in dogs, myocardial deformations, as assessed by 2D-STE, differed according to myocardial contractile direction. Thus, assessments of multidirectional myocardial deformations may be important for better assessment of clinical cardiac function in dogs with CMVI."

Valvular Heart Disease: Little Dogs, Bigger and Bigger Hearts. Matthew W. Miller. WSAVA 2013 Congress.

Medical Therapy of Congestive Heart Failure: The Essentials. Matthew W. Miller. WSAVA 2013 Congress. Quote: "Clinical Findings: Endocardiosis is most common in toy and small breeds (Poodle, Dachshund, Yorkshire terrier, Cavalier King Charles Spaniel (the CKCS), Schnauzer, Cocker Spaniel) and the condition is an incidental finding in many aged dogs. Some breeds (such as the CKCS) are affected relatively early in life. ... Syncope is a particularly bothersome problem and may be related to insufficient forward flow, pulmonary hypertension, arrhythmias, or neurocardiogenic syncope (inappropriate bradycardia and vasodilation triggered by sympathetic surges or coughing). Treatment: Treatment of the asymptomatic dog with a murmur caused by endocardiosis is not currently recommended unless there is evidence of impending heart failure (dramatic cardiomegaly and pulmonary venous distension). Scandinavian studies in the CKCS dog have failed to reveal any benefit in asymptomatic dogs; results from a North American study suggest a possible benefit, but were by no means conclusive. When left-sided CHF occurs and pulmonary edema is evident, therapy should be initiated. Initial treatment includes furosemide for diuresis (2–4 mg/kg, IV, IM or SQ q6–8h), oxygen if needed to raise the pO2, and nitroglycerine ointment (¼ to ½ inch q12h in small dogs) to dilate veins. If pulmonary edema is severe, and if systolic ABP is at least 90 mm Hg, an arterial vasodilator should be given to reduce the MR fraction. Hydralazine (1–2 mg/kg PO q8–12h) or sodium nitroprusside (0.5 to 5 mg/kg/minute) can be administered to rapidly unload the LV and reduce MR fraction. An angiotensin converting enzyme inhibitor (ACEI) also lowers blood pressure, but in emergent conditions, the onset of action is slower than with direct vasodilators. Following successful diuresis, therapy is switched to oral medications. Baseline chronic therapy of CHF from endocardiosis involves: furosemide, an ACEI, dietary modifications, and pimobendan. Furosemide (2–4 mg/kg PO q8–24h) is administered to effect to prevent sodium retention, edema and ascites. An ACEI (enalapril, benazepril, ramipril, or quinapril) is begun initially at 0.5 mg/kg PO q24h with the intent to increase the dose to q12h as CHF worsens. A reasonable reduction of dietary sodium should be recommended. Pimobendan in our clinic is prescribed in any patient that is furosemide dependent (has radiographic evidence of pulmonary edema), as well as moderate to advanced CHF. The initial dose of pimobendan is 0.25–0.3 mg/kg PO q12h. Common additions for refractory heart failure include hydrochlorothiazide (starting at 1–2 mg/kg q12–24 hours), and/or a second vasodilator, such as amlodipine (0.25–0.75 mg/kg PO q24h; beware of hypotension) to further reduce the MR fraction. Airway dilators (theophylline) and cough suppressants (hydrocodone, butorphanol) may be added for symptomatic relief if control of CHF does not alleviate the respiratory signs."

In vitro effect of pimobendan on platelet aggregation in dogs. Eryn A. Shipley, Daniel F. Hogan, Nonya N. Fiakpui, Aliya N. Magee, Henry W. Green III, Kimberly A. Sederquist. Amer,J,Vety.Res. March 2013. 74(3):403-407. Quote: "Objective: To determine whether pimobendan has in vitro antithrombotic properties through inhibition of platelets in canine blood samples. Animals: 10 healthy adult dogs.  ... Results: Compared with findings for 0.0μM pimobendan, composite platelet aggregation (area under the curve [AUC]) and maximal platelet aggregation (aggregation units [AUs]) at 10.0μM pimobendan were significantly decreased for collagen-induced aggregation (AUC, 349.7 ± 58.4 vs 285.1 ± 72.2; maximal platelet aggregation, 196.2 ± 25.8 AUs vs 161.5 ± 38.0 AUs), and the AUC and velocity of aggregation at 10.0μM pimobendan were significantly decreased for ADP-induced aggregation (AUC, 268.5 ± 35.1 vs 213.4 ± 77.2; velocity of aggregation, 15.7 ± 2.9 AUs/min vs 11.8 ± 3.5 AUs/min). Pimobendan had no significant effect on plasma thromboxane concentration or thromboelastographic variables, regardless of concentration. Conclusions and Clinical Relevance: In vitro, pimobendan had an antiplatelet effect in canine blood samples at a concentration 1,000-fold higher than that clinically achievable. These antiplatelet properties do not appear to contribute to the positive clinical profile of the drug in dogs. Pimobendan administration would not appear to confer a risk for bleeding and does not have to be avoided in dogs with thrombocytopenia or those concurrently receiving antiplatelet drugs."

The history of veterinary cardiology. James W. Buchanan. J. Vety Cardiology; March 2013; 15(1):65-85.  Quote: "Chronic mitral valve disease (MVD), also known as degenerative MVD, myxomatous MVD and endocardiosis is the most common heart disease in dogs, the most frequent cause of canine congestive heart failure, and has been recognized for over 100 years. Tricuspid valve disease often coexists but usually is not as severe as MVD. Valve thickening occurs mainly in the contact zone especially in the insertion areas of the chordae tendineae. Whitney distinguished 4 degrees of valve thickening with involvement of chordae tendineae in the most severe forms. Ruptured chordae tendineae were found frequently in severe cases especially in dogs with ruptured left atria. Epidemiologic studies in the 1960s revealed greater frequency in small breed dogs, especially Cocker spaniels, Dachshunds and Poodles. Since the late 1980s Cavalier King Charles spaniels have shown striking breed predisposition evidenced by mitral systolic murmurs in 50% of 5-year-old Cavaliers and 95 - 100% of 10-year-old ones."

Morphological changes to endothelial and interstitial cells and to the extra-cellular matrix in canine myxomatous mitral valve disease (endocardiosis). R.I. Han, C.H. Clark, A. Black, A. French, c, G.J. Culshaw, c, S.A. Kempson, B.M. Corcoran. Vety.J. March 2013. Quote: "Morphological and functional changes in endothelial and interstitial cells are considered central to myxomatous degeneration of the canine mitral valve (endocardiosis). The aim of this study was to describe and quantify changes in valve endothelial cells (VECs), interstitial cells (VICs) and the extra-cellular matrix (ECM) of the sub-endothelial zone of diseased valves using a combination of transmission electron microscopy, stereology and computer-aided image analysis. Marked degradation of the endothelium was evident in diseased valves, which coincided with significant degradation of the local ECM (P < 0.001). There were decreases and increases in the numbers of VECs and VICs, respectively, in diseased valves, with particular accumulation of VICs subjacent to the valve surface (P < 0.01). Overall, VICs were more pleomorphic than VECs in both normal and diseased valves, but for VECs, the degree of pleomorphism was significantly different in diseased valves (P < 0.0001). The findings of the study confirm that canine myxomatous mitral valve disease is associated with marked endothelial damage, with attendant proliferation of subjacent activated myofibroblasts. The fact that similar endothelial changes are present in normal valves suggests these processes not only contribute to valve pathology, but may also represent life-long valve remodelling." Study  included "a 13-year old male Cavalier King Charles spaniel" with severe MVD.

Chronic Therapy with a Partial Adenosine A1 Receptor Agonist, Improves Left Ventricular Function and Remodeling in Dogs with Advanced Heart Failure. Hani N. Sabbah, Ramesh C. Gupta, Smita Kohli, Mengjun Wang, Sharad Rastogi, Kefei Zhang, Katja Zimmermann, Nicole Diedrichs, Barbara E. Albrecht-Küpper. Circulation: Heart Failure. April 2013;6(4). Quote: Background: Adenosine (AD) elicits cardioprotection through A1-receptor (A1R) activation. Therapy with AD A1R agonists, however, is limited by undesirable actions of full agonism such as bradycardia. This study examined the effects of capadenoson (CAP), a partial AD A1R agonist, on left ventricular (LV) function and remodeling in dogs with heart failure (HF). Methods and Results: 12 dogs with microembolization-induced HF were randomized to 12 weeks oral therapy with CAP (7.5 mg Bid, n=6) or to no therapy (Control, n=6). LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), plasma norepinephrine (NE) and n-terminal pro-brain natriuretic peptide (nt-pro BNP) were measured before (PRE) and 1 and 12 weeks after therapy (POST). LV tissue obtained at POST was used to assess volume fraction of interstitial fibrosis (VFIF), SERCA-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, EDV and ESV increased and EF decreased significantly from PRE to POST (EF: 30±2 vs. 27±1 %, p<0.05). In CAP-treated dogs, EDV was unchanged; EF increased significantly after one week (36±2 vs. 27±2 %, p<0.05) with a further increase at POST (39±2 %, p<0.05) while ESV decreased. CAP significantly decreased VFIF, normalized SERCA-2a activity and expression of UCP-2 and -3, and GLUT-1 and -2 and significantly decreased NE and nt-pro BNP. Conclusions: In HF dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial AD A1R agonists for the treatment of chronic HF.

Cardiac Troponin-I Concentration, Myocardial Arteriosclerosis, and Fibrosis in Dogs with Congestive Heart Failure because of Myxomatous Mitral Valve Disease. T. Falk, I. Ljungvall, N.E. Zois, K. Höglund, L.H. Olsen, H. D Pedersen, J. Häggström. J.Vet.Int.Med. May 2013; 27(3):500-506. Quote: "Background: Few previous studies have investigated the association between biomarkers and cardiac disease findings in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Aim: To investigate if histopathological changes at necropsy could be reflected by in vivo circulating concentrations of cTnI and aldosterone, and renin activity, in dogs with naturally occurring congestive heart failure because of MMVD. Animals: Fifty privately owned dogs with MMVD and heart failure [including 20 cavalier King Charles spaniels]. Methods: Longitudinal Study. Dogs were prospectively recruited and examined by clinical and echocardiographical examination twice yearly until time of death. Blood was stored for batched analysis of concentrations of cTnI and aldosterone, and renin activity. All dogs underwent a standardized necropsy protocol. Results: cTnI were associated with echocardiographic left ventricular end-diastolic dimension (P < .0001) and proximal isovolumetric surface area radius (P < .004). Furthermore, in vivo cTnI concentrations reflected postmortem findings of global myocardial fibrosis (P < .001), fibrosis in the papillary muscles (P < .001), and degree of arterial luminal narrowing (P < .001) Aldosterone or renin activity did not reflect any of the cardiac disease variables investigated. Conclusion and clinical importance: Cardiac fibrosis and arteriosclerosis in dogs with MMVD are reflected by circulating cTnI concentration, but not by aldosterone concentration or renin activity. Cardiac troponin I could be a valuable biomarker for myocardial fibrosis in dogs with chronic cardiac diseases."

Plasma atrial natriuretic peptide is an early diagnosis and disease severity marker of myxomatous mitral valve disease in dogs. Takashi Ebisawa, Yuzuru Ohta, Marina Funayama, Shigeki Yamano, Masashi Mizuno, Takeshi Mizuno, Arane Kasuya, Tamotsu Sawada, Junseok Lee, Takahiro Mizukoshi, Masami Uechi. Res.Vety.Sci. June 2013;94(3):717-721. Quote: "The aim of this study was to retrospectively assess the clinical usefulness of plasma atrial natriuretic peptide (ANP) concentrations for determining the severity of myxomatous mitral valve disease (MMVD) in dogs. Plasma ANP levels were found to be significantly higher in dogs with MMVD compared to healthy dogs, and plasma ANP levels increased significantly in dogs with progressive heart failure. In [36] dogs with MMVD [none were cavalier King Charles spaniels], stepwise regression analysis revealed that the left atrium/aorta ratio and fractional shortening could be used to predict the plasma ANP concentration. ... atrial enlargement causes an increase in plasma ANP concentration, and ANP level was a good indicator of decompensation in Cavalier King Charles Spaniels. ... These results indicated that plasma ANP rose with an increase in the volume overload of the left side of the heart. Plasma ANP discriminated cardiomegaly from non-cardiomegaly caused by asymptomatic MMVD. We conclude, therefore, that plasma ANP concentrations may be a clinically useful tool for early diagnosis of asymptomatic MMVD in dogs."

The diagnostic relevance of NT-proBNP and proANP 31–67 measurements in staging of myxomatous mitral valve disease in dogs. Johanna Wolf, Nicola Gerlach, Karin Weber, André Klima, Gerhard Wess. Vety. Clinical Pathol. Apr. 2013;42(2):196-206. Quote: "Background: There is no agreement in current publications regarding the reliability of serum concentrations of natriuretic peptides (NPs) to detect dogs with subclinical myxomatous mitral valve disease (MMVD) and to differentiate between asymptomatic stages. Objectives: We sought to compare N-terminal pro-B-type natriuretic peptide (NT-proBNP) and pro-atrial natriuretic peptide 31-67 (proANP) concentrations between various stages of canine MMVD and to investigate the influence of age, weight, and sex. Methods: In this prospective study, dogs were classified in different disease stages using the modified Canine Heart failure International Expert Forum (CHIEF) system. Serum NP concentrations were compared between groups. Results: A total of 559 samples from 116 healthy dogs [including 16 cavalier King Charles spaniels (CKCS)] and 236 dogs with MMVD [including 16 CKCSs] were analyzed. Using cut-off values (1207 pmol/L for NT-proBNP, 1578 fmol/mL for proANP), dogs with MMVD with and without congestive heart failure (CHF) could be differentiated with a sensitivity of 83% for both and specificities of 85% and 86%, respectively. Dogs staged in CHIEF B1 and B2 could not be distinguished based on NP concentrations due to wide variation within the groups. Intact females (means 598 pmol/L and 1036 fmol/mL, respectively) had significantly higher values of both NPs than intact males (315 pmol/L and 836 fmol/mL). Conclusions: NPs in canine MMVD are useful to discriminate between asymptomatic dogs and dogs with CHF. Due to a large overlap of NP-concentrations between the groups, NPs do not seem to be useful to differentiate between dogs in stages B1 and B2. Interpretation of NT-proBNP and proANP values should include consideration of sex-specific differences."

Chronic Kidney Disease in Dogs in UK Veterinary Practices: Prevalence, Risk Factors, and Survival. D.G. O’Neill, J. Elliott, D.B. Church, P.D. McGreevy, P.C. Thomson, and D.C. Brodbelt. J.Vet.Intern.Med. May 2013. Quote: "Background: The prevalence for chronic kidney disease (CKD) in dogs varies widely (0.05–3.74%). Identified risk factors include advancing age, specific breeds, small body size, and periodontal disease. Hypothesis/Objectives: To estimate the prevalence and identify risk factors associated with CKD diagnosis and survival in dogs. Purebred dogs were hypothesized to have higher CKD risk and poorer survival characteristics than crossbred dogs. Animals: A merged clinical database of 107,214 dogs attending 89 UK veterinary practices over a 2-year period (January 2010–December 2011). Methods: A longitudinal study design estimated the apparent prevalence (AP) whereas the true prevalence (TP) was estimated using Bayesian analysis. A nested case-control study design evaluated risk factors. Survival analysis used the Kaplan-Meier survival curve method and multivariable Cox proportional hazards regression modeling. Results: The CKD AP was 0.21% (95% CI: 0.19–0.24%) and TP was 0.37% (95% posterior credibility interval 0.02–1.44%). Significant risk factors included increasing age, being insured, and certain breeds (Cocker Spaniel, Cavalier King Charles Spaniel). Cardiac disease was a significant comorbid disorder. Significant clinical signs included halitosis, weight loss, polyuria/polydipsia, urinary incontinence, vomiting, decreased appetite, lethargy, and diarrhea. The median survival time from diagnosis was 226 days (95% CI 112–326 days). International Renal Interest Society stage and blood urea nitrogen concentration at diagnosis were significantly associated with hazard of death due to CKD. Conclusions and Clinical Importance: Chronic kidney disease compromises dog welfare. Increased awareness of CKD risk factors and association of blood biochemistry results with survival time should facilitate diagnosis and optimize case management to improve animal survival and welfare."

Decreased Right Ventricular Systolic Function In Dogs with Myxomatous Mitral Valve Disease. LH Olsen, MJ Reimann, JE Møller, J Häggström, SE Jangdin, T Falk, AT Uggla, NE Zois. J.Vet.Int.Med. May 2013; 27(3):604 (C-6). Quote: "Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs and the cavalier King Charles spaniel (CKCS) seems predisposed. Right ventricular (RV) dysfunction is associated with poor prognosis in human patients with mitral regurgitation. The aim of this study was to evaluate RV systolic function in dogs with different degrees of MMVD. Clinical examination including chocardiography was performed in 103 privately-owned dogs (16 controls dogs (Beagles), 70 CKCSs with different degrees of MR and 17 dogs of different breeds with clinical signs of heart failure (HF) due to MMVD). Right ventricular systolic function was estimated by tricuspid annular plane systolic excursion (TAPSE) assessed by 2D guided M-mode and tricuspid annular peak systolic velocity (TDPW) evaluated by pulsed tissue Doppler imaging. Influence of MMVD disease group, age, gender, heart rate (HR), severity of tricuspid regurgitation (TR) and pulmonary hypertension on RV systolic function was evaluated using analyses of covariance. TAPSE (P = 0.009) and TDPW (P = 0.005) were significantly associated with disease group. On post-hoc comparisons, CKCSs with heart murmur but without left atrial enlargement had significantly lower TAPSE (P = 0.004) and PWTD (P = 0.02) than control dogs. In addition, TDPW was lower in HF dogs compared to control dogs (P = 0.004). An influence of concomitant TR on TDPW was found (P = 0.02). TAPSE (P = 0.008) and TDPW (P = 0.03) increased with advancing age. TDPW increased with increasing HR (P = 0.002). In conclusion, echocardiographic measurements of RV function indicate decreased RV systolic function in dogs with MMVD. Studies are needed to elucidate prognostic significance of the findings."

Phosphodiesterase 5a Polymorphisms and Their Functional Effects in Dogs. JA Stern, Y Reina Doreste, L Chdid, KM Meurs. J.Vet.Int.Med. May 2013; 27(3):604 (C-9). Quote: "The phosphodiesterase 5A gene (PDE5A) encodes for cyclic guanosine monophosphate (cGMP) specific phosphodiesterase. It is a key physiologic regulator of cGMP and pharmacologic target of drugs used to treat pulmonary hypertension and erectile dysfunction such as sildenafil. PDE5A polymorphisms in human beings have been described that may predict response to therapy with sildenafil and nitric oxide. We hypothesized that polymorphisms in the PDE5A gene exist in dogs and that basal levels of cGMP would be significantly affected by these changes. Genomic DNA from 15 unrelated dogs of 3 breeds (Golden Retriever, Norwich Terrier, Cavalier King Charles Spaniel) was utilized. Exonic, splice-site, and untranslated regions of the PDE5A gene were sequenced and compared to the dog and human reference sequences. Nucleotide substitutions were recorded and evaluated with commercially available software for potential damage to protein structure and function. Polymorphism frequency was evaluated in a larger cohort of 55 additional, unrelated, healthy dogs of 14 breeds. Plasma cGMP levels were measured in 40 PDE5A genotyped dogs and compared using an unpaired t test by genotype group. An exonic, amino-acid substituting polymorphism was observed in a highly conserved region of the PDE5A gene in 61/70 dogs (21 homozygous, 40 heterozygous). The exonic polymorphism was evaluated and judged to be damaging based on protein modeling and change of amino acid charge and acid-base status. A statistical difference was observed with the reported amino acid substitution. Dogs that match the reference sequence amino acid structure were significantly higher in cGMP when compared to the pooled group of heterozygous and homozygous genotype dogs (P = 0.007). A series of 5 linked single nucleotide polymorphisms was observed in 44/70 dogs (11 homozygous, 33 heterozygous). The linked SNPs were evaluated and determined to result in significant changes to secondary protein structure. There were no statistical differences observed in plasma cGMP with the 5 linked polymorphisms or based upon age, breed or gender. The PDE5A gene of dogs contains multiple polymorphisms and an exonic amino acid substitution that suggests a functional role. Further investigation into genotype specific PDE5A function and response to drug therapy may be warranted."

Influence of R-R Interval Variations on the Degree of Mitral Regurgitation in Dogs with Myxomatous Mitral Valve Disease. MJ Reimann, JE Møller, J Häggström, B Markussen, AEW Holen, T Falk, LH Olsen. J.Vet.Int.Med. May 2013; 27(3):604 (C-30). Quote: "Mitral regurgitation (MR) due to myxomatous mitral valve disease (MMVD) is a common finding in cavalier Kings Charles spaniels (CKCSs). In addition, sinus arrhythmia is often more pronounced in dogs compared to other mammal species. The aim of the study was to evaluate whether duration of the R-R interval influences degree of MR assessed by echocardiography in dogs. Clinical examination including echocardiography was performed in 103 privately-owned dogs (16 controls dogs (Beagles), 70 CKCSs with different degree of MR and 17 dogs of different breeds with clinical signs of heart failure due to MMVD). Severity of MR was evaluated in apical 4-chamber view using colour Doppler flow mapping (maximum% of the left atrium area) and colour Doppler M-mode (duration in msec). The influence of the ratio between present and preceding R-R interval on MR severity was evaluated in 10 consecutive R-R intervals using a linear mixed model for repeated measurements. MR severity was observed to increase when a short R-R interval was followed by a long R-R interval in CKCSs with different degrees of MR (P < 0.003 when adjusted for multiple testing). The relationship was not significant in control dogs (also including dogs with minimal MR) or in dogs with clinical signs of heart failure due to MMVD. In conclusion, MR severity increases in long R-R intervals when these follow a short R-R interval in CKCSs with different degrees of MR due to asymptomatic MMVD. Thus, the degree of sinus arrhythmia may affect the echocardiographic grading of MR in dogs."

Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy. Francesco S. Loffredo, Matthew L. Steinhauser, Steven M. Jay, Joseph Gannon, James R. Pancoast, Pratyusha Yalamanchi, Manisha Sinha, Claudia Dall’Osso, Danika Khong, Jennifer L. Shadrach, Christine M. Miller, Britta S. Singer, Alex Stewart, Nikolaos Psychogios, Robert E. Gerszten, Adam J. Hartigan, Mi-Jeong Kim, Thomas Serwold, Amy J. Wagers, Richard T. Lee. Cell. May 2013;153(4):828-839. Quote: "The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGFβ superfamily member GDF11 [growth differentiation factor 11] as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a new therapeutic opportunity for cardiac aging."

Relationships between heart rate and age, bodyweight and breed in 10,849 dogs. M. J. Hezzell, K. Humm, S. G. Dennis, L. Agee, A. Boswood. J.Sm.Anim.Prac. June 2013; 54(6):318-324. Quote: "Objectives: To evaluate relationships between heart rate and clinical variables in healthy dogs and dogs examined at a referral hospital. Methods: Clinical data were extracted from the electronic patient records of a first opinion group (5000 healthy dogs) and a referral hospital (5849 dogs). Univariable and multi-variable general linear models were used to assess associations between heart rate and clinical characteristics. Separate multi-variable models were constructed for first opinion and referral populations. Results: In healthy dogs, heart rate was negatively associated with bodyweight (P<0·001) but was higher in Chihuahuas. The mean difference in heart rate between a 5 and 55 kg dog was 10·5 beats per minute. In dogs presenting to a referral hospital, heart rate was negatively associated with bodyweight (P<0·001) and the following breeds; border collie, golden retriever, Labrador retriever, springer spaniel and West Highland white terrier and positively associated with age, admitting service (emergency and critical care, emergency first opinion and cardiology) and the following breeds; Cavalier King Charles spaniel, Staffordshire bull terrier and Yorkshire terrier. Clinical Significance: Bodyweight, age, breed and disease status all influence heart rate in dogs, although these factors account for a relatively small proportion of the overall variability in heart rate."

Left Atrial Ejection Fraction Assessed by Real-Time 3-Dimensional Echocardiography in Normal Dogs and Dogs with Myxomatous Mitral Valve Disease. A. Tidholm, K. Höglund, J. Häggström, A. Bodegård-Westling, I. Ljungvall. J.Vet.Int.Med. June 2013. Quote: "Background: Real-time 3-dimensional (RT3D) echocardiography provides a novel technique for assessing left atrial ejection fraction (LAEF) in dogs. Hypothesis: Left atrial ejection fraction is associated with severity of myxomatous mitral valve disease (MMVD). Animals: Privately owned dogs; 101 with MMVD and 52 healthy control dogs. [Cavalier King Charles Spaniel (16)] Methods: Prospective observational study using RT3D echocardiographic estimations of LA volumes at atrial end-diastole and atrial end-systole to calculate LAEF in comparison with conventional 2-dimensional echocardiographic variables. Results: Left atrial ejection fraction decreased with increasing LA to aortic ratio (LA/Ao), percentage increase in left ventricular (LV) internal dimension, corrected for body weight (BW), in diastole (LVIDd inc%) and systole (LVIDs inc%), and age for MMVD dogs, and with BW for control dogs. The final models in the multiple regression analyses included LVIDd inc% and age for MMVD dogs, and BW alone for control dogs. LAEF varied widely in both MMVD dogs and control dogs. Conclusion and clinical importance: The wide variation of LAEF and the fact that LAEF does not appear to be an independent marker of disease severity suggest that the clinical importance of determining LAEF in dogs with MMVD might be limited."

Left Ventricular Twist and Circumferential Strain in Dogs with Myxomatous Mitral Valve Disease. N.E. Zois, N.T. Olsen, S.G. Moesgaard, C.E. Rasmussen, T. Falk, J. Häggström, H.D. Pedersen, J.E. Møller, L.H. Olsen. J.Vet.Int.Med. June 2013. Quote: "Background: During the cardiac cycle, the ventricle undergoes a twisting motion because of the oblique orientation of the left ventricular (LV) myofibers. This can be quantified by speckle-tracking echocardiography (STE). In mitral regurgitation (MR) in humans, the short axis deformation has been suggested as being pivotal to LV function. Decreased and delayed LV twist has been described in experimental MR, but has not been studied in myxomatous mitral valve disease (MMVD). Hypotheses: (1) Magnitude (CSt) and rate (CSRs) of systolic circumferential deformation decrease before the onset of congestive heart failure (CHF); (2) magnitude and rate of LV twist decrease, and onset of untwist is delayed, with increasing MMVD severity. Animals: A total of 97 privately owned small- to medium-sized dogs. [62 CKCSs] Methods: Severity of MMVD was assessed by echocardiography and presence of clinical signs of CHF. Magnitude and rate of LV twist and circumferential deformation were evaluated by STE. Results: Dogs with CHF receiving treatment had increased CSt, CSRs, early diastolic untwisting rate, and delayed onset of untwist compared to dogs with minimal MMVD and increased systolic twist compared to dogs with mild MMVD (all P < .01). CSt and time to onset of untwist increased with echocardiographic variables of MR severity (all P < .002). CSRs and several LV twist variables decreased with increasing systolic LV internal diameter (all P < .01). Conclusions and Clinical Importance: No STE-derived variable was decreased before onset of CHF. In dogs with CHF receiving treatment, the delayed onset of relaxation might indicate LV dysfunction and the hyperdynamic CSt and LV twist reflect compensatory mechanisms."

Augmentation of Left Ventricular Wall Thickness With Alginate Hydrogel Implants Improves Left Ventricular Function and Prevents Progressive Remodeling in Dogs With Chronic Heart Failure. Hani N. Sabbah, Mengjun Wang, Ramesh C. Gupta, Sharad Rastogi, Itamar Ilsar, Michael S. Sabbah, Smita Kohli, Sam Helgerson, Randall J. Lee. J. Amer. Col. of Cardiology - Heart Failure. June 2013;1(3):252-258. Quote: "Objectives: The study tested the hypothesis that augmentation of the left ventricular (LV) wall thickness with direct intramyocardial injections of alginate hydrogel implants (AHI) reduces LV cavity size, restores LV shape, and improves LV function in dogs with heart failure (HF). Methods: Studies were performed in 14 dogs with HF produced by intracoronary microembolizations. Dogs were randomized to AHI treatment (n = 8) or to sham-operated control (n = 6). During an open-chest procedure, dogs received either intramyocardial injections of 0.25 to 0.35 ml of alginate hydrogel (Algisyl-LVR, LoneStar Heart, Inc., Laguna Hills, California) or saline. Seven injections were made ∼1.0 to 1.5 cm apart (total volume 1.8 to 2.1 ml) along the circumference of the LV free wall halfway between the apex and base starting from the anteroseptal groove and ending at the posteroseptal groove. Hemodynamic and ventriculographic measurements were made before treatment (PRE) and repeated post-surgery for up to 17 weeks (POST). Results: Compared to control, AHI significantly reduced LV end-diastolic and end-systolic volumes and improved LV sphericity. AHI treatment significantly increased EF compared to the decreased EF seen in control dogs. AHI treatment was well tolerated and was not associated with increased LV diastolic stiffness. Conclusions: In HF dogs, circumferential augmentation of LV wall thickness with AHI improves LV structure and function. The results support continued development of AHI for the treatment of patients with advanced HF."

Comparative assessment of left ventricular function variables determined via cardiac computed tomography and cardiac magnetic resonance imaging in dogs. Anne K. Sieslack, Peter Dziallas, Ingo Nolte, Patrick Wefstaedt. Am. J. Vet. Res. July 2013;74(7):990-998. Quote: Objective: To evaluate the accuracy and reproducibility of left ventricular (LV) volumetric and function variables determined via contrast-enhanced cardiac CT and cardiac MRI in healthy dogs. Animals: 10 healthy Beagles. Procedures: Cardiac MRI and cardiac CT were performed in anesthetized Beagles; both examinations were conducted within a 2-hour period. Cardiac MRI was performed with a 3.0-T magnet, and contrast-enhanced cardiac CT was performed with a 64-row detector CT machine. Data sets were acquired during apnea with simultaneous ECG gating. Short-axis images were created to determine functional variables via the Simpson method. Results: Cardiac CT values for mean end-diastolic and end-systolic LV volumes had excellent correlation (r = 0.95) with cardiac MRI measurements, whereas LV stroke volume (r = 0.67) and LV ejection fraction (r = 0.75) had good correlations. The only variable that differed significantly between imaging modalities was end-diastolic LV volume. For each pair of values, Bland-Altman analysis revealed good limits of agreement. Conclusions & Clinical Relevance: The 3-D modalities cardiac CT and cardiac MRI were excellent techniques for use in assessing LV functional variables. Similar results were obtained for LV volume and function variables via both techniques. The major disadvantage of these modalities was the need to anesthetize the dogs for the examinations.

Identification of DNA variants in the canine beta-1 adrenergic receptor gene. B.A. Maran, K.L. Mealey, S.M. Lahmers, O.L. Nelson, K.M. Meurs. Research in Vet.Sci. Aug 2013; 95(1):238-240. Quote: "Beta-adrenergic receptor antagonists are utilized for the management of several cardiac diseases in the dog. In humans the beneficial effects of beta-adrenergic receptor antagonists are variable and are associated with a genetic variability in the beta one adrenergic receptor gene (ADRB1). To determine if DNA variants were present in the canine ADRB1 gene, DNA from five breeds of dogs was evaluated. Two deletions were identified within the region of the gene that encodes the cytoplasmic tail of ADRB1. The functions of this region are not well understood although it is important in differentiating subtypes of adrenergic receptors and may be associated with control of receptor downregulation. The functional consequences of these identified variants deserve further study."

Short-Term Effects of Atorvastatin in Normal Dogs and Dogs with Congestive Heart Failure Due to Myxomatous Mitral Valve Disease. S.M. Cunningham, J.E. Rush, L.M. Freeman. J.Vet.Int.Med. July 2013;27(4):985-989. Quote: "Background: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may improve heart failure class and survival in people with congestive heart failure (CHF) of various etiologies. Hypothesis/Objectives: To evaluate the tolerability of atorvastatin in healthy dogs, and the short-term effects of atorvastatin on clinical markers of disease severity, lipid profiles, and markers of systemic inflammation and oxidative stress in dogs with CHF. Animals: Eleven normal dogs and 12 client-owned animals with CHF attributable to myxomatous mitral valve disease [two CHF dogs were cavalier King Charles spaniels]. Methods: Prospective nonblinded observational study. Normal dogs (n = 11) were first treated with atorvastatin and re-evaluated after 14 and 30 days for clinical tolerability and alterations in certain laboratory results. Subsequently, dogs with CHF (n = 12) were treated with atorvastatin at a dosage of 2 mg/kg q24h for 8 weeks. Echocardiography, blood pressure (BP), quality of life questionnaire, and blood sampling were performed pre and post atorvastatin administration. Results: Atorvastatin was well tolerated and did not result in apparent adverse effects or biochemical abnormalities in healthy dogs and in dogs with CHF. Healthy dogs experienced a decrease in total cholesterol (TC) concentration (P = .03) after atorvastatin administration. Decreases in TC concentration (P = .02), non-HDL cholesterol concentration (P = .02), total white blood cell count (P = .03), neutrophils (P = .01), and systolic BP (P = .01) were noted in the CHF group after 8 weeks of atorvastatin. Conclusions and Clinical Importance: Atorvastatin was well tolerated at clinically relevant doses in healthy dogs and dogs with CHF. ... In this small study, we did not observe any significant short-term effects on echocardiographic or ECG parameters, quality of life questionnaire, or NT-proBNP. The lack of observed improvement in these clinical parameters may indicate that statins are not helpful in dogs with nonischemic heart failure, but the lack of observed effect also could relate to the small number of dogs, short duration of this trial or both. The modest decreases in systolic blood pressure seen in dogs with CHF after atorvastatin administration may have resulted from statin treatment, habituation to the hospital environment, or the effects of concomitant cardiac medications. Currently there is no clear consensus on the use of statins in people with CHF and it is clear that more trials are needed in both people and veterinary patients to better ascertain the effects of statins in the heart failure setting."

Clinical usefulness of an assay for measurement of circulating N-terminal pro-B-type natriuretic peptide concentration in dogs and cats with heart disease. Mark A. Oyama, Adrian Boswood, David J. Connolly, Stephen J. Ettinger, Philip R. Fox, Sonya G. Gordon, John E. Rush, D. David Sisson, Rebecca L. Stepien, Gerhard Wess, Faiez Zannad. JAVMA. July 2013;243(1):71-82.

Veterinary cardiology: a journey through time. Adrian Boswood. Vet.Rec. June 2013;172(26):678-682. Quote: "Adrian Boswood poses the question of which diagnostic tool veterinary cardiologists would choose today if they were allowed only one. He then looks back over the past 125 years, considering the development of different diagnostic aids and explains how they have affected the discipline."

Serum Serotonin Concentration Is Associated with Severity of Myxomatous Mitral Valve Disease in Dogs. I. Ljungvall, K. Höglund, I. Lilliehöök, M.A. Oyama, A. Tidholm, H. Tvedten and J. Häggström. J.Vet.Int.Med. Sept. 2013;27(5):1105-1112. Quote: "Background: The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has recently been suggested to play a role in the development of naturally acquired myxomatous mitral valve disease (MMVD) in dogs. Aim: To investigate the association between serum 5-HT concentration and MMVD severity in dogs, and to assess potential associations between serum 5-HT concentrations and dog characteristics, echoca rdiographic variables, heart rate, systolic blood pressure, presence of macrothrombocytosis, and plateletcrit. Animals: A total of 120 client-owned dogs [including 92 cavalier King Charles spaniels]. Material and Methods: Dogs were prospectively recruited and were classified by standard echocardiography into healthy (dogs of breeds predisposed to MMVD, but without echocardiographic evidence of the disease), mild, moderate, or severe MMVD groups. Serum 5-HT concentrations were analyzed using an ELISA. Results: Dogs with severe MMVD had lower serum 5-HT concentrations than healthy dogs (P = .0025) and dogs with mild MMVD (P = .0011). Unilinear and multiple regression analyses showed that serum 5-HT concentrations decreased with increasing left atrial to aortic root ratio (LA/Ao), were higher in Cavalier King Charles Spaniel (CKCS) dogs compared to dogs of other breeds, and were higher in female dogs than in male dogs. The LA/Ao was the variable most strongly associated with serum 5-HT concentration. Conclusions and Clinical Importance: The finding of higher serum 5-HT concentrations in dogs of breeds predisposed to the early onset of MMVD (CKCS) and dogs with mild MMVD suggests that alterations in 5-HT signaling might play a role in progression of early stages of MMVD." [See also the November 2012 version of this report.]

Safety of Spironolactone in Dogs with Chronic Heart Failure because of Degenerative Valvular Disease: A Population-Based, Longitudinal Study. H.P. Lefebvre, E. Ollivier, C.E. Atkins, B. Combes, D. Concordet, V. Kaltsatos and L. Baduel. J.Vet.Int.Med. Sept. 2013;27(5):1083-1091. Quote: "Background: Spironolactone treatment in humans is associated with an increased risk of hyperkalemia and renal dysfunction. Hypothesis: Dogs with cardiac disease treated with spironolactone, in addition to conventional therapy, are not at higher risk for adverse events (AEs) than those receiving solely conventional therapy. Animals: One hundred and ninety-six client-owned dogs with naturally occurring myxomatous mitral valve disease. ... Cavalier King Charles Spaniel (8.2%, n = 16). ... Methods: Prospective, double-blinded field study with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin-converting enzyme inhibitor, plus furosemide and digoxin if needed). Safety was compared between treatment groups, using the frequency of AEs, death caused by cardiac disease, renal disease, or both, and variations in serum sodium, potassium, urea, and creatinine concentrations. For the latter, population-specific reference intervals were established and out of range values (ORV) analyzed. Results: The number of AEs was similar in the spironolactone and reference groups (188 and 208, respectively), when followed for median duration of 217 days (range [2–1,333]). At each study time point, the percentage of dogs showing ORV was similar between groups. There were a higher number of deaths because of cardiac disease, renal disease or both in the reference group (30.7% versus 13.7%) (P = .0043). Conclusions and Clinical Importance: Dogs with heart failure receiving spironolactone in addition to conventional treatment are not at a higher risk for AEs, death caused by cardiac disease, renal disease, or both, hyperkalemia, or azotemia."

Systolic arterial blood pressure in small-breed dogs with degenerative mitral valve disease: A prospective study of 103 cases (2007–2012). A.M. Petit, V. Gouni, R. Tissier, E. Trehiou-Sechi, C. Misbach, J.-L. Pouchelon, H.P. Lefebvre, V. Chetboul. Vet.J. July 2013. Quote: "The objective of this prospective observational study was to assess systolic arterial blood pressure (SABP) in small-breed dogs with degenerative mitral valve disease (MVD) from different International Small Animal Cardiac Health Council (ISACHC) heart failure classes. For this purpose, 103 client-owned dogs ... with Cavalier King Charles spaniels (n = 39/103; 38%) ... weighing <20 kg (mean ± standard deviation, 8.5 ± 3.0 kg; aged 9.8 ± 2.9 years) and presenting with MVD diagnosed by echo-Doppler examination were enrolled. Nineteen healthy dogs (9.9 ± 2.3 years; 8.7 ± 4.2 kg) were concurrently recruited as controls. SABP was measured in unsedated dogs using the Doppler method according to the recommendations in the American College of Veterinary Medicine consensus statement. SABP was significantly increased in dogs in ISACHC class 1 (n = 53; median, interquartile range 140 mmHg, 130–150 mmHg) and class 2 (n = 21; 140 mmHg, 130–150 mmHg), compared to the control group (n = 19; 130 mmHg, 120–140 mmHg; P < 0.01 and P < 0.05, respectively), but remained within the reference interval (⩽160 mmHg). Conversely, dogs in ISACHC class 3 showed a significantly lower SABP (n = 29, 120 mmHg, 110–130 mmHg) than those from all other ISACHC classes (P < 0.001) and the controls (P < 0.05). Additionally, SABP < 120 mmHg was recorded in 13/103 dogs (13%). The 13 dogs were all ISACHC class 3 (3a or 3b) and were under medical treatment for heart failure. In conclusion, MVD was often associated with SABP values that were within the reference interval, but at its upper end. However, a significant decrease in SABP was observed in dogs with ISACHC heart failure class 3. Whether such low SABP values resulted from an MVD-related decrease in cardiac output, an afterload reduction owing to cardiac treatment, or both, remains to be determined."

Canine Acquired Heart Disease: Advances in Medical Treatment. Emily Dutton, Simon Swift. Vet. Times. August 2013;12-16. Quote: "The most commonly diagnosed acquired heart disease in dogs is degenerative mitral valve disease (DMVD) with cavalier King Charles spaniels, Yorkshire terriers, miniature poodles and dachshunds being over-represented. ... The ability to diagnose and treat acquired heart diseases in dogs is an active area of ongoing research. In particular, improving quality of life as well as increasing longevity is very important. Early detection of acquired heart disease and effective, targeted monitoring of the condition is important to help optimise the treatment plan long term."

Effect of furosemide and high-dosage pimobendan administration on the renin-angiotensin-aldosterone system in dogs. Marisa K. Ames, Clarke E. Atkins, Andrea C. Lantis, and Stephen R. Werre. Am.J.Vet.Res. Aug. 2013;74(8):1084-1090. Quote: "Objective: To determine whether a high dosage of pimobendan, when administered concurrently with moderate-dosage furosemide to healthy dogs, would activate the renin-angiotensin-aldosterone system (RAAS) more than furosemide alone. Animals: 12 healthy dogs. Procedures: 6 dogs received furosemide (2.0 mg/kg, PO, q 12 h) only, as an RAAS activator, for 10 days. The other 6 dogs received furosemide (2.0 mg/kg, PO, q 12 h) and pimobendan (0.6 mg/kg, PO, q 12 h) for 10 days. The effect of these drugs on the RAAS was determined by measurement of the aldosterone-to-creatinine ratio (A:C) in urine collected in the morning and evening of study days −2, −1, 1, 5, and 10. Results: Although there was an increase in the urine A:C during the study period in both groups, it was significant only for dogs that received both drugs. The urine A:C only differed significantly between groups on day 1, at which time A:C was greater in the group that received both drugs. Conclusions and Clinical Relevance: High-dosage pimobendan administration neither substantially suppressed nor potentiated the RAAS when administered with furosemide in healthy dogs."

Identification of DNA variants in the canine beta-1 adrenergic receptor gene. B.A. Maran, K.L. Mealey, S.M. Lahmers, O.L. Nelson, K.M. Meurs. Research in Vet.Sci. Aug. 2013;95(1):238-240. Quote: "Beta-adrenergic receptor antagonists are utilized for the management of several cardiac diseases in the dog. In humans the beneficial effects of beta-adrenergic receptor antagonists are variable and are associated with a genetic variability in the beta one adrenergic receptor gene (ADRB1). To determine if DNA variants were present in the canine ADRB1 gene, DNA from five breeds of dogs was evaluated. ... Cavalier King Charles Spaniel (CKCS) (6) ... Two deletions were identified within the region of the gene that encodes the cytoplasmic tail of ADRB1. The functions of this region are not well understood although it is important in differentiating subtypes of adrenergic receptors and may be associated with control of receptor downregulation. The functional consequences of these identified variants deserve further study."

Vertebral Scale System to Measure Heart Size in Dogs in Thoracic Radiographs. Mudasir Bashir Gugjoo, Mozammel Hoque, Abhishek Chander Saxena, Malik Mohammed Shamsuz Zama, Amarpal. Adv.Anim.Vet.Sci. 2013;1(1):1–4. Quote: "The vertebral heart score may be useful in assessing the change in size of the heart in a patient over time as there is good correlation between the growth of different visceral organs and vertebral body length. ... VHS is one of the easily available, applicable and interpretable cardiac diagnostic techniques as it does not require any sophisticated equipment. However, the problems related to inter-observer variability in relation to reference point selection and also due to breed specific values, should be considered while interpreting the radiograph."

Comparative Effect of Carperitide and Furosemide on Left Atrial Pressure in Dogs with Experimentally Induced Mitral Valve Regurgitation. S. Suzuki, R. Fukushima, Y. Yamamoto, T. Ishikawa, L. Hamabe, S. Kim, R. Yoshiyuki, T. Fukayama, N. Machida and R. Tanaka. J.Vet.Int.Med. Sept. 2013;27(5):1097-1104. Quote: "Background: The effects of carperitide on left atrial pressure (LAP) in dogs with mitral valve disease (mitral regurgitation, MR) have not been documented. Objective: The objective was to compare the short-term effects of carperitide versus furosemide on LAP and neurohumoral factors in MR dogs. Animals: Six healthy Beagle dogs weighing 9.8–12.6 kg (2 males and 4 females; aged 3 years) were used. ... Results: This study demonstrated that LAP was decreased similarly with carperitide 0.1 μg/kg/min or furosemide 0.17 mg/kg/h in dogs with experimentally induced MR. Secondly, carperitide was more effective than furosemide in afterload reduction. Thirdly, furosemide was more effective than carperitide in diuretic effect. Finally, plasma renin activity and plasma aldosterone were not elevated after the administration of carperitide. ... Conclusions and Clinical Importance: Carperitide significantly decreased LAP in dogs with acute MR caused by experimental chordal rupture. Carperitide can have additional benefits from the viewpoint of minimal activation of neurohumoral factors in the treatment of dogs with MR. Additional studies in dogs with spontaneous disease are warranted."

Effect of furosemide and high-dosage pimobendan administration on the renin-angiotensin-aldosterone system in dogs. Marisa K. Ames, Clarke E. Atkins, Andrea C. Lantis, Stephen R. Werre. AmJ.Vet.Res. Aug. 2013;74(8):1084-1090. Quote: "Objective: To determine whether a high dosage of pimobendan, when administered concurrently with moderate-dosage furosemide to healthy dogs, would activate the renin-angiotensin-aldosterone system (RAAS) more than furosemide alone. Animals: 12 healthy dogs. Procedures: 6 dogs received furosemide (2.0 mg/kg, PO, q 12 h) only, as an RAAS activator, for 10 days. The other 6 dogs received furosemide (2.0 mg/kg, PO, q 12 h) and pimobendan (0.6 mg/kg, PO, q 12 h) for 10 days. The effect of these drugs on the RAAS was determined by measurement of the aldosterone-to-creatinine ratio (A:C) in urine collected in the morning and evening of study days −2, −1, 1, 5, and 10. Results: Although there was an increase in the urine A:C during the study period in both groups, it was significant only for dogs that received both drugs. The urine A:C only differed significantly between groups on day 1, at which time A:C was greater in the group that received both drugs. Conclusions and Clinical Relevance: High-dosage pimobendan administration neither substantially suppressed nor potentiated the RAAS when administered with furosemide in healthy dogs."

Update zur Mitralklappenendokardiose [Update on mitral valve endocardiosis]. Markus Killich. ATF-Anerkannte Interaktive Fortbildung. August 2013. Quote: "Myxomatous mitral valve degeneration (MMVD) or degenerative mitral valve disease is the most common cardiac disease in dogs. The disease prevalence is age-related with small-sized breeds being more commonly affected than large breed dogs. MMVD typically affects older dogs with the exception of the Cavalier King Charles Spaniel and bull terrier, both of which can develop the disease at an early age. The initiating stimuli are not completely understood but a variety of chemical and biomechanical mechanisms seem to be responsible for the valvular degeneration. The course of the disease is generally regarded as benign, with only 10% of dogs developing clinically significant disease. The gold standard for diagnosis is still echocardiography. Echocardio-graphically, not only the left ventricular and left atrial dimensions can be assessed but also intracardiac pressures can be measured. Therapy is dependent on disease severity. Mild diseases do not require any therapy, whereas congestive heart failure should be treated with a triple therapy consisting of pimobendan, an ace-inhibitor and furosemide. Surgical mitral valve repair has become an option for treatment and has recently shown promising results. The major drawback of open-heart surgery, the immense technical effort in combination with high costs, could potentially be overcome by the development of catheter-based methods."

Sound advice for heart murmurs. Simon Dennis. J.Sm.Anim.Prac. Sept. 2013;54(9):443-444.

Sleeping and resting respiratory rates in dogs with subclinical heart disease. Dan G. Ohad, Mark Rishniw, Ingrid Ljungvall, Francesco Porciello, Jens Häggström. J.Am.Vet.Med.Assn. September 2013;243(6):839-843. Quote: "Objective: To characterize sleeping respiratory rates (SRRs) and resting respiratory rates (RRRs), collected in the home environment, of dogs with subclinical heart disease that could result in left-sided congestive heart failure. Design: Prospective cross-sectional study. Animals: 190 adult dogs with subclinical left-sided heart disease. Procedures: Most dogs had mitral valve disease or dilated cardiomyopathy of various severities. Clients collected ten 1-minute SRRs or RRRs during a period ranging from 1 week to 6 months. Clinicians provided echocardiographic and medical data on each patient. Results: The within-dog mean SRR (SRRmean; 16 breaths/min) was significantly lower than the within-dog mean RRR (RRRmean; 21 breaths/min). Seven dogs had SRRmean and 33 dogs had RRRmean > 25 breaths/min; 1 dog had SRRmean and 12 dogs had RRRmean > 30 breaths/min; these dogs mostly had a left atrial (LA)-to-aortic ratio > 1.8. Dogs with moderate LA enlargement had a significantly higher SRRmean than did other dogs. However, median SRRmean for each of 4 levels of LA enlargement was < 20 breaths/min; median RRRmean for each of 4 levels of LA enlargement was < 25 breaths/min. Both within-dog SRR and RRR remained stable for 10 consecutive measurements. Treatment with cardiac medications or presence of pulmonary hypertension was not associated with SRRmean or RRRmean. Conclusions and Clinical Relevance: Results suggested that dogs with confirmed subclinical left-sided heart disease of various severities generally had SRRmean < 25 breaths/min, which was infrequently exceeded at any time, and that SRR and RRR remained stable, regardless of individual within-dog SRRmean or RRRmean."

Validation of a commercially available enzyme immunoassay for measurement of plasma antidiuretic hormone concentration in healthy dogs and assessment of plasma antidiuretic hormone concentration in dogs with congestive heart failure. Katherine F. Scollan, Barret J. Bulmer, D. David Sisson. AmJ.Vet.Research. September 2013;74(9):1206-1211. Quote: "Objective: To validate the use of a human enzyme immunoassay (EIA) kit for measurement of plasma antidiuretic hormone (ADH) concentration in dogs and evaluate plasma ADH concentrations in dogs with congestive heart failure (CHF) attributable to acquired cardiac disease, compared with findings in healthy dogs. Animals: 6 healthy dogs and 12 dogs with CHF as a result of chronic degenerative valve disease or dilated cardiomyopathy. Procedures: Plasma samples from the 6 healthy dogs were pooled and used to validate the EIA kit for measurement of plasma ADH concentration in dogs by assessing intra-assay precision, dilutional linearity, and spiking recovery. Following validation, plasma ADH concentrations were measured in the 6 healthy dogs and in the 12 dogs with CHF for comparison. Results: The EIA kit measured ADH concentrations in canine plasma samples with acceptable intra-assay precision, dilutional linearity, and spiking recovery. The intra-assay coefficient of variation was 11%. By use of this assay, the median plasma concentration of ADH in dogs with CHF was 6.15 pg/mL (SD, 3.2 pg/mL; range, 4.18 to 15.47 pg/mL), which was significantly higher than the median concentration in healthy dogs (3.67 pg/mL [SD, 0.93 pg/mL; range, 3.49 to 5.45 pg/mL]). Conclusions and Clinical Relevance: Plasma ADH concentrations in dogs can be measured with the tested EIA kit. Plasma ADH concentrations were higher in dogs with CHF induced by acquired cardiac disease than in healthy dogs. This observation provides a basis for future studies evaluating circulating ADH concentrations in dogs with developing heart failure."

Effects of a Sustained-Release Form of Isosorbide Dinitrate on Left Atrial Pressure in Dogs with Experimentally Induced Mitral Valve Regurgitation. Y. Yamamoto, S. Suzuki, L. Hamabe, D. Aytemiz, H. Huai-Che, S. Kim, R. Yoshiyuki, T. Fukayama, R. Fukushima, R. Tanaka. J. Vet. Intern. Med. September 2013;27(6):1421-1426. Quote: Background: The effects of isosorbide dinitrate (ISDN) have not been sufficiently investigated in conscious dogs with mitral valve regurgitation (MR). Objective: The objective was to investigate the effects of a sustained-release form of ISDN (sr-ISDN) on hemodynamics and the autonomic nervous system in dogs with MR. Animals: Six healthy Beagles weighing 11.2 2.2 kg (2 years of age; 2 males and 4 females) were used. Methods: Experimental, crossover, and interventional study. Dogs with experimentally induced MR were administered placebo, 2, 5, and 10 mg/kg sr-ISDN PO on separate days with a 7-day washout period between randomized dosings. Left atrial pressure (LAP) had been recorded continuously from 30 minutes before administration of sr-ISDN to 12 hours after administration. Results: LAP was significantly decreased after administration in the 5 and 10 mg/kg groups. Significant decrease was observed at 3 and 4 hours after administration in the 5 mg/kg group. In the 10 mg/kg group, significant decrease was observed at 2, 3, 4, 5, 6, 7, 10, and 11 hours after administration. The lowest value was observed at 4 hours after administration in the 5 and 10 mg/kg groups (20.9 ± 4.2 to 15.9 ± 3.9 mmHg, P < .01, and 21.3 ± 4.0 to 13.6 ± 4.2 mmHg, P < .001). Conclusions and Clinical Importance: Sustained-release form of ISDN showed significant decrease of LAP in the 5 mg/kg and 10 mg/kg groups, and duration of effect was dose related.

Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Myxomatous Mitral Valve Disease Receiving Pimobendan or Benazepril: The QUEST Study. J. Häggström, A. Boswood, M. O'Grady, O. Jöns, S. Smith, S. Swift, M. Borgarelli, B. Gavaghan, J.-G. Kresken, M. Patteson, B. Åblad, C.M. Bussadori, T. Glaus, A. Kovačević, M. Rapp, R.A. Santilli, A. Tidholm, A. Eriksson, M.C. Belanger, M. Deinert, C.J.L. Little, C. Kvart, A. French, M. Rønn-Landbo, G. Wess, A. Eggertsdottir, M. Lynne O'Sullivan, M. Schneider, C.W. Lombard, J. Dukes-McEwan, R. Willis, A. Louvet and R. DiFruscia. J.Vet.Int.Med. September 2013. Quote: "Background: Myxomatous mitral valve disease (MMVD) is an important cause of morbidity and mortality in dogs. Objectives: To compare, throughout the period of follow-up of dogs that had not yet reached the primary endpoint, the longitudinal effects of pimobendan versus benazepril hydrochloride treatment on quality-of-life (QoL) variables, concomitant congestive heart failure (CHF) treatment, and other outcome variables in dogs suffering from CHF secondary to MMVD. Animals: A total of 260 dogs in CHF because of MMVD [including 82 cavalier King Charles spaniels]. Methods: A prospective single-blinded study with dogs randomized to receive pimobendan (0.4–0.6 mg/kg/day) or benazepril hydrochloride (0.25–1.0 mg/kg/day). Differences in outcome variables and time to intensification of CHF treatment were compared. Results: A total of 124 dogs were randomized to pimobendan and 128 to benazepril. No difference was found between groups in QoL variables during the trial. Time from inclusion to 1st intensification of CHF treatment was longer in the pimobendan group (pimobendan 98 days, IQR 30–276 days versus benazepril 59 days, IQR 11–121 days; P = .0005). Postinclusion, dogs in the pimobendan group had smaller heart size based on VHS score (P = .013) and left ventricular diastolic (P = .035) and systolic (P = .0044) dimensions, higher body temperature (P = .030), serum sodium (P = .0027), and total protein (P = .0003) concentrations, and packed cell volume (P = .030). Incidence of arrhythmias was similar in treatment groups. Conclusions and Clinical Importance: Pimobendan versus benazepril resulted in similar QoL during the study, but conferred increased time before intensification of CHF treatment. Pimobendan treatment resulted in smaller heart size, higher body temperature, and less retention of free water." (See also 2008 QUEST study report.)

Effects of a Sustained-Release Form of Isosorbide Dinitrate on Left Atrial Pressure in Dogs with Experimentally Induced Mitral Valve Regurgitation. Y. Yamamoto, S. Suzuki, L. Hamabe, D. Aytemiz, H. Huai-Che, S. Kim, R. Yoshiyuki, T. Fukayama, R. Fukushima, R. Tanaka. J.Vet.Int.Med. September 2013. Quote: "Background: The effects of isosorbide dinitrate (ISDN) have not been sufficiently investigated in conscious dogs with mitral valve regurgitation (MR). Objective: The objective was to investigate the effects of a sustained-release form of ISDN (sr-ISDN) on hemodynamics and the autonomic nervous system in dogs with MR. Animals: Six healthy Beagles weighing 11.2 ± 2.2 kg (2 years of age; 2 males and 4 females) were used. Methods: Experimental, crossover, and interventional study. Dogs with experimentally induced MR were administered placebo, 2, 5, and 10 mg/kg sr-ISDN PO on separate days with a 7-day washout period between randomized dosings. Left atrial pressure (LAP) had been recorded continuously from 30 minutes before administration of sr-ISDN to 12 hours after administration. Results: LAP was significantly decreased after administration in the 5 and 10 mg/kg groups. Significant decrease was observed at 3 and 4 hours after administration in the 5 mg/kg group. In the 10 mg/kg group, significant decrease was observed at 2, 3, 4, 5, 6, 7, 10, and 11 hours after administration. The lowest value was observed at 4 hours after administration in the 5 and 10 mg/kg groups (20.9 ± 4.2 to 15.9 ± 3.9 mmHg, P < .01, and 21.3 ± 4.0 to 13.6 ± 4.2 mmHg, P < .001). Conclusions and Clinical Importance: Sustained-release form of ISDN showed significant decrease of LAP in the 5 mg/kg and 10 mg/kg groups, and duration of effect was dose related.

Red blood cell distribution width in dogs with chronic degenerative valvular disease. Carlo Guglielmini, Helen Poser, Angela Dalla Pria, Michele Drigo, Elisa Mazzotta, Michele Berlanda, Alessia Luciani. J.Am.Vet.Med.Assn. September 2013;243(6):858-862. Quote: "Objective: To evaluate RBC distribution width (RDW) in dogs with chronic degenerative valvular disease (CDVD) with compensated or decompensated heart failure. Design: Retrospective case-control study. Animals: 27 healthy dogs and 135 dogs with CDVD (87 dogs with compensated heart failure and 48 dogs with decompensated heart failure)[Cavalier King Charles Spaniels (6)]. Procedures: The RDW and various CBC and serum biochemical variables were compared among groups. Correlations between RDW and various echocardiographic variables were evaluated. Results: Mean ± SD RDW in dogs with CDVD (13.1% ± 1.0%) was not significantly different from that of healthy dogs (12.8% ± 0.8%). The RDW of dogs with CDVD and compensated heart failure (13.0% ± 1.0%) was not significantly different from that of dogs with CDVD and decompensated heart failure (13.2% ± 1.1%). The RDW had a significant, weak, negative correlation with Hct (correlation coefficient, −0.250), hemoglobin concentration (correlation coefficient, −0.219), and mean corpuscular volume (correlation coefficient, −0.211). The RDW had a significant, weak, positive correlation with 1 echocardiographic index of CDVD severity (ie, the left atrium-to-aorta ratio [correlation coefficient, 0.183]). Conclusions and Clinical Relevance: In this study population, RDW did not seem to be associated with the presence of heart failure or CDVD."

Left atrial volume and phasic function in clinically healthy dogs of 12 different breeds. M. Höllmer, J. L. Willesen, A.Tolver, J. Koch. Vet. J. September 2013; doi: 10.1016/j.tvjl.2013.05.045. Quote: The left atrium (LA) of the heart is a validated marker of clinical and subclinical cardiovascular disease. Since the LA is a three-dimensional structure, volume-based methods of chamber quantification might be more accurate than linear methods. The aims of this study were to establish the feasibility and reproducibility of biplane two-dimensional echocardiographic LA volume measurements and to provide reference ranges for LA volume and phasic function in adult dogs (n = 237) without cardiovascular disease [including 21 (8.8%) cavalier King Charles spaniels]. The study also assessed the effects of bodyweight (BW), breed, sex, age and heart rate (HR) on LA volume and function. The biplane area–length method was used to calculate LA volumes from the left apical four- and two-chamber views. LA volume and function were correlated with body size and there were significant breed differences. ... We provided breed-specific reference ranges for 12 breeds and clinical reference ranges for use in all dogs based on BW. The results indicate that the upper limit of normal for maximal LA volume is 0.92 mL/kg. These values of LA volume might provide a better basis for assessing LA size than linear LA dimensions when examining dogs with heart disease, since small increases in linear dimensions can reflect significant increases in LA volume due to the asymmetrical nature of LA dilatation. Since body size is a major determinant of LA size, LA volume should be indexed to a measure of body size to allow meaningful comparison. ... Even when the effects of body size were taken into account, these data showed significant breed differences for LA volume. Thus, LA volume measurements in dogs of the same weight can differ slightly among breeds. It would be ideal to establish breed-specific reference values due to the differences in type of breed, size and conformation of the thorax. ... There was no correlation between age or sex and LA volume or LA reservoir function, but conduit function decreased and booster pump function increased with age. LA volume and function varied with HR. LA size was calculated using the biplane area–length method, with good reproducibility and little inter-observer variability. The reference ranges presented for LA volume and function in healthy dogs could be used to refine the diagnostic criteria for the assessment of LA enlargement and altered function by conventional echocardiography.

Short Term Echocardiographic and Clinical Effects of Ramipril on Dogs with Asymptomatic Degenerative Mitral Valve Disease. Prakit Kohkayasit and Sirilak Surachetpong. Thai J Vet Med. 2013. 43(3): 337-346. Quote: "Angiotensin converting enzyme (ACE) inhibitors have beneficial effects on degenerative mitral valve disease (DMVD) dogs with stages C and D (ACVIM classification) and on dogs with congestive heart failure. However, ACE inhibitors’ effects on stage B2 or asymptomatic DMVD dogs have still been uncertain. Ramipril is an ACE inhibitor that has lipophilic effects and can suppress ACE in cardiac tissue effectively. We hypothesized that ramipril had beneficial effects on dogs with naturally occurring DMVD in stage B2. Twenty dogs with stage B2 DMVD, weighing between 3-12 kg and being older than 6 years, were recruited into the study. The dogs were single blinded randomized and divided into 2 groups. Owners made decisions whether or not to supplement their dogs with ramipril. Dogs in the ramipril group (n = 10) received ramipril once a day at dose of 0.22 mg/kg PO. The control group (n = 10) did not receive any drugs for 91 days. Complete physical examination, electrocardiography and echocardiography were performed on days 0, 28, 56 and 91. Echocardiographic examination was used to determine cardiac sizes and structural changes. Independent t-test was performed to compare differences between dogs in ramipril and control groups. Repeated ANOVA was used to compare differences within groups between days 0, 28, 56 and 91. P < 0.05 was considered statistically significant. Cardiac chamber size, systolic function and severity of mitral regurgitation were not significantly different between the 2 groups throughout the study period. In conclusion, ramipril did not affect cardiac size, severity of mitral regurgitation and systolic function in 91-day study period."

2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation /American Heart Association Task Force on Practice Guidelines. Circulation. October 2013;128(16):e240-327. Quote: HF [heart failure] is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. The cardinal manifestations of HF are dyspnea [difficult or labored breathing] and fatigue, which may limit exercise tolerance, and fluid retention, which may lead to pulmonary and/or splanchnic congestion and/or peripheral edema. Some patients have exercise intolerance but little evidence of fluid retention, whereas others complain primarily of edema, dyspnea, or fatigue. Because some patients present without signs or symptoms of volume overload, the term “heart failure” is preferred over “congestive heart failure.” There is no single diagnostic test for HF because it is largely a clinical diagnosis based on a careful history and physical examination.

Contrast echocardiography to assess left ventricular volume and function in Beagle dogs: Comparison with 3-Tesla dual source parallel cardiac magnetic resonance imaging. J.H. Kim, M.S. Lee, S.Y. Lee, S.Y. Kim, S.Y. Lee, S.J. Lee, Y.W. Park, J.H. Yeo, S.H. Song, N.W. Park, S.W. Hong, S.I. Choi, K.D. Eom. Vet. J. November 2013;198(2):450-456. Quote: "This study was performed to evaluate the effect and feasibility of contrast echocardiography (CE) compared with unenhanced echocardiography (UE) and cardiac magnetic resonance imaging (CMRI) to assess left ventricular (LV) volume and function, including end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) in six healthy Beagles. When the dogs were conscious, LV measurements using CE were significantly higher than those obtained using UE, except for EF, and were similar to the values obtained using CMRI. Additionally, EDV, SV, and EF obtained using UE from anesthetized dogs were significantly lower than those obtained using CE or CMRI. Measurements of EDV, SV and EF using CE were not significantly different from the corresponding measurements obtained using CMRI (31.13 ± 2.18 vs. 32.88 ± 1.17 mL, 18.41 ± 1.25 vs. 17.92 ± 0.96 mL, 59.29 ± 2.29% vs. 53.33 ± 1.69%, respectively). Inter-observer agreements for UE (0.74 ± 0.05) were lower than those for CE (0.80 ± 0.04) and CMRI (0.92 ± 0.03). In conclusion, LV function was assessed reproducibly using CE, and the measurements obtained were consistent with reference standard measurements obtained using CMRI. Measurements made using CE agreed more closely with CMRI than those made using UE."

Short-Term Hemodynamic and Neuroendocrine Effects of Pimobendan and Benazapril in Dogs with Myxomatous Mitral Valve Disease and Congestive Heart Failure. J. Häggström, P.F. Lord, K. Höglund, I. Ljungvall, O. Jöns, C. Kvart and K. Hansson. J.Vet.Int.Med. Nov. 2013;27(6):1452-1462. Quote: "Background: Pimobendan and benazepril are frequently used with diuretics to treat dogs in congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD). Aim: To compare the short-term effects of pimobendan versus benazepril on pump function, heart size, and neuroendocrine profile in dogs with CHF caused by MMVD. Animals: Sixteen client-owned dogs [including eleven cavalier King Charles spaniels]. Material and methods: Seven-day prospective single-blinded study of dogs stabilized on furosemide monotherapy, randomized to pimobendan (0.4–0.6 mg/kg/day) or benazepril (0.25–1.0 mg/kg/day). Dogs had first-pass radionuclide angiocardiography, and heart size was measured by radiography and echocardiography. Circulating neuroendocrine hormones were measured. Results: Baseline variables did not differ between treatment groups. Greater decreases in the pimobendan than in the benazepril group were found for heart rate (P = .001), heart rate-normalized pulmonary transit time (P = .02), left atrial size (P = .03), and systolic and diastolic left ventricular diameters (P < .001 and P = .03, respectively) and volumes (P < .001 and P = .02, respectively), whereas ejection fraction increased more (P = .02) in the pimobendan group. Of the neuroendocrine hormones, only N-terminal proatrial natriuretic peptide (NT-ProANP) differed (P = .04) between groups. Within groups, plasma aldosterone increased (P = .01), and NT-proANP (P = .01) and NT-proB-type (P = .02) natriuretic peptide decreased in the pimobendan group, and NT-proANP (P = .02) and plasma vasopressin (P = .01) decreased in the benazepril group. Conclusions and Clinical Importance: ... This study shows that in dogs with CHF caused by MMVD, pimobendan significantly reduces HR, LV and LA dimensions, nPPT, and NT-proANP, and increases EF in comparison to benazepril. Decreases in nPTT were associated with decreases in NT-proANP, but not NT-proBNP. The reduction in heart size in response to pimobendan treatment in dogs with CHF secondary to MMVD is in agreement with previous studies, whereas reductions in HR, NT-proANP, and nPTT in response to pimobendan treatment have, to our knowledge, not previously been described in naturally occurring MMVD. ... Pimobendan improves short-term cardiac function more than benazepril in dogs with CHF caused by MMVD. Pimobendan treatment enables the heart to work at smaller end-systolic and diastolic dimensions while maintaining adequate forward stroke volume. Some of the treatment responses found in neuroendocrine profile might have therapeutic relevance."

Neurohumoral response and pathophysiologic changes during progression of mitral regurgitation in the Cavalier King Charles spaniel. Eriksson-Palojärvi Anders. Univ. Helsinki doctoral diss. Nov. 2013. Quote: "Myxomatous mitral valve disease causing mitral regurgitation (MR) is a common cause of heart failure in dogs. However, many aspects of pathophysiology affecting diagnostic measurements are poorly defined. The objective of this study was to add to the knowledge of different pathophysiological processes affecting measures used. Focus was put on plasma parameters, including N-terminal pro A-type natriuretic peptide (NT-proANP) and nitric oxide (NO), and first pass radionuclide angiocardiography to evaluate heart pump function and possible right sided heart enlargement associated with pulmonary hypertension. Echocardiography and thoracic radiographs were used as reference methods. ... Specific normal values for natriuretic peptides should be established for different age groups of dogs. Heart rate, murmur and NT-proANP can be used to predict risk of and time to heart failure in dogs with MR. Heart rate normalized PTT (nPTT) is a robust measure of heart pump function in MR. Both nPTT and pulmonary blood volume increase before onset of CHF. Apparent right-sided heart enlargement on radiographs is due to them being displaced by left heart chambers as they enlarge only in severe MR."

Animal Models of Cardiovascular Disease. Meg Sleeper. Chapter 3 of "Handbook of Laboratory Animal Science, Volume III, Third Edition: Animal Models." Edited by Jann Hau, Steven J. Schapiro. 2013. Quote: "Myxomatous degeneration of the mitral valve (and sometimes the tricuspid valve) is the most common acquired cardiac disease in dogs, occurring most frequently in middle-aged to old, small- to medium-sized dogs. In Cavalier King Charles Spaniels (CKSPs), the disease often occurs at a younger age, and the prevalence in dogs that are older than 10 years of age is 90%. Other studies have demonstrated similar levels of prevalence. One study performed in the United Kingdom demonstrated that 59% of CKSPs older than 4 years of age had evidence of the disease. Similar results were noted in a study performed in the United States, which demonstrated that 56% of CKSP dogs were affected at 4 years of age. The disease starts with the formation of small nodules followed by progressive thickening and contraction of the mitral valve cusps and leakage of the valve. The disease is characterized by a long preclinical period. ... At present, it is not known how chronic valve degeneration is inherited. although a recent study identified two loci associated with the disease in CKSPs."

Effect of Body Weight Loss on Cardiopulmonary Function Assessed by 6-Minute Walk Test and Arterial Blood Gas Analysis in Obese Dogs. J. Manens, R. Ricci, C. Damoiseaux, S. Gault, B. Contiero, M. Diez and C. Clercx. J.Vet.Internal Med. Dec. 2013. Quote: "Background: Few studies show the detrimental effect of canine obesity on cardiopulmonary function (CPF). The 6-Minute Walk Test (6MWT) is a noninvasive exercise test easy to perform in clinical settings. Objective: The aim of this study was to investigate the effect of obesity and body weight loss (BWL) on CPF assessed by the 6MWT and arterial blood gas analysis. Animals: Six experimental Beagles and 9 privately owned obese dogs [including one cavalier King Charles spaniel] were enrolled in a diet-induced BWL program. Methods: Arterial blood gas analysis and 6MWT were repeated in obese subjects (BCS 8-9/9), in the middle of BWL (overweight, BCS 6-7/9), and in lean dogs (BCS 5/9). Heart rate (HRp) and oxygen saturation (SpO2) were measured by pulse oximetry before the 6MWT, at midtest, and during a 5-minute recovery period. Results: Twelve dogs completed the BWL program (initial BW, 27.3 ± 2.9 kg; final BW, 20.85 ± 2.9, lsmeans ± SE, P ≤ .001). BWL caused a significant increase in 6MWT walked distance (WD; obese: 509 ± 35 m; overweight: 575 ± 36 m; lean: 589 ± 36 m; P ≤ .05). Resting arterial blood gas results were not influenced by BWL. Including all time points, obese dogs showed higher HRp and lower SpO2 compared to overweight and lean dogs. SpO2 at the end of the walk was significantly lower in obese dogs. Conclusion and Clinical Importance: Obesity negatively affects 6MWT performances in dogs. The 6MWT may be used to demonstrate the efficacy of BWL to improve CPF and quality of life in obese dogs. Although BWL induced significant improvement of cardiopulmonary parameters before ideal BW, WD improved until the end of the BWL program."

Biopterin status is associated with disease severity and human cardiovascular risk factors in dogs with myxomatous mitral valve disease. M.J. Reimann, J. Häggström, A. Mortensen, J. Lykkesfeldt, J.E. Møller, L.H. Olsen. 23rd ECVIM-CA Congress. J.Vet.Int.Med. Dec. 2013. Quote: "Endothelial dysfunction represents a therapeutic target and has been suggested to be associated with myxomatous mitral valve disease (MMVD) in dogs. Tetrahydrobiopterin (BH4) is an important cofactor for production of the endothelium-derived vasodilator nitric oxide (NO). Under conditions of oxidative stress, BH4 is oxidised to the biologically inactive form dihydrobiopterin (BH2). Thus, plasma levels of BH2 and BH4 have been suggested to reflect endothelial function. The aim of the study was to determine plasma concentrations of BH2 and BH4 in dogs with different degrees of naturally occurring MMVD. Clinical examination including echocardiography was performed in 84 privately-owned dogs (13 control dogs (Beagles), 57 cavalier King Charles spaniels with different degrees of MMVD and 14 dogs of different breeds with clinical signs of congestive heart failure (CHF) due to MMVD). Plasma levels of BH2 and BH4 were measured by high performance liquid chromatography (HPLC) and fluorescence detection. Differences in BH2, BH4 and BH4/BH2-ratio between disease groups were tested using multiple linear regression. Dogs in CHF had significantly higher BH4 and BH2 levels than other dog groups (P < 0.009). BH2 and BH4/BH2 levels were found to increase with advancing age (P < 0.04). Females had higher levels of BH4 and BH4/BH2 (P < 0.0001). Other risk factors such as passive smoking (P = 0.01) and increased body weight (P = 0.02) were associated with decrease in BH4 levels. In conclusion, age, gender, body weight, passive smoking and plasma and cardiac status correlate with plasma BH2 and BH4 concentrations in dogs."

Role of inflammation and extracellular matrix remodelling in dogs with cardiac and systemic diseases. Fonfara, Sonja. Univ. of Helsinki doctoral dissertation. Dec. 2013. Quote: "In cardiac diseases, activation of the neurohormonal and inflammatory systems contribute to cardiac remodelling through degradation or increased deposition (fibrosis) of the extracellular matrix (ECM). Important factors in this process are cytokines as mediators of inflammation, matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of metalloproteinases; TIMP) as regulators of the myocardial ECM composition. Recently, there was evidence that also leptin plays a role in human cardiac diseases. However, the precise mechanisms that cause pathological cardiac remodelling in both humans and other mammalian species are incompletely understood. Furthermore, functional impairment of the heart and cardiomyocyte damage are observed in human and canine patients with systemic diseases, again without current knowledge on the underlying process. The aim of the present studies was to investigate cardiac remodelling in canine patients with cardiac and systemic diseases. For this purpose, a quantitative assessment of the transcription of cytokines and leptin in the blood of healthy dogs and dogs with cardiac diseases and in the myocardium of dogs with cardiac diseases, dogs with systemic diseases not involving the heart as well as healthy control dogs was obtained. In comparison to healthy dogs, which constitutively transcribed most markers in blood, dogs with cardiac diseases exhibited a selective increase or reduction of inflammatory and ECM remodelling markers and an increase of leptin. In contrast, in the myocardium of dogs with cardiac and systemic diseases, the transcription of all markers was significantly higher than in hearts of healthy control dogs. This suggests myocardial inflammation and remodelling not only in association with cardiac diseases, but also with systemic diseases that do not involve the heart. The results also indicate a localised myocardial inflammation and remodelling in dogs with cardiac diseases, not secondary to a systemic inflammatory response. Interestingly, transcription levels of most markers exhibited regional differences in diseased dogs in general, with significantly higher mRNA levels in atria than in ventricles. This indicates differences in the remodelling processes depending on localisation, which was reflected by more severe histological changes in the atria of dogs with cardiac diseases. In conclusion, the results of the thesis provide evidence of myocardial inflammation and remodelling with regional quantitative differences in dogs with cardiac and systemic diseases and suggest a role for leptin in canine cardiac disease. The results provide further insights into the complex process of cardiac remodelling, which might influence clinical management and the assessment of prognoses in future."

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2014

Echocardiographic assessment of left ventricular function in mitral regurgitation. Nora E. Zois, Henrik D. Pedersen, Jens Häggström, Lisbeth H. Olsen. Cardiovascular Endocrinology. January 2014;3(1):9-14. Quote: Accurate identification of incipient myocardial deterioration is crucial to optimally time interventional surgery. Nonetheless, this issue is still an object of controversy. In this respect, studies of left ventricular (LV) function in dogs with MMVD [myxomatous mitral valve disease] could potentially be useful. The present review compares the results obtained in echocardiographic studies of LV function in humans and dogs with MMVD. Although different study designs pose a limitation and results within the two species are not entirely concordant, it appears that LV function is better preserved in small-sized and medium-sized dogs than in humans. This may limit the usefulness of dogs as a model for LV function in MMVD.

R-R interval variations influence the degree of mitral regurgitation in dogs with myxomatous mitral valve disease. M.J. Reimann, J.E. Møller, J. Häggström, B. Markussen, A.E.W. Holen, T. Falk, L.H. Olsen. Vet.J. March 2014;199(3):348-354. Quote: "Mitral regurgitation (MR) due to myxomatous mitral valve disease (MMVD) is a frequent finding in Cavalier Kings Charles spaniels (CKCSs). Sinus arrhythmia and atrial premature complexes leading to R-R interval variations occur in dogs. The aim of the study was to evaluate whether the duration of the R-R interval immediately influences the degree of MR assessed by echocardiography in dogs. Clinical examination including echocardiography was performed in 103 privately-owned dogs: 16 control Beagles, 70 CKCSs with different degree of MR and 17 dogs of different breeds with clinical signs of congestive heart failure due to MMVD. The severity of MR was evaluated in apical four-chamber view using colour Doppler flow mapping (maximum% of the left atrium area) and colour Doppler M-mode (duration in ms). The influence of the ratio between present and preceding R-R interval on MR severity was evaluated in 10 consecutive R-R intervals using a linear mixed model for repeated measurements. MR severity was increased when a short R-R interval was followed by a long R-R interval in CKCSs with different degrees of MR (P < 0.005 when adjusted for multiple testing). The relationship was not significant in control dogs with minimal MR and in dogs with severe MR and clinical signs of heart failure. In conclusion, MR severity increases in long R-R intervals when these follow a short R-R interval in CKCSs with different degrees of MR due to asymptomatic MMVD. Thus, R-R interval variations may affect the echocardiographic grading of MR in CKCSs.

Holter Monitoring of Small Breed Dogs with Advanced Myxomatous Mitral Valve Disease with and without a History of Syncope. C.E. Rasmussen, T. Falk, A. Domanjko Petrič, M. Schaldemose, N.E. Zois, S.G. Moesgaard, B. Åblad, H.Y. Nilsen, I. Ljungvall, K. Höglund, J. Häggström, H.D. Pedersen, J.M. Bland and L.H. Olsen. J.Vet.Int.Med. March 2014;28(2):363-370. Quote: "Background: Syncope is a transient loss of consciousness occasionally occurring in dogs with advanced myxomatous mitral valve disease (MMVD). Objective: (1) To study ECG changes during syncopal episodes in dogs with advanced MMVD and (2) to compare the occurrence of arrhythmias and changes in heart rate variability (HRV) between dogs with advanced MMVD with and without a history of syncope. Animals: Forty-three privately owned dogs (<15 kg) with advanced MMVD: 21 with [including 6 cavalier King Charles spaniels] and 22 without a history of syncope [including 10 CKCSs]. Methods: Prospective study with dogs recruited for an evaluation including history, physical examination, echocardiography, and arrhythmia and HRV analysis performed on 24-hour Holter recordings. Results: A syncopal episode was observed during Holter monitoring in 4 dogs: 3 dogs had sinus rhythm and 1 dog had sinus arrest followed by escape rhythm. An arrhythmia variable representing sinus arrhythmia was significantly lower in dogs with a history of syncope than in those without (P = .008). Eight of 26 HRV variables were significantly different between dogs with and without a history of syncope. Conclusions and Clinical Importance: Compared with dogs without a history of syncope, dogs with advanced MMVD and a history of syncope did not have a higher occurrence of arrhythmias, but had less sinus arrhythmia, and had changes in HRV variables representing decreased overall HRV, decreased parasympathetic, and increased sympathetic modulation of heart rate."

Dobutamine Stress Echocardiography for Assessment of Systolic Function in Dogs with Experimentally Induced Mitral Regurgitation. R. Suzuki, H. Matsumoto, T. Teshima, Y. Mochizuki, H. Koyama. J.Vet.Int.Med. Jan. 2014. Quote: "Background: Systolic dysfunction is associated with poor outcomes in dogs with myxomatous mitral valve disease. However, assessment of systolic variables by conventional echocardiographic methods is difficult in these dogs because of mitral regurgitation (MR). Hypothesis: We hypothesized that assessment of systolic function by dobutamine stress may identify systolic dysfunction in dogs with MR, and that 2-dimensional speckle-tracking echocardiography (2D-STE) could quantitatively evaluate myocardial function. Animals: Five healthy male Beagles. Anesthetized dogs with experimentally induced MR. Methods: Dogs were examined for systolic myocardial deformations using 2D-STE during dobutamine infusion before and 3 and 6 months after MR induction. We evaluated peak systolic rotation and rotation rate in each basal and apical view; peak systolic torsion and torsion rate were also calculated. Results: Invasive peak positive first derivatives of left ventricular pressure (dp/dt) were significantly decreased in dogs 6 months after induction of MR compared with pre-MR results. After 3 and 6 months of MR, dogs had diminished peak systolic torsion values and torsion rates in response to dobutamine infusion compared with pre-MR results (3 months, P < .001 and P = .006; 6 months, P = .003 and P = .021). These results were significantly correlated with overall invasive dp/dt (r = 0.644, P < .001; r = 0.696, P < .001). Conclusions and Clinical Importance: Decreased torsion during dobutamine infusion in dogs with MR may reflect latent systolic dysfunction. Dobutamine infusion, therefore, may be useful for the assessment of systolic function in dogs with MR."

Relation of Vitamin D Status to Congestive Heart Failure and Cardiovascular Events in Dogs. M.S. Kraus, K.M. Rassnick, J.J. Wakshlag, A.R.M. Gelzer, A.S. Waxman, A.M. Struble, and K. Refsal. J.Vet.Int.Med. Jan. 2014;28(1):109-115. Quote: "Background: Vitamin D plays a pivotal role in cardiac function, and there is increasing evidence that vitamin D deficiency is associated with the development of congestive heart failure (CHF) in people. Hypothesis: Serum vitamin D concentration is lower in dogs with CHF compared with unaffected controls and serum vitamin D concentration is associated with clinical outcome in dogs with CHF. Animals: Eighty-two client-owned dogs [31 with CHF -- 20 with acquired valve disease (AVD) and 11 with dilated cardiomyopathy (DCM) -- and 51 unaffected control dogs (all over 5 years old)] . Methods: In this cross-sectional study, we examined the association between circulating 25-hydroxyvitamin D [25(OH)D], a measure of vitamin D status, and CHF in dogs. In the prospective cohort study, we examined whether 25(OH)D serum concentration was associated with clinical outcome in dogs with CHF. Results: Mean 25(OH)D concentration (100 ± 44 nmol/L) in 31 dogs with CHF was significantly lower than that of 51 unaffected dogs (123 ± 42 nmol/L; P = .023). The mean calculated vitamin D intake per kg of metabolic body weight in dogs with CHF was no different from that of unaffected dogs (1.37 ± 0.90 μg/kg metabolic body weight versus 0.98 ± 0.59 μg/kg body weight, respectively, P = .097). There was a significant association of serum 25(OH)D concentration on time to clinical manifestation of CHF or sudden death (P = .02). Conclusion and Clinical Relevance: These findings suggest that low concentrations of 25(OH)D may be a risk factor for CHF in dogs. Low serum 25(OH)D concentration was associated with poor outcome in dogs with CHF. Strategies to improve vitamin D status in some dogs with CHF may prove beneficial without causing toxicity."

Impact of Vagal Nerve Stimulation on Left Atrial Structure and Function in a Canine High-Rate Pacing Model. Kenya Kusunose, Youhua Zhang, Todor N. Mazgalev, David R. Van Wagoner, James D. Thomas, Zoran B. Popović. Circulation: Heart Failure. January 2014;7:320-326. Quote: "Background: Cervical vagal nerve stimulation (VNS) can improve left ventricular dysfunction in the setting of heart failure (HF). However, little is known about the impact of VNS on left atrial (LA) function. The aim of this study was to compare LA mechanics and histology between control and VNS-treated animals during HF development. Methods and Results: Fifteen mongrel dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 beats per minute for the first 4 weeks to develop HF and another 4 weeks at 180 beats per minute to maintain HF). LA contractile function (LA negative peak strain), conduit function (LA positive peak strain), and reservoir function (LA total strain) were measured from speckle tracking in 2 groups. At the end of the terminal study, the LA appendage was obtained. Baseline LA strains were comparable in the control and VNS-treated dogs. At 4 and 8 weeks of ventricular pacing, all LA strains were decreased and LA volumes were increased in the control group compared with the VNS group (P<0.05). Histological evaluation of the left atrium revealed that percent fibrosis was significantly lower in the VNS versus the control group (8±1% versus 13±1%; P<0.001). Finally, transmitral flow showed decreased atrial contribution to left ventricular filling in the control group (P<0.05). Conclusions: VNS improved LA function and volumes and suppressed LA fibrosis in the canine high-rate ventricular pacing model. VNS is a novel and potentially useful therapy for improving LA function during HF."

Longitudinal Electrocardiographic Evaluation of Dogs with Degenerative Mitral Valve Disease. J. López-Alvarez, A. Boswood, W. Moonarmart, M.J. Hezzell, N. Lotter, J. Elliott. J.Vet.Int.Med. Feb. 2014. Quote: "Background: Increased heart rate (HR) and decreased heart rate variability (HRV) are evident in some dogs with degenerative mitral valve disease (DMVD). Objectives: Evaluation of the factors influencing HR and HRV (assessed by the vasovagal tonus index; VVTI) and their change over time in dogs with DMVD. Animals: Client-owned dogs (n = 257) [including 99 cavalier King Charles spaniels] with DMVD recruited from first opinion practice. Methods: Prospective longitudinal follow-up at six-monthly intervals of dogs with DMVD. Dogs followed up for at least 18 months (n = 102) were grouped according to their outcome as dogs dying/euthanized because of cardiac disease (n = 28; Group 1), noncardiac disease (n = 40; Group 2) and dogs alive (n = 34; Group 3). HR and VVTI were measured on 1-minute ECG recordings. Repeated measures linear models were constructed to investigate the factors that influence HR and VVTI and their changes over time. Results: Heart rate and VVTI were affected by disease severity and were different in Cavaliers compared to other breeds. Group 1 and Group 2 dogs underwent an increase in HR and decrease in VVTI, evident at least 18 months before death. Group 1 had a further decrease in VVTI followed by an increase in HR approximately 1 year and 6 months before death, respectively. ... When age and breed were included in the model, only group class (P < .001) and being a CKCS (P = .016) were independently associated with a higher HR. ... The final multivariable model for the HR showed that being a CKCS, receiving cardiac medication and having increased NT-proBNP and FS are independent predictors of increased HR. ... Conclusions and Clinical Importance: Dogs with DMVD have an increase in HR and decrease in HRV over a year before death, with greater changes in those dogs dying/euthanized because of cardiac disease. Both HR and VVTI can potentially be regarded as biomarkers for all-cause mortality. ... The multivariable model for factors affecting VVTI showed that CKCS have lower VVTI than non-CKCS once age, weight, and other parameters were controlled for. In addition, only group and breed independently affected the progression of HR and VVTI over time. A related finding has already been shown by Rasmussen et al. [Holter Monitoring in Clinically Healthy Cavalier King Charles Spaniels, Wire-Haired Dachshunds, and Cairn Terriers] who showed that CKCS have lower HRV. In addition, a recent cross sectional study evaluating urinary catecholamines in healthy dogs showed breed differences in blood pressure, HR, and also in both epinephrine to creatinine ratio and norepinephrine to creatinine ratio, implying breed variation in autonomic tone."

Pimobendan Improves Clinical Signs in Short Term Compared to Digoxin or Placebo in Dogs with Heart Failure Due to Chronic Degenerative Mitral Valve Disease. Maria Helena Matiko Akao Larsson, Denise Saretta Schwartz, Guilherme Teixeira Goldfeder, Valéria Marinho Costa de Oliveira, Paula Hiromi Itikawa, Ariane Marques Mazini, Priscylla Ramos Rosa Melo, Fabrício Lorenzini Aranha Machado, Francisco Ferreira Lima Júnior, Khadine Kazue Kanayama, Arine Pellegrino, Alexandre Gonçalves Teixeira Daniel, Raul Ossada. Acta Scientiae Veterinariae, Feb. 2014;42:1175. Quote: "Background: The purpose of this prospective, randomized, double blind clinical trial was to evaluate the clinical response and QoLQ [quality of life] in heart failure (HF) dogs treated with digoxin [DIG] or pimobendan [PIMO] in addition to conventional therapy (furosemide and benazepril). Materials, Methods & Results: Inclusion criteria: dogs in class III or stabilized class IV (NYHA). Exclusion criteria: use of positive inotrope and antiarrhythmic, presence of atrial fibrillation, renal or hepatic disease or neoplasia. Thirty three dogs were included and randomly assigned to DIG (n = 11), PIMO (n = 14) and placebo (PL) (n = 8) and followed up weekly. Data was evaluated for days zero, 7, 14 and 28. Increasing score was assigned to each variable depending on worsening of clinical evaluation (history and physical exam, QoLQ and echocardiogram (echo).Three dogs died during treatment due to worsening of HF, one of PL group and two of DIG group; furthermore, one of PIMO group was censored due to worsening of heart failure. There was no significant difference between and within groups for echo and radiography. PL and DIG groups did not show any significant difference throughout the 28 days of treatment. PIMO group showed lower physical exam score and increased early mitral inflow velocity on day 28. Serum creatinine increased on days 14 and 28 compared to baseline, but within normal limits. The groups were similar within each evaluation day. Discussion: This is the first short term prospective randomized double blind study comparing PIMO to DIG or PL additionally to conventional therapy (ACEi and furosemide) for dogs with HF due to CDMVD. It was observed an early significant clinical improvement in dogs receiving PIMO compared to those receiving DIG or PL. The increase in early mitral inflow velocity (E-wave) on day 28 for PIMO group is suggestive of diastolic dysfunction improvement, but this is only one variable related to diastolic function. Creatinine concentration increased in PIMO group, although it remained within normal range. In the present study, although all the three groups received furosemide, only PIMO group showed increase in blood creatinine between baseline and days 7 and 28. This result must be explored in later studies. Regarding the exercise intolerance assessment in a QoLQ, it must be aware that the owner evaluation is strongly influenced by the level of exercise that the dog is regularly submitted. Considering that most of the times, small breed dogs in a more advanced age is probably more sedentary and this fact surely precludes the owner to assess the exercise capacity. A more objective evaluation of the exercise tolerance should be considered in further clinical trials. Probably because of the small number of animals included in this study, differences in other studied variables were not found. The short-term follow-up of these patients may also have infl uenced the lack of differences among groups. Considering that stronger clinical evidence is needed to guide clinical decisions, longer prospective studies are also needed to compare the effects of DIG and PIMO, as well as to consider the benefits of the use or not of DIG associated with PIMO for dogs in HF due to CDMVD."

Heart rate variability and arrhythmias evaluated with Holter in dogs with degenerative mitral valve disease. M.S. Oliveira; R.A.L. Muzzi; R.B. Araújo, L.A.L. Muzzi; D.F. Ferreira; E.F. Silva. ScienLo Brasil; Arq. Bras. Med. Vet. Zootec. Feb 2014;66(2):425-432. Quote: "Cardiac diseases promote alterations in the autonomic control of the heart, leading to an increase in heart rate and, as a result, a decrease in heart rate variability (HRV).The aim of this study was to evaluate if the development of heart failure secondary to degenerative mitral valve disease (DMVD) concurs with changes in autonomic modulation of heart rhythm which are assessed by long electrocardiography examination (Holter). 27 dogs were evaluated by clinical examination and echocardiography in order to be categorized into the following groups: Control (healthy; n=6), DMVD (disease without heart failure; n=8), and DMVD heart failure (disease with heart failure; n=13). Arrhythmias and frequency domain HRV were determined by Holter. Diseased animals, when compared to healthy, had significantly lower total power, which indicates overall HRV. DMVD heart failure dogs also showed other disturbances such as high incidence of supraventricular arrhythmias, high heart rate, little amount of pauses (2.0s long between consecutive heartbeats), longer time in tachycardia, shorter time in bradycardia, low high frequency (parasympathetic control), and high low frequency (sympathetic and parasympathetic control) when compared to control (p<0.05). In DMVD dogs, Holter-derived variables changed with the development of heart failure."

Breed Differences in Natriuretic Peptides in Healthy Dogs. K. Sjöstrand, G. Wess, I. Ljungvall, J. Häggström, A-C. Merveille, M. Wiberg, V. Gouni, J. Lundgren Willesen, S. Hanås, A-S. Lequarré, L. Mejer Sørensen, J. Wolf, L. Tiret, M. Kierczak, S. Forsberg, K. McEntee, G. Battaille, E. Seppälä, K. Lindblad-Toh, M. Georges, Hannes Lohi, V. Chetboul, M. Fredholm and K. Höglund. J.Vet.Int.Med. March 2014;28(2):451–457. Quote: "Background: Measurement of plasma concentration of natriuretic peptides (NPs) is suggested to be of value in diagnosis of cardiac disease in dogs, but many factors other than cardiac status may influence their concentrations. Dog breed potentially is 1 such factor. Objective: To investigate breed variation in plasma concentrations of pro-atrial natriuretic peptide 31-67 (proANP 31-67) and N-terminal B-type natriuretic peptide (NT-proBNP) in healthy dogs. Animals: 535 healthy, privately owned dogs of 9 breeds [including 34 (6.4%) cavalier King Charles spaniels] were examined at 5 centers as part of the European Union (EU) LUPA project. Methods: Absence of cardiovascular disease or other clinically relevant organ-related or systemic disease was ensured by thorough clinical investigation. Plasma concentrations of proANP 31-67 and NT-proBNP were measured by commercially available ELISA assays. Results: Overall significant breed differences were found in proANP 31-67 (P < .0001) and NT-proBNP (P < .0001) concentrations. Pair-wise comparisons between breeds differed in approximately 50% of comparisons for proANP 31-67 as well as NT-proBNP concentrations, both when including all centers and within each center. Interquartile range was large for many breeds, especially for NT-proBNP. Among included breeds, Labrador Retrievers and Newfoundlands had highest median NT-proBNP concentrations with concentrations 3 times as high as those of Dachshunds. German Shepherds and Cavalier King Charles Spaniels had the highest median proANP 31-67 concentrations, twice the median concentration in Doberman Pinschers. Conclusions and Clinical Importance: Considerable interbreed variation in plasma NP concentrations was found in healthy dogs. Intrabreed variation was large in several breeds, especially for NT-proBNP. Additional studies are needed to establish breed-specific reference ranges."

Comparative Evaluation of Calcium-Sensitizing Agents, Pimobendan and SCH00013, on the Myocardial Function of Canine Pacing-Induced Model of Heart Failure. Lina Hamabe, Keisuke Kawamura, Soo-Min Kim, Rieko Yoshiyuki, Toshiharu Fukayama, Miki Shimizu, Ryuji Fukushima, Ryo Tanaka. J. Pharmacological Sci. March 2014;124(3):386-393. Quote: "Pimobendan and SCH00013 are calcium sensitizers that possess dual action of calcium sensitization and phospho-diesterase-III inhibition. This study was conducted to comparatively evaluate the effect of these medications on the myocardial function of the canine pacing-induced heart failure model using echocardiography. Heart failure was induced in 20 dogs, to which pimobendan and two different doses of SCH00013 were administered orally to 15 dogs for 3 weeks, and the remaining 5 dogs served as the control. Cardiac evaluations were performed at baseline, week 1, week 2, and week 3. Significant thinning and dilation of the left ventricles, with systolic dysfunction, indicated by reduction of fractional shortening (FS) and strain values, were observed with a low dose of SCH00013. Whereas, although systolic dysfunction was observed with reduction of FS and radial strain, significant dilation and thinning of the left ventricles and reduction of circumferential strain were not observed with pimobendan. Pimobendan had a potent positive inotropic effect, with little effect on synchronicity, while low-dose SCH00013 had a weaker positive inotropic effect but was able to sustain synchronicity. Although, it failed to show significant statistical differences, the results of this study allow speculations that administration of pimobendan and SCH00013 may have differing effect on the myocardial function in the canine pacinginduced heart failure model."

Cardiovascular proteomics and mitral valve disease in dogs: searching for a serological biomarker. Giulia Riscazzi. Università degli studi di Milano. March 2014. Quote: "The objective of the present study was to search one or more than one serological biomarkers in dogs affected by MVD, comparing blood samples from the healthy dogs of the groups with blood samples from the dogs affected by different stages of MVD. The proteomics results were then matched with the clinical and echocardiographic data obtained in the clinical trial of all the patients included in the study, to find a connection available in the clinical practice. 64% of the Cirneco dell’Etna dogs included in the study were affected by MVD, and all the dogs older than 6 years had echocardiographic signs of MVD. The proteomic analysis of the Cirneco samples gave the following results: the alpha-1-antytripsina (A1AT) was up-regulated in the patients affected by MVD, according to the severity of the pathology, while the complement C3 was down-regulated with the development of MVD, according to the stage of the disease. Among the Cavalier King Charles breed there was a high prevalence of MVD (63%) and a very low medium age of onset (4 years). The proteomic analysis of the Cavalier King Charles Spaniel samples produced the following results: the serum albumin was down-regulated, according to the severity of the pathology, while it was observed a strong up-regulation of some specific types of IgG and IgM, according to the severity of the pathology. Based on our study results, the Cirneco dell’Etna breed is a primitive hunting breed predisposed to the development of MVD, with an early onset of the pathology. All the CdE dogs older than 6 years should be therefore evaluated for MVD, and included in a screening program. We confirmed that Cavalier King Charles Spaniel is a breed with a high prevalence of MVD and an early onset too, as previously reported. The proteomic analysis conducted on our samples and correlated to the clinical results, indicate that the MVD is a pathology that is strictly connected to a chronic inflammation state. The up-regulation of A1AT, IgG, IgM, and the down-regulation of complement C3 and serum albumin are connected with an inflammatory status, that cause a depletion of the components of the complement system, an activation of the acute phase proteins and of the components of immunity response like IgG and IgM immunoglobulins. The hypothesis that MVD could be related to a chronic inflammation was already speculated in the last years, and, based on the present study results, we think that the analysis of the inflammatory mediators in MVD patients could be a great chance to uncover the pathogenic mechanism at the base of mitral valve disease."

Diagnosis of heart failure in dogs with mitral valve disease. Phillip Speer. Vet. Times. March 31, 2014;22-24. Quote: "The standard therapies for canine mitral valve disease (ACE inhibitors, spironolactone, pimobendan and furosemide) are all indicated from the onset of heart failure. It is therefore vital a correct diagnosis of heart failure is made, to ensure appropriate treatments are given and that therapy is started at the optimal time."

Heart Disease: Diagnosis & Treatment. Amara Estrada. Clinician's Brief. March 2014:91-95.

Should I treat an asymptomatic heart disease? Ingrid Ljungvall. 82nd Int'l SCIVAC Congress. March 2014. Quote: "Myxomatous mitral valve disease: Several drug trials have been conducted in Stage B MMVD dogs, but none of these studies could show a prophylactic effect in delaying the onset of CHF. The ACE-inhibitors are, by far, the most intensively studied pharmacological modality studied in class B MMVD dogs. The currently available database for this type of therapy in class B MMVD dogs includes a number of clinical trials, which in veterinary medicine is to be regarded a substantial documentation. The rationale for using this type of therapy is that suppression of the renin-angiotensin-aldosterone system (RAAS) has the potential to lead to a more favorable hemodynamic situation by vasodilatation of systemic arteries, by counteracting fluid retention, and by counteracting the progressive left ventricular and left atrial remodeling process occurring in response to mitral regurgitation (MR). Two prospective placebo controlled clinical trials in dogs (the SVEP and the VetProof studies) investigated the effects of enalapril compared to placebo in delaying the onset of CHF in dogs with MMVD. The two trials showed a comparably similar outcome with a non-significant difference in the primary outcome variable (time from initiation of therapy until diagnosed CHF) between the two treatment groups. These are interesting findings because one trial only included 229 Cavalier King Charles Spaniels (the SVEP trial) in class B1 (n=122) and B2 (n=107),4 whereas the other included 124 dogs of multiple breeds (the VetProof study) in class B 2 only. These findings, in combination with the results from the clinical trials outlined above, question the efficacy of the ACE-inhibitors in class B2 MMVD dogs. Furthermore, ACE-inhibitor therapy in asymptomatic (primary) mitral regurgitation is not endorsed in the most recent treatment guidelines of valvular heart disease provided by the American College of Cardiology/American Heart Association and the European Society of Cardiology. Currently, there are other large clinical trials ongoing where the prophylactic effect of substances other than ACE-inhibitors are tested versus placebo in dogs in stage B MMVD, but results are not expected to be available in the near future."

Decreased sympathetic tone after short-term treatment with enalapril in dogs with mild chronic mitral valve disease. Chayanon Chompoosan, Chollada Buranakarl, Narongsak Chaiyabutr, Winai Chansaisakor. Research in Vet.Sci. April 2014;96(2):347-354. Quote: "Heart rate variability (HRV) and echocardiography were performed in 14 dogs with mitral regurgitation (MR) before and after 14 days of 0.5 mg/kg/day of enalapril treatment. All dogs were in heart failure stages B1 and B2. After enalapril treatment, left ventricular end diastolic diameter (LVEDd), left ventricular end diastolic diameter normalized for body weight (LVEDdN) and percent mitral regurgitant jet decreased (P < 0.05). The diastolic blood pressure decreased (P < 0.05). Increased time domain parameters of HRV were found. For frequency domain analysis, the total frequency (TF) increased significantly (P < 0.05). The normalized low frequency (LF norm) decreased while normalized high frequency (HF norm) increased causing significant reduction in LF/HF (P < 0.05). Before enalapril treatment, LF was correlated with end diastolic volume (EDV) (P < 0.01) and LVEDd (P < 0.05). In conclusion, MR dogs receiving enalapril treatment for 14 days had increased cardiac parasympathetic tone while sympathetic tone was suppressed. The decreased sympathetic activity corresponded to the reduction in cardiac preload and afterload."

First-in-class angiotensin receptor neprilysin inhibitor LCZ696 modulates the dynamics of the renin cascade and natriuretic peptides system with significant reduction of aldosterone exposure. Jonathan Mochel; Bryan F. Burkey; Martin Fink; Roberto Garcia; Mathieu Peyrou; Jerome Giraudel; Didier Renard; Meindert Danhof. J. Am. Coll. Cardiol. April 2014;63(12_S). Quote: "Background: There is growing evidence that high aldosterone (AL)exposure is associated with reduced survival in patients with cardiovascular diseases. Further, the potent cardiorenal actions of natriuretic peptides (NP) that include vasodilatation, natriuresis and diuresis offer an innovative therapeutic option in the management of hypertension and heart failure. We report the results of a preclinical study investigating the effect of LCZ696, a novel angiotensin receptor neprilysin(NEP) inhibitor providing simultaneous neprilysin inhibition and AT1-receptor blockade, on the dynamics of the renin and NP cascades. Methods: Eighteen healthy beagle dogs were placed on a low-salt diet to activate the renin-angiotensin system. The effect of 10 days of treatment (p.o.,q.d.) with LCZ696 (15 and 45 mg/kg) was compared to placebo, valsartan (60 mg/kg) and benazepril (0.33 mg/kg), using a cross-over design. Biomarkers of the renin cascade and cGMP were measured in plasma on days 1, 5 and 10 of dosing and analyzed as a mean of the 3 days using random effect-repeated measures ANOVA. Results: Compared to placebo, benazepril modestly reduced AL (p=0.08). In contrast, valsartan, LCZ696 15 and 45 mg/kg decreased AL levels to a significant extent (-23%, -45% and -43%, respectively, p<0.05). The greatest reductions were observed in the LCZ696 groups, where LCZ696 15 mg/kg at 2 hours reduced AL 2-fold lower than valsartan (p<0.05). Administration of LCZ696 at 45 mg/kg resulted in a 180% increase of cGMP relative to placebo (p<0.0001), which is consistent with enhanced NP action consecutive to NEP inhibition. Neither valsartan nor benazepril changed cGMP levels. In LCZ696 45 mg/kg treated dogs, an ~2.5-fold (1.8-3.7) increase from placebo was found for renin activity (p<0.0005), angiotensin I (p<0.005) and angiotensin II (p<0.05), reflecting a known compensatory up-regulation of the renin-angiotensin system to AT1-receptor blockade. Conclusion: The greater reduction of AL with LCZ696 over valsartan is consistent with the simultaneous blockade of the AT1-receptor and enhancement of the NP system. These results support further development of LCZ696 for the management of cardiovascular diseases."

Analytical validation and clinical evaluation of a commercially available high-sensitivity immunoassay for the measurement of troponin I in humans for use in dogs. Randolph L. Winter, Ashley B. Saunders, Sonya G. Gordon, Matthew W. Miller, Katharine T. Sykes, Jan S. Suchodolski, Jörg M. Steiner. J.Vet.Cardiology. April 2014. Quote: "Objective: To analytically validate a commercially available high-sensitivity immunoassay for measurement of cardiac troponin I (cTnI) in humans for use in dogs and to evaluate serum cTnI concentrations in healthy dogs and 3 well-defined groups of dogs with common cardiac diseases. Animals: Canine serum samples were used for validation. 85 client-owned dogs including 24 healthy controls, 20 with myxomatous mitral valve disease, 19 with congenital heart disease, and 22 with arrhythmias. Methods: Four serum samples were used to analytically validate the ADVIA Centaur TnI-Ultra assay by assessing intra-assay variability, inter-assay variability, spiking recovery, and dilutional parallelism. Dogs were grouped based on examination, echocardiography, and additional testing as clinically indicated, and serum cTnI concentrations were compared. Results: Analysis of the serum samples used for validation revealed an intra-assay coefficient of variation between 3.6% and 5.7%, and an inter-assay coefficient of variation between 2.4% and 5.9%. Observed to expected ratios for spiking recovery were 97.9 ± 8.6% (mean, SD). Observed to expected ratios for dilutional parallelism were 73.0 ± 11.5% (mean, SD). Dogs with cardiac disease had significantly higher serum cTnI concentrations (P < 0.005) than healthy dogs. Conclusions: The ADVIA Centaur TnI-Ultra's low limit of detection allows measurement of serum cTnI in the majority of dogs even with no or mild cardiac disease. Dilution of samples for measurement of values above the upper limit of detection is not reliable and therefore not recommended. Serum cTnI concentrations are significantly higher in dogs with cardiac disease compared to healthy dogs."

Stress-related Biomarker Measurement in Cavalier King Charles Spaniels with Mitral Valve Disease. Thea Katrine Manley. Master's thesis. Copenhagen University. April 2014. Quote: "With general increasing interest in animal welfare, a reliable method for assessment of animal welfare is needed. Animal welfare can be defined in multiple ways, but one way is the absence of long-term stress. Cortisol has been established as a biomarker for stress, with hair cortisol being a measure of chronic stress, while saliva and plasma are measures of acute stress. A common chronic disease in Cavalier King Charles Spaniels is mitral valve disease. The purpose of this thesis is to determine whether mitral valve disease have an effect on the biomarkers for long- and short-term stress (hair and plasma/saliva cortisol respectively). Also, to evaluate other factors which might influence hair cortisol concentration and compare cortisol concentrations in different matrices. In this study, blood, saliva and hair samples were collected from 45 Cavalier King Charles Spaniels and 13 Beagles enrolled in a screening project for Mitral Valve Disease. The dogs were divided into groups according to their disease status. The thesis concludes that mitral valve disease did not have a significant effect on hair, saliva or plasma cortisol concentration. Plasma and saliva cortisol concentration was significantly correlated, but neither were significantly correlated with hair cortisol concentration. Hair color had a significant effect on hair cortisol concentration. None of the other factors evaluated had any effect on hair cortisol concentration."

Echocardiography and conventional Doppler examination in clinically healthy adult Cavalier King Charles Spaniels: effect of body weight, age, and gender, and establishment of reference intervals. Charlotte Misbach, Hervé P. Lefebvre, Didier Concordet, Vassiliki Gouni, Emilie Trehiou-Sechi, Amandine M.P. Petit, Cécile Damoiseaux, Alice Leverrier, Jean-Louis Pouchelon, Valérie Chetboul. J.Vet.Cardio. June 2014;16(2):91–100. Quote: Objectives: The objectives of this study were (1) to assess the potential effect of body weight (BW), age, and gender on the most commonly used echocardiographic and conventional Doppler variables in a large population of healthy Cavalier King Charles Spaniels (CKCS), and (2) to establish the corresponding reference intervals (RI). Animals: 134 healthy adult CKCS. Methods: Ultrasound examinations were performed by trained observers in awake dogs. M-mode variables included left ventricular (LV) end-diastolic and end-systolic diameters, LV free wall and interventricular septal thicknesses at end-diastole and end-systole, and LV fractional shortening (FS%). ... Measurements of the aortic (Ao) and left atrium (LA) diameters were obtained at end-diastole with a 2D method from the right parasternal transaortic short axis view and using the calipers position described by Hansson et al. The LA/Ao was then calculated. ... Pulsed-wave Doppler variables included peak systolic aortic and pulmonary flow velocities, mitral E and A waves, and E/A ratio. Effects of BW, age, and gender on these 15 variables were tested using a general linear model, and RIs were determined by applying the statistical procedures recommended by the Clinical and Laboratory Standards Institute. Results: [LA/Ao median 0.74; range (minimum - maximum) 0.47 - 0.94. FS median 39.1%; range 30.7% - 51.9%. E/A median 1.4; range 1.5 - 2.4.] A significant BW effect was observed for all variables, except LA/Ao, FS%, and mitral E/A ratio. A significant but negligible effect of gender and age was also observed for 5/15 and 4/15 of the tested variables, respectively. Only the BW effect on M-mode variables was considered as clinically relevant and the corresponding regression-based RIs were calculated. Conclusions: Body weight should be taken into account when interpreting echocardiographic values in CKCS, except for LA/Ao, FS%, and mitral E/A ratio.

High-level serotonin-binding in subpopulation of highly-activated platelets in cavalier King Charles spaniels with myxomatous mitral valve disease. S.E. Cremer, A.T. Kristensen, M.J. Reimann, N.B. Eriksen, S.F. Petersen, C.B. Marschner, I. Tarnow, M.A. Oyama, L.H. Olsen. J.Vet.Int.Med. Apr. 2014;28(3). Quote: Circulating (platelet-derived) serotonin (5HT) concentration is elevated in early stages of myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS). CKCS are predisposed to early-onset MMVD and approximately 33% exhibit non-clinical macrothrombocytopenia (TCP). By means of flow cytometry, we investigated percent (%) and level (mean-fluorescence-intensity/MFI) of platelet-activation (CD62 surface expression) and surface-bound 5HT in platelet rich plasma (PRP) in CKCS with MMVD. Dogs with TCP were included, but only normal-size platelets were analyzed. Effect of disease-group, age, gender, body weight, hematocrit and TCP were included in multiple linear regression analyses. Disease-groups (assessed echocardiographically) were: healthy (n = 14), mild MMVD (n = 18), moderate-severe MMVD (n = 19) and severe MMVD in treatment for heart-failure (n = 10). There was an overall difference in level of platelet-activation (P = 0.04) with a tendency to higher activation level in moderate-severe MMVD (1661MFI (1356-2379)) (median (interquartile range)) and heart-failure (1452MFI (989-3242)) compared to healthy dogs (1325MFI (904-2505) (both P = 0.07)). In 28 dogs, a subpopulation of platelets with high 5HT-binding (5HT-P) was identified. These dogs (compared to non-5HT-P dogs) had higher percent of 5HT-positive platelets (10.4% (7.8-15.4) versus 5.7% (3.3-8.6), P < 0.0001), 5HT-binding level (30360MFI (26400-39260) versus 1230MFI (810-2830), P < 0.0001) and platelet-activation level (2360MFI (1520-2830) versus 1170MFI (890-1360), (P = 0.002). 5HT-P were present in 93.8% of dogs with TCP and in 29.6% of non-TCP dogs. In conclusion, a potential association between level of platelet activation and MMVD-severity was found. Interestingly, a highly-activated platelet subpopulation with high-level 5HT-binding was identified and strongly associated with TCP. Further investigation into significance of 5HT-P in CKCS is warranted.

Histamine concentration is involved in canine valvular disease. Mitsuhiro Isaka, Masahiko Befu, Nami Matsubara, Mayuko Ishikawa, Yurie Arase, Shinichi Namba. Vet.Sci.Dev. 2014;4:5123; pgs. 15-17. Quote: "It has been known for many years that there are histamine receptors (H) in the heart. Histamine displays chronotropic, inotropic activity, and cardiovascular diseases are thought to be a systemic inflammatory disease. During heart failure, the histamine concentration is elevated. In addition, H2 blockers prolonged the survival period for human patients with heart failure. The aim of this study was to evaluate whether blood concentration of histamine is associated with canine valvular disease (CVD). ... Client-owned dogs suffering from chronic valvular disease (mitral regurgitation; n=21) and healthy controls (n=7) were examined. ... Control: Cavalier King Charles Spaniel n=3, T. Poodle n=1, Mix breed n=1, G. Retriever n=1, Pomeranian n=1. For the CVHD grades, class I: Cavalier King Charles Spaniel n=2, Pug n=1, Papillon n=1, Mix breed n=1, Pomeranian n=1. Class II: Norfolk Terrier n=1, Chihuahua n=1, Maltese n=1, Cavalier King Charles Spaniel n=1, Shih Tzu n=1, Mix breed n=1. Class III: Chihuahua n=2, Shih Tzu n=2, French Bulldogs n=1, Cavalier King Charles Spaniel n=2, Beagle n=1, Mix breed n=1. ... The histamine concentrations of dogs with CVD are significantly higher than those of healthy dogs. The histamine concentration gradually increases during CVD and is highly correlated with the grade of heart murmur. In conclusion, the histamine concentration was higher in the population of dogs with CVD compared with the healthy controls. Although the etiopathogenesis of CVD is complex and incompletely understood, it likely involves histamine. Ultimately additional studies are required to determine whether histamine blockers might be useful for the management of dogs with cardiac valvular disease."

Assessment of Mitral Regurgitation Severity by Doppler Color Flow Mapping of the Vena Contracta in Dogs. M. Di Marcello, E. Terzo, C. Locatelli, V. Palermo, E. Sala, E. Dall'Aglio, C.M. Bussadori, I. Spalla, P.G. Brambilla. J.Vet.Int.Med. June 2014. Quote: "Background: Quantitative and semiquantitative methods have been proposed for the assessment of MR severity, and though all are associated with limitations. Measurement of vena contracta width (VCW) has been used in clinical practice. Objective: To measure the VCW in dogs with different levels of MR severity. Animals: Two hundred and seventy-nine dogs were classified according to 5 levels of MR severity. Most of the dogs were mongrels (44%) and among the breeds, the most common were Poodles (13%), Yorkshire Terriers (8%), and Shih-tzus (5%). Methods: This was a retrospective study. EROA and regurgitant volume calculated by the PISA method, were measured and indexed to BSA. Descriptive statistics were calculated for VCW and VCW index for all categories of MR severity. Spearman's rank correlation coefficients (ρs) were calculated to compare the results of the different methods (VCW and VCW index vs RV PISA, RV PISA index, EROA, EROA index), and between VCW and VCW index versus MR severity. Results: All Spearman's rank correlation coefficients were significant (P < .001). The median values of VCW resulted of 2.9 mm (IQR 3.4–2.5) and of 4.6 mm (IQR 5.4–4.1) in the groups previously classified as mild-to-moderate and moderate-to-severe, respectively. The median values of VCW index resulted of 4.4 mm/m2 (IQR = 5.5–4.2) in mild-to-moderate MR and of 10.8 mm/m2 (IQR = 12.8–9.4) in moderate-to-severe MR. Conclusion and Clinical Importance: This is not a validation study against any previously validated invasive gold standard, the VCW method has proved easy to employ and it might be an additional tool in quantifying disease severity that supports, rather than replace, data coming from other techniques in daily clinical practice and research."

Year in Review: Congestive Heart Failure. John D. Bonagura. ACVIM Forum. June 2014. Quote: "Congestive heart failure (CHF) is a clinical syndrome triggered by impaired cardiac systolic or diastolic function and characterized by stereotypical changes in neurohormonal activation, renal sodium retention, and cardiac and vascular remodeling. Functional characteristics of heart failure include impaired exercise capacity, secondary pulmonary dysfunction, and metabolic disturbances related to impaired organ perfusion. Both quality and duration of life are limited by cardiac failure. From the end of 2012 through early 2014 a number of manuscripts were published that expand our understanding of CHF in dogs and cats. These recent publications can be considered within the general categories of pathophysiology, epidemiology, diagnosis, prevention, therapy, staging, and prognosis. The purpose of this lecture is to highlight some of this interesting work and offer a personal perspective regarding the clinical impact of these reports within the context of the topics addressed. This presentation is directed to the generalist in clinical practice. ... When there is a potential for benefit based on favorable effects on markers of disease or ambiguous results of clinical trials, some clinicians will empirically recommend therapy; however, clients should understand the lack evidence and also appreciate the costs of such treatment as well as potential unintended adverse effects. ... Finally, the most pressing issue for any of us trying to perform clinical investigation is that near total lack of independent (foundation, university, or government) funding for veterinary clinical research. While industry funding of research is valued, the issues addressed are typically those of priority to the sponsor, not necessary to those practicing in the field. Although this is a relatively incomplete list of issues, it highlights some of the points readers might consider when evaluating journal articles that purport to change the way we practice cardiology."

The Role of Calcium-Sensitizer Levosimendan for the Treatment of Heart Failure. Mohammad Asif. Amer. J. Cardiovascular Disease Research;2014;2(1):9-16. Quote: "In the treatment of heart failure, clinical signs are low cardiac output, therapy with positive inotropic agents in an acute cardiac care is mandatory. Three classes of inotropic drugs are currently used, including beta-adrenergic agonists (especially dobutamine), phosphodiesterase inhibitors (such as milrinone) and the recently developed calcium sensitizers such as levosimendan. The classic inotropic drugs offer short-term haemodynamic enhancement in heart failure patient and their use has been connected with poor prognosis. The inotropic drugs, the Ca2+-sensitizers, may offer a choice of long-lasting result."

Serotonin concentration is elevated in platelet rich plasma and left ventricular myocardial and mitral valve leaflet tissue in dogs with myxomatous mitral valve disease. S.E. Cremer, G.E. Singletary, L.H. Olsen, K. Wallace, J. Häggström, I. Ljungvall, K. Höglund, C.A. Reynolds, N. Pizzinat, M.A. Oyama. J.Vet.Int.Med. July 2014;28(4):1351. Quote: "Heightened serotonin (5HT) signaling is postulated in the development and/or progression of myxomatous mitral valve disease (MMVD) in dogs. Little is known regarding platelet, myocardial, or valvular 5HT concentration ([5HT]) in affected dogs. We sought to quantify [5HT] in platelet-rich (PRP), platelet-poor plasma (PPP), left ventricular myocardium (LV), and mitral valve leaflet tissue (MV) using HPLC. PPP/PRP was prepared from 45 dogs comprising 4 different plasma groups (pG1, healthy non-Cavalier King Charles Spaniels [CKCS], n = 8; pG2, healthy CKCS, n = 12; pG3, MMVD CKCS, n = 14; pG4, MMVD non-CKCS, n = 11). PRP [5HT] was greater than PPP [5HT] (P < 0.0001) indicating platelets as the primary source of circulating 5HT. Median PRP platelet [5HT] was significantly different between groups (P = 0.003). PRP [5HT] was greater in pG2 (1.83 femtograms/platelet[range,0.2-4.76];P = 0.002), pG3 (1.58,0.70-4.03;P = 0.005), and pG4 (1.72,0.85-4.44;P = 0.003) vs. pG1 (0.915,0.63-1.3). There was no significant difference in median PPP [5HT] between groups. At euthanasia, LV and MV tissue was obtained from 24 dogs comprising 3 different tissue groups (tG1, MMVD, n = 8; tG2, dilated cardiomyopathy [DCM]/arrhythmogenic right ventricular cardiomyopathy [ARVC], n = 7; tG3, extra-cardiac disease, n = 9). Median LV [5HT] was significantly different (P = 0.0024) between groups. LV [5HT] was higher in tG1 (11.8 ng/mg,3.96-104.83) vs. tG2 (0.87,0-10.1;P = 0.011) and vs. tG3 (2.46,0-6.94;P = 0.001). MV [5HT] was significantly different between groups (P = 0.033) namely between tG1(32.4 ng/mg,8.36-106.73) vs. tG3(3.59,0-28.26;P = 0.01). In conclusion, platelet [5HT] was elevated in healthy and MMVD CKCS compared to healthy non-CKCS. LV [5HT] was elevated in MMVD compared to DCM/ARVC or non-cardiac disease. MV [5HT] was elevated in MMVD compared to non-cardiac disease."

Novel vasodilator prototype drug (LASSBio 897) and its action on the cardiovascular system of dogs. P.R. Nasciutti, I.P. Bittar, A.R. Fayad, F.O. Carvalho, V. De Oliveira, A.B. Fraga, E.J. Barreiro, R. Oliveira Alves. J.Vet.Int.Med. July 2014;28(4):1351. Quote: "LASSBio 897 is a new prototype drug produced from safrole substrate, a compound extracted from the “sassafras oil”, found in Brazilian plants like “canela-branca” (Ocotea pretiosa) which showed vasodilatory effects in in vitro (aorta of normotensive rats) and in vivo tests (rats). It was developed by Evaluation and Synthesis of Bioactive Substances Laboratory (LASSBio®) from Federal University of Rio de Janeiro. It is believed that the mechanism of action is mediated by muscarinic receptors with subsequent activation of the nitric oxide/cyclic guanosine monophosphate. Due to its pharmacological profile and the possibility of a new therapeutic strategy, an investigation of the effects on the cardiovascular system of dogs was held. Thus, six adult Beagles, five females and one male, healthy, were used. The dogs showed no clinical or behavioral changes during the study. Regarding urinary, hematological and serum biochemical evaluations, although statistical differences between times were observed, the parameters remained within the reference values for the species, similar to the results obtained by Pereira et al. (2005) in a study administering benazepril. No dog had heart rhythm abnormalities. In Doppler echocardiographic evaluation, values obtained for stroke volume (SV) and cardiac output (CO) were lower than that described as normal for dogs, with the lowest values found after four (SV: 14.57 mL; CO: 1.26 L/min) and six (SV: 16.39 mL; CO: 1.34 L/min) hours of administration. In the assessment of systolic blood pressure, a decrease was observed after two hours (p = 0.009), for all three doses of LASSBio 897 administered, similar to the results obtained with administration of benazepril, demonstrating the molecule's potential vasodilatory activity in addition to its safety, since no hypotension occurred. Considering the results obtained and the conditions under which this experiment was conducted, it can be concluded that the oral administration of LASSBio 897 in doses of 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg did not cause side effects in healthy Beagles, demonstrating that the prototype drug is safe. All doses caused vasodilation after two hours of their administration, similar to what was observed with benazepril, a drug extensively used to treat hypertension in dogs."

Investigation of dietary factors with possible associations with canine degenerative mitral valve disease. J.L. Sauer, L.M. Freeman, J.E. Rush. J.Vet.Int.Med. July 2014;28(4):1354. Quote: "The pathophysiologic cause of degenerative mitral valve disease (DMVD) remains unclear. Although there are a number of ways in which diet could play a role in DMVD, including the serotonin (5-hydroxytryptamine [5HT]) pathway, dietary factors related to the development of DVMD have not been investigated. Therefore, the objective of this study was to measure dietary amino acids, choline, carnitine, serotonin, and ergovaline as possible factors that could play a role in the pathophysiology of DMVD. Thirteen commercially-available diets were selected for analysis based on a previous study comparing dogs with and without DMVD and diet histories from clinical cases. Diets were analyzed for macronutrients; amino acids; ergovaline; the indoleamines, 5HT and melatonin; choline, and free L-carnitine. There was a wide range in the concentrations of all analytes in the diets tested. No essential amino acids were below the Association of American Feed Control Officials (AAFCO) minimums. Taurine, although not an essential amino acid for dogs, was below the AAFCO Cat Food Nutrient Profile for taurine in 9 of 13 diets. Tryptophan ranged from 0.19-0.59% dry matter (median = 0.28% dry matter). All 13 samples tested had undetectable ergovaline concentrations. One sample tested positive for 5HT, and melatonin was detected in 8 diets. There also was wide variation (3-fold and >100-fold difference, respectively) in choline and free L-carnitine concentrations among diets. Additional research is needed on the effects of varying dietary intake of tryptophan and other amino acids, 5HT, choline, and carnitine on cardiac valve metabolism."

Usefulness of plasma concentration of chromogranin a as an indicator of sympathetic tone in dogs with myxomatous mitral valve disease. K. Höglund, M. Stridsberg, O. Höglund, A. Tidholm, J. Häggström, I. Ljungvall. J.Vet.Int.Med. July 2014;28(4):1354. Quote: "Chromogranin A (CgA) is stored in secretory cells of sympathetic nerve endings and the adrenal medulla and is co-released with catecholamines, while the CgA-derived peptide Catestatin acts sympathoinhibitory. The stability of these molecules in plasma makes them interesting candidates for assessment of the sympathetic nervous system. In humans, CgA is also present in ventricular myocardium, co-localized with B-type natriuretic peptide (BNP). The aim of the study was to investigate whether plasma Catestatin concentration was associated with myxomatous mitral valve disease (MMVD) severity in dogs, and to assess potential associations between plasma Catestatin concentration and dog characteristics, echocardiographic variables, heart rate (HR), systolic blood pressure (SBP) and N-terminal proBNP. 70 client-owned dogs with MMVD of varying severity were prospectively recruited. Dogs were classified according to MMVD severity (healthy, or mild, moderate or severe disease). Three dogs were in decompensated congestive heart failure (CHF). Plasma concentration of Catestatin was analyzed using radioimmunoassay. No association between Catestatin concentration and MMVD severity groups was found. HR was higher in severely affected dogs than healthy and mildly affected, but was not associated with Catestatin concentration. Very weak negative association with left atrial and ventricular size (R2 = 0.08, P = 0.01 for both) and very weak positive association with SBP (R2 = 0.07, P = 0.02) was found for Catestatin concentration, while remaining variables were non-significant. In the present study population, Catestatin was not associated with severity of MMVD and HR seemed to be a better indicator of sympathetic tone than Catestatin. Including more dogs in decompensated CHF might have given different results."

Heart Health for Pets: Drugs or Herbaceutical Functional Intervention? Ihor Basko. Complementary Vet. Med. New Zealand Vet. Assn. July 2014;14-27. Quote: "From the evidence presented it is clear that cardio tonic and cardio protective herbs and nutraceuticals can benefit patients with heart disease. Most importantly, they can be used to help prevent diseases such as cardiomyopathy, and improve the quality of life and longevity in animals with congestive heart failure. The concept of 'nutritional functional intervention' (NFI) with nutraceuticals (and herbaceuticals) is growing in acceptance and will eventually become the 'gold standard' for treating heart patients by human naturopaths, acupuncturists, and wholistic veterinarians. Using any one of the mentioned pro-biologically acting substances can be of benefit. Pharmaceutical drugs do not heal or cure anything. They just “buy some time.” The majority of these drugs have 1 or 2 physiologic-kinetic affects on the heart, and can cause severe side-effects with inappropriate dosing, and chronic use. Herbs and nutritceuticals support healing and regeneration by: 1.) decreasing hydroxy radicals and lipid peroxidation and therefore decreasing myocardium tissue death with antioxidants. (Vit. E, C, Se, Mg, taurine, dan shen, zizzyphus, Coenzyme Q10.) 2.) protecting the negative effects of stress on the myocardium with adaptogens or cardio protective agents: (Siberian Ginseng, pycnogenols, Taurine, etc.) 3.) improving cardiac function, glucose utilization and contractile strength: (Ginsengs, Hawthorne, CoenzymeQ10, Mg, carnitine & taurine.) 4.) nutrition that facilitates repair of damaged myocardium, and the prevention of deficiencies that would cause cardiomypathies ( taurine, carnitine, Vit e & Se, K, Mg.) 5.) after a cardiac crisis, or heart surgery… 'damage control' and repair to limit oxidative stress and support healing (Coenzyme Q10, antioxidants, magnesium, and Oriental cardio-therapeutic herbs such as Dan Shen, and Eleutherococcus.) Clinical practice studies and research must continue in the understanding of how cases of severe congestive heart failure can be treated with or without drugs. More research from other countries (especially former communist block countries, and the Orient) needs to be translated into English and studied.
We have focused too long and have gotten too 'dependent' on drugs for the answers in the treatment of heart disease in animals. Little attention is focused on prevention and maintaining heart health. In the past 10 years, the principles of NFI have become the quintessential foundation for the prevention and treatment of modern-day diseases by complementary medicine veterinarians in the management of disease. When used without drugs, the appropriate combination of herbaceuticals will exhibit little or no side-effects, and benefit the quality and duration of life."

Homeopathy and Cardiovascular Disease. Wendy Dixon. Complementary Vet. Med. New Zealand Vet. Assn. July 2014;32-35. Quote: "Cardiac disease in the veterinary setting is often fairly well managed with the use of conventional medicine, especially for those lucky enough to be able to afford the newer medications that have become available over the last decade. However, there are still situations where the employment of complementary therapies can provide additional benefits, especially when used alongside conventional medicine. Most of the cardiac cases I have treated with homeopathic preparations have either already been on a full complement of conventional medication, or the owner has not been able to afford the next stage of medical intervention. I have also found homeopathy to be of value when the first mild symptoms of congestive heart failure have appeared and the owner is keen to avoid conventional intervention as long as possible, or where it is known that the heart has a problem (such as a murmur detected as an incidental finding during a consultation) but no symptoms are currently manifest. In these cases, supplements and remedies known to have a supportive action in cardiac disease are employed (although there are no studies to prove that this preventative intervention does delay the onset of clinical signs). ... Case Examples: Ellie, a 10-year-old Cavalier King Charles Spaniel with cardiac cough due to mitral valve disease: Ellie was on all the usual medications to control her mitral valve disease including diuretics, but her cough remained. It was thought that the cough was caused by an enlarged atrium physically pressing against the thoracic trachea. Her cough was dry and non-productive and on questioning I discovered that the cough improved after eating. On this basis I prescribed Spongia 30c once per day. On followup the cough was noticeably improved. ... It is worth considering homeopathic remedies as an additional support for cardiac disease in situations where conventional medicine is either unaffordable or is failing to control the symptoms adequately. Of course the results will be dictated by how advanced the disease is and we need to be realistic when discussing the options with our clients. The remedies can be used safely on their own, though I would recommend using them in conjunction with conventional medication."

Traditional Chinese Medicine in Cardiac support. Dr. Tony Frith. Complementary Vet. Med. New Zealand Vet. Assn. July 2014;37-40. Quote: "It should be remembered that TCM uses a number of herbs in each formula as indicated in many cases by the name of the product. E.g Zizyphus 18. Most formula have two or three groupings of activity (a primary focus ,a support focus, and background support for secondary issues. Now, also consider that each herb in each of these groups may have one or more primary peaks of activity and often several supporting peaks of activity, (Perhaps up to 60 or 70 peaks of activity) The difference in the model between Western medicine supported by statistical evidence and TCM is vastly different . It could be considered to give a 'shotgun effect' which is really quite useful. However, please do not denigrate this methodology until you understand it because the deeper you go into the “'epths of the temple' (the body) the more you can refine your therapies and tune them to the individual. I arrived at this place by not being content to suppress symptoms but also wanted to modify the causative factors to 'prevent disease'. Symptom>>>>cause>>>>proximate causes>>>> contributory factors."

Hyperbaric Oxygen Therapy; The Benefits for Heart Disease. Liza Schneider. Complementary Vet. Med. New Zealand Vet. Assn. July 2014;43-46. Quote: "Clinical experience suggests that most animals tolerate the hyperbaric chamber without the use of sedatives and experience very little discomfort for the duration of therapy. Treatment generally lasts sixty to ninety minutes (usually fifteen minutes of compression, sixty minutes at the desired pressure and fifteen minutes of decompression) and may be used once or twice a day depending on the severity of the condition being treated. The number of treatments required is also dependent on the nature of the condition but animals typically respond very well to one to five treatment sessions, although up to ten sessions may be required for severe conditions."

Increased NT–proANP predicts risk of congestive heart failure in Cavalier King Charles spaniels with mitral regurgitation caused by myxomatous valve disease. Anders S. Eriksson, Jens Häggström, Henrik Duelund Pedersen, Kerstin Hansson, Anna-Kaisa Järvinen, Jari Haukka, Clarence Kvart. J. Vet. Cardiology. Sept. 2014;16(3):141-154. Quote: "Objectives: To evaluate the predictive value of plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) and nitric oxide end-products (NOx) as markers for progression of mitral regurgitation caused by myxomatous mitral valve disease. Animals: Seventy-eight privately owned Cavalier King Charles spaniels with naturally occurring myxomatous mitral valve disease. Methods: Prospective longitudinal study comprising 312 measurements over a 4.5 year period. Clinical values were recorded, NT-proANP concentrations were measured by radioimmunoassay, and NOx were analyzed colorimetrically. To predict congestive heart failure (CHF), Cox proportional hazards models with time-varying covariates were constructed. Results: The hazard ratio for NT-proANP (per 1000 pmol/l increase) to predict future CHF was 6.7 (95% confidence interval, 3.6–12.5; p < 0.001). The median time to CHF for dogs with NT-proANP levels >1000 pmol/l was 11 months (95% confidence interval, 5.6–12.6 months), compared to 54 months (46 – infinity) for dogs with concentrations ≤1000 pmol/l (p < 0.001). Due to intra- and inter-individual variability, most corresponding analyses for NOx were insignificant but dogs reaching CHF had a lower mean NOx concentration than dogs not reaching CHF (23 vs. 28 μmol/l, p = 0.016). Risk of CHF increased with increase in heart rate (>130 beats per minute) and grade of murmur (≥3/6). Conclusions: The risk of CHF due to mitral regurgitation is increased in dogs with blood NT-proANP concentrations above 1000 pmol/l. Measurement of NT-proANP can be a valuable tool to identify dogs that may develop CHF within months."

Plasma and platelet serotonin concentrations in healthy dogs and dogs with myxomatous mitral valve disease. Tanawan Mangklabruks, Sirilak Disatian Surachetpong. J.Vet.Cardiology. Sept. 2014;16(3):155-162. Quote: "Objectives: Serotonin has been implicated in canine myxomatous mitral valve disease (MMVD); however, the sources of serotonin have not been fully elucidated. This study compared the concentration of serotonin in plasma and platelets of normal healthy small breed dogs with predisposition to MMVD and dogs with naturally occurring MMVD. Animals: 43 small-breed client-owned dogs with an approximate weight of < 10kg and age of 6 years or above were divided into 2 groups: a healthy control group (n=20) and a group with echocardiographic evidence of MMVD (n=23). Results: Median plasma serotonin concentration was not significantly different (p=0.3630) between normal healthy dogs (3.7 ng/ml) and dogs with MMVD (4.3 ng/ml). Males had higher plasma serotonin concentration than females (4.7 and 2.9 ng/ml respectively, p=0.0043). Platelet serotonin concentration was not different between healthy dogs and dogs with MMVD (128.6 ng/109 platelets and 176.6 ng/109 platelets respectively, p=0.4575). Age, echocardiographic indices and platelet count showed no correlation with plasma or platelet serotonin concentration. Conclusions: Circulating plasma serotonin is unlikely a major source of serotonin signaling in canine MMVD. Platelets could be a source of serotonin in canine MMVD through platelet adhesion to the mitral valve; however, the amount of serotonin stored in platelets of healthy dogs and dogs with MMVD is not different."

Echocardiographic Investigation of Canine Myxomatous Mitral Valvular Disease. Wesselowski, Sonya Rae (thesis). Va.Tech.Univ. July 2014. Quote: "Objectives: To further characterize the echocardiographic anatomy of the canine mitral valve in healthy dogs and those affected by myxomatous mitral valve disease (MMVD), and to compare the level of agreement between two methods of assessment of left atrial size in identification of left atrial enlargement in dogs with MMVD. Animals: Sixty dogs with MMVD [27 different breeds, including 9 cavalier King Charles spaniels] and 22 normal dogs were prospectively studied with 2-dimensional echocardiography. Methods: The length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet and the diameter of the mitral valve annulus in systole (MVAs) and diastole (MVAd) were measured. Left atrial size was evaluated with the left atrial to aortic root ratio (LA:Ao) and by measuring left atrial volume indexed to body weight (LA Vol/BW). All patients were staged using published ACVIM guidelines and separated into groups B1 and B2/C. Results: Measurements of AMVL, AMVW, AMVA, MVAs and MVAd were all significantly greater in the B2/C group than in the control group. AMVW was significantly greater in group B1 than control. Twelve dogs had left atrial enlargement identified with LA Vol/BW that were considered normal using LA:Ao. Diagnostic disagreement between these two measurements was significant (P = 0.00012). The majority of dogs with diagnostic disagreement had concurrent echocardiographic evidence of more advanced mitral regurgitation. Conclusions: Relative to normal dogs, AMVL, AMVW, AMVA, MVAs and MVAd are greater in patients with advanced MMVD. LA Vol/BW may be superior to LA:Ao for identification of mild left atrial enlargement." (See also: Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, below.)

Discrepancies in Identification of Left Atrial Enlargement Using Left Atrial Volume versus Left Atrial-to-Aortic Root Ratio in Dogs. S. Wesselowski, M. Borgarelli, N.M. Bello, J. Abbott. J.Vet.Int.Med. July 2014;28:1527–1533. Quote: Background: Left atrial size is prognostically important in dogs with myxomatous mitral valve disease (MMVD). Hypothesis/Objectives: To compare the level of agreement in identification of left atrial enlargement (LAE) between the left atrial-to-aortic root ratio (LA : Ao) and left atrial volume using the biplane area-length method indexed to body weight (LA Vol/BW). Animals: Sixty dogs with MMVD [27 different breeds, including 9 cavalier King Charles spaniels] and 22 normal dogs were prospectively studied with 2-dimensional echocardiography. Methods: The upper limit of normal for LA Vol/BW was defined as 1.1 mL/kg. LA : Ao was deemed normal if ≤1.5. To define overall disease severity, each dog was assigned a mitral regurgitation severity score (MRSS) based on echocardiographic parameters that did not include left atrial size. ACVIM staging also was utilized. Results: Of 60 affected dogs, 20 were ACVIM Stage B1, 25 were Stage B2, and 15 were Stage C. LA Vol/BW identified LAE in 12 cases in which LA : Ao was normal; 7 of these were Stage B1 and 5 were Stage B2. This diagnostic disagreement was significant (P = .00012). Of the 12 cases in which diagnostic discrepancies were identified, 5/5 of the B2 dogs and 3/7 B1 dogs had a moderate MRSS, whereas 4/7 B1 dogs had a mild MRSS. No diagnostic discrepancies between LA : Ao and LA Vol/BW were apparent in dogs with a severe MRSS. Conclusions and Clinical Importance: This study shows evidence of diagnostic disagreement between LA : Ao and LA Vol/BW for assessment of LAE. LA Vol/BW may be superior to LA : Ao for identification of mild LAE. ... Similarly, limitations specific to canine anatomy or simple variability from individual to individual may contribute to asymmetric enlargement of the left atrium inthe dog. This is further supported by our finding thatmost of the variability observed in LA Vol/BW measurements was explained by dog-specific factors (ie, dog-to-dog variance).

Safety and Biocompatibility of the Mitrex Epicardial Annuloplasty Device in a Chronic Model. Jeffrey Adam Solomon, Pierluca Lombardi, Evan Anderson, Tachi Callas, Mark Juravic, Mark Cunningham, Thomas Fogarty. Vet.Surgery. August 2014;43:E201-202. This study evaluated the safety of the myocardial compression required to perform epicardial annuloplasty and the biocompatibility of the Mitrex device. Ten swine (seven test and three control) were used. The Mitrex device was placed in all subjects in order to reduce septal-lateral dimension of the mitral valve by 15–35%. Devices were secured in the test group and removed from the animals in the control group. Echocardiography and angiography were performed pre implant, post implant and at term. Necropsy was performed at 180 days. Hearts were pressure fixed and analyzed. Test devices were placed without incident. Coronary flow, ejection fraction, left ventricular wall motion and mitral valve function were normal post implantation and at term. There were no remarkable postoperative events and all subjects survived to term with the exception of one test animal that was euthanized due to a presumed non device related complication (refractory pleural effusion). Devices were well tolerated causing only minimal to mild fibrosis and chronic inflammation. No significant changes were observed in the myocardium except for muscle fiber atrophy near the tip of the anterior arm. There appeared to be ample tissue over the tip and no danger of perforation in all but one subject. No meaningful changes were noted in cardiac shape, ventricular wall thickness, chamber size, heart valves, and blood vessels. The myocardial compression necessary to perform epicardial annuloplasty was well tolerated. The Mitrex device was safe and biocompatible."

Magnetic targeting of cardiosphere-derived stem cells with ferumoxytol nanoparticles for treating rats with myocardial infarction. Magnetized Cardiac Stem Cells DiagramAdam C. Vandergriff, Taylor M. Hensley, Eric T. Henry, Deliang Shen, Shirena Anthony, Jinying Zhang, Ke Cheng. Biomaterials; Oct. 2014;35(30):8528-8539. Quote: "Stem cell transplantation is a promising therapeutic strategy for acute or chronic ischemic cardiomyopathy. A major limitation to efficacy in cell transplantation is the low efficiency of retention and engraftment, due at least in part to significant early 'wash-out' of cells from coronary blood flow and heart contraction. We sought to enhance cell retention and engraftment by magnetic targeting. Human cardiosphere-derived stem cells (hCDCs) were labeled with FDA-approved ferumoxytol nanoparticles Feraheme® (F) in the presence of heparin (H) and protamine (P). FHP labeling is nontoxic to hCDCs. FHP-labeled rat CDCs (FHP-rCDCs) were intracoronarily infused into syngeneic rats, with and without magnetic targeting. Magnetic resonance imaging, fluorescence imaging, and quantitative PCR revealed magnetic targeting increased cardiac retention of transplanted FHP-rCDCs. Neither infusion of FHP-rCDCs nor magnetic targeting exacerbated cardiac inflammation or caused iron overload. The augmentation of acute cell retention translated into more attenuated left ventricular remodeling and greater therapeutic benefit (ejection fraction) 3 weeks after treatment. Histology revealed enhanced cell engraftment and angiogenesis in hearts from the magnetic targeting group. FHP labeling is safe to cardiac stem cells and facilitates magnetically-targeted stem cell delivery into the heart which leads to augmented cell engraftment and therapeutic benefit."

Serotonin Concentrations in Platelets, Plasma, Mitral Valve Leaflet, and Left Ventricular Myocardial Tissue in Dogs with Myxomatous Mitral Valve Disease. S.E. Cremer, G.E. Singletary, L.H. Olsen, K. Wallace, J. Häggström, I. Ljungvall, K. Höglund, C.A. Reynolds. N. Pizzinat, M.A. Oyama. J.Vet.Int.Med.;Sept. 2014;28(5):1534-1540. Quote: "Hypothesis/Objectives: Altered serotonin (5-hydroxytryptamine, 5HT) signaling is postulated in development and progression of canine myxomatous mitral valve disease (MMVD). Little is known regarding platelet, plasma, valvular, or myocardial 5HT concentration ([5HT]) in affected dogs. We quantified [5HT] in platelet-rich plasma (PRP), platelet-poor plasma (PPP), mitral valve leaflets (MV), and left ventricular myocardium (LV). Animals: Forty-five dogs comprised 4 plasma groups of Cavalier King Charles Spaniels (CKCS) or non-CKCS, either healthy (CON) or MMVD affected: CKCS CON (n = 12); non-CKCS CON (n = 8); CKCS MMVD (n = 14); non-CKCS MMVD (n = 11). Twenty-four dogs comprised 3 tissue groups: MMVD (n = 8); other-HD (heart disease) (n = 7); non-HD, extracardiac disease (n = 9). Methods: High-performance liquid chromatography measured PRP, PPP, MV, and LV [5HT]. Results: Platelet-rich plasma platelet [5HT] was greater in CKCS CON (1.83 femtograms/platelet [fg/plt]; range, 0.20–4.76; P = .002), CKCS MMVD (1.58 fg/plt; range, 0.70–4.03; P = .005), and non-CKCS MMVD (1.72 fg/plt; range, 0.85–4.44; P = .003) versus non-CKCS CON (0.92 fg/plt; range, 0.63–1.30). There was no group difference in PPP [5HT]. MV [5HT] was significantly higher in MMVD (32.4 ng/mg; range, 8.4–106.7) versus non-HD (3.6 ng/mg; range, 0–28.3; P = .01) and LV [5HT] was significantly higher in MMVD (11.9 ng/mg; range, 4.0–104.8) versus other-HD (0.9 ng/mg; range, 0–10.1; P = .011) and non-HD (2.5 ng/mg; range, 0–6.9; P = .001). Conclusions and Clinical Importance: Platelet [5HT] was highest in healthy CKCS and both MMVD groups, but plasma [5HT] showed no group differences. Tissue [5HT] was highest in MV and LV of MMVD-affected dogs, suggesting altered 5HT signaling as a potential feature of MMVD. Interactions of platelet, valvular, and myocardial 5HT signaling warrant further investigation."

Murmur intensity in small-breed dogs with myxomatous mitral valve disease reflects disease severity. I. Ljungvall, M. Rishniw, F. Porciello, L. Ferasin, D. G. Ohad. J. Small Animal Practice. November 2014;55(11):545-550. Quote: Objectives: To determine whether murmur intensity in small-breed dogs with myxomatous mitral valve disease reflects clinical and echocardiographic disease severity. Methods: Retrospective multi-investigator study. Records of adult dogs Ä20 kg with myxomatous mitral valve disease were examined. Murmur intensity and location were recorded and compared with echocardiographic variables and functional disease status. Murmur intensities in consecutive categories were compared for prevalences of congestive heart failure, pulmonary hypertension and cardiac remodelling. Results: 578 dogs [107 with “soft” (30 Grade I/VI and 77 II/VI), 161 with “moderate” (Grade III/VI), 160 with “loud” (Grade IV/VI) and 150 with “thrilling” (Grade V/VI or VI/VI) murmurs] were studied. No dogs with soft murmurs had congestive heart failure, and 90% had no remodelling. However, 56% of dogs with “moderate”, 29% of dogs with “loud” and 8% of dogs with “thrilling” murmurs and subclinical myxomatous mitral valve disease also had no remodelling. ... Cardiac remodelling was defined as an increase in at least two of the three echocardiographic variables (LA:Ao, wLA and wLVID) above previously established reference intervals (Brown et al. 2003). Dogs were assigned into one of three categories, according to the ACVIM Consensus statement on diagnosis and treatment of MMVD: those without evidence of remodelling (i.e. less than two variables greater than reference intervals) were coded as Stage B1, those with evidence of remodelling (two or more variables greater than reference intervals) but without evidence of CHF were coded as Stage B2 and those with evidence of CHF (treated or untreated) were coded as Stage C (Atkins et al. 2009).  ... Probability of a dog having congestive heart failure or pulmonary hypertension increased with increasing murmur intensity. Clinical Significance: A 4-level murmur grading scheme separated clinically meaningful outcomes in small-breed dogs with myxomatous mitral valve disease. Soft murmurs in small-breed dogs are strongly indicative of subclinical heart disease. Thrilling murmurs are associated with more severe disease. Other murmurs are less informative on an individual basis. ... This scheme could provide collaborating researchers with a uniform method of identifying remodelling, because it relies on multiple variables to be outside the reference intervals to identify enlargement, removing some of the subjective inter-observer variability in identifying remodelling. Finally, it could provide clinicians with a reasonable and practical method of stratifying their patients and support clinical recommendations for additional diagnostic tests.

Associations between N-terminal procollagen type III, fibrosis and echocardiographic indices in dogs that died due to myxomatous mitral valve disease. Melanie J. Hezzell, Torkel Falk, Lisbeth Høier Olsen, Adrian Boswood, Jonathan Elliott. J. Vet. Cardiology. Sept. 2014. Quote: "Objectives: To evaluate associations between N-terminal procollagen type III (PIIINP), a serum biomarker of collagen biosynthesis, and myocardial fibrosis in dogs with naturally-occurring myxomatous mitral valve disease (MMVD). Animals: Twenty-two dogs with echocardiographically-confirmed MMVD were prospectively recruited from a hospital population. All died as a result of MMVD and their hearts were available for post mortem examination. Methods: Echocardiographic measurements and serum PIIINP concentrations were obtained from all dogs prior to death or euthanasia. Serum PIIINP concentrations (μg/mL) were measured using a validated commercially available radioimmunoassay. Myocardial tissue samples were collected post mortem and myocardial fibrosis was scored. The average fibrosis score for all cardiac sites in the heart was designated the global fibrosis score (GFS). The average fibrosis score for all papillary muscle sites was designated the papillary fibrosis score (PFS). Univariate and multivariate linear regression analyses were used separately to evaluate associations between GFS and PFS, respectively, and PIIINP and echocardiographic variables. Results: Left ventricular end-diastolic diameter normalized for body weight (LVEDDN) and PIIINP were weakly independently positively associated with both GFS and PFS. LVEDDN and PIIINP were weakly negatively correlated. Conclusions: Both LVEDDN and serum PIIINP increase with increasing fibrosis score, although these relationships were not strong enough to be clinically useful. Although LVEDDN and PIIINP were positively correlated with fibrosis, PIIINP decreased with increasing LVEDDN, suggesting a complex interplay between fibrosis and remodeling in MMVD."

Aldosterone breakthrough with benazepril in furosemide-activated renin-angiotensin-aldosterone system in normal dogs. A. C. Lantis, M. K. Ames, C. E. Atkins, T. C. DeFrancesco, B. W. Keene, S. R. Werre. J. Vet. Pharmacology & Therapeutics; February 2015.38(1):65–73. Quote: "Pilot studies in our laboratory revealed that furosemide-induced renin-angiotensin-aldosterone system (RAAS) activation was not attenuated by the subsequent co-administration of benazepril. This study was designed to evaluate the effect of benazepril on angiotensin-converting enzyme (ACE) activity and furosemide-induced circulating RAAS activation. Our hypothesis was that benazepril suppression of ACE activity would not suppress furosemide-induced circulating RAAS activation, indicated by urinary aldosterone concentration. Ten healthy hound dogs were used in this study. The effect of furosemide (2 mg/kg p.o., q12h; Group F; n = 5) and furosemide plus benazepril (1 mg/kg p.o., q24h; Group FB; n = 5) on circulating RAAS was determined by plasma ACE activity, 4–6 h posttreatment, and urinary aldosterone to creatinine ratio (UAldo:C) on days −1, −2, 1, 3, and 7. There was a significant increase in the average UAldo:C (μg/g) after the administration of furosemide (Group F baseline [average of days −1 and −2] UAldo:C = 0.41, SD 0.15; day 1 UAldo:C = 1.1, SD 0.56; day 3 UAldo:C = 0.85, SD 0.50; day 7 UAldo:C = 1.1, SD 0.80, P < 0.05). Benazepril suppressed ACE activity (U/L) in Group FB (Group FB baseline ACE = 16.4, SD 4.2; day 1 ACE = 3.5, SD 1.4; day 3 ACE = 1.6, SD 1.3; day 7 ACE = 1.4, SD 1.4, P < 0.05) but did not significantly reduce aldosterone excretion (Group FB baseline UAldo:C = 0.35, SD 0.16; day 1 UAldo:C = 0.79, SD 0.39; day 3 UAldo:C 0.92, SD 0.48, day 7 UAldo:C = 0.99, SD 0.48, P < 0.05). Benazepril decreased plasma ACE activity but did not prevent furosemide-induced RAAS activation, indicating aldosterone breakthrough (escape). This is particularly noteworthy in that breakthrough is observed at the time of initiation of RAAS suppression, as opposed to developing after months of therapy. ... In conclusion, we have shown a nearly threefold increase in urinary aldosterone secretion, as indicated by the urine UAldo:C, with furosemide monotherapy. This was maintained for the 7 days of the study. We also found an expected >60% reduction in plasma ACE activity 4–6 h posttreatment in the furosemide and benazepril-treated group (FB), without a concomitant, consistent decrease in mean urinary aldosterone excretion.  ... While the results of this study must be confirmed in clinical patients, given the present data and data from dogs with CHF (Bernay et al., 2010), it appears that standard CHF therapy (Atkins et al., 2009) should be accompanied by an aldosterone antagonist in dogs."

Biopterin Status in Dogs with Myxomatous Mitral Valve Disease is Associated with Disease Severity and Cardiovascular Risk Factors. M.J. Reimann, J. Häggström, A. Mortensen, J. Lykkesfeldt, J.E. Møller, T. Falk and L.H. Olsen. J.Vet.Int. Med.;Sept. 2014;28(5):1520–1526. Quote:  "Background: Endothelial dysfunction (ED) has been suggested to be associated with myxomatous mitral valve disease (MMVD) in dogs. Tetrahydrobiopterin (BH4) is an important cofactor for production of the endothelium-derived vasodilator nitric oxide (NO). Under conditions of oxidative stress, BH4 is oxidized to the biologically inactive form dihydrobiopterin (BH2). Thus, plasma concentrations of BH2 and BH4 may reflect ED and oxidative stress. Objective: To determine plasma concentrations of BH2 and BH4 in dogs with different degrees of MMVD. Animals: Eighty-four privately owned dogs grouped according to ACVIM guidelines (37 healthy control dogs including 13 Beagles and 24 Cavalier King Charles Spaniels [CKCSs], 33 CKCSs with MMVD of differing severity including 18 CKCSs [group B1] and 15 CKCSs [group B2], and 14 dogs of different breeds with clinical signs of congestive heart failure [CHF] because of MMVD [group C]). ... Dogs were staged based on American College of Veterinary Internal Medicine (ACVIM) consensus statement classification guidelines as: control group (healthy dogs with no auscultatory heart murmur including 13 Beagles and 24 CKCSs), group B1 (CKCSs with auscultatory heart murmur and LA/Ao ≤ 1.5), group B2 (CKCSs with auscultatory heart murmur and LA/Ao > 1.5), and group C (dogs in CHF including 9 CKCSs ...) ... Methods: Dogs underwent clinical examination including echocardiography. Plasma concentrations of BH2 and BH4 were measured using high-performance liquid chromatography with fluorescence detection. Results: Higher plasma BH4 and BH2 concentrations were found with dogs in CHF compared with all other groups (control, B1 and B2; P ≤ .001). Females had higher concentrations of BH4 and BH4/BH2 (P ≤ .0003). BH4/BH2 was found to decrease with age (P < .0001). Cardiovascular risk factors in humans such as passive smoking (P ≤ .01) and increased body weight (P ≤ .009) were associated with lower BH4 concentrations. Conclusions and Clinical Importance: Age, sex, body weight, passive smoking, and cardiac status are associated with plasma biopterin concentration in dogs. Additional studies should clarify the clinical implications of the findings."

When to use and not to use ACE-inhibitors. Clarke E. Atkins. WSAVA Congress 2014. Sept. 2014. Proceedings Book pp. 145-147. Quote: "Of the commonly used therapeutic strategies, loop-diuretic therapy has the greatest potential for adverse side-effects (hypotension, azotemia, activation of RAAS, electrolyte disturbances and fatal arrhythmias). Therefore, except in emergencies, furosemide should not be used as a monotherapy and should be used at the lowest dosage preventing signs of CHF. Salt restriction has similar, but lesser effects on RAAS activation, and potentiates diuretic- and ACE-I induced tendencies toward azotemia. Therefore, moderate, rather than severe salt restriction, is indicated until signs of heart failure become refractory. Of the off-loading therapies under discussion, only ACE-I have been shown to benefit heart failure while blunting other pathophysiological processes (RAAS activation, electrolyte abnormalities, aldosterone- and angiotension II induced cardiac remodeling, and renal dysfunction). Therefore, if either azotemia or hypotension is noted in a patient being managed for heart failure, the diuretic should first be discontinued or the dosage reduced, being reinstituted as necessary. Reduction or cessation of ACE-I is employed only if altering the diuretic dosage is ineffectual. Though ACE-I are generally safe, BUN and creatinine, as well as serum potassium concentration and systemic blood pressure should be monitored periodically, particularly if sodium restriction and/or diuretic therapy are utilized concurrently. Finally, when any of these agents are utilized, either alone or in combination, if caution is exercised and hypotension avoided, there is little risk of significant renal impairment. Beta-blockers are indicated in DCM (NYHA Phase I, II, and III). Although theoretically indicated, a recent trial failed to show benefit in asymptomatic MR. Aldosterone receptor blockers are useful in CHF and probably should be used whenever and ACE-inhibitor is employed."

Sedation and anaesthesia for pets with cardiac disease. Dan G. Ohad. WSAVA Congress 2014. Sept. 2014. Proceedings Book pp. 166-169.

Mitral valve plasty in small and toy dogs. Isamu Kanemoto. WSAVA Congress 2014. Sept. 2014. Proceedings Book pp. 340-341. Quote: "Introduction: There are two mitral valve operations for mitral regurgitation (MR); mitral valve plasty (MVP) and mitral valve replacement (MVR). In MVP, the self-valve is preserved and repaired. The advantage is no reaction of a foreign substance, though it requires the skilled techniques. On the other hand, the MVR technique is simple, but anticoagulant therapy is needed during life. As in humans, the first choice is MVP in dogs. MVP Method: There are mainly three methods in MVP; 1) Annuloplasty for dilated mitral valve ring, 2) valvuloplasty for deformed valve leaflet, and 3) chordal reconstruction for ruptured or prolonged chorda tendineae. 1. Annuloplasty for dilated mitral valve ring: ... 2. Valvuloplasty for deformed valve leaflet: Valvuloplasty is possible for a deformed valve leaflet. Triangle resection and rectangle resection are adapted to resect the redundant leaflet part due to ruptured and/or elongated chordae. This technique is used in most MVP for human MR, especially involving the posterior leaflet. However, we do not use this technique because the resection decreases the valve area and coaptation area, and there is almost never a redundant leaflet part in small dogs. This technique is definitely needed for any annuloplasty and ring annuloplasty commonly used in human MR. We had a case using this triangle resection of the anterior leaflet with posterior commissural annuloplasty in a small dog in 1990. It was the first successful clinical case of MVP in the dog. We now use the valve cusp direct suture technique on the severely damaged posterior leaflet to remove valve cleft in severe MR cases in small dogs. 3. Chordal reconstruction for ruptured or prolonged chorda tendineae: On chordal reconstruction, shortening of prolonged chorda, and shifting of approximate chorda technique are very difficult in small dogs. Chordal reconstruction using pericardium, silk, nylon, Teflon or Dacron sutures was used in the past, but has been discontinued because of the calcification or deterioration. Recently, chordal reconstruction using e-PTFE (Gore-Tex) suture has been designed and used in most MVP for human MR. We studied this suture experimentally in the dog and presented it at the WASAVA Congress in 1995. Five years later, we presented MVP by chordal reconstruction using e-PTFE suture in a small MR dog (Kanemoto I, et al presented it in part at the 1999 ACVS Symposium, San Francisco). MVP Challenges in Small and Toy Dogs: Future challenges of MVP in small and toy dogs are stated below: CPB methods will involve: 1) ongoing miniaturization of the circuit and oxygenator to prevent excessive hemodilution; 2) development of low-flow CPB to moderate-flow CPB by increasing venous drain volume; 3) the eventual change from deep HT (20°C) to moderate HT (25-28°C); 4) improvement of cardioplegia to provide prolongation of aortic cross-clamp time, and perfect repair of MVP; and 5) improvement of ICU to assure fewer complications, and better results. New operative methods will include: 1) development of MVP in small and toy dogs; and 2) development of bioprosthetic valve (MVR) in small and toy dogs."

Pimobebdan -- Help or Hype? Mark D. Kittleson. WSAVA Congress 2014. Sept. 2014. Proceedings Book pp. 502-504. Quote: "Currently there is a clinical trial ongoing that is looking to see if pimobendan slows the progression to heart failure in dogs with mitral regurgitation due to MMVD. It is named EPIC. The study’s aim is to enroll 300 dogs, half on placebo and half on pimobendan and so a similar design to the PROTECT study. It is supposed to finish in 2015. Currently there is only one study that has looked at the effects of pimobendan in dogs with MMVD prior to the onset of heart failure. This study looked at 12 Beagles from a research colony with mild MMVD where half were placed on pimobendan and half on benazepril for 512 days. As expected, the shortening fraction increased in the dogs on pimobendan. However, the severity of the mitral regurgitation appeared to worsen and, more importantly, the myxomatous degeneration worsened when examined histologically. Because this study found pimobendan to be detrimental to dogs with MMVD it is the opinion of the author that further study was warranted prior to exposing 150 dogs to it in a large clinical trial (the EPIC study). Primum non nocere (first do no harm). It is also the opinion of the author that pimobendan should not be administered to dogs with MMVD prior to the onset of heart failure until the results of the EPIC trial are published. In conclusion, there is no doubt that pimobendan prolongs survival in dogs in heart failure due to MMVD and little doubt it does the same for Doberman Pinschers with DCM. ... Will it prolong the time until a dog with MMVD goes into heart failure? That remains to be seen. Given the one study that has been done to date I don’t believe you can give this anything more than a 50:50 chance. And so, once again, it is my recommendation that pimobendan not be administered to dogs with mitral regurgitation due to MMVD prior to the results of the EPIC study being published in a peer-reviewed journal."

Congestive heart failure when the owner has no money. Philip R Fox. WSAVA Congress 2014. Sept. 2014. Proceedings Book pp. 631-632. Quote: "Patient Evaluation: Outpatient therapy can often be successful when financial constraints preclude generating a large data base or permitting hospitalization. A thorough history is paramount. Clinical signs are ultimately associated with acute pulmonary edema due to mitral regurgitation or occasionally DCM, and are caused by elevated left ventricular filling pressures which result in pulmonary edema. Respiratory distress is acute, generally less than 24 hours. If signs are intermittent and suddenly worse, then acute exacerbation of respiratory disease- not CHF, should be suspected. A chest radiograph should be performed to confirm CHF if the diagnosis is in question. GOALS Treatment goals include 1) rapid resolution of pulmonary edema through preload and afterload reduction; 2) patient stabilization, and 3) avoidance of acute renal injury. Many cases of first time acute CHF with limited client funds can be managed if the pet can be treated for 4-6 hours in your hospital as follows: Initial Therapies: Preload Reduction: Firstly, give an IV bolus of furosemide (2 to 4 mg per kg). Ideally, this should be done via quick IV catheter placement. Obtain blood for serum creatinine and electrolytes and for PCV/TS if possible. Afterload Reduction: Secondly, give hydralazine, 0.75 mg per os. Inodilator Administration: Thirdly, administer pimobendan, 0.5mg/kg per os. Measure systolic BP: This is very helpful to guide further therapies Supplemental O2: Ancillary Tests: Record an ECG if tachycardic or arrhythmic. Tap chest if severe effusion. Repeat steps 1, 2, 4,5 hourly until respiratory rate and effort and lung crackles substantially diminish (or skip one or more treatments if hypotension occurs). Most dogs respond markedly within 4-6 hours and can be discharged on cardiac medications, to return for re-evaluation the next day."

Relationship of Plasma N-terminal Pro-brain Natriuretic Peptide Concentrations to Heart Failure Classification and Cause of Respiratory Distress in Dogs Using a 2nd Generation ELISA Assay. P.R. Fox, M.A. Oyama, M.J. Hezzell, J.E. Rush, T.P. Nguyenba, T.C. DeFrancesco,. L.B. Lehmkuhl, H.B. Kellihan, B. Bulmer, S.G. Gordon, S.M. Cunningham, J. MacGregor, R.L. Stepien, B. Lefbom, D. Adin, K. Lamb. J.Vet. Internal Medicine; Oct. 2014;29(1):171-179 . Quote: "Background: Cardiac biomarkers provide objective data that augments clinical assessment of heart disease (HD). Hypothesis/Objectives: Determine the utility of plasma N-terminal pro-brain natriuretic peptide concentration [NT-proBNP] measured by a 2nd generation canine ELISA assay to discriminate cardiac from noncardiac respiratory distress and evaluate HD severity. Animals: Client-owned dogs (n = 291) ... The most common breeds with MMVD included: Cavalier King Charles Spaniel (n = 38; 13%), ... Methods: Multicenter, cross-sectional, prospective investigation. Medical history, physical examination, echocardiography, and thoracic radiography classified 113 asymptomatic dogs (group 1, n = 39 without HD; group 2, n = 74 with HD), and 178 with respiratory distress (group 3, n = 104 respiratory disease, either with or without concurrent HD; group 4, n = 74 with congestive heart failure [CHF]). HD severity was graded using International Small Animal Cardiac Health Council (ISACHC) and ACVIM Consensus (ACVIM-HD) schemes without knowledge of [NT-proBNP] results. Receiver-operating characteristic curve analysis assessed the capacity of [NT-proBNP] to discriminate between dogs with cardiac and noncardiac respiratory distress. Multivariate general linear models containing key clinical variables tested associations between [NT-proBNP] and HD severity. Results: Plasma [NT-proBNP] (median; IQR) was higher in CHF dogs (5,110; 2,769–8,466 pmol/L) compared to those with noncardiac respiratory distress (1,287; 672–2,704 pmol/L; P < .0001). A cut-off >2,447 pmol/L discriminated CHF from noncardiac respiratory distress (81.1% sensitivity; 73.1% specificity; area under curve, 0.84). A multivariate model comprising left atrial to aortic ratio, heart rate, left ventricular diameter, end-systole, and ACVIM-HD scheme most accurately associated average plasma [NT-proBNP] with HD severity. Conclusions and Clinical Importance: Plasma [NT-proBNP] was useful for discriminating CHF from noncardiac respiratory distress. Average plasma [NT-BNP] increased significantly as a function of HD severity using the ACVIM-HD classification scheme."

Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and transforming growth factor-β (TGF-β) in advanced canine myxomatous mitral valve disease. S.G. Moesgaard, H. Aupperle, M.M. Rajamäki, T. Falk, C.E. Rasmussen, N.E. Zois, L.H. Olsen. Research in Vet. Sci. October 2014. Quote: "This study investigated mitral valve and myocardial protein and gene expression of matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and transforming growth factor-β (TGF-β) and plasma MMP and TGF-β concentrations in age-matched dog groups euthanized due to either advanced myxomatous mitral valve disease (MMVD) or other reasons. Furthermore, echocardiographic data and lumen/area ratio were correlated with tissue and plasma levels of MMPs, TIMPs and TGF-βs. Mitral valve and myocardial gene expression of MMP2, MMP14, TGF-β1 and TGF-β2 were increased and plasma MMP9 was decreased in advanced MMVD dogs. Myocardial gene expression of TIMP2 and TIMP3 were increased in advanced MMVD. All affected markers correlated to echocardiographic parameters. Significantly narrowed lumen/area ratio was associated with increased myocardial expression of MMP2, MMP14, TIMP2 and TIMP3. No differences in tissue protein expression were recorded."

Prognostic Value of Left Atrial Function in Dogs with Chronic Mitral Valvular Heart Disease. K. Nakamura, T. Osuga, K. Morishita, S. Suzuki, T. Morita, N. Yokoyama, H. Ohta, M. Yamasaki, M. Takiguchi. J.Vet. Internal Medicine. November 2014;28(6):1746-1752. Quote: "Background: A strong correlation between left atrial (LA) dysfunction and the severity of cardiac disease has been described in human patients with various cardiac diseases. The role of LA dysfunction in dogs with chronic mitral valvular heart disease (CMVHD) has not been addressed. Objectives: To investigate the correlation between LA function and the prognosis of dogs with CMVHD. Animals: Thirty-eight client-owned dogs with CMVHD. Methods: Prospective clinical cohort study. Dogs were divided into 2 groups (survivors and nonsurvivors) based on the onset of cardiac-related death within 1 year. Physical examination and echocardiographic variables were compared between the groups. For the assessment of the comparative accuracy in identifying patients with cardiac-related death, receiver operating characteristic (ROC) curves and multivariate logistic analysis were used. Results: The highest accuracy was obtained for the LA active fractional area change (LA-FACact), with an area under the ROC curve (AUC) of 0.95, followed by the left atrial to aortic root ratio (LA/Ao), with an AUC of 0.94; peak early diastolic mitral inflow velocity (E), with an AUC of 0.85; and LA total fractional area change (LA-FACtotal), with an AUC of 0.85. In the multivariate logistic regression analysis, LA-FACact emerged as the only independent correlate of cardiac-related death within 1 year (odds ratio = 1.401, P = .002). Conclusions and Clinical Importance: The findings of this study indicate that LA size and function are strongly correlated with early death in dogs with CMVHD. Although several echocardiographic parameters were significantly different between the 2 groups, LA-FACact, the parameter corresponding to the booster pump function, was the most significant independent predictor of mortality in this study. ... However, LA enlargement does not always result in its functional incompetence. During chronic MR, the left atrium enlarges in size and the LA chamber becomes more compliant. Thus, the enlarged left atrium appears to exert an important compensatory mechanism by buffering the rise in pressure in the atrium and by providing an adequate ventricular filling volume. ... Similarly, this study showed that severe MR is associated with a significant reduction in LA reservoir function. ... Active LA contraction, the booster pump function, finalizes LV filling during late diastole. It depends on LA afterload (LV compliance and end-diastolic filling pressure) and LA intrinsic contractility. In this study, impaired LA booster pump function was observed to a greater degree in nonsurvivor dogs, and it was the most significant independent predictor of mortality in this study; it may be related to the decreased LA contractility and increased LA afterload. ... In conclusion, both LA size and function are strongly correlated with the prognosis of dogs with CMVHD. Booster pump function was the most significant independent predictor of mortality in this study. The assessment of LA function can provide further insights about the pathophysiology and prognosis in dogs with CMVHD. ... Regarding both the size and function, the LA has a strong correlation with the prognosis of dogs with CMVHD. The most significant independent predictor of mortality in this study was LA-FACact."

Histological characterization of myocardial tissue from dogs affected by myxomatous mitral valve disease degeneration. Kristina Larsdotter Törnvall. Swedish Univ. of Agricultural Sciences. October 2014. Quote: "Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disease in dogs. Dogs that develop the disease are often middle aged or elderly and of small to middle sized breeds. Some breeds, like Cavalier King Charles spaniel, are sometimes affected at two to three years of age. Recent studies have identified genetic loci associated with early development of the disease. The disease is characterized by a myxomatous degeneration of the mitral valve which leads to thickening of the valves. Because of the abnormal valve morphology, blood starts leaking in to the left atrium leading to enlargement of the left heart chambers. Dilatation of the left ventricle and atrium causes changes in the myocardium. The structure of extracellular matrix changes, myocyte fiber elongate and accumulation of collagen fibers occur. Eventually the elasticity of the cardiac wall decreases and the systolic function reduce. In the end stage it is not uncommon that the dogs develop congestive heart failure due to the disease. In this study microscopic changes in the left ventricular wall have been assessed in 14 dogs [11 CKCSs] affected by MMVD and in 11 [1 CKCS, a 3-year old male] healthy control dogs. Amount of fibrosis, appearance of the myocytes, fat infiltration and size of arteries have been investigated. This study showed that dogs with MMVD had significant thicker arteries than the healthy control dogs. The analysis did not show a significant difference between affected and healthy dogs according to the amount of fat in the myocardium. The amount of fibrosis was almost statistically significant between affected dogs and control dogs, meaning that dogs with MMVD had more fibrosis. This information is important for deeper knowledge about the development of MMVD."

Myxomatous Mitral Valve Disease Research. Brendan Corcoran. November 2014. UK CKCS Club. Quote: "Valve Pathology: ... the changes in the valves of CKCSs are similar to that seen in all dogs affected with the disease. This is important as it means information gleaned from any dog with the disease can be applied to the CKCS breed with a high degree of confidence. The further implication would be that any genetic cause of CKCSs likely affects the age of onset of the disease and not the eventual pathology. Genetics: ... there are readily identifiable groups of CKCSs who do not get MMVD and another group who do later in life and remain unaffected. This suggests that MMVD in CKCSs is heterogeneous (has different forms) in the way it develops and provides a powerful model to allow us to identify the genes that drive this disease. At present we are examining, heart scanning, and collecting DNA from a large number of CKCSs across the UK. ... The material and information we have collected probably gives us the best opportunity to identify what if any is the genetic basis for MMVD in the CKCS. Genomics: We have generated a lot of useful data on the genes that are switched on and switched off in the severely affected CKCS valves. This gives us some insight into the possible mechanisms that might be driving the disease, but the problem is determining what is "cause" and what "effect" is. ... We are interested to know how the expression of these genes might change as dogs get older and as the disease becomes more severe. We have also managed to identify from this study small pieces of genetic material which might be potential new drug targets. This is part of an exciting new scientific area called epigenetics, whereby genes themselves are controlled by other factors, including other genes. If we can manipulate these factors, and there is evidence from other diseases that this is possible, then we might be able to slow progression or even reverse the changes seen. A grant application has been submitted to try and get funds to answer this question. Tissue Engineering: ... So what if we could grow our own valves in the laboratory? That is what we are trying to do and we have funding to complete work started by one of our PhD students with the aim to have a working prototype within 12 months. If successful we can ask any biological questions we want and have a limitless supply of artificial valves to help us."

Canine Acquired Heart Disease: Advances in Medical Treatment. Emily Dutton, Simon Swift. Vet. Times. 2014. Quote: "The most commonly diagnosed acquired heart disease in dogs is degenerative mitral valve disease (DMVD) with cavalier King Charles spaniels, Yorkshire terriers, miniature poodles and dachshunds being over-represented."

Associations between N-terminal procollagen type III, fibrosis and echocardiographic indices in dogs that died due to myxomatous mitral valve disease. Melanie J. Hezzell, Torkel Falk, Lisbeth Høier Olsen, Adrian Boswood, Jonathan Elliott. J. Vet. Cardiology. December 2014;16(4):257-264. Quote: "Objectives: To evaluate associations between N-terminal procollagen type III (PIIINP), a serum biomarker of collagen biosynthesis, and myocardial fibrosis in dogs with naturally-occurring myxomatous mitral valve disease (MMVD). Animals: Twenty-two dogs [including cavalier King Charles spaniels] with echocardiographically-confirmed MMVD were prospectively recruited from a hospital population. All died as a result of MMVD and their hearts were available for post mortem examination. Methods: Echocardiographic measurements and serum PIIINP concentrations were obtained from all dogs prior to death or euthanasia. Serum PIIINP concentrations (μg/mL) were measured using a validated commercially available radioimmunoassay. Myocardial tissue samples were collected post mortem and myocardial fibrosis was scored. The average fibrosis score for all cardiac sites in the heart was designated the global fibrosis score (GFS). The average fibrosis score for all papillary muscle sites was designated the papillary fibrosis score (PFS). Univariate and multivariate linear regression analyses were used separately to evaluate associations between GFS and PFS, respectively, and PIIINP and echocardiographic variables. Results: Left ventricular end-diastolic diameter normalized for body weight (LVEDDN) and PIIINP were weakly independently positively associated with both GFS and PFS. LVEDDN and PIIINP were weakly negatively correlated. Conclusions: Both LVEDDN and serum PIIINP increase with increasing fibrosis score, although these relationships were not strong enough to be clinically useful. Although LVEDDN and PIIINP were positively correlated with fibrosis, PIIINP decreased with increasing LVEDDN, suggesting a complex interplay between fibrosis and remodeling in MMVD."

Use of discriminant analysis based on echocardiography for classification of congestive heart failure in dogs with myxomatous mitral valve disease.  A. C. Silva, R. A. L. Muzzi, L. A. L. Muzzi, D. F. Ferreira, D.F., G. Oberlender, M. S. Oliveira, R. B. Nogueira,L. B. Ticle. Arquivo Brasileiro de Medicina Veterinária e Zootecnia. December 2014;66n(6):1727-1734. Quote: "Mixomatous mitral valve disease (MMVD) is one of the most common cardiac abnormalities in dogs and humans that can lead to cardiac heart failure (CHF). Its diagnosis remains based on echocardiography and clinical signs. However, the early diagnose of MMVD can contribute to a better prognosis and avoid CHF. The aim of this study was to evaluate the clinical, radiographic and echocardiographic presence of CHF in dogs with MMVD in combination with a statistical model as a mathematical tool. ... A total of 81 dogs met the inclusion criteria [none were CKCSs]. ... For this purpose, dogs were divided into three groups (healthy; MMVD without CHF; and MMVD with CHF), according the clinical, radiographic and echocardiographic evaluation findings. Thus, linear discriminant functions were obtained by analyzing the variables weight, body surface area, aortic diameter, the ratio of the left atrium/aortic diameter, the ratio between the mitral regurgitation jet area and the left atrial area, vena contracta diameter and mitral valve proximal isovelocity surface area. Then, mathematical equations were established for each group of dogs. Statistical functions obtained in this study enabled to classify the dogs, regarding the presence of CHF with a probability of correct classification of 90.4%. Thus the statistical model demonstrated that it could be used as an auxiliary method for identifying CHF in dogs with MMVD."

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2015

Myxomatous Mitral Valve Disease in Dogs - an Update and Perspectives. Aleksandra Domanjko Petrič. Macedonian Vet. Rev. Jan. 2015;38(1):i-viii. Quote: "Myxomatous mitral valve disease is a common cause of congestive heart failure in geriatric dogs. Many studies have been done in terms of epidemiology, pathology, associated neurohormonal changes in the disease progression, prognostic factors, and survival and treatment modalities. The presented paper presents a review of some of the studies in the mitral valve disease story."

Increased left heart size predicts risk of congestive heart failure in cavalier King Charles spaniels with mitral regurgitation caused by myxomatous valve disease. S. Eriksson-Palojarvi, K. Hansson, H. Duelund Pedersen, J. Haukka, J. Häggström. Vet. Int. Med. January 2015;ECVIM-CA Congress, September 2014;ESVC-O-5. Quote: "Mitral regurgitation (MR) progresses slowly, but dogs living long enough often develop congestive heart failure (CHF). However, tools to predict onset of CHF are sparse. 225 echocardiographic examinations in 78 [CKCS] dogs were performed in a longitudinal, multicenter study with a surveillance time of up to 4.5 years. Client-owned dogs were enrolled at the University Hospitals in Finland, Sweden and Denmark (subset to the SVEP study). Left ventricular end diastolic (LVIDd) and systolic (LVIDs) diameters, fractional shortening (FS), left atrial (LA) and aortic root (Ao) diameters were estimated. Values were normalized for body size (nLVIDd, nLVIDs, and nLA, respectively) and, for comparison, ratios to aortic root were calculated (LVIDd/Ao, LVIDs/Ao and LA/Ao, respectively). A Cox's proportional hazard analysis with a counting process approach was used. Spline smoothed graphical models were constructed to evaluate linearity of hazards. Curves were then used to find cut-off values for interval hazard ratios (HRs).  ... HRs for values normalized to Ao diameter behaved in a parallel way. We conclude that FS, left ventricular and atrial size may be used to predict CHF. However, because the value of a HR is dependent on the unit used and, more essentially, does not account for nonlinear change in hazard, interpretation of hazards is challenging. In contrast, interval hazards are only dependent on the reference interval used. Therefore they are easier to implement in every day clinical work."

Predictive model for the detection of pulmonary hypertension in dogs with myxomatous mitral valve disease. Shoma Mikawa, Yuichi Miyagawa, Noriko Toda, Yoshinori Tominaga, Naoyuki Takemura. J. Vet. Med. Sci. January 2015;77(1):7–13. Quote: "Pulmonary hypertension (PH) often occurs due to a left heart disease, such as myxomatous mitral valve disease (MMVD), in dogs and is diagnosed using Doppler echocardiography and estimated pulmonary arterial pressure. Diagnosis of PH in dogs requires expertise in echocardiography: however, the examination for PH is difficult to perform in a clinical setting. Thus, simple and reliable methods are required for the diagnosis of PH in dogs. The purpose of this study was to develop models using multiple logistic regression analysis to detect PH due to left heart disease in dogs with MMVD without echocardiography. The medical records of dogs with MMVD were retrospectively reviewed, and 81 dogs [10 cavalier King Charles spaniels] were included in this study and classified into PH and non-PH groups. Bivariate analysis was performed to compare all parameters between the groups, and variables with P values of <0.25 in bivariate analysis were included in multiple logistic regression analysis to develop models for the detection of PH. In multiple logistic regression analysis, the model included a vertebral heart scale short axis of >5.2 v, and a length of sternal contact of >3.3 v was considered suitable for the detection of PH. The predictive accuracy of this model (85.9%) was judged statistically adequate, and therefore, this model may be useful to screen for PH due to left heart disease in dogs with MMVD without echocardiography."

Echocardiographic predictors of survival in dogs with myxomatous mitral valve disease. Julia Sargent, Ruthnea Muzzi, Rajat Mukherjee, Sharlene Somarathne, Katherine Schranz, Hannah Stephenson, David Connolly, David Brodbelt, Virginia Luis Fuentes. J.Vet.Cardiology. March 2015:17(1):1-12. Quote: "Objectives: To evaluate vena contracta and other echocardiographic measures of myxomatous mitral valve disease (MMVD) severity in a multivariable analysis of survival in dogs. Animals: 70 dogs [including 34 cavalier King Charles spaniels] diagnosed with MMVD from stored echocardiographic images that met study inclusion criteria. Methods: Left heart dimensions were measured as well as mitral regurgitant jet area/left atrial area (JAR), early mitral filling velocity (Evel), extent of mitral valve prolapse in right and left views (ProlR, ProlL), Prol indexed to aortic diameter (ProlR:Ao, ProlL:Ao), presence of a flail leaflet (FlailR, FlailL), and mitral regurgitation vena contracta diameter (VCR, VCL) indexed to aortic diameter (VCR:Ao, VCL:Ao). Follow-up from referring veterinarians was obtained by questionnaire or telephone to determine survival times. Inter- and intra-observer agreement was evaluated with Bland–Altman plots and weighted Kappa analysis. Survival was analyzed using Kaplan–Meier curves, logrank tests and Cox's proportional hazards. Results: Logrank analysis showed VCL:Ao, VCR:Ao, FlailL, ProlR:Ao, ProlL:Ao, left ventricular internal dimension in diastole indexed to aortic diameter (LVIDD:Ao) >2.87, left atrium to aorta ratio (LA/Ao) >1.6, and Evel >1.4 m/s were predictors of cardiac mortality. In a multivariable analysis, the independent predictors of cardiac mortality were Evel >1.4 m/s [hazard ratio (HR) 5.0, 95% confidence interval (CI) 2.5–10.3], FlailL (HR 3.1, 95% CI 1.3–7.9), and ProlR:Ao (HR 2.8, 95% CI 1.3–6.3). Conclusions: Echocardiographic measures of mitral regurgitation severity and mitral valve pathology provide valuable prognostic information independent of chamber enlargement in dogs with MMVD."

Polymorphisms in the canine and feline renin–angiotensin–aldosterone system genes. Kathryn M. Meurs, Lhoucine Chdid, Yamir Reina-Doreste, Joshua A. Stern. Anim. Genet. January 2015;46:224–226. Quote: We hypothesized that polymorphisms may exist in the canine and feline RAAS genes. The objective of this study was to evaluate canine and feline DNA samples for the presence of common RAAS gene polymorphisms observed in human beings. Methods: DNA samples from 15 cats of five breeds and 15 dogs of three breeds (... Cavalier King Charles Spaniel) were evaluated. Genomic DNA samples were prepared from whole blood samples. Results/conclusions: Polymorphisms were identified in the majority of animals evaluated. Most of the polymorphisms were single base pair variants although two deletions were observed in intron 16 of the feline ACE gene. Four polymorphisms changed an amino acid, but all were predicted to be benign changes based on the POLYPHEN-2 analysis. No variants were shared between species, and no previously reported human RAAS gene polymorphisms were identified. Although polymorphisms were identified, the functional importance of these changes has yet to be determined. Characterizing the significance of these polymorphisms will require additional functional and clinical studies. Nonetheless, the RAAS genes of dogs and cats are polymorphic, and further studies to evaluate the functional importance of the polymorphisms observed are warranted.

Usefulness of Conventional and Tissue Doppler Echocardiography to Predict Congestive Heart Failure in Dogs with Myxomatous Mitral Valve Disease. J.-H. Kim. H.-M. Park. J. Vet. Internal Medicine. January 2015;29(1):132-140. Quote: "Background: Systolic and diastolic functions have been evaluated to predict outcome in congestive heart failure (CHF). Recently, tissue Doppler imaging (TDI) has become useful for the estimation of myocardial function in cardiac diseases of humans and animals. Objective: This study was designed to assess whether myocardial function as assessed by TDI is associated with the occurrence of CHF in dogs with myxomatous mitral valve disease (MMVD) and whether additional information is gained over conventional Doppler variables. Animals: Forty-one privately owned dogs (15 healthy dogs and 26 dogs with MMVD [none were CKCSs]) were included. Dogs with MMVD were divided into non-CHF (n = 10) and CHF groups (n = 16). Methods: Conventional echocardiographic examinations were performed. In addition, TDI-derived variables, including radial and longitudinal velocities, strain, and strain rate were assessed. Results: Several (12 of 47, 26%) conventional and tissue Doppler echocardiography variables were significant predictors of CHF in a univariate analysis (P < .05). However, TDI-derived E/Em sept was the only load-independent significant predictor of CHF (P < .05) after multivariate logistic regression analysis. The E/Em sept cut-off value of >18.7 had a sensitivity of 56% and specificity of 90% in predicting CHF in dogs with MMVD. Conclusions and Clinical Importance: The combination of TDI of the mitral annulus and mitral inflow velocity provided better estimates of diastolic dysfunction in dogs with MMVD and CHF. Additional study is warranted to assess TDI-derived E/Em sept, an index of diastolic function that could contribute to the management of dogs with MMVD and CHF."

Canine Pancreatic-Specific Lipase Concentrations in Dogs with Heart Failure and Chronic Mitral Valvular Insufficiency. D. Han, R. Choi, C. Hyun. J. Vet. Internal Medicine. January 2015;29(1);180-183. Quote: "Background: Chronic mitral valvular insufficiency (CMVI) in dogs is very common and might cause clinical signs of congestion and poor tissue perfusion. Hypothesis: Poor tissue perfusion from CMVI causes pancreatitis in dogs, as indicated by serum pancreatic lipase concentrations. Animals: Sixty-two client-owned dogs consisting of 40 dogs [none were cavalier King Charles spaniels] with different stages of heart failure from CMVI and 22 age-matched healthy dogs, based on full cardiac exam and routine laboratory tests. Methods: Prospective, controlled, observational study. Serum canine pancreatic lipase immunoreactivity (cPLI) concentrations were determined by quantitative cPLI test in healthy and CMVI groups. Results: Serum cPLI concentrations were 54.0 μg/L (IQR: 38.0–78.8 μg/L) in control, 55.0 μg/L (IQR: 38.3–88.8 μg/L) in ISACHC I, 115.0 μg/L (IQR: 45.0–179.0 μg/L) in ISACHC II and 223.0 μg/L (IQR: 119.5–817.5 μg/L) in ISACHC III. Close correlation to serum cPLI concentration was found in the left atrial to aorta (LA/Ao) ratio (r = 0.597; P = .000) and the severity of heart failure (r = 0.530; P = .000). Conclusions and Clinical Importance: ... This study clearly found the increase in cPL in dogs with advanced heart failure, suggesting that the risk of pancreatitis might be increased with the worsening of heart failure signs in dogs. ... This study found CMVI is associated with pancreatic injury in congestive heart failure caused by CMVI. ... There were several limitations to this study. First, the study population was small and may not have provided sufficient statistical power to adequately reflect the correlation of cPLI to the severity of heart failure in CMVI dogs. Second, the influence on renal dysfunction by cardiac medication and/or heart failure was not assessed in our study population and diminished renal clearance can cause the increase in cPLI in dog with more advanced stage of heart failure. Thirdly, many dogs diagnosed as pancreatitis by cPLI test have never been confirmed by the histopathological exam, although the diagnostic value of the cPLI on pancreatitis has been clearly proven in dogs.[13, 14] Fourthly, the dogs showing subclinical pancreatitis were not more carefully assessed for malassimilation, yet maldigestion and malabsorption are known to occur in dogs with advanced stages of heart failure.[18] Finally, we did not demonstrate the presence of gastrointestinal findings with increased serum PLI concentrations, thereby weakening any conclusions that clinical pancreatitis may arise as a complication of heart failure in dogs with CMVI. Despite these study limitations, our study results clearly suggest that the increased serum PLI concentration, to levels accepted as indicating pancreatitis, is a common comorbidity with congestive heart failure. Therefore, regular check-up for serum PLI level is warranted for early detection of pancreatitis from chronic heart diseases."

Listen to the sound: what is normal? Sonja Fonfara. J. Small Animal Practice. January 2015;56(2):75-76.

Culture and characterisation of canine mitral valve interstitial and endothelial cells. M.-M. Liu, T.C. Flanagan, C-C. Lu, A.T. French, D.J. Argyle, B.M. Corcoran. Vet, J. January 2015. Quote: "Valve interstitial cells (VICs) have an important role in the aetiopathogenesis of myxomatous mitral valve disease (MMVD) in the dog. Furthermore, there is evidence that valve endothelial cells (VECs) also contribute to disease development. In addition to examining native valve tissue to understand MMVD, another strategy is to separately examine VIC and VEC biology under in vitro culture conditions. The aim of this study was to isolate and characterise canine mitral VICs and VECs from normal dog valves using a combination of morphology, immunohistochemistry and reverse transcription PCR (RT-PCR)."

Carvedilol Effects on ECG and Heart Fractional Shortening in Dog. Mahyar Yasari, Ali Namvaran-Abbas-Abad, Seyed Ali Shabestari Asl, Gholam Reza Asad Nasab, Navid Saranjam. Advances in Bioresearch. January 2015;6(1):141-149. Quote: "Carvedilol is non-selective beta blocker/alpha-1 blocker indicated for hypertension and cardiomyopathy treatment in humans. Despite numerous studies on effects of carvedilol in medical practice, there is a little information available for small animal medicine. The aim of this study was to evaluate carvedilol therapy on the electrocardiogram and fractional shortening in dogs.In this study, nine stray dogs with heart disease were involved. After preparation, ECG and fractional shortening was obtained and any abnormalities in cardiac conductive system and fractional shortening were determined. 3 hours after carvedilol (0.75 mg.kg-1 BW) administration, electrocardiography was taken and for assessment of fractional shortening ultrasound examination was performed immediately after admission ECG. A week after initial administration, the dogs were treated with 1.5 mg.kg-1 (High normal dose) and 3 mg.kg-1 (Toxic dose) of carvedilol and tested with electrocardiogaraphy and fractional shortening. The results indicated that in all dogs the drug reduced fractional shortening and also caused first degree block and sinus arrest. Nevertheless, the results of ECG just had a negative effect on heart rate. According to results it seems this medication can be used to treat dogs with acute hypertension, but nonetheless it is felt using of this drug requires further evaluation in long-term."

The challenges of pedigree dog health: approaches to combating inherited disease. Lindsay L Farrell, Jeffrey J Schoenebeck, Pamela Wiener, Dylan N Clements, Kim M Summers. Canine Genetics & Epidemiology. February 2015;2(3):1-14. Quote: "The issue of inherited disorders and poor health in pedigree dogs has been widely discussed in recent years. With the advent of genome-wide sequencing technologies and the increasing development of new diagnostic DNA disease tests, the full extent and prevalence of inherited disorders in pedigree dogs is now being realized. In this review we discuss the challenges facing pedigree dog breeds: the common pitfalls and problems associated with combating single gene mediated disorders, phenotypic selection on complex disorders, and ways of managing genetic diversity. ... The Cavalier King Charles Spaniel (CKCS) breed is susceptible to 25 inherited disorders, the most common of which is early-onset myxomatous mitral valve disease (MMVD). In a 2004 survey, 42.8% of all UK CKCS died due to cardiac causes and there is increasing evidence that CKCS mitral valve disease is genetic in origin, with a heritability of between 0.33 and 0.67. ... Breeding strategies incorporating screening schemes have been shown to be successful in significantly reducing the prevalence of an inherited disorder and improving the overall health in certain breeds. However, with 215 breeds officially recognized by the Kennel Club in the United Kingdom and 396 inherited disorders currently identified, many breeds have reached the point at which successfully breeding away from susceptible individuals at a population-wide scale will require new genomic selection strategies in combination with currently available breeding schemes. Whilst DNA-based tests identifying disease causing mutation(s) remain the most informative and effective approach for single gene disorder disease management, they must be used along with current screening schemes, genomic selection, and pedigree information in breeding programs in the effort to maintain genetic diversity while also significantly reducing the number of inherited disorders in pedigree dogs."

Transcatheter Mitral Valve Therapies. E. Christopher Orton. Chapter 56 of Veterinary Image-Guided Interventions. Editors Chick Weisse, Allyson Berent. John Wiley & Sons, Ltd, Oxford. February 2015. Quote: "Degenerative mitral regurgitation (MR) is widely regarded as the most important acquired heart disease in dogs. Several devices are under development for indirect transcatheter mitral annuloplasty. All exploit the proximity of the coronary sinus and great cardiac vein to the mitral annulus and are designed to apply circumferential traction on the mitral annulus via the great cardiac vein. Transcatheter mitral repair is based on the edge-to-edge technique for open mitral valve repair. Development of transcatheter mitral valve implantation (TMVI) is based upon the success the Sapien device, which is approved for transcatheter aortic valve implantation (TAVI) in humans. The Sapien device employs a bioprosthetic valve in a ductal stent that can be deployed into a calcified stenotic aortic valve. The MitralSeal device (Avalon Medical) is being developed specifically for TMVI in dogs. The device is a bioprosthetic valve mounted within a self-expanding Nitinol stent."

Effects of castration on cortisol and serotonin levels in dogs: Correlations between hormones and behavior. Elin Larsson. Swedish Univ. of Ag. Sciences. February 2015. Quote: "How behavior in dogs is affected by castration is unclear but there are increasing numbers of castrated dogs in Sweden and a common reason for castration is the owner hoping for behavioral problems to decrease. To study if the concentrations of behaviorally associated hormones are changing after castration and if the changes correlates with alteration in behavior may contribute to more knowledge about how castration affect dogs. In this study, seven bitches and three male dogs [including a male cavalier King Charles spaniel] were studied before and until four weeks after castration by analyzing cortisol and serotonin levels in urinary samples and through behavioral questionnaires to the dog owners. Cortisol is an important stress hormone and the serotonin system is largely involved in mental well-being. Creatinine was also analyzed in purpose of calculating hormone levels as hormone and creatinine concentration ratios, to minimize urinary density affecting the hormone levels. The females had significantly lower cortisol levels after castration than before. Among the bitches, the serotonin levels tended to increase after castration. The male dogs were few in number and no obvious changes in hormone levels were shown. It was not possible to see any clear behavioral changes but the bitches showed tendencies to be more active, more playful and more willing to be close to their owners. In order to draw reliable conclusions about effects of castration on hormone levels in dogs and if there is connection with any changes in behavior, more studies with larger numbers of dogs and more detailed behavioral studies are needed. It would also be interesting to study hormone levels and behavior during a longer period of time after castration."

Genetic causality of dogs cardiovascular diseases. O.S. Koshtura, S. A. Kostenko, M. A. Kravchenka. National Univ. of Life & Environmental Sci. of Ukraine. February 2015. Quote: "The purpose of the work was to study the mechanisms of genetic conditions diseases of the cardiovascular system in dogs.  ... The highest disease susceptibility was observed in dogs breed Cavalier King Charles Spaniel. Polygenic inheritance is supposed influence of gender and age. ... Mutations in the gene IGF1 [insulin-like growth factor-1] is a major cause of decline in body size in dogs, if the heart is not reduced to the same scale as small dogs, this one mutation may be responsible for the excessive compression that leads to vice valve. In addition, IGF1 has a direct impact on the growth of the heart, which could cause a defect in the selection of small breeds. ... We considered various mechanisms to explain the excess of small and dwarf breeds in the list of those who have the greatest risk. One possible cause of heart disease can be that small dogs have more heart in relation to body size than large dogs. This can be checked by measuring the size of the heart and overall body size, including the volume of the chest dogs of different sizes to determine whether there is a significant difference in relation to small breeds. ...  Conclusions: 1. Endokardiosis of mitral valve is the most common cardiac violations in dogs, especially small breeds. 2. Cardiovascular disease dogs of small breeds may be due to a mutation of the gene IGF1, which is one of the main reasons for the decline in body size in dogs. If the heart is not reduced to the same scale as small dogs, this one mutation may be responsible for excessive compression, which leads to vice valve. 3. Distribution endokardiosis of mitral valve may be due to the fact that mutations that cause it emerged in areas closely linked to the gene candidate small dogs STC2, which has a selective value. Since this gene closely linked site NKX2 -5, in which mutations associated with multiple congenital heart defects."

Mitral valve repair due to severe DMVD in a 6-year old Cavalier King Charles Spaniel: Our Case Of The Month February 2015. Mitral Valve Surgery by Dr. Peter ModlerPeter Modler. SonoPath.com. February 2015. Quote: "History: A 6-year-old MN Cavalier King Charles Spaniel was referred for mitral valve repair because of severe DMVD. At that time he was already on Pimobendan, Furosemide (12 mg/kg/d) and ACEI. He presented with increased respiratory effort and mild pulmonary edema. ... Outcome: Because of his rapid deterioration and the poor prognosis with medical therapy alone, mitral valve repair under CPB was discussed with the owners. Even though the prognosis was guarded given the marked systolic dysfunction (large enddiastolic diameter in the face of severe volume overload, FS 38%, hyperkinesia of the septum, severe hypokinesia of the free wall) the owners decided for the surgery. The procedure was scheduled four weeks later. In the mean time Pimobendan was increased to tid, and Spironolactone was added. On the day of surgery, Henri still had some degree of pulmonary edema. Thus, Torasemide was given 6 hrs before surgery. Systolic dysfunction had increased and some ventricular runs were noted on the Sono-ECG. Open heart mitral valve repair was performed (mitral annuloplasty, chordal replacement with Gore-Tex) on cardiopulmonary bypass (right). Cross-Clamp time was 85 min. After clamp removal and electrical defibrillation the heart started spontaneously in a sinus rhythm and blood pressure was immediately restored. The patient woke up 5 hrs after surgery and was able to walk a short distance after 7 hrs. He is now doing quite well, starts eating and walks around in the yard. The mitral valve coadaption has increased with mild residual regurgitation. Systolic function is markedly impaired but is improving day to day. Comments: 'The prognosis for this patient is still guarded given the number of possible complications and the fact that it is uncertain if systolic function will improve. Still, for the population of dogs suffering from MMVD it might be a step in the right direction. Ideally, this surgery should be done in dogs at high risk of rapid progression and before systolic dysfunction begins. Increasing surgical experience will hopefully enable us to optimise mitral leaflet coadaption and improve long time survivial." Peter Modler DVM, Dipl.-Tzt."

Gene network and canonical pathway analysis in canine myxomatous mitral valve disease: a microarray study. C-C Lu, M-M Liu, G Culshaw, M Clinton, D A Argyle, B M Corcoran. Vet. J. April 2015;204(1):23-31. Quote: "Myxomatous mitral valve disease (MMVD) is the single most common acquired heart disease of the dog and is particularly common in small pedigree breed dogs such as the Cavalier King Charles spaniel (CKCS). There are limited data on the mitral valve transcriptome and the aim of this study was to use the microarray technology in conjunction with bioinformatics platforms to analyse transcript changes in MMVD in CKCS compared to normal dogs (non-CKCS). Differentially expressed genes (n = 5397) were identified using cut-off settings of fold change, false discovery rate (FDR) and P < 0.05. In total, 4002 genes were annotated to a specific transcript in the Affymetrix canine database, and after further filtering, 591 annotated canine genes were identified: 322 (55%) were up-regulated and 269 (45%) were down-regulated. Canine microRNAs (cfa-miR; n = 59) were also identified. Gene ontology and network analysis platforms identified between 6 and 10 significantly different biological function clusters from which the following were selected as relevant to MMVD: inflammation, cell movement, cardiovascular development, extracellular matrix organisation and epithelial-to-mesenchymal (EMT) transition. Ingenuity pathway analysis identified three canonical pathways relevant to MMVD: caveolar-mediated endocytosis, remodelling of epithelial adherens junctions, and endothelin-1 signalling. Considering the biological relevance to MMVD, the gene families of importance with significant difference between groups included collagens, ADAMTS peptidases, proteoglycans, matrix metalloproteinases (MMPs) and their inhibitors, basement membrane components, cathepsin S, integrins, tight junction cell adhesion proteins, cadherins, other matrix-associated proteins, and members of the serotonin (5-HT)/transforming growth factor -β signalling pathway."

Evaluation of Plasma D-Dimer Concentration in Dogs with Chronic Mitral Valve Insufficiency. Joungsoon Park, Sang-IL Suh, Yeonsu Oh, Changbaig Hyun. J. Vet. Clinics. March 2015;32(1):5-8. Quote: "D-dimer is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. D-dimer concentration is widely used for determining thrombosis and thromboembolism. Because one major cause of thromboembolism is congestive heart failure in humans, we investigated the degree and risk of thromboembolism in dogs with different stages of congestive heart failure caused by chronic mitral valvular insufficiency (CMVI). The plasma level of d-dimer was evaluated in 20 healthy dogs and 30 dogs with different stages of congestive heart failure caused by CMVI. The d-dimer concentrations were measured by a commercialized assay kit. The plasma levels of d-dimer were not significantly different between healthy and CMVI dogs. Furthermore, there was no association of d-dimer concentrations to left atrium to aorta (LA/Ao) ratio, left ventricular dimension at diastole to aorta (LVIDd/Ao) ratio and severity of heart failure in our study population. Our study results implied that the degree of thromboembolism in canine heart failure might be minimal or the plasma d-dimer test might not be reliable for detecting thromboembolism in dogs."

The effect of enalapril on furosemide-activated renin–angiotensin–aldosterone system in healthy dogs. A. C. Lantis, M. K. Ames, S. Werre, C. E. Atkins. J. Vet. Pharmacology & Therapeutics. March 2015. Quote: "Studies in our laboratory have revealed that furosemide-induced RAAS activation, evaluated via the urine aldosterone-to-creatinine ratio (UAldo:C), was not attenuated by the coadministration of benazepril, while enalapril successfully suppressed amlodipine-induced urinary aldosterone excretion. This study was designed to evaluate the efficacy of enalapril in suppressing ACE activity and furosemide-induced circulating RAAS activation. Failure to do so would suggest that this failure may be a drug class effect. We hypothesized that enalapril would suppress ACE activity and furosemide-induced circulating RAAS activation. Sixteen healthy hound dogs. The effect of furosemide (2 mg/kg PO, q12 h; Group F) and furosemide plus enalapril (0.5 mg/kg PO, q12 h; Group FE) on circulating RAAS was determined by plasma ACE activity, 4–6 h post-treatment, and urinary A:C on days −1, −2, 1, 4, and 7. There was a significant increase in the average urine aldosterone-to-creatinine ratio (UAldo:C) after administration of furosemide (P < 0.05). Enalapril inhibited ACE activity (P < 0.0001) but did not significantly reduce aldosterone excretion. A significant (P < 0.05) increase in the UAldo:C was maintained for the 7 days of the study in both groups. Enalapril decreased plasma ACE activity; however, it did not suppress furosemide-induced RAAS activation, as determined by the UAldo:C. While enalapril blunts ACE activity, the absence of circulating RAAS suppression may be due to angiotensin II reactivation, alternative RAAS pathways, and furosemide overriding concurrent ACE inhibition, all indicating the existence of aldosterone breakthrough (ABT). Along with similar findings with benazepril, it appears that failure to suppress aldosterone suppression with furosemide stimulation may be a drug class effect. The discrepancy between the current data and the documented benefits of enalapril likely reflects the efficacy of this ACE inhibitor in suppressing tissue RAAS, variable population responsiveness to ACE-inhibition, and/or providing additional survival benefits, possibly through as yet unknown mechanisms."

Prevalence and Prognostic Importance of Pulmonary Hypertension in Dogs with Myxomatous Mitral Valve Disease. M. Borgarelli, J. Abbott, L. Braz-Ruivo, D. Chiavegato, S. Crosara, K. Lamb, I. Ljungvall, M. Poggi, R.A. Santilli and J. Haggstrom. J. Vet. Int. Med. March 2015;29(2):569-574. Quote: "Background: Pulmonary hypertension (PH) is common in dogs with myxomatous mitral valve disease (MMVD) but its effect on clinical outcome has not been investigated. Hypothesis/objectives: The presence of PH worsens the outcome in dogs with MMVD. To compare survival times of dogs with MMVD and PH to those without PH. Animals: Two hundred and twelve client-owned dogs [including 30 cavalier King Charles spaniels]. Methods: Case review study. Medical records of dogs diagnosed with ACVIM stage B2 and C MMVD between January 2010 and December 2011 were retrospectively reviewed. Long-term outcome was determined by telephone interview or from the medical record. End of the observation period was March 2013. PH was identified if tricuspid regurgitation peak velocity was >3 m/s. Results: Two hundred and twelve were identified. Eighty-three dogs (39%) had PH. PH was more commonly identified in stage C compared to B2 (P < .0001). One hundred and five (49.5%) dogs died during the observation period. Median survival time for the entire study population was 567 days (95% CI 512–743). Stage C (P = .003), the presence of PH (P = .009), left atrial to aortic root ratio (LA/Ao) >1.7 (P = .0002), normalized left-ventricular end-diastolic diameter (LVEDn) >1.73 (P = .048), and tricuspid regurgitation pressure gradient (TRPG) >55 mmHg (P = .009) were associated with worse outcomes in the univariate analyses. The presence of TRPG >55 mmHg (HR 1.8 95% CI 1–2.9; P = .05) and LA/Ao > 1.7 (HR 2 95% CI 1.2–3.4; P = .01) remained significant predictors of worse outcome in the multivariate analysis. Conclusions and Clinical Importance: In dogs with MMVD, moderate to severe PH worsens outcome."

Stage-dependent benefits and risks of pimobendan in mice with genetic dilated cardiomyopathy and progressive heart failure. Miki Nonaka, Sachio Morimoto, Takashi Murayama, Nagomi Kurebayashi, Lei Li, Yuan-Yuan Wang, Masaki Arioka, Tatsuya Yoshihara, Fumi Takahashi-Yanaga and Toshiyuki Sasaguri. British J. of Pharmacology. March 2015. Quote: "Background and Purpose: The Ca2+ sensitizer pimobendan is a unique inotropic agent that improves cardiac contractility with less of an increase in oxygen consumption and potentially fewer adverse effects on myocardial remodelling and arrhythmia, compared with traditional inotropes. However, clinical trials report contradictory effects of pimobendan in patients with heart failure (HF). We provide mechanistic experimental evidence of the efficacy of pimobendan using a novel mouse model of progressive HF. Experimental Approach: A knock-in mouse model of human genetic dilated cardiomyopathy, which shows a clear transition from compensatory to end-stage HF at a fixed time during growth, was used to evaluate the efficacy of pimobendan and explore the underlying molecular and cellular mechanisms. Key Results: Pimobendan prevented myocardial remodelling in compensated HF and significantly extended life span in both compensated and end-stage HF, but dose-dependently increased sudden death in end-stage HF. In cardiomyocytes isolated from end-stage HF mice, pimobendan induced triggered activity probably because of early or delayed afterdepolarizations. The L-type Ca2+ channel blocker verapamil decreased the incidence of triggered activity, suggesting that this was from over-elevated cytoplasmic Ca2+ through increased Ca2+ entry by PDE3 inhibition under diminished sarcoplasmic reticulum Ca2+ reuptake and increased Ca2+ leakage from sarcoplasmic reticulum in end-stage HF. Conclusions and Implications: Pimobendan was beneficial regardless of HF stage, but increased sudden cardiac death in end-stage HF with extensive remodelling of Ca2+ handling. Reduction of cytoplasmic Ca2+ elevated by PDE3 inhibition might decrease this risk of sudden cardiac death."

Alpha-Smooth Muscle Actin and Serotonin Receptors 2A and 2B in Dogs with Myxomatous Mitral Valve Disease. S.E. Cremer, S.G. Moesgaard, C.E. Rasmussen, N.E. Zois, T. Falk, M.J. Reimann, S. Cirera, H. Aupperle, M.A. Oyama, L.H. Olsen. Research in Vet. Sci. June 2015;100:197-206. Quote: "Canine Myxomatous mitral valve disease (MMVD) is an age-related disease. Serotonin (5-HT) is implicated in the pathogenesis as locally-produced or platelet-derived. Involvement of the 5-HT2A receptor (R) and 5-HT2BR in the induction of myxomatous-mediating valvular myofibroblasts (MF) has been suggested. In an age-matched population of dogs with non-clinical and clinical MMVD, the objectives were to investigate 1) gene expression of 5-HT2AR and 5-HT2BR, 2) protein expression and spatial relationship of 5-HT2AR, 5-HT2BR and MF in the mitral valve (MV) and the cardiac anterior papillary muscle (AP) and 3) serum 5-HT concentrations. Gene expression of 5-HT2BR was significantly higher in MV and AP among dogs with clinical MMVD. This was not found for 5-HT2BR protein expression, though association of 5-HT2BR with myxomatous pathology and co-localization of 5-HT2BR and MF in MV and AP support a functional relationship, perhaps perpetuation of clinical MMVD. 5-HT2AR-expression and serum 5-HT showed no differences between groups."

Clinical Severity Score System in Dogs with Degenerative Mitral Valve Disease. J. López-Alvarez, J. Elliott, D. Pfeiffer, Y.-M. Chang, M. Mattin, W. Moonarmart, M.J. Hezzell, A. Boswood. J. Vet. Int. Med. March 2015;29(2):575-581. Quote: "Background: Several risk factors already have been determined for dogs with degenerative mitral valve disease (DMVD). Risk factors often have been considered in isolation and have not always taken into account additional information provided by the history and physical examination (PE). Hypothesis/Objectives: Data obtained from history and PE of dogs with DMVD provide prognostic information and can be used for risk stratification. Animals: Client-owned dogs (n = 244) with DMVD [including 97 cavalier King Charles spaniels] recruited from first opinion practice. Methods: Prospective longitudinal follow-up of dogs with DMVD. History and PE data were obtained at 6-month intervals and analyzed with time-dependent Cox models to derive relative risk of cardiac death. Independent hazard ratios were used to derive a clinical severity score (CSS), the prognostic value of which was evaluated by analyzing the median survival times for different risk groups and ROC analysis. Analysis of the progression of CSS over time also was undertaken. Results: History of cough, exercise intolerance, decreased appetite, breathlessness (difficulty breathing) and syncope with PE findings of heart murmur intensity louder than III/VI and absence of respiratory sinus arrhythmia were independently associated with outcome and allowed development of the CSS. ... The findings support our original hypothesis. Several commonly observed historical and clinical findings in dogs with DMVD are independently predictive of a worse outcome. Affected dogs that die of their disease show a progressively higher number of these signs as their disease progresses, and finding several of these signs in combination is much more strongly predictive of a worse outcome than any individual sign in isolation. ... Clinical severity score distinguished groups of dogs with significantly different outcomes. Conclusions and Clinical Importance: Routinely obtained clinical findings allow risk stratification of dogs with DMVD. Results of ancillary diagnostic tests may be complementary to history and PE findings and always should be interpreted in conjunction with these findings."

Chronic valvular disease in dogs. Rebecca L. Stepien. IVIS Vet. Focus. March 2015;25(1):3-12. Quote: "CVD is a disease of middle-aged to older dogs, although earlier onset has been noted in some breeds (e.g., Cavalier King Charles spaniels). Although the etiology has not been ascertained in most dogs, a genetic tendency toward development of CVD has been proven in Cavalier King Charles Spaniels and Dachshunds, and a genetic basis for at least some of the changes noted is suspected in other breeds. ... 'Endocardiosis', 'myxomatous valve disease', and 'degenerative valve disease' are all terms used to describe chronic valvular disease in dogs, which is the commonest acquired canine heart disease. Use of the ACVIM classification system allows staging of the degree of heart disease and development of a treatment plan. Taking resting respiratory rates at home is an important method for monitoring chronic valve disease patients. Treatment of first-time congestive heart failure due to chronic valvular disease usually consists of 'triple therapy': furosemide, pimobendan, and an angiotensin-converting enzyme inhibitor. ... ACVIM Stage B2 heart disease: When cardiomegaly is severe and CHF seems likely in the near future, the author typically recommends initiation of angiotensin-converting enzyme inhibitor (ACEI) therapy. In patients with cough due to cardiomegaly, ACEI therapy, antitussive therapy (e.g., butorphanol) or a combination of the two may be used. Currently there is no proven benefit to routine initiation of pimobendan therapy at this stage."

Prevalence of and Risk Factors for Degenerative Mitral Valve Disease in Dogs Attending Primary-care Veterinary Practices in England. M.J. Mattin, A. Boswood, D.B. Church, J. López-Alvarez, P.D. McGreevy, D.G. O'Neill, P.C. Thomson, D.C. Brodbelt. J. Vet. Int. Med. May 2015;29(3):847-854. Quote: "Background: To date, epidemiological studies on degenerative mitral valve disease (DMVD) in dogs have largely reported referral caseloads or been limited to predisposed breeds. Analysis of primary-care data to identify factors associated with DMVD would help clinicians identify high-risk individuals and improve understanding. Objectives: To estimate the prevalence of and identify risk factors for DMVD in dogs attending primary-care veterinary practices in England. Animals: Cases were identified within the electronic patient records of 111,967 dogs attending 93 practices. Four hundred and 5 dogs were diagnosed with DMVD (diagnosed cases) [The breeds most frequently diagnosed with DMVD were CKCS (n = 131, 32.4% of dogs with diagnosed DMVD), crossbreds (n = 45, 11.1%), Yorkshire Terriers (n = 25, 6.2%), and Jack Russell Terriers (n = 22, 5.4%).] and a further 3,557 dogs had a heart murmur (HM) consistent with DMVD (possible cases) [The most frequently diagnosed breeds were crossbred dogs (n = 677, 17.1%), CKCS (n = 657, 16.6%), Jack Russell Terriers (n = 322, 8.1%), and Yorkshire Terriers (n = 215, 5.4%).]. ... In the multivariable analysis, males had higher odds of diagnosed DMVD than did females (odds ratio [OR] 1.40, 95% CI: 1.12–1.74). Insured dogs had increased odds of DMVD compared with noninsured dogs (OR 3.56, 95% CI: 2.79–4.55) and dogs ≥20 kg had approximately half the odds of DMVD diagnosis compared with dogs <20 kg (OR 0.51, 95% CI: 0.36–0.74). Strong associations between a DMVD diagnosis and individual breeds and age were identified. ... The data support our hypothesis that CKCS and Poodles have among the highest odds of DMVD. ... the models for both diagnosed DMVD and HM cases identified that CKCS, King Charles Spaniels, Chihuahuas, Whippets, Poodles, and Shih Tzus are predisposed to DMVD. ... Conclusions and Clinical Importance: Degenerative mitral valve disease was a common disorder in practice-attending dogs. Knowledge of identified risk factors for DMVD could improve clinical diagnosis and direct future research."

Prevalence of disorders recorded in Cavalier King Charles Spaniels attending primary-care veterinary practices in England. Jennifer F Summers, Dan G O’Neill, David B Church, Peter C Thomson, Paul D McGreevy, David C Brodbelt. Canine Genetics and Epidemiology. April 2015;2:4. Quote: "This study used large volumes of health data from UK primary-care practices participating in the VetCompass animal health surveillance project to evaluate in detail the disorders diagnosed in a random selection of over 50% of dogs recorded as Cavalier King Charles Spaniels (CKCSs). Confirmation of breed using available microchip and Kennel Club (KC) registration data was attempted. Results: In total, 3624 dogs were recorded as CKCSs within the VetCompass database of which 143 (3.9%) were confirmed as KC-registered via microchip identification linkage of VetCompass to the KC database. ...  Microchip data were available in 1692 (46.7%) of the 3624 identified CKCSs. It was possible to crosslink microchip data with KC-registration details in 143 of these dogs; this represented 8.5% of all identified CKCSs with microchip data, and 3.9% of all identified CKCSs. The remaining 3481 dogs were classified as of unknown KC-registration status. The 52% randomly selected sample of all identified CKCSs totalled 1875 dogs: 1800 with unknown and 75 with confirmed KC-registration status. These 1875 dogs were seen at 109 individual clinics during the study period, including 90 (83%) Medivet and 19 (17%) Vets4Pets sites located from north-east to southern England.  ...1875 dogs (75 KC registered and 1800 of unknown KC status, 52% of both groups) were randomly sampled for detailed clinical review. Clinical data associated with veterinary care were recorded in 1749 (93.3%) of these dogs. ... Median ages at first and last consultation were 4.0 and 5.25 years, respectively (ranges one month - 17.2 years for both age measures). The most frequent coat colours were Blenheim (44.3%) and tri-colour (30.8%) (Table 1). Of the 1521 dogs with more than one clinical data entry, median time contributed to the study was 1.3 years (range 1 day to 3.6 years).  ... The most common specific disorders recorded during the study period were heart murmur (541 dogs, representing 30.9% of study group), diarrhoea of unspecified cause (193 dogs, 11.0%), dental disease (166 dogs, 9.5%), otitis externa (161, 9.2%), conjunctivitis (131, 7.4%) and anal sac infection (129, 7.4%). The five most common disorder categories were cardiac (affecting 31.7% of dogs), dermatological (22.2%), ocular (20.6%) [The largest group of ocular disorders were corneal diseases (43%), with unspecified corneal problems and KCS most frequently recorded.], gastrointestinal (19.3%) and dental/periodontal disorders (15.2%). Discussion and conclusions: Study findings suggest that many of the disorders commonly affecting CKCSs are largely similar to those affecting the general dog population presented for primary veterinary care in the UK. However, cardiac disease (and MVD in particular) continues to be of particular concern in this breed. ... Far fewer KC registered dogs had reported murmurs compared to dogs of unknown registration status. It is possible that this finding reflects a genuinely lower prevalence of murmurs (and by implication existing or developing heart disease) in KC-registered CKCSs. Bias could have also been introduced (in either direction) by the comparative willingness of breeders to screen for heart murmurs in animals intended to produce puppies for KC registration, but it was not possible to explore this finding using the study data available.  ... Further work This work highlights the value of veterinary practice based breed-specific epidemiological studies to provide targeted and evidence-based health policies. Further studies using electronic patient records in other breeds could highlight their potential disease predispositions."

Variation in the management of congestive cardiac failure in dogs. T. Davies, S. Everitt, M. Cobb. Vet. Rec. April 25, 2015. Table 1Quote: "Given the multiple therapeutic options for the management of CCF in the dog and the evidence available to support their use, the purpose of this study was to investigate the decisions made with reference to the management of CCF caused by both canine degenerative valve disease (CDVD) and dilated cardiomyopathy (DCM) in the dog in the UK. ... The questionnaire was written in the style of clinical vignettes, two short clinical cases describing dogs with CCF, one on each page; the first case was based on a dog with CDVD* ... The following four identical questions were asked about the management of each case: 1. Which drugs, if any, would you prescribe for this case? 2. Would you make any other recommendations regarding management of the case? 3. Would you carry out any further investigations to diagnose or treat this case? 4. When would you want to see this case again? In total, 65 of 604 questionnaires were returned (11 per cent), of which 9 questionnaires could not be analysed; 56 questionnaires were therefore analysed. ... In total, 37 vets (66 per cent) would see case 1 within seven days. ... The final response rate (11 per cent) was low compared with previous studies in this field; nevertheless, it is interesting that there is significant Table 3variation in the reported management of identical cases even in this relatively small sample. ... The guidelines for CDVD (Atkins and others 2009) include recommendations regarding pharmacological and dietary therapy for patients with heart failure of different degrees of severity. For the case described in the vignette, furosemide, angiotensin-converting enzyme inhibitor and pimobendan therapy would have been recommended, along with a homebased programme, to optimise body weight and appetite and monitor heart and respiratory rates. While the majority of vets did make recommendations regarding the management of the cases, the most common was advising a change in the animal’s exercise regime, which is not something covered in the guidelines for CDVD. ... The second most common recommendation was recommending the monitoring of, or encouraging loss of, the animal’s weight, which is interesting since there was no mention made of weight management in the vignette and suggests that the respondents have gone beyond the vignette, supplementing the scenario with their own clinical experience. Only a small proportion of the respondents made any dietary recommendation. The guidelines for CDVD (Atkins and others 2009) also make recommendations regarding diagnostic testing, which may be appropriate for cases with different degrees of congestive cardiac failure. For the case described in the vignette, radiography and ideally echocardiography and a serum biochemical profile would probably be recommended. In this study, less than half the respondents would carry out any additional diagnostic tests despite being told in the vignette that money was not a limiting factor. ... In conclusion, this study has demonstrated that profound variation exists in the management of heart failure in general veterinary Table 4practice in the UK despite considerable reliable published evidence supporting the use of many of the agents, and recently guidelines on the management of CCF due to canine degenerative valve disease (Atkins and others 2009); goals of future research should be to investigate why this is the case and importantly what the impact of this variation in approach might have on patient survival."

*Case 1: Breed: Cavalier King Charles spaniel. Age: 9 years. Gender: Male neutered. Color: Blenheim. Weight 8 kgs (17.6 lbs.) Scenario: Mr. Green presents you with Toby. From your practice records you see that Toby has had no previous health problems. You take a thorough history and perform a full physical exam. History: The owner reported his dog has developed a productive cough that is exacerbated by exercise, and the dog shows signs of tachypnoea at rest. Toby has been reluctant to go for walks for several weeks and gets tired 'sooner than normal'. Following radiography you have diagnosed left sided congestive heart failure associated with mitral valve disease (MVD) in a 9 year old Cavalier King Charles Spaniel weighing 8kgs.

An Up-Regulation of Galectin-3 in Cardiac Muscles and Circulation in Dogs with Degenerative Mitral Valve Disease. S. Sakarin, A. Rungsipipat, S. Disatian Surachetpong. 14th Chulalongkorn Univ. Vet. Conf. April 2015. CUVC 2015:103-104. Quote: "Several human researches indicated that cardiac fibrosis is one of the pathological changes resulted from cardiovascular diseases. DMVD dogs also have cardiac fibrosis. Gal-3 [Galectin-3] is suggested to play an important role in cardiac fibrosis and found up-regulated in hearts of CHF human patients. Circulating Gal-3 concentration has been proved as a marker of cardiac fibrosis. Recently, Gal-3 expression in canine heart has not been studied and the concentration of Gal-3 in circulation of dogs with DMVD is unknown. The aims of this study were to determine the expression of Gal-3 in cardiac muscles and measure level of plasma Gal-3 in CHF dogs with DMVD. ... In conclusion, DMVD dogs have more cardiac fibrosis with strongly expression of Gal-3 compare to normal dogs. Plasma Gal-3 concentration was increased in DMVD dogs. The results suggested that the expression of Gal-3 associated with cardiac fibrosis. Plasma Gal-3 concentrations might be a potential candidate of cardiac fibrosis markers in DMVD dogs." See also,this January 2016 article.

Effect of cardiac and respiratory cycles on vertebral heart score measured on fluoroscopic images of healthy dogs. Julien Olive, Romain Javard, Swan Specchi, Marie-Claude Bélanger, Catherine Bélanger, Guy Beauchamp, and Kate Alexander. JAVMA. May 2015;246(10):1091-1097. Quote: "Objective: To assess the variability in vertebral heart score (VHS) measurement induced by cardiac and respiratory cycles in dogs. Design: Prospective observational study. Animals: 14 healthy Beagles. Procedures: Dogs underwent fluoroscopic examination by 4 observers, and VHS was measured at end-tidal inspiration and end-tidal expiration during end systole and end diastole in left and right lateral recumbency. Mean VHS was compared within and among cardiac and respiratory phases and recumbency type, and correlation between VHS and heart rate was investigated. Interobserver variability was assessed. Results: Mean VHS for each combination of respiratory and cardiac cycle was larger on images obtained in right lateral versus left lateral recumbency. The greatest differences were observed between VHS measured in the diastolic inspiratory phase (mean ± SD, 10.59 ± 0.49 vertebral units [VU] and 10.35 ± 0.50 VU for right and left lateral recumbency, respectively) and the systolic expiratory phase (10.11 ± 0.37 VU and 9.92 ± 0.50 VU for right and left lateral recumbency, respectively). The combination of respiratory and cardiac cycles induced a maximal difference in VHS of up to 0.97 VU and 1.11 VU in the inspiratory and expiratory phases, respectively. Heart rate was not correlated with the difference between VHS in systolic and diastolic phases. Conclusions and Clinical Relevance: Clinicians should be aware of the potential influence of these factors when assessing VHS in dogs; in addition to allowing optimal pulmonary assessment, consistently taking radiographs at end-inspiratory tidal volume may help to limit VHS variability attributable to the respiratory cycle. Further research is needed to assess the effects of cardiac and respiratory phases on VHS in dogs with cardiac or respiratory disease."

Management of incidentally detected heart murmurs in dogs and cats. Etienne Côté, N. Joel Edwards, Stephen J. Ettinger, Virginia Luis Fuentes, Kristin A. MacDonald, Brian A. Scansen, D. David Sisson, Jonathan A. Abbott. JAVMA. May 2015;246(10):1076-1088. Quote: "Successful management of an animal with an incidentally detected heart murmur requires a correct diagnosis to accomplish the goals of accurate prognostication, appropriate initiation of treatment if needed, and having a satisfied client who fully understands the implications of the murmur, including the impact of the underlying disorder on the animal’s health. This document provides current information by species and age group to help veterinarians make appropriate decisions and initial diagnostic plans after incidental detection of a murmur in a dog or cat. ... In adult small-breed dogs with incidentally detected murmurs, serial follow-up of cardiac size on thoracic radiographs can be a useful tool to monitor disease progression. For example, CKCS [cavalier King Charles spaniels] with DMVD may have a VHS that is stable and may not have clinical signs for years, followed by a rapid increase in VHS and, eventually, the development of CHF. In a longitudinal study of 94 CKCS with DMVD, the median VHS was 11 at 3.5 to 4 years, 11 at 2.5 to 3 years, 11.25 at 1.5 to 2 years, and 11.7 at 0.5 to 1 year before diagnosis of CHF; at the onset of CHF, the median VHS had increased to 13.25. Thus, in a typical case, an unchanging VHS of 10.6 to 11.3 in an adult CKCS with an incidentally identified left apical systolic murmur is unlikely to reflect extensive cardiac changes or imminent CHF. ... In the absence of any other clinical signs possibly related to heart disease, geriatric small-breed dogs with systolic murmurs that have a point of maximal intensity over the left apex can be evaluated by thoracic radiography. As mentioned for adult small-breed dogs, thoracic radiographs can provide important prognostic and therapeutic information for patients with presumed or confirmed DMVD: a cardiac silhouette of normal size and shape in a dog that has no overt signs of decompensated heart disease is consistent with mild DMVD, and no treatment currently available appears to alter the progression of DMVD at this stage. Additionally, such radiographs may then provide baseline information for comparison as the disease progresses. ... It is easy to recommend that all patients with incidentally detected heart murmurs undergo echocardiography. A true understanding of the realities and imperatives of clinical practice says otherwise. This report is intended to provide a summary of the patient-, client-, and veterinarian-based factors that can help attending veterinarians recommend whether or not to pursue further diagnostic evaluation of patients with incidentally detected murmurs and the advantages and suitability of various diagnostic approaches."

Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease. S. Wesselowski, M. Borgarelli, G. Menciotti, J. Abbott. J.Vet.Cardiology, May 2015. Quote: "Objectives: To further characterize the echocardiographic anatomy of the canine mitral valve apparatus in normal dogs and in dogs affected by myxomatous mitral valve disease (MMVD). Animals: Twenty-two normal dogs and 60 dogs with MMVD [27 different breeds, including 9 cavalier King Charles spaniels] were prospectively studied. Methods: The length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet were measured in the control group and the affected group, as were the diameters of the mitral valve annulus in diastole (MVAd) and systole (MVAs). The dogs with MMVD were staged based on American College of Veterinary Internal Medicine (ACVIM) guidelines and separated into groups B1 and B2/C. All measurements were indexed to body weight based on empirically defined allometric relationships. Results: There was a statistically significant relationship between all log10 transformed mitral valve dimensions and body weight. The AMVL, AMVW, AMVA, MVAd and MVAs were all significantly greater in the B2/C group compared to the B1 and control groups. The AMVW was also significantly greater in the B1 group compared to the control group. Interobserver % coefficient of variation (% CV) was <10% for AMVL, AMVA, MVAd and MVAs, but was 29.6% for AMVW. Intraobserver % CV was <10.4% for all measurements. Conclusions: Measurements of the anterior mitral valve leaflet and the mitral valve annulus in the dog can be indexed to body weight based on allometric relationships. Preliminary reference intervals have been proposed over a range of body sizes. Relative to normal dogs, AMVL, AMVW, AMVA, MVAd and MVAs are greater in patients with advanced MMVD."

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs. M. Yata, A. J. McLachlan, D. J. R. Foster, S. W. Page and N. J. Beijerink. J. Vet. Pharmacology & Therapeutics. May 2015;39(1):45-53. Quote: Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography–mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2–4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.

Plasma and serum serotonin concentrations and surface-bound platelet serotonin expression in Cavalier King Charles Spaniels with myxomatous mitral valve disease. Signe E. Cremer, Annemarie T. Kristensen, Maria J. Reimann, Nynne B. Eriksen, Stine F. Petersen, Clara B. Marschner, Inge Tarnow, Mark A. Oyama, Lisbeth H. Olsen. Amer. J. Vet. Research. June 2015;76(6):520-51. Quote: "Objective: To investigate serum and plasma serotonin concentrations, percentage of serotonin-positive platelets, level of surface-bound platelet serotonin expression (mean fluorescence intensity [MFI]), and platelet activation (CD62 expression) in platelet-rich plasma from Cavalier King Charles Spaniels with myxomatous mitral valve disease (MMVD). Animals: Healthy dogs (n = 15) and dogs with mild MMVD (18), moderate-severe MMVD (19), or severe MMVD with congestive heart failure (CHF; 10). Procedures: Blood samples were collected from each dog. Serum and plasma serotonin concentrations were measured with an ELISA, and surface-bound platelet serotonin expression and platelet activation were determined by flow cytometry. Results: Dogs with mild MMVD had higher median serum (746 ng/mL) and plasma (33.3 ng/mL) serotonin concentrations, compared with MMVD-affected dogs with CHF (388 ng/mL and 9.9 ng/mL, respectively), but no other group differences were found. Among disease groups, no differences in surface-bound serotonin expression or platelet activation were found. Thrombocytopenic dogs had lower serum serotonin concentration (482 ng/mL) than nonthrombocytopenic dogs (731 ng/mL). In 26 dogs, a flow cytometry scatterplot subpopulation (FSSP) of platelets was identified; dogs with an FSSP had a higher percentage of serotonin-positive platelets (11.0%), higher level of surface-bound serotonin expression (MFI, 32,068), and higher platelet activation (MFI, 2,363) than did dogs without an FSSP (5.7%, 1,230, and 1,165, respectively). An FSSP was present in 93.8% of thrombocytopenic dogs and in 29.5% of nonthrombocytopenic dogs. Conclusions and Clinical Relevance: A substantive influence of circulating serotonin on MMVD stages prior to CHF development in Cavalier King Charles Spaniels was not supported by the study findings. An FSSP of highly activated platelets with pronounced serotonin binding was strongly associated with thrombocytopenia but not MMVD."

Effect of pimobendan on the incidence of arrhythmias in small breed dogs with myxomatous mitral valve degeneration. Geri A. Lake-Bakaar, Manreet K. Singh, Philip H. Kass, Leigh G. Griffiths. J.Vet.Cardiology, May 2015. Quote: "Objective: To determine if pimobendan, a phosphodiesterase III inhibitor and calcium sensitizer with positive survival benefits, has an effect on incidence of arrhythmias compared to placebo in small breed dogs with congestive heart failure (CHF) due to myxomatous mitral valve degeneration (MMVD). Animals: Eight client-owned small breed dogs (<15 kg) with CHF due to MMVD. Methods: A prospective double-blind randomized placebo-controlled crossover study design was used. Data were recorded at baseline and 2 weeks post-administration of placebo or pimobendan. Average heart rate and incidence of arrhythmia were determined from 24 h Holter analysis. Owners completed a quality of life (QOL) questionnaire at each time point and recorded sleeping respiratory rates (SRR). Mixed effects analysis of variance, with dog as the random variable was used to compare values obtained between baseline, placebo, and pimobendan. Results: Compared to baseline, QOL scores were significantly improved following administration of either placebo or pimobendan (p = 0.021 and p < 0.001, respectively). No significant differences in type or incidence of supraventricular or ventricular arrhythmia were identified. Average heart rate with pimobendan was significantly lower than baseline (p < 0.001). Compared to baseline, SRR was significantly lower with pimobendan (p = 0.004), and significantly different from placebo (p = 0.045). Conclusions: No significant difference between pimobendan and placebo was found on incidence of supraventricular or ventricular arrhythmia. The decrease in average heart rate and SRR may be reflective of superior heart failure control achieved with pimobendan therapy."

Prime esperienze cliniche sull’uso del pimobendan per via endovenosa nell’insufficienza cardiaca acuta del cane. (First clinical experiences on the use of pimobendan intravenously in acute heart failure in dogs.) Blanca Serrano, Danitza Pradelli, Claudio Bussadori. Clinica Veterinaria Gran Sasso. June 2015;29(3):1-7. Quote: "Background: Pimobendan is an inodilatator drug, inhibitor of the phosphodiesterase III, which plays a sensitizing activity on calcium channels. It is usually prescribed for the treatment of chronic heart failure (CHF). The objective of this study is to verify the effect of the use of the new injectable formulation of pimobendan in the treatment of hyperacute and severe congestive heart failure in dogs. Material and Methods: Descriptive clinical study performed in three patients with heart diseases assessed during the acute congestive heart failure and after diuretic therapy in combination with pimobendan EV. Results and conclusions: The use of pimobendan EV in association with diuretic therapy in the acute phase of congestive heart failure resulted in the improvement of clinical signs in three patients of the study, as a consequence of the hemodynamic improvement."

Echocardiographic findings in an aged population of cavalier King Charles spaniels. Jorge Prieto-Ramos, Simon Swift, Andrea Corda, Brendan Corcoran , Kim Summers, Iñigo Sanz, Anne French. J.Vet.Int.Med. July 2015;29(4):1122–1256;C-21. Quote: "Cavalier King Charles Spaniels (CKCS) are predisposed to degenerative atrioventricular valve disease. The prevalence of echocardiographic changes in aged CKCS has not been reported. In this study 126 CKCS (35% males, 65% females) aged 8.0–16.2 years (mean 10.6) underwent echocardiography. Animals ≥ 8 years were recruited from UK regional breed clubs. Echocardiographic examinations were performed by a boarded-certified cardiologist or a cardiology resident under supervision of a boarded-certified cardiologist. Echocardiographic parameters measured/calculated comprised: left ventricular diameter diastole/systole (LVDd/s), left atrial (LA) diameter long-axis view, LA to aorta ratio (LA:Ao) in 2D short-axis, mitral valve (MV) thickening, MV prolapse, MV regurgitation, tricuspid valve regurgitation (TR), pulmonary hypertension (TR velocity> 2.8 m/s) and fractional shortening. Markers of remodelling were defined as increased LVDd, LVDs, LA size, LA:Ao ratio (>1.5). All dogs had mitral valve thickening and regurgitation. MV prolapse was found in 111/126 (88%), of which 20/111 (18%) were severe. TR was seen in 98%. Pulmonary hypertension was identified in 19/109 dogs (17%). LA:Ao was increased in 49/126 (39%) whereas LA by long-axis view was enlarged in 59/126 (47%). LVDd was increased in 46/126 (37%) and LVDs was increased in 8/126 (6%). 14%, 21%, 20%, 3% had one, two, three and four markers of remodelling increased respectively. One or more markers of remodelling were reported in 73/126 (58%). In this population of aged CKCS, 100% showed echocardiographic evidence of degenerative atrioventricular valve disease however a low prevalence of markers of disease severity were found."

Pre-specified escalation of medical therapy reduces plasma NT-proBNP concentrations in dogs with stable CHF due to mitral valve disease. Melanie Hezzell, Chloe Thorn, Danielle Laughlin, Mark Oyama. J.Vet.Int.Med. July 2015;29(4):1122–1256;C-03. Quote: "There is evidence in human patients with congestive heart failure (CHF) that therapy designed to achieve a certain reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) improves outcomes. In one previous study, dogs with CHF that experienced lower NT-proBNP following conventional therapy survived longer than those with persistently high measurements. It is unknown whether it is possible to purposely change plasma NT-proBNP concentration by adjusting medical therapy in dogs. The aim of the present study was to determine whether a prespecified therapeutic algorithm would result in reductions in plasma NT-proBNP concentration in dogs with chronic CHF secondary to MMVD. Dogs were recruited within 21 days of initial diagnosis of CHF secondary to MMVD. All dogs were clinically stable at the time of recruitment and were receiving at least 2 mg/kg furosemide per day, 0.5 mg/kg enalapril BID and 0.25 mg/kg pimobendan BID. Dogs were excluded for any of the following: more than 1 episode of CHF requiring medical therapy, receipt of diuretics prior to the onset of CHF, history of chronic kidney disease, systemic hypertension, supraventricular tachyarrhythmia or significant other disease. Dogs were examined on up to 3 occasions at 7–10 days intervals. At the first visit, blood pressure measurement, radiography, echocardiography and measurement of NT-proBNP, blood urea nitrogen (BUN) and creatinine was performed. If NT-proBNP was <1500pmol/L no adjustments to existing medications were made and only a physical examination and measurement of circulating markers was performed at the next visit (group 0). If NT-proBNP was ≥1500pmol/L and creatinine was ≤3.0 mg/dL, (group 1) therapy was escalated as follows; if the current furosemide dose was <6 mg/kg/day, this dose was increased by 50%; if the current furosemide dose was ≥6 mg/kg/day, Aldactazide (1 mg/kg SID) was added; if the current dose of furosemide was ≥6 mg/kg/day and the dog was already receiving Aldactazide, the daily pimobendan dose was increased by 50–100%. If any dose adjustments were made, all diagnostic tests were repeated at the next visit. If creatinine was ≥3.0 mg/dL the dog was withdrawn from the study. Repeated measures mixed models were used to evaluate changes in variables over time. Fifteen dogs were recruited. At the first visit, 8 dogs were assigned to group 0 and 7 dogs to group 1. At the second visit, NT-proBNP was <1500pmol/L in two dogs in group 1, and no further dose adjustments were made. Thus, in 5 dogs, treatment was again escalated based on NT-proBNP≥1500pmol/L. Plasma NT-proBNP decreased significantly over time in group 1 (B = -156.1pmol/L/day (95% confidence interval (CI) -245.8 to -66.5), P = 0.001) but did not change in group 0 dogs (B = 51.7pmol/L/day (95% CI -30.7 to 134.1), P = 0.209); these rates of change were significantly different between groups (P < 0.001). Serum BUN (B = 1.27 mg/dL/day (95% CI 0.42 to 2.12), P = 005) and creatinine (B = 0.018 mg/dL/day (95% CI 0.004 to 0.033), P = 0.016) increased significantly over time in group 1 but did not change in group 0 dogs (P = 0.376 and 0.928, respectively); these rates of change were not significantly different between groups (P = 0.449 and 0.350, respectively). Serum creatinine was ≥3.0 mg/dL in one dog at its third visit. Vertebral heart size decreased significantly over time in group 1 (P = 0.027), whereas left atrial to aortic ratio did not change in this group (P = 0.879). In conclusion, a pre-specified treatment escalation algorithm in dogs with stable CHF due to MMVD and with NT-proBNP ≥1500pmol/L resulted in significant decreases in plasma NTproBNP concentration over time. Serum BUN and creatinine measurements significantly increased over baseline in these dogs, suggesting that careful monitoring of renal function is necessary during therapeutic escalation. Further study is warranted to determine whether targeted reductions in NT-proBNP result in improved outcomes in dogs with CHF secondary to MMVD."

Clinical efficacy and safety of imidapril in dogs with congestive heart failure. Wonjung Kim, Heemyung Park. J. Vet. Int. Med. July 2015;29(4):1122–1256;C-35. Quote: "The aim of this study was to compare the clinical efficacy and safety between angiotensin converting enzyme inhibitor (ACEI) imidapril and ramipril in dogs with myxomatous mitral valve disease (MMVD). The medical history of canine patients with MMVD which had been treated with imidapril or ramipril was reviewed. The dogs were treated with either an imidapril solution containing 2.5 mg per ml or ramipril tablets containing 1.25 or 2.5 mg per tablet. Both treatments were administered orally once a day. The dose of imidapril and ramipril was 0.25 mg/kg and 0.125 mg/kg, respectively. Treatment efficacy was evaluated with the clinical efficacy scale (5 stages). Overall clinical efficacy 28 days after the initiation of the treatment was shown to be very good or good in 15/16 (94%) dogs in the imidapril group versus 10/15 (67%) dogs in the ramipril group. However, there was no statistically significant difference in overall clinical efficacy between the treatment groups rated as very good or good (p = 0.056) or in the distribution over the 5 efficacy score levels (p = 0.096). No adverse events associated with treatment in both groups were observed during the study period. In conclusion, this study demonstrated that the ACEI imidapril has a good clinical efficacy in the treatment of dogs with congestive heart failure (CHF) caused by MMVD. Moreover, the results indicate that imidapril is not inferior to the earlier ACEI ramipril, and treatment with the imidapril is well-tolerated."

Evaluation of Left Ventricular Tei Index in the Normal Dogs and Dogs with Mitral Valve Degenerative Disease. In Lee, Jung-Woo Lee, Soo-Young Choi, Woo-Sok Han, Ki-Ja Lee, Young-Won Lee, Ho-Jung Choi. J. Vet. Clinics. May 2015;32(2):162-167. Quote: "Tei index, also called the myocardial performance index (MPI), is an echocardiographic parameter for the assessment of global myocardial function and includes both diastolic and systolic time intervals. The index is defined as the sum of isovolumic contration time (IVCT) and isovolumic relaxation time (IVRT) divided by ejection time (ET). Tei index can be calculated from pulse-wave Doppler (PW) and tissue Doppler image (TDI). ... Tei-index has been reported as one of reliable echocardiographic factors for evaluating cardiac function in human and small animals. In this study, Tei-index were measured and evaluated with other echocardiographic parameters in normal thirteen beagle dogs and thirty-one dogs with mitral valve degeneration. Normal range of Tei index with tissue Doppler obtained at septum and left ventricular free wall was 0.58 ± 0.07 and 0.60 ± 0.07, respectively. The values between septum and left ventricular free wall did not show significant difference. Tissue Doppler derived tei index showed better reproducibility and significantly lower values than the results obtained by pulsed wave Doppler. Tei index obtained in either method increased with the progression of clinical signs. Therefore, the increase of Tei index in dogs with mitral regurgitation is thought to be an useful factor reflecting left ventricular dysfunction."

Degenerative mitral valve disease: Survival of dogs attending primary-care practice in England. M.J. Mattin, A. Boswood, D.B. Church, P.D. McGreevy, D.G. O’Neill, P.C. Thomson, D.C. Brodbelt. Preventive Vet. Med. May 2015. Quote: "This study aimed to evaluate survival of dogs with degenerative mitral valve disease (DMVD). A retrospective cohort study of dogs with DMVD attending primary-care practices in England was undertaken. Cases of DMVD were identified within the electronic patient records (EPRs) of practices sharing data with VetCompass. Kaplan-Meier curves were used to explore survival and Cox regression models identified factors associated with hazard of death. The EPRs from 111,967 dogs, attending 93 veterinary practices between January 2010 and December 2011 identified 405 cases diagnosed with DMVD giving a prevalence of diagnosed DMVD of 0.36% (95% CI: 0.29–0.45%). A further 3557 dogs were classified as possible cases (heart murmurs consistent with DMVD). Overall, a total of 3962 dogs were classified as heart murmur cases (possible and diagnosed DMVD), giving a prevalence of 3.54% (95% CI: 3.26–3.84%). One hundred and sixteen (28.6%) of the diagnosed DMVD cases were incident, newly diagnosed with DMVD. The mean age at diagnosis was 9.52 years (95% CI: 8.98–10.14 years). Fifty-eight (50.0%) of the incident cases died during the study period. The median survival time (MST) for all-cause mortality was 25.4 months (95% CI: 20.4–34.4 months) after disease detection for DMVD cases. For possible cases, 121 (29.7%) from a random sample of 407 possible DMVD cases were incident cases (newly detected heart murmur consistent with DMVD during the study period). The mean age at which a heart murmur was first recorded in possible cases was 9.73 years (95% CI: 9.02–10.44 years). Forty-nine (40.5%) possible cases died during the study period. The MST for all-cause mortality was 33.8 months (95% CI: 23.7–43.1 months) after a heart murmur was initially detected. In the multivariable survival analysis for possible and diagnosed cases, Cavalier King Charles Spaniels (CKCSs) and other purebreds had higher hazards of death than crossbreds. Dogs weighing ≥ 20.0 kg and older dogs had an increased hazard of death compared with those < 20.0 kg and younger dogs, respectively."

Systolic cardiac function assessment by feature tracking echocardiography in dogs with myxomatous mitral valve disease. M. M. Mantovani, R. A. L. Muzzi, G. G. Pereira, R. J. Yamato, A. C. Silva, G. F. Reis, L. A. L. Muzzi and E. C. Guimarães. J. Small Animal Prac. June 2015;56(6):383-392. Quote: "Objectives: To evaluate endomyocardial and epimyocardial left ventricular circumferential and longitudinal peak systolic strain and strain rate in dogs with myxomatous mitral valve disease using two-dimensional feature tracking imaging echocardiography. Materials and Methods: Epimyocardial and endomyocardial global and regional myocardial peak systolic strain and strain rate using two-dimensional feature tracking imaging were evaluated in healthy dogs and those in stages B1, B2 and C of myxomatous mitral valve disease. Strain and strain rate in circumferential and longitudinal aspect were evaluated in 48 small- and medium-sized dogs. Results: Global endomyocardial circumferential strain and global epimyocardial circumferential strain systolic peak were lower in stage C than in stage B2 (P=0·04 and P=0·02) and similar to healthy dogs. Endomyocardial circumferential strain rate in septal and inferior segments were lower in stage C compared to B2 (P=0·0007 and P=0·0056), but not different from healthy dogs. There were no statistical differences in the epimyocardial circumferential strain rate, longitudinal strain and strain rate between healthy and affected dogs. Clinical Significance: Two-dimensional feature tracking imaging determination of myocardial deformation in epimyocardial and endomyocardial layers allows detection of increased compensatory circumferential left ventricular myocardial systolic performance due to volume overload and absence of this response as disease advances to congestive heart failure."

D-Ribose aids heart failure patients with preserved ejection fraction and diastolic dysfunction: a pilot study. Melike Bayram, J.A. St Cyr, William T. Abraham. Ther. Adv. Cardiovasc. Dis. June 2015;9(3):56–65. Quote: "Objectives: The incidence of heart failure continues to escalate with >550,000 newly diagnosed patients annually worldwide. More than half of the patients with heart failure have preserved ejection fraction or isolated diastolic dysfunction, for which no current effective therapies for diastolic dysfunction exist. Every cell requires adequate levels of high energy phosphates to maintain integrity and function. Previous studies have demonstrated that diastolic function is energy dependent and supplemental D-ribose has shown to improve diastolic dysfunction. This study investigated what role D-ribose might play in congestive heart failure patients with preserved systolic function and diastolic dysfunction. Methods: A total of 11 patients, New York Heart Association class II–IV, with clinical symptoms, normal left ventricular systolic function and echocardiographic evidence of diastolic dysfunction were enrolled after meeting inclusion criteria. Each patient received oral D-ribose (5 g/dose) for 6 weeks. Echocardiographic evaluation, cardiopulmonary metabolic testing and subjective questionnaire assessment were performed at baseline, 6 weeks and at 9 weeks (3 weeks after discontinuing D-ribose). Results: An improvement in their tissue Doppler velocity (E′), which was maintained at 9 weeks, was demonstrated in 64% of the patients. Five patients showed an improvement in their ratio of early diastolic filling velocity (E) to early annulus relaxation velocity (E′). There was no appreciable difference in these measurements during valsalva or with leg raising and handgrip exercises. Four patients also had an improvement in their maximum predicted VO2 values; two demonstrated a worsening effect and no differences were noted in the remaining patients. Subjective assessment revealed a benefit in only one patient, worsening symptoms in one patient and no change in the remaining cohort.

Safety and biocompatibility of the Mitrex® epicardial annuloplasty device in a chronic model. Jeffrey Solomon, Thomas Fogarty, Evan Anderson, Pierluca Lombardi. J.Vet.Int.Med. June 2015. Quote: "This study evaluated the safety of the myocardial compression required to perform epicardial annuloplasty and the biocompatibility of the Mitrex® device. Ten swine (seven test and three control) were used. The Mitrex® device was placed in all subjects such that the septo-lateral dimension of the mitral valve was reduced by 15–35%. Echocardiography and angiography were performed pre implant, post implant and at term. Test devices were secured in the test group and removed from the animals in the control group. Necropsy was performed at 180 days. Hearts were pressure fixed and analyzed. Test devices were placed without incident. Coronary flow, ejection fraction, left ventricular wall motion and mitral valve anteroposterior dimension were normal post implantation and at term. There were no remarkable postoperative events and all subjects survived to term with the exception of one test animal that was euthanized due to a non device related complication (refractory pleural effusion). Devices were well tolerated causing only minimal to mild fibrosis and chronic inflammation. No significant changes were observed in the myocardium except for muscle fiber atrophy near the tip of the anterior arm. There appeared to be ample tissue over the tip and no danger of perforation in all but one subject. No meaningful changes were noted in cardiac shape, ventricular wall thickness, chamber size, heart valves, and blood vessels. Myocardial compression necessary to perform epicardial annuloplasty was well tolerated. The Mitrex® device was safe and biocompatible."

Expression Profiling of Circulating MicroRNAs in Canine Myxomatous Mitral Valve Disease. Qinghong Li, Lisa M. Freeman, John E. Rush, Dorothy P. Laflamme. Int'l J. Molecular Sci. June 2015. Quote: "MicroRNAs (miRNAs) are small non-coding RNAs that have shown promise as noninvasive biomarkers in cardiac disease. This study was undertaken to investigate the miRNA expression profile in dogs with myxomatous mitral valve disease (MMVD). 277 miRNAs were quantified using RT-qPCR from six normal dogs (American College of Veterinary Internal Medicine Stage A), six dogs with MMVD mild to moderate cardiac enlargement (ACVIM Stage B1/B2) and six dogs with MMVD and congestive heart failure (ACVIM Stage C/D). Eleven miRNAs were differentially expressed (False Discovery Rate < 0.05). Dogs in Stage B1/B2 or C/D had four upregulated miRNAs, including three cfa-let-7/cfa-miR-98 family members, while seven others were downregulated, compared to Stage A. Expression of six of the 11 miRNAs also were significantly different between dogs in Stage C/D and those in Stage B1/B2. The expression changes were greater as disease severity increased. ... Our study suggests that there is an opportunity for using some of these circulating miRNAs as biomarkers for diagnosis, prognosis or monitoring response to treatment in MMVD in dogs. ... These miRNAs may be candidates for novel biomarkers and may provide insights into genetic regulatory pathways in canine MMVD."

Veterinary Medicine and Multi-Omics Research for Future Nutrition Targets: Metabolomics and Transcriptomics of the Common Degenerative Mitral Valve Disease in Dogs. Li Qinghong, Freeman Lisa M., Rush John E., Huggins Gordon S., Kennedy Adam D., Labuda Jeffrey A., Laflamme Dorothy P., Hannah Steven S. OMICS: A Journal of Integrative Biology. July 2015. Quote: "Canine degenerative mitral valve disease (DMVD) is the most common form of heart disease in dogs. The objective of this study was to identify cellular and metabolic pathways that play a role in DMVD by performing metabolomics and transcriptomics analyses on serum and tissue (mitral valve and left ventricle) samples previously collected from dogs with DMVD or healthy hearts. Gas or liquid chromatography followed by mass spectrophotometry were used to identify metabolites in serum. Transcriptomics analysis of tissue samples was completed using RNA-seq, and selected targets were confirmed by RT-qPCR. Random Forest analysis was used to classify the metabolites that best predicted the presence of DMVD. Results identified 41 known and 13 unknown serum metabolites that were significantly different between healthy and DMVD dogs, representing alterations in fat and glucose energy metabolism, oxidative stress, and other pathways. The three metabolites with the greatest single effect in the Random Forest analysis were γ-glutamylmethionine, oxidized glutathione, and asymmetric dimethylarginine. Transcriptomics analysis identified 812 differentially expressed transcripts in left ventricle samples and 263 in mitral valve samples, representing changes in energy metabolism, antioxidant function, nitric oxide signaling, and extracellular matrix homeostasis pathways. Many of the identified alterations may benefit from nutritional or medical management. Our study provides evidence of the growing importance of integrative approaches in multi-omics research in veterinary and nutritional sciences."

6 Practical Tips from Cardiologists: Heart Failure in Dogs. Ashley B. Saunders, Sonya G. Gordon. Today's Vet. Prac. July 2015;24-29. Quote: "This article describes canine heart failure, provides in-depth information about the most common diseases that lead to heart failure, and offers practical tips for diagnosis and management. Definition: Heart failure is a complex condition that can develop from congenital or acquired heart disease in dogs. Depending on the specific disease process, it can affect the left and right sides of the heart, manifesting in respiratory signs and weakness due to: • Fluid retention: Congestion; sometimes called backward failure; • Pump failure: Low cardiac output; sometimes called forward failure. ... Degenerative Mitral Valve Disease: DMVD is the most common acquired heart disease in dogs. Common clinical signs and pathophysiology include: • Heart murmur due to mitral valve (and, sometimes, tricuspid valve) regurgitation, leading to left atrial and left ventricular dilatation; • Progressive dilatation of the left ventricle, ultimately leading to systolic dysfunction; • Significant left atrial enlargement, leading to atrial (supraventricular) arrhythmias; • Development of pulmonary hypertension, which can contribute to clinical signs, such as respiratory distress and syncope. Not all dogs with DMVD will develop heart failure, characterized by pulmonary edema. In general, dogs with heart enlargement are at greater risk for heart failure, but only 30% of dogs with asymptomatic DMVD develop clinical signs and require heart failure therapy. ... Certain breeds are predisposed to specific disease processes. Classic examples include DMVD incidence in small breeds, such as miniature poodles and Cavalier King Charles spaniels, and DCM incidence in large breeds, such as Doberman pinschers and Great Danes. Specific examples include: • Incidence of DMVD in Cavalier King Charles spaniels increases with age but, in general, DMVD occurs at a younger age in this breed compared with other breeds. A mitral murmur can become evident at or after 4 years of age, but despite early age of onset, rate of progression is reportedly no different than progression rate in other breeds."

Serum activity of matrix metalloproteinase-2, -9 and -14 in dogs with myxomatous mitral valve disease. Martin Uhrenfeldt. Swedish Univ. of Agriculture thesis. July 2015. Quote: "Matrix metalloproteinases (MMPs) is a group of proteolytic enzymes, which degrade components of the extracellular matrix (ECM) of different tissues. These proteins play an important role in different physiological and pathological processes. The enzymes are thought to be important in various kinds of heart disease because of their effect on the composition of ECM. The MMP activity is inhibited by TIMPs (tissue inhibitors of metalloproteinases) which are specific inhibitors of the enzymes. Balance between production and degradation of the ECM is crucial for maintaining normal stucture and function of the heart parenchyma. The activity of certain MMPs (e.g. MMP-2, -9 and -14) has been described to have part in the development of myxomatous mitral valve disease in dogs. Myxomatous mitral valve disease (MMVD) is the most common acquired heart disease in adult dogs. In MMVD, the mitral valve undergo degenerative changes leading to altered valve architecture, resulting in prolapse of the mitral valve into the atrium and mitral insufficiancy. A large number of dogs live with the disease without showing clinical signs of disease, whilst others develop signs of non-compensated congetive heart failure. The aim of this thesis was to investigate the activity of MMP-2, -9 and -14 in serum from dogs with different stages of MMVD. A total of 66 dogs was included in the study, of which 21 were classified as healthy. ... The study included a total of 66 dogs (36 females and 30 males) with a median age of 7.9 years (interquartile range, IQR, 5.9 to 9.7 years) and a median weight of 9.6 kg (IQR 7.7 -10.5 kg). 49 of the dogs were CKCS [cavalier King Charles spaniels] ...  No overall significance was found between the activity levels of the different MMPs and the different stages of MMVD. The results showed that the activity of MMP-14 increased with decreasing systolic blood pressure (P=0,031) and that total MMP-9 (proMMP-9 + MMP-9) decreased with increasing fractional shortening (FS) of the left ventricle (P=0,027). These results can be interpreted as follows: The activity of MMP-14 increases and the activity of MMP-9 decreases when systolic function is impaired. Activity of both enzymes vary during pathogenesis which may implicate that they are involved in different stages of disease progression. This study suggests that MMP-2 play a minor role in dogs with MMVD."

Tricuspid valve dysplasia and its therapeutic management in a dog. R.D. Velhankar, Prakash Khangal, Mukesh Srivastava, R.V. Gaikwad, D.G. Dighe, S.M. Metkari, H.V. Mali. Indian J. Canine Prac. June 2015;7(1). Quote: "Three year male Labrador dog weighing about 32 kg was presented with primary complaints of anorexia, severe ascites, exercise intolerance and weakness. Right side heart enlargement was evident on thoracic radiography, while electrocardiogram revealed sinus tachycardia, increased duration of P wave and QRS complex, right electrical axis shift and suppression of R wave amplitude. Echocardiography confirmed the enlargement of the right atrium and right ventricle along with tricuspid dysplasia. Based on the findings of diagnostic investigations, the case was diagnosed as tricuspid valve dysplasia, regurgitation. The dog was medically managed with furosemide, enalapril, spironolactone and pimobendan. ... Due the severity of the present case, the combination therapy using furosemide and ACE was not enough for the retardation of fluid accumulation. After the addition of inotropes, it may delay the further accumulation of ascitic fluid. Therefore, on the basis of therapeutic management, it was suggested that addition of inotropes might be the good option for slowing fluid accumulation frequently seen in the right sided heart failure."

Short-term heart rate variability (HRV) in healthy dogs. Sz. Bogucki, A. Noszczyk-Nowak. Polish J. of Vet. Sci. July 2015;18(2):307-312. Quote: "Heart rate variability (HRV) is a well established mortality risk factor in both healthy dogs and those with heart failure. While the standards for short-term HRV analysis have been developed in humans, only reference values for HRV parameters determined from 24-hour ECG have been proposed in dogs. The aim of this study was to develop the reference values for short-term HRV parameters in a group of 50 healthy dogs of various breeds (age 4.86 ± 2.74 years, body weight 12.2 ± 3.88 kg). The ECG was recorded continuously for at least 180 min in a dark and quiet room. All electrocardiograms were inspected automatically and manually to eliminate atrial or ventricular premature complexes. Signals were transformed into a spectrum using the fast Fourier transform. The HRV parameters were measured at fixed times from 60-min ECG segments. The following time-domain parameters (ms) were analyzed: mean NN, SDNN, SDANN, SDNN index, rMSSD and pNN50. Moreover, frequency-domain parameters (Hz) were determined, including very low frequency (VLF), low frequency (LF) and high frequency (HF) components, total power (TP) and the LF/HF ratio. The results (means ± SD) were as follows: mean NN = 677.68 ± 126.89; SDNN = 208.86 ± 77.1; SDANN = 70.75 ± 30.9; SDNN index = 190.75 ± 76.12; rMSSD = 259 ± 120.17, pNN50 = 71.84 ± 13.96; VLF = 984.96 ± 327.7; LF = 1501.24 ± 736.32; HF = 5845.45 ± 2914.20; TP = 11065.31 ± 3866.87; LF/HF = 0.28 ± 0.11. ... Rasmussen et al. (2012) found an increase in the heart rate/min (HR) and mean HR in Cavalier King Charles Spaniels with advanced chronic mitral valve disease and a decrease in most of the measured HRV parameters (total power – TP, ultra low frequency- ULF, very low frequency – VLF, % of successive NN-intervals that differ more than 50 ms – pNN50 and the square root of the mean squared differences of successive NN-intervals – RMSSD) compared to healthy dogs and those with minimal mitral regurgitation. ... We observed an age-related increase in SDNN and SDANN and a decrease in HF. Although none of these relationships reached the threshold of statistical significance, this observation should be considered a clinically relevant finding as most dogs with MVD are usually older than 6 years. ... As the age-related decrease in the amplitude of the HF component was also documented in humans, the trend observed in healthy dogs seems to confirm the significant effect of aging on HRV parameters. Heart rate variability is an outcome of autonomic and humoral regulation of heart rate in response to various stimuli. ... As the values of the HF component vary depending on the respiratory rate, the ECG recordings for HRV analysis in dogs should always be obtained during normal rhythmic breathing. We did not document significant differences in the HRV parameters of males and females, which suggests that the same reference values for HRV parameters can be used irrespective of the dog’s gender. Similar to studies in humans, we found a number of significant correlations between the values of time- and frequency-domain parameters."

Pathologic Manifestations on Surgical Biopsy and Their Correlation with Clinical Indices in Dogs with Degenerative Mitral Valve Disease. J. Lee, M. Mizuno, T. Mizuno, K. Harada, M. Uechi. JVIM. July 2015. Quote: "Background: Evaluation of myocardial function is clinically challenging in dogs with degenerative mitral valve disease (DMVD). Although myocardial dysfunction is caused by pathologic degeneration, histopathologic progression is poorly understood. Objectives: To characterize myocardial and pulmonary pathologic changes according to severity in dogs with naturally occurring DMVD, and to investigate whether or not pathologic degeneration is reflected by traditional clinical indices. Animals: One hundred and seventeen dogs with naturally occurring DMVD [including 25 cavalier King Charles spaniels]. Methods: Prospective observational study. Biopsied left atrium (LA), left ventricle (LV), and lung were evaluated histologically, and an attempt was made to correlate pathologic findings with clinical indices. Results: Severe myocardial changes were observed in all International Small Animal Cardiac Health Council classes. [ISACHC I: Dogs with subclincal evidence of heart disease. 17 dogs inluding 1 CKCS. ISACHC II: Dogs with clinical signs of mild to moderate heart failure. 30 dogs inluding 6 CKCSs. ISACHC III: Dogs with clinical signs of advanced heart failure usually requiring hospitalization. 70 dogs inluding 19 CKCSs.] In the lung, heart failure cell levels were significantly increased in class III patients (P < .0001). In a paired comparison, the LA showed significantly more severe degeneration than the LV, including myocardial fatty replacement, immune cell infiltration, and interstitial fibrosis (P < .0001). In contrast, myocardial cells were more hypertrophied in the LV than in the LA (P < .0001). Left ventricular end-diastolic dimension (LVEDd) was associated with fatty replacement (P = .033, R2 = 0.584) and myocardial vacuolization (P = .003, R2 = 0.588) in the LA. Conclusions and Clinical Importance: In DMVD, although severe pathologic changes may be evident even in early stages, there may be pathologic discrepancy between the LA and the LV. Myocardial degeneration may be reflected by clinical indices such as LVEDd [left ventricular end-diastolic dimension] and EF [ejection fraction]."

Fortekor Plus. European Medicines Agency. July 2015. Quote: "Summary of opinion (initial authorisation): FORTEKOR PLUS. International non-proprietary names (INN): pimobendan / benazepril. On 9 July 2015, the Committee for Medicinal Products for Veterinary Use (CVMP) adopted a positive opinion2, recommending the granting of a marketing authorisation for the veterinary medicinal product FORTEKOR PLUS 1.25 mg/2.5 mg and 5 mg/10 mg tablets, intended for the treatment of congestive heart failure due to atrioventricular valve insufficiency or dilated cardiomyopathy in dogs. The applicant for this veterinary medicinal product is Elanco Europe Ltd. FORTEKOR PLUS is a fixed combination product containing benazepril hydrochloride and pimobendan. (ATCvet QC09BX90) as active substance. Benazepril hydrochloride is an angiotensin converting enzyme (ACE) inhibitor. Benazepril inhibits ACE which leads to reduced conversion of inactive angiotensin I into angiotensin II and therefore reduction in the effects mediated by angiotensin II, including vasoconstriction of both arteries and veins, retention of sodium and water by the kidney and remodelling effects (including pathological cardiac hypertrophy and degenerative renal changes). Pimobendan is a non-sympathomimetic, non-glycoside inotropic substance with potent vasodilating properties. It increases the calcium sensitivity of cardiac myofilaments and inhibits phosphodiesterase (type III). It also exhibits a vasodilatory action through the inhibition of phosphodiesterase type III activity. The benefit of FORTEKOR PLUS is its efficacy in the treatment of congestive heart failure due to atrioventricular valve insufficiency or dilated cardiomyopathy in dogs. FORTEKOR PLUS is a fixed dose combination and should only be used in patients whose clinical signs are successfully controlled by administration of the same doses of the individual components (pimobendan and benazepril hydrochloride) given concurrently. The most common side effects are of a non-serious nature and would include increased heart rate, occasional vomiting, incoordination or signs of fatigue."

Mitral valve repair. Masami Uechi. ECVS proceedings 2015. July 2015. Quote: "Mitral valve repair was developed as an alternative treatment option for mitral regurgitation and has demonstrated results superior to mitral valve replacement in humans. Valve replacement and long term survival have been reported in dogs. However, the primary issue associated with mitral valve replacement is the subsequent need for life-long antithrombotic treatment, which is not required following mitral valve repair. At present, the long-term outcome in dogs after mitral valve repair is poorly documented. We present the long-term outcome of small-breed dogs after mitral valve repair. We evaluated cardiac reverse remodeling after mitral valve repair under cardiopulmonary bypass (CPB) for mitral regurgitation in small breed dogs. Three hundred seventy dogs with mitral regurgitation were treated between 2006 and 2014. The cardiac murmur was grade 4/6–6/6. The preoperative thoracic radiographs showed cardiac enlargement (vertebral heart scale (VHS) 11.0–13.1). Echocardiography showed severe mitral regurgitation and left atrial enlargement (LA/Ao 2.0–4.2). ... CPB was initiated by use of a CPB circuit connected to carotid artery and jugular vein catheters. After inducing cardiac arrest, the left atrium was sectioned and chordae tendineae rupture was confirmed. The chordae tendineae were replaced with expanded polytetrafluoroethylene. A mitral annulus plasty was performed, and the left atrium was closed. ... After MVR, the heart rate significantly decreased from 118–164 bpm to 75–138 bpm. The grade of cardiac murmur was significantly reduced to 0/6–3/6, three months postoperatively, and the cardiac silhouette was reduced (VHS 9.8–11.5) in the chest X-rays. Echocardiography confirmed the marked reduction in both the mitral regurgitant ratio (62–87% to 4–64%, P<0.05) and the left atrial dimensions (LA/Ao 1.2–2.2). Mitral valve repair reduced cardiac size by reduction of the regurgitant rate. After surgery, clinical signs improved and patients were discharged within 12 days post operatively. Several dogs died within 10 days after surgery as a result of bleeding or pancreatitis. In the postoperative physical examination, cough was no longer present, and the animal’s appetite had improved. In addition, with the improvement in general condition, body weight increased. The clinical signs had essentially disappeared by 1 month after surgery. In addition, cardiac reverse remodelling was also observed at 1 month post operatively. Based on the reduction in class of The International Small Animal Cardiac Health Council classification, the clinical signs had improved after MVR. In addition, the number of medications used decreased by 1 month post operatively. By 3 months after the surgery, many dogs did not require medication. ... Artificial chordal replacement with expanded polytetrafluoroethylene (ePTFE) is an established technique for mitral valve repair with good long-term results, which is usually used for prolapse of the anterior and/or posterior mitral leaflet. Open heart surgery using CPB can be performed safely in small breed dogs. Mitral valve repair is an effective therapy for DMVD with severe MR. Postoperative complications include pancreatitis and thrombosis, which may be reduced by future advancement in techniques."

Effect of furosemide on diuresis and renin-angiotensin aldosterone activation in dogs: a model-based dose-response approach. B. Bieth, B. Bornkamp, C. Toutain, R. Garcia, J. Mochel. J. Vet. Pharm. & Therap. July 2015;38(Suppl. 1):37. Introduction: Congestive heart failure (CHF) is a leading cause of morbidity and mortality which is commonly associated with fluid overload and shortness of breath in canine populations. Furosemide is a non-potassium sparing loop diuretic prescribed for the majority of patients suffering from heart diseases. Although furosemide provides an overt clinical benefit in reducing fluid retention, it also has the disadvantage of activating the reninangiotensin aldosterone system (RAAS) (Novo et al., 1987), which further contributes to the accelerated progression of CHF. Despite the widespread use of loop diuretics and concerns regarding activation of the RAAS in dog patients, no detailed information on the dose-response relationship of furosemide is presently available. Our objective was to quantify the effect of several increasing doses of furosemide on diuresis, renin activity (RA) and aldosterone (AL) in dogs, using a model-based approach. Materials & Methods: 24 healthy beagle dogs were allocated to 4 treatment groups (saline control, furosemide 1, 2, and 4 mg kg 1 I.M., q12 h for 5 days). Dogs were placed in metabolism cages for collection of urine. RA was determined using a dedicated enzyme immunoassay, while AL concentrations were quantified in plasma by mass spectrometry. Data from rough RA and AL values, as well as 24-hr diuresis were analyzed at steady state using dose-response modelling based on a multiple comparison procedure and modelling (MCP-Mod) approach (Bretz et al., 2005). To cover a broad range of anticipated dose-response shapes, a set of candidate models was characterized, and a multiple contrast test was performed to assess the presence of a dose response signal (MCP part). Finally, a model averaging technique was used to derive the dose-response curve for each endpoint of interest (Mod part). Results: Sigmoid Emax models were found to adequately describe the dose-response relationships of furosemide. The derived ED50 and ED90 values were estimated to be lower for 24-hr diuresis (0.6 and 1.3 mg kg 1 q12 h, respectively), compared with RA (1.0 and 1.9 mg kg 1) and AL (1.0 and 2.1 mg kg 1). Conclusions: Model-based dose-response modeling is a powerful tool for evaluating dose-response relationships in veterinary pharmacology. Our data show that furosemide produces a sub-maximal effect on diuresis at doses lower than those identified to activate the circulating RAAS.

Myocardial infarct associated with a partial thickness left atrial tear in a dog with mitral insufficiency. Meg M. Sleeper, Meredith E. Maczuzak, Susan J. Bender. J. Vet. Cardiology. August 2015;17:229-236. Quote: A 10-year-old male neutered cavalier King Charles Spaniel with a 1-year history of degenerative mitral valve disease presented for dyspnea and severe weakness. He was diagnosed with congestive heart failure, systolic dysfunction, presumptive myocardial infarction and a left atrial thrombus based on thoracic radiographs, electrocardiogram and echocardiographic findings. Clinical signs also suggested right foreleg embolism. The dog was euthanized due to the grave prognosis and a postmortem evaluation was performed. The postmortem examination confirmed myocardial infarction and was thought to be due to embolic showering from the thrombus attached to a partial thickness left atrial endocardial tear.

Evaluation of Muscle Blood Flow in Dogs with Chronic Degenerative Mitral Valve Disease under Treatment. Rodrigo Bernardes Nogueira, Alice Fonte Basso, Lucas Anacretto Pereira. Asian J. Animal & Vet. Advances. August 2015. Quote: "In humans with clinically established heart failure, it has been widely suggested that many symptoms are attributable to peripheral perfusion abnormalities located, above all, in the skeletal muscle and not to central cardiac haemodynamic measurements. In veterinary patients, little is known about the real associated of muscle blood flow alterations in different clinical disorders. In dogs, the most common cause of heart failure is Chronic Degenerative Mitral Valve Disease (CDMVD). Thus, the aim of this work was to compare different quantitative measures related to peripheral muscular blood flow in healthy dogs and in dogs with advanced CDMVD under treatment. For this, the transcutaneous Doppler ultrasound, that is a non-invasive quantitative method to evaluate blood flow changes, was used. The data were obtained from femoral artery of seven healthy dogs and seven dogs with CDMVD that were receiving cardiovascular treatment at home. The results demonstrated that the resistance parameters of the femoral blood flow were significantly higher in dogs with CDMVD, compared with those of healthy dogs. The mean values of the femoral blood volume were lower in dogs with CDMVD in relation to healthy dogs. In conclusion, this study suggests that despite the cardiac therapy, the dogs may have variations in muscle blood flow that could contribute to the progression of heart disease and impair peripheral perfusion."

Developmental pathways and endothelial to mesenchymal transition in canine myxomatous mitral valve disease. Chi-Chien Lu, Meng-Meng Liu, Michael Clinton, Geoff Culshaw, David J. Argyle, Brendan M. Corcoran. Vet. J. December 2015;206(3):377-384. Quote: "Epithelial to mesenchymal transition (EMT), and the cardiovascular equivalent, endothelial to mesenchymal transition (EndoMT), contribute to a range of chronic degenerative diseases and cancer metastasis. Chronic valvulopathies exhibit some features of EndoMT and activation of developmental signalling pathways, such as osteogenesis and chondrogenesis, expression of cell differentiation markers, basement membrane damage and endothelial transformation. the aim of the present study was to examine the possibility of re-activation and recruitment of developmental processes in canine MMVD, based on analysis of transcriptomic data (Lu et al., 2015), further investigated by real time quantitative PCR and immunohistochemistry.  ... For immunohistochemistry, myxomatous mitral valve leaflets (n = 14) were collected at necropsy from cavalier King Charles Spaniels (CKCS; n = 9) and mixed breed dogs (n = 5) presented to the Hospital for Small Animals, Royal (Dick) School of Veterinary Studies and The Roslin Institute. ... There was significant differential expression for genes typically associated with valvulogenesis and EndoMT, including markers of inflammation (IL6, IL18 and TLR4), basement membrane disarray (NID1, LAMA2 and CTSS), mesenchymal and endothelial cell differentiation (MYH11 and TAGLN) and EndoMT (ACTA2, SNAI1, CTNNB1, HAS2, CDH5, and NOTCH1), with fold changes from +15.35 (ACTA2) to -5.52 (LAMA2). These changes in gene expression were confirmed using RT-PCR, except for HAS2. In silico analysis identified important gene networks and canonical pathways in MMVD that have associations with development and organogenesis, including inflammation, valve morphogenesis and EMT, as well as components of the basement membrane and extra-cellular matrix. Immuno-histochemistry identified changes in expression of hyaluronic acid synthase (Has2), Snai1, α-smooth muscle actin (α-SMA) and VE-cadherin (CDH5), and co-expression of Has2 with α-SMA. These research findings strongly suggest involvement of developmental signalling pathways and mechanisms, including EndoMT, in the pathogenesis of canine MMVD. This is the first report of involvement of development signalling pathways and endothelial to mesenchymal transition in canine myxomatous mitral valve disease (MMVD). The finding is significant in that it recognises mechanisms previously reported for fibrotic conditions and cancer metastasis, rather than a degenerative condition such as MMVD. Information is provided on biological mechanisms that have therapeutic potential for new drug discovery.

Correlation of serum cardiac troponin I and acute phase protein concentrations with clinical staging in dogs with degenerative mitral valve disease. Zoe S. Polizopoulou, Christos K. Koutinas, José J. Cerón, Asta Tvarijonaviciute, Silvia Martínez-Subiela, Anastasia Dasopoulou, Malcolm J. York, Ian F. Roman, Mitul Gandhi, Sonal Patel, Peter J. O'Brien. Vet. Clinical Pathology. August 2015. Quote: "Background: Cardiac troponin I (cTnI) correlates with severity of myocardial injury. Nonspecific inflammation in congestive heart failure (CHF) could be assessed by C-reactive protein (CRP), haptoglobin (Hp), and ceruloplasmin (Cp) measurements. Objectives: The aim of the study was to determine whether serum cTnI, CRP, Hp, and Cp concentrations differ among various stages of mitral valve disease (MVD) in dogs. Materials and methods: Dogs with MVD were allocated to 3 groups (I – asymptomatic; II – mild to moderate CHF; III advanced CHF) according to the scheme of the International Small Animal Cardiac Healthy Council (ISACHC). Concentrations of cTnI, CRP, Cp, and Hp were measured in all dogs upon admission, and cTnI and CRP were measured bimonthly during a 4-month follow-up period. Results: In total 46 dogs with MVD were enrolled for the cross-sectional part (21 Group I, 11 Group II, 14 Group III), and 35 dogs were included in the longitudinal study. Initial mean Cp concentrations were similar among all groups. There was a statistically significant difference in Hp and CRP concentrations between group I (n = 21, P = .019) and III (n = 14, P < .001). There was a statistically significant decrease in CRP (P = .033) and cTnI (P = .009) concentrations over the longitudinal study (all groups). CRP concentrations were significantly higher in group I than III (P = .004). During the 6-month monitoring period of 35 dogs, there was a statistically significant positive correlation between cTnI and CRP (P < .001). Conclusion: Differences in CRP concentrations between clinical stages of MVD suggest a clinically and therapeutically relevant inflammatory component."

Chronic mitral valve disease in the dog. Crosara, S.; Borgarelli, M. Veterinaria (Cremona). August 2015;29(2):31-37. Quote: "Myxomatous mitral valve disease (MMVD) is the most common acquired cardiovascular disease in dogs and for this reason it is the subject of many research. MMVD has a long asymptomatic phase and in many patients does not progress to heart failure. Despite being extensively studied, the pathogenesis of the disease is not completely understood. Recently, surgical valvular repair or mitral valve replacement have been demonstrated being feasible in dog and preliminary results have been encouraging. Real time-echocardiography has been recently introduces in veterinary medicine and preliminary data suggest it can represent a useful tool for studying mitral morphology and function and it might be crucial for surgical treatment."

Using Cardiac Biomarkers in Veterinary Practice. Mark A. Oyama. Clinics in Lab. Med. September 2015;35(3):555-566. Quote: "Blood-based assays for cardiac biomarkers can assist in the diagnosis of heart disease in dogs and cats. The most established applications are differentiation of cardiac versus noncardiac causes of respiratory signs and the detection of preclinical cardiomyopathy. Cardiac biomarkers are best used as part of the overall clinical cardiac workup that includes the medical history, physical examination, electrocardiogram, thoracic radiographs, and echocardiography. The selection of proper patient populations in which to test is key to obtaining reliable results. Future applications might include the use of cardiac biomarkers to help guide therapy and improve patient outcomes."

Amlodipine. Ashley E. Allen, Michael Shaer. Plumb's Therapeutics Brief. September 2015.

Echocardiographic assessment of right ventricular systolic function in conscious healthy dogs following a single dose of pimobendan versus atenolol. Lance C. Visser, Brian A. Scansen, Nicole V. Brown, Karsten E. Schober, John D. Bonagura. J. Vet. Cardiol. September 2015;17(3):161-172. Quote: Objective: To quantify drug-induced changes in right ventricular (RV) systolic function after administration of pimobendan and atenolol. Animals: 80 healthy privately-owned dogs [including 2 cavalier King Charles spaniels]. Methods: Using a prospective, blinded, fully-crossed study design with randomized drug administration, RV systolic function was determined twice at two time periods; before and 3 h after administration of pimobendan (0.25 mg/kg PO) or atenolol (1 mg/kg PO). Indices of RV systolic function included tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), pulsed-wave tissue Doppler-derived systolic myocardial velocity of the lateral tricuspid annulus (S′), and speckle-tracking-derived global longitudinal RV free wall strain and strain rate. The effect of treatment on percent change from baseline RV function was analyzed with a linear mixed model including the covariates heart rate, body weight, age, gender, drug sequence, and time period. Results: All indices showed a significant (p < 0.0001) increase and decrease from baseline following pimobendan and atenolol, respectively. Significant differences from baseline were attributed to drug treatment (p < 0.0001); whereas, effects of other covariates were not significant. The greatest percent changes, but also highest variability, were observed for S′ and strain rate (p < 0.0001). Post-atenolol, a significantly greater proportion of dogs exceeded the repeatability coefficient of variation for FAC and S′ compared to TAPSE (p ≤ 0.007). Conclusions: Echocardiographic indices in healthy dogs tracked expected changes in RV systolic function following pimobendan and atenolol and warrant study in dogs with cardiovascular disease.

Cardiovascular–renal axis disorders in the domestic dog and cat: a veterinary consensus statement. J. L. Pouchelon, C. E. Atkins, C. Bussadori, M. A. Oyama, S. L. Vaden, J. D. Bonagura, V. Chetboul, L. D. Cowgill, J. Elliot, T. Francey, G. F. Grauer, V. Luis Fuentes, N. Sydney Moise, D. J. Polzin, A. M. Van Dongen, N. Van Israël. J.Small Animal Prac. September 2015;56(9):537-552. Quote: "Objectives: There is a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease. The medical profession has adopted the term “cardiorenal syndrome” (CRS) to describe the pathophysiological relationship between the kidney and heart in disease. CRS has yet to be formally defined and described by the veterinary profession and its existence and importance in dogs and cats warrant investigation. The CRS Consensus Group, comprising nine veterinary cardiologists and seven nephrologists from Europe and North America, sought to achieve consensus around the definition, pathophysiology, diagnosis and management of dogs and cats with “cardiovascular-renal disorders” (CvRD). To this end, the Delphi formal methodology for defining/building consensus and defining guidelines was utilised. Methods: Following a literature review, 13 candidate statements regarding CvRD in dogs and cats were tested for consensus, using a modified Delphi method. As a new area of interest, well-designed studies, specific to CRS/CvRD, are lacking, particularly in dogs and cats. Hence, while scientific justification of all the recommendations was sought and used when available, recommendations were largely reliant on theory, expert opinion, small clinical studies and extrapolation from data derived from other species. Results: Of the 13 statements, 11 achieved consensus and 2 did not. The modified Delphi approach worked well to achieve consensus in an objective manner and to develop initial guidelines for CvRD. Discussion: The resultant manuscript describes consensus statements for the definition, classification, diagnosis and management strategies for veterinary patients with CvRD, with an emphasis on the pathological interplay between the two organ systems. By formulating consensus statements regarding CvRD in veterinary medicine, the authors hope to stimulate interest in and advancement of the understanding and management of CvRD in dogs and cats. The use of a formalised method for consensus and guideline development should be considered for other topics in veterinary medicine. ... This consensus statement is meant to increase the awareness of and codify the definition, classification and means of identification and provide provisional information on management of CvRD."

The effect of enalapril on furosemide-activated renin–angiotensin–aldosterone system in healthy dogs. A. C. Lantis, M. K. Ames, S. Werre, C. E. Atkins. J. Vet. Pharmacology & Therapeutics. October 2015;38(5):513-517. Quote: "Studies in our laboratory have revealed that furosemide-induced RAAS activation, evaluated via the urine aldosterone-to-creatinine ratio (UAldo:C), was not attenuated by the coadministration of benazepril, while enalapril successfully suppressed amlodipine-induced urinary aldosterone excretion. This study was designed to evaluate the efficacy of enalapril in suppressing ACE activity and furosemide-induced circulating RAAS activation. Failure to do so would suggest that this failure may be a drug class effect. We hypothesized that enalapril would suppress ACE activity and furosemide-induced circulating RAAS activation. Sixteen healthy hound dogs. The effect of furosemide (2 mg/kg PO, q12 h; Group F) and furosemide plus enalapril (0.5 mg/kg PO, q12 h; Group FE) on circulating RAAS was determined by plasma ACE activity, 4–6 h post-treatment, and urinary A:C on days −1, −2, 1, 4, and 7. There was a significant increase in the average urine aldosterone-to-creatinine ratio (UAldo:C) after administration of furosemide (P < 0.05). Enalapril inhibited ACE activity (P < 0.0001) but did not significantly reduce aldosterone excretion. A significant (P < 0.05) increase in the UAldo:C was maintained for the 7 days of the study in both groups. Enalapril decreased plasma ACE activity; however, it did not suppress furosemide-induced RAAS activation, as determined by the UAldo:C. While enalapril blunts ACE activity, the absence of circulating RAAS suppression may be due to angiotensin II reactivation, alternative RAAS pathways, and furosemide overriding concurrent ACE inhibition, all indicating the existence of aldosterone breakthrough (ABT). Along with similar findings with benazepril, it appears that failure to suppress aldosterone suppression [excretion?] with furosemide stimulation may be a drug class effect. The discrepancy between the current data and the documented benefits of enalapril likely reflects the efficacy of this ACE inhibitor in suppressing tissue RAAS, variable population responsiveness to ACE-inhibition, and/or providing additional survival benefits, possibly through as yet unknown mechanisms."

Pathologic Manifestations on Surgical Biopsy and Their Correlation with Clinical Indices in Dogs with Degenerative Mitral Valve Disease. J. Lee, M. Mizuno, T. Mizuno, K. Harada, M. Uechi. J. Vet. Int. Med. September 2015;29(5):1313-1321. Quote: "Background: Evaluation of myocardial function is clinically challenging in dogs with degenerative mitral valve disease (DMVD). Although myocardial dysfunction is caused by pathologic degeneration, histopathologic progression is poorly understood. Objectives: To characterize myocardial and pulmonary pathologic changes according to severity in dogs with naturally occurring DMVD, and to investigate whether or not pathologic degeneration is reflected by traditional clinical indices. Animals: e hundred and seventeen dogs with naturally occurring DMVD [including 26 cavalier King Charles spaniels]. Methods: Prospective observational study. Biopsied left atrium (LA), left ventricle (LV), and lung were evaluated histologically, and an attempt was made to correlate pathologic findings with clinical indices. Results: Severe myocardial changes were observed in all International Small Animal Cardiac Health Council classes. In the lung, heart failure cell levels were significantly increased in class III patients (P < .0001). In a paired comparison, the LA showed significantly more severe degeneration than the LV, including myocardial fatty replacement, immune cell infiltration, and interstitial fibrosis (P < .0001). In contrast, myocardial cells were more hypertrophied in the LV than in the LA (P < .0001). Left ventricular end-diastolic dimension (LVEDd) was associated with fatty replacement (P = .033, R2 = 0.584) and myocardial vacuolization (P = .003, R2 = 0.588) in the LA. Conclusions and Clinical Importance: In DMVD, although severe pathologic changes may be evident even in early stages, there may be pathologic discrepancy between the LA and the LV. Myocardial degeneration may be reflected by clinical indices such as LVEDd and EF [ejection fraction]."

Overdose Ingestion of Pimobendan in a Dog. Tsuyoshi Tokuriki, Yuichi Miyagawa, Naoyuki Takemura. J-Stage. September 2015. Quote: "The present report describes the clinical condition of a dog who exhibited previously unreported temporary increases in the T wave amplitude in addition to hypertension, tachycardia, increased grades of cardiac murmurs, increased fractional shortening (FS), and systolic anterior motion of the mitral valve (SAM) following the overingestion of pimobendan. ... A 15-year-old castrated male Shih Tzu (weight 8.5 kg) with myxomatous mitral valve disease ingested 8.24 mg/kg of pimobendan (approximately 33 times the recommended dose). On presentation, tachycardia and systemic hypertension were observed. Echocardiography revealed systolic anterior motion of the mitral valve (SAM) and increased fractional shortening. Electrocardiography revealed an increased T wave to R wave amplitude ratio (T/R). SAM disappeared 12 hr after hospitalization. T/R normalized after 24 hr, although the mechanism of the increase in this ratio and its clinical significance remain unclear. Systemic hypertension disappeared 36 hr after hospitalization. These findings suggest that it is necessary to monitor T/R, SAM, and systemic hypertension in dogs who have ingested a large amount of pimobendan."

Connecting structural changes to cell transformation patterns in the canine degenerative mitral valve. Kaitlin Marie Abbott. Colorado State Univ. master's thesis. September 2015. Quote: "Degenerative mitral valve disease (DMVD) is a significant problem in the canine population and also affects humans. ... Breeds such as Cavalier King Charles Spaniels have been shown to have a genetic predisposition for developing DMVD both earlier and more frequently than other dogs, and studies have attempted to identify these breeds and understand what they have in common in order to narrow down genetic causes. ... Recent studies have provided insight into molecular and cellular mechanisms that likely contribute to disease progression. Better understanding of the cellular processes that mediate the degenerative process could lead to treatments that prevent or slow this degeneration benefiting both canine and human patients. Structural changes to degenerative valves such as nodules, leaflet thickening, increased opacity, loss of elasticity and loss of valve architecture have been well documented. Abnormal cell transformation patterns such as the transformation of valvular interstitial cells to activated myofibroblasts have been characterized in degenerative mitral valve tissue, as well as other irregular cell behavior such as the overproduction of glycosaminoglycan and matrix remodeling factors that have become hallmarks of the disease. Despite these important discoveries, much remains unknown about cell signaling in degenerative mitral valve disease and how cell activity changes a normal valve to the diseased phenotype. An overarching hypothesis of this study is that investigating signaling mechanisms active in degenerative valves could provide insight into cellular processes mediating the disease. A specific hypothesis that emerged from initial results is that endothelial to mesenchymal transition (EndMT), a process important in valvulogenesis, could be active in degenerative mitral valves. The first goal of this study was to compare protein abundance in degenerative and normal mitral valves to determine if there exists previously unidentified signaling molecules that could be initiating or perpetuating the cellular transformations and abnormalities present in DMVD. The second goal was to investigate these proteins using immunohistochemistry to characterize their activity in the tissue matrix and show evidence of their contribution to structural changes of the valve. The first goal was accomplished by doing a targeted microarray analysis of signaling proteins comparing their relative abundance in normal and degenerative mitral valves. This analysis yielded an increased abundance of signaling proteins that have been associated with EndMT. The second goal was accomplished by immunohistochemistry to determine the spatial distribution of selected proteins from the microarray analysis with markers of endothelial cells and mesenchymal cells (activated myofibroblasts). Targeted microarray analysis of signaling proteins revealed increased abundance of 18 proteins including the growth factor HB-EGF, its partner molecule ADAM17, and the cell adhesion molecule integrin β3, all possible mediators of EndMT (Chapter 4). Immunohistochemistry studies demonstrated the presence of cells positive for the endothelial marker CD31 within the valve interstitum. These CD31 positive cells co-localized with areas of myofibroblast transformation in degenerative valves identified by positive staining for α-smooth muscle actin (αSMA). Expression of signaling proteins including HB-EGF and ADAM17 also co-localized to these areas (Chapter 5). In conclusion, these results support active EndMT in canine degenerative mitral valves. EndMT could be contributing to the formation of high cellular density myofibroblast transformation which has been postulated to mediate mitral valve degeneration."

Pilot study of a myostatin antagonist in dogs with cardiac cachexia. Lisa M. Freeman, John E. Rush, Suzanne M. Cunningham, Vicky K. Yang, Barret J. Bulmer. J. Vet. Cardiology. September 2015. Quote: "Objectives: Cardiac cachexia, a loss of lean body mass caused by heart disease, often accompanies congestive heart failure (CHF). Blocking myostatin, which is a protein that inhibits muscle growth, appears to greatly enhance muscle size and strength in rodent models and human clinical trials. The objective of this study was to evaluate a dog-specific myostatin antagonist (CAP-031) in a pilot study to test its safety and efficacy in dogs with CHF and cardiac cachexia. Animals: Dogs with CHF and cardiac cachexia. Methods: Eligible dogs received four weekly subcutaneous injections of CAP-031. Endpoints were body weight, body condition score (BCS, on a 1–9 scale), muscle condition score (MCS, on a five-point scale, where 0 = no muscle loss and 4 = severe muscle loss), appetite, and a quality of life (QOL) score. Results: Seven dogs with CHF and moderate-to-severe cachexia were enrolled in the study. For the six dogs that completed the study, the median age was 8.8 years (range 6.4–10.6). At baseline, the median body weight was 27.0 kg (range 17.3–62.0), the median BCS was 4 (2–5), and median MCS was 3 (3–4). There were no significant changes in body weight, BCS, appetite, or QOL score. The change in MCS (from a median of 3 at baseline to a median of 2.5 at week 4) was not statistically significant (p = 0.06). Conclusions: The myostatin antagonist appeared to be well tolerated in most dogs. Earlier identification of cachexia is important, and randomized, controlled trials of myostatin antagonists or other drugs to treat cardiac cachexia are needed."

Diagnostic Value of Selected Echocardiographic Variables to Identify Pulmonary Hypertension in Dogs with Myxomatous Mitral Valve Disease. A. Tidholm, K. Höglund, J. Häggström, I. Ljungvall. J. Vet. Int. Med. September 2015. Quote: "Background: Pulmonary hypertension (PH) is commonly associated with myxomatous mitral valve disease (MMVD). Because dogs with PH present without measureable tricuspid regurgitation (TR), it would be useful to investigate echocardiographic variables that can identify PH. Aim: To investigate associations between estimated systolic TR pressure gradient (TRPG) and dog characteristics and selected echocardiographic variables. Animals: 156 privately owned dogs ... Cavalier King Charles spaniel (27). ... Materials and Methods: Prospective observational study comparing the estimations of TRPG with dog characteristics and selected echocardiographic variables in dogs with MMVD and measureable TR. Results: Tricuspid regurgitation pressure gradient was significantly (P < .05) associated with body weight corrected right (RVIDDn) and left (LVIDDn) ventricular end-diastolic and systolic (LVIDSn) internal diameters, pulmonary arterial (PA) acceleration to deceleration time ratio (AT/DT), heart rate, left atrial to aortic root ratio (LA/Ao), and the presence of congestive heart failure. Four variables remained significant in the multiple regression analysis with TRPG as a dependent variable: modeled as linear variables LA/Ao (P < .0001) and RVIDDn (P = .041), modeled as second order polynomial variables: AT/DT (P = .0039) and LVIDDn (P < .0001) The adjusted R2-value for the final model was 0.45 and receiver operating characteristic curve analysis suggested the model's performance to predict PH, defined as 36, 45, and 55 mmHg as fair (area under the curve [AUC] = 0.80), good (AUC = 0.86), and excellent (AUC = 0.92), respectively. Conclusion and Clinical Importance: In dogs with MMVD, the presence of PH might be suspected with the combination of decreased PA AT/DT, increased RVIDDn and LA/Ao, and a small or great LVIDDn."

Comparison of Systolic Blood Pressure between Normal and Asymptomatic Degenerative Mitral Valve Diseased in Small Breed Dogs. Surachetphong, Sirilak Disatian; Pradit, Kamonwan; Chongsawat, Panyarat; Titada, Salinrat; Suwantarat, Sasita. The Thai Journal of Veterinary Medicine. September 2015;45(3):315-322. Quote: "Degenerative mitral valve disease (DMVD) is the major cause of mitral valve regurgitation and heart failure in dogs. The regurgitation of mitral valve may affect blood pressure without clinical presentation. The aims of this study were to compare the systolic blood pressure between normal dogs and dogs affected with asymptomatic DMVD (class B ACVIM classification) and to determine the relationship between echocardiographic values and blood pressure levels. The systolic blood pressure of small breed dogs, weighing less than 10 kilogram, that were normal (n=22) and newly diagnosed with DMVD (n=21) was measured. The average of systolic blood pressure determined by Doppler ultrasonic device and Oscillometer of dogs in the DMVD group was higher than that of the normal group. Three DMVD dogs had systolic blood pressure higher than 160 mmHg. The echocardiographic values did not correlate with blood pressure. In conclusion, blood pressure of asymptomatic DMVD dogs is maintained. Some diseased dogs may have systolic blood pressure higher than normal limit."

Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned? Jonathan Paul Mochel, Meindert Danhof. Reviews of Physiology, Biochemistry & Pharmacology. October 2015. Quote: "Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes. ... The research summarized herein is not a static and completed piece of work but is, instead, a starting point for further data integration and hypothesis testing."

Assessment of mitral regurgitation in dogs: comparison of results of echocardiography with magnetic resonance imaging. J. Sargent, D. J. Connolly, V. Watts, P. Mõtsküla, H. A. Volk, C. R. Lamb, V. Luis Fuentes. J. Sm. Ani. Prac. October 2015. Quote: "Objectives: Echocardiography is used routinely to assess mitral regurgitation severity, but echocardiographic measures of mitral regurgitation in dogs have not been compared with other quantitative methods. The study aim was to compare echocardiographic measures of mitral regurgitation with cardiac magnetic resonance imaging-derived mitral regurgitant fraction in small-breed dogs. ... A recent study used cMRI as a gold standard reference method with which to compare measurements of LV volume and function made using contrast echocardiography. ... In experimental dog models, cMRI imaging has been shown to be highly accurate in quantifying LV volumes and has been used as a gold standard comparison technique for echocardiographic measurements of SV and ejection fraction. To the authors’ knowledge, no studies have validated phase-velocity encoded imaging for measurement of aortic stroke volume or to calculate cMRI-RF in dogs, but this method has been used to compare effects of two anesthetic protocols on aortic flow. ... Methods: Dogs with myxomatous mitral valve disease scheduled for magnetic resonance imaging assessment of neurological disease were recruited. Correlations were tested between cardiac magnetic resonance imaging-derived mitral regurgitant fraction and the following echocardiographic measures: vena contracta/aortic diameter, transmitral E-wave velocity, amplitude of mitral prolapse/aortic diameter, diastolic left ventricular diameter:aortic diameter, left atrium:aortic diameter, mitral regurgitation jet area ratio and regurgitant fraction calculated using the proximal isovelocity surface area method. Results: Measurement of cardiac magnetic resonance imaging-derived mitral regurgitant fraction was attempted in 21 dogs. ... There were 15 Cavalier King Charles spaniels. ... Twelve consecutive, complete studies were obtained and 10 dogs were included in the final analysis: vena contracta/aortic diameter (r=0·89, p=0·001) and E-wave velocity (r=0·86, p=0·001) had the strongest correlations with cardiac magnetic resonance imaging-derived mitral regurgitant fraction. E velocity had superior repeatability and could be measured in all dogs. The presence of multiple jets precluded vena contracta/aortic diameter measurement in one dog. Clinical Significance: Measurement of cardiac magnetic resonance imaging-derived mitral regurgitant fraction is feasible but technically demanding. The echocardiographic measures that correlated most closely with cardiac magnetic resonance imaging-derived mitral regurgitant fraction were vena contracta/aortic diameter and E-wave velocity."

Association between breed, gender and age in relation to cardiovascular disorders in insured dogs in Japan. Inoue M, Hasegawa A, Hosoi Y, Sugiura K.  J. Vet. Med. Sci. October 2015. Quote: "The association between breed, gender and age and cardiovascular disorders in the insured dog population in Japan was investigated, using multiple logistic regression analysis and data from 299,555 dogs insured between April 2010 and March 2011. The overall annual prevalence of cardiovascular disorder diagnosis was 2.1%. Using the Miniature Dachshund as the reference breed, Cavalier King Charles Spaniel had the highest odds of cardiovascular disorder with a ratio of 16.2 (95% confidence interval: 14.4-18.2), followed by Maltese, Pomeranian, Chihuahua and Shih Tzu. [Of the CKCSs, diagnostic reports of 5,743 were included, of which 779 had at least one claim of a cardiovascular disorder, for a prevalence of 13.6%.] Male dogs had increased odds of 1.2 (1.1-1.3). The dogs had increased odds of having cardiovascular disorder by 1.5 times as their age increased by one year."

Severity of Mitral Valve Degeneration Is Associated with Chromosome 15 Loci in Whippet Dogs. Joshua A. Stern, Weihow Hsue, Kun-Ho Song, Eric S. Ontiveros, Virginia Luis Fuentes, Rebecca L. Stepien. PlosOne. October 2015. Quote: "Mitral valve degeneration (MVD) is the most common form of heart disease in dogs, frequently leading to left-sided congestive heart failure and cardiac mortality. Although breed-specific disease characteristics and overrepresentation point towards a genetic origin for MVD, a causative mutation and complete molecular pathogenesis are unknown. ... MVD can occur in all breeds, but is most prevalent in small to medium-sized dog breeds such as Cavalier King Charles Spaniels, Dachshund, Miniature Poodle, Maltese, Pomeranian, Yorkshire Terrier and Chihuahua. One study, recently reported 2 loci weakly associated with development of MVD by GWAS in the Cavalier King Charles Spaniel breed. Some over-represented breeds have an incredibly high disease frequency with dogs such as the CKCS showing >80 affection rates in populations >8yrs of age. A clear problem exists when considering MVD as a disease amenable to case vs. control genome wide association analysis (GWAS). It is well documented that canine MVD has age-related penetrance making it difficult to accurately phenotype an individual as a control. Determining an age cutoff that accurately predicts MVD development is challenging and provides an imperfect control population hence underscoring the relative failures of previous techniques. ... Whippet dogs are overrepresented in incidence of MVD, suggesting an inherited component in this breed. Expressivity of this condition is variable with some dogs showing evidence of more severe disease at earlier ages than other dogs. This phenomenon makes a traditional case versus control genetic study prone to phenotyping error. This study sought to avoid these common pitfalls by identifying genetic loci associated with severity of MVD in Whippets through a genome-wide association study (GWAS). 138 Whippet dogs were characterized for MVD by echocardiographic examination and a novel disease severity score was developed and adjusted for age in each subject. Single nucleotide polymorphism (SNP) genotype data (170k Illumina CanineHD SnpChip) was obtained for DNA isolated from blood of each study subject. Continuous variable genome wide association was performed after correction for population stratification by efficient mixed model association expedited (EMMAX) in 130 dogs. A genome wide significant association was identified on chromosome 15 (peak locus 57,770,326; Padj = 0.049) and secondary loci of suggestive association were identified on chromosome 2 (peak locus 37,628,875; Padj = 0.079). Positional candidate genes were identified within the primary and secondary loci including follistatin-related protein 5 precursor (FSTL5) and Rho GTPase-activating protein 26 (ARHGAP26). These results support the hypothesis that severity of MVD in whippets has a genetic basis and warrants further study by either candidate gene sequencing or next-generation techniques."

Diuretic dose equipotency between torsemide and furosemide in healthy dogs. Marc Schneider, Samir Abtout, Sylvie Bonavaud, Julie Ménard, Frédérique Woehrlé. So. European. Vet. Conf. October 2015. Quote: The objective of the study was to determine an equipotent dose of torasemide versus furosemide. As there is no validated animal model for this chronic disease, healthy dogs were used as surrogates. ... Thus in healthy dogs a single oral torasemide dose is about 20 times more potent than a single oral furosemide dose for inducing diuresis. This potency difference has to be taken into account when switching from furosemide to torasemide for the treatment of clinical signs of congestive heart failure. As this result was obtained in healthy dogs after a single oral dose, for dogs suffering from congestive heart failure, other considerations (tolerance, disease status...) should also be taken into account.

Pulmonary Vein-to-Pulmonary Artery Ratio is an Echocardiographic Index of Congestive Heart Failure in Dogs with Degenerative Mitral Valve Disease. A.-C. Merveille, G. Bolen, E. Krafft, E. Roels, S. Gomart, A.-L. Etienne, C. Clercx, K. Mc Entee. J. Vet. Int. Med. November 2015;29(6):1502-1509. Quote: "Background: Early recognition of left-sided congestive heart failure (CHF) in dogs with degenerative mitral valve disease (DMVD) is important because it influences medical therapy, timing of follow-up, and outcome. Hypothesis: Pulmonary vein diameter-to-pulmonary artery diameter ratio (PV/PA) measured by echocardiography can predict CHF. Animals: Ninety-eight client-owned dogs, 37 controls, and 61 dogs with DMVD ... Cavalier King Charles Spaniel (14). ... Methods: Prospective clinical cohort study. History, physical examination and Doppler-echocardiography were performed. Dogs were classified as International Small Animal Cardiac Health Council class I, II or III. Congestive heart failure was identified in a subset of 56 dogs based on radiographic findings. The PV/PA was measured in bidimensional (2D) and M-mode by 2 investigators blinded to the radiologists’ conclusions. Results: Interobserver coefficients of variation for PV/PA acquisition and measurement were <10%. The PV/PA in control dogs was approximately 1 and increased with class of heart failure. The presence of CHF could be best predicted by measuring PV/PA in 2D echocardiography (cut-off, 1.7; area under the curve, 0.98; CI, 0.97–0.98; P < .001) with a sensitivity of 96% and a specificity of 91%. Conclusion and clinical importance: The PV/PA is a simple and reproducible echocardiographic variable that increases with class of heart failure and may help discriminate dogs in CHF from asymptomatic dogs with DMVD. Additional studies are required to determine whether PV/PA might provide additional information in the integrated interpretation of Doppler-echocardiographic indices of left ventricular filling pressures and could be used for rapid assessment of CHF in dogs in a critical care setting."

Vitamin D Status in Different Stages of Disease Severity in Dogs with Chronic Valvular Heart Disease. T. Osuga, K. Nakamura, T. Morita, S.Y. Lim, K. Nisa, N. Yokoyama, N. Sasaki, K. Morishita, H. Ohta, M. Takiguchi. J. Vet. Int. Med. November 2015;29(6):1518-1523. Quote: "Background: In humans with heart disease, vitamin D deficiency is associated with disease progression and a poor prognosis. A recent study showed that serum 25-hydroxyvitamin D [25(OH)D] concentration, the hallmark of vitamin D status, was lower in dogs with heart failure than in normal dogs, and a low concentration was associated with poor outcome in dogs with heart failure. Objectives: To elucidate the vitamin D status of dogs with chronic valvular heart disease (CVHD) at different stages of disease severity. Animals: Forty-three client-owned dogs with CVHD [4 cavalier King Charles spaniels]. Methods: In this cross-sectional study, dogs were divided into 3 groups (14 dogs in Stage B1, 17 dogs in Stage B2, and 12 dogs in Stage C/D) according to ACVIM guidelines. Dogs underwent clinical examination including echocardiography. Serum 25(OH)D concentrations were measured in each dog. Results: Serum 25(OH)D concentration was significantly lower in Stage B2 (median, 33.2 nmol/L; range, 4.9–171.7 nmol/L) and C/D (13.1 nmol/L; 4.9–58.1 nmol/L) than in Stage B1 (52.5 nmol/L; 33.5–178.0 nmol/L) and was not significantly different between Stage B2 and Stage C/D. Among clinical variables, there were significant negative correlations between 25(OH)D concentration and both left atrial-to-aortic root ratio and left ventricular end-diastolic diameter normalized for body weight. Conclusions and Clinical Importance: These results indicate that vitamin D status is associated with the degree of cardiac remodeling, and the serum 25(OH)D concentration begins to decrease before the onset of heart failure in dogs with CVHD."

Effects of Pimobendan on Myocardial Perfusion and Pulmonary Transit Time in Dogs with Myxomatous Mitral Valve Disease: A Pilot Study. G. Menciotti, S.M. Apple, L. Braz-Ruivo, S. Crosara, J. Häggström, M. Borgarelli. 25th ECVIM-CA Congress; J. Vet. Intern. Med. September 2015. Quote: "The objectives of this study were to describe pulmonary transit time and myocardial perfusion normalized to heart rate (nPTT and nMP, respectively), evaluated by means of contrast echocardiography, in dogs with stable stage C ACVIM myxomatous mitral valve disease (MMVD), and to assess short-term effects of pimobendan on these parameters. We hypothesized that nPTT and nMP are increased in dogs with MMVD compared to normal dogs. Additionally, we hypothesized that treatment with pimobendan will decrease both variables in dogs with MMVD. We prospectively enrolled 6 normal dogs and 12 dogs with stable stage C ACVIM MMVD. All dogs had a standard and contrast echocardiographic examination at the beginning of the study. At this time, MMVD dogs were randomly assigned to receive either pimobendan (0.4 - 0.6 mg/kg) or not. All dogs with MMVD were re-evaluated by means of standard and contrast echocardiography after 1 week (T1), by operators blinded to the dog's treatment. Our results show that nPTT was significantly increased in dogs with MMVD (P = 0.0039), compared to normal dogs. nPTT was significantly decreased at T1 in dogs receiving pimobendan (P = 0.0250). nMP was not significantly different in dogs with MMVD, compared to healthy dogs (P = 0.6639), and it was not significantly different at T1 in the treatment group (P = 0.8798). In conclusion, contrast echocardiography is a valid, complementary tool for echocardiographic analysis of dogs with MMVD. Pimobendan decreases nPTT in dogs affected by MMVD. Myocardial perfusion is not different in dogs with MMVD and is not changed by pimobendan treatment." See also this September 2016 article.

Morphological Investigations of the Anterior Leaflet and its Chordae Tendineae in Canine Mitral Valves. Takuma Aoki, Yoko Fujii. Hiroshi Sunahara, Keisuke Sugimoto, Yoshito Wakao. Intern J Appl Res Vet Med. October 2015;13(3):159-163. Quote: "Although mitral valve repair (MVR) — for mitral regurgitation (MR) secondary to chronic valvular heart disease (CVHD) — is becoming more common in veterinary medicine, there is little information about the morphology of the mitral valve apparatus that is used to guide veterinary surgeons. Therefore, we investigated the locations of MR using echocardiography in 12 client-owned dogs with MR. ... Of these 12 dogs, 5 were Cavalier King Charles spaniels, 2 were Shih Tzu, and 1 each was Maltese, miniature schnauzer, papillon, Shetland sheepdog, and mixed breeds. ... Nine (75%) of these dogs had MR arising from the tip of the anterior leaflet (AL). (See diagram below.) In addition, we investigated the morphology of the AL and its chordae tendineae by examining the heart specimens of 10 healthy beagles. The tip of the AL—determined by echocardiography as the cause of MR—was secured by the chordae tendineae (CT), which were thinner than those attached to the base of the AL on each papillary muscle (anterior and posterior capillary muscle; p = 0.0186 and p = 0.0198, respectively). In the normal AL, the free edge of the posterior half was broader than that of the anterior half (p = 0.0001). ... As observed in humans, the strut chordae was wider than the marginal chordae in the present study. The strength of a material is proportional to its cross-sectional area. Therefore, although the marginal chordae has smaller loads than the strut chordate, they might be prone to elongation because of their thin nature. The thinner CT might be more sensitive to breaking caused by fatigue. Conversely, because of their large cross-sectional area, the strut chordae might be strong enough to bear the heavy repeated load. Indeed, strut chordae bear the heaviest blood pressure load of all the CT. Mitral Valve CoaptationHowever, mitral valve coaptation improved in ischemic MR when the strut chordae were severed. Furthermore, the marginal chordae — and not the strut chordae—are reportedly vital for mitral valve coaptation. (See diagram at right.) These studies suggest that although the CT that are attached to the base of the AL might be slightly elongated, they were not the main cause of MR. As observed in humans, the pathological investigation in dogs with MR revealed that the pathological change was more severe in the posterior half of the AL than in the anterior half. The posterior half of the AL might be more affected than the anterior half because of its broader area, which subjects it to larger blood pressure loads. In addition, the posterior half of the AL needs more artificial chords during MVR because of its large valve cusp and pressure load. There are several limitations to the present study. First, the breed of dogs used for the morphological investigation only included beagles. Second, the cross-sectional areas of the CT should be investigated because the cross-sectional surface of canine CT might not be a true circle, like that in humans. In addition, the role of the posterior leaflet should be considered because the bileaflets were affected in approximately half of the dogs with MR. In conclusion, the CT attached to the tip of the AL might contribute to MR in dogs because they are thin. They should be reconstructed during MVR since they secure the tip of the valve cusp in the left ventricle for good coaptation of the mitral valve. The posterior half of the AL might require more artificial chords because it is broader than the anterior half of the AL.."

Dietary considerations for dogs suffering from cardiac disease. Marge Chandler. October 2015. Vet Times.

Breeding Restrictions Decrease the Prevalence of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels over an 8- to 10-Year Period. A.C. Birkegård, M.J. Reimann, T. Martinussen, J. Häggström, H.D. Pedersen (HDP), L.H. Olsen (LHO). J. Vet. Int. Med. November 2015. Quote: "Background: Cavalier King Charles Spaniels (CKCS) are predisposed to myxomatous mitral valve disease (MMVD). Studies have indicated a strong genetic background. Objective: The aim of this study was to evaluate the effect of a breeding scheme involving auscultation and echocardiography. Animals: In the Danish Kennel Club mandatory breeding scheme, 997 purebred CKCS were examined during the period 2002–2011. Each dog was evaluated 1–4 times with a total of 1,380 examinations. Methods: Auscultation and echocardiography were performed to evaluate mitral regurgitation murmur severity and degree of mitral valve prolapse (MVP). ... Echocardiographic Assessment of MVP: The degree of MVP was evaluated by LHO or HDP (MVP observers). The degree of MVP was assessed as 0 (≤1.5 mm as the sum of the maximum protrusion of the cranial, caudal and coaption point of the mitral valve according to annulus plane), 1 (>1.5 and ≤4.5 mm), 2 (>4.5 and ≤7.5 mm), and 3 (>7.5 mm). One of the MVP observers (HDP) evaluated the MVP echocardiograms from the debut of the breeding scheme until November 2004, hereafter the recordings were evaluated by the other MVP observer (LHO). ... Breeding Guidelines and Cardiac Health Criteria: Dogs examined ≥1½ years of age were approved for breeding until 4 years of age if cardiac health criteria were fulfilled. To continue breeding in DKCS after 4 years of age dogs had to be reexamined. From January 2007, an additional restriction was decided introducing an additional reexamination after 6 years of age for male dogs. At all examination time points, dogs were excluded from breeding if they had MVP grade 3 (first a criterion from 2007) or a mitral regurgitation murmur grade ≥3. Dogs with grade 2 murmurs were excluded if they had MVP grades 2 or 3. Thus, cardiac health criteria for breeding in the MMVD breeding scheme of the DKCA were as follows: Mitral regurgitation murmur of 1 at a maximum combined with a MVP grade 2 at a maximum; or a grade 2 murmur combined with a degree of MVP not >1. Before 2007, dogs with a grade 3 MVP were approved if they had a murmur grade not >1. ... Mitral regurgitation murmur intensity and MVP status of all examined dogs became freely available from DKCA homepage after examination. Each parent needed to fulfill the cardiac health criteria for registration of their puppies in DKCA. ... The odds of having mitral regurgitation murmur or MVP > grade 1 in 2010–2011 compared to 2002–2003 were estimated using logistic regression analysis including age and sex as covariates. Odds were estimated for dogs that were products of the breeding scheme (defined as dogs with both parents approved by the breeding scheme before breeding) and non-products of the breeding scheme (defined as dogs with at least 1 parent with unknown cardiac status). Results: ... The odds of having mitral regurgitation murmur in 2010–2011 compared to 2002–2003 were 0.27 if the dogs in 2010–2011 were PB [products of the breeding scheme], reflecting a 73% decreased risk (P < .0001; Table 3 and Fig 2). Similarly, within 2010–2011, the odds of having mitral regurgitation murmur for dogs that was PB was 0.31 compared to non-PB, reflecting 69% decreased risk (P < .0001). If non-PB examined in 2010–2011 were compared with dogs examined in 2002–2003, no statistical difference in odds of having mitral regurgitation murmur was found (P = .4873). There was no significant influence of sex on odds of murmur. Odds of having a murmur were higher with advancing age. ... Our study shows that a breeding scheme based on cardiac auscultation and echocardiography markedly decreased the risk of having a mitral regurgitation murmur caused by MMVD after an 8- to 10-year period. The reduction in risk was only significant for offspring where both parents had been approved by the breeding scheme (PB), not for offspring where 1 or both parents not were approved by the breeding scheme (non-PB). The risk of having moderate to severe MVP (MVP > 1) was not decreased after the 8- to 10-year period, but PB had lower risk of MVP > 1 than did non-PB within the years 2010 and 2011. ... Conclusion and Clinical Importance: A mandatory breeding scheme based on auscultation and echocardiography findings significantly decreased the prevalence of MMVD over the 8- to 10-year period. Such a breeding scheme therefore is recommended for CKCS."

Quantitative assessment of muscle in dogs using ultrasound. Lisa M. Freeman, James Sutherland-Smith, Lori R. Prantil, Amy F. Sato, John E. Rush. Journal of Cachexia, Sarcopenia and Muscle. 8th Conf. on Cachexia, Sarcopenia and Muscle Wasting. December 2015;6(4):414(#1-39). Quote: "Background and aims: Cardiac cachexia occurs in >50% of pet dogs with naturally-occurring congestive heart failure (CHF), but muscle loss is difficult to quantify because most technologies (eg, CT, DEXA) require general anesthesia. Therefore, clinically relevant methods for quantifying muscle loss are needed. We previously validated an ultrasound method of quantifying muscle size in dogs of a single breed using CT as the gold standard. To further develop this ultrasound method, the goal of this study was to assess its feasibility and validity in other dog breeds, especially those predisposed to cardiac disease (eg, the Cavalier King Charles Spaniel, in which 80-90% of dogs develop mitral valve prolapse). Methods: Pet dogs of 5 different breeds of varying sizes and body conformation were studied (n=10/breed). All were healthy and between 1-5 years old. Static ultrasound images were obtained and maximal transverse right epaxial muscle height and area at the level of the 13th thoracic vertebrae were obtained (mean of 3 measurements). Length of the 4th thoracic vertebrae (T4) was measured from thoracic radiography. Ratios of the muscle height and area to vertebral length (height/T4 and area/T4, respectively) were calculated to account for differences in body size among breeds. Reproducibility testing was performed on 20% (n=10) of the dogs to determine inter-investigator, within-probe placement, and inter-probe placement variability. Methods: Mean height/T4 = 1.00 ± 0.22 and mean area/T4 = 2.94 ± 1.47. There was no significant difference for height/T4 (P=0.42) among breeds, but breeds were significantly different in area/T4 (P<0.001). Reproducibility was significantly higher for height/T4 than for area/T4. Conclusions: The ratio of epaxial muscle height to vertebral length (height/T4) was valid and reproducible for healthy dogs of different sizes and body conformation. Studies assessing this method in dogs with CHF and other diseases associated with muscle loss are warranted."

Canine Degenerative Valve Disease: Has a New York Veterinarian Found a Cure? K9 Magazine. November 2015. Quote: "Medical therapy for severe degenerative valve disease is palliative at best in both dogs and in man. The definitive treatment for severe degenerative valve disease in man is surgical valve replacement or repair. Surgical valve repair options in dogs have intrinsic limitations and is not available at most veterinary specialty centers or universities. Transcatheter valve replacement is a potential new therapeutic option that avoids the limitations and complications of open heart valve replacement or repair. It would also be more accessible, less expensive and much less invasive compared to surgical repair or replacement. Ultravet Medical Devices, a veterinary medical device company located in Bohemia, New York, ... is currently hard at work developing a transcatheter valve device which can be used to treat dogs with degenerative mitral/tricuspid valve disease. A Pilot Study: Ultravet Medical Devices performed a pilot study in 2013. The purpose of this study was to demonstrate that transcatheter valve replacement is a viable therapeutic treatment in dogs with degenerative valve disease. Three Labrador Retrievers with severe tricuspid valve dysplasia were selected for transcatheter valvular replacement. All three dogs had severe right-sided heart enlargement, large tricuspid regurgitations and heart failure. All of these dogs were on multiple cardiac medications that could not stop the worsening heart failure. An experimental, prototype transcatheter valve was designed and manufactured by Ultravet Medical Devices. The device was named the Tucker valve, after Dr. George Kramer’s dog Tucker who was one of the dogs in the study. The device was passed down the jugular vein under fluoroscopic and ultrasonic guidance, fixed into the apex at the right ventricle and deployed between the tricuspid leaflets. Intra-operative and post-op echocardiography showed marked reduction of the tricuspid regurgitant jet in all three patients. The Tucker Valve™ was successfully deployed into the right ventricle via the transcatheter jugular approach in all three dogs. The device resulted in significant reduction of the naturally occurring tricuspid regurgitation in all three dogs. This study shows that transcatheter valve replacement is possible in dogs and can dramatically reduce the amount of regurgitation."

Management of incidentally detected heart murmurs in dogs and cats. Etienne Côté, N. Joel Edwards, Stephen J. Ettinger, Virginia Luis Fuentes, Kristin A. MacDonald, Brian A. Scansen, D. David Sisson, Jonathan A. Abbott. J. Vet. Cardiology. November 2015. Quote: "A dog or a cat has an incidentally detected heart murmur if the murmur is an unexpected discovery during a veterinary consultation that was not initially focused on the cardiovascular system. This document presents approaches for managing dogs and cats that have incidentally-detected heart murmurs, with an emphasis on murmur characteristics, signalment profiling, and multifactorial decision-making to choose an optimal course for a given patient. ... In adult small-breed dogs with incidentally detected left apical systolic murmurs, serial follow-up of cardiac size on thoracic radiographs can be a useful monitoring tool. For example, Cavalier King Charles spaniels (CKCS) with DMVD may have a vertebral heart score (VHS) that is stable and may not have clinical signs for years, followed by a rapid increase in VHS and, eventually, the development of congestive heart failure (CHF). In a longitudinal study of 94 CKCS with DMVD, the median VHS was 11 at 3.5–4 years, 11 at 2.5–3 years, 11.25 at 1.5–2 years, and 11.7 at 0.5–1 year before diagnosis of CHF; at the onset of CHF, the median VHS had increased to 13.25. Thus, in a typical case, an unchanging VHS of 10.6–11.3 in an adult CKCS with an incidentally identified left apical systolic murmur is unlikely to reflect extensive cardiac changes or imminent CHF."

Kopi The Cavalier King Charles Spaniel: Congestive Heart Failure. November 2015.

Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs. Marisa K. Ames, Clarke E. Atkins, Seunggon Lee,Andrea C. Lantis, James R. zumBrunnen. Am. J. Vet. Res. December 2015;76(12):1041-1050. Quote: "Objective: To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide-activated renin-angiotensin-aldosterone system (RAAS). Animals: 6 healthy Beagles. Procedures: 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days −1, 3, and 7; serum aldosterone concentration on days −2, −1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days −2, −1, 1, 3, and 7. Results: High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C. Conclusions & Clinical Relevance: In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose-independent effect of ACE inhibitors."

Innocent Cardiac Murmur in Puppies: Prevalence, Correlation with Hematocrit, and Auscultation Characteristics. V. Szatmàri, M.W. van Leeuwen, E. Teske. J. Vet. Intern. Med. November 2015. Doi: 10.1111/jvim.13632 Quote: Background: The aims of this study were to establish the prevalence of innocent cardiac murmurs in clinically healthy puppies, to investigate a possible correlation between the presence of an innocent murmur and hematocrit, and to describe the auscultation characteristics of innocent murmurs. Hypothesis: Lower hematocrit contributes to the genesis of innocent murmurs. Animals: Five hundred and eighty-four client-owned clinically healthy puppies, between 20 and 108 days old. Methods: Two cross-sectional surveys with a 1-year (n = 389 pups) pilot and a half-year (n = 195 pups) principal study periods. Cardiac auscultation was performed by a single, board-certified cardiologist. Hematocrit was measured with an automatized hematology analyzer. Echocardiography was performed only on puppies with a cardiac murmur in the principal study. Results: In the pilot study, 15% of the dogs had a murmur. Innocent murmur was diagnosed in 28% of the 195 dogs in the principal study. Innocent murmurs were systolic, mostly with a musical character and with a maximal intensity of 2 of 6, and mostly with the point of maximal intensity in the left cardiac base. The hematocrit was significantly lower in the group with a murmur compared to the group without (P = .023). Conclusions and Clinical Importance: Innocent murmur was a common finding in puppies at the age when the first veterinary controls usually take place. Physiologic anemia contributes to the genesis of innocent murmurs in puppies. Rising hematocrit in growing puppies can explain the spontaneous disappearance of innocent murmurs with aging. Hematocrit did not differentiate innocent murmurs from abnormal murmurs.

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2016

Sleeping and resting respiratory rates in dogs and cats with medically-controlled left-sided congestive heart failure. F. Porciello, M. Rishniw, I. Ljungvall, L. Ferasin, J. Haggstrom, D.G. Ohad. Vet. J. January 2016;207:164-168. Quote: Sleeping and resting respiratory rates (SRR and RRR, respectively) are commonly used to monitor dogs and cats with left-sided cardiac disease and to identify animals with left-sided congestive heart failure (L-CHF). Dogs and cats with subclinical heart disease have SRRmean values <30 breaths/min. However, little is known about SRR and RRR in dogs and cats with CHF that is well controlled with medical therapy. In this study, SRR and RRR were measured by the owners of 51 dogs and 22 cats with stable, well-controlled CHF. Median canine SRRmean was 20 breaths/min (7–39 breaths/min); eight dogs were ≥25 breaths/min and one dog only was ≥30 breaths/min. Canine SRRmean was unrelated to pulmonary hypertension or diuretic dose. Median feline SRRmean was 20 breaths/min (13–31 breaths/min); four cats were ≥25 breaths/min and only one cat was ≥30 breaths/min. Feline SRRmean was unrelated to diuretic dose. SRR remained stable during collection in both species with little day-to-day variability. The median canine RRRmean was 24 breaths/min (12–44 breaths/min), 17 were ≥25 breaths/min, seven were ≥30 breaths/min, two were >40 breaths/min. Median feline RRRmean was 24 breaths/min (15–45 breaths/min); five cats had RRRmean ≥25 breaths/min; one had ≥30 breaths/min, and two had ≥40 breaths/min. These data suggest that most dogs and cats with CHF that is medically well-controlled and stable have SRRmean and RRRmean <30 breaths/min at home. Clinicians can use these data to help determine how best to control CHF in dogs and cats. Highlights: • Dogs and cats with stable left-sided congestive heart failure have sleeping and resting respiratory rates <30 breaths/min. • Resting respiratory rates are usually slightly higher than sleeping respiratory rates. • Sleeping respiratory rates vary slightly from day to day.

Evaluation of growth differentiation factor 11 (GDF11) levels in dogs with chronic mitral valve insufficiency. S.T. Ahn, S.I. Suh, H. Moon, C. Hyun. Canadian J. of Vet. Res. January 2016;80(1):90-92. Quote: "Growth differentiation factor 11 (GDF11) regulates cell growth and differentiation in both embryonic and adult tissues. Circulating GDF11 levels have recently been reported to be significantly lower in aging mice and restoration of GDF11 reversed age-related cardiac hypertrophy in old mice. Here, we evaluated the potential of serum levels of GDF11 as a circulating biomarker in dogs at different stages of heart failure, due to chronic mitral valve insufficiency (CMVI). We found no significant differences in serum GDF11 levels between dogs at different stages of CMVI-associated heart failure. Furthermore, the circulating levels of GDF11 did not correlate with age, body weight, echocardiographic variables, and the severity of CMVI-induced heart failure in dogs."

The diagnostic value of cardio-thoracic ratio in detecting heart size changes in dog. Andrei Baisan, Oana Bîrsan, V. Vulpe. Rev. Romanian Med. Vet. January 2016;26(3):5-9. Quote: The aim of the study was to assess the diagnostic value and the discrimination potential between the normal heart size and microcardia or cardiomegaly of a method which calculates the cardia-thoracic ratio (CTR) on X-rays, using the vertebral heart scale method (VHS) as reference for the cardiac size, in dogs. 42 dog thoracic X-rays were accepted into study. The dogs belonged to different small breeds aged between 1 and 15 years (mean ± SD 8.4±3.6). The analogic X-rays were scanned and transferred to a computer and the VHS and CTR were calculated with a commercial software. Data was collected and processed in a statistical analysis software. The dogs were distributed in three groups according to VHS measurements: group A - microcardia, group B- normal heart size and group C- cardiomegaly. A strong positive correlation was found between the VHS and CTR (~ = 0.763, P < 0.01). The CTR measurement showed a statistically significant difference between microcardia (P=0.002) and cardiomegaly (P=0.003) groups with respect to normal heart size group. No statistically difference in the CTR values between males and females (P=0.489) was obtained. The CTR can be considered a valid method being able to discriminate between the patients with microcardia and cardiomegaly from those with normal heart size.

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs. M. Yata, A. J. McLachlan, D. J. R. Foster, S. W. Page, N. J. Beijerink. Vet. Pharmacology & Therapeutics. February 2016;39(1):45-53. Quote: "Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography–mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2–4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs."

The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs. E. T. Bell, J. L. Devi, S. Chiu, P. Zahra, T. Whittem. Vet. Pharmacology & Therapeutics. February 2016;39(1):54-61. Quote: "Pimobendan is a benzimidazole-pyridazinone derivative, marketed as a racemic mixture for the management of canine heart failure. Pharmacokinetics of the enantiomers of pimobendan and its oral bioavailability have not been described in dogs. ... The objective of this study was to describe the pharmacokinetics in dogs of two new preparations of pimobendan, an oral solution formulation and an intravenous formulation, which are planned for regulatory submission for approval. This study aimed to describe the absolute and relative bioavailabilities of a new oral pimobendan solution and the pioneer capsule formulations, with a primary hypothesis that the new oral solution would be bioequivalent to the reference capsule formulation. ... In conclusion, the pharmacokinetics of the two oral formulations after a single dose of 0.25 mg/kg was similar, with the exception of a more rapid rate of absorption after administration of the liquid formulation. This faster absorption is likely to result in a more rapid onset of action. The novel liquid formulation represents an alternative formulation which may have practical advantages over the existing capsule and tablet formulations. An intravenous dose of 0.125 mg/kg of pimobendan in aqueous solution resulted in a maximal blood concentration of pimobendan greater than that obtained with the 0.25 mg/kg orally. Intravenous pimobendan may be a useful adjunctive therapy for the emergency treatment of dogs with congestive heart failure due to dilated cardiomyopathy or valvular endocardiosis, but the dosage suitable for such use should take in to account the difference in bioavailability between oral and intravenous formulations."

Galectin-3 in cardiac muscle and circulation of dogs with degenerative mitral valve disease. S. Sakarin, A. Rungsipipat, S.D. Surachetpong. J. Vet. Cardiology. March 2016;18(1):34-36. Quote: "Objectives: This study aimed to determine the association of cardiac fibrosis with the galectin-3 (Gal-3) expression, a fibrosis marker in the myocardium and to compare plasma Gal-3 levels in normal and degenerative mitral valve disease (DMVD) dogs. Animals: Studies of muscle expression and plasma levels of Gal-3 were performed in separate groups of dogs. The tissue study was performed on cardiac tissues collected from 22 dogs. The plasma study was performed on 46 client-owned dogs. Methods: Papillary muscle and left ventricular (LV) wall obtained from 10 normal and 12 DMVD dogs were stained with Masson trichrome and Gal-3 immunohistochemistry to determine fibrosis areas and Gal-3 expression. Plasma samples were collected from 19 normal and 27 DMVD dogs for Gal-3 measurement by ELISA. Results: Percentage of fibrosis was higher in papillary muscle and LV wall of DMVD dogs (66.13 ± 5.58%; 52.98 ± 8.45%) than in normal dogs (35.40 ± 8.46%; 27.41 ± 7.91%; p < 0.0001). Gal-3 was higher in papillary muscle and LV wall of DMVD dogs (27.95 ± 6.94%; 17.25 ± 8.76%) than in normal dogs (1.08 ± 0.67%; 0.52 ± 0.42%; p < 0.0001). Fibrosis areas correlated strongly with the Gal-3 expression (r = 0.821, p < 0.0001). Plasma Gal-3 levels were increased in DMVD dogs (1.50; 0.87–2.36 ng/mL) compared to normal dogs (0.42; 0.27–0.63 ng/mL; p < 0.0001). Conclusions: Gal-3 expression in cardiac muscle was associated with cardiac fibrosis and was higher in DMVD dogs than in normal dogs. DMVD dogs had higher plasma Gal-3 concentrations than normal dogs. Tissue Gal-3 is a candidate of fibrosis biomarker in DMVD; however, further investigation of associations between plasma Gal-3 and myocardial fibrosis is necessary." See also, this April 2015 abstract.

A comparison of the histopathologic pattern of the left atrium in canine dilated cardiomyopathy and chronic mitral valve disease. Izabela Janus, Agnieszka Noszczyk-Nowak, Marcin Nowak, Rafał Ciaputa, Małgorzata Kandefer-Gola, Urszula Pasławska. BMC Vet. Research. January 2016;12:3. Quote: "Background: Dilated cardiomyopathy (DCM) and chronic mitral valve disease (CMVD) in dogs are associated with heart chamber enlargement, also of the left atrium. DCM is often accompanied by rhythm disturbances (mainly atrial fibrillation or ventricular arrhythmias). In CMVD, arrhythmias are observed less frequently. It is still unclear whether left atrial enlargement in these diseases results from volume overload or if it is also connected with other factors (e.g. rhythm disturbances). This study was conducted on the left atrial myocardial specimens from 31 dogs, including those from 16 dogs with clinically diagnosed DCM and 15 dogs with CMVD [none were cavalier King Charles spaniels] ... (10 mixed-breed dogs, 2 dachshunds, 1 Cairn terrier, 1 miniature pinscher, and 1 German pinscher, aged 8–19 years, including 11 males and 4 females). Dogs with dilated cardiomyopathy show a different distribution of connective tissue, have less severe intra-myocardial arterial narrowing, and have more severe degenerative changes in the cardiomyocytes of the left atrium compared to dogs with chronic mitral valve disease. The changes noted in the atrial tissue from dogs in both groups resemble lesions noted in the ventricular tissue of dogs with the same diseases. Those differences may indicate that the atrial enlargement noted in DCM and CMVD has a different, disease-specific underlying mechanism and does not result only from volume overload."... After fixation and staining (using haematoxylin-eosin and Masson-Goldner trichrome stain), the specimens underwent evaluation. Parenchymal changes (fibrosis, fatty infiltration, and vessel narrowing), degenerative changes (loss of striation, changes in cardiomyocyte structure, and abnormal cell nuclei) and the presence of inflammatory infiltrates were assessed. Results: More interstitial fibrosis (median 4 vs. 2.5 grid fields; p<0.05) and less perivascular fibrosis (median score 1 vs. 2; p<0.05) was observed in the DCM group compared to the CMVD group. Moreover, less distinct vessel narrowing was observed in the DCM group than in the CMVD group (median lumen area ratio 0.3 vs. 0.26 respectively; p<0.05). Dogs with DCM showed more strongly defined degenerative changes than the CMVD dogs (median nuclei enlargement score 3 vs. 1, median loss of striation score 3 vs. 2 and median structural alterations score 3 vs. 2, respectively; p<0.05). Conclusion: The obtained results indicate a different nature of changes occurring in the left atrial myocardium of dogs with DCM compared to dogs with mitral valve disease, including differences in vessel narrowing, cardiomyocyte degeneration and in the distribution of connective tissue. ... Dogs with dilated cardiomyopathy show a different distribution of connective tissue, have less severe intra-myocardial arterial narrowing, and have more severe degenerative changes in the cardiomyocytes of the left atrium compared to dogs with chronic mitral valve disease. The changes noted in the atrial tissue from dogs in both groups resemble lesions noted in the ventricular tissue of dogs with the same diseases. Those differences may indicate that the atrial enlargement noted in DCM and CMVD has a different, disease-specific underlying mechanism and does not result only from volume overload."

Prognostic Value of Right Ventricular Tei Index in Dogs with Myxomatous Mitral Valvular Heart Disease. K. Nakamura, T. Morita, T. Osuga, K. Morishita, N. Sasaki, H. Ohta, M. Takiguchi. J. Vet. Int. Med. January 2016. Quote: "Background: The right ventricular (RV) Tei index (TX) has a significant correlation with the severity of pulmonary hypertension. However, the role of RV dysfunction in dogs with myxomatous mitral valvular heart disease (MMVD) has not been addressed. ... The Tei index (TX), also known as the myocardial performance index, is an index of global myocardial function, including systolic and diastolic performance. TX has been used to evaluate the RV function in dogs with right heart disease, including tricuspid regurgitation (TR) and pulmonary hypertension (PH). To the best of our knowledge, no previous study has investigated the relationship between the prognosis and right ventricular Tei-index (RVTX) in dogs with MMVD. Thus, in this study, we investigated the correlation between RVTX and survival in dogs with MMVD. ... Objectives: To investigate the correlation between right ventricular Tei-index (RVTX) and the prognosis for dogs with MMVD. Animals: Thirty client-owned dogs with MMVD. Methods: Clinical cohort study. Dogs were divided into two groups on the basis of the onset of cardiac-related death within 1 year of the first echo-cardiographic examination. Physical examination and echocardiographic variables were compared between the groups. Receiver operating characteristic (ROC) curves and multivariate logistic analysis were used to assess the comparative accuracy when identifying dogs with cardiac-related death. Results: ... Dogs were divided into two groups for statistical analysis based on whether they survived for more than 1 year after the first echocardiographic examination (Group A, 'survivors') or whether they experienced cardiac-related death within 1 year of the first echocardiographic examination (Group B, 'nonsurvivors'). Cardiac-related death was defined as death occurring because of the progression of clinical signs of congestive heart failure (CHF) without any other identifiable cause of death. ... TR [tricuspid regurgitation] velocity and sPAP could not be measured in 4 of 19 dogs in Group A and 2 of 11 dogs in Group B because of the absence of TR. ... After a median follow-up period of 437 (178–576) [5–658] days, cardiac-related death occurred in all nine dogs with increased RVTX (≥0.61) and 3 of 21 dogs with preserved RVTX (<0.61). Remaining 18 dogs with preserved RVTX were alive when the study ended. The Kaplan–Meier survival analysis showed that dogs with increased RVTX had significantly shorter survival times than dogs with preserved RVTX. ... The highest accuracy was obtained for RVTX with an area under the ROC curve (AUC) of 0.95 (95% confidence interval [CI] 0.81–0.99) followed by the left atrial to aortic root ratio with an AUC of 0.91 (95% CI 0.74–0.98), peak early diastolic mitral inflow velocity with an AUC of 0.84 (95% CI 0.64–0.94), and Doppler estimates of systolic pulmonary artery pressure with an AUC of 0.84 (95% CI 0.61–0.95). According to the multivariate logistic regression analysis, RVTX was the only independent correlate of cardiac-related death within 1 year. ... The results of the present study indicate that RVTX is strongly correlated with early death in dogs with MMVD. Although several echocardiographic variables were significantly different between the two groups, we found that RVTX, a variable that corresponds to the RV function, was the most significant independent predictor of mortality. This study demonstrates that RV function analysis may be the most reliable prognostic indicator for dogs with MMVD. ... Conclusions and Clinical Importance: Right ventricular Tei-index has a strong correlation with the prognosis for dogs with MMVD. The most significant independent predictor of death was RVTX in this study."

Assessment of mitral valve morphology using three-dimensional echocardiography. Feasibility and reference values. G. Menciotti, M. Borgarelli, M. Aherne, J. Haggstrom, I. Ljungvall, S.M. Lahmers, J.A. Abbott. J. Vet. Card. January 2016. Quote: "Objectives: To evaluate the feasibility of real time transthoracic threedimensional echocardiography (RT3DE) for evaluation of normal canine mitral valves (MVs), and to provide reference values for this technique. Animals: Forty-three cardiologically healthy, not sedated dogs. Methods: Transthoracic RT3DE mitral datasets were acquired during two consecutive 6-month periods. The datasets were analyzed using commercially available software. An MV model was drawn using a semiautomated procedure and MV variables were obtained and calculated. The ratio between annulus height and commissural diameter was used as an index of the annulus’ saddle-shaped non-planarity. After evaluation of associations between measured variables and body size, the datasets were used to generate reference intervals. Coefficients of variation (CVs), variance components, and repeatability coefficients were calculated for the evaluation of intra-observer, inter-observer, and day-to-day variability. Results: Datasets could be analyzed in 34 of 43 (79%) dogs. 68 percent of datasets obtained during the first 6-month period could be analyzed and 90% obtained during the second period could be analyzed. An allometric relationship was identified for most MV variables. The MV annulus appeared elliptical and saddle-shaped. Inter- and intra-observer CVs were less than 20%. Coefficient of variation greater than 20% was calculated for the inter-day variation for some variables. Operator and observer were primarily responsible for the variation of most of the variables. Conclusions: Evaluation of canine mitral valves by transthoracic RT3DE is feasible. Canine MVs of healthy dogs analyzed using RT3DE are elliptical and saddle-shaped. Reference intervals for the measured MV variables are proposed."

Comparison of cellular changes in Cavalier King Charles spaniel and mixed breed dogs with myxomatous mitral valve disease. C.-C. Lu, M.-M. Liu, G. Culshaw, A. French, B. Corcoran. J. Vet. Cardiology. February 2016. Quote: "Introduction: The aim of this study was to determine if there are differences in cellular changes in Cavalier King Charles spaniel (CKCS) myxomatous mitral valves compared to non-CKCS dogs. Animals: Cavalier King Charles spaniels (n = 6) and age-matched mixed breed (n = 6) with severe myxomatous mitral valve disease (MMVD), and normal mixed breed (n = 4) dogs. Materials and Methods: Immunohistochemistry staining and qualitative and quantitative analysis of mitral valves sections, examining for the presence of CD11c and CD45, vimentin, alpha smooth muscle actin (α-SMA) and embryonic smooth muscle myosin heavy chain (Smemb), von Willebrand factor and CD31 and Ki-67. Results: Vimentin positive cell numbers were increased in the MMVD dogs and distributed throughout the valve with greatest density close to the endothelium. There were no significant differences in cell marker expression for the two diseased groups, but cell numbers were significantly increased compared to controls for α-SMA (CKCS only) and Smemb (CKCS and mixed breed: p < 0.05). Alpha smooth muscle actin+ cells were primarily located at the valve edge, with Smemb+ cells similarly located, but also present throughout the valve stroma. A small number of cells close to the valve edge co-expressed α-SMA and Smemb. Endothelial von Willebrand factor expression was identified in all valves, with evidence of disrupted endothelium in the diseased, but was also found in diseased valve stroma. There was no staining for CD11c, CD45 or CD31 in any valve. Ki-67+ cells formed linear clusters at the leaflet tip and were sparsely distributed throughout both myxomatous valve groups. Conclusions: ... In conclusion, this study confirms that there is no evidence for inflammatory cell involvement in canine MMVD, that the cell changes appear similar for CKCS as for other dogs, and that the changes in cell numbers in MMVD are possibly due to cell proliferation. This study suggests that MMVD is not a heterogeneous disease, at least in terms of cellular changes and that the CKCS form of the disease differs only in its time of onset and speed of progression. However, the pathogenesis of MMVD is unknown and it is possible different mechanisms could result in the same end-stage findings. From these studies it would be reasonable to presume that studies of any dog with MMVD are applicable to all dogs and breeds."

UK Kennel Club 2014 Cavalier Breed Health Survey Results. Bonnie Wiles. UK Kennel Club. Summary: Forms were received representing 1,256 living dogs & 223 deceased dogs. The most commonly reported disease condition in live dogs was Heart (cardiac) murmur. The most commonly reported cause of death was Cardiac (heart) Failure. The median longevity for the Cavalier King Charles Spaniel was 10 years. Cause of death: cardiac related: 37.67%. (Compare the 2004 Cavalier Breed Health Survey Results.)

Increased serum C-reactive protein concentrations in dogs with congestive heart failure due to myxomatous mitral valve disease. M.J. Reimann, I. Ljungvall, A. Hillström, J.E. Møller, R. Hagman, T. Falk, K. Höglund, J. Häggström, L.H. Olsen. Vet. J. March 2016;209:112-118. Quote: "Cardiovascular disease in humans and dogs is associated with mildly increased circulating concentrations of C-reactive protein (CRP). Few studies have evaluated associations between circulating CRP and canine myxomatous mitral valve disease (MMVD) and the results reported have been divergent. The aim of this study was to investigate whether serum concentrations of CRP, determined using a novel automated canine-specific high-sensitivity CRP assay (Gentian hsCRP), were associated with severity of MMVD and selected clinical variables in dogs. The study included 188 client-owned dogs with different severities of MMVD. Dogs were classified based on ACVIM consensus statement guidelines (group A, n = 58  [including 52 cavalier King Charles spaniels]; group B1, n = 56  [including 51 cavalier King Charles spaniels]; group B2, n = 38  [including 31 cavalier King Charles spaniels]; group C, n = 36  [including 22 cavalier King Charles spaniels]). Data was analysed using descriptive statistics and multiple regression analysis. Dogs with congestive heart failure (CHF; group C) had significantly higher CRP concentrations (median, 2.65 mg/L; quartile 1 - quartile 3, 1.09-5.09) compared to dogs in groups A (median, 0.97 mg/L; quartile 1 - quartile 3, <0.50-1.97; P = 0.001), B1 (median, 0.78 mg/L; quartile 1 - quartile 3, <0.50-1.73, P < 0.0001) and B2 (median, 0.60 mg/L; quartile 1 - quartile 3, <0.50-1.23; P < 0.0001). Other variables reflecting disease severity, including left atrial to aortic root ratio (P = 0.0002, adjusted r2 = 0.07) and left ventricular end-diastolic diameter normalised for bodyweight (P = 0.0005, adjusted r2 = 0.06), were positively associated with CRP concentration, but the association disappeared if dogs with CHF were excluded from analysis. In conclusion, slightly higher CRP concentrations were found in dogs with CHF whereas severity of asymptomatic MMVD showed no association with CRP concentrations."

Cytokine expression in peripheral blood mononuclear cells of dogs with mitral valve disease. A. Mavropoulou, S. Guazzetti, P. Borghetti, E. De Angelis, C. Quintavalla. Vet. J. March 2016. Quote: "Inflammation plays an important role in the pathogenesis of congestive heart failure (CHF). In humans with CHF, increased production and high plasma concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1, IL-8 and transforming growth factor-β (TGF-β) have been associated with disease progression and a negative prognosis. The aim of this study was to investigate whether differences in cytokine blood mRNA expression exist between clinically healthy dogs and dogs with myxomatous mitral valve disease (MMVD); to determine if the expression is related to the severity of MMVD, and to detect any correlations with echocardiographic parameters of cardiac remodelling. Twenty-three dogs with MMVD of varying severity and six clinically healthy dogs were included in the study. Whole blood samples were obtained for measurement of mRNA expression of IL-1α, IL-1β, IL-6, IL-8, TGF-β1, TNF-α by reverse transcriptase-PCR (RT-PCR). There were statistically significant differences between clinically healthy dogs and dogs with MMVD for IL-8 and TGF-β1 gene expression. IL-8 expression increased with increasing MMVD severity and TGF-β1 expression was higher in asymptomatic dogs with echocardiographic signs of cardiac remodelling (American College Veterinary Internal Medicine [ACVIM] class B2) than in all other groups. These results could suggest the involvement of these cytokines at different stages of the disease."

Effects of intravenous dexmedetomidine on cardiac characteristics measured using radiography and echocardiography in six healthy dogs. Hsien-Chi Wang, Cih-Ting Hung, Wei-Ming Lee, Kui-Ming Chang, Kuan-Sheng Chen. Vet. Radiology & Ultrasound. January 2016;57(1):8-15. Quote: "Dexmedetomidine is a highly specific and selective α2-adrenergic receptor agonist widely used in dogs for sedation or analgesia. We hypothesized that dexmedetomidine may cause significant changes in radiographic and echocardiographic measurements. The objective of this prospective cross-sectional study was to test this hypothesis in a sample of six healthy dogs. Staff-owned dogs were recruited and received a single dose of dexmedetomidine 250 μg/m2 intravenously. Thoracic radiography and echocardiography were performed 1 h before treatment, and repeated 10 and 30 min after treatment, respectively. One observer recorded cardiac measurements from radiographs and another observer recorded echocardiographic measurements. Vertebral heart score and cardiac size to thorax ratio on the ventrodorsal projection increased from 9.8 ± 0.6 v to 10.3 ± 0.7 v (P = 0.0007) and 0.61 ± 0.04 to 0.68 ± 0.03 (P = 0.0109), respectively. E point-to-septal separation and left ventricle internal diameter in diastole and systole increased from 2.4 ± 1.1 to 6.6 ± 1.9 mm, 32.3 ± 8.1 to 35.5 ± 8.8 mm, and 19.4 ± 6 to 27.0 ± 7.2 mm, respectively (P < 0.05). Fractional shortening and sphericity index decreased from 40.7 ± 5.8 to 24.4 ± 2.9%, and 1.81 ± 0.07 to 1.58 ± 0.04, respectively (P < 0.05). Moderate-to-severe mitral regurgitation and mild pulmonic regurgitation occurred in all dogs after dexmedetomidine administration. Findings indicated that dexmedetomidine could cause false-positive diagnoses of valvular regurgitation and cardiomegaly in dogs undergoing thoracic radiography and echocardiography."

Tonometry of the femoral artery in healthy dogs and in those with chronic degenerative mitral valve disease. Rodrigo Bernardes Nogueira1, Lucas Anacretto Pereira1, Luciene Barbosa Gomide. Ciência Animal Brasileira. January 2016;17(1). Quote: "Applanation tonometry is a method capable of measuring blood pressure in an artery. In addition to speculation about the reason for the variations in amplitude of femoral pulse waves in dogs with chronic degenerative mitral valve disease (CDMVD), in medicine, it has been demonstrated that many symptoms of heart failure in people are attributable to peripheral vascular functional abnormalities, and they are not highly associated with central hemodynamic parameters. Thus, this study aimed to verify the applicability of the vascular tonometry in dogs, to evaluate the pressure measures of the femoral artery in healthy dogs, and compare them with those of dogs with mitral regurgitation due to CDMVD. Moreover, the parameters established for tonometry were correlated with cardiac index obtained by echocardiography. For this, the data were obtained from 10 healthy dogs and 10 dogs with CDMVD with mitral regurgitation on echocardiography. We observed that the pre-conduction period of the femoral pulse wave was significantly lower in CDMVD than in healthy animals. There was a strong correlation between systolic pressure of the femoral artery with determining parameters of cardiac systolic function in healthy animals. The applanation tonometry of the femoral artery was an applicable technique in dogs."

Comparison of four echocardiographic methods to determine left atrial size in dogs. M. Höllmer, J.L. Willesen, A. Tolver, J. Koch. J. Vet. Cardiology. March 2016. Quote: "Objectives: To compare a linear and three volume-based two-dimensional echocardiographic methods for measuring LA size: left atrium to aorta ratio (LA/Ao ratio), biplane area-length, biplane modified Simpson and monoplane area-length. Animals: One hundred seventy-six client-owned dogs of different breeds, 88 healthy dogs [including 20 cavalier King Charles spaniels] and 88 [including 28 cavalier King Charles spaniels] dogs with myxomatous mitral valve disease of different disease severity. Methods: The left apical four- and two-chamber views were used to measure LA volumes. The right parasternal short-axis view at the level of the heart base was used to measure the LA/Ao ratio. Results: The biplane area-length method yielded 2.8% larger values than those of the biplane modified Simpson method, consistent across the full range of LA volumes. The monoplane area-length method derived on average 5.8% larger values of LA volume than the biplane area-length method. The difference between these two methods was most pronounced at larger LA volumes. The relation between the LA/Ao ratio and LA volume was curvilinear and with increasing LA size these two methods derived very dissimilar values. Conclusions: All methods showed good feasibility and reproducibility, with the volume-based methods having the most favourable intra- and inter-observer variabilities. The LA/Ao ratio underestimates at higher values of LA size compared to the biplane area-length method. LA volume methods may be superior to the LA/Ao ratio in quantification of LA size. The biplane area-length method and biplane modified Simpson method can be used interchangeably. The monoplane area-length measurement may be used as a quick and reliable method for assessment of LA size in clinical practice. "

Systolic arterial blood pressure estimated by mitral regurgitation velocity, high definition oscillometry, and Doppler ultrasonography in dogs with naturally occurring degenerative mitral valve disease. A.S. Hanzlicek, R.D. Baumwart, M.E. Payton. J. Vet. Cardiology. September 2016;18(3):226-233. Quote: "Introduction: To determine if systolic blood pressure estimated by mitral regurgitation (MR) velocity can be used interchangeably with that estimated by high definition oscillometry (HDO) and Doppler ultrasonography (DU) in dogs with naturally occurring mitral valve disease (MVD). Animals: Forty-nine client-owned dogs with naturally occurring MVD. ...  Three dogs had measurements at 2 separate visits resulting in data from 52 hospital visits being included in the study. Fourteen dogs were from mixed breeding. Breeds with more than one dog included Cavalier King Charles Spaniel (n = 6), Chihuahua (6), Schnauzer (5), Maltese (4), Great Dane (2), and Weimaraner (2). The median (interquartile range) body weight was 8.7 kg (8.6). The median age was 10.0 years (3.0).  ... Materials and Methods: This is a retrospective study. Medical records were reviewed and dogs with MR caused by degenerative MVD were included if systolic blood pressure was estimated from MR velocity determined by continuous wave Doppler (CW), DU and HDO at the same visit. A Pearson product moment correlation coefficient was determined for each combination of measures and tested for significance with a paired t-test. Limits of agreement between 2 measures were determined by the 95% confidence interval of the average difference of the means and illustrated by Bland–Altman plots. Results: Systolic pressure estimated from CW was significantly but only moderately correlated to DU (r = 0.42, p=0.0015) and HDO (r = 0.40, p=0.0021). Pressure estimated from DU was significantly but only moderately correlated to HDO (r = 0.57, p≤0.0001). Limits of agreement were wide for all measures including DU and CW (−61.9to 44.6 mmHg), HDO and CW (−65.2to 26.9 mmHg), and HDO and DU (−63.1 to 42.06 mmHg). Discussion: Systolic blood pressure estimated by CW cannot be used interchangeably with HDO or DU in dogs with naturally occurring MVD."

Comparison of the effects of long-term pimobendan and benazepril administration in normal cats. Yuichi Miyagawa, Noboru Machida, Noriko Toda, Yoshinori Tominaga, Naoyuki Takemura. J. Vet. Med. Sci. March 2016. Quote: "Pimobendan (PIMO) can cause adverse effects, such as mitral valve degeneration, in dogs. ... Despite the benefits of treatment, adverse effects have been reported with the use of PIMO in dogs. In a case report of two dogs with mitral insufficiency, a long-term administration of PIMO worsened mitral regurgitation and ventricular hypertrophy. Similarly, in dogs with mild mitral insufficiency, the long-term administration of PIMO was shown to worsen mitral regurgitation and valve lesions. Adverse effects on mitral valves were considered to occur because of increasing cardiac contraction, but it was unclear whether PIMO directly affected the mitral valves."

Vertebral Heart Scale. Amara Estrada, Stacey Fox-Alvarez. Clinician's Brief. April 2016. Quote: "The vertebral heart scale system (ie, vertebral heart size) was developed as a means to objectively evaluate cardiac size among dogs of different breeds and thoracic conformations. Uses of Vertebral Heart Scale: The VHS was established to create a more objective way of diagnosing cardiomegaly via thoracic radiography. Individual dogs can have values that fall outside of the normal range without cardiac disease, so it should not be used as the only means of diagnosing cardiac disease in any given patient. ... Serial measurements and rate of change of VHS have been demonstrated to be predictive of the onset of congestive heart failure in Cavalier King Charles spaniels with mitral valve regurgitation. Several studies Table_1in this breed have shown that the rate of change of VHS on serial radiography (ie, every 6-12 months) remains steady up until 6-12 months prior to onset of CHF, when it increases at a much faster rate. The ACVIM consensus statement on degenerative MVD recommends baseline thoracic radiography for dogs with a new murmur, then annually thereafter. For practitioners adhering to these guidelines, annual calculation of VHS and rate of change from previous imaging should become standard practice and may help identify those patients at higher risk of developing CHF in the coming year. The published range for a normal VHS is 9.2-10.3 on a lateral radiograph, with 10.5 suggested as the cutoff for clinical determination of cardiomegaly in adult dogs. The original guidelines for VHS were designed to be applicable across breeds and conformations, and most dog breeds studied individually fall within the normal range. However, several breeds have normal VHS values that would suggest cardiomegaly using the original scale. Of the breeds evaluated to date, the boxer, bulldog (French and English), Boston terrier, Cavalier King Charles spaniel, Labrador retriever, pug, Pomeranian, and whippet have been found to have average values that are much higher than other dog breeds. New sets of normal values have been developed for use in these breeds. (Table 1).

Assessment of inherited disorders and disorders related to breed standards in pedigree dogs and cats. Douma, P.M. Utrecht Univ. April 2016. Quote: "Concerns about dog breeding within closed populations and thus inevitable inbreeding leading to health issues aren’t new but have taken a flight in the last decade. The Dutch media eagerly pays attention and adds to the growing awareness by means of television and the Internet. Especially unhealthy breed characteristics are getting more and more attention. For the Dutch purebred population valid scientific data are to date not available. In order of the Ministry of Economics a large study has been started that basically wants to answer the pressing questions: Are purebreds really less healthy than crossbreeds? Is there a difference even between a purebred with pedigree and its look-alike without? And, consequently, what can be done if so. Our study is a pilot part of that larger scale study and four breeds (three canine, one feline) have been selected to research the main question: To what extend occur harmful breed characteristics and heritable disorders in The Bernese Mountain Dog, The Dutch Shepherd Dog, the Cavalier King Charles Spaniel and the Maine Coon Cat in the Netherlands. To answer this question we first extensively studied literature to get quantitative information and form an initial idea of the problems occurring within these breeds. We categorised those in three lists. Secondly, we analysed information collected from the clinical database of the University Clinic for Companion Animals (UKG) in Utrecht, the Netherlands, which provide us with qualitative information. In result we combined the two to form a final A-list: a list with the most important disorders for this breed in the Netherlands."

Cardiac contractility: Correction strategies applied to telemetry data from a HESI-sponsored consortium. Emmanuel Boulay, Michael K. Pugsley, Vincent Jacquemet, Alain Vinet, Michael V. Accardi, Maxim Soloviev, Eric Troncy, Jennifer M. Doyle, Jennifer Beck Pierson, Simon Authiera. J. Pharma. & Toxicol. Methods. April 2016. Quote: Introduction: QT has a long history of heart rate (HR) correction but limited investigations have been undertaken to assess the impact of cardiovascular parameters on left ventricular (LV) contractility in drug safety testing. Cardiac contractility is affected by preload (Cyon-Frank-Starling law), afterload (Anrep effect) and HR (Bowditch effect). We evaluated multi-parameter correction methods to help with dP/dtmax interpretation. Methodology: Modeling was undertaken using data from dogs in single or double 4 × 4 Latin square studies. Correction models (16 fitting formulas × 2 modeling approaches (universal and individualized) × 2 correction approaches (linear or proportional)) were evaluated. 3D/2D cloud analysis of the beat-to-beat data for the control, pimobendan, and either itraconazole or atenolol groups were used to evaluate correlations between parameters and derive an optimal correction method. Results: Cardiac contractility (i.e., dP/dtmax) was best correlated to HR and systolic LV pressure with a correlation coefficient of 0.8. In decreasing order, dP/dtmin, mean arterial blood pressure (BP), systolic BP, diastolic BP, arterial pulse pressure and LV end diastolic pressure (LVEDP) showed a reduced correlation to dP/dtmax. Subject-specific models improved the correction by up to 14% when compared to universal correction models. The non-linear correction model was superior to the linear model. Discussion: Results suggest that the optimal correction formula for dP/dtmax would be subject-specific, non-linear and would include HR and LV systolic pressure. Correcting contractility for HR and systolic LV pressure may enhance data interpretation in non-clinical drug safety assessments. Similar correction methods could be evaluated for other species used in safety pharmacology.

Two-dimensional left atrium–to–aorta ratios and left ventricular M-mode transthoracic echocardiographic measurements in clinically normal adult Dachshunds. Chee Kin Lim, Geoffrey T. Fosgate, Henry W. Green III, Robert M. Kirberger. Amer. J. Vet. Res. April 2016;77(4):374-382. Quote: Objective: To estimate the left atrium–to–aorta ratio (LA:Ao) and establish 95% prediction intervals for left ventricular M-mode transthoracic echocardiographic measurements in clinically normal adult Dachshunds. Animals: 40 healthy Dachshunds. Procedures: For each dog, 3 standard 2-D echocardiographic methods (diameter, circumference, and cross-sectional area) were used to measure the left atrium and aorta and calculate the LA:Ao from right parasternal short axis (RPSA) images obtained at the level of the aortic valve cusps. Left ventricular M-mode measurements were acquired from RPSA images obtained at the chordal level immediately below the mitral valve. Descriptive data were generated, and the 95% prediction intervals were calculated by use of an allometric scaling equation and linear regression and compared with those calculated on the basis of data obtained from dogs of multiple breeds in a previous study. Results: The mean (SD) LA:Ao was 1.40 (0.13), 2.09 (0.17), and 2.85 (0.48) for the diameter, circumference, and cross-sectional area methods, respectively. The 95% prediction intervals for the left ventricular M-mode measurements determined by an allometric scaling equation on the basis of Dachshund-specific data were narrower than those determined on the basis of data obtained from dogs of multiple breeds. For that allometric equation, scaling exponents on the basis of Dachshund-specific data ranged from 0.129 to 0.397 and did not absolutely conform to the presumed index for linear measurements (ie, body weight0.333). Conclusions and Clinical Relevance: The LA:Aos and 95% prediction intervals calculated in this study can be used as preliminary guidelines for echocardiographic measurements of clinically normal Dachshunds. ... The mean LA:Ao for the clinically normal Dachshunds of the present study was markedly different from the mean LA:Ao for clinically normal CKCSs in another study, even though the body weights for the Dachshunds (range, 5.0 to 12.6 kg) and CKCSs (5.5 to 11.9 kg) were similar. The LA:Ao as determined by the diameter method was < 1.67 for all the Dachshunds of the present study and < 1.28 for all the CKCSs of that other study. The difference in the LA:Ao between those 2 breeds may be attributable to sample population differences, observer variability, or breed differences. The present study did not include any Dachshunds with MMVD; therefore, the proportion of Dachshunds with MMVD that might have a LA:Ao less than the upper limit observed for the clinically normal Dachshunds of this study is unknown.

Evidence-based medicine has been hijacked: a report to David Sackett. John P. A. Ioannidis. J. Clinical Epidemiology. May 2016. Quote: This is a confession building on a conversation with David Sackett in 2004 when I shared with him some personal adventures in evidence-based medicine (EBM), the movement that he had spearheaded. The narrative is expanded with what ensued in the subsequent 12 years. EBM has become far more recognized and adopted in many places, but not everywhere, for example, it never acquired much influence in the USA. As EBM became more influential, it was also hijacked to serve agendas different from what it originally aimed for. Influential randomized trials are largely done by and for the benefit of the industry. Meta-analyses and guidelines have become a factory, mostly also serving vested interests. National and federal research funds are funneled almost exclusively to research with little relevance to health outcomes. We have supported the growth of principal investigators who excel primarily as managers absorbing more money. Diagnosis and prognosis research and efforts to individualize treatment have fueled recurrent spurious promises. Risk factor epidemiology has excelled in salami-sliced data-dredged articles with gift authorship and has become adept to dictating policy from spurious evidence. Under market pressure, clinical medicine has been transformed to finance-based medicine. In many places, medicine and health care are wasting societal resources and becoming a threat to human well-being. Science denialism and quacks are also flourishing and leading more people astray in their life choices, including health. EBM still remains an unmet goal, worthy to be attained. ... With clinical evidence becoming an industry advertisement tool and with much “basic” science becoming an annex to Las Vegas casinos, how about the other pieces of EBM, for example, diagnosis and prognosis and individualizing care?

Comparison of four echocardiographic methods to determine left atrial size in dogs. M. Höllmer, J.L. Willesen, A. Tolver, J. Koch. J. Vet. Cardiology. June 2016;18(2):137-145. Quote: Objectives: To compare a linear and three volume-based two-dimensional echocardiographic methods for measuring LA size: left atrium to aorta ratio (LA/Ao ratio), biplane area-length, biplane modified Simpson and monoplane area-length. Animals: One hundred seventy-six client-owned dogs of different breeds, 88 healthy dogs and 88 dogs with myxomatous mitral valve disease of different disease severity. Methods: The left apical four- and two-chamber views were used to measure LA volumes. The right parasternal short-axis view at the level of the heart base was used to measure the LA/Ao ratio. Results: The biplane area-length method yielded 2.8% larger values than those of the biplane modified Simpson method, consistent across the full range of LA volumes. The monoplane area-length method derived on average 5.8% larger values of LA volume than the biplane area-length method. The difference between these two methods was most pronounced at larger LA volumes. The relation between the LA/Ao ratio and LA volume was curvilinear and with increasing LA size these two methods derived very dissimilar values. Conclusions: All methods showed good feasibility and reproducibility, with the volume-based methods having the most favourable intra- and inter-observer variabilities. The LA/Ao ratio underestimates at higher values of LA size compared to the biplane area-length method. LA volume methods may be superior to the LA/Ao ratio in quantification of LA size. The biplane area-length method and biplane modified Simpson method can be used interchangeably. The monoplane area-length measurement may be used as a quick and reliable method for assessment of LA size in clinical practice.

Beyond Furosemide: the Role of Diuretics in Congestive Heart Failure Part 2: Spironolactone. Marisa K. Ames, Clarke E. Atkins. Today's Vet. Pract. J. May 2016. Quote: Diuretics are a critical component of the pharmacotherapy of congestive heart failure (CHF). In humans with heart failure, 90% receive at least one diuretic. If these, loop diuretics—furosemide, bumetanide, and torsemide—are the most potent and commonly used diuretics. ... Loop diuretics are pyridine-3-sulfonurea drugs that act on the thick portion of the nephron’s ascending loop of Henle, where they inhibit the sodium–potassium–chloride (Na+–K+–2Cl–) cotransporter, leaving sodium (and other ions) to be lost, with water, in the urine. ... When a single drug is administered in humans, furosemide is given 87% of the time. Furosemide has been, and remains, the diuretic of choice for acute and chronic management of CHF in both humans and animals since its release in 1966. However, other interesting options are now available, including: • Torsemide, a loop diuretic that can be used as an adjunct or alternative to furosemide; • Spironolactone, a weak, potassium-sparing diuretic and mineralocorticoid receptor (MR) blocker that is used primarily for additional blockade of the renin–angiotensin–aldosterone system (RAAS). In heart failure, it typically accompanies a more potent diuretic, such as furosemide.

Characterization of an investigative safety pharmacology model to assess comprehensive cardiac function and structure in chronically instrumented conscious beagle dogs. Regan CP, Stump GL, Detwiler TJ, Chen L, Regan HK, Gilberto DB, DeGeorge JJ, Sannajust FJ. J. Pharmacol. Toxicol. Methods. May 2016. Quote: There has been an increasing need to conduct investigative safety pharmacology studies to complement regulatory-required studies, particularly as it applies to a comprehensive assessment of cardiovascular (CV) risk. Methods: We describe refined methodology using a combination of telemetry and direct signal acquisition to record concomitant peripheral hemodynamics, ECG, and left ventricular (LV) structure (LV chamber size and LV wall thickness) and function, including LV pressure-volume (PV) loops to determine load independent measures of contractility (end systolic elastance, Ees, and preload recruitable stroke work, PRSW) in conscious beagle dogs. Following baseline characterization, 28days of chronic rapid ventricular pacing (RVP) was performed and cardiac function monitored: both as a way to compare measures during development of dysfunction and to characterize feasibility of a model to assess CV safety in animals with underlying cardiac dysfunction. Results: While ±dP/dT decreased within a few days of RVP and remained stable, more comprehensive cardiac function measurements, including Ees and PRSW, provided a more sensitive assessment confirming the value of such endpoints for a more clear functional assessment. After 28days of RVP, the inodilator pimobendan was administered to further demonstrate the ability to detect changes in cardiac function. Expectedly pimobendan caused a leftward shift in the PV loop, improved ejection fraction (EF) and significantly improved Ees and PRSW. Discussion: In summary, the data show the feasibility and importance in measuring enhanced cardiac functional parameters in conscious normal beagle dogs and further describe a relatively stable cardiac dysfunction model that could be used as an investigative safety pharmacology risk assessment tool.

Emerging Interventions for Mitral Regurgitation. Christopher Orton. ACVIM Forum 2016. Quote: Mitral regurgitation (MR) is classified etiologically as primary (organic) or functional (secondary). Primary MR is defined as MR caused by a primary leaflet abnormality. Causes of primary MR include degenerative (myxomatous) disease, endocarditis, congenital defects, rheumatic heart disease, and certain serotoninergic drugs. Functional MR (FMR) results from left ventricular remodeling and/or dysfunction associated with primary cardiomyopathies. In dilated forms of primary cardiomyopathy (idiopathic, ischemic), FMR results from the combined effects of displacement of the papillary apparatus leading to restrictive leaflet motion and dilation of the mitral annulus. For purposes of surgical mitral valve repair, MR has been classified functionally by Carpentier as Type I (annular dilation), Type II (leaflet prolapse), and Type III (restrictive leaflet motion).1 For chronic severe degenerative MR, the functional classification would include both a Type I and Type II defect. Interventional therapies for correction of MR take into consideration both its etiologic and functional classification.

Efficacy of bronchial stenting in dogs with myxomatous mitral valve disease and bronchial collapse. Dar Ozer, Samantha Siess, Brienne Williams, Nikki Gaudette, George Kramer. J. Vet. Int. Med. June 2016. 2016 ACVIM Forum Abstract C-03. Quote: Chronic airway disease and myxomatous mitral valve disease (MMVD) are frequent comorbidities in small breed dogs. Bronchial collapse can cause coughing, tachypnea and hypoxemia. Pulmonary hypertension can be seen with both MMVD and chronic airway disease. The purpose of this study was to review outcomes in dogs that had bronchial stents placed due to bronchial collapse. It was hypothesized that moderate to severe MMVD or the presence of pulmonary hypertension would not have a negative effect on lifespan after stent placement. Medical records of 18 small breed dogs that had bronchial stent placement for chronic coughing secondary to bronchial collapse were reviewed. A hierarchical multiple linear regression analysis was conducted to predict lifespan after bronchial stent placement based on age at time of stent placement, severity of MMVD and the presence of pulmonary hypertension. Eighteen dogs had bronchial stents placed over a period of 7 years. Age at the time of stent placement ranged from 6.5 years to 14 years of age (M = 10.47 1.85). Breeds represented included Cavalier King Charles spaniel (2), beagle (2), Chihuahua (4), Pomeranian (3), toy poodle (2), Yorkshire terrier (2), Maltese (1), Coton de Tulear (1) and shih tzu (1). There were 11 males and 7 females. Twelve dogs (66.67%) had evidence of moderate to severe MMVD and 4 (22.22%) had evidence of pulmonary hypertension. Six dogs (33.33%) had CHF prior to stent placement and 6 dogs (33.33%) had CHF after stent placement. Syncope was reported in 6 dogs prior to stent placement and 5 dogs after stent placement. The average lifespan after stent placement was 203.56 250.72 days. Three dogs are currently alive post-stent placement (1013, 559 and 411 days). A hierarchical multiple linear regression was calculated to predict lifespan after placement of a bronchial stent based on age at the time of stent placement, the presence of pulmonary hypertension, and severity of MMVD. In stage one, age at the time of stent placement significantly predicted lifespan after placement of a bronchial stent (b = 7.10, P < .02); with lifespan decreasing by 7.10 days for each additional month of age at the time of stent placement. The presence of pulmonary hypertension did not significantly predict lifespan (b = 235.32, P = .10). Severity of MMVD did not contribute significantly to the model in stage two (b = 101.38, P = 0.43). Results from this study indicate that the severity of MMVD or the presence of pulmonary hypertension did not negatively affect lifespan after bronchial stent placement. As such, moderate to severe MMVD and the presence of pulmonary hypertension should not be viewed as exclusion criteria when assessing candidates for possible bronchial stenting. Prospective studies should be conducted to further investigate the clinical benefit of bronchial stenting in dogs with severe bronchial collapse.

Medical management and survival time associated with congestive heart failure Stage D: a retrospective study. Amelie Beaumier, John E. Rush, Lisa M. Freeman. J. Vet. Int. Med. June 2016. 2016 ACVIM Forum Abstract C-09. Quote: Degenerative mitral valve disease (DMVD) is the most common acquired heart disease in dogs. The ACVIM consensus statement for dogs with DMVD provided recommendations for diagnosis and management of Stages A through D. Recommendations for Stage D were limited by the paucity of published information for dogs with advanced congestive heart failure (CHF). The objective of this retrospective study was to investigate the survival and treatment of dogs diagnosed with stage D CHF. For the purpose of this study, we defined stage D as the persistence of CHF despite receiving the label-approved dose of pimobendan, an angiotensin-converting-enzyme inhibitor (ACEI), and furosemide ≥4 mg/kg/day. Dogs receiving a dosage of furosemide <4 mg/kg/day were enrolled only if the dose was increased to ≥4 mg/kg/day and if a new medication to control CHF was introduced at the same visit. Forty-three dogs (27 male and 16 female, all neutered) met eligibility criteria and were included in the study. Mean age at the time of diagnosis of Stage D CHF was 10.1 ± 1.8 years. The most common breeds represented were Cavalier King Charles spaniel (n = 9), Chihuahua (n = 4), Dachshund (n = 4), and Shih Tzu (n = 3). Twelve dogs were hospitalized on the day of diagnosis of stage D CHF [median duration of hospitalization = 1 day (range, 1–3 days)]. The median duration between the first diagnosis of CHF and diagnosis of stage D was 157 days (range, 11–743 days). At the time of diagnosis of stage D, 29 dogs had medications added [1 medication added (n = 26), >1 medication added (n = 3)], the diuretic dose was escalated in 27 dogs, and the pimobendan dose was increased to >0.6 mg/kg/day in 20 dogs. Thirty-two (74%) dogs had subsequent additional changes in medications during the course of stage D CHF. Most dogs (n = 31; 72%) dogs were ultimately receiving at least 5 cardiac medications for the management of stage D CHF. Ultimate medication dosages during Stage D were: Furosemide (7.4 ± 2.7 mg/kg/day), pimobendan (1.0 ± 0.3 mg/kg/day), and ACEI (0.9 ± 0.2 mg/kg/day). Additional medications administered to these dogs included spironolactone (n = 31), sildenafil (n = 21), torsemide (n = 16), digoxin (n = 8), and hydrochlorothiazide with spironolactone (n = 8). Median survival time after onset of Stage D CHF was 311 days (range, 9–658 days), with 14 dogs still alive at the time of analysis. Multiple medication adjustments were necessary to manage dogs with stage D CHF. However, the survival time may be encouraging to the dedicated owner.

Immunohistochemical study of the pronatriuretic peptide convertase corin in severe canine myxomatous mitral valve disease. Alex Sahagian, Chris Lam, Bob Bao, Sanaz Maleki, Brett Hambly, Niek Beijerink. J. Vet. Int. Med. June 2016. 2016 ACVIM Forum Abstract C-11. Quote: Corin is expressed by cardiomyocytes and converts pro-natriuretic peptides to their mature forms, which play a key role in fluid homeostasis and cardiac remodelling. In mice and human with failing hearts, myocardial corin protein levels have been reported to be increased, however without a concomitant increase in corin activity. These findings can partly explain the clear paradox in congestive heart failure (CHF) in that the natriuretic peptides are elevated, yet the body is fluid retaining (ultimately resulting in CHF). Interestingly in the Cavalier King Charles Spaniel, 2 loci associated with development of myxomatous mitral valve disease (MMVD) have been identified. Corin is on one of these loci on the latest dog assembly. This further raises the question whether deficiencies in myocardial corin expression or activity could be a mechanism explaining the progression of heart disease and CHF in dogs as well. The purpose of this study therefore was to characterize the immunohistochemical expression of corin in myocardial tissue in normal dogs and in dogs with severe MMVD. Two groups of dogs of a variety of breeds were recruited including 5 control dogs (euthanized for severe non-cardiac disease; age range 4 months-12 years), and 6 dogs with severe MMVD (euthanized for refractory CHF; age range 9-14 years). Samples were collected from the right atrium (RA), right ventricle (RV), left atrium (LA), left ventricle (LV) and interventricular septum (IVS). Immunohistochemical staining of all tissues with a polyclonal rabbit anti-human antibody against corin was carried out, and computational quantification was used to compare the staining density between the two groups and between cardiac regions. Positive transmembrane and intracellular immunostaining for corin was widely observed in all parts of the myocardium in both groups. Corin expression was not up- or downregulated in any of the cardiac chambers of the dogs with severe MMVD (figure 1), nor was any difference seen between the chambers within each group. Our results indicate that corin expression might be a rate-limiting step in dogs with CHF due to MMVD. A lack of an increase in corin expression or activation can be postulated to be a possible important pathophysiological mechanism responsible for the natriuretic peptide paradox in dogs with CHF, and warrants further investigation.

Figure 1: Quantitative corin expression in myocardial tissue in control dogs, and in dogs with congestive heart failure secondary to myxomatous mitral valve disease.Figure 1: Quantitative corin expression in myocardial tissue in control dogs, and in dogs with congestive heart failure secondary to myxomatous mitral valve disease.

Low-density lipoprotein oxidation is breed and gender dependent in dogs with myxomatous mitral valve disease. Maria Josefine Reimann, Jens Häggström, Jacob Eifer Møller, Jens Lykkesfeldt, Torkel Falk, Lisbeth Høier Olsen. J. Vet. Int. Med. June 2016. 2016 ACVIM Forum Abstract C-14. Quote: Oxidative stress has been associated cardiovascular disease and suggested to contribute to cardiac remodeling in human patients with mitral regurgitation. Few previous studies have evaluated the relationship between oxidative stress and myxomatous mitral valve disease (MMVD) in dogs. The objective of this study was to determine plasma concentrations of certain markers of oxidative stress and investigate if they were associated with MMVD severity, selected clinical variables and disease progression in dogs with no or different severities of MMVD. The study included 89 privately-owned dogs: 14 healthy control Beagles, 59 cavalier King Charles spaniels (CKCS) with different severities of MMVD, and 16 dogs of different breeds with clinical signs of congestive heart failure due to MMVD. Markers of oxidative stress including malondialdehyde (MDA), oxidized low-density lipoprotein (oxLDL) and vitamin E (a-tocopherol and c-tocopherol) were measured in plasma and their influence on 2-year progression of MMVD was determined. Plasma oxLDL concentration was significantly lower in control Beagles compared to CKCS (P = 0.0005) and females had a significantly lower oxLDL plasma concentration compared to males (P = 0.007). Plasma vitamin E concentrations were associated with body condition score (BCS) (a-tocopherol, P = 0.002; c-tocopherol, P = 0.01). All the markers of oxidative stress (MDA, oxLDL, vitamin E) were positively associated with serum cholesterol (P ≤ 0.02) but none of the markers were associated with severity or progression of MMVD. The effect of BCS disappeared when adjusting for serum cholesterol concentration. In conclusion, Beagles and female dogs appear to have lower plasma concentrations of oxLDL. The results cannot confirm a role of oxidative stress in dogs with MMVD.

Angiotensin converting enzyme activity in cavalier King Charles spaniels with an ACE gene polymorphism. Kathryn Meurs, Maria Josefine Reimann, Lisbeth Høier Olsen. J. Vet. Int. Med. July 2016;30(4):1428(C17). Quote: The Cavalier King Charles Spaniel is one of the most commonly reported breeds of dogs affected with myxomatous mitral valve disease (MMVD). Angiotensin converting enzyme (ACE) inhibitors are frequently recommended for management of dogs with MMVD. However, the benefit of ACE inhibition in MMVD before congestive heart failure has developed is controversial with different studies showing conflicting results. A variable response to ACE inhibitor therapy has also been observed in human beings with heart disease and has been attributed to a polymorphism in the ACE gene. We have previously demonstrated a polymorphism in the canine ACE gene in small breed dogs. We hypothesized that the polymorphism would be common in CKCS dog and that this would impact ACE activity. We collected DNA and plasma samples from CKCS with MMVD. All dogs were genotyped for the known ACE polymorphism. Plasma samples were collected and analyzed for ACE activity measurement with a radioimmunoassay. A t test was used to compare ACE activity in the wildtype (control sequence) and DNA variant groups. Sixty-two dogs were evaluated. Genotypes of 38 (61%) dogs were homozygous for the DNA variant, 3 (5%) were heterozygous and 21 (34%) were homozygous for the wild type (normal canine sequence). Samples from 40 dogs were submitted for ACE analysis including 20 homozygous for the wild type and 20 homozygous for the variant. Median baseline ACE activity was significantly lower for dogs homozygous for the DNA variant (25.0 U/L) than for dogs with the wildtype sequence (31.0 U/L) (P = 0.02). We conclude that the ACE polymorphism appears to be common in the CKCS and dogs that are homozygous for the ACE variant have lower baseline levels of ACE activity. Further study is warranted to evaluate the clinical importance of these findings. (See also this December 2017 article.)

Why Most Clinical Research Is Not Useful. John P. A. Ioannidis, PLOS Medicine. June 2016. Quote: Practicing doctors and other health care professionals will be familiar with how little of what they find in medical journals is useful. The term “clinical research” is meant to cover all types of investigation that address questions on the treatment, prevention, diagnosis/screening, or prognosis of disease or enhancement and maintenance of health. Experimental intervention studies (clinical trials) are the major design intended to answer such questions, but observational studies may also offer relevant evidence. “Useful clinical research” means that it can lead to a favorable change in decision making (when changes in benefits, harms, cost, and any other impact are considered) either by itself or when integrated with other studies and evidence in systematic reviews, meta-analyses, decision analyses, and guidelines. Blue-sky research cannot be easily judged on the basis of practical impact, but clinical research is different and should be useful. It should make a difference for health and disease outcomes or should be undertaken with that as a realistic prospect. Many of the features that make clinical research useful can be identified, including those relating to problem base, context placement, information gain, pragmatism, patient centeredness, value for money, feasibility, and transparency. Many studies, even in the major general medical journals, do not satisfy these features, and very few studies satisfy most or all of them. Most clinical research therefore fails to be useful not because of its findings but because of its design. The forces driving the production and dissemination of nonuseful clinical research are largely identifiable and modifiable. Reform is needed. Altering our approach could easily produce more clinical research that is useful, at the same or even at a massively reduced cost.

Anaesthesia of the patient with cardiovascular disease part 2: anaesthesia for specific disorders. Stefania Scarabelli, Carl Bradbrook. UK-Vet Companion Anim. June 2016;21(6):337-344. Quote: Specific disease considerations: Myxomatous mitral valve disease: Myxomatous mitral valve disease (MMVD) is the most common cause of mitral valve regurgitation (MVR) in small animals, with a prevalence of approximately 30% in small breed dogs over the age of 10 years. The time course of the disease influences the clinical symptoms. If MVR occurs slowly, there is time for compensation and the animal may be asymptomatic; if MVR develops acutely, the clinical signs can be very severe. With MVR there is a decrease in stroke volume because part of the outflow of the left ventricle (LV) is directed back to the left atrium (LA). The regurgitant fraction causes volume overload of the LA and LV, according to Laplace’s law. Volume overload increases wall stress, which in turn requires greater adenosine triphosphate (ATP) and O2 consumption. As a compensatory mechanism, myocardial hypertrophy occurs. The chronic volume overload of the LA can lead to dilation of the atrium, with increased pressure and pulmonary congestion, resulting in pulmonary oedema and congestive heart failure (CHF). Possible complications of MMVD are right-sided CHF, due to direct involvement of the tricuspid valve or as a consequence of pulmonary hypertension (PH), and arrhythmias, such as atrial fibrillation (AF), due to atrial enlargement.

Electrocardiographic Changes in Dogs with Degenerative Mitral Valve Disease Treated with Pimobendan: a Retrospective Study of 29 Cases. Sirilak Disatian Surachetpong, Nisarat Boonlue, Pasorn Pupa, Waratsarin Boonsathitanan, Sumanee Rakthaidee, Tanawan Mangklabruks, Siriwan Sakarin. Thai J. Vet. Med. June 2016;46(2):243-249. Quote: The aim of this retrospective study was to evaluate changes in electrocardiograms (ECG) and cardiac arrhythmias in 29 dogs with degenerative mitral valve disease (DMVD) treated with pimobendan chronically. All dogs had normal ECG before pimobendan administration. The dogs were classified according to ECG after pimobendan administration into 2 groups: normal ECG (n=19) and abnormal ECG (n=10). Age, sex, breed, serum alkaline phosphatase, concurrent digoxin administration, total daily dosage of pimobendan and digoxin, duration of pimobendan administration, and ECG parameters including heart rate, P wave, PR interval, QRS complex, and QT interval were analyzed. Nineteen dogs had normal ECG and ten dogs had abnormal ECG after treated with pimobendan. ... Eight of the ten dogs had increased alkaline phosphatase after being treated with pimobendan. ... Five dogs were treated with pimobendan for a month. Two out of these dogs had abnormal ECG. Eight of fourteen dogs treated with pimobendan for more than a month had abnormal ECG. ... The earliest time to detect cardiac arrhythmias in the population of dogs in this study was a month after the pimobendan treatment. Types of cardiac arrhythmias included atrial fibrillation, sinus tachycardia, second degree AV block, ventricular premature beat, and junctional premature beat. These arrhythmias were similar to the evaluation study of safety and effectiveness of pimobendan (Vetmedin, 2007). The majority of dogs with cardiac arrhythmias in the present study had atrial fibrillation. ... In conclusion, cardiac arrhythmias may develop in some dogs treated chronically with pimobendan, especially in dogs treated with a higher dosage of pimobendan and/or in combination with digoxin. ECG monitoring should be performed in dogs chronically administered with pimobendan.

Pre-Operative Left Ventricular Torsion, QRS Width/CRT, and Post-Mitral Surgery Outcomes in Patients With Nonischemic, Chronic, Severe Secondary Mitral Regurgitation. Yuichi Notomi, Tadashi Isomura, Shunichi Kanai, Masami Maeda, Joji Hoshino, Taichi Kondo, Yasuhisa Fukada, Koji Furukawa. JACC: Basic to Translational Science. June 2016;1(4):193-202. Quote: Highlights: • Determining which patients with nonischemic, chronic, secondary severe mitral regurgitation (NICSMR) will benefit from mitral surgery (MS) is a clinical dilemma. • Left ventricle (LV) torsion (which is a shear strain, not volume strain such as ejection fraction and originates in LV myocardial architectures) may reveal the myopathic conditions and reflect intra-LV electrical conduction. • The LV torsional profile predicted post-MS outcomes in NICSMR patients with a narrow QRS combination of the Q wave, R wave and S wave) but not in those with a wide QRS. • The findings may help to resolve the clinical dilemma and identify appropriate candidates for mitral surgery (and other resources) in patients with NICSMR.

Concise Review: Stem Cell Trials Using Companion Animal Disease Models. Andrew M. Hoffman, Steven W. Dow. Stem Cells. July 2016;34(7):1709-1729. Quote: Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more realistic animal models. In veterinary medicine, companion animals naturally develop many diseases that resemble human conditions, therefore, representing a novel source of preclinical models. To understand how companion animal disease models are being studied for this purpose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in dogs and cats, excluding laboratory animals, induced disease models, cancer, and case reports. Disease models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopathy, inflammatory bowel diseases, Crohn's fistulas, meningoencephalomyelitis (multiple sclerosis-like), keratoconjunctivitis sicca (Sjogren's syndrome-like), atopic dermatitis, and chronic (end-stage) kidney disease. Stem cells evaluated in these studies included mesenchymal stem-stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autologous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints and protocols were feasible, and the stem cell therapies were reportedly safe and elicited beneficial patient responses in all but two of the trials. In conclusion, companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. However, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models.

Impact of collaborative care on survival time for dogs with congestive heart failure and revenue for attending primary care veterinarians. Bonnie K. Lefbom, Neal K. Peckens. J. Amer. Vet. Med. Assn. July 2016;249(1):72-76. Quote: Objective: To assess the effects of in-person collaborative care by primary care veterinarians (pcDVMs) and board-certified veterinary cardiologists (BCVCs) on survival time of dogs after onset of congestive heart failure (CHF) and on associated revenue for the attending pcDVMs. Design: Retrospective cohort study. Animals: 26 small-breed dogs treated for naturally occurring CHF secondary to myxomatous mitral valve disease at a multilocation primary care veterinary hospital between 2008 and 2013. Procedures: Electronic medical records were reviewed to identify dogs with confirmed CHF secondary to myxomatous mitral valve disease and collect information on patient care, survival time, and pcDVM revenue. Data were compared between dogs that received collaborative care from the pcDVM and a BCVC and dogs that received care from the pcDVM alone. Results: Dogs that received collaborative care had a longer median survival time (254 days) than did dogs that received care from the pcDVM alone (146 days). A significant positive correlation was identified between pcDVM revenue and survival time for dogs that received collaborative care (ie, the longer the dog survived, the greater the pcDVM revenue generated from caring for that patient). Conclusions and Clinical Relevance: Findings suggested that collaborative care provided to small-breed dogs with CHF by a BCVC and pcDVM could result in survival benefits for affected dogs and increased revenue for pcDVMs, compared with care provided by a pcDVM alone.

Serum Fatty Acid Compositions in Dogs with Mitral Insufficiency. Hiroki Yoshimatsu, Hirotaka Matsumoto, Masanari Minamoto, Ryohei Suzuki, Yohei Mochizuki, Takahiro Teshima, Hidekazu Koyama. Advances in Animal Cardiology. July 2016;49(1):11-16. Quote: Fatty acids are a major source of energy in the normal myocardium and are taken up passively from the bloodstream. However, with heart failure, the use of fatty acids decreases in the myocardium. Therefore, serum fatty acid concentrations in dogs with mitral insufficiency (MI) might differ from those in normal dogs. The present study was designed to determine the serum fatty acid compositions in dogs with different severities of MI according to the classification proposed by the International Small Animal Cardiac Heart Council (ISACHC) and to elucidate the relationships between the determined compositions and echocardiographic parameters. In total, 30 dogs with MI were divided into 3 groups (I [13 dogs including 4 CKCSs], II [8 dogs, no CKCSs], and III [9 dogs, including 3 CKCSs]) according to the ISACHC classification of MI severity. The healthy group consisted of 12 dogs [1 CKCS] matched with the MI groups for age and body weight. The serum concentrations of 13 fatty acids were measured by gas chromatography. The levels of linoleic acid (LA), docosatetraenoic acid (DTA), and arachidonic acid (AA) in group I were significantly lower than those in the healthy group (p<0.05). The levels of eicosapentaenoic acid (EPA) and AA in group II were significantly lower than those in the healthy group (p<0.05). The level of EPA in group III was significantly lower than that in the healthy group (p<0.05). In addition, the ratio of EPA to AA levels (EPA/AA ratio) in group III was significantly lower than that in the healthy group (p<0.05). With regard to the relationships between fatty acid concentrations in all MI groups (I through III) and echocardiographic parameters, the levels of AA and DTA showed a significant positive correlation with the ratio of left ventricular end-diastolic internal diameter to aortic diameter (LVIDd/Ao ratio) (AA, r=0.396 and p=0.048; DTA, r=0.426 and p=0.027). In addition, the docosapentaenoic acid (DPA) level correlated negatively with fractional shortening (r=-0.437 and p=0.023). Furthermore, the EPA/AA ratio correlated negatively with the ratio of left atrial to aortic diameters (r=-0.383 and p=0.048). The fatty acid concentrations and ratios in the dogs with 3 types of MI according to the ISACHC classification differed from those in healthy dogs. Some of these concentrations and ratios correlated with echocardiographic parameters.

Evaluation of whole blood hemostasis with thromboelastography in Cavalier King Charles spaniels with different severities of myxomatous mitral valve disease. J. Öberg, I. Lilliehöök, K. Höglund, I. Ljungvall. Vet. Clinical Pathology. July 2016. Quote: Background: Previous studies investigating hemostatic function in Cavalier King Charles spaniel (CKCS) dogs with different severities of myxomatous mitral valve disease (MMVD) have shown divergent results. Macrothrombocytosis, commonly seen in CKCS, is possibly affecting the hemostatic function. Objective: Investigate potential associations between thromboelastographic (TEG) variables (R, angle, K, MA, G) and dog characteristics, echocardiographic variables, heart rate, systolic blood pressure, and presence of macrothrombocytosis in CKCS. Methods: A total of 50 prospectively recruited client-owned CKCS dogs were evaluated by echocardiography and classified into healthy, mild, and moderate to severe MMVD groups. Blood samples were analyzed using TEG and hematology analyzers. Macrothrombocytosis assessment was based on mean platelet volume. Results: No differences were detected between MMVD severity groups and TEG variables. Unilinear regression analyses showed that left ventricular (LV) fractional shortening (FS%) increased with decreasing TEG K (r² = .23, P = .0004), and TEG R (r² = .09,P= .041), and with increasing angle (r² = .22, P = .0006), MA (r² = .13, P = .01) and G (r² = .15, P = .0067). Associations between LV FS% and TEG variables were confirmed in the multiple regression analysis. Macro-thrombocytosis was associated with increased TEG MA and G. An association between increasing age and a more hypercoagulable pattern was demonstrated by TEG variables. Conclusions and Clinical Importance: Increased LV FS%, macrothrombocytosis, and age were shown to be associated with a more activated hemostasis, which might have an implication in MMVD progression in CKCS.

Platelet function and activation in Cavalier King Charles Spaniels with subclinical chronic valvular heart disease. Linda J. Tong, Giselle L. Hosgood, Anne T. French, Peter J. Irwin, Robert E. Shie. Amer. J. Vet. Res. August 2016;77(8):860-868. Quote: Objective: To assess platelet closure time (CT), mean platelet component (MPC) concentration, and platelet component distribution width (PCDW) in dogs with subclinical chronic valvular heart disease. Animals: 89 Cavalier King Charles Spaniels (CKCSs) and 39 control dogs (not CKCSs). Procedures: Platelet count, MPC concentration, PCDW, and Hct were measured by use of a hematology analyzer, and CT was measured by use of a platelet function analyzer. Murmur grade and echocardiographic variables (mitral valve regurgitant jet size relative to left atrial area, left atrial-to-aortic diameter ratio, and left ventricular internal dimensions) were recorded. Associations between explanatory variables (sex, age, murmur grade, echocardiographic variables, platelet count, and Hct) and outcomes (CT, MPC concentration, and PCDW) were examined by use of multivariate regression models. Results: A model with 5 variables best explained variation in CT (R2, 0.74), with > 60% of the variance of CT explained by mitral valve regurgitant jet size. The model of best fit to explain variation in MPC concentration included only platelet count (R2, 0.24). The model of best fit to explain variation in PCDW included platelet count and sex (R2, 0.25). Conclusions and Clinical Relevance: In this study, a significant effect of mitral valve regurgitant jet size on CT was consistent with platelet dysfunction. However, platelet activation, as assessed on the basis of the MPC concentration and PCDW, was not a feature of subclinical chronic valvular heart disease in CKCSs.

The dog aging project: translational geroscience in companion animals. Matt Kaeberlein, Kate E. Creevy, Daniel E. L. Promislow. Mamm Genome. August 2016;27(7-8):279-288. Quote: Studies of the basic biology of aging have identified several genetic and pharmacological interventions that appear to modulate the rate of aging in laboratory model organisms, but a barrier to further progress has been the challenge of moving beyond these laboratory discoveries to impact health and quality of life for people. The domestic dog, Canis familiaris, offers a unique opportunity for surmounting this barrier in the near future. In particular, companion dogs share our environment and play an important role in improving the quality of life for millions of people. Here, we present a rationale for increasing the role of companion dogs as an animal model for both basic and clinical geroscience and describe complementary approaches and ongoing projects aimed at achieving this goal.

Effects of pimobendan on myocardial perfusion and pulmonary transit time in dogs with myxomatous mitral valve disease: a pilot study. SM Apple, G Menciotti, L Braz-Ruivo, S Crosara, J Häggström, M Borgarelli. Australian Vet. J. September 2016;94(9):324-328. Quote: Objectives: To describe pulmonary transit time (nPTT) and myocardial perfusion (nMP) normalised to heart rate in dogs with stable ACVIM stage C myxomatous mitral valve disease (MMVD) and to assess short-term effects of pimobendan on these variables. We hypothesised that nPTT and nMP would increase in dogs with MMVD compared with normal dogs. Additionally, we hypothesised that treatment with pimobendan would decrease nMP and nPTT in dogs with MMVD. Design: Prospective, single-blind study involving 6 normal dogs and 12 dogs with MMVD. Methods: Dogs with MMVD were treated with enalapril and furosemide for at least 1 month prior to examination. All dogs underwent standard and contrast echocardiographic examinations at the beginning of the study (T0). At this time, MMVD dogs were randomly assigned to receive either pimobendan (0.4–0.6 mg/kg) or not. All dogs with MMVD were re-evaluated by standard and contrast echocardiography after 1 week (T1) and nPTT and nMP were measured. Results: nPTT was significantly increased in dogs with MMVD (P = 0.0063), compared with normal dogs. It was significantly decreased at T1 in dogs receiving pimobendan (P = 0.0250). The nMP was not significantly different in dogs with MMVD, compared with healthy dogs (P = 0.2552), and it was not significantly different at T1 in the treatment group (P = 0.8798). Conclusions: Contrast echocardiography was a valid, complementary tool for echocardiographic analysis of dogs with MMVD. Pimobendan decreased nPTT in dogs affected by MMVD. Myocardial perfusion was not different in dogs with severe MMVD. See also this September 2015 abstract.

Serum Concentrations of Leptin and Adiponectin in Dogs with Myxomatous Mitral Valve Disease. H.-S. Kim, J.-H. Kang, E.-B. Jeung, M.-P. Yang. J. Vet. Int. Med. September 2016;30(5):1589-1600. Quote: Background: The concentrations of circulating adipokines in dogs with myxomatous mitral valve disease (MMVD) have not been investigated in detail. Objectives: To determine whether serum concentrations of adipokines differ between healthy dogs and dogs with MMVD and whether circulating concentrations depend on the severity of heart failure resulting from MMVD. Animals: In the preliminary study, 30 healthy dogs and 17 client-owned dogs with MMVD, and in the subsequent study, 30 healthy dogs and 46 client-owned dogs with MMVD. Methods: Prospective case-controlled observational study. In the preliminary study, serum concentrations of leptin, adiponectin, resistin, visfatin, interleukin (IL)-1β, IL-6, IL-10, IL-18, and tumor necrosis factor-α were measured. In the subsequent study, MMVD dogs were divided into three groups according to the International Small Animal Cardiac Health Council (ISACHC) classification, and serum concentrations of leptin and adiponectin were measured. Results: In the preliminary study, serum leptin and adiponectin concentrations differed significantly between dogs with MMVD and healthy dogs. Serum leptin (P = .0013) concentrations were significantly higher in dogs with MMVD than in healthy dogs, whereas adiponectin (P = .0009) concentrations were significantly lower in dogs with MMVD. However, we observed no significant differences in the other variables. In the subsequent study, dogs classified as ISACHC class 3 had higher serum concentrations of leptin (P = .0022) than healthy dogs but ISACHC class 1 or 2 dogs did not. Serum adiponectin concentrations were significantly lower in ISACHC class 1 (P < .0001) dogs than in healthy dogs, whereas adiponectin concentrations in ISACHC class 3 dogs were significantly higher than in ISACHC class 1 dogs (P = .0081). Conclusions and Clinical Importance: Circulating concentrations of leptin and adiponectin might be altered in dogs with MMVD.

Anesthesia for Dogs with Myxomatous Mitral Valve Disease. Khursheed Mama, Marisa Ames. Clinician's Brief. August 2016. Quote: Proper anesthetic management of patients with cardiac disease depends on the nature and severity of the disease. In a broad sense, the anesthetic approach to the cardiac patient is different for compensated vs decompensated heart disease. In addition, concurrent disease and requisite supportive therapies can cause decompensation of previously compensated heart disease. Understanding the underlying structural abnormalities and resultant physiologic consequences can influence the anesthesia protocol, periprocedural monitoring, and plans for emergency interventions. This discussion focuses on the anesthetic management of dogs with varying stages of myxomatous mitral valve disease and commonly observed comorbidities.

Comparative study of the Vertebral Heart Scale (VHS) and the Cardiothoracic Ratio (CTR) in healthy poodle breed dogs. Gisllyana Medeiros Azevedo, Gerson Tavares Pessoa, Laecio da Silva Moura, Francisco das Chagas Araújo Sousa, Renan Paraguassu de Sá Rodrigues, Marina Pinto Sanches, Rayssa Dourado Fontenele, Maria Angélica Parentes da Silva Barbosa, Willams Costa Neves, João Macedo de Sousa, Flávio Ribeiro Alves. Acta Scientiae Veterinariae. September 2016;44:1387. Quote: Background: Veterinary cardiology has been widely divulged, especially because of the search for diagnostic methods that allow early identification of heart disease in companion animals. Several techniques are available, such as digital radiography (DR), computerized tomography (CT) and magnetic resonance (MR) that are being applied to patients with various diseases. VHS has been widely used in clinical practice in veterinary medicine as a way to diagnose heart size increases in lateral thoracic radiography in small animals. Cardiothoracic ratio (CTR) is a predictive factor for cardiac insufficiency in humans. In veterinary medicine, this index is still little used. The objective of the present study was to compare the vertebral heart scale (VHS) and cardiothoracic ratio (CTR) to assess changes in the size of the cardiac silhouette dogs in thoracic radiographs. Materials, Methods & Results: The VHS and CTR of forty healthy poodle breed dogs (20 males and 20 females) from University Veterinary Hospital at the Federal University of Piauí were assessed. The animals were placed in supine and lateral decubitus, to obtain radiographic images in dorsoventral (DV) and right and left laterolateral projections of the thoracic region. The images acquired on the photosensitive radiographic chassis were analyzed by digital radiographic image system installed in the Image Diagnosis Service of the University Veterinary Hospital -HVU/UFPI. VHS (Vertebral Heart Scale) measurements were taken using the sum of the heart length and heart width at its greatest diameter, comparing with the vertebral bodies from the fourth thoracic vertebra (T4). The CTR was assessed by comparing the greatest width of the heart silhouette and the distance between the thoracic walls at height T8. The heart width was measured from the two greatest distances (ML and MR), from the vertical line that divides the limit between the right and left sides of the heart, at the point of its greatest diameter. Similarly, the thoracic width was measured at the point of greatest thoracic diameter (MTD). The mean of the VHS and CTR in the males was 9.83 ± 0.85v and 0.48 ± 0.05, respectively. The females showed values of 9.65 ± 0.65v and 0.50 ± 0.03, respectively (P > 0.05). The mean of the VHS and CTR, considering males and females, was 9.72 ± 0.73v and 0.48 ± 0.04, respectively. VHS and weight correlated positively (r = 0.96), as the CTR and weight (r = 0.94). VHS and age showed high correlation (r = 0.96) as CTR and age (r = 0.93). VHS and CTR showed high correlation (r = 0.96). Discussion: Although congenital malformations and genetic diseases can occur, the acquired heart diseases correspond to most of the complications found in dogs. VHS increases considerably 6 to 12 months before the development of congestive heart failure (CHF). The poodles studied, considering the universe of males and females (P < 0.05), presented mean VHS values of 9.72 ± 0.73v. Similarly, there was no significant difference between genders for VHS measured in right and left decubitus in normal dogs. The cardiothoracic ratio measured for the poodles studied showed mean values of 0.48 ± 0.05. In humans, values below 0.5 are considered normal, while values above this may indicate the presence of cardiomegaly. The CTR is intimately related to the volume of the left ventricle and CTR values above 0.5 in humans are pathological. Our results demonstrated that VHS and CTR showed strong correlation in their measurements, suggesting that CTR, constantly used in humans, could be considered as a tool to assess the size of the heart silhouette in dogs of the poodle breed.

Correlation between the clinical stage, echocardiographic findings and systemic blood pressure in dogs with Degenerative Disease of the Mitral Valve. Alina Berrío, María Patricia Arias, Víctor Leonel Ramírez. Rev. CES Med. Zootec. August 2016;11(2):61-72. Quote: Background: most studies about Degenerative Mitral Valve Disease (DMVD) in dogs have focused on studying the echocardiographic (ECG) changes without considering changes in systolic, diastolic or mean blood pressure. Objective: to relate echocardiographic alterations and systemic pressure with the clinical stage in patients with DMVD. Methods: a random sample of 23 dogs with DMVD was obtained. A clinical classification of patients was performed based on criteria of the ACVIM. Blood pressure was taken with high-definition oscillometry equipment (HDO-2112-Vet) and then, patients underwent echocardiographic examination. Ultrasonographic features of the valve apparatus were assessed qualitatively, specifically the presence of thickening and prolapse of leaflets and remodelative changes, heart rate (HR), left atrium and aorta ratio (LA/AO), fractional shortening (FS), trans-valvular flows and pressure gradients were calculated as well. The confidence level was set at 95%. An univariate analysis was employed, as well as an ANOVA followed by a Fisher's test; Pearson's correlation was applied. Results: in the echocardiographic evaluation, statistically significant differences were observed between stages B1, B2 and C for the variables LA/AO, FS, and mitral gradient. There was a direct correlation between FS and mitral gradient (r= 0.66), LA/AO and mitral gradient (r= 0.70), and LA/AO and FS, (r= 0.75). An inverse correlation was found between systolic arterial pressure and FS (r= 0.51). Conclusions: patients with EDVM on stage C tended to have lower values tension; therefore, clinical evaluation with repeated blood pressure measurements in the same patient can help in decision-making and classification of the disease process. Among echocardiographic variables, the FS and LA/AO ratio were directly related to the clinical stage of the DMVD.

Efficacy of pimobendan on survival and reoccurrence of pulmonary edema in canine congestive heart failure. Masashi Mizuno, Shigeki Yamano, Shuichi Chimura, Atsushi Hirakawa, Yoshimi Ukai, Tamotsu Sawada, Shigeki Maetani, Arane Takahashi, Takeshi Mizuno, Kayoko Harada, Asako Shinoda, Shuhei Uchida, Junichiro Takeuchi, Takahiro Mizukoshi, Masaaki Endo, Masami Uechi. J. Vet. Med. Sci. September 2016. Quote: The aim of this study was to evaluate the efficacy of pimobendan with conventional therapies on survival and reocurrence of pulmonary edema in dogs with congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD). Records of 197 client-owned dogs from 14 veterinary hospitals were included in this study [including 12 cavalier King Charles spaniels]. Dogs were administered conventional treatments [diuretics, angiotensin-converting enzyme inhibitors (ACEIs), and digoxin] with or without pimobendan. Sixty-four dogs received a standard dose of pimobendan (0.20–0.48 mg/kg every 12 hr (q12hr)), 49 dogs received a low dose of pimobendan (0.05–0.19 mg/kg q12hr) and 84 dogs received conventional therapy alone. Dogs in the standard-dose and low-dose pimobendan groups had significantly longer median survival times than dogs in the conventional group (334, 277 and 136 days, respectively; P<0.001). The reoccurrence rate of pulmonary edema in the standard-dose group was significantly lower than in the low-dose and conventional groups (43%, 59% and 62%, respectively; P<0.05). Combination of pimobendan with a conventional treatment regimen significantly prolonged survival time after an initial episode of pulmonary edema in dogs with CHF caused by MMVD. There was no difference in survival between dogs administered standard and low doses of pimobendan, but pimobendan did prevent the reoccurrence of pulmonary edema in a dose-dependent manner.

Electrocardiographic changes in chronic valvular disease and dilated cardiomyopathy in dog. Radu A. Baisan, Oana Bîrsan, Vasile Vulpe. Human & Vet. Med. September 2016;18(2):98-102. Quote: Introduction: Two of the most common acquired cardiac diseases in dogs are chronic valvular disease and dilated cardiomyopathy. Morphological and structural changes in the myocardium during disease progression may induce alterations of the nodal system resulting in arrhythmias. Electrocardiography is the golden method for detecting arrhythmias. The aim of this study is to discuss the most frequent electrocardiographic changes in chronic valvular disease and dilated cardiomyopathy and to underline the electrocardiographic diferences between the two pthologies. Materials and method: Twenty-seven client-owned dogs distributed in two groups according to diagnostic were included in the study. Eighteen dogs [inclulding 3 cavalier King Charles spaniels] were diagnosed with chronic valvular disease and nine dogs with dilated cardiomyopathy. Dogs have been submitted to a physical examination, electrocardiography and cardiac ultrasonography. Results: Within chronic valvular disease group, 9 dogs had signs of left cardiomegaly, 3 dogs had sinus tachycardia, 2 dogs had signs of myocardial hypoxia, one dog had sinus arrest, one had ventricular tachycardia and ventricular premature complexes and 2 dogs had normal ECG trace, while in the dilated cardiomyopathy group 4 dogs had atrial fibrillation, 3 dogs had generalised cardiomegaly signs with sinusal rhythm, 1 dog had atrial fibrillation with ventricular premature complexes and 1 dog had sinus rhythm with presence of ventricular premature complexes. A significant difference (p&lt;0.05) was found between the duration of the QRS complex [Q-wave; R-wave; and J-point of S-wave] in the two groups (mean±SD of 68.16±10.72 in CVD group and 85.88±15.33 in DCM group). Conclusion: Supraventricular rhythm was the most common rhythm disturbance in dilated cardiomyopathy group, while in chronic valvular disease the sinus rhythm is predominant. The duration of QRS complex was significanly higher in dilated cardiomyopathy group.

Determination of left atrial volume in healthy dogs and dogs with myxomatous mitral valve disease. Rodrigo P. Franco, Evandro Zacche, Rafael R. Camacho, Marlos G. Sousa, Aparecido A. Camacho. Pesquisa Veterinária Brasileira. September 2016;36(8):743-748. Quote: The left atrial volume (LAV) can be obtained using the biplane Simpson’s method via echocardiography. Although in medicine this parameter has been considered to be a prognostic marker of left atrial enlargement in several cardiac diseases, in dogs with myxomatous mitral valve degeneration (MMVD), a valvulopathy characterized by left atrial (LA) volume overload, atrial enlargement is usually assessed by the LA-to-Aorta ratio (LA:Ao). Therefore, the body surface area (BSA)-indexed LAV was measured in healthy dogs and in dogs with MMVD using the biplane Simpson’s method. For this purpose, a total of 107 healthy dogs (control) and 81 dogs with MMVD in ACVIM stages B1, B2 and C were assessed, with LAV being calculated during atrial diastole (d) and systole (s) through the biplane Simpson’s method. Two-dimensional apical four-chamber (4C) and two-chamber (2C) images were obtained in every dog through the left parasternal window. The values obtained from healthy dogs were correlated with body weight using Pearson’s test. An analysis of variance (ANOVA) and Tukey’s test were used to compare healthy and MMVD dogs, as well as to investigate differences according with MMVD stages. A strong positive correlation was documented between either LAVd (r> 0.77) or LAVs (r> 0.73) and body weight in healthy dogs. The BSA-indexed LAV calculated for MMVD dogs was significantly different (p<0.01) from that obtained for the control group. Also, LAV was significantly different (P<0.05) when stages B2 and C, and B1 and C were compared. In conclusion, this study provided a reference for left atrial volume and the applicability of this technique to assess atrial overload in dogs with varying-stage MMVD.

Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study—A Randomized Clinical Trial. A. Boswood, J. Häggström, S.G. Gordon, G. Wess, R.L. Stepien, M.A. Oyama, B.W. Keene, J. Bonagura, K.A. MacDonald, M. Patteson, S. Smith, P.R. Fox, K. Sanderson, R. Woolley, V. Szatmári, P. Menaut, W.M. Church, M. L. O'Sullivan, J.-P. Jaudon, J.-G. Kresken, J. Rush, K.A. Barrett, S.L. Rosenthal, A.B. Saunders, I. Ljungvall, M. Deinert, E. Bomassi, A.H. Estrada, M.J. Fernandez Del Palacio, N.S. Moise, J.A. Abbott, Y. Fujii, A. Spier, M.W. Luethy, R.A. Santilli, M. Uechi, A. Tidholm, P. Watson. J. Vet. Int. Med. November 2016;30(6):1765-1779. Quote: Background: Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. Hypothesis/Objectives: Administration of pimobendan (0.4–0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia. Animals: 360 client-owned dogs with MMVD with left atrial-to-aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7, and vertebral heart sum >10.5. [161 (45.5%) were Cavalier King Charles Spaniels (CKCS)] [To be eligible for inclusion, a dog had to be 6 years of age or older, have a body weight ≥4.1 and ≤15 kg, have a characteristic systolic heart murmur of moderate to high intensity (≥ grade 3/6) with maximal intensity over the mitral area, have echocardiographic evidence of advanced MMVD defined as characteristic valvular lesions of the mitral valve apparatus, MR on the color Doppler echocardiogram, and have echocardiographic evidence of left atrial and left ventricular dilatation, defined as a left atrial-to-aortic root ratio (LA/Ao) ≥ 1.6 and body weight normalized left ventricular internal diameter in diastole (LVIDDN) ≥ 1.7, in addition to radiographic evidence of cardiomegaly (vertebral heart sum (VHS) > 10.5)] Methods: Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia. [A dog was considered to have left-sided CHF when there was radiographic evidence of cardiogenic pulmonary edema as indicated by an interstitial or alveolar lung pattern. In addition to these radiographic findings, the dog must have been showing contemporaneous clinical signs consistent with left-sided CHF including increased respiratory effort and rate by comparison with previously noted values for this patient.] Results: Median time to primary endpoint was 1228 days (95% CI: 856–NA) in the pimobendan group and 766 days (95% CI: 667–875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47–0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952–NA) in the pimobendan group and 902 days (95% CI: 747–1061) in the placebo group) (P = .012). Conclusions and Clinical Importance: Chronic oral administration of pimobendan to dogs with echocardiographic and radiographic evidence of cardiomegaly secondary to MMVD, in the absence of concurrent cardiovascular medication, results in the prolongation of the preclinical period, and is safe and well tolerated. The median time to the onset of CHF or cardiac-related death was prolonged by approximately 15 months, and the risk of a dog experiencing this event was reduced by approximately one-third; the majority of the benefit observed was attributable to delaying the onset of CHF. This substantial degree of prolongation of the preclinical period is of clinical relevance and is of importance to veterinarians and owners of dogs affected by this common disease.

Cardiogenic Pulmonary Edema in a Dog Following Initiation of Therapy for Concurrent Hypoadrenocorticism and Hypothyroidism. Jooyae Paik, Ji-Houn Kang, Dongwoo Chang, Mhan-Pyo Yang. JAAHA. September 2016. Quote: A 5-year-old intact female cocker spaniel dog weighing 7.8 kg was referred with anorexia, vomiting, and depression. At referral, the dog was diagnosed initially with typical hypoadrenocorticism, and 2 d later, concurrent primary hypothyroidism was detected. Hormonal replacement therapies, including fludrocortisone, prednisolone, and levothyroxine, were initiated, but a few days later the dog became abruptly tachypneic, and thoracic radiographs indicated the development of pulmonary edema. Echocardiography showed that there were abnormalities indicating impaired left ventricular function, although the heart valves were normal. Following treatment with pimobendan and furosemide, the pulmonary edema resolved. The dog had no recurrence of the clinical signs after 10 mo of follow-up, despite being off all cardiac medications; consequently, the cardiac failure was transient or reversible in this dog. The case report describes the stepwise diagnosis and successful treatment of cardiogenic pulmonary edema after initiation of hormonal replacement therapy for concurrent hypoadrenocorticism and hypothyroidism in a dog.

Evaluation of serum cystatin-C and symmetric dimethylarginine concentrations in dogs with heart failure from chronic mitral valvular insufficiency. Bum-Sul Choi, Hyeong-Sun Moon, Sang-Hyuk Seo, Changbaig Hyun. Vet. Med. Sci. September 2016. Quote: Reduction in glomerular filtration rate (GFR) is a common complication in advanced stages of heart failure (HF). The convenient and precise assessment for GFR would be useful for early detection of renal impairment in HF dogs. Our hypothesis of this study was the GFR would be reduced in advanced stages of HF from chronic mitral valvular disease (CMVI), as indicated by renal markers including serum cystatin-C (Cys-C) and symmetric dimethylarginine (SDMA) concentrations. Forty-three client-owned dogs consisting of 33 dogs with different stages of HF from CMVI and 10 age-matched healthy dogs were enrolled in this study. Serum Cys-C and SDMA concentrations along with other renal (i.e., urea nitrogen and creatinine) and echocardiographic markers were evaluated in healthy and CMVI dogs. Serum Cys-C concentrations were 1.4 ± 0.4 mg/l in control, 2.1 ± 0.9 mg/l in ISACHC I, 2.9 ± 0.8 mg/l in ISACHC II and 3.6 ± 0.6 mg/l in ISACHC III dogs, whereas serum SDMA concentrations were 8 ± 2 ug/dl in control, 14 ± 3 ug/dl in ISACHC I, 18 ± 6 ug/dl in ISACHC II and 22 ± 7 ug/dl in ISACHC III dogs. There was close correlation of serum Cys-C and SDMA concentrations to serum creatinine, urea nitrogen and the severity of HF. Our study demonstrated that the GFR was decreased in dogs with CMVI having earlier stages of HF.

Atrial septal aneurysm mimicking cor triatriatum in a Cavalier King Charles dog. Ekrem Çağatay Çolakoğlu, Hadi Alihosseini, Ece Aydemir, Fatma Cansiz, Aslan Kalinbacak. Ankara Üniv Vet Fak Derg. October 2016;63(4):411-414. Quote: Atrial septal aneurysm is a rare deformity of interatrial septum extending to changeable directions during cardiaccycle. A 9 year old Cavalier King Charles Spaniel referred to Small Animal Hospital with a history of acute onset of respiratoric distress and abdominal distension. Routine blood work, electrocardiography and thorax radiography were performed. Echocardiography revealed mitral valve disease and severe left atrial dilatation with an atrial septal aneurysm as a bulging of interatrial septum into the right atrium and nearly prolapsing into the tricuspid orifice. Color flow Doppler revealed a left-to-right shunt flow atrial septal defect. The dog died suddenly 2 weeks later. The owner declined postmortem examination. To the best of authors’ knowledge, this was the first report of atrial septal aneurysm with concomitant atrial septal defect in a dog. The purpose ofthis case report is to point out atrial septal aneurysm as the possible complication of mitral valve disease in a Cavalier King Charles Spaniel.

Comparison of continuous versus intermittent furosemide administration in dogs with acute heart failure. Zita Filipejová, Carlos Fernando Agudelo Ramírez, Michal Crha. Acta Vet. Brno. October 2016;85(3):239-245. Quote: Pulmonary oedema is a life-threatening condition which should be treated promptly in the emergency room with oxygen, cage rest, and diuretic therapy. Traditionally, bolus administration of furosemide is the treatment of choice. However, there is emerging information that continuous rate infusion might be more effective than bolus injections in relieving clinical signs and producing a lower rate of complications such as azotaemia, dehydration, and electrolyte imbalances. We tested the effect of furosemide both in bolus (4–6 mg/kg intravenously) and continuous rate infusion (1 mg/kg/h) in 30 dogs that had been presented with fulminant pulmonary oedema during 2 days of hospitalization. No differences in the selected biochemical indicators between the groups were found. There were significant differences in blood urea nitrogen in the bolus injection group and creatinine and phosphorus in the continuous rate infusion group between days 1 and 2. The results of this study showed no differences in the approach of furosemide administration in the management of pulmonary oedema. Both methods may cause renal and electrolyte complications, however, further studies with a larger number of patients are recommended.

Mitral Valve Repair in Toy Breed Dogs with Degenerative Mitral Valve Disease. Masami Uechi. Amer. College of Vet. Surgeons. Surgery Summit Scientific Abstracts. October 2016. Quote: We present the long-term outcome of small-breed dogs (body weight < 5 kg) after mitral valve repair. We evaluated cardiac reverse remodeling after mitral valve repair under cardiopulmonary bypass (CPB) for mitral regurgitation in small breed dogs. CPB was started by using a CPB circuit connected to carotid artery and jugular vein catheters. After inducing cardiac arrest, the left atrium was sectioned and chordae tendineae rupture confirmed. The chordae tendineae were replaced with expanded polytetrafluoroethylene. A mitral annulus plasty was also done, and the left atrium was closed. After de-clamping for restarting the heart, the chest was closed. The grade of cardiac murmur was significantly reduced to 0/6–3/6 three months postoperatively, and the heart shadow was reduced in the chest X-rays. Echocardiography confirmed the marked reduction in mitral regurgitant ratio and the left atrial dimensions. Mitral valve repair reduced enlarged cardiac size by reduction of regurgitant rate. Properly performed mitral repair for DMVD confers excellent durability and long-term clinical outcomes in humans. Surgical repair of DMVD normally incorporates 2 components: leaflet or chordal repair to correct prolapse and annuloplasty to restore normal annular geometry, increase leaflet coaptation, reduce tension on suture lines, and prevent future annular dilation. Artificial chordal replacement with expanded polytetrafluoroethylene (ePTFE) is an established technique for mitral valve repair with good long-term results, which is usually used for prolapse of the anterior and/or posterior mitral leaflet. Some cases of MR in dogs require cardiac surgery when other treatments cannot address the signs of severe MR. We performed mitral valve repair more than 600 dogs. Currently perioperative survival rate is 98% and discharge rate is 92%. After surgery, clinical symptoms improved were discharged within 12 days. In the postoperative physical examination, cough was found to have disappeared, and the animal’s appetite had improved. In addition, with the improvement in general condition, body weight increased. On uscultation, the chest wall thrill related to the cardiac murmur had disappeared, and the grade of the cardiac murmur was reduced. On the chest X-ray, the VHS was found to have decreased and there was confirmed improvement, seen as reductions in cardiac shadow, tracheal elevation, and pulmonary edema. Left atrium to aorta ratio was decreased and there was a remarkable reduction in MR. In addition, the number of medications used decreased by 1 month after the operation. By 3 months after the operation, many dogs were not on medication. Open heart surgery using CPB can be performed safely in small breed dogs. Mitral valve repair is an effective therapy for DMVD with severe MR. Postoperative complications include pancreatitis and thrombosis, which may be reduced by future advanced techniques.

Prevalence and Prognosis of Anemia in Dogs with Degenerative Mitral Valve Disease. Ivarosa Bing-Ye Yu, Hui-Pi Huang. BioMed Res. Int'l. October 2016;4727054. Quote: In humans, heart failure (HF) and renal insufficiency (RI) have negative reciprocal effects, and anemia can exacerbate their progression. In this retrospective study, the prevalence and prognostic significance of anemia in 114 dogs with degenerative mitral valve disease (DMVD) was investigated. Pretreatment clinical parameters, prevalence of anemia and azotemia, and survival time were analyzed in relation to HF severity. The prevalence of anemia was highest in dogs with the modified New York Heart Association (NYHA) class IV HF (33.3%), followed by classes III (15.2%) and II (0%; p < 0.001). The presence of anemia was associated with HF severity and blood creatinine > 1.6 mg/dL (both p < 0.001). Anemic dogs had a shorter median survival [13 months; 95% confidence interval (CI): 0.7–19.1] than nonanemic dogs (28 months; 95% CI: 15.3–40.7; p < .001). NYHA class IV (hazard ratio (HR): 3.1, 95% CI: 2.2–4.3; p < 0.001), left atrium/aorta ratio > 1.7 (HR: 2.7, 95% CI: 1.7–4.2; p = 0.001), and presence of anemia (HR: 1.43, 95% CI: 1.1–1.9; p = 0.004) emerged as predictors of mortality. A cardiorenal-anemia syndrome-like triangle was observed and anemia was a prognostic factor for survival in dogs with DMVD. ... In this study, we found that Hb [hemoglobin] concentration and PCV [packed cell volume] decreased with increasing severity of NYHA functional status in dogs with DMVD. Meanwhile, BUN levels, blood creatinine levels, prevalence of anemia, and prevalence of blood creatinine > 1.6mg/dL increased with increasing HF severity. Anemia was associated with a poor outcome and emerged as a predictor of mortality.

Heart testing scheme should be adopted. Simon Swift. Veterinary Times. October 31, 2016. Quote: As an RCVS and European specialist in cardiology, having been involve in heart testing and a cardiology advisor to the Cavalier King Charles Spaniel (CKCS) for the past 20 years, I read the correspondence regarding breed testing (29 August issue) with interest. As many readers will be aware, a heart testing scheme for CKCSs based upon simple auscultation, was established by Peter Darke in 1991 and refined in 2006. The CKCS Club has been very proactie in breed screening, and I and many colleagues have given up weekends attending dog shows or "health days" up and down the country to ensure as many dogs as possible were examined. The database now contains details of more than 17,000 examinations in more than 9,000 dogs, with may dogs examined multiple times. Unfortunately, degenerative valve disease is an acquired disease that starts to manifest from three to four years and, by that time, a dog's show career is over. So having show winners tested would not be an effective solution. Instead, show dogs should have certificated indicating both parents -- or all four grandparents if they are too young -- reached the age of five before developing a murmur. While this may not seem a difficult hurdle, it should be remembered up to 50 per cent of CKCSs develop heart murmurs by six years. Examining dogs on the database for the period between 2006 and 2010 showed only four per cent of dogs had followed this breeding advice -- that is, had parents or grandparents tested clear older than five years. Despite this, I have shown the average age female dogs develop heart murmurs has increased significantly during the course of the scheme, so we are having an effect, and the CKCS Club should be congratulated for its efforts. ... It should be noted about 20 per cent of CKCS puppies registered by The Kennel Club are bred by members of the CKCS Club, which runs the only heart testing scheme for the breed.

Assessment of left ventricular volume and function in healthy dogs by use of one-, two-, and three-dimensional echocardiography versus multidetector computed tomography. Katherine F. Scollan, Susanne M. Stieger-Vanegas, D. David Sisson. Am. J. Vet. Res. November 2016;77(11):1211-1219. Quote: Objective: To compare left ventricle (LV) volume and function variables obtained by use of 1-D, 2-D, and real-time 3-D echocardiography versus ECG-gated multidetector row CT (MDCT) angiography, which was considered the criterion-referenced standard. Animals: 6 healthy, purpose-bred dogs. Procedures: Dogs were anesthetized and administered a constant rate infusion of esmolol, and 1-D, 2-D, and 3-D echocardiography and ECG-gated, contrast-enhanced MDCT were performed. End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume, and ejection fraction (EF) were calculated by use of the Teichholz method for 1-D echocardiography, single-plane and biplane modified Simpson method of disks (MOD) and area-length method for 2-D echocardiography, and real-time biplane echocardiography (RTBPE) and real-time 3-D echocardiography (RT3DE) for 3-D echocardiography. Volumes were indexed to body surface area and body weight. Median values, correlations, and limits of agreement were compared between echocardiographic modalities and MDCT. Results: EDV and ESV measured by use of RTBPE and RT3DE had the strongest correlations with results for MDCT. Values obtained for EDV, ESV, stroke volume, and EF did not differ significantly between echocardiographic methods and MDCT. Use of RT3DE and RTBPE slightly underestimated EDV, ESV, and EF, compared with values for MDCT, as determined with Bland-Altman analysis. Conclusions & Clinical Relevance: Values for EDV and ESV obtained by use of 3-D echocardiography, including RTBPE and RT3DE, had the highest correlation with slight underestimation, compared with values obtained by use of MDCT. This was similar to results for 3-D echocardiography in human medicine.

The Use of Nutri-Plus Gel in Cardiology. J. Bouvard, C. Misbach, V. Gouni, C. Damoiseaux, A.M.P. Petit, V. Arqued-Soubeyran, E. Trehiou-Sechi, J.L. Pouchelon, G. Chaix, V. Chetboul. Scholars J. Med. Case Rep. November 2016;4(11):800-814. Quote: Appropriate nutritional management is indispensable to ensure the quality of life in animals suffering from heart diseases. Complementary feeds, still little used in veterinary medicine but increasingly employed in humans, represent a worthwhile option for the nutritional management of animals with heart diseases. Nutri-Plus Gel® is a complementary feed composed of high-energy ingredients (glucose syrup, soybean oil and cod liver oil), hydrolyzed animal proteins, vitamins and oligo-elements. Due to its high-energy content and excellent palatability, Nutri-Plus Gel® is used for nutritional recovery and convalescence in dogs and cats. It is also used during periods of high-energy requirement and intense physical effort (e.g. hunting season, sled-dog races…). This collection of cases illustrates 5 routine clinical situations encountered in veterinary cardiology in which the use of a palatable high-energy complementary feed is of practical value. These situations include facilitation of restraint during an examination (e.g., echocardiography), promoting treatment compliance (notably during long-term multitherapy), and providing nutritional support during periods of lack of appetite associated with advanced heart diseases and post-operative recuperation. In any case, complementary feed should always be used as a complement to the appropriate diet, rather than a replacement of the later. ... CASE REPORT 4: A 13-year old 5.2 kg [11.5 lb.] female Cavalier King Charles (Figure 10), treated during 5 years for DMVD (primary chordal rupture regarding the anterior mitral valve leaflet, and secondary acute CHF 18 months earlier) was presented for fatigability, hyporexia and moderate diarrhoea (soft faeces without melena or hematochezia) worsening progressively for the past 5 days. At the last visit, one year earlier, the heart condition was no longer associated with signs of CHF (stage C1), despite severe systolic PAHT (systolic pulmonary arterial pressure = 93 mmHg) and global cardiomegaly (echocardiographic stage 5). The current oral treatment consisted of diuretics (altizidee and furosemide), an ACEi (benazepril), an inodilator (pimobendan), and a competitive aldosterone receptor antagonist combined with altizidee (spironolactone). The dog was up to date with vaccination and endoparasitic treatment, and no change in eating habits was reported. Blood tests performed by the referring veterinarian the day before the consultation, were unremarkable (thus excluding, amongst other things, a cardio-renal syndrome). On physical examination, the dog was thin (BCS 4/9) and had lost 600 g [1.3 lb] in one month. The mucous membranes were pink and the capillary refill time was two seconds. Cardio-respiratory auscultation evidenced a left apical grade V/VI systolic heart murmur (already recorded for the past 3 years) associated with regular tachycardia (heat rate = 176 bpm) as well as the presence of end-inspiratory crackles in the caudo-dorsal region of the lung fields. The femoral arterial pulse was distinct, symmetrical and synchronous with the heart beats. Abdominal palpation was normal. The rectal examination confirmed the presence of soft faeces. The rest of the physical examination was unremarkable. Figure 11The medical and clinical history (weight loss, hyporexia, fatigability, tachycardia and abnormal respiratory auscultation) was suggestive of stage C2 CHF (versus C1). Thoracic radiographs were performed for confirmation (Figures 11A and 11B, at right). They revealed mild interstitial pulmonary oedema in the perihilar region associated with global cardiomegaly and severe left atrial dilation. Echocardiography did not show any significant change in the heart disease, as compared to the previous examination, except for a greater increase in systolic pulmonary arterial pressure (139 mmHg versus 93 mmHg). The left atrium measured using the two-dimensional mode was severely dilated, but nevertheless stable as compared to the previous control. The current treatment was continued, but the furosemide dosage was increased (1.9 mg/kg, BID). As the owner did not desire any further investigation of the cause of diarrhoea (including abdominal ultrasound examination), a symptomatic oral treatment of metronidazolel (15 mg/kg, BID) and diosmectitem (150 mg/kg, TID) was first prescribed for 10 days. Nutri-Plus Gel®a (Figure 10) was also prescribed to stimulate appetite, limit the already considerable loss in body weight (10% of the initial weight in one month), and facilitate treatment compliance (six drugs in all, requiring eleven oral doses). During the follow-up visit one week later, the owner reported that the digestive and cardiac symptoms had disappeared (stage C1). One month later, a gain in weight was noted (200 g [0.44 lb.]). Two years after this episode, the dog was in good general condition and no change in the medical treatment was proposed, as the symptoms had not returned. As the animal’s weight is now stable, Nutri-Plus Gel®a is recommended solely on demand, during phases of hyporexia (infrequent to date, according to the owner).

Neladenoson, a Partial Adenosine A1-receptor Agonist, Improves Mitochondrial Function in Left Ventricular Cardiomyocytes Isolated From Dogs With Chronic Heart Failure. Hani N Sabbah, Ramesh C Gupta, Vinita Singh-Gupta, Kefei Zhang, Jiang Xu, Barbara Albrecht-Küpper. Circulation. November 2016;134(S1):Abstract 12977. Quote: Background: Mitochondria (MITO) of failing cardiomyocytes (CMs) manifest structural and functional abnormalities characterized by hyperplasia, reduced organelle size and reduced respiration. These abnormalities lead to reduced rate of ATP synthesis and excess production of reactive oxygen species. We previously showed that chronic therapy with a partial adenosine A1-receptor agonist (pA1RA) improves LV function and normalizes tissue levels of MITO uncoupling proteins 2 and 3 in dogs with heart failure (HF). Hypothesis: Neladenoson, a new pA1RA, improves MITO function in freshly isolated CMs from dogs with chronic HF. Methods: CMs were isolated from LV of 7 microembolization-induced HF dogs (LV ejection fraction <30%) and from 6 normal (NL) dogs using a collagenase-based enzymatic process that yielded ~70% rod-shaped CMs that excluded trypan blue. Equal aliquotes of CMs were incubated in 0 (vehicle), 3, 10, and 30 nM concentration of Neladenoson for one hour at 37°C. MITO ADP-stimulated state-3 respiration, maximum rate of ATP synthesis and complex-IV activity (COX-IV) were measured at end of incubation. Respiration was measured with a Strathkelvin respirometer and COX-IV activity was measured polarographically and both expressed as nAtom Oxygen/min/mg protein. Rate of ATP synthesis was measured using the bioluminescent ApoSENSOR assay and quantified in RFU/μg protein. Results: Data are shown in the table. Increasing concentration of Neladenoson had no effect on measures of MITO function in CMs from NL dogs. In CMs from HF dogs, depressed levels of MITO respiration, ATP synthesis and COX-IV increased significantly and in a dose-dependent manner after exposure to Neladenoson. Conclusions: Neladenoson has beneficial effects on MITO function in CMs from HF dogs. Furthermore, the improvement in MITO function after treatment with Neladenoson can occur early after initiation of therapy (within one hour) and is dose-dependent up to concentrations of 30 nM.

“DOs and DONʼTs” for Lasix Use in Dogs. Janet Olson. Veterinary Cardiology Specialists. December 2016. Quote: DOs: 1) Prior to prescribing lasix, a renal panel with electrolytes and a urine specific gravity should always be performed. 2) Any time the lasix dose is increased, a renal panel with electrolytes should be performed. 3) When performing a lasix trial, a dose of 2 mg/kg of lasix PO BID is recommended. DONʼTs: 1) Donʼt start a dog on lasix just because the NTproBNP level is elevated, even if they are coughing or having respiratory distress. 2) Donʼt start a dog on lasix just because it has a heart murmur and respiratory signs such as coughing or labored breathing. 3) Donʼt base your lasix trial on improvement of clinical signs alone. 4) Donʼt taper down and then discontinue the use of lasix once your patient starts breathing comfortably. 5) Donʼt prescribe lasix and then tell the owner to give a particular dose two to three times daily as needed. 6) Donʼt keep increasing the dose of lasix in a patient that is not responding.

Quantitative evaluation of left atrial volume and function by one-dimensional, two-dimensional, and three-dimensional echocardiography in a population of normal dogs. N. LeBlanc, K. Scollan, D. Sisson. J. Vet. Cardio. December 2016;18(4):336-349. Quote: Objectives: The primary goal of this study was to compare left atrial (LA) volume and functional indices in a population of normal dogs using transthoracic one-dimensional M-mode, two-dimensional (2D), and three-dimensional (3D) echocardiography. Animals: Forty clinically normal dogs of various breeds were stratified into four groups based on weight. Methods: Left atrial volume (LAV) was estimated by converting single linear measurements derived from M-mode and 2D images into volumes via the cube and sphere formulas. 2D echocardiography was employed to estimate LAV using linear measures and rectangular and ellipsoid formulas, as well as area-length and the monoplane method of disks. LAV was estimated using the biplane area-length method on 4- and 2-chamber 2D images. LAV was directly measured using 3D volume data obtained over four consecutive cardiac cycles. LAV estimates were compared amongst methods, correlated to body size, and evaluated for reproducibility. Functional indices derived from these various echocardiographic methods were compared to identify any systematic differences based on imaging modality. LA functional indices included LA ejection fraction (LAEF), total LA emptying volume, passive LA emptying volume/fraction, active LA emptying volume/fraction, and LA expansion index. Results: The M-mode derived estimates of LAV were significantly smaller than all 2D- and 3D-derived LAV (p<0.0001). The left-sided 3D LAV had the highest correlation with body weight (r2 = 0.8806) for all phases of the LA cycle with acceptable interobserver variability (CV 11%). Conclusions: 3D echocardiography is a feasible, non-invasive method to measure LAV in a population of normal dogs.

The immunohistochemical evaluation of selected markers in the left atrium of dogs with end-stage dilated cardiomyopathy and myxomatous mitral valve disease – a preliminary study. Izabela Janus, Małgorzata Kandefer-Gola, , Rafał Ciaputa, Agnieszka Noszczyk-Nowak, Urszula Pasławska, Massimiliano Tursi, Marcin Nowak. Irish Vet. J. December 2016;69:18. Quote: Background: Dilated cardiomyopathy (DCM) and myxomatous mitral valve disease (MMVD) are the most common diseases noted in dogs. Although their pathogenesis varies, both include a significant enlargement of the left atrium. The study was carried out on left atrial specimens obtained from 56 dogs, including those from 34 dogs with clinically diagnosed MMVD, 15 dogs with DCM and 7 dogs without heart disease (control group). Dogs in the MMVD and the DCM groups presented with left atrial enlargement and stage D heart failure. The specimens underwent immuno-histochemical examination using desmin, vimentin, periostin and caspase-3 antibodies. Results: There were alterations in the expression of the studied proteins in the study groups compared to the control group. The changes included: irregularity of desmin cross-striation and desmosomes, a higher amount of vimentin-positive cells, a change in the periostin expression pattern from cytoplasmic to extracellular, and a lower expression of caspase-3. The alterations were more pronounced in the DCM group than in the MMVD group. Conclusions: During heart failure, the pattern of desmin, vimentin, periostin and caspase-3 expression alters in the left atrium, regardless of the cause. The changes are more pronounced in dogs with DCM than in dogs with MMVD and similar left atrial enlargement, suggesting that volume overload may not be the only cause of myocardial changes in DCM.

Diastolic Function Is Impaired in Dogs with Myxomatous Mitral Valve Disease. R. R. Camacho, M. G. Sousa, R. P. Franco, F. N. Gava, A. A. Camacho. Ars Veterinaria. December 2016;32(1):16-23. Quote: Myxomatous mitral valve disease (MMVD) is the most common cardiac disease in dogs, and the echocardiogram is required to investigate the degree of remodeling and the intensity of cardiac dysfunction. Therefore, the aim of this study was to assess diastolic function in dogs with MMVD in different stages, and to compare them with healthy animals. This study enrolled 12 mature dogs with MMVD, which were subdivided in two groups: stage B2 (n=7) and stage C (n=5). Also, 9 healthy adult dogs were recruited to serve as controls. Several echocardiographic data were obtained for the assessment of diastolic function, as well as some parameters intended to evaluate the cardiac structure and systolic function, which were used to search for correlations with the diastolic parameters. Concerning diastolic function, a significant difference was found to exist between groups for the peak velocity of left ventricular slow filling, the isovolumic relaxation time, and the mitral annular velocities at early and late diastole. These findings are associated with the structural and hemodynamic changes ascribed to the progression of MMVD and the intensification of congestive heart failure. The indices calculated from the peak velocity of left ventricular rapid filling and the mitral annular velocities obtained at early and late diastole also differed between healthy and diseased dogs. Because some of these indices are surrogates for left ventricular filling pressure and the congestive status of the patient, the results of this study are supportive of the relationship between the progression of MMVD and diastolic impairment, besides the eccentric structural remodeling attributable to this cardiac disease.

Role of COL1A2 Gene Polymorphisms in Myxomatous Mitral Valve Disease in Poodle Dogs Genetic Study of Mitral Valve Disease. Torres-García, O., Rey-Buitrago, M., Acosta-Virgüez, E., Bernal-Rosas, Y., Infante-González, J., Gómez-Duarte, L. IOSR J. Agriculture & Vet. Sci. December 2016;9(12 ver. II):113-118. Quote: Introduction - Myxomatous mitral valve disease is a common heart disease in dogs, characterized by chronic progressive, degenerative lesions of the mitral valve. The disease has many similarities with the human condition mitral valve prolapse; this is a polygenic disease in which more than one genetic locus is likely to contribute to disease susceptibility and clinical expression. ... Recently, a genome-wide association study performed in Cavalier King Charles Spaniels dogs, identified a 1.58 Mb region on CFA13 and a 1.68 Mb region on CFA14 associated with the development of MMVD. Interestingly, the COL1A2 gene is located in the region on CFA14. All these data are in accordance with our results and support a potential role of these region in the susceptibility to MMVD. ... Objective - Assess the implication of intronic variants rs9006567 and rs22372411 of COL1A2 gene in canine susceptibility to myxomatous mitral valve disease. Materials and methods - Case-control association study. Fifty canine [Poodle] patients with MMVD and 80 matched canine controls were evaluated. ... All dogs were unrelated at the parental level. ... DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for two intronic variants COL1A2 gene polymorphisms (rs9006567 A/G and rs22372411 C/T) using an allelic discrimination assay. Results - No significant differences were observed in genotype distribution among patients with MMVD and controls for the rs9006567 COL1A2 gene variant. However, the allele T of the rs22372411 variant was over-represented in MMVD patients compared with healthy controls (P = 0.009; OR = 1.98; 95% CI = 1.18 - 3.34). Conclusions and Clinical Relevance - Our results show for the first time an association of the rs22372411 COL1A2 gene variant with susceptibility to canine myxomatous mitral valve disease.

Breakthrough in Cardiology Care. Philip R. Fox. rDVM Quarterly. Fall 2016;pg. 6. Quote: How will this [the EPIC Study report] affect diagnosis and management of canine heart diseases? In light of these findings, clinicians should change how they diagnose and manage MVD. Dogs with heart murmurs should be screened early, rather than wait for clinical signs of coughing or respiratory distress to develop. Assessment can be effectively made using history and physical examination along with the added benefit of chest radiography and/or echocardiography.

The EPIC Trial: Pimobendan in Preclinical Myxomatous Mitral Valve Disease. Cardiac Education Group. December 2016. Quote: How does the CEG advise practitioners to apply these [EPIC trial] results? • Documentation of substantial cardiac enlargement (Figure 1 & algorithm) is critical to determine whether or not to start pimobendan in dogs with preclinical mxyomatous mitral valve disease. • If substantial cardiac enlargement is not documented by echocardiography and the VHS is <10.5, reevaluation is advised in 12 months. • If the VHS is between 10.5 and 11.5 and an echocardiogram is not performed or does not exceed enlargement criteria, reevaluation is advised in 6 months. • If an echocardiogram is not available and only thoracic radiographs are performed, the CEG recommends starting pimobendan in dogs with heart murmurs of grade 3/6 or louder only when the VHS exceeds 11.5 vertebral bodies or an incremental increase of greater than 0.5 vertebral bodies per 6 months is accurately documented. ... While both thoracic radiography and echocardiography can be used to identify cardiac enlargement, the echocardiogram is generally preferred if the cause of the systolic murmur is uncertain and to more precisely measure chamber sizes. If there is evidence of cardiomegaly/ remodeling on the echocardiogram, then radiographs are also suggested to measure vertebral heart size (VHS), evaluate the cardiac chambers subjectively, and obtain a “baseline” for the appearance of pulmonary vasculature and parenchyma. In situations where the client declines echocardiography, the thoracic radiograph path can be followed in the primary care practice. ACVIM guidelines recommend both imaging methods for optimal evaluation of a dog with suspected MMVD. The EPIC trial did not investigate a cutoff for cardiac enlargement by VHS alone at which to start pimobendan therapy. This algorithm represents the consensus of the CEG to initiate therapy when echocardiography is not available, but is not based on evidence.

2-dimensional long-axis echocardiographic ratios for assessment of left atrial and ventricular size in healthy dogs and dogs with mitral regurgitation. Strohm LE, Visser LC, Drost WT, Bonagura JD. Vet. Radiol. & Ultrasound. November 2016;57(6):670. Quote: Preliminary studies indicate that LV and LA to aorta ratios might offer a simple and more sensitive method to identify cardiomegaly. The aims of this study were to (1) establish canine reference values for long-axis aortic ratios in healthy dogs; and (2) test the utility of this method in dogs with different stages of chronic MR. ... Reference values were: LV/Ao: 1.8–2.4; LA/Ao: 1.8–2.4; LA/LV: 0.9–1.1. The ratios of LV/Ao, LA/Ao, and LA/LV were significantly greater in dogs with MR (P < 0.001). Of the 25 dogs with MR, 68% of the dogs demonstrated LV dilation using the LV/Ao ratio method, whereas only 28% exceeded previously published values for LV diastolic dimension (P = 0.002). The LA/Ao ratio was increased in 92% of the dogs with MR. ... This study establishes normal two-dimensional, long-axis LV and LA to aorta ratios based on a relatively large sample of healthy dogs of different body weights. The ratios increased in dogs with MR and appeared more sensitive for identifying LV enlargement than an oftenused method based on a meta-analysis of multiple M-mode studies. This method provides a simple and sensitive approach to detecting LV and LA enlargement in dogs and has clinical applicability across a range of body weights.

Canine pulmonary vein-to-pulmonary artery ratio: echocardiographic technique and reference intervals. F. Birettoni, D. Caivano, V. Patata, N.S. Moïse, C. Guglielmini, M. Rishniw, F. Porciello. J. Vet. Cardiol. December 2016; doi: 10.1016/j.jvc.2016.07.004. Quote: Objectives: The size of the pulmonary veins (PVs) and pulmonary arteries (PAs) changes in response to hemodynamic alterations caused by physiological events and disease. We sought to create standardized echocardiographic methods for imaging the right ostium of the pulmonary veins (RPVs) and the right pulmonary artery (RPA) using specific landmarks and timing to quantify vessel diameters and phasic changes during the cardiac cycle. Animals: Fifty client-owned healthy dogs prospectively recruited. Methods: M-mode and 2-dimensional images were obtained from modified right parasternal long and short axis views. Right ostium of the pulmonary veins and RPA measurements were timed with electrical [peak of the QRS complex (RPVQRS and RPAQRS) and end of T wave (RPVT and RPAT)] or mechanical events [RPV and RPA vessels at their respective maximal (RPVMAX; RPAMAX) and minimal (RPVMIN; RPAMIN) diameters]. Right ostium of the pulmonary veins and RPA measurements were also indexed to the aorta. Results: In normal dogs regardless of the echocardiographic view or time in the cardiac cycle, the RPV/RPA ratio approximated 1.0. Mechanically timed fractional changes (distensibility indices) in RPV and RPA diameters did not differ (p=0.99; 36.9% and 36.8%, respectively). ECG-timed fractional changes (distensibility indices) in RPV and RPA diameter were at least 50% smaller than mechanically timed changes (p<0.05). RPV:Ao and RPA:Ao ranged between 0.3 and 0.6, with lower values obtained in diastole and larger values in systole (p<0.0001). Multiple positive and negative deflections were identified on the RPV and RPA M-mode tracings. Conclusion: This study provides detailed methodology and 2D and M-mode reference intervals for the RPV and RPA dimensions and the phasic changes during the cardiac cycle of the dog using echocardiography.

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2017

Degenerative Valve Disease. Mikaela Mueller. BluePearl Library. January 2017. Quote: As doctors, we want to be able to fix problems for our patients. Sadly, this is one disease that we cannot fix (yet). We have been frustrated alongside our clients with nothing to offer them in this common preclinical stage. One intervention that has gotten a lot of research attention is ACE-inhibitors. We seem to really want them to make a difference in delaying the time to onset of congestive heart failure, maybe because we can make physiological justifications for why ACE-inhibitors should, theoretically, help. Multiple studies have shown “trends” to improvement, but no statistical significance (VETPROOF, SVEP). Many arguments suggest that we simply haven’t performed the right study to find the benefit, but one could also argue that if multiple different studies didn’t show a statistical difference, then the true benefit is likely modest, at best. That said, I think many of us have prescribed ACE-inhibitors in the preclinical stage just in case it does help. It makes us, and our clients, feel like we are doing something that may possibly help, while we are, in all honesty, in a position where our hands are tied. All of that changed with the release of the EPIC study results at ACVIM in June 2016. ... . Patients in the pimobendan group did not live as long as the placebo group after the onset of congestive heart failure, but overall survival time (all-cause mortality) was increased. Said another way, patients that receive pimobendan starting in the preclinical stage (ACVIM Stage B2) live longer than those who don’t and spend less of their life battling clinical signs of congestive heart failure. ... One of the major concerns with the EPIC study is that many dogs with only mild enlargement never experience clinical signs of congestive heart failure in the first place, so treating them long-term with pimobendan does not change their clinical outcome. Luckily, it appears to be a very safe medication for the majority of patients, but it is not a cheap medication to give for years when it does not change the outcome. Since we do not have a good way of predicting which dogs with mild disease will progress to clinical signs, it becomes difficult to decide whether or not to recommend pimobendan for some patients. This is where the art of clinical practice comes into play. Each patient is an individual who deserves personalized thought and attention. If a patient has mild cardiomegaly and is already 16 years old, it is far less likely that the patient will progress to congestive heart failure during his or her lifetime than a different patient with similar disease who is only 5 years old. Also, does the patient have other clinical diseases that otherwise limit its lifetime? Potentially, these patients will not be expected to benefit from chronic pimobendan administration. Since the EPIC study was announced, I have started to recommend giving pimobendan with increased urgency to patients of mine with progressive cardiomegaly.

Three-dimensional echocardiographic comparison of mitral valve morphology in cavalier King Charles spaniels to mitral valve morphology in dogs of other breeds.  A three-dimensional echocardiographic analysis. G. Menciotti, J. Häggström, I. Ljungvall, M. Aherne, S.Wesselowski, J. A. Abbott, M. Borgarelli. ECVIM 26th Congress; ESVC-O-23. September 2016. J. Vet. Int. Med. January 2017. Quote: Cavalier King Charles Spaniels (CKCS) have a high prevalence of myxomatous mitral valve disease (MMVD) and early onset of the disease. Mitral valve (MV) morphology is a key factor in distributing forces over the MV apparatus, and abnormal loads could have a role in the etiology of MMVD. We therefore sought to evaluate the morphology of the MV of healthy CKCS and compare them to findings in healthy dogs of other breeds using real-time three-dimensional echocardiography (3DE). We hypothesized that, compared to other breeds, the MV of healthy CKCS was morphologically different. To be enrolled dogs had to be healthy based on physical and echocardiographic examinations. A total of 63 dogs were enrolled in the study: 22 CKCS and 41 dogs from 18 other breeds. The median (IQR) body weight (BW) was 14kg (8.8kg – 20kg). Three-dimensional echocardiographic datasets were analyzed off-line with a dedicated software package and 16 morphologic variables were measured. Variables with known association to BW were indexed using previously reported scaling factors. Differences between CKCS and all the other breeds were analyzed using unpaired Student’s T-test or Mann-Whitney U-test as appropriate for data distribution. Compared to healthy dogs, CKCS had significantly smaller BW (p<0.0001), normalized anterolateral-posteromedial annulus diameter (p=0.0320), annulus height (p=0.0255), tenting height (P<0.0001), tenting area (p<0.0001), normalized tenting volume (p=0.0001), posterior leaflet length (p=0.0012), normalized posterior leaflet area (p=0.0258), and a greater annulus sphericity index (p=0.0417). In conclusion, the MV of healthy CKCS was more circular and had less tenting, compared to other breeds.

Evaluating urinary 5-hydroxyindoleacetic acid (5-HIAA) as a biomarker of myxomatous mitral valve disease in cavalier King Charles spaniels. L.B. Christiansen, S.E. Cremer, A. Helander, T.Madsen, M.J. Reimann, J.E. Møller, K. Höglund, I. Ljungvall, J. Häggström, L.H. Olsen. ECVIM 26th Congress; ESVC-O-25. September 2016. J. Vet. Int. Med. January 2017. Quote: Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs with a high prevalence among Cavalier King Charles Spaniels (CKCS). Valvular changes may cause mitral regurgitation (MR) and over time, some dogs can progress into congestive heart failure. Increased circulating concentrations of serotonin are suggested to be involved in the pathogenesis of MMVD in CKCS. 5-Hydroxyindoleacetic acid (5-HIAA) is a serotonin metabolite excreted in urine. Urine 5-HIAA is commonly used in human medicine as a biomarker of serotonin-secreting tumors. The aim of the present study was to investigate if urinary 5-HIAA is associated with MMVD severity in CKCS. We hypothesized that the urine 5-HIAA concentration was increased in CKCS with MMVD and that urine 5-HIAA concentration would correlate with the serotonin concentration in serum or plasma. Serum, plasma and urine samples were collected from 80 dogs above 4 years of age divided into four groups: control dogs (Beagles) with no evidence of heart disease (CON, n = 17), CKCS with no or minimal MR due to MMVD (nMR, n = 18), CKCS with mild MR due to MMVD (mMR, n = 22) and CKCS with moderate to severe MR due to MMVD (sMR, n = 23). Urinary 5-HIAA was analyzed by high-performance liquid chromatography (HPLC) and creatinine (to correct for variations in urine dilution) by the Jaffe method. Serotonin concentrations in serum and platelet poor plasma were determined by a validated enzyme-linked immunosorbent assay. The results from preliminary analyses in a subset of dogs from three of the four groups (CON, nMR and sMR) with a mean age of 8.5 years (range: 4.1–13.3) are presented as the median (25–75% interquartile range). Analyses of the remaining samples are ongoing. No significant difference in urinary 5-HIAA to creatinine ratio (5-HIAA/CREA, lmol/mmol) was found between the CON dogs (n = 6; 2.37(1.52-2.58)), nMR dogs (n = 6; 2.77 (2.23–3.20)) and sMR dogs (n = 6; 2.94 (1.65–3.32)) (overall P = 0.48). Female dogs (n = 11) showed significantly higher 5-HIAA/CREA than male dogs (n = 7; 3.05 (2.47–3.32) versus 1.65 (1.50–2.49), P = 0.011). The preliminary data did not reveal any association of 5-HIAA/CREA with age (P = 0.844; R2=0.003), serum serotonin concentration (P = 0.396; R2=0.045) or plasma serotonin concentration (P = 0.3801; R2=0.048). In conclusion, the preliminary data indicate that urinary 5-HIAA concentrations are dependent on the sex, but not the age of the dog. Further analyses are necessary to draw final conclusions regarding the possible associations between urinary 5-HIAA concentrations and MMVD severity in dogs. (See also this June 2019 article.)

Degenerative Valvular Disease in the Cavalier King Charles Spaniel: Results of the UK Breed Scheme 1991–2010. S. Swift, A. Baldin, P. Cripps. J. Vet. Int. Med. January 2017;31(1):9-14. Quote: Background: Cavalier King Charles spaniels (CKCSs) are predisposed to degenerative mitral valve disease (DMVD) and studies have indicated a genetic cause. Animals: A total of 8,860 CKCSs were examined at shows or private clinics from 1991 to 2010. Objectives: To analyze the effects of a breed scheme for CKCS on the age at which a murmur consistent with DMVD was first detected. Methods: The presence or absence of a murmur consistent with mitral regurgitation was noted and age a murmur was first detected recorded. Results: A total of 16,887 examinations were performed on 8,860 dogs. The median age dogs developed a murmur were slightly younger in male than female dogs (7.8 versus 8.3 years, 95% confidence interval [CI] 7.4–8.1 versus 8.0–8.4, P < .001) and cardiologists detected murmurs in younger dogs than did general practitioner (GP) veterinary surgeons (7.2 versus 8.6 years, 95% CI 7.0–7.4 versus 8.3–8.7 P < .001). In bitches examined by GP vets during the study, there was a significantly increased age of detection of murmurs over time (8.6–9.2 years, 95% CI 8.3–9.1 and 8.5–10.9, P = .001) but not for male dogs examined by GP vets or dogs of either sex examined by cardiologists. Conclusions and Clinical Importance: This study suggests that the age incidence of murmurs associated with DMVD might be increased by application of breeding guidelines based on auscultation alone. This benefit was only seen in a subgroup and compliance of breeders with this voluntary scheme was poor.

A retrospective study of degenerative mitral valve disease in small-breed dogs: Survival and prognostic variables. Hyun-Tae Kim, Sei-Myoung Han, Woo-Jin Song, Boeun Kim, Mincheol Choi, Junghee Yoon, Hwa-Young Youn. J. Vet. Sci. January 2017. Quote: Small-breed (n= 168 dogs [no CKCSs]; weight < 15 kg) diagnosed with MMVD based on a routine clinical examination, radiology, an electrocardiogram, and echocardiography at the Seoul National University Veterinary Medical Teaching Hospital were included. The survival periods were ascertained and a significant difference was observed in the survival rates between the International Small Animal Cardiac Health Council classes. The mean follow-up period was 14.3 ± 12.1 months. Univariate analysis revealed that dyspnea, pulmonary edema, and vertebral heart score were significantly associated with the survival times (P < 0.05). Additionally, age, left atrial-to-aortic root ratio, ejection fraction, and left ventricular end diastolic volume were associated with increased risk of death (P < 0.1), while body weight, body condition score, systolic blood pressure, arrhythmia, syncope, fractional shortening, and end systolic volume were not associated with the risk of death. These results suggest that, among the variables, dyspnea, pulmonary edema, and vertebral heart score could be useful prognostic factors when giving information about patients to owners.

Real-Time 3-Dimensional Echocardiographic Assessment of Effective Regurgitant Orifice Area in Dogs With Myxomatous Mitral Valve Disease. A. Tidholm, A. Bodegård-Westling, K. Höglund, J. Häggström, I. Ljungvall. J. Vet. Int. Med. January 2017. Quote: Background: Effective regurgitant orifice area (EROA), calculated from the vena contracta width (VCW) as the narrowest portion of the proximal regurgitant jet, might be used to estimate severity of mitral regurgitation. However, this simplified assumption only holds when the EROA is circular, which might not be true in dogs with myxomatous mitral valve disease (MMVD). Hypothesis: Effective regurgitant orifice area in dogs with MMVD is noncircular, and using color Doppler real-time 3-dimensional (RT3D) echocardiography, measured EROA in the en face view will be significantly different from calculated EROA. Animals: A total of 158 privately owned dogs of 41 breeds were included in the study: Cavalier King Charles spaniel (34), Miniature Schnauzer (18), Dachshund (15), mixed breed (11), Chinese Crested (9), Chihuahua (6), and <5 dogs of 35 other breeds. There were 94 (59%) males and 64 (41%) females. Age at presentation ranged from 3.8 to 15.3 years, median 10.3 years (IQR, 8.4–11.8 years). Body weight ranged from 2 to 36.7 kg, median 9.8 kg (IQR, 6.9–12.7 kg). According to the ACVIM classification of MMVD, 32 (20%) dogs were classified with congestive heart failure (CHF) (2 in Class C1 and 30 in Class C2) and 126 (80%) dogs did not have CHF (115 dogs in Class B1 and 11 dogs in Class B2). Heart rate ranged from 80 to 222 beats/min, median 130 (IQR, 117–144 beats/min). Sinus rhythm was present in all dogs. At the time of examination, 41 (26%) dogs underwent medical treatment, in which 38 dogs received pimobendan, 32 dogs furosemide, 31 dogs benazepril, 3 dogs spironolactone, 2 dogs digoxin, and 1 dog sildenafil. Materials and Methods: Prospective observational study comparing en face view of EROA with calculated EROA using VCW in 4-chamber (4Ch) and 2-chamber (2Ch) view only or combined 4Ch and 2Ch views using RT3D echocardiography. Results: The calculated EROA using the 2Ch view showed a systematic underestimation of 17% compared with the measured en face EROA corrected for body surface area. The calculated EROA using 4Ch and 4Ch + 2Ch views showed less agreement with the en face EROA, and the difference between methods increased with increasing EROA. The difference between calculated and measured EROA showed a systematic underestimation of the calculated EROA by 36% (4Ch) and 33% (4Ch + 2Ch), respectively, compared to measured en face EROA. Conclusion and Clinical Importance: When replacing measured EROA with calculated EROA using VCW measurements, the 2Ch view is preferred in dogs with MMVD.

Hartdieet voor de hond (Canine cardiac diets: efficacy unproven). Anton C. Beynen. Dier-en-Arts. January 2017;1/2:18-21. Quote: In heart disease, the renin-angiotensin-aldosterone system is activated. High aldosterone maintains inflammation and fibrosis of the heart and leads to accumulation of body sodium and water. At regular sodium intakes, healthy dogs excrete at least 90% of ingested sodium with urine. This is only about 2% for dogs with induced or spontaneous heart failure. Sodium restriction in dogs with heart disease further raises plasma aldosterone. Dogs with induced heart failure were fed diets containing 53, 275 or 1226 mg sodium/MJ . The items assessed were: brisk walking, appetite, respiratory rate, muscle atrophy, ascites and left ventricular ejection fraction. With increasing sodium intakes plasma aldosterone concentration dropped and the clinical profile improved. ... There is no evidence that sodium restriction improves clinical signs in canine cardiac disease. Worse still, there are good reasons for contraindication.

Comparative echocardiographic studies of dogs with mixomatous degeneration of the mitral valve, dependent on the presence or absence of pulmonary edema, consecutively indexed by the linear and weight idealizing aortic size. Atanas Pankov. Trad. & Modern. in Vet. Med. January 2017;2(3):61-65. Quote: Echocardiographic dimensions of 20 dogs with myxomatous degeneration of the mitral valve were compared in this paper. The patients were decided into two groups depending on the presence or absence of pulmonary edema. ERIs were obtained after consecutive indexing of Aom and Aow. ... After concluding the results from both methods for indexing the M-mode echocardiographic measurements, it was found that the ratios measured based on the weight idealized aortic size are obtained with higher reliability in comparison to the results obtained with the indexing of the same dimensions with the linear aortic size. I suppose that the differences obtained in the two ways of compiling the ratios are due to the weight loss in patients, which is associated with the progression of the cardiac decompensation. Under these conditions the indexing of the raw echocardiographic dimensions and the lower body weight leads to higher values of the ratios and register of a higher reliability. The question that arises is – which is the more correct indexation? When developing a clean left-sided heart failure the isolated development of pulmonary edema cannot significantly affect the body weight. On the other hand, the real weight loss is another sign of the advancing heart disease and as such it should not be excluded when reporting the progression of the process. Conclusions: 1. Upon the indexing of the raw M-mode echocardiographic measurements with the weight idealized measured aortic size, the results obtained are with a higher reliability in comparison with the indexing of the same dimensions with the linear aortic size. 2. Based on the reasoning in the discussion of the results, I believe that as far as the mixomatous valvular disease is concerned, the indexing of M-mode echocardiographic measurements with weight aortic size is more suitable in comparison to the indexing with the linear aortic size, where in the case of this indexing the weight loss with progression of the heart failure is also noted.

Biologic variability of N-terminal pro-brain natriuretic peptide in healthy dogs and dogs with myxomatous mitral valve disease. Randolph L. Winter, Ashley B. Saunders, Sonya G. Gordon, Jesse S. Buch, Matthew W. Miller. J. Vet. Cardiol. April 2017;19(2):124--131. Quote: Introduction: Biologic variability (BV) is defined as the change in analyte concentration that occurs independently of the disease status of the patient. Specifically, this refers to changes in analyte concentration when multiple samples are obtained from either a healthy subject or from a patient with stable disease. Treatment recommendations and prognosis frequently depend on disease status, therefore establishing the BV is necessary for understanding the clinical importance of changes in the longitudinal measurement of analytes. ... The objectives of this study were to measure NTproBNP in healthy dogs and dogs with MMVD classified into American College of Veterinary Internal Medicine (ACVIM) stages B1, B2, or C-stable in order to estimate BV and calculate the Index of Individuality (IoI) of this analyte to determine if population-based reference ranges are appropriate. A secondary objective was to calculate the critical change value (CCV) for percent difference in NTproBNP concentration needed in order to suggest a change in disease in each group of dogs. ... Animals: Thirty-eight privately owned dogs: 28 with MMVD ["Dogs with MMVD included 14 Cavalier King Charles Spaniels"] and 10 healthy controls. Materials and methods: Prospective clinical study with comprehensive evaluation used to group dogs as healthy or into three stages of MMVD based on current guidelines. ... Briefly, dogs were classified as stage B1 MMVD if they had no echocardiographic evidence of cardiomegaly even if the VHS was >10.7. To be classified as stage B2, dogs were required to fulfill at least two out of three criteria for cardiomegaly. Dogs were classified as stage B2 if they had evidence of cardiomegaly defined as left atrium to aorta (LA/Ao) ratio in short axis ≥ 1.6 or radiographic vertebral heart size (VHS) >10.7. In addition, all dogs with stage B2 MMVD were required to have a left ventricular internal dimension (LVID) in diastole normalized to body weight ≥ 1.7. The selected cutoff value for normalized LVID in diastole was based on a study that found higher values, although technically within the normal reported range (<1.85), predicted increased risk of death in dogs with MMVD. ... NTproBNP was measured hourly, daily, and weekly. For each group, analytical (CVA), within-subject (CVI), and between-subject (CVG) coefficients of variability were calculated in addition to percent critical change value (CCV) and index of individuality (IoI). Results: For healthy dogs, calculated NTproBNP values were: CVA = 4.2%; CVI = 25.2%; CVG = 49.3%; IoI = 0.52, and CCV = 70.8%. For dogs with MMVD, calculated NTproBNP values were: CVA = 6.2%; CVI = 20.0%; CVG = 61.3%; IoI = 0.34, and CCV = 58.2%. Conclusions: Biologic variability affects NTproBNP concentrations in healthy dogs and dogs with MMVD. ... Given the increasing awareness of the clinical utility of cardiac biomarkers such as NTproBNP in veterinary medicine, it is important for veterinarians to have an understanding of how much a biomarker value could change over time due to randomness vs. disease progression in an individual dog. Few veterinary studies have assessed the variability of cardiac biomarkers. In one study, NTproBNP was measured in healthy dogs once per week for 3 consecutive weeks, and the majority of dogs had a greater than 100 pmol/L change in NTproBNP values. In a second study, cardiac troponin I (cTnI) and NTproBNP were measured weekly for seven weeks in normal dogs and nine dogs with heart disease not staged with current guidelines. In that study, reduced individual NTproBNP variability was observed in dogs with heart disease compared to control dogs, a result that is consistent with our findings. ... Monitoring serial individual changes in NTproBNP may be clinically relevant in addition to using population-based reference ranges to determine changes in disease status.

Markers of Oxidative Stress in Dogs with Myxomatous Mitral Valve Disease are Influenced by Sex, Neuter Status, and Serum Cholesterol Concentration. M.J. Reimann, J. Häggström, J.E. Møller, J. Lykkesfeldt, T. Falk, L.H. Olsen. J Vet. Int. Med. January 2017. Quote: Background: Cardiovascular disease has been associated with oxidative stress, which has been suggested to contribute to myocardial remodeling in human patients. Little is known about the relationship between myxomatous mitral valve disease (MMVD) and oxidative stress in dogs. Objective: To determine whether clinical stage of MMVD is associated with changes in the plasma concentrations of certain markers of oxidative stress in clinically healthy dogs and dogs with MMVD. Animals: Seventy five privately owned dogs: 59 cavalier King Charles Spaniels (CKCS) with different severities of MMVD and 16 dogs of different breeds with clinical signs of congestive heart failure (CHF) caused by MMVD. ... Clinical stage of MMVD was determined according to American College of Veterinary Internal Medicine (ACVIM) consensus statement guidelines as follows: group A (Cavalier King Charles Spaniels [CKCS] with no auscultatory heart murmur and normal echocardiogram [MR < 20%]), group B1 (CKCS with auscultatory heart murmur or MR ≥ 20% and LA/Ao ≤ 1.5), group B2 (CKCS with auscultatory heart murmur or MR ≥ 20% and LA/Ao > 1.5), and group C (dogs of various breeds with CHF). The inclusion of dog breeds other than CKCS in group C was carried out to increase the number of dogs. Classification of CHF included dogs with previous or current clinical signs of CHF (eg, cough, dyspnea, tachypnea, nocturnal restlessness, exercise intolerance), echocardiographic and radiographic changes compatible with CHF caused by MMVD, and response to treatment with diuretics. ... Methods: Markers of oxidative stress including malondialdehyde (MDA), oxidized low-density lipoprotein (oxLDL), and vitamin E (α-tocopherol and γ-tocopherol) were measured in plasma and their association with clinical stage of MMVD was assessed by regression analyses. Results: Plasma oxLDL concentration was significantly lower in female dogs compared with males (P = .01). Significantly higher plasma γ-tocopherol concentrations were found in neutered (P = .003) dogs. Vitamin E (α-tocopherol [P = .0004] and γ-tocopherol [P = .003]) was associated with body condition score (BCS), but the association disappeared when cholesterol was included in the analyses. All markers of oxidative stress (MDA, oxLDL, and vitamin E) were positively associated with serum cholesterol concentration (P ≤ .04), but none were associated with clinical stage of MMVD. Conclusions: In conclusion, markers of oxidative stress are associated with sex, BCS, neuter status, and cholesterol. The results cannot confirm a relationship between oxidative stress and clinical stage of the disease in dogs with MMVD.

Effects of ivabradine on left ventricular function in dogs with congestive heart failure. Sajika Sri-ngam, Soontaree Petchdee. Thai J. Vet. Med. January 2017;47(1):71-78. Quote: Ivabradine is an essential drug administered in current standard therapy for human heart failure and is expected to be beneficial to congestive heart failure dog. Ivabradine is a selective If Channel inhibitor. It reduces cardiac pacemaker activity and slows heart rate. There are a few reports of ivabradine in veterinary applications. The aim of this study was to investigate the effects of ivabradine on left ventricular function in dogs with congestive heart failure. Thirteen client-owned dogs with systolic and/or diastolic heart failure were included in this study. The dogs were assigned to two groups: (i) the active control group, given propranolol at 0.5 mg/kg, and (ii) the group treated with ivabradine at an initial dose of 0.5 mg/kg twice a day for 7 days, followed by a maintenance dose of 0.3 mg/kg twice a day. Types of arrhythmias were confirmed by lead II ECG, blood pressure, and echocardiography were measured before and 15 and 30 days after treatment of ivabradine. Results showed decrease in heart rate and improvement in score of quality of life. Ejection fraction and left ventricular size remained normal. These results indicate that the treatment with ivabradine can decrease heart rate and improve quality of life in dogs with congestive heart failure with no adverse effects on cardiac contractility.

Comparative echocardiographic examinations in dogs with myxomatous degeneration of the mitral valve depending on the presence or absence of pulmonary edema. Atanas Pankov, Hristina Shukerova, Geno Angelov. Tradition & Modernity in Vet. Med. January 2017;2(1(2)):13-16. Quote: In the article echocardiographic studies of 12 dogs with myxomatous degeneration of the mitral valve were compared. ... For the purpose of fulfilling the study objective, the dogs with left apical systolic murmur underwent X-ray and ultrasound examination. Based on the results, they were divided into two groups. First group included MVD dogs with pulmonary edema while the second group included dogs with MVD without pulmonary edema. ... The second group was formed by six dogs aged 8 to 14 years, of body weight 4.8 kg to 10 kg, and included 4 males and 2 females. Breeds were as follows: 1 Cavalier King Charles, ... The echocardiographic measurements were indexed to Ao - size. We received significant difference (p = 0.0077) only for LA / Ao, but this ratio can not be a predicator for the development of heart failure.

Left Atrial Strain at Different Stages of Myxomatous Mitral Valve Disease in Dogs. K. Nakamura, S. Kawamoto, T. Osuga, T. Morita, N. Sasaki, K. Morishita, H. Ohta, M. Takiguchi. J. Vet. Int. Med. February 2017. Quote: Background: Decreased function of the left atrium (LA) is a useful prognostic indicator in dogs with myxomatous mitral valve disease (MMVD). In humans, LA strain is a novel severity indicator of mitral regurgitation, but its clinical utility in dogs has not been confirmed. Objectives: To examine whether LA strain as evaluated with speckle-tracking echocardiography is associated with MMVD stage in dogs. Animals: A total of 52 dogs with MMVD were enrolled, including 24 dogs in stage B1, 15 dogs (2 Cavalier King Charles Spaniels) in stage B2, 10 dogs in stage C, and 3 dogs in stage D. Methods: Cross-sectional study. Dogs were classified as stage B1, B2, C, or D, according to the American College of Veterinary Internal Medicine consensus. Physical examination findings and echocardiographic variables were compared among the groups. To assess the comparative accuracy of echocardiographic variables in identifying dogs with the presence or history congestive heart failure (CHF), receiver operating characteristic curves and multivariate logistic analysis were used. Results: There were no significant differences in parameters of LA strain between B1 and B2 groups. However, LA longitudinal strain during atrial contraction (εA) (median, 19.1%; interquartile range, 15.3–24.3% in B1, 19.6%; 14.1–21.4% in B2, 6.2%; 3.18–11.2% in C/D) and during ventricular systole (εS) (32.7%; 28.9–39.2% in B1, 35.6%; 31.7–41.9% in B2, 23.6%; 16.9–26.1% in C/D) were significantly lower in stages C/D than in stages B1 and B2. In multivariate logistic regression analysis, εA and peak early diastolic mitral inflow velocity were identified as independent indicators of stage C/D. Conclusions and Clinical Importance: εA [LA longitudinal strain during atrial contraction] was the best predictor of the presence or history of CHF. Further studies are needed to determine the clinical implications of these findings for treatment decisions and prognosis determination.

Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease. M. Höllmer, J.L. Willesen, A. Tolver, J. Koch. J. Vet. Cardio. February 2017;19(1):24-34. Quote: Objective: Myxomatous mitral valve disease (MMVD) induces progressive left atrial (LA) enlargement. The LA modulates left ventricular filling and performance through its reservoir, conduit, and contractile function. Assessment of LA size and function may provide valuable information on the level of cardiac compensation. Left atrial function in dogs with naturally occurring MMVD remains largely unexplored. The objective of this study was to evaluate LA volume and function in dogs with naturally occurring MMVD. Animals: This prospective study included 205 client-owned dogs of different breeds, 114 healthy dogs [21 Cavalier King Charles spaniels], and 91 dogs [28 CKCSs] with MMVD of different disease severities. Methods: Using two-dimensional echocardiography, the biplane area-length method was applied to assess LA volume and calculate volumetric indices of LA reservoir, conduit, and contractile function. Results: Left atrial volume and LA stroke volume increased, whereas LA reservoir and contractile function decreased with increasing disease severity. A maximal LA volume <2.25mL/kg was the optimal cut off identified for excluding congestive heart failure in dogs with chronic MMVD with a sensitivity of 96% and a specificity of 100%. An active LA emptying fraction <24% and/or a LA expansion index <126% were suggestive of congestive heart failure in dogs with chronic MMVD with a sensitivity of 77% and a specificity of 89% and a sensitivity of 82% and a specificity of 82%, respectively. Conclusion: Dogs with MMVD appear to have larger LA volumes with poorer LA function. Deteriorating LA function, characterized by a decreasing reservoir and active contractile function, was evident in dogs with MMVD with increasing disease severity.

Serum proteomic profiles in CKCS with Mitral valve disease. Chiara Locatelli, Cristian Piras, Giulia Riscazzi, Isabella Alloggio, Ilaria Spalla, Alessio Soggiu, Viviana Greco, Luigi Bonizzi, Paola Roncada and Paola G. Brambilla. BMC Vet. Res. February 2017. Quote: Background: Myxomatous mitral valve disease (MVD) is the most common acquired heart disease in dogs, and the Cavalier King Charles Spaniel (CKCS) is the most studied breed because of the high prevalence, early onset and hereditary component evidenced in the breed. MVD has different severity levels, and there are many practical limitations in identifying its asymptomatic stages. Proteomic techniques are valuable for studying the proteins and peptides involved in cardiovascular diseases, including the period prior to the clinical onset of the disease. The aim of this study was to identify the serum proteins that were differentially expressed in healthy CKCS and those affected by MVD in mild to severe stages. ... A convenience sample of 12 CKCS was enrolled, 4 healthy dogs (control group) and 8 dogs affected by MVD. ... Proteomics analysis was performed using two-dimensional gel electrophoresis separation and a bioinformatics analysis for the detection of differentially expressed spots. In a comparative analysis, protein spots with a p < 0.05 (ANOVA) were considered statistically significant and were excised from the gels for analysis by MALDI-TOF-MS for protein identification. Results: Eight proteins resulted differentially expressed among the groups and significantly related to the progression of the disease. In mild affected group versus healthy dogs complement factor H isoform 2, inhibitor of carbonic anhydrase, hemopexin, dystrobrevin beta isoform X7 and CD5 molecule-like resulted to be down-regulated, whereas fibronectin type-III domain-containing protein 3A isoform X4 was up-regulated. In severe affected dogs versus healthy group complement factor H isoform 2, calpain-3 isoform X2, dystrobrevin beta isoform X7, CD5 molecule-like and l-2-hydroxyglutarate dehydrogenase resulted to be down-regulated. Complement factor H isoform 2, calpain-3 isoform X2, dystrobrevin beta isoform X7, CD5 molecule-like and hydroxyglutarate dehydrogenase were found to be down-regulated in mild affected group versus healthy dogs. All of these proteins except complement factor H followed a decreasing trend according to the progression of the pathology. Conclusion: The genetic and the proteomics studies of MVD are important for providing additional information for the comprehension of this pathology and for the evaluation of the outcome of this disease. Obtained results and further studies on these different parameters may contribute to the improvement of the genetic selection of pure breeds to reduce the incidence of this pathology. Moreover, protein identified that were found to be positively or negatively related to the pathology may be helpful in the future for the diagnosis, for choosing the best therapeutic approach and for evaluating the therapeutic response to improve the quality of life and the clinical outcome in dogs affected by MVD.

Asymptomatic heart valve dysfunction in healthy middle-aged companion dogs and its implications for cardiac aging. Silvan R. Urfer, Tammi L. Kaeberlein, Susan Mailheau, Philip J. Bergman, Kate E. Creevy, Daniel E. L. Promislow, Matt Kaeberlein. GeroScience. February 2017;39(1):43-50. Quote: Heart disease is the leading cause of death in the USA, accounting for about one in every four deaths. Age is the greatest risk factor for heart disease in both people and dogs; however, heart disease is generally not considered as a major cause of morbidity or mortality in dogs. As part of the preliminary selection process for a veterinary clinical trial, 40 companion dogs with no history of cardiac pathology that were at least 6 years old and weighed at least 18 kg underwent a cardiac screening using Doppler echocardiography. Eleven dogs from this cohort were diagnosed with valvular regurgitation by echocardiography, and seven of these cases were of sufficient severity to warrant exclusion from the clinical trial. In only one case was a heart murmur detected by auscultation. Serum alkaline phosphatase levels were significantly higher in the dogs with moderate to severe valvular regurgitation compared to the rest of the cohort. These observations suggest that asymptomatic degenerative valvular disease detectable by echocardiography, but not by a standard veterinary exam including auscultation, may be present in a significant fraction of middle-aged companion dogs, indicating a previously underappreciated similarity between human and canine aging. Further, these data suggest that companion dogs may be a particularly useful animal model for understanding mechanisms of age-related degenerative valve disease and for developing and testing interventions to ameliorate cardiac disease. Future studies should address whether dogs with asymptomatic valve disease are at higher risk for subsequent morbidity or early death.

Radiographic assessment of the cardiac silhouette in clinically normal large- and small-breed dogs. Ayman A. Mostafa, Clifford R. Berry. Amer. J. Vet. Res. February 2017;78(2):168-177. Quote: Objective: To determine manubrium heart scores (MHSs) from measurements of cardiac short-axis length (cSAL) and long-axis length (cLAL) relative to the corresponding manubrium length (ML) on thoracic radiographic views of dogs and assess correlation of MHSs with vertebral heart scores (VHSs). ... The manubrium of the sternum was selected because it is a relatively prominent, regularly elongated, bullet-shaped or rectangular bone segment that is easily identified and can be readily measured on lateral thoracic radiographic views. ... Animals: 120 clinically normal large-breed dogs (LBDs) and small-breed dogs (SBDs) [including one cavalier King Charles spaniel]. Manubrium Heart ScoreProcedures: On right lateral views (RLVs) and ventrodorsal views (VDVs) for each dog, cSAL and cLAL were measured and expressed as a ratio; the cSAL:ML ratio (short-MHS), cLAL:ML ratio (long-MHS), and cSAL-and-cLAL:ML ratio (overall-MHS) were also calculated. The VHS was determined from the RLV. Correlation of VHS with MHS was assessed. Results: On RLVs and VDVs, mean cSAL:cLAL ratios were 0.77 (SD, 0.05) and 0.72 (SD, 0.05), respectively, in 60 LBDs and 0.81 (SD, 0.06) and 0.78 (SD, 0.06), respectively, in 60 SBDs. In LBDs, mean short-MHS, long-MHS, and overall-MHS were 2.1 (SD, 0.22), 2.7 (SD, 0.24), and 4.8 (SD, 0.5), respectively, on RLVs and 2.3 (SD, 0.26), 3.2 (SD, 0.34), and 5.4 (SD, 0.6), respectively, on VDVs. In SBDs, mean short-MHS, long-MHS, and overall-MHS were 2.4 (SD, 0.39), 2.9 (SD, 0.50), and 5.3 (SD, 0.83), respectively, on RLVs and 2.5 (SD, 0.44), 3.2 (SD, 0.51), and 5.8 (SD, 0.92), respectively, on VDVs. Mean VHSs were 10.73 (SD, 0.52) and 10.27 (SD, 0.81) in LBDs and SBDs, respectively. A significant correlation was identified between VHS and each MHS in LBDs. ... Additionally, on the basis of the right lateral radiographic findings in this study, the possible variation in the intervertebral disk spaces (eg, intervertebral disk space narrowing) may be another possible factor contributing to the relative weak correlation between the VHS and the corresponding cSAL and cLAL. However, the canine manubrium is rarely affected by disease, and it is a single prominent, elongated bone segment that can be easily identified on lateral thoracic radiographs. In addition, in the present study, there were strong correlations between the cSAL and cLAL and the corresponding ML. Therefore, we propose that the ML can be used as an appropriate reference value for assessment of the corresponding cSAL and cLAL in dogs. ... Conclusions and Clinical Relevance: In the dogs evaluated, radiographic cardiac dimensions and MHSs were correlated. Validity of the MHS for cardiac dimension assessment in other healthy dogs and dogs with cardiac disease warrants investigation.

Mitral valve morphology assessed by three-dimensional transthoracic echocardiography in healthy dogs and dogs with myxomatous mitral valve disease. G. Menciotti, M. Borgarelli, M. Aherne, S. Wesselowski, J. Häggström, I. Ljungvall, S.M. Lahmers. J. Vet. Cardio. April 2017;19(2):113-123. Quote: Objective: To assess differences in morphology of the mitral valve (MV) between healthy dogs and dogs affected by myxomatous mitral valve disease (MMVD) using real-time transthoracic three-dimensional echocardiography (RT3DE). Animals: 113 dogs were enrolled; 61 were female and 52 male. The most represented breeds were mixed breed (25), Cavalier King Charles Spaniel (13), Beagle (7), Border Collie (7), Dachshund (5), Shih Tzu, (5) and less than five dogs for each of 33 other breeds. Thirty-four dogs were healthy [no CKCSs], while 79 were affected by different stages of MMVD: 29 dogs were in stage B1 [3 CKCSs], 39 in stage B2 [8 CKCSs], and 11 in stage C [2 CKCSs]. Methods: Real-time transthoracic three-dimensional echocardiography mitral datasets were digitally recorded and analyzed using dedicated software. The following variables were obtained and compared between healthy dogs and dogs with MMVD at different stages: antero-posterior annulus diameter, anterolateral-posteromedial annulus diameter, commissural diameter, annulus height, annulus circumference, annulus area, anterior leaflet length, anterior leaflet area, posterior leaflet length, posterior leaflet area, non-planar angle, annulus sphericity index, tenting height, tenting area, tenting volume, the ratio of annulus height and commissural diameter. Results: Dogs with MMVD had a more circular MV annulus compared to healthy dogs as demonstrated by an increased annulus sphericity index (p=0.0179). Affected dogs had a less saddle-shaped MV manifest as a decreased annulus height to commissural width ratio (p=0.0004). Tenting height (p<0.0001), area (p<0.0001), and volume (p<0.0001) were less in affected dogs. Conclusions: Real-time transthoracic three-dimensional echocardiography analysis [RT3DE] demonstrated that dogs affected by MMVD had a more circular and less saddle-shaped MV annulus, as well as reduced tenting height area and volume, compared to healthy dogs. Multiple variables differed between dogs at different stages of MMVD. ... This study demonstrated that the MV of dogs affected by MMVD differed from that of healthy dogs in several morphological aspects. Affected dogs had an increased sphericity and a decreased saddle shape of the MV annulus, as well as a decreased tenting height, area and volume. This study also demonstrated significant differences in multiple RT3DE MV measurements between dogs with varying severities of MMVD. ... Diagnostic and prognostic utility of these variables, and the significance of these changes in the pathogenesis and natural history of MMVD, require further attention.

Breed-Specific Vertebral Heart Scale for the Dachshund. Ryan Birks, Deborah M. Fine, Stacey B. Leach, Sarah E. Clay, Bryan D. Eason, Lisa G. Britt, Kenneth E. Lamb. J. Amer. Anim. Hosp. Assn. March 2017;53(2):73-79. Quote: The objectives of this study were to determine a breed-specific vertebral heart scale (VHS) range for the dachshund and compare results to the established reference range of 9.7 6 0.5, calculate inter-observer variability, and correlate VHS with chocardiography. Fifty-one normal dachshunds had radiographs and an echocardiogram performed. Five observers measured VHS to the nearest 0.25 vertebra. The datawas analyzed using one-way analysis of variance,Wilcoxon Rank Sum test,Mann-Whitney rank sumtest, calculation of reference and confidence intervals, Spearman rank-order correlations, and generation of intra-class correlations and confidence intervals. P , .05 was considered significant. The median for right lateral VHS was significantly larger than left (10.3 [range 9.25–11.55] versus 10.1 [range, 8.7–11.31], p , .0001). VHS for femaleswas significantly larger than formales (left: 10.56 [9.2–11.31] versus 9.74 [8.7–10.88] and right: 10.8 [9.5–11.55] versus 9.99 [9.25–10.8], p¼.0002). Observer consistency was high with an intra-class correlation coefficient of 0.95. No significant correlationwas found between left atrial echocardiographic parameters and VHS. Results indicate normal dachshunds have a median VHS above the published generic canine reference range, and VHS can be reliably performed by observers with varying degrees of clinical experience. ... The VHS method can be used to aid in the radiographic assessment of the dachshund cardiac silhouette. Use of breed-specific VHS may aid in the early recognition of cardiac abnormalities in asymptomatic dachshunds. Results indicate normal dachshunds have a median VHS above the published generic canine reference range. Based on this study, a VHS greater than 11.0 in the dachshund should be considered strongly supportive of cardiac enlargement. In these cases, further clinical investigation such as echocardiography is appropriate to investigate for the presence of underlying heart disease.

Outcome of bioprosthetic valve replacement in dogs with tricuspid valve dysplasia. P. Bristow, J. Sargent, V. Luis Fuentes, D. Brockman. J. Sm. Anim. Pract. March 2017. Quote: Objectives: To describe the short-term and long-term outcome in dogs with tricuspid valve dysplasia undergoing tricuspid valve replacement under cardiopulmonary bypass. Methods: Data were collected from the hospital records of all dogs that had undergone tricuspid valve replacement under cardiopulmonary bypass between 2006 and 2012. Dogs were considered candidates for tricuspid valve replacement if they had severe tricuspid valve regurgitation associated with clinical signs of cardiac compromise. Results: Nine dogs of six different breeds were presented. Median age was 13 months (range 7 to 61 months), median weight 26·5kg (range 9·7 to 59kg). Eight bovine pericardial valves and one porcine aortic valve were used. One non-fatal intraoperative complication occurred. Complications during hospitalisation occurred in six dogs, four of which were fatal. Of the five dogs discharged, one presented dead due to haemothorax after minor trauma seven days later. The four remaining dogs survived a median of 533 days; all of these dogs received a bovine pericardial valve. Clinical Significance: Based on our results, tricuspid valve replacement with bovine or porcine prosthetic valves is associated with a high incidence of complications. ... The reason tissue valves were chosen as the prosthesis for these dogs was because human patients with tissue valves do not require life-long anticoagulant therapy once the exposed elements of the valve are coated with native endothelium. In addition, (Orton et al. 2005) concluded that long-term anticoagulant therapy was difficult to monitor and control in a report of a series of dogs that underwent mitral valve replacement using a bi-leaflet mechanical valve and thrombus-related valve failure was a frequent event (Orton et al. 2005). Again, it is not clear why our results differ from those of Arai et al. (2011) because the variation in anticoagulant therapy (with the exception of one dog) is minor and would have been more likely to reduce coagulation-related problems. The group at Colorado State University have published several reports on the use of warfarin in dogs (Monnet & Morgan 2005, Orton et al. 2005, Arai et al. 2011), so we conclude that some of our complications were due to our relative inexperience, but also that this remains problematic even in the hands of those more experienced in its use. ... The reasons for the poor outcome in the study reported here remain unclear. With so many variables (surgery team, anaesthesia team, cross clamp time, bypass time, total surgery time, valve type used, weight, etc) that could affect outcome, a larger number of dogs undergoing this procedure would have to be studied. Based on the results reported here, we have to conclude that, at least in our hands, bioprosthetic tricuspid valve replacement in dogs has poor results with a high short-term mortality rate and a short survival time postoperatively.

Long-term effect of sildenafil on echocardiographic parameters in dogs with asymptomatic myxomatous mitral valve degeneration. Anusak Kijtawornrat, Siripen Komolvanich, Nakkawee Saengklub, Prapawadee Pirintr, Pakit Boonpala, Chollada Buranakar. J. Vet. Med. Sci. March 2017;16-0372. Quote: Myxomatous mitral valve degeneration (MMVD) is the most common acquired heart disease in older dogs. This disease affects small breed dogs more than larger breeds, and some breeds are predisposed to the heart disease, especially the Cavalier King Charles Spaniel. The process begins with valve thickening which prevents complete valve closure resulting in backward flow of blood into the left atrium known as mitral regurgitation. Several compensatory mechanisms are triggered including the stimulation of sympathetic nervous system (SNS) and the renin-angiotensin aldosterone system (RAAS). Unfortunately, in small animal veterinary medicine, there are no medications that are proven to prevent left ventricular remodeling or delay the MMVD progression. Once the clinical signs develop, angiotensin converting enzyme inhibitor (ACEi), diuretic and pimobendan are mostly prescribed. ... Sildenafil is a selective phosphodiesterase-5 inhibitor that has been demonstrated to delay ventricular remodeling in humans and experimental animals. The aim of this prospective study was to assess the chronic effects of sildenafil administration on echocardiographic indices and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in dogs with naturally occurring, asymptomatic myxomatous mitral valve degeneration. Thirty client-owned dogs with ACVIM class B1 or B2 were enrolled. [None were cavaliers.] Dogs were randomly assigned to treatment (sildenafil 1–3 mg/kg, PO, BID for 180 days) or control groups. A total of 12 dogs completed the 180 days trial in the sildenafil group, whereas 10 dogs remained in control group. When comparing the difference from baseline values obtained over time between groups, the stroke volume (SV) at day 30 was significantly higher in the sildenafil group (P=0.038). The LA/Ao and the MR jet area were significantly lower beginning at day 30 (only MR jet area; P=0.006), day 90 (P=0.006 and P=0.027, respectively) and day 180 (P=0.029 and P=0.032, respectively). The 2D-LA was significantly lower at day 90 when compared with control group (P=0.028). The differences of NTproBNP from baseline were significantly lower when compared with control group at the same timepoint (D90, P=0.017 and D180, P=0.013). In conclusion, this study suggested that long-term treatment with sildenafil prevented aggravation of disease progression as suggested by several echocardiographic indices (i.e. SV, LA/Ao, MR jet area, 2D-LA) and reduced NTproBNP level at the indicated timepoints in dogs with asymptomatic mitral valve degeneration.

Correlation between serum homocysteine concentration and severity of mitral valve disease in dogs. Chang-Min Lee, Da-Min Jeong, Min-Hee Kang, Seung-Gon Kim, Jae-Ik Han, Hee-Myung Park. Amer. J. Vet. Res. April 2017;78(4):440-446. Quote: Objective: To measure serum homocysteine concentrations in dogs with myxomatous mitral valve disease (MMVD) and identify any association between this variable and stage of MMVD. ... Homocysteine is an essential amino acid metabolite of methionine that is recycled into methionine or converted into cysteine by vitamin B. ... Animals: 53 client-owned dogs with MMVD and 10 healthy control Beagles. Procedures: Dogs with MMVD were allocated to 3 groups in accordance with the staging system for chronic valvular heart disease in dogs and cats of the American College of Veterinary Internal Medicine. Blood samples were collected from all dogs, and serum homocysteine and cardiac troponin 1 concentrations were measured by enzyme immunoassay and chemiluminescence immunoassay, respectively. Analyte values were tested for associations with each other and with stage of MMVD. Results: A significant correlation was identified between serum homocysteine concentration and stage of MMVD. Mean ± SD concentrations were 6.72 ± 1.65 μmol/L for control dogs, 13.37 ± 4.16 μmol/L for dogs with stage B MMVD, 18.86 ± 6.73 μmol/L for dogs with stage C disease, and 28.26 ± 4.48 μmol/L for dogs with stage D disease. In addition, serum homocysteine concentration was correlated with serum cardiac troponin 1 (r = 0.34) and creatinine (r = 0.46) concentrations, systolic blood pressure (r = 0.57), and left atrium-to-aortic root ratio (r = 0.28), all of which were positively correlated with stage of MMVD. Conclusions & Clinical Relevance: Serum homocysteine concentrations of dogs with MMVD were significantly higher than those of control dogs, and significant correlations were identified between these values and several risk factors for heart failure. Measurement of serum homocysteine concentration may be useful in the prediction of severity of disease in dogs with MMVD.

Plasma coenzyme Q10 concentration, antioxidant status, and serum N-terminal pro-brain natriuretic peptide concentration in dogs with various cardiovascular diseases and the effect of cardiac treatment on measured variables. Alenka Nemec Svete, Barbara Verk, Alenka Seliškar, Katerina Tomsič, Petra Jazbec Križman, Aleksandra Domanjko Petrič. April 2017;78(4):447-457. Quote: Objective: To determine the plasma total antioxidant capacity, erythrocyte superoxide dismutase activity, whole blood glutathione peroxidase activity, and plasma coenzyme Q10 (CoQ10) concentration in dogs with various stages of cardiovascular diseases and in healthy dogs; assess the influence of cardiac treatment on the levels of antioxidant variables, plasma CoQ10 concentration, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, and determine any correlation between the disease severity (NT-proBNP concentration) and antioxidant variables or CoQ10 concentration. Animals: 43 dogs with various types and stages of cardiovascular diseases (congenital and acquired) ... myxomatous mitral valve disease predominated (22 dogs) ... and 29 healthy dogs. Procedures: Blood samples were collected from all dogs for spectrophotometric assessment of antioxidant variables. Plasma CoQ10 concentration was determined with a high-performance liquid chromatography–atmospheric pressure chemical ionization–tandem mass spectrometry method. Serum NT-proBNP concentration was measured with an ELISA. Results: Values for antioxidant variables did not differ among groups of dogs with cardiovascular diseases, regardless of disease stage or treatment. Plasma CoQ10 concentration was significantly increased in treated dogs with congestive heart failure (CHF), compared with untreated patients. However, plasma CoQ10 concentration did not differ among heart failure classes. A significant, negative correlation between serum NT-proBNP and plasma CoQ10 concentrations was identified in treated CHF-affected dogs, suggesting that low plasma CoQ10 concentration may be associated with increased severity of CHF. Conclusions & Clinical Relevance: The antioxidant variables evaluated were not altered in dogs with CHF, regardless of cardiac disease stage or treatment. Further investigation into the possible effects of CoQ10 supplementation in dogs with advanced stages of CHF is warranted.

Assessment of Lung Ultrasound B-Lines in Dogs with Different Stages of Chronic Valvular Heart Disease. T. Vezzosi, T. Mannucci, A. Pistoresi, F. Toma, R. Tognetti, E. Zini, O. Domenech, E. Auriemma, S. Citi. J. Vet. Intern. Med. March 2017. Quote: Background: In dogs with chronic valvular heart disease (CVHD), early recognition of pulmonary edema (PE) is of paramount importance. Recent studies in dogs showed that lung ultrasound examination (LUS) is a useful technique to diagnose cardiogenic PE. Objectives: To describe LUS features in dogs with different stages of CVHD, and to determine its diagnostic accuracy in detecting PE using thoracic radiography as the reference standard. Animals: Sixty-three dogs with CVHD. [No breeds were identified.] ... Dogs with CVHD were classified into stages B1, B2, C, and D according to the ACVIM classification scheme. Stage B was defined as subclinical heart disease without (B1) or with (B2) evidence of left cardiomegaly, defined as LA/Ao ≥ 1.6, LVIDDn > 1.73, or both. Dogs were assigned to stage C if they had a history or current clinical signs of CHF in conjunction with past or current evidence of PE on thoracic radiographs. ... Methods: Prospective, multicenter, cross-sectional study. Each dog underwent physical examination, echocardiography, thoracic radiography, and LUS. The LUS findings were classified as absent, rare, numerous, or confluent B-lines. Sensitivity, specificity, and positive and negative predictive values of LUS B-lines to identify PE were calculated using thoracic radiography as the reference standard. Results: Dogs in stage B1 had absent or rare B-lines in 14 of 15 cases (93.3%). Dogs in stage B2 had absent or rare B-lines in 16 of 18 cases (88.9%). All dogs in stage C, without radiographic signs of PE, had absent or rare B-lines. Dogs in stage C, with radiographic signs of PE, had numerous or confluent B-lines in 18 of 20 cases (90%). Lung ultrasound examination detected PE with a sensitivity of 90%, specificity of 93%, and with positive and negative predictive values of 85.7 and 95.2%, respectively. ... Lastly, dogs in stage C had a higher value of LVIDDn (median, 2.21; range, 1.63–2.86) in comparison with stage B2 (median, 1.87; range, 1.39–2.34); and stage B1 (median, 1.48; range, 1.25–1.85). The LVIDDn in stage B2 was significantly larger than in stage B1. ... Conclusions and Clinical Importance: ... Our findings indicate that LUS has good diagnostic accuracy in identifying cardiogenic PE and might be useful in the staging of dogs with CVHD. Lung ultrasound examination is a new, quick, and noninvasive diagnostic tool for the cardiologist, radiologist, or intensive care specialist. It should be considered as complementary to thoracic radiography, and particularly useful when radiographic findings are unclear or in severely dyspneic dogs. In the future, it would be interesting to evaluate the utility of LUS in the chronic management and serial monitoring of dogs with CVHD under treatment.

Quality of Life Score as a Predictor of Death in Dogs with Degenerative Mitral Valve Disease. Célia M. C. Strunz, Mário Marcondes-Santos, Julio Yoshio Takada, Fernanda S. Fragata, Antônio de Pádua Mansur. Arquivos Brasileiros de Cardiologia. March 2017; doi: 10.5935/abc.20170032. Quote: Background: The knowledge of the variables predicting mortality is important in clinical practice and for therapeutic monitoring in mitral valve disease. Objectives: ... The aim of this study was to investigate whether a score obtained with the Functional Evaluation of Cardiac Health, a quality of life questionnaire, could be used as a predictor of death in dogs with DMVD (degenerative mitral valve disease). ... Methods: Thirty-six client-owned dogs [23 Poodles, five mixed-breed dogs, one Basset hound, one Beagle, one Cocker Spaniel, one Dachshund, one Lhasa Apso, and three Pinschers] with mitral valve disease underwent clinical, laboratory, and echocardiographic evaluations at baseline and were monitored for 6 months. Cardiovascular death was the primary outcome. ... the Functional Evaluation of Cardiac Health quality of life questionnaire was developed based on widely accepted clinical signs of cardiac disease in dogs. The questionnaire consists of 17 questions answered by the dog owner, who grades the severity of symptoms on a scale from 0 to 5, in which 0 = few symptoms and 5 = several symptoms , with higher scores indicating a poorer health-related quality of life. The questions are mainly related to respiratory signs, difficulties with mobility (such as walking and climbing stairs), physical activity, irritability, appetite, sleepiness, and frequency of urination and vomiting. The score was established using information obtained from the owner by a veterinarian during the anamnesis. ... Results: The 36 dogs were classified as survivors or nonsurvivors. ... Furthermore, animals with higher concentrations of NT-proBNP or a higher quality of life score had a higher risk of death. ... Higher values of the following variables were obtained at baseline in the nonsurviving group (12 dogs): amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, plasma norepinephrine, heart rate, quality of life score, diastolic left ventricular internal dimension to aortic root ratio, systolic left ventricular internal dimension to aortic root ratio, and left atrium to aortic root ratio. NT-proBNP levels and quality life score were independently associated with death in the multivariable analysis. Conclusion: The quality life score was an independent variable for cardiac death in dogs with DMVD. This result is encouraging, as this score is easy to apply and does not require any technology, only a veterinarian and an observant owner.

Myxomatous Degeneration of the Canine Mitral Valve: From Gross Changes to Molecular Events. G. Markby, K. M. Summers, V. E. MacRae, J. Del-Pozo, B. M. Corcoran. J. Comp. Path. April 2017;156:371-383. Quote: Myxomatous mitral valve disease (MMVD) is the single most common acquired heart disease of the dog, but is also of emerging importance in human medicine, with some features of the disease shared between both species. There has been increased understanding of this disease in recent years, with most research aiming to elucidate the cellular and molecular events of disease pathogenesis. For gross and histological changes, much of our understanding is based on historical studies and there has been no comprehensive reappraisal of the pathology of MMVD. This paper reviews the gross, histological, ultrastructural, cellular and molecular changes in canine MMVD. ... There have been major advances in understanding of the pathobiology of canine MMVD in the last 10 years and research activities are ongoing and expanding at various centres. In addition, there is a large amount of comparative data emerging from studies of human MMVD and associated diseases, but caution must be exercised in extrapolating new findings between man and the dog. The availability of dog-specific molecular tools has allowed the linking of pathological events to effects at the levels of gene and protein expression. However, since the pathological data are more than 30 years old, there is also a need to reappraise the morphological changes seen withMMVDat the gross, histological and ultrastructural levels. An observation of the same problems in human MMVD research has recently been reported showing that fundamental aspects of valve pathology, particularly the fibrotic response, have been overlooked.

Open heart surgery with deep hypothermic cardiopulmonary bypass and more than 90 minutes of aortic cross clamp time in 10 small dogs. Kippei Mihara, Isamu Kanemoto, Keiichi Sato, Takuya Mori, Hirokazu Abe, Seiya Niimi, Koji Yamada, Kenji Ohira, Takanori Andou, Atsushi Hirakawa. Vet. Sci. Devel. April 2017;7:6442[pp 83-86]. Quote: No previous reports have described cardiopulmonary bypass (CPB) techniques involving long aortic cross clamp (ACC) times in small-breed dogs. We previously described open heart surgery under deep hypothermic CPB in small and toy dogs with an approximate ACC time limit of 1 hour, given the low success rate beyond 90 minutes of ACC time. Herein, we describe improvements in cardiac anesthesia, CPB, and cardioplegia [intentional and temporary cessation of cardiac activity] that led to a high success rate of open heart surgery with a long ACC time in small dogs. Ten small-breed dogs with severe mitral regurgitation [including one cavalier King Charles spaniel] were subjected to mitral valve plasty that necessitated cardiopulmonary bypass (CPB) beyond 90 minutes of ACC time. In the present study, all dogs survived surgery; 7 survived to discharge [including the CKCS]. In other words, we achieved a high success rate of 70% with mitral valve plasty beyond 90 minutes of ACC time (mean, 105.1 minutes: range, 90-117 minutes). For small dogs, successful open heart surgery with a long ACC time may require cardiac balanced anesthesia, CPB with increased drainage and, importantly, thorough cardioplegia without hemodilution [decreased concentration of cells and solids in the blood].

Long-term survival of two dogs after mitral valve plasty. Isamu Kanemoto, Daisuke Taguchi, Kippei Mihara, Koudai Kawase, Keiichi Sato, Kazuya Iwata, Kouji Iwanaga. Vet. Sci. Devel. April 2017;7(1):6335[pp 51-54]. Quote: Two small 9-year-old dogs [a Maltese and a Shi Zhu] received mitral valve plasty (MVP) for severe mitral regurgitation that could not be controlled via drug administration. MVP consisted of chordal reconstruction using expanded polytetra-fluoroethylene (ePTFE) sutures and semicircular suture annuloplasty using polypropylene sutures. In both cases, the clinical signs dramatically improved after MVP, although postoperative echocardiography revealed slight residual mitral regurgitant flow. Both dogs survived for several years after MVP without any signs of cardiac distress; one dog survived for 9 years and 1 month, and the other dog survived for 7 years and 10 months. These findings highlight the durability of ePTFE sutures as artificial chordae and the excellence of semicircular suture annuloplasty in small dogs.

Short- and long-term results of chordal reconstruction using artificial suture material (polytetrafluoroethylene and polypropylene) in the dog. Isamu Kanemoto, Tomonari Masumoto, Kiminari Ohara, Yusuke Kimura, Noboru Machida. Vet. Sci. Devel. April 2017;7(1):6683[pp 78-82]. Quote: No previous reports have compared the suitability of expanded polytetrafluoroethylene (ePTFE) and polypropylene as artificial suture materials for chordal reconstruction in mitral valve plasty (MVP) in the dog. Twelve normal dogs were subjected to MVP using surfaceinduced deep hypothermia. In the short-term group (1.5-4 months after surgery), all ePTFE sutures were covered by a tissue sheath including the paired suture arms, which gave the appearance of native chordae from 2 months after surgery. In contrast, all polypropylene sutures were not covered by tissue, and appeared the same as the paired polypropylene suture arms at the operation. In the long-term group (12 months after surgery), all ePTFE sutures were covered by a tissue sheath, which appeared the same as that in the short-term group, and had flexibility without increased thickness with time. In contrast, although the polypropylene suture was covered completely by a tissue sheath in 1 dog, all the other polypropylene sutures were exposed except for both ends of the suture. ePTFE may be superior to polypropylene as an artificial suture material for chordal reconstruction in MVP.

Prevalence of mitral valve regurgitation in 79 asymptomatic Norfolk terriers. A. Bodegård-Westling, A. Tidholm, J.Häggström. J. Vet. Cardio. April 2017;19(2):107-112.

Serum nitrotyrosine concentration in dogs with myxomatous mitral valve disease. Jun-Seok Kim, Jun-Seok Park, Hyung-Jin Park, Kyoung-Won Seo, Kun-Ho Song. Korean J. Vet. Res. April 2017;57(1):17-21. Quote: The aim of this study was to compare serum nitrotyrosine concentrations in healthy dogs with those in dogs with myxomatous mitral valve disease (MMVD). Fifty client-owned dogs were included in this study. Based on echocardiographic results, dogs were categorized into healthy (control), mild-, moderate-, and severe-MMVD groups. Serum nitrotyrosine concentrations were determined from enzyme-linked immunosorbent assays. No significant difference between control dogs and dogs with mild MMVD was detected (p = 0.31). However, dogs with moderate MMVD had significantly higher serum concentrations of nitrotyrosine (p = 0.04) than that in controls, and dogs with severe MMVD had significantly lower serum concentrations of nitrotyrosine (p = 0.03) than that in moderate MMVD dogs. There were negative correlations in the association of serum nitrotyrosine with age (n = 30, R<sup>2</sup>= 0.067, p = 0.27), left atrial-to-aortic root diameter ratio (n = 30, R<sup>2</sup>= 0.02, p = 0.57), and platelet count (n = 30, R<sup>2</sup>= 0.39, p = 0.003); however, only the platelet correlation was significant. Among dogs with MMVD, there was no significant difference in serum nitrotyrosine concentration between males and females. The results of this study suggest that tyrosine nitration end-products might be potential biomarkers for the detection of MMVD in dogs.

Assessment of Left Atrial Deformation and Function by 2-Dimensional Speckle Tracking Echocardiography in Healthy Dogs and Dogs With Myxomatous Mitral Valve Disease. M. Baron Toaldo, G. Romito, C. Guglielmini, A. Diana, N.G. Pelle, B. Contiero, M. Cipone. J. Vet. Int. Med. April 2017. Quote: Background: The assessment of left atrial (LA) function by 2-dimensional speckle tracking echocardiography (STE) holds important clinical implications in human medicine. Few similar data are available in dogs. Objectives: To assess LA function by STE in dogs with and without myxomatous mitral valve disease (MMVD), analyzing LA areas, systolic function, and strain. Animals: One hundred and fifty dogs [including 10 cavalier King Charles spaniels] were divided according to the American College of Veterinary Internal Medicine classification of heart failure: 23 dogs in class A, 52 in class B1 [8 CKCSs], 36 in class B2 [2 CKCSs], and 39 in class C + D. Methods: Prospective observational study. Conventional morphologic and Doppler variables, LA areas, and STE-based LA strain analysis were performed in all dogs and results were compared among groups. Correlation analysis was carried out: between LA STE variables and other echocardiographic variables. Results: Variability study showed good reproducibility for all the tested variables (coefficient of variation <16%). Left atrial areas, fractional area change, peak atrial longitudinal strain (PALS), peak atrial contraction strain, and contraction strain index (CSI) differed significantly between groups B2 and C + D and all the other groups (overall P < .001), whereas only PALS differed between groups B1 and A (P = .01). Left atrial areas increased with progression of the disease, whereas LA functional parameters decreased. Only CSI increased nonsignificantly from group A to group B1 and then progressively decreased. Thirty-one significant correlations (P < .001, r > .3) were found between conventional left heart echocardiographic variables and LA areas and strain variables. Conclusions and Clinical Importance: Left atrial STE analysis provides useful information on atrial function in the dog, highlighting a progressive decline in atrial function with worsening of MMVD.

Biologic variability of cardiac troponin I in healthy dogs and dogs with different stages of myxomatous mitral valve disease using standard and high-sensitivity immunoassays. Randolph L. Winter, Ashley B. Saunders, Sonya G. Gordon, Matthew W. Miller, Geoffrey T. Fosgate, Jan S. Suchodolski, Jörg M. Steiner. Vet. Clin. Path. April 2017. Quote: Background: Biologic variability (BV) is one aspect of interpreting changes in biomarker concentrations known to be clinically important in people with cardiac disease, but it has not been adequately addressed in dogs so far. Objectives: The purpose of the study was to determine BV of cardiac troponin I (cTnI) in healthy dogs and dogs with 3 stages of myxomatous mitral valve disease (MMVD). Methods: Healthy dogs and dogs with 3 stages of MMVD were prospectively assigned to groups based on comprehensive clinical evaluation using current guidelines. ... Dogs with MMVD were classified according to the ACVIM guidelines. Briefly, dogs with Stage B1 MMVD had no echocardiographic evidence of cardiac chamber enlargement. Dogs were classified as Stage B2 if 2 of the following 3 criteria were met including left atrium to aorta (LA/Ao) ratio in short-axis ≥ 1.6, radiographic vertebral heart size (VHS) > 10.515, or left ventricular internal dimension (LVID) in diastole normalized to body weight ≥ 1.7. ... Cavalier King Charles Spaniels were overrepresented in the MMVD group, as they are predisposed for and may be diagnosed earlier with MMVD. ... Concentrations of cTnI were measured hourly, daily, and weekly using standard and high-sensitivity immunoassays. Within- (CVI) and between-subject (CVG) coefficients of variability, percent reference change value (RCV), and index of individuality (IoI) were calculated. Results: All 10 healthy dogs and 76/112 (68%) of samples from 28 MMVD dogs [including 14 (50%) cavalier King Charles spaniels] had cTnI concentrations below the limit of detection (LOD) using a standard sensitivity immunoassay. Only 49/160 (31%) of healthy dog samples and no MMVD samples had cTnI below the high-sensitivity immunoassay LOD. Data analysis for the high-sensitivity immunoassay revealed CVI of 48.1%, CVG of 60.1%, RCV of 134.0%, and IoI of 0.804 in healthy dogs. In MMVD dogs, CVI was 39.6%, CVG was 80.7%, RCV was 110%, and IoI was 0.494. Of all MMVD dogs, those with Stage B2 had the lowest RCV of 91%. Conclusions: Biologic variability affects cTnI concentrations in healthy dogs and dogs with MMVD. Consideration of BV may be clinically relevant when monitoring individual changes in cTnI values, using high-sensitivity immuno-assays. ... Furthermore, longitudinal investigation of cTnI in dogs with MMVD likely would profit from high-sensitivity cTnI immunoassays and knowledge of BV. Specifically, longitudinal monitoring of cardiac biomarker changes helped predicting specific clinical end-points such as onset of heart failure or death. In fact, serial measurement of cTnI may provide more information for predicting survival time than a single measurement that is compared to an RI established with healthy dogs, and this may prove useful in guiding therapy in dogs with MMVD.

Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study – A Randomized Clinical Trial. Mark Rishniw. Advances in Sm. Anim. Med. & Surg. April 2017;30(4). Quote: This is the first study to demonstrate a benefit of medication in subclinical MMVD in small-breed dogs. As such, clinicians are likely to begin prescribing this drug to many patients with this disease. However, several caveats exist, some of which were addressed by the authors and some which are addressed below. The authors selected dogs that had evidence of left atrial and left ventricular enlargement according to both echocardiographic and radiographic criteria. Given that many clinicians struggle to correctly identify cardiomegaly in small-breed dogs from radiographs and tend to over-interpret cardiac enlargement, the investigators stressed that the diagnosis should be made with the benefit of echo-cardiography. Obviously, many clients will not be able to afford echocardiography, and clinicians will be faced with the decision based on radiographic evidence alone. The authors also stress that dogs without cardiomegaly might not benefit, therefore, clinicians should avoid the temptation to treat every old small-breed dog with an apical murmur with pimobendan. clinicians should avoid the temptation to treat every old small-breed dog with an apical murmur with pimobendan. ... It should be noted that all the benefit was in delaying CHF, not in preventing cardiac (sudden) death. ... On the face of it, this sounds great. Based on this information alone, every dog with MMVD and left atrial enlargement (correctly identified!) would benefit from pimobendan treatment. Not so fast! The decision to treat a dog requires additional information to be considered. First, the baseline risk of developing CHF needs to be determined, i.e., what is the chance that this dog will actually develop CHF at some point in the future? ... Is “earlier” treatment better than “later” treatment? The survival curves provide clues to this answer. ... Now, if there was a clear benefit of “earlier” rather than “later,” we might expect the survival curves to diverge, ie., continue to move further and further apart. But they don’t. For the majority of the study, they remain parallel. So, the benefit with more severely affected dogs is about 300 days, and the benefit with the least severely affected dogs is about 300 days. This suggests that taking the more measured approach of waiting until a dog exhibits evidence of disease progression before instituting therapy is not compromising that dog nor reducing the benefit of the drug. And, dogs that were never going to progress to more severe disease and never develop CHF would not be subjected to needless drug administration (and needless expenses).

A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Silvan R. Urfer, Tammi L. Kaeberlein, Susan Mailheau, Philip J. Bergman, Kate E. Creevy, Daniel E. L. Promislow, Matt Kaeberlein. GeroScience. April 2017;39(2):117-127. Quote: Age is the single greatest risk factor for most causes of morbidity and mortality in humans and their companion animals. As opposed to other model organisms used to study aging, dogs share the human environment, are subject to similar risk factors, receive comparable medical care, and develop many of the same age-related diseases humans do. In this study, 24 middle-aged healthy dogs received either placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. All dogs received clinical and hematological exams before, during, and after the trial and echocardiography before and after the trial. Our results showed no clinical side effects in the rapamycin-treated group compared to dogs receiving the placebo. Echocardiography suggested improvement in both diastolic and systolic age-related measures of heart function (E/A ratio, fractional shortening, and ejection fraction) in the rapamycin-treated dogs. Hematological values remained within the normal range for all parameters studied; however, the mean corpuscular volume (MCV) was decreased in rapamycin-treated dogs. Based on these results, we will test rapamycin on a larger dog cohort for a longer period of time in order to validate its effects on cardiac function and to determine whether it can significantly improve healthspan and reduce mortality in companion dogs.

Cardiac Drug and Supplement Information: D-Ribose. Nick Schroeder. LeadER Animal Specialty Hospital. May 2017. Quote: "D-ribose is a carbohydrate (sugar) that is important for the body’s cellular metabolism through the production of a substance known as ATP (adenosine trisphosphate). Patients suffering from severe heart disease, especially heart diseases such as dilated cardiomyopathy, may have severely depleted stores of ATP within heart muscle tissue. A small study in humans with congestive heart failure suggested that supplementation with ribose may improve heart muscle function. Reported minor side effects included diarrhea, gastrointestinal upset and nausea. D-ribose may be found at most supplement sections in pharmacies, Publix®, Whole Foods® or other places like the General Nutrition Center®."

Reflections on clinical trials – the distance from results to action. A. Boswood. J. Sm. Anim. Pract. May 2017;58(5):255-256. Quote: In order to be enrolled to a study, patients usually need to meet a number of specific criteria; these are often referred to as inclusion and exclusion criteria. The purpose of these criteria is to establish that the enrolled patients definitely have the disease of interest at an appropriate stage. In order to show that they meet these criteria patients need to undergo a series of diagnostic tests before inclusion in the trial. ... To illustrate this point with a current example – in order to ensure that the patients recruited to the EPIC study definitely had primary mitral valve disease and enlargement of their heart they underwent both echocardiography and radiography before study entry. If I am now asked by a practitioner – “should I treat this dog, which I believe has preclinical mitral valve disease, with pimobendan?” – my response will typically be “to be certain that therapy is indicated the dog will need to undergo echocardiography and ideally also radiography.” Had the dogs in the study not undergone those tests our results would have been (justifiably) doubted by our peers because the severity of the recruited dogs’ heart disease would not have been known ...

Feasibility, safety, and tolerance of subcutaneous synthetic canine B-type natriuretic peptide (syncBNP) in healthy dogs and dogs with stage B1 mitral valve disease. M.A. Oyama, P.F. Solter, C.L. Thorn, J.A. Stern. J. Vet. Cardio. May 2017. Quote: Introduction: An important aspect of heart failure is the progressive ineffectiveness of the salutary natriuretic peptide system and its secondary messenger, 3′,5′-cyclic guanosine monophosphate (cGMP). In humans with acute heart failure, administration of exogenous natriuretic peptide is associated with improvement in clinical signs and reduction of cardiac filling pressures. This study aimed to determine the feasibility, tolerance, and safety of subcutaneous (SC) synthetic canine B-type natriuretic peptide (syncBNP) administration in dogs. Animals: Six privately owned dogs. Materials and methods: Dogs were enrolled in a modified 3 + 3 phase I trial. Three dogs initially received doses of 2.5 and 5 μg/kg SC syncBNP followed by an additional three dogs dosed at 5 and 10 μg/kg. Hemodynamic monitoring was performed for 120 min after each injection. Blood and urine samples were collected at 45 and 120 min after injection of 5 μg/kg. Major adverse clinical events that would potentially halt testing were pre-defined. Results: Four healthy dogs and two dogs with stage B1 mitral valve disease were recruited. ... Dogs included four mixed breed, one Cocker Spaniel, and one Cavalier King Charles Spaniel. ... Synthetic canine B-type natriuretic peptide was well tolerated at all doses. Synthetic canine B-type natriuretic peptide at 5 μg/kg significantly increased median plasma cGMP (baseline cGMP, 131.5 pmol/mL [range, 91.9–183.6 pmol/mL]; 45 min, 153.6 pmol/mL [140.3–214.3 pmol/mL]; 120 min, 192.7 pmol/mL [139.1–240.1 pmol/mL]; p=0.041). Discussion and conclusions: We report for the first time administration of syncBNP in privately owned dogs. Administration of SC syncBNP was feasible, well tolerated, safe, and increased plasma cGMP concentration. Further studies using exogenous syncBNP for treatment of heart disease are warranted.

NPA7, an innovative multivalent designer natriuretic peptide: Co-therapy with Furosemide to mediate renoprotection in experimental ADHF. LMG Meems, Y Chen, GJ Harty, GE Harders, BK Huntley, SR Iyer, DM Heublein, JC Burnett Jr. Euro. J. Heart Failure. May 2017;19(S1):6(#32). Acute decompensated heart failure (ADHF) is a heart failure syndrome with high morbidity and mortality. Current initial therapy focuses on relief of signs and symptoms using diuretics, such as Furosemide (FURO). Diuretic therapy however may induce Cardiorenal Syndrome, which itself is a predictor of mortality and worse outcome. This warrants novel therapeutic strategies to protect the heart and kidney. We have previously reported the engineering of a highly novel multivalent cardiorenoprotective designer peptide that we call NPA7. In this study we test the renoprotective properties of NPA7 in a large animal model of ADHF compared with FURO. We furthermore investigate the actions of NPA7 and FURO co-therapy including the importance of NPA7 pre- or post-therapy, and hypothesized that the timing of NPA7 treatment is an important factor in obtainingmaximal renoprotection. Ten male mongrel canines were paced at 240 beats per minute for 10 days. On day 11, canines randomly received 45 minutes infusion of NPA7 (8.66 pmol/L) or FURO (1mg/kg), followed by NPA7 + FURO or FURO + NPA7 co-therapy respectively. Hemodynamic parameters were monitored and continuous urines were collected. Results are presented as mean baseline changes±standard deviation. In canines with ADHF, NPA7 decreased systemic vascular resistance (SVR) and reduced pulmonary capillary wedge pressure while increasing renal blood flow (RBF). Secondly, NPA7 increased urinary flow (UV) and urinary sodium excretion (UNaV), albeit it to a lesser extent than FURO. In contrast to NPA7, FURO lacked vasodilatory actions, impaired kidney function and activated the renin-angiotensin-aldosterone system (RAAS). Importantly, NPA7 + FURO co-therapy had synergistic natriuretic and diuretic efficacy while preserving RBF and eGFR, which was not observed with FURO followed by NPA7 infusion. In conclusion, in experimental ADHF, NPA7 is a vasodilatory therapeutic with cardiac unloading, diuretic and natriuretic actions. FURO is more diuretic, but is associated with significant renal impairment, vasoconstriction and RAAS-activation. In addition, pre-treatment with NPA7 enhances natriuresis and diuresis while preserving kidney function. Priming with NPA7 may therefore represent a novel renoprotective strategy for treatment of ADHF. Importantly, this study underscores the need for future studies assessing the impact of timing of diuretics on treatment effects of novel therapies in patients with ADHF.

Neladenoson, a partial adenosine A1-receptor agonist, improves mitochondrial function in skeletal muscle of dogs with chronic heart failure. HN Hani Sabbah, RC Gupta, V Singh-Gupta, K Zhang, J Xu, B Albrecht-Kuepper. Euro. J. Heart Failure. May 2017;19(S1):511(#2009).  Background: Exercise intolerance (Ex-Int) is a feature of chronic heart failure (HF) and in particular, HF with preserved ejection fraction (HFpEF) and attributable, in part, to skeletal muscle (SM) abnormalities of fiber type composition and mitochondrial (MITO) dysfunction. In patients and dogs with HF, SM aerobic, MITO-dependent, type-I fibers decrease in number while anaerobic type-II fibers increase; a maladaptation that contributes to Ex-Int. We previously showed that chronic therapy with capadenoson, a partial adenosine A1-receptor agonist (pA1RA), improves LV function in HF dogs and therapy with neladenoson (NELA), a novel pA1RA, normalizes MITO function in failing cardiomyocytes. This study examined the effects of NELA on MITO function in SM biopsies from normal (NL) dogs and dogs with microembolization-induced HF. Methods: Fresh SM open biopsies (˜6 grams) were obtained from the hind leg Vastus Lateralis muscle of 6 NL and 6 HF anesthetized dogs. Samples were cut into thin sections, divided into 4 equal portions, and one portion each incubated in 0 (vehicle), 3, 10, and 30 nM concentration of NELA respectively for one hour at 37∘C. At end of incubation, MITO were isolated from SM and their function assessed. MITO ADP-stimulated state-3 respiration (ADPresp) was measured using a Strathklein respirometer, MITO complex-IV (COX-IV) activity was measured polarographically and MITO maximum rate of ATP synthesis (ATPsyn) was measured using the bioluminescent ApoSENSOR assay kit. Results: Increasing concentration of NELA had no effect on measures of MITO function in SM from NL dogs (Table). In SM from HF dogs, depressed levels of MITO ADPresp, ATPsyn, and COX-IV activity increased significantly in a dose-dependent manner after exposure to NELA (Table). Conclusions: The results indicate that NELA improves MITO function of SM of dogs with HF. These improvements can potentially reduce/reverse Ex-Int in HF.

Advanced Echocardiographic Imaging In Dogs With Myxomatous Mitral Valve Disease. Giulio Menciotti. Va. Poly. Inst. & State Univ. thesis. May 2017. Quote: In the studies presented in this dissertation, we used advanced non-invasive ultrasonographic techniques to investigate the mechanisms involved in this disease. We hypothesized that a different shape of the MV in some dogs could contribute to the development of the disease. We used 3D ultrasounds to build models of the MV and analyze the shape of it. We first demonstrated that using this technique in dogs was feasible and repeatable, and that the MV of normal dogs was elliptical and saddle-shaped. We then compared the shape of the MV of normal dogs, to the shape of the MV of dogs affected with MMVD. We found that dogs with the disease have a MV that is flatter and more circular. In our next study, we examined the shape of the MV of a breed of dogs that is predisposed to develop MMVD: Cavalier King Charles Spaniels (CKCSs). Our study found that healthy CKCSs have an overall flatter MV when compared with the other breeds, and that the normal MV of CKCSs is similar to the MV of affected dogs of other breeds. This finding support our hypothesis that an abnormal shape of the MV could contribute to the development of the disease. In another study, we saw to evaluate whether we could use 3D ultrasounds for investigating the shape of the hole that creates on affected MV. We concluded that this technique still requires more standardization before being used for evaluation of dogs. In another study, of which some preliminary results are presented in this dissertation, we are testing how accurate it is to evaluate the pressure of the pulmonary artery using ultrasonography. We are doing this by comparing this technique to a direct measurement of the pressures with a catheter in the pulmonary artery. We found that measurements obtained with the two techniques do not agree very well, which most likely indicates the evaluation of the pulmonary artery pressure using ultrasonography requires caution.

Comparison of the Mitral Valve Morphologies of Cavalier King Charles Spaniels and Dogs of other Breeds using Real-time 3D Transthoracic Echocardiography. G. Menciotti, M. Borgarelli, M. Aherne, P. Camacho, J. Häggström, I. Ljungvall, S. M. Lahmers, J. A. Abbott. Va. Poly. Inst. & State Univ. May 2017. Quote: Objectives: To determine whether the mitral valve (MV) morphology of healthy Cavalier King Charles Spaniels (CKCSs) differs from the morphology of healthy dogs of other breeds using transthoracic real time 3D echocardiography (RT–3DTTE). Animals: 35 healthy CKCSs and 41 healthy dogs of other breeds. Methods: Dogs underwent physical examination, conventional echocardiography, and RT– 3DTTE. RT–3DTTE datasets were analyzed using dedicated software for MV morphologic analysis. Morphologic variables were compared between CKCSs and dogs of other breeds. Results: The MV of healthy CKCSs has a smaller anterolateral-posteromedial diameter (p=0.0387), annulus height (p=0.0021), tenting height (p<0.0001), tenting area (p<0.0001), tenting volume (p=0.0001) and area of the posterior leaflet (p=0.0080) compared to healthy dogs of other breeds. Conclusions: The MV of CKCSs is flatter and has reduced tenting compared to the MV of other breeds. (See Figure 2 below.) These morphologic features could confer a mechanical disadvantage, and play a role in the predisposition of this breed to the early development of myxomatous mitral valve disease.

Comparison of Mitral Valve Morphologies-Fig-2

Accuracy of Noninvasively Determined Pulmonary Artery Pressure in Dogs with Myxomatous Mitral Valve Disease. G.Menciotti, M. Borgarelli, M. Aherne, J.A. Abbott. Va. Poly. Inst. & State Univ. May 2017. Quote: The present study is still ongoing, and only preliminary results are presented in this dissertation. Two different observers measured the invasive pressure tracings and the echocardiographic images (JA and MB, respectively), blind to the results obtained by the other observer. The pressure values obtained from the same dog with the two techniques were then matched by a third observer unrelated to the study, and both dogs’ identity and the nature of the technique used for obtaining each value were anonymized. The resulting table of matched pairs of pressures was then analyzed. Results: Thirteen dogs were enrolled in the study in a period comprised between 5/14/2014 to 2/23/2017. ... The most represented breeds were CKCSs, Whippet, and Mixed breed, with two dogs enrolled per each breed. ... Comment: The preliminary analysis reported here indicates that the two techniques used for obtaining the systolic PA pressure are significantly related, but they do not present good agreement. The 95% limits of agreement reported here are narrower than what previously reported in a canine experimental model of pulmonary embolism [5], but it must be noticed that the range of pressures examined in the present study is significantly narrower than the one in the experimental model. However, the entity of the limits of agreement reported here indicates that one method could either underestimate or overestimate the other by about 15mmHg. ... Conclusions: In conclusion, analyzing the MV of dogs using RT–3DTTE is feasible, repeatable, and provides valuable information. The morphology of the MV is generally elliptical and saddle-shaped in healthy dogs, with most of the morphologic variables related to the size of the dogs in an allometric fashion. Dogs affected by MMVD have a MV with a disrupted morphology, which is overall more circular and flatter than the MV of healthy dogs. Some morphologic characteristics are related to the severity of the disease. The height of the annulus and the degree of leaflets’ tenting are reduced in dogs at early stages of the disease, before significant cardiac remodeling has occurred. The MV of healthy CKCSs presents the same morphologic alterations when compared to the MV of a mixed population of healthy dogs of other breeds. Given the importance of MV biomechanics, and the known link between abnormal valvular stress and development of myxomatous degeneration, this supports speculations on whether these morphologic characteristics represent predisposing factors for the disease development in dogs. A longitudinal study is required in order to confirm this hypothesis. From the results of the studies reported here, we can also conclude that RT–3DTTE is a feasible way to measure AROA in dogs with MMVD, and that AROA is different between dogs with mild and severe MMVD. However, we must also conclude that the technique used in our study is poorly repeatable and reproducible, most likely for a lack of standardization of the technique and for technical constraints.

Myths in clinical cardiology. Ivan Sosa. VetBloom. May 2017. Quote: It is generally accepted that, in order to provide good quality work, we need to keep our knowledge up to date, mainly through continuous education courses, reading articles, etc. However, some of the diagnostic procedures, historical and physical examination findings or laboratory analysis that we have learned during our veterinary training and after graduation have been taught as dogma, with little evidence to support their validity. Sometimes, these misconceptions make it to veterinary medicine as extrapolated information from human medicine. Relying on false assumptions can be dangerous to your patient. This lecture will review a list of myths involving cardiac disease with little evidence to support their validity. ... The combination of coughing and crackles in a patient with a heart murmur seems to be a common source of misdiagnosis of congestive heart failure. ... The association between dental disease and degenerative valvular disease in dogs is likely the biggest myth in veterinary cardiology.

Mitral Valve Disease in Dogs- Truly Epic. Kristin Jacob. May 2017. Quote: DMVD has been proven to be inherited in the Cavalier King Charles Spaniel and the Dachshund but several other breeds are predisposed, such as Bichons, poodles, Chihuahuas, Miniature Schnauzers, Boston Terriers. ... The EPIC trial (Evaluation of Pimobendan In Cardiomegaly) was published in September 2016 in JVIM. In this study, small breed dogs were confirmed to have DMVD and cardiomegaly. So, had typical heart murmur, on chest radiographs had VHS > 10.5 and then had echocardiograms with board-certified cardiologist (Left atrial:aortic ratio > 1.6, LVEDDN > 1.7 (left ventricular dimension in diastole normalized to body weight). Most of the inclusion criteria for the study were echocardiographic measurements. Results of the study demonstrated that Pimobendan delayed the onset of CHF compared to placebo by ~ 15 months. The study demonstrates that Pimobendan has the greatest monotherapy benefit to delay the onset of heart failure in small dogs with stage B2 DMVD. There is always some risk to medications so we definitely want to choose the right patients to place on Pimobendan - so want to confirm that they are advanced enough to require medications via echocardiogram. However, now we know that early diagnosis can lead to better long-term outcomes. The data from this landmark study supports the use of Pimobendan once signs of significant left atrial and left ventricular dilation are present but not when the heart size is normal or even mildly enlarged. We do not yet know whether further improvement in survival is possible if Pimobendan is used in combination with other medications. The EPIC trial was a well-designed study and will change the way we treat patients with DMVD. Treatment for advanced stage B2 (based on chest radiographs + echocardiogram with cardiologist):
● Pimobendan (0.25 mg/kg PO q. 12 hr) - off label use
● +/- ACE inhibitor (0.5 mg/kg PO q. 12 hr - adjust dose depending on renal/liver function/electrolytes).

Tricuspid annular plane systolic excursion in dogs with myxomatous mitral valve disease with and without pulmonary hypertension. H. Poser, M. Berlanda, M. Monacolli, B. Contiero, A. Coltro, C. Guglielmini. J. Vet. Cardio. June 2017. Quote: Objectives: To evaluate tricuspid annular plane systolic excursion (TAPSE) in dogs with myxomatous mitral valve disease (MMVD) with or without pulmonary hypertension (PH) and to study the correlations with clinical and echocardiographic parameters. Animals: The study population included 99 dogs with MMVD and tricuspid regurgitation [including 2 cavalier King Charles spaniels]. Methods: This is a prospective clinical study. All dogs received a transthoracic echocardiographic evaluation, including 2D, M-mode, echo-Doppler, and tissue Doppler measurements. The TAPSE was measured from the left apical four-chamber view and normalized for the effect of body weight (nTAPSE). The dogs were grouped according to the severity of MMVD (American College of Veterinary Internal Medicine guidelines) and presence/absence and severity of PH. [One CKCS was in Stage B1 and the other CKCS was in Stage C/D.] Significant differences between TAPSE or nTAPSE and echocardiographic parameters were analyzed among the MMVD and PH severity groups. Correlations between TAPSE or nTAPSE and echocardiographic parameters were calculated. Results: Tricuspid annular plane systolic excursion or nTAPSE were not significantly different among dogs of the MMVD or PH severity groups. Significant correlations were obtained between TAPSE and body weight, left ventricular and atrial dimensions, early diastolic septal and early diastolic and systolic tricuspid annulus velocity (p<0.001); nTAPSE was significantly correlated with normalized end-diastolic left ventricular dimension and fractional shortening (p<0.001). Conclusions: The results show that neither TAPSE nor nTAPSE are reduced in dogs with MMVD with or without PH. It remains unclear if the right ventricle function is not reduced or if a reduced right ventricle function is masked by the contraction of the left ventricle through ventricular interdependence.

Comparative Evaluation of the Echocardiographic Parameters of Dogs with Chronic Mitral Valve Regurgitation Treated with Amlodipine or Pimobendan. Orson Nobumitsu Kamakura, Guilherme Teixeira Goldfeder, Paula Hiromi Itikawa, Rebecca Bastos Pessoa, Maria Helena Matiko Akao Larsson. Acta Sci. Vet. May 2017;45:1-6(1440). Quote: Background: Chronic mitral valve regurgitation is the most common heart disease in dogs. It is caused by myxomatous mitral valve degeneration, an acquired degenerative disease that can lead to congestive heart failure. Pimobendan is a mixed action drug, with inotropic and vasodilator proprieties, widely used to treat such dogs. Amlodipine is a pure vasodilator drug used as an anti-hypertensive agent, with no inotropic effects. This study aimed to compare echocardiographic, electrocardiographic and blood pressure parameters between dogs with congestive heart failure treated with pimobendan and those treated with amlodipine in addition to conventional therapy. Materials, Methods & Results: A prospective, randomized, double-blind study was conducted in dogs with stage C chronic mitral valve regurgitation according to the 2009 American College of Veterinary Internal Medicine (ACVIM) guidelines, who weighed up to 15 kg. ... The animals were randomized into two groups based on the drug they received. Group A received pimobendan (n = 10) and group B received amlodipine (n = 11). All animals were also treated with furosemide and enalapril maleate and evaluated three times over a period of sixty days (T0, T30, T60). Changes in echodopplercardiographic and electrocardiographic parameters and systolic blood pressure were investigated. There were no significant differences in electrocardiographic parameters or systolic blood pressure between the groups at any time. Among the echo-cardiographic parameters, only early diastolic myocardial peak velocity (Em) and late diastolic myocardial peak velocity (Am) showed a significant difference between groups. Discussion: This was the first prospective randomized double-blind study comparing pimobendan and amlodipine in the treatment of dogs with stage C chronic mitral valve regurgitation according to the ACVIM consensus statement. The use of pimobendan in these patients has been debated because myocardial inotropism is generally preserved in them. Some authors argue that early use of the drug can even lead to deleterious effects on the heart. In the present study, the groups showed no statistically significant differences in systolic blood pressure or electrocardiographic parameters. Among the echocardiographic parameters, statistically significant differences were only observed in the speed of Em waves between groups at T0, in the speed of Em waves in the amlodipine group between T0 and T60 times, and in the speed of Am waves in the amlodipine group between T30 and T60 times. Both parameters are indices of diastolic function and may indicate a change in early myocardial relaxation. From the findings of this study, we could not conclude whether one drug was superior to the other.

Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease. M.K. Ames, C.E. Atkins, A. Eriksson, A.M. Hess. J. Vet. Cardiol. May 2017. Quote: Introduction: Aldosterone breakthrough (ABT) is the condition in which angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers fail to effectively suppress the activity of the renin angiotensin aldosterone system. The objective of this study was to determine if ABT occurs in dogs with naturally occurring myxomatous mitral valve disease receiving an ACEI, using the urine aldosterone to creatinine ratio (UAldo:C) as a measure of renin angiotensin aldosterone system activation. Animals, Materials and Methods: This study includes 39 dogs with myxomatous mitral valve disease. A UAldo:C cut-off definition (derived from a normal population of healthy, adult, and client-owned dogs) was used to determine the prevalence of ABT in this population. Spearman analysis and univariate logistic regression were used to evaluate the relationship between UAldo:C and ABT (yes/no) and eight variables (age, serum K+ concentration, serum creatinine concentration, ACEI therapy duration and ACEI dosage, furosemide therapy duration and furosemide dosage, and urine sample storage time). Finally, the UAldo:C in dogs receiving spironolactone, as part congestive heart failure (CHF) therapy, was compared to dogs with CHF that were not receiving spironolactone. Results: The prevalence of ABT was 32% in dogs with CHF and 30% in dogs without CHF. There was no relationship between either the UAldo:C or the likelihood of ABT and the eight variables. Therapy with spironolactone lead to a significant elevation of the UAldo:C. Discussion: Using the UAldo:C and a relatively stringent definition of ABT, it appears that incomplete RAAS blockade is common in dogs with MMVD receiving an ACEI. The prevalence of ABT in this canine population mirrors that reported in humans. While the mechanism of ABT is likely multifactorial and still poorly understood, the proven existence of ABT in dogs offers the potential to improve the prognosis for MMVD with the addition of a mineralocorticoid receptor blocker to current therapeutic regimens. Conclusions: Approximately 30% of dogs being treated for heart disease and CHF satisfied the definition of ABT. Identifying patient subpopulations experiencing ABT may help guide future study design and clinical decision-making.

Mitral valve repair in dogs using an ePTFE chordal implantation device: a pilot study. M. Borgarelli, O. Lanz, N. Pavlisko, J.A. Abbott, G. Menciotti, M. Aherne, S.M. Lahmers, K.K. Lahmers, J.S. Gammie. J. Vet. Cardiol. May 2017. Quote: Objective: Mitral valve (MV) regurgitation due to degenerative MV disease is the leading cause of cardiac death in dogs. We carried out preliminary experiments to determine the feasibility and short-term effects of beating-heart MV repair using an expanded polytetrafluorethylene (ePTFE) chordal implantation device (Harpoon TSD-5) in dogs. Animals: This study involved six healthy purpose-bred Beagles (weight range 8.9–11.4 kg). Material and Methods: Following a mini-thoracotomy performed under general anesthesia, the TSD-5 was used to place 1 or 2 artificial ePTFE cords on the anterior MV leaflet or the posterior MV leaflet via a left-ventricular transapical approach. The procedure was guided and monitored by transesophageal echocardiography. Postoperative antithrombotic treatment consisted of clopidogrel or a combination of clopidogrel and apixaban. Dogs were serially evaluated by transthoracic echocardiography at day 1, 7, 14, 21, and 30. The hearts were then examined for evaluation of tissues reactions and to detect signs of endothelialization. Results: One or two chords were successfully implanted in five dogs. Four dogs completed the 30 days follow-up. One dog died intra-operatively because of aortic perforation. One dog died early post-operatively from a hemorrhagic pleural effusion attributed to overly aggressive antithrombotic treatment. One dog developed a thrombus surrounding both the knot and the synthetic cord. Postmortem exam confirmed secure placement of ePTFE knots in the mitral leaflets in all dogs and the presence of endothelialization of the knots and chords. Conclusions: This pilot study has demonstrated feasibility of using the Harpoon TSD-5 device to place and anchor ePTFE artificial chords to the MV of small dogs and that endothelialization of the synthetic cord and knots can start within 30 days.

The Longitudinal Outcome of Mitral Valve Disease (LOOK-Mitral) Study: Preliminary Results. Michele Borgarelli. 2017 ACVIM Forum #171.

Characterization of Gene Expression Profiles Linked to Degenerative Mitral Valve Disease in Small Breed Dogs. E.M. Oxford, N.S. Moise, E.J. Rice, A.R. Boyko, C.G. Danko. J. Vet. Int. Med. June 2017;2017 ACVIM Forum Abstract C05. Quote: The purpose of this study was to use a genome-wide association study (GWAS) and precision nuclear run-on and sequencing (PRO-seq), to identify novel gene candidates and expression profiles linked to DMVD in small breed dogs. Blood samples from 249 (95 control, 154 DMVD) client-owned dogs (<20 kg) were used for the GWAS. Tissue samples from the anterior mitral valve leaflets were available from 2 DMVD and 5 control dogs for Western blot and PRO-seq analysis. DMVD dogs had a murmur and mitral regurgitation associated with leaflet thickening and/or prolapse on echocardiography. Control dogs were >9 years of age with no murmur, and no abnormalities on echocardiography. A GWAS was performed with genomic DNA using a custom single nucleotide polymorphism (SNP) genotyping array containing 185,850 markers. ... The GWAS revealed the strongest association signal on Chromosome 17 (P = 7.7 9 10 6), near the CTNNA2 gene, which codes for alpha-catenin. Fine mapping of CTNNA2 did not detect a mutation within the coding regions of the gene. However, Western blot analysis revealed a 53% decrease in normalized alpha-catenin levels and an 86% decrease in beta-catenin (P-Y142 isoform) compared to control samples. ... A > 2-fold change was noted in 187 genes; with functions such as wound healing, regulation of muscle contraction, and muscle structure development. This study identified a candidate gene (CTNNA2), which codes for alpha-catenin, an essential protein of the adherens junctions and modulator of the canonical Wnt pathway. Although a mutation was not detected within the coding regions of the gene or within upstream enhancers of CTNNA2, Western blot revealed decreased levels of alpha-catenin (and the phosphorylated form of beta-catenin) in DMVD valves. These preliminary data may support the presence of a mutation located within the non-coding regions controlling CTNNA2 transcription and further investigation is warranted.

Heart-Fatty Acid Binding Protein – a Potential Marker for Canine Cardiac Diseases. C. Lam, D.C. Sorrosal, G. Monteith, S. Fonfara. J. Vet. Int. Med. June 2017;2017 ACVIM Forum Abstract C12. Quote: Heart-Fatty Acid Binding Protein (hFABP) is produced primarily in cardiomyocytes, mainly responsible for fatty acid homeostasis, and has been proposed as an early and sensitive biomarker in human cardiac diseases. Its potential use as a cardiac biomarker in veterinary medicine has yet to be investigated. This study aims to assess hFABP as a prospective biomarker for canine cardiac diseases compared to cardiac Troponin-I (cTnI). Twenty-one healthy dogs (control), 23 dogs with degenerative mitral valve disease (MVD), and 13 dogs with dilated cardiomyopathy (DCM) of various cardiac disease stages were studied. Serum measurements of HFABP and cTnI, routine bloodwork and echocardiography were performed at initial presentation for all dogs and at 1 and 3 months for the diseased dogs, and followed up until 12 months to verify survival. Levels recorded during the initial presentation showed significantly elevated hFABP with highest levels found in ACVIM stage C disease regardless of cause, followed by stage B and controls. cTnI differed stage C from both B and controls, but was unable to differentiate between stage B and controls. DCM patients had higher hFABP and cTnI levels over MVD patients, but cTnI was indistinguishable between MVD dogs and controls. Reduction of hFABP and cTnI during the follow up period was also observed from initial presentation among both DCM and stage C dogs. hFABP was the most significant predictor for death when multivariate study was performed. This study showed the potential value of hFABP as a cardiac marker to differentiate stages and disease type in dogs.

Changes in Neurohumoral Factors in 9 Dogs That Received Carperitide and Presented with Pulmonary Edema. M. Enokizono, N. Kanno, H. Suzuki, S. Yamada, K. Matsuura. J. Vet. Int. Med. June 2017;2017 ACVIM Forum Abstract C29. Quote: The purpose of this study was to clarify the treatment effects of carperitide in veterinary cases. Nine dogs presenting with pulmonary edema due to mitral valve insufficiency were treated with a continuous infusion of carperitide. Dogs with hypotension were excluded from the study. Blood sampling was performed twice: once before the administration of carperitide (Pre) and then after the administration of carperitide (Post). Neurohumoral factors, such as atrial natriuretic peptide (ANP), N-terminal pro b-type natriuretic peptide (NT-proBNP), and aldosterone levels, were measured at both time points. In addition, chest radiography, echocardiography, and blood pressure measurements were performed depending on the specific cases. Seven of the 9 dogs showed improvements post-treatment, although 2 cases did not show any improvement. ANP levels increased post-treatment in all cases. NT-proBNP levels increased in 4 cases and decreased in 5 cases. Aldosterone level increased only in one case. In addition, the left atrial aortic root ratio (LA/Ao), E-wave, vertebral heart score (VHS), and blood pressure decreased. Carperitide is a human ANP agent, which is why we expected higher ANP levels post-treatment. We observed a decrease in NT-proBNP levels in all cases that were treated for more than 7 hours. This is thought to be due to a time lag until the half-life period of NT-proBNP and the stretch stimulation of the ventricular muscle, which are reflected in the blood concentration of NT-proBNP. In addition, the ventricular muscle stretch was inhibited by the decrease in left atrial pressure following the administration of carperitide, which lasted for more than 7 hours. Lastly, the decrease in aldosterone levels was thought to be due to the inhibitory effects of carperitide on the renin-angiotensin-aldosterone system. This study suggested that carperitide administration is effective since pulmonary edema is improved and aldosterone is suppressed.

Soluble ST2 Biomarker in Heart Failure Secondary to Chronic Mitral Valve Disease in Dogs. A.M. Gimenes, J. Ribeiro de Castro, M.M. Mantovani, C.N. Duarte, L.C. Petrus, M.Y. Ueda, G.T. Goldfeder, M.H.M.A. Larsson, D.S. Schwartz. J. Vet. Int. Med. June 2017;2017 ACVIM Forum Abstract C34. Quote: The soluble fraction of ST2 (sST2) is considered a cardiac biomarker, which is induced mechanically by the stretch of cardiomyocytes and fibroblasts. This biomarker has prognostic value in human cardiology, and it is considered an important independent mortality predictor. However, studies assessing sST2 in dogs are still lacking. Therefore, this study aimed to determine the utility of sST2, compared to NT-proBNP and cardiac troponin I (cTnI), for assessment of dogs with chronic mitral valve disease (CMVD). With this purpose, 151 dogs in different stages of CMVD were submitted to clinical exam, laboratory tests, cardiologic exams and measurement of sST2, NT-proBNP and cTnI. The results demonstrate that sST2 was higher in dogs in CHF compared to non-CHF dogs. However, when dogs were stratified according to CMVD stages, it was not possible to differentiate the stages based on sST2 concentrations. NT-proBNP and cTnI were higher in CHF dogs, as well as in more advanced stages of CMVD. There was correlation between sST2 and NT-proBNP and cTnI. ... As for prognosis assessment, sST2 concentrations higher than 40 pg/mL indicated higher mortality compared to groups with lower sST2 values. Results suggest that sST2’s performance as a standalone diagnostic test is limited and inferior to the other studied biomarkers. However, sST2 seems to be a useful independent prognostic marker, and mortality predictor in dogs with CMVD.

Galectin-3 as Biomarker in Heart Failure Secondary to Chronic Mitral Valve Degeneration in Dogs. J. Ribeiro de Castro, A.M. Gimenes, M.M. Mantovani, C.N. Duarte, M.Y. Ueda, L.C. Petrus, G.T. Goldfeder, M.H.M.A. Larsson, D.S. Schwartz. J. Vet. Int. Med. June 2017;2017 ACVIM Forum Abstract C48. Quote: In order to follow the progression of heart failure (HF), galectin-3 (Gal-3) has been applied as a biomarker to identify pre-clinical cardiac diseases, progression and decompensation in human patients. This study aimed to establish the utility of this new biomarker, isolated or in association with Type B natriuretic pro-peptide (NTproBNP) and cardiac troponin I (cTnI) to estimate short term prognosis in dogs with HF caused by chronic mitral valve degeneration (CMVD). ... One hundred thirty nine dogs were distributed among five groups with rigorous selection criteria, according to ACVIM CMVD staging (Control group: stage A- 60 healthy small breed dogs, predisposed to CMVD; 28 dogs in stage B1, 20 dogs in stage B2, 20 dogs in stage C and 11 dogs in stage D), recruited from a Veterinary Teaching Hospital. Groups B1, B2, C and D had a second blood sampling at day 60. Measurements were obtained for human Gal-3, NT-proBNP and cTnI. ... We concluded that the magnitude and variation observed in Gal-3 did not allow for detection of differences between stages of CMVD nor were capable of identifying patients in HF, compared to the other measured biomarkers, NT-proBNP and cTnI, already established for canine HF evaluation.

Asymptomatic Canine Degenerative Valve Disease: Current and Future Therapies. Sonya G. Gordon, Ashley B. Saunders, Sonya R. Wesselowski. Vet. Clinics of No. Amer. Sm. Anim. Pract. September 2017;47(5):955-975. Quote: Although dogs of any breed can develop DVD [degenerative valve disease], some breeds, such as the Cavalier King Charles spaniel (CKCS) are known to suffer from a higher incidence overall and may be affected at younger ages, although their typical course of progression in not different from other small-breed dogs. ... The etiology of DVD remains unknown, but there is likely a genetic component in some breeds, such as the CKCS. ...  Asymptomatic mature dogs with systolic heart murmurs characteristic of mitral regurgitation should undergo diagnostics to determine the presence or absence of heart enlargement and to document that the dog is normotensive. ... The [normal] reference range for LVIDDN is 1.27 to 1.85. An LVIDD of ≥1.7 was used to select dogs for the EPIC study. The reason for selection of an LVIDDN that was not above the upper normal reference range is related to a previous study that demonstrated dogs with DVD and an LVIDDN ≥1.7 had a worse clinical outcome than dogs with an LVIDDN less than 1.7, although it was within the reported normal range. ... Treatment is not recommended in dogs with stage B1 degenerative valve disease (asymptomatic with normal heart size); this recommendation remains unchanged by new evidence. Treatment with pimobendan has been shown to extend symptom-free and overall survival of dogs with stage B2 degenerative valve disease (asymptomatic with heart enlargement). Scheduled follow-up and client communication regarding monitoring for the development of clinical signs associated with disease progression remains a cornerstone of management in all stages of degenerative valve disease. Left mainstem bronchial compression and pulmonary hypertension represent common sequelae of degenerative valve disease that can lead to the development of clinical signs requiring therapy before the onset of congestive heart failure.

Echocardiographic evaluation of mitral regurgtant volume after mitral valve repair in dogs. Yusuke Nakamura, Takeshi Mizuno, Kayoko Harada, Masashi Mizuno, Takahiro Mizukoshi, Shuhei Uchida, Arane Kasuya, Tamotsu Sawada, Asako Shinoda, Masami Uechi. J. Vet. Cardio. Med. June 2017;1(1):2-9. Quote: Objectives: The efficacy of mitral valve repair, an established treatment for mitral regurgitation (MR) in dogs, is unclear. We evaluated the outcome of mitral valve repair in dogs by quantitating the mitral regurgitant volume. Methods: Dogs that underwent mitral valve repair for naturally occurring MR between December 2008 and October 2012 were included. Stroke mitral regurgitant volume and minute mitral regurgitant volume were calculated by echocardiography preoperatively and at 1 and 3 months postoperatively. Severity of MR was classified by mitral regurgitant fraction (trivial, <30%; mild, 30-49%; moderate, 50-79%; and severe, ≥80%). Results: A total of 65 dogs [including 12 cavalier King Charles spaniels]were included (body weight, 3.75 [1.55-16.45] kg; age, 8 [5-12] years). The postoperative mitral inflow volume was significantly lower, whereas the aortic outflow volume was significantly higher than preoperative values. Thus, the stroke mitral regurgitant volume and the minute mitral regurgitant volume significantly decreased. Additionally, the postoperative mitral regurgitant fraction was significantly lower than the preoperative value. Severe MR was detected in 38 dogs preoperatively, but in none postoperatively. Clinical Significance: Mitral valve repair in dogs decreased MR volume, leading to hemodynamic improvement. Quantitating the MR volume proved to be an effective method for evaluating the efficacy of mitral valve repair.

Mitral regurgitation severity and left ventricular systolic dimension predict survival in young cavalier King Charles spaniels. M.J. Reimann, J.E. Møller, J. Häggström, T. Martinussen, S.S.C. Zatrazemi, L. Svanholm, L.B.M. Nielsen, H.D. Pedersen, L.H. Olsen. ECVIM 26th Congress; ESVC-O-24.  J. Vet. Int. Med. July 2017;31(4):1008-1016. Quote: Development and progression of myxomatous mitral valve disease (MMVD) in dogs are difficult to predict. Identification at a young age of dogs at high risk of developing congestive heart failure in the future is desirable. The aim of the study was to investigate the predictive value of selected clinical and echocardiographic characteristics associated with MMVD obtained at a young age for prediction of long-term cardiac and all-cause mortality in Cavalier King Charles Spaniels (CKCS). The study included 1125 privately-owned CKCS examined at the age of 1-3 years between January 1996 and June 2012. Longterm outcome was assessed by telephone interview with owners. The value of variables for predicting mortality (cardiac and allcause) was investigated by Cox Proportional Hazard and Kaplan-Meier analyses. Presence of mild to severe mitral regurgitation (MR) (hazard ratio (HR)=3.03, 95% confidence interval (95%CI)=1.48–6.23, P = 0.003) or intermittent MR (HR=2.23, 95%CI=1.48–6.23, P = 0.04) on echocardiography was significantly associated with increased hazard of cardiac death. An interaction between MR and sex was significant for all–cause mortality (P = 0.04) showing that males with mild to severe MR had a higher all–cause mortality compared to males with no MR (HR=2.38, 95%CI=1.27–4.49, P = 0.007), whereas no difference was found between female MR groups. The risk of cardiac (HR=1.37, 5%CI=1.14–1.63, P = 0.0008) and all–cause (HR=1.13, 95%CI=1.02–1.24, P = 0.02) mortality increased with increasing left ventricular end-systolic internal dimension normalized for body weight (LVIDSN). In conclusion, mild to severe MR, intermittent MR and decreased LVIDSN in dogs <3 years of age were associated with cardiac death later in life in CKCS.

Evaluation of a fixed dose combination of benazepril and pimobendan in dogs with congestive heart failure; a randomized non-inferiority clinical trial. Jonathan N. King, Atsushi Hirakawa, Junko Sonobe, Hiroshi Otaki, Nobuhiro Sakakibara, Wolfgang Seewald, Sophie Forster. J. Vet. Sci. July 2017. Quote: A new fixed dose combination tablet of benazepril and pimobendan (Fortekor Plus) was tested in dogs with congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD) in a prospective, multi-center, parallel-group, three-arm, masked, randomized, non-inferiority clinical trial in 67 dogs [9 cavalier King Charles spaniels] in Japan. The test group received Fortekor Plus twice daily (n=34). Two control groups received the registered formulations of benazepril (Fortekor) and pimobendan (Vetmedin) with administration of pimobendan twice daily and benazepril twice (Control I, n=14) or once (Control II, n=19) daily. Diuretics were used in 22 dogs (32.8%). The Global Clinical Score, assessed by veterinarians, decreased significantly from baseline in all groups. There were no significant differences between groups, and non-inferiority of Fortekor Plus was demonstrated compared to the Control I, Control II and combined Control I+II groups. There were no significant differences between groups for relevant clinical chemistry and hematology variables or frequency of all adverse events. The frequency of emesis was significantly (P=0.0042) lower in the Fortekor Plus (8.8%) compared to the Control I+II (39.4%) group. In conclusion, Fortekor Plus had non-inferior efficacy and was associated with significantly less emesis compared to administration of Fortekor and Vetmedin in dogs with CHF caused by MMVD. (See also this January 2018 version of the same study.)

Circulating exosome microRNA associated with heart failure secondary to myxomatous mitral valve disease in a naturally occurring canine model. Vicky K. Yang, Kerry A. Loughran, Dawn M. Meola, Christine M. Juhr, Kristen E. Thane, Airiel M. Davis, Andrew M. Hoffman. J. Extracellular Vesicles. July 2017;6(1): 1350088. Quote: Circulating exosomes contain small RNA, including miRNA, which reflect cell physiology and pathology. This study explored the association between circulating exosomal miRNA (ex-miRNA) content and MMVD, heart failure due to MMVD (MMVD-CHF) and ageing, which is strongly associated with MMVD. Ex-miRNA was isolated from old normal/healthy dogs (n = 6), young normal dogs (n = 7), dogs with MMVD (n = 7 [including 5 cavalier King Charles spaniels]) and dogs with MMVD-CHF (n = 7 [including 4 CKCSs]). Separately, total plasma miRNA was isolated from normal dogs (n = 8), dogs with MMVD (n = 8 [including 4 CKCSs]) and dogs with MMVD-CHF (n = 11 [including 4 CKCSs]). Using reverse transcription quantitative polymerase chain reaction, exosomal miR-181c (p = 0.003) and miR-495 (p = 0.0001) significantly increased in dogs with MMVD-CHF compared to the other three groups. Exosomal miR-9 (p = 0.002) increased in dogs with MMVD and MMVD-CHF compared to age-matched (old) normal dogs. Exosomal miR-599 (p = 0.002) decreased in dogs with MMVD compared to old normal dogs. In total plasma, 58 miRNA were deemed significantly different (p < 0.04) between normal dogs, dogs with MMVD and dogs with MMVD-CHF. However, in contrast to ex-miRNA, none of the miRNA in total plasma remained statistically significant if the false discovery rate was <15%. Changes in ex-miRNA are observed in dogs as they age (miR-9, miR-495 and miR-599), develop MMVD (miR-9 and miR-599) and progress from MMVD to CHF (miR-181c and miR-495). Ex-miRNA expression-level changes appear to be more specific to disease states than total plasma miRNA.

Sildenafil improves heart rate variability in dogs with asymptomatic myxomatous mitral valve degeneration. Prapawadee Pirintr, Nakkawee Saengklub, Vudhiporn Limprasutr, Suwanakiet Sawangkoon, Anusak Kijtawornrat. J. Vet. Med. Sci. July 2017. Quote: Myxomatous mitral valve degeneration (MMVD) causes an imbalance of sympathovagal activity resulted in poor cardiac outcomes. Phosphodiesterase-5 inhibitors have been revealed cardioprotective effect in patients with heart diseases. This study aimed to 1) compare the heart rate variability (HRV) between asymptomatic MMVD and healthy dogs and 2) assess long-term effects of sildenafil and enalapril on time- and frequency-domains analyzes. Thirty-four dogs with MMVD stage B1 or B2 and thirteen healthy dogs were recruited into the study. MMVD dogs were divided into 3 subgroups: control (n=13), sildenafil (n=12) and enalapril (n=9). HRV was analyzed from 1-hr Holter recording at baseline (D0) in all dogs and at 30, 90 and 180 days after treatment. The results showed that MMVD dogs had significant higher heart rate (HR), systemic blood pressures, the ratio of low to high frequency (LF/HF) and had significant decreased standard deviation of all normal to normal RR intervals (SDNN) and the percentage of the number of normal-to-normal sinus RR intervals with differences >50 msec computed over the entire recording (pNN50) when compared with healthy dogs (P<0.05). Neither time nor frequency domain parameters were different among subgroups of MMVD dogs at D0. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in asymptomatic MMVD dogs suggesting that sildenafil should be used in the MMVD dogs to restore the sympathovagal balance.

Treatment of dogs with compensated myxomatous mitral valve disease with spironolactone—a pilot study. M.J. Hezzell, A. Boswood, J. López-Alvarez, N. Lötter, J. Elliott. J. Vet. Cardio. August 2017;19(4):325-338. Quote: Objectives: Spironolactone improves outcome in dogs with advanced myxomatous mitral valve disease (MMVD). Its efficacy in preclinical MMVD is unknown. The hypothesis was the administration of spironolactone to dogs with compensated MMVD demonstrating risk factors for poorer prognosis will decrease the rate of disease progression. The aim was to provide pilot data to evaluate preliminary effects and sample size calculation for a definitive clinical trial. Animals: Twenty-five client-owned dogs with MMVD with at least one of the following; left atrial to aortic ratio (LA:Ao) ≥ 1.5, normalized left ventricular internal diameter in diastole ≥ 1.6), N-terminal pro-B-type natriuretic peptide (NT-proBNP) > 550 pmol/L, cardiac troponin I > 0.025 ng/mL. Methods: Prospective, single-center, equally randomized, placebo-controlled, double-blinded, parallel grouped pilot study. No dogs were receiving medications for cardiac disease before the enrollment. Results: Twelve dogs received placebo; 13 received spironolactone. One dog in the spironolactone group died suddenly, 1 developed congestive heart failure, and 2 received suboptimal spironolactone doses. At enrollment, NT-proBNP was significantly higher in the spironolactone group (p=0.005). Left atrial to aortic ratio (p=0.002) and left ventricular internal diameter in diastole (p=0.005) increased over time in the placebo group, but not the spironolactone group; the change did not differ significantly between groups. The change in biomarker concentrations did not differ significantly between groups; there was a tendency toward an increase in NT-proBNP over time in the placebo group. Enrollment of 76 dogs would be necessary to demonstrate a difference in the change in LA:Ao over 6 months between the groups. Conclusions: Preliminary results support undertaking a larger clinical trial of treatment of dogs with preclinical MMVD with spironolactone.

Myocardial Adiponectin Isoform Shift in Dogs with Congestive Heart Failure—A Comparison to Hibernating Brown Bears (Ursus arctos horribilis). O. Lynne Nelson, Rachael M. Wood, Jens Häggström, Clarence Kvart, Charles T. Robbins. Vet. Sci. July 2017;4(3):35-45. Quote: Adiponectin is the most abundant plasma adipokine, and is well known for its role in energy homeostasis and cardiac protection. In humans with dilated cardiomyopathy, myocardial adiponectin protein expression is reduced compared to normal hearts and has been implicated in the pathology of cardiomyopathy. Serum adiponectin levels are often conflicting, with higher levels associated with poor survival in humans with congestive heart failure (CHF). We evaluated adiponectin serum concentrations and myocardial protein expression in dogs with naturally occurring myxomatous mitral valve disease and CHF. ... Canine left ventricular (LV) myocardium was collected from six normal dogs euthanized for reasons unrelated to this study and six dogs that died or were euthanized due to CHF caused by MMVD [including 3 cavalier King Charles spaniels]. ... We compared the findings to active and hibernating brown bears as bears are adapted to endure an extreme period of low cardiac output during their annual hibernation. Bears exhibited largely the active high-molecular weight (HMW) versus the low-molecular weight isoforms of myocardial adiponectin (HMW:LMW = 6.3) during both the active period and hibernation, while healthy dogs exhibited a more balanced mix of isoforms. Dogs with CHF expressed predominately HMW isoforms of adiponectin (HMW:LMW = 12.5), appearing more similar to bears. In contrast to humans, serum adiponectin was significantly lower in dogs with CHF and lowest levels in the severest CHF class. In both dogs and bears, myocardial adiponectin was expressed independent of circulating adiponectin concentrations, suggesting a local regulatory mechanism within the heart.

Comparative Transcriptomic Profiling and Gene Expression for Myxomatous Mitral Valve Disease in the Dog and Human. Greg R. Markby, Kim M. Summers, Vicky E. MacRae, Brendan M. Corcoran. Vet. Sci. July 2017;4(3):34-46. This review will briefly examine the comparative valve pathology and then, in more detail, the transcriptomic profiling and gene expression reported so far for both species [dog and human]. ... Conclusions: To date there are a limited number of transcriptomic profiling studies for canine and human MMVD, often with low sample numbers, making the drawing of categorical conclusions problematic. More data, as well as data from a wider range of stages of disease, are needed to increase interpretative confidence and to understand disease pathogenesis in full. Nevertheless, the current data gives an insight into the signalling pathways involved in the MMVD, and so allows for more focused hypothesis and mechanism-driven studies examining function. Furthermore, although there is a similar gross pathology, and some of those similarities are carried through to molecular differences, the transcriptomic data clearly show differences between canine and human MMVD that reflect the contribution of fibrosis to end-stage disease pathology in humans. Additional studies will be needed to examine local tissue gene expression and protein translation, to address why dogs do not develop fibrosis and humans do, and hence the validity of the dog disease as a model of human MMVD.

The effect of heart disease on anesthetic complications during routine dental procedures in dogs. Jennifer E. Carter, Alison A. Motsinger-Reif, William V. Krug, Bruce W. Keene. J. Amer. Anim. Hosp. Assn. July 2017;53(4):206-213. Quote: Dental procedures are a common reason for general anesthesia, and there is widespread concern among veterinarians that heart disease increases the occurrence of anesthetic complications. Anxiety about anesthetizing dogs with heart disease is a common cause of referral to specialty centers. To begin to address the potential effect of heart disease on anesthetic complications in dogs undergoing anesthesia for routine dental procedures, we compared anesthetic complications in 100 dogs with heart disease severe enough to trigger referral to a specialty center (cases) to those found in 100 dogs without cardiac disease (controls) that underwent similar procedures at the same teaching hospital. Medical records were reviewed to evaluate the occurrence of anesthetic complications. No dogs died in either group, and no significant differences were found between the groups in any of the anesthetic complications evaluated, although dogs in the heart disease group were significantly older with higher American Society of Anesthesiologists scores. Midazolam and etomidate were used more frequently, and alpha-2 agonists used less frequently, in the heart disease group compared to controls. This study suggests dogs with heart disease, when anesthetized by trained personnel and carefully monitored during routine dental procedures, are not at significantly increased risk for anesthetic complications.

Supraventricular trigeminy in a dog with myxomatous mitral valve disease. Frederico Aécio Carvalho Soares. Ciência Rural. August 2017;47(9):1-4. Quote: Supraventricular trigeminy is an uncommon cardiac impulse formation disturbance. Detecting and treating cardiac arrhythmias is an important therapeutic goal in cardiology. The aim of this note is to report an occurrence of supraventricular trigeminy in a dog with myxomatous mitral valve disease (MMVD). A 15-year-old intact male mongrel dog weighing 13kg and with a history of heart murmur, cough, dyspnea, and ascites was referred for cardiac evaluation. Echocardiographic findings were consistent with a diagnosis of myxomatous mitral and tricuspid valves disease with a severe hemodynamic compromise. Electrocardiography (ECG) revealed a sinus arrhythmia with isolated supraventricular premature complexes, supraventricular couplets, and periods of supraventricular trigeminy. Previous retrospective and prospective studies that evaluated cardiac arrhythmias in dogs have not reported supraventricular trigeminy. The present report showed that supraventricular trigeminy may occur in dogs with MMVD with severe hemodynamic compromise, probably related to atrial enlargement. In addition, this case reinforces the importance of performing ECG in dogs with MMVD, since it complements the echocardiogram and enables a better therapeutic approach.

Diagnostic accuracy of electrocardiographic P wave related parameters in the assessment of left atrial size in dogs with degenerative mitral valve disease. Ángel Soto-Bustos, Alicia Caro-Yadillo, Elena Martínez-De-Merlo, Elisa González Alonso-Alegre. J.Vet.Med.Sci. August 2017. Quote: The purpose of this research was to compare the accuracy of newly described P wave-related parameters (P wave area, Macrux index and mean electrical axis) with classical P wave-related parameters (voltage and duration of P wave) for the assessment of left atrial (LA) size in dogs with degenerative mitral valve disease. One hundred forty-six dogs (37 healthy control dogs and 109 dogs with degenerative mitral valve disease) were prospectively studied. Two-dimensional echocardiography examinations and a 6-lead ECG were performed prospectively in all dogs. Echocardiography parameters, including determination of the ratios LA diameter/aortic root diameter and LA area/aortic root area, were compared to P wave-related parameters: P wave area, Macrux index, mean electrical axis voltage and duration of P wave. The results showed that P wave-related parameters (classical and newly described) had low sensitivity (range=52.3% to 77%; median=60%) and low to moderate specificity (range=47.2% to 82.5%; median 56.3%) for the prediction of left atrial enlargement. The areas under the curve of P wave-related parameters were moderate to low due to poor sensitivity. In conclusion, newly P wave-related parameters do not increase the diagnostic capacity of ECG as a predictor of left atrial enlargement in dogs with degenerative mitral valve disease.

Chronic Degenerative Valve Disease in Dogs. Dennis Burkett. Hope Veterinary Specialists. August 2017. Chronic Degenerative Valvular Disease (CDVD) is the most common cardiac disease of dogs. It is the most common cause of a heart murmur in an adult dog. It estimated to account for approximately three-quarters of all cases of cardiac disease seen in veterinary practices. Small breed dogs (<20 kg, <44 lb) are approximately twice as likely to have CDVD than medium and large breed dogs (>20 kg, 44 lb), with a particularly high prevalence in certain breeds (Table 1). Males dog are about 50% more likely to be affected than females. CDVD develops more frequently with age. In one study, 100% of Cavalier King Charles Spaniels over 10 years of age had some degree of CDVD. While the exact cause for CDVD is not known, the knowledge of dog size, dog breed, gender, and age predispositions indicate that the most important factors are genetics and time. This is supported by studies that have identified genetic associations with CDVD in dogs. There is no convincing evidence of an association with dental disease, infections, obesity or diet.

Effect of Body Position, Exercise, and Sedation on Estimation of Pulmonary Artery Pressure in Dogs with Degenerative Atrioventricular Valve Disease. J.D. Rhinehart, K.E. Schober, B.A. Scansen, V. Yildiz, J.D. Bonagura. J.Vet.Intern.Med. November 2017;31(6):1611-1621. Quote: Background: Severity of pulmonary hypertension (PH) in dogs is related to clinical signs and prognosis. Hypothesis/Objectives: We hypothesized that Doppler echocardiographic (DE) indices of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) are influenced by independent factors that create clinically important variability of DE-based estimates of PH in dogs. Animals: Thirty-eight client owned dogs [including 13 cavalier King Charles spaniels] with naturally acquired degenerative atrioventricular valve disease and tricuspid regurgitation (TR). Methods: Dogs were prospectively enrolled, and target variables were acquired during 4 echocardiographic study periods (lateral recumbency, standing, lateral recumbency after a 6-minute walk test [6MWT], and lateral recumbency after sedation with butorphanol 0.25 mg/kg IM). Statistical methods included repeated measures ANOVA, mixed model analysis, and Chi-squared test of association. Results: There was a significant increase in peak TR flow velocity (TRFV; P < 0.01) after sedation in 78% of dogs, with TRFV increasing by >0.4 m/s in 42% of dogs, independent of stroke volume. A significant effect of study period on DE-estimated PVR was not found (P = 0.15). There were negligible effects of sonographer, body position, and 6MWT on echocardiographic variables of PH. Clinically relevant cyclic variation of TRFV was found. There was an association between estimation of right atrial pressure based on subjective assessment and estimation based on cranial vena cava collapsibility (P = 0.03). Conclusions and Clinical Importance: The increase in TRFV observed with sedation could change assessment of PH severity and impact prognostication and interpretation of treatment response. Further studies with invasive validation are needed.

Mitral regurgitation in Dachshund dogs without heart murmurs. Magdalena Garncarz, Marta Parzeniecka-Jaworska, Magdalena Hulanicka, Michał Jank, Olga Szaluś-Jordanow, Anna Kurek. J.3) Vet. Research. September 2017;61(3). Quote: Introduction: Older small breed dogs are considered at risk for heart failure secondary to chronic mitral valve disease. However, few data are available on the onset of this disease in such dogs. ... The Cavalier King Charles spaniel has been categorised as an exception in that chronic mitral valve disease in this breed may appear at a very early age. These dogs often present with early onset heart murmurs as a prequel to symptomatic valvular heart disease. ...  This study was performed to determine if auscultation alone can be used to eliminate clinically relevant mitral valve regurgitation seen in echocardiography in Dachshund dogs. Material and Methods: Clinical and echocardiographic data were obtained from 107 dogs without heart murmurs. Results: The study revealed that [68] 63.6% of the dogs had mitral regurgitation. Numbers increased with age and a larger percentage of male Dachshunds were affected than female Dachshunds. Mitral valve prolapse and thickening were mild, and the regurgitant area inextensive in most dogs. Conclusions: The study shows that mitral valve regurgitation is prevalent (63.6%) in Dachshunds without heart murmurs. Typical lesions often become apparent during echocardiographic examinations in dogs under 5 years of age. ... This study shows that the prevalence of mitral valve regurgitation is underestimated when looking solely at dogs with heart murmurs. Echocardiographic studies in dog breeds predisposed to chronic mitral valve disease without heart murmurs are warranted first of all as a preventative diagnostic method for heart disease if we are to eliminate suspicion of subclinical chronic mitral valve disease, and secondly to enable a better global picture of the prevalence of the disease since studies of dogs with heart murmurs underestimate the number of affected animals. The drawbacks of this study include its retrospective character, a lack of longitudinal followup, and the small number of dogs in different age groups which makes it impossible to more precisely analyse the effect of age on the presence of mitral regurgitation. Also, the study did not allow for distinction between acquired mitral valve disease and congenital valve defects such as mitral valve dysplasia, but rather relied on previously published data on the prevalence of CMVD in Dachshunds. ... The question remains whether we could further decrease the prevalence of CMVD if echocardiography, not auscultation, was used as a screening tool and a recent study shows that this is in fact possible. ... Although most dogs with CMVD do not progress to more advanced stages of congestive heart failure, it is beneficial to know that the disease is present, especially for scientific studies.

Review of Diagnostic and Therapeutic Approach to Canine Myxomatous Mitral Valve Disease. Giulio Menciotti, Michele Borgarelli. Vet. Sciences. September 2017;4(4):47-61. Quote: The most common heart disease that affects dogs is myxomatous mitral valve disease. In this article, we review the current diagnostic and therapeutic approaches to this disease, and we also present some of the latest technological advancements in this field. ... In 2016, the conclusion of a multicenter, double-blind, placebo-controlled clinical trial investigating the efficacy of pimobendan for delaying the onset of CHF in dogs with preclinical MMVD (EPIC study) with LA and LV enlargement (i.e., ACVIM Stage B2) suggested that administration of pimobendan was associated with a prolongation of the preclinical period by approximately 15 months, compared to the placebo group. ... It is very important to remark, however, that ACVIM Stage B2 dogs represent a heterogeneous group of patients. Therefore, the benefit observed in the EPIC study can be inferred only for dogs that respect inclusion criteria of this study. In fact, for being enrolled in the aforementioned trial, dogs had to have evidence of significant left cardiac enlargement both at echocardiographic examination (LA/Ao ≥ 1.6, LVIDd divided by allometric scaled BW ≥ 1.7) and on thoracic radiographs (Vertebral Heart Score > 10.5).

Anatomic regurgitant orifice area obtained using 3D-echocardiography as an indicator of severity of mitral regurgitation in dogs with myxomatous mitral valve disease. S. Müller, G. Menciotti, M. Borgarelli. J. Vet. Cardiology. September 2017. DOI:10.1016/j.jvc.2017.07.001 Quote: Objectives: To determine feasibility and repeatability of measuring the anatomic regurgitant orifice area (AROA) using real-time three-dimensional transthoracic echocardiography (RT3DE) in dogs with myxomatous mitral valve disease (MMVD), and to investigate differences in the AROA of dogs with different disease severity and in different American College of Veterinary Internal Medicine (ACVIM) stages. Animals: Sixty privately-owned dogs [of 25 breeds] diagnosed with MMVD [including 11 cavalier King Charles spaniels]. Methods: The echocardiographic database of our institution was retrospectively searched for dogs diagnosed with MMVD and RT3DE data set acquisition. Dogs were classified into mild, moderate, or severe MMVD according to a Mitral Regurgitation Severity Score (MRSS), and into stage B1, B2 or C according to ACVIM staging. The RT3DE data sets were imported into dedicated software and a short axis plane crossing the regurgitant orifice was used to measure the AROA. Feasibility, inter- and intra-observer variability of measuring the AROA was calculated. Differences in the AROA between dogs in different MRSS and ACVIM stages were investigated. Results: The AROA was measurable in 60 data sets of 81 selected to be included in the study (74%). The inter- and intra-observer coefficients of variation were 26% and 21%, respectively. The AROA was significantly greater in dogs with a severe MRSS compared with dogs with mild MRSS (p=0.045). There was no difference between the AROA of dogs in different ACVIM clinical stages. Conclusions: ... This study shows that it is feasible to obtain the AROA in dogs with MMVD using RT3DE. The AROA of patients with severe MR, as assessed by a combination of conventional echocardiographic variables, is greater than the one of patients with mild MR. Further standardization of the technique is required to improve inter- and intra-observer variability, and investigate the diagnostic and prognostic potential of this variable.

Short-Term Efficacy and Safety of Torasemide and Furosemide in 366 Dogs with Degenerative Mitral Valve Disease: The TEST Study. V. Chetboul, J.-L. Pouchelon, J. Menard, J. Blanc, L. Desquilbet, A. Petit, S. Rougier, L. Lucats, F. Woehrle. J. Vet. Intern. Med. October 2017. Quote: Background: Furosemide is the only loop diuretic recommended by the ACVIM consensus guidelines for treatment of congestive heart failure (CHF) in dogs related to degenerative mitral valve disease (DMVD). Torasemide is another potent loop diuretic with a longer half-life and a higher bioavailability. Objectives: (1) To demonstrate that torasemide given once a day (q24h) is noninferior to furosemide given twice a day (q12h) for treating dogs with CHF; (2) and to compare the effect of the 2 drugs on the time to reach a composite cardiac endpoint “spontaneous cardiac death, euthanasia due to heart failure or CHF class worsening.” Animals: A total of 366 dogs with CHF attributable to DMVD [including 46 cavalier King Charles spaniels]. Methods: Analysis of 2 prospective randomized single-blinded reference-controlled trials was performed. Dogs orally received either torasemide q24h (n = 180) [including 24 CKCSs] or furosemide q12h (n = 186) [including 22 CKCSs] in addition to standard CHF therapy over 3 months. The primary efficacy criterion was the percentage of dogs with treatment success assessed in each study. The time to reach the composite cardiac endpoint was used as secondary criterion in the overall population. Results: Torasemide was noninferior to furosemide (Ptorasemide − Pfurosemide = +7%; 95% CI [−8%; +22%] and Ptorasemide − Pfurosemide = +1%; 95% CI [−12%; +14%], respectively, in Study 1 and Study 2). Torasemide (median dose = 0.24 mg/kg/d q24h; range = 0.10–0.69 mg/kg/d) was associated with a 2-fold reduction in the risk of reaching the composite cardiac endpoint (adjusted HR = 0.47; 95% CI = 0.27–0.82; P = 0.0077) as compared with furosemide (median dose = 1.39 mg/kg q12h; range = 0.70–6.30 mg/kg q12h). Conclusions and Clinical Importance: Torasemide q24h is an effective oral diuretic in dogs with CHF.

Diagnostic value of echocardiographic indices and cardiac biomarkers in dogs with chronic mitral valve insufficiency. Hyun-Seok Kim, Sang-Il Suh, Changbaig Hyun. Thai J. Vet. Med. September 2017;47(3):373-382. Quote: Because all dogs having heart diseases are not in symptomatic heart failure stage, it is important to determine the stage of heart failure in dogs with heart diseases. Therefore, this study evaluated the diagnostic value of several echocardiographic parameters and cardiac biomarkers for differentiating dogs with heart disease from healthy dogs and dogs with symptomatic heart failure from dogs with asymptomatic heart failure. The study population consisted of 51 dogs having chronic mitral valvular insufficiency (CMVI) with varying degrees of heart failure and 18 healthy control dogs. [None were cavalier King Charles spaniels; the breeds were Maltese, Shih Tzu, Yorkshire terrier, toy Poodle, Pekingese, miniature Schnauzer, Pomeranian, mixed, and Chihuahua.] Several echocardiographic parameters and cardiac biomarkers were evaluated to achieve the study aims. The study found that there were significant differences in indexed left atrial diameter (iLA), left atrial to aorta ratio (LA/Ao), left ventricular diastolic dimension to aorta ratio (LVIDd/Ao), transmitral E-peak (E-peak), septal E/Ea ratio (sE/Ea), parietal E/Ea ratio (pE/Ea) and N-terminal probrain natriuretic peptide (NT-proBNP) between the control dogs and the CMVI dogs (P<0.05), and also between the asymptomatic dogs and the symptomatic dogs (P<0.05). The cut-off values for indicating heart disease in this study population were iLA >11.9 mm, LA:Ao >1.32, LVIDd/Ao >1.91, E-peak >80 cm/sec, sE/Ea >7.0, pE/Ea >6.9, and NT-proBNP >980 pmol/L, while the cut-off values for indicating heart failure were iLA >12.7 mm, LA:Ao >1.58, LVIDd/Ao >2.08, E-peak >90 cm/sec, sE/Ea >9.0, pE/Ea >8.9, and NT-proBNP >1200 pmol/L. ... In conclusion, this study evaluated the diagnostic values of known echocardiographic parameters and cardiac biomarkers for detecting heart disease and heart failure in a single study population (dogs with CMVI) consisting of small breeds of dogs, which could more closely reflect affected canine population in Asian countries. Based on the ROC analyses of each echocardiographic parameters and cardiac biomarkers for assessing the predictive accuracy for detecting heart disease and heart failure in this study population, iLA, LA/Ao, E-peak, E/Ea and NT-proBNP were the most reliable and consistent parameters for detecting heart disease and differentiating symptomatic heart failure dogs from asymptomatic dogs with CMVI. This is the first canine study to comprehensively evaluate known echocardiographic markers and cardiac biomarkers in a single study population.
Echocardiographic variables for predicting progression of heart failure

Serum cardiac troponin I concentrations in dogs with generalised seizures. E. Dutton, N. Carmichael, U. Michal, P. J. Cripps, A. Boswood. J. Sm. Anim. Pract. October 2017. Quote: Objectives: To determine if serum cardiac troponin I concentrations – measured with both a first-generation assay and a high-sensitivity assay – were greater in dogs with generalised seizures than in controls and to identify clinical variables associated with cardiac troponin I concentration. Materials & Methods: Prospective study of 30 dogs with recent generalised seizures [including 2 cavalier King Charles spaniels] and 30 healthy controls [including 1 cavalier]. Serum cardiac troponin I concentration was measured using two commercially available assays, and the correlation of clinical factors with concentration was examined. Results: Serum concentrations of cardiac troponin I were higher in dogs that had recent seizures compared to controls when measured by both assays. The predictors most clearly associated with cardiac troponin I concentration were number of seizures and age. Both predictors were positively associated with increasing concentrations of troponin I. Clinical Significance: Serum cardiac troponin I concentration was significantly elevated in dogs that had recent generalised seizures when compared to controls, and concentrations were higher in dogs that experienced more seizures. This association may indicate that generalised seizures are associated with damage to the myocardium.

Two-dimensional echocardiographic estimates of left atrial function in healthy dogs and dogs with myxomatous mitral valve disease. David Dickson, Domenico Caivano, Jose Novo Matos, Nuala Summerfield, Mark Rishniw. J. Vet. Cariol. October 2017. DOI: 10.1016/j.jvc.2017.09.003. Quote: Objectives: To provide reference intervals for 2-dimensional linear and area-based estimates of left atrial (LA) function in healthy dogs and to evaluate the ability of estimates of LA function to differentiate dogs with subclinical myxomatous mitral valve disease (MMVD) and similarly affected dogs with congestive heart failure (CHF). Animals: Fifty-two healthy adult dogs, 88 dogs with MMVD of varying severity. Methods: Linear and area measurements from 2-dimensional echocardiographs in both right parasternal long and short axis views optimized for the left atrium were used to derive estimates of LA active emptying fraction, passive emptying fraction, expansion index, and total fractional emptying. Differences for each estimate were compared between healthy and MMVD dogs (based on ACVIM classification), and between MMVD dogs with subclinical disease and CHF that had similar LA dimensions. Diagnostic utility at identifying CHF was examined for dogs with subclinical MMVD and CHF. Relationships with bodyweight were assessed. Results: All estimates of LA function decreased with increasing ACVIM stage of mitral valve disease (p<0.05) and showed negative relationships with increasing LA size (all r2 values < 0.2), except for LA passive emptying fraction, which did not differ or correlate with LA size (p=0.4). However, no index of LA function identified CHF better than measurements of LA size. Total LA fractional emptying and expansion index showed modest negative correlations with bodyweight. Conclusions: Estimates of LA function worsen with worsening MMVD but fail to discriminate dogs with CHF from those with subclinical MMVD any better than simple estimates of LA size.

Angiotensin-converting enzyme activity and inhibition in dogs with cardiac disease and an angiotensin-converting enzyme polymorphism. Kathryn M Meurs, Joshua A Stern, Clarke E Atkins, Darcy Adin, Brent Aona, Julia Condit, Teresa DeFrancesco, Yamir Reina-Doreste, Bruce W Keene, Sandy Tou, Jessica Ward, Kathleen Woodruff. J. Renin-Angiotensin-Aldosterone Sys. October 2017:1-4. Quote: Objective: The objective of this study was to evaluate angiotensin-converting enzyme (ACE) activity in dogs and with and without an ACE polymorphism in the canine ACE gene, before and after treatment with an ACE inhibitor. ... In humans, an ACE gene insertion/deletion (I/D) in intron 16, has been shown to impact ACE activity with the deletion allele (D) associated with higher levels of ACE activity then the insertion allele (I). The polymorphism has been associated with a variable response to ACE inhibitors. Humans with this polymorphism have increased baseline ACE activity, increased levels of angiotensin II production and require higher doses of ACE inhibitors to achieve an adequate response to ACE inhibition. We have previously identified a single nucleotide polymorphism (SNP) in the same intron in the canine ACE gene. We hypothesized that this SNP in the canine ACE gene could be associated with a variable response to ACE inhibitor therapy in the dog. ... In the study presented here we evaluated dogs with myxomatous mitral valve disease, the most common form of heart disease in the dog, with and without the ACE gene polymorphism and assessed ACE activity and systolic blood pressure before and after ACE inhibition with enalapril. ... Methods: Thirty-one dogs [10 cavalier King Charles spaniels] (20 wild-type [4 CKCSs], 11 ACE polymorphism [6 CKCSs]) with heart disease were evaluated with ACE activity measurement and systolic blood pressure before and after administration of an ACE inhibitor (enalapril). ... There was no significant difference in cardiac enlargement between the two groups. The median VHS for the wild-type dogs was 11.3 (11.2–12.2), and the median VHS for the ACE polymorphism dogs was 11.8 (11.29–13.04).Results: Median pre-treatment ACE activity was significantly lower for ACE polymorphism dogs than for dogs with the wild-type sequence. After two weeks of an ACE inhibitor, ACE activity was significantly reduced for both genotypes; mean post-therapy ACE activity was no different between the groups. Conclusion: An ACE polymorphism is associated with lower levels of ACE activity. Dogs with the polymorphism still experience suppression of ACE activity in response to an ACE inhibitor. It is possible that the genetic status and ACE activity of dogs may impact the response of dogs with this variant to an ACE inhibitor. ... In this study, 12 different breeds of dogs were evaluated. The ACE polymorphism was identified in five of the 12 breeds, but was observed most commonly in the Cavalier King Charles spaniel (six of 10 dogs).

Degenerative myxomatous valvular disease (DMVD) in dogs: a new combined parameter dividing patients without pulmonary edema from those with pulmonary edema. Atanas Pankov. IOSR J. Agri. & Vet. Sci. October 2017;10(10):43-47. Quote: The current study compares the possibilities of some M-mode echocardiographic and radiographic dimensions to determine the extent of the progression of MVD. There is also a new LA/AO x VHS ratio that 100% separates the dogs included in the study in regard to the absence or presence of pulmonary edema, due to the development of decompensated heart failure. The size we are introducing LA / AO x VHS multiplies the heart enlargement from the X-rays and the M-mode ultrasound imaging. The mean value of this multiplication in group 1 was (16.3350 ± 2.7968) which is statistically significantly (0.0009) lower than the mean value in the edema group (26.0268 ± 5.8358). [One cavalier King Charles spaniel was included in the edema group.] ... Numerous studies have been conducted to determine a single ultrasound parameter that could predict the onset of heart failure in MVD. In this connection, Borgarelli et al. in a study conducted with a large number of animals, demonstrated that as a predictor of survival, when only cardiac-related deaths were included in dogs with MVD, only the LA/Ao ratio maintained statistical significance. The left atrial enlargement reflects the degree of severity and the chronic nature of mitral regurgitation. In our study, the detailed analysis of this ratio (Tables 1 and 2) shows that in 4 patients from the first group (= 57%) and in 2 dogs from the second group (= 18%), values overlap from 1,541 to 1,765. Below these values, the patients are without pulmonary edema, and above these values they have pulmonary edema. In this regard, we believe that LA/AO can be used as an important indicator in the interpretation of data in group studies, but it cannot conclusively demonstrate the need for a medical intervention in the individual. In order to enhance the predictive effect of the LA/AO ratio, Le Bobinnec, introduces a new index that includes the left ventricular diastolic score. MVD has a very variable evolution, and the unresolved issue in this disease is still: when should we start treatment? ... The ratios LA/AO; LC/AO and the values of VHS, despite the statistically significant differences between the two treatment groups, cannot be used as a marker to initiate therapy in patients with MVD, due to the overlapping values obtained in this study.

Long-term Stability of a Compounded Suspension of Torsemide (5 mg/mL) for Oral Administration. D. Adin, P.R. Johnson, C.H. Kim, T. Nguyenba, S. Rosen. J. Vet. Intern. Med. November 2017;31(6):1822-1826. Quote: Background: Torsemide use for congestive heart failure (CHF) has been reported, but prescription frequency is unknown. Commercially available tablet sizes in North America limit dosing precision, indicating a need to evaluate its strength and stability in suspension. Objectives: To determine the frequency of torsemide prescriptions and to determine a beyond use date (BUD) of a compounded suspension of torsemide for oral administration stored under 2 temperature conditions for 90 days. Animals: No animals used. Methods: Pharmacy records were retrospectively reviewed for torsemide and furosemide prescriptions from 2008 to 2015 at 2 veterinary referral centers. After preliminary strength testing, compounded torsemide suspension (5 mg/mL) for oral administration was prepared using torsemide tablets suspended in OraPlus:OraSweet 1:1, buffered to a pH of 8.3 and stored at refrigeration (2–8°C) and room temperature (20–25°C) in 2 oz amber plastic bottles. Samples were analyzed by reverse phase high-performance liquid chromatography (RP-HPLC) on days 0, 14, 30, 60, and 90. Results: Prescriptions for torsemide increased from 2008 to 2015. Analysis of the torsemide 5 mg/mL suspension for oral administration at each time point met United States Pharmacopeia (USP) requirements for torsemide content of 90–110% of label claim. The average strength at 90 days decreased to 92 ± 3% at 2–8°C and 95 ± 2% at 20–25°C. Stability testing did not detect unknown impurities. Conclusions: Increasing torsemide use warrants availability of a validated and stable compounded formulation. Our results support the assignment of a 90-day BUD for torsemide 5 mg/mL suspension for oral administration compounded in OraPlus:Sweet 1:1 buffered to a pH of 8.3.

Clinical trial results extend drug license. Veterinary Record. November 4, 2017;181:466. Quote: Melanie Hezzell, senior lecturer in cardiology at Bristol university, said the treatment option was a useful addition but it was likely to be several years before it would fully embed in UK practice – due to a shortage of cardiologists. ‘Ideally dogs should undergo echocardiography before treatment with pimobendan. Unfortunately, even if cost was not an issue, there are not enough cardiologists in the UK to perform echos on all dogs with a murmur.’ ‘Can we train more people to do basic echo accurately, repeatably and reproducibly enough? Four or five years down the line I think we can. But we’re not there yet. There’s a need for us to do that.’ Hezzell hoped the development would encourage vets to take further continuing professional development in echocardiography to enable them to diagnose dogs with stage B2 MMVD and ensure the correct dogs are receiving appropriate treatment. ‘Hopefully this will result in everybody becoming more skilled’, she said. She warned the EPIC results could lead to owners asking for pimobendan when their dog does not require it. But she said some websites expressing negative opinions could put owners off treatment with pimobendan and dogs could miss out of receiving high quality care as a result. ‘These are all conversations vets can expect to have with clients as prescribing changes take place.’

Utility of VHS to Predict Echocardiographic EPIC Trial Inclusion Criteria in Dogs with Myxomatous Mitral Valve Disease: a Retrospective Multicentre Study. J.P. Vitt, S. Gordon, R.C. Fries, J.D. Rhinehart, S.E. Achen, I. Sosa, A.H. Estrada, J.A. Carlson, R.L. Winter, S. Kadotani, K.E. Lamb. ECVIM Abstract ESVC-O-1, J. Vet. Intern. Med. November 2017;pg. 16. Quote: The EPIC Trial reported three cardiac size inclusion criteria including radiographic vertebral heart size (VHS) >10.5, and echocardiographically derived normalized left ventricular internal dimension in diastole (LVIDDN) ≥1.7 and left atrial to aortic ratio (LA:Ao) ≥1.6 as measured by the Swedish method. However, echocardiography may not always be available and, therefore, there is interest in identification of a VHS cutoff that predicts EPIC echocardiography inclusion criteria (EPIC-ECHO+) in dogs with preclinical myxomatous mitral valve disease (MMVD). Medical records from 8 sites were searched for MMVD cases that had contemporaneous thoracic radiographic and echocardiographic studies. A total of 247 cases were identified and descriptive statistics are reported as mean, median, and interquartile range for VHS (11.4, 11.2, 10.8–11.9), LVIDDN (1.80, 1.79, 1.58–2.05), and LA:Ao (1.78, 1.69, 1.42–2.06). Dogs that were EPIC-ECHO+ (N = 126) were identified and compared to the remaining population (N = 121). Receiver operator curves were constructed for VHS and performance was explored for optimal cutoffs. The percent correct, sensitivity, specificity, false positive and negative rates for a VHS of 11.1(72%, 0.730, 0.707, 12%, 16%), 11.7(60%, 0.439, 0.85, 6%, 34%) and 11.9(58%, 0.365, 0.90, 4%, 38%) were determined. Based on these data, dogs with MMVD and a VHS >11.7 have a high likelihood of meeting EPIC-ECHO+ (85% specificity) and an acceptable false positive rate (6%), however approximately 34% dogs with a VHS between 10.6–11.7 may meet EPIC-ECHO+ and warrant further echocardiographic evaluation. These results may help veterinarians apply the results of the EPIC Trial to dogs with preclinical MMVD when an echocardiogram is not readily available.

Major Histocompatibility Complex Class II Haplotypes Associated with Remodeling in Cavalier King Charles Spaniels with Chronic Valvular Heart Disease. L. Bree, R.E. Shiel, A.T. French, L.J. Tong, J. Prieto-Ramos, L.J. Kennedy. ECVIM Abstract ESVC-O-13, J. Vet. Intern. Med. November 2017;pg. 20. Quote: Chronic valvular heart disease is common in the Cavalier King Charles spaniel (CKCS). However, genetic factors contributing to development or progression of the disease are unknown. Although classically considered a non-inflammatory disease, upregulated expression of genes involved in inflammation and immune function has been identified in affected valvular tissue. Therefore, genetic determinants of the immune response could influence disease progression in individual dogs. The aims of this study were to document major histocompatibility haplotype (MHC) dog leukocyte antigen (DLA) class II haplotypes in the CKCS, and to examine potential associations between individual haplotypes and progression of disease. DLA three-locus haplotypes were determined in 190 CKCS from the UK (n = 95) and Australia (n = 95) using sequence-based typing methods. Six haplotypes were identified. Echocardiography was performed in 187 dogs; 72 had evidence of remodeling and 115 did not. Three dogs were not tested. Remodeling was defined as increased left-atrial-to-aortic ratio (>1.5) or increased left ventricular internal diameter during diastole or systole (normalized to bodyweight) (LVIDDi>1.85 or LVIDSi>1.26). Associations between individual haplotypes and the presence of remodeling were investigated using the Fisher’s exact test. Odds ratios (OR) and 95% confidence intervals (CI) were also calculated. The age of the dogs ranged from 0.6 to 16.3 years. When data from all 187 dogs were considered, two haplotypes (DRB1*01101/ DQA1*00201/ DQB1*01303 and DRB1*02001/ DQA1*00401/ DQB1*01303 were significantly associated with the presence of remodelling (P = 0.0239 and P = 0.0357; OR 3.562 (95% CI: 1.188–10.68) and 0.5181 (0.2831–0.9482), respectively). Echocardiographic evidence of remodelling was present in 24 dogs <9 years old and absent in 37 dogs ≥9 years old. DRB1*01101/DQA1*00201/DQB1*01303 was significantly (P = 0.035) associated with the presence of remodelling at a younger age (odds ratio 3.562, (1.188–10.68)). These results suggest an association between MHC DLA haplotype and the progression of chronic valvular heart disease in the CKCS. Further studies are recommended to explore the potential role of the immune system in the pathogenesis of this disease.

Effects of Funny Channel Blockers on Myocardial Oxygen Consumption in Dogs with Mitral Valve Regurgitation. Prapawadee Pirintr, Vudhiporn Limprasutr, Parnpradub Pavinadol, Hathaisiri Kuecharoen, Napat Yapao, Natthakarn Limvanicharat, Anusak Kijtawornrat. J. Pharm. & Toxicol. Meths. November 2017;88(2):223-224 (abstract 181). Quote: Introduction: Dogs with mitral regurgitation (MR) possess high sympathetic tone resulting in increasing heart rate (HR). Ivabradine is a funny channel blocker that has been shown to modify the HR response to autonomic stimuli. Rate-pressure product (RPP) is a surrogate measure of myocardial oxygen consumption (MVO2). This study aimed to determine effects of single oral dose of ivabradine on HR, BP and RPP in dogs with MR. Methods: Four beagle dogs with MR were underwent four study periods of 24-h. All dogs were given either one dose of placebo or ivabradine (0.5-, 1- and 2-mg/kg, orally) in a single-blind randomized crossover study. The animals were instrumented with Holter recorder for measuring HR continuously while BP were obtained four times per hour by using PetMAP. All parameters were assessed hourly for the first 12-h and at the end of the 24-h study period. The RPP, a product of HR and systolic BP, was calculated hourly. Results: HR decreased significantly (pb0.05) in a dose-dependent manner with peak negative chronotropic effects observed during 5-6 hours after ivabradine. At 24-h after dosing, HR was returned to the baseline value. The systolic, diastolic and mean BP were not changed over the 24 hour periods. The MVO2 as estimated by the RPP was significantly reduced (pb0.05) for ivabradine at doses of 1 and 2 mg/kg. Conclusion: This findings indicated that a single oral dose of ivabradine lowers HR and RPP with no clinical discernable side effect. Hence, ivabradine is safe to use in dogs with MR.

Treatment of severe mitral regurgitation caused by lesions in both leaflets using multiple mitral valve plasty techniques in a small dog. Satoko Yokoyama, Isamu Kanemoto, Kippei Mihara, Takanori Ando, Koudai Kawase, Yasuaki Sahashi, Kazuhito Iguchi. Open Vet. J. November 2017;7(4):328-331. Quote: Mitral valve plasty (MVP) is preferred over mitral valve replacement (MVR) for mitral regurgitation in humans because of its favorable effect on quality of life. In small dogs, it is difficult to repair multiple lesions in both leaflets using MVP. Herein, we report a case of severe mitral regurgitation caused by multiple severe lesions in the posterior leaflet (PL) in a mixed Chihuahua. Initially, we had planned MVR with an artificial valve. However, MVP combined with artificial chordal reconstruction of both leaflets, semicircular suture annuloplasty, and valvuloplasty using a newly devised direct scallop suture for the PL was attempted in this dog. ... The margins of both leaflets were hypertrophied and deep gaps in the PL were noted (Fig. 3A)[below]. Therefore, we [used] three MVP techniques in this surgery: artificial chordal reconstruction (CR) [for ruptured or elongated chordae tendineae], semicircular suture annuloplasty (AP) [for a dilated mitral annulus to increase the coaptation area of the {anterior leaflet} AL and {posterior leaflet} PL], and valvuloplasty (VP) [for deformed or redundant valve leaflets] ... using a pair of e-PTFE sutures. ... The dog recovered well and showed no adverse cardiac signs, surviving two major [subsequent] operations [a splenectomy for a splenic tumor at 9 months and a right lung lobectomy for lung cancer at 3 years and 5 months post-MVP]. The dog died 4 years and 10 months after the MVP due to non-cardiovascular disease. Our additional technique of using a direct scallop suture seemed useful for PL repair involving multiple scallops in a small dog.

Figure 3 A&B

Objective Assessment of the Radiographic Cardiac Size in Dogs - a Review of the Heart Size Measurements. A. Baisan, M. Ciocan, Oana Bîrsan, V. Vulpe. Lucrări Ştiinţifice Medicina Veterinară. November 2017;L(2):16-23. Quote: Radiographic examination of cardiac diseases in dogs is focused on the evaluation of the size and shape of the cardiac silhouette. Radiographic interpretation can be performed through multiple methods, using subjective examination or by using different measurements, such as width or height of the heart, vertebral heart scale or cardiothoracic ratio. The aim of this review is to discuss and explain the objective methods of cardiac evaluation described in the literature. Knowing the interbreed variations in the thoracic conformation and selection of proper reference value may further enhance the value of the quantitative measurements. A good general principle is that the heart should be considered radiographically normal unless there is an obvious change in size or shape, however a radiographically normal heart by no means can exclude a cardiac disease and the interpretation should be in correspondence with the physical and special exams.

MCT-based nutrition blend for cardiac protection and treating degenerative mitral valve disease in companion animals. Qinghong Li, Dorothy P. Laflamme, Brittany Vester Boler, Hui Xu, Sandeep Bhatnagar. U.S. Patent Application 20170332686. November 2017. Quote: A method of treating degenerative mitral valve disease (DMVD) in a companion animal having DMVD, a method of preventing DMVD in a companion animal at risk thereof, and a method of maintaining or improving cardiac health in a companion animal. The methods include orally administering to the companion animal a composition containing medium chain triglycerides and optionally one or more of omega-3 fatty acids, vitamin E, lysine, taurine, magnesium, or sulfur-containing amino acids. ... To the best knowledge of the present Figure 1inventors, currently there is no effective product for managing canine cardiac disease and more specifically, DMVD. For example, no existing cardiac diets are designed to address the alterations in energy metabolism that occur in dogs with DMVD. The present inventors conducted a gene expression and metabolomics study on dogs with DMVD. The study indicated that long chain fatty acid beta-oxidation, branch chain fatty acid alpha oxidation, and ketolysis were compromised in these dogs, while glycolysis and glucose metabolism increased in dogs with DMVD compared with healthy controls. Several proteins and enzymes were compromised which are involved in transport of long chain fatty acids from outside the cell to the mitochondria inner matrix and activation of the long chain fatty acid in the cytoplasm. Without being bound by theory, the present inventors believe that MCT is able to enter the mitochondria matrix more quickly and easily with little assistance, and thus provide the critically needed energy of the ailing heart. Consequently, nutritional management can be very effective in prevention and early treatment of DMVD. Accordingly, in a general embodiment, a method of maintaining or improving cardiac health in a companion animal is provided. The method comprises orally administering a composition comprising a therapeutically effective amount of medium chain triglycerides to the companion animal. ... Figure 2Example 1: Cardiac Health Blend Study for Canines with DMVD: 19 healthy dogs and 21 with cardiac murmurs were selected for a 6-month study. All dogs were examined by a board-certified veterinary cardiologist using echocardiography and were confirmed as either healthy or having early stage degenerative mitral valve disease (DMVD). Dogs in each group were randomized by age, gender, breed, body weight, and murmur grades into two dietary treatment groups. The control diet provides complete and balanced nutrition manufactured by the Nestle Purina PetCare Company to meet or exceed the requirements as defined by the Association of American Feed Control Officials (AAFCO). The test diet contained all the ingredients in the control diet with the following additional ingredients: medium chain triglycerides (MCTs) in an amount of 5.000 wt %, omega-3 fatty acids in an amount of 0.7489 wt %, lysine in an amount of 2.3000 wt %, methionine and cysteine in an amount of 2.1000 wt %, magnesium sulfate in an amount of 0.1500 wt %, vitamin E in an amount of 0.9206 IU/g, and taurine in an amount of 0.2162 wt %. In the DMVD group, there were 10 dogs in the control diet group and 11 in the test diet group, while in the healthy group, there were 9 in the control diet group and 10 in the test diet group. Dogs were individually fed to maintain their body weights. Energy intake for maintenance (MER) was estimated using the equation: MER=139*BW0.67 (kilocalories), where BW is the body weight of the dog in kilograms. Dogs were weighed weekly and Tables 2 & 3their amount of food offered was increased or decreased by 5% if their BW decreased or increased more than 5% over their initial BW, respectively. Echocardiographic parameters were measured by the cardiologist at the baseline, 3-month, and 6-month post treatment. Dogs received routine healthcare by the staff veterinarians. One DMVD dog of the control diet group was removed after 3 months due to health issues. As shown in FIG. 1, echocardiograms were performed at baseline, 3 months, and 6 months post treatment. Changes between 3 months and baseline in the 4 cardiac measurements, left atrial to aortic root ratio (LA/Ao), left atrial diameter (LA), and left ventricular diameter (LV), and mitral regurgitation rate (MVR), were calculated. Mann-Whitney U test was performed to compare the differences between dogs fed control diet and dogs fed MCT diet and P values were obtained. While control diet-fed dogs had shown declines in all 4 measurements, improvements were observed in the test diet-fed dogs. Statistical significance (P<0.05) was denoted using an asterisk. As shown in FIG. 2, echocardiograms were performed at baseline, 3 months, and 6 months post treatment. Changes between 6 months and baseline in the 4 cardiac measurements, mitral regurgitation grade (MR), left atrial to aortic root ratio (LA/Ao), left atrial diameter (LA), and left ventricular diameter (LV), were calculated. Mann-Whitney U test was performed to compare the differences between dogs fed control diet and dogs fed MCT diet and P values were obtained. While control diet-fed dogs had shown declines in all 4 measurements, improvements were observed in the test diet-fed dogs. Statistical significance (P<0.05) was denoted using an asterisk. The data in FIGS. 1-2 demonstrate that while the control diet-fed DMVD dogs showed declines in key echocardiographic parameters over the course of the study, the test diet-fed DMVD dogs showed improvements. No significant difference was observed between the dietary groups in healthy dogs.

Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study. A. Boswood , S.G. Gordon, J. Häggström, G. Wess, R.L. Stepien, M.A. Oyama , B.W. Keene, J. Bonagura, K.A. MacDonald, M. Patteson, S. Smith, P.R. Fox , K. Sanderson, R. Woolley, V. Szatmari , P. Menaut, W.M. Church, M.L. O’Sullivan, J.-P. Jaudon, J.-G. Kresken, J. Rush, K.A. Barrett, S.L. Rosenthal, A.B. Saunders, I. Ljungvall, M. Deinert, E. Bomassi, A.H. Estrada, M.J. Fernandez Del Palacio, N.S. Moise, J.A. Abbott , Y. Fujii, A. Spier, M.W. Luethy, R.A. Santilli , M. Uechi, A. Tidholm, C. Schummer, P. Watson. J. Vet. Intern. Med. December 2017. DOI: 10.1111/jvim.14885. Quote: Background: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. Objectives: To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF. Animals: Three hundred and fifty-four dogs [161 cavalier King Charles spaniels -- 45.5%] with MMVD and cardiomegaly. Materials and Methods: Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4–0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored. Results: At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN −0.06 (IQR: −0.15 to +0.02), P < 0.0001, and LA:Ao −0.08 (IQR: −0.23 to +0.03), P < 0.0001. ... A small but significant reduction in left atrial size (LA/Ao) was also seen in the placebo group. ... Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in ΔLVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in ΔLA:Ao was 1.14, P = 0.0002. ... There were no consistent differences observed between treatment groups in quality of life scores, change in heart murmur intensity, change in heart disease stage, and change in BCS when they were compared at each visit up to the scheduled visit at 24 months, although heart failure score was worse at 20 months, and respiratory effort score was worse at 24 months in the placebo group. ... At onset of CHF, groups were similar. ... Only the difference in change in exercise tolerance was significantly different between groups, with a greater number of dogs in the pimobendan group experiencing deterioration in exercise tolerance at the onset of CHF. ... Quality of life was perceived by owners to be improved after 1 month of treatment for both the placebo and pimobendan groups. At the onset of CHF, dogs receiving pimobendan were indistinguishable from those receiving placebo, and both groups had larger hearts and worse quality of life compared to baseline. ... Of the dogs enrolled in the EPIC study, 135 (38%) were confirmed to have developed CHF. ... Conclusions and Clinical Importance: Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo.

Evaluation of genes associated with human myxomatous mitral valve disease in dogs with familial myxomatous mitral valve degeneration. K.M. Meurs, S.G. Friedenberg, B. Williams, B.W. Keene, C.E. Atkins, D. Adin, B. Aona, T. DeFrancesco, S. Tou, T. Mackay. Vet. J. December 2017. DOI:10.1016/j.tvjl.2017.12.002. Quote: Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is believed to be heritable in Cavalier King Charles spaniels (CKCS) and Dachshunds. Myxomatous mitral valve disease is a familial disease in human beings as well and genetic mutations have been associated with its development. We hypothesized that a genetic mutation associated with the development of the human form of MMVD was associated with the development of canine MMVD. DNA was isolated from blood samples from 10 CKCS and 10 Dachshunds diagnosed with MMVD, and whole genome sequences from each animal were obtained. Variant calling from whole genome sequencing data was performed using a standardized bioinformatics pipeline for all samples. After filtering, the canine genes orthologous to the human genes known to be associated with MMVD were identified and variants were assessed for likely pathogenic implications. No variant was found in any of the genes evaluated that was present in least eight of 10 affected CKCS or Dachshunds. Although mitral valve disease in the CKCS and Dachshund is a familial disease, we did not identify genetic cause in the genes responsible for the human disease in the dogs studied here. ... Cavalier King Charles spaniels: No variant present in at least eight of 10 affected CKCS and absent in our control population of medium- and large-breed dogs was found in any of the genes of interest. A single coding variant was found in the gene encoding for collagen type V, alpha 1 (COL5A1) in nine of 10 affected CKCS and in the rare pipeline. The variant was a missense mutation that was predicted to be benign (Table 2). Two intronic variants in COL5A1 and two in FBN1 were present in nine of 10 affected CKCS and in the rare pipeline (Table 2). None of these variants met our criteria for conservation or were predicted to create or change a splice site.

Echocardiographic Estimates of Right Ventricular Systolic Function in Dogs with Myxomatous Mitral Valve Disease. E.H.  Chapel, B.A. Scansen, K.E. Schober, J.D. Bonagura. J.Vet. Intern. Med. December 2017. DOI: 10.1111/jvim.14884. Quote: Background: Right ventricular (RV) dysfunction independently predicts outcomes in human myxomatous mitral valve disease (MMVD). There is limited information regarding RV systolic function in dogs with MMVD. ... The aim of this study was to analyze several echocardiographic indices of RV systolic function in dogs with MR caused by MMVD not yet receiving medical therapy. ... Hypothesis: Right ventricular systolic function differs among stages of disease, decreasing in decompensated MMVD. ... and that dogs in CHF exhibit lethargic RV systolic function. ... Animals: Thirty-six client-owned dogs [breeds not identified] with MMVD not receiving oral cardiovascular medications. Methods: Prospective clinical study. Dogs were categorized according to disease severity as ACVIM Stage B1, B2, or C. Seven echocardiographic indices of RV systolic function were measured. ... Dogs were divided into 3 groups based on the ACVIM classification of valvular heart disease. The ACVIM staging does not specify a specific method for determining remodeling, and both radiographic and echocardiographic criteria were used in this study. Specifically, asymptomatic dogs with a VHS ≤ 10.5, LVIDDN ≤ 1.6, and absence of left atrial dilatation (long-axis LA:Ao ≤ 2.4)c were classified as stage/group B1 (MR without remodeling); asymptomatic dogs with a VHS > 10.5, LVIDDN > 1.6, and LA:Ao > 2.4 were classified as stage/group B2; and dogs with VHS > 10.5, LVIDDN > 1.6, and LA:Ao > 2.4 and with radiographic and clinical evidence of left-sided CHF were classified as stage/group C. ... Groups were compared by 1-way ANOVA and Tukey's HSD test. Frequencies of cases with cardiac remodeling falling outside previously established reference intervals were compared using Fisher's exact test. Intra- and interobserver measurement variability was calculated for each RV function index. Results: The indices TAPSE (P = 0.029), RV StL (P = 0.012), and RV StRL (P = 0.041) were significantly different between groups. A greater proportion of B2 dogs (7 of 12) had TAPSE values above reference intervals compared with B1 (2 of 12) or C (2 of 12) dogs (P = 0.027). Measurement variability of TAPSE, RV S', and RV StG was clinically acceptable. ... The results of this study suggest that RV systolic function mirrors that of the LV in dogs with MMVD. ... In the present study, dogs with advanced, compensated MMVD (stage B2) had measures of TAPSE above published reference intervals, demonstrating a hyperdynamic state. While the RV is not directly affected by mitral regurgitation, its shared structures with the LV could explain these similarities. ... Conclusions and Clinical Importance: Right ventricular systolic function differs between stages of MMVD, increasing in stage B2, and declining in stage C. The prognostic importance of RV function indices, particularly TAPSE, might be worth evaluating in dogs with MMVD. ... The conclusions of this study are different from previous reports, where no difference in RV systolic function was measured between ACVIM stages of MMVD. This discrepant result might be because of the administration of load-altering and positive inotropic agents in some dogs in the previous studies. Positive inotropic medications are known to positively influence RV systolic function in healthy dogs39 and would likely have a similar effect in dogs with MMVD.

Inflammatory Profile in Dogs with Myxomatous Mitral Valve Disease. Rafael Rodrigues Camacho, Elizabeth Regina Carvalho, Evandro Zacché Pereira, Fabio Nelson Gava, Aparecido Antonio Camacho, Marlos Gonçalves Sousa. Archives Vet. Sci. December 2017;22(4):1-8. Quote: Inflammatory substances such as interleukins (IL), tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP) have been demonstrated to play a role in heart failure progression. The aims of this study were two-fold: to investigate the concentration of circulating cytokines in dogs with myxomatous mitral valve disease (MMVD) in different stages, and to assess the relationship between these substances and cardiac morphology and function. For this purpose, twelve dogs with MMVD (7 stage-B2; 5 stage-C) and nine healthy controls underwent a transthoracic echocardiogram and had their serum concentrations of IL-1β, 4, 6, 10, TNF-α and CRP assessed. Data was submitted to Shapiro-Wilk normality test, groups were compared with ANOVA or Krukal-Wallis test according to distribution, and correlation coefficients were obtained with Spearman test. The IL-1β levels were different (P: 0.0056) between groups. Also, a positive correlation existed between IL-1β and left ventricular end-diastolic diameter (R: 0.56), left atrium-to-aorta ratio (R: 0.63) and echocardiography congestion surrogates. Similarly, IL-4 exhibited moderate-to-strong positive correlation with parameters of cardiac remodeling and congestion, while IL-6 was negatively correlated with the shortening fraction (R: -0.49). ... Conclusion: Our major findings are as follows. (1) The serum levels of interleukin 1β increases in dogs with myxomatous mitral valve disease, and even higher levels are observed in overtly symptomatic animals; (2) there is an important correlation between cardiac remodeling and congestion as assessed by echocardiography and the circulating levels of IL-1β and IL-4; (3) the serum levels of interleukin-6 and the left-ventricular shortening fraction are negatively correlated.

Home Respiratory Rate Monitoring in Dogs & Cats. Brian A. Scansen. Clinician's Brief. December 2017:60-63. Quote: Resting respiratory rate (RRR) is the rate of breathing when a patient is calm but awake; sleeping respiratory rate (SRR) is the breathing rate when a patient is asleep. The most accurate rates are obtained in the patient’s home environment. Respiratory rates measured at the veterinary practice are also of value but are more likely to be increased because of stress or recent activity, complicating interpretation. Pet owners can be trained to measure, record, and track their pet’s RRR and SRR at home to collect data that the veterinary team can use to assess cardiopulmonary status. Increased RRR and SRR may indicate early decompensation and the need for veterinary care before the next scheduled appointment. Early intervention (ie, before respiratory distress occurs) can help avoid costly hospitalization or death. Several studies have demonstrated a correlation between increased RRR or SRR and congestive heart failure (CHF). ... Instruction should include what constitutes a breath (ie, one full cycle of chest movement in and out) and how long to count (ie, typically 30 seconds). The number of breaths counted in 30 seconds is then doubled to determine the rate per minute. RRR and SRR should be obtained with the patient in lateral or sternal recumbency. RRR should be measured only when the patient is calm and has not exercised in the past 30 minutes. For SRR, the patient should be restful or have been asleep for at least 15 minutes but not in active sleep with paddling or twitching. Owners should be reminded not to count RRR if the dog is panting. RRR and SRR should be recorded on a daily basis or at least once or twice per week to identify any trends in rate; measurement should be obtained at the same time each day. Typically, measurements obtained during the first week are used to define a baseline as long as the animal is not showing clinical signs. Many apps are available for recording values.

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2018

Vasovagal tonus index in dog with myxomatous mitral valve disease. Bruna C. Brüler, Amália T. Giannico, Gustavo Dittrich, Marlos G. Sousa. Pesquisa Veterinária Brasileira. January 2018;37(10):1181-1186. Quote: The vasovagal tonus index (VVTI) is a useful and assessable index, obtained from standard ECG recordings, that is used to estimate heart rate variability (HRV), and may provide valuable information regarding the likelihood of progression into congestive heart failure (CHF). In this paperwork, we investigated how the vasovagal tonus index (VVTI) behaves in dogs with naturally-occurring myxomatous mitral valve disease (MMVD) Electrocardiographic (ECG) recordings and echocardiographic data of 120 patients diagnosed with MMVD were reviewed. The VVTI was calculated from twenty consecutive RR intervals for each dog enrolled in the study. Lower VVTI values were found in MMVD patients in American College of Veterinary Internal Medicine (ACVIM) stage C compared with stages B1 and B2. Values were also lower in patients with severe cardiac remodeling. When a cut-off value of 6.66 is used, VVTI was able to discriminate MMVD patients in stage C from B1 and B2 dogs with a sensitivity of 70 per cent and a specificity of 77 per cent. MMVD dogs in which VVTI is lower than 6.66 are 30% more likely to develop congestive heart failure (CHF).

White blood cell differentials in dogs with congestive heart failure (CHF) in comparison to those in dogs without cardiac disease. J. Hamilton-Elliott, E. Ambrose, R. Christley, J. Dukes-McEwan. J. Sm. Anim. Pract. January 2018. DOI: 10.1111/jsap.12809. Quote: Objectives: To determine if dogs with congestive heart failure have different white blood cell differential cell counts than dogs without cardiac disease. Materials and Methods: In total, 72 dogs [17 cavalier King Charles spaniels] with congestive heart failure and 143 [4 CKCSs] controls were included in this retrospective study. Signalment, white blood cell differential counts and echocardiography data were retrieved. ... Cavalier King Charles spaniels were over-represented in the cases. ... Basic statistical analysis was performed on white blood cell differential counts, and principal component analysis was used to compare these counts between cases and controls, with age, gender and case/control status as supplementary variables. Cases and controls were compared with binary logistic regression for the principal components identified and individual white blood cell differential counts. Principal component analysis of cases alone was conducted with age, gender, weight and mitral E wave:isovolumic relaxation time as supplementary variables. Linear regression analysis was used to explore the association between mitral E wave:isovolumic relaxation time and the principal components, weight, gender, age and diagnosis (mitral valve disease or dilated cardiomyopathy). Results: Among cases and controls, the largest variance in data (component 1) was associated with neutrophils, band neutrophils, monocytes and case status (P<0·01). The odds of an individual being a case increased 2·5-fold (95% confidence interval: 1·4 to 4·4) for each unit increase in component 1. Among the cases, mitral E wave:isovolumic relaxation time was associated with neutrophil count and case/control category. Clinical Significance: Dogs with congestive heart failure had a statistically significant increase in neutrophils, band neutrophils and monocytes in comparison with those without cardiac disease but the cell counts remained within normal reference intervals. ... The clinical significance of these findings is unclear, but it is possible that relative neutrophilia could be due to physiological stress in CHF patients. ... We did not distinguish the underlying cause for the relative neutrophilia observed in the CHF cases, and as other markers of systemic inflammation, such as C-reactive protein (CRP), were not assayed, we cannot conclude that our results are consistent with a systemic inflammatory response, as is suggested in the human literature.

Evaluation of a fixed-dose combination of benazepril and pimobendan in dogs with congestive heart failure: a randomized non-inferiority clinical trial. Jonathan N. King, Atsushi Hirakawa, Junko Sonobe, Hiroshi Otaki, Nobuhiro Sakakibara, Wolfgang Seewald, Sophie Forster. J. Vet. Sci. January 2018;19(1):117-128. Quote: A fixed-dose combination tablet of benazepril and pimobendan (Fortekor Plus; Elanco Animal Health) was tested in [67] dogs with congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD) [including 9 cavalier King Charles spaniels] in a three-arm, masked, randomized, non-inferiority clinical trial in Japan. The test group (n = 34) received Fortekor Plus twice daily. Two control groups received registered formulations of benazepril (Fortekor; Elanco Animal Health) and pimobendan (Vetmedin; Boehringer Ingelheim Vetmedica) with administration of Vetmedin twice daily and Fortekor twice (Control I, n = 14) or once (Control II, n = 19) daily. Diuretics were used in 22 dogs (32.8%). Global clinical scores decreased significantly from baseline in all groups; there were no significant differences between groups, and non-inferiority of Fortekor Plus compared to Control I, Control II, and combined Control I + II groups was demonstrated. There were no significant differences between groups for relevant clinical chemistry and hematology variables or frequency of all adverse events. Frequency of emesis was significantly (p = 0.0042) lower in the Fortekor Plus (8.8%) group than in the Control I + II (39.4%) group. In conclusion, Fortekor Plus had non-inferior efficacy and was associated with significantly less emesis compared to Fortekor and Vetmedin in dogs with CHF caused by MMVD. (See also this July 2017 version of the same study.)

Assessing the relative importance of health and conformation traits in the cavalier king Charles spaniel. Katrien Wijnrocx, Liesbeth François, Peter Goos, Nadine Buys, Steven Janssens. Canine Genetics & Epidemiology. January 2018. DOI 10.1186/s40575-017-0056-2. Quote: Background: The selection of a future breeding dog is a complicated task, in which disease characteristics and different traits have to be combined and weighed against one another. Truncation selection, that is the exclusion of affected animals, may be very inefficient when selecting on a large number of traits, and may result in a reduction of the genetic diversity in a population or breed. Selection could be facilitated by the use of a selection index that combines multiple traits or breeding values into one score. This however requires a consideration of their relative value according to their economic weight, which is difficult to express in monetary units for health traits. The use of a choice experiment to derive non-market values might be a solution to this problem. This is a pilot study to assess the potential use of choice experiments to ascertain the public preference and relative importance attached to health- and conformation traits in the selection of a Cavalier King Charles spaniel. ... Our study also indicated that the “level of inbreeding” is considered important by breeders and owners. ... This study invited breeders and owners to express their attitudes towards the importance of traits in the selection of a CKCS by means of a choice experiment. ... The focus was on two prevalent disorders, mitral valve disease and syringomyelia, and on several important conformation traits such as muzzle length and eye shape. Based on available prior information, a Bayesian D-optimal design approach was used to develop a choice experiment and the resulting choice sets. Results: Every participant (breeder or owner) in the choice experiment was presented with a total of 17 choice sets, in which at most four traits could vary to reduce the cognitive burden. ... As the number of attributes in a choice experiment is limited to reduce the cognitive burden of the respondents, only following attributes were considered to be of major interest in the choice of a CKCS: shape of the eyes, coat colour, muzzle length, level of inbreeding, purchase price of the dog, syringomyelia status, eye disease status, and mitral valve disease status. ... A total of 114 respondents [Respondents were Belgian, Danish, UK and USA breeders and owners] participated in the choice experiment and results showed that respondents (breeders/owners) current attitudes were directed towards health (syringomyelia and mitral valve disease), followed by eye shape and level of inbreeding. ... The choice experiment showed that no difference in preference between breeders or owners, they both attached most importance to the health traits such as SM and MVD. ... Conclusions: This approach identifies the value breeders and owners attach to certain traits in the breeding objective. The resulting relative weights, represented as the logworths obtained from the choice experiment, could be an alternative to economic weights. They could be implemented as a weight when breeding values are available, but more study on this topic will be necessary. A challenge in this approach is to scale up the experiment with additional traits. Moreover, for other traits, the genetic parameters and correlations should be known first, in order to include them in the health selection index as well.

Understanding D-Ribose and Mitochondrial Function. Diane E. Mahoney, John B. Hiebert, Amanda Thimmesch, John T. Pierce, James L. Vacek, Richard L. Clancy, Andrew J. Sauer, Janet D. Pierce. Advances in Biosci. & Clin. Med. January 2018;6(1):1-5. Quote: Mitochondria are important organelles referred to as cellular powerhouses for their unique properties of cellularenergy production. With many pathologic conditionsandaging, mitochondrial function declines, and there is a reduction in the production of adenosine triphosphate. The energy carrying molecule generated by cellular respiration and by pentose phosphate pathway, an alternative pathway of glucose metabolism. D-ribose is a naturally occurring monosaccharide found in the cells and particularly in the mitochondria is essential in energy production. Without sufficient energy, cells cannot maintain integrity and function. Supplemental D-ribose has been shown to improve cellular processes when there is mitochondrial dysfunction. When individuals take supplemental D-ribose, it can bypass part of the pentose pathway to produce D-ribose-5- phosphate for the production of energy. In this article, we review how energy is produced by cellular respiration, the pentose pathway, and the use of supplemental D-ribose.

Angiotensin-converting enzyme activity in Cavalier King Charles Spaniels with an ACE gene polymorphism and myxomatous mitral valve disease. Meurs KM, Olsen LH, Reimann MJ, Keene BW, Atkins CE, Adin D, Aona B, Condit J, DeFrancesco T, Reina-Doreste Y, Stern JA, Tou S, Ward J, Woodruff K. Pharmacogenet Genomics. February 2018;28(2):27-40.. Quote: Objectives: Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is particularly common in the Cavalier King Charles Spaniel (CKCS) breed and affected dogs are frequently managed with angiotensin-converting enzyme inhibitors (ACE-I). We have previously identified a canine ACE gene polymorphism associated with a decrease in angiotensin-converting enzyme (ACE) activity. The aim of this study was to evaluate for the prevalence of the ACE polymorphism in CKCS with mitral valve disease and to determine whether the presence of the polymorphism is associated with alterations in ACE activity at different stages of cardiac disease. Methods: Seventy-three dogs with a diagnosis of mitral valve disease were evaluated and a blood sample was drawn for ACE polymorphism genotyping and ACE activity measurement. Results: Forty-three dogs were homozygous for the ACE polymorphism; five were heterozygous and 25 were homozygous wild type. The mean age and the median severity of disease were not different for dogs with the polymorphism and dogs with the wild-type sequence. The median baseline ACE activity was significantly lower for the ACE polymorphism (27.0 U/l) than the wild-type sequence dogs (31.0 U/l) (P=0.02). Dogs with more severe disease and the ACE polymorphism had significantly lower levels of ACE activity than dogs with the wild-type sequence (P=0.03). Conclusion: The CKCS appears to have a high prevalence of the ACE variant. Dogs with the ACE variant had lower levels of ACE activity even in more advanced mitral valve disease than dogs without the variant. The clinical significance of this finding and its impact on the need for ACE-I in dogs with the polymorphism and heart disease deserves further study. (See also this July 2016 abstract.)

Serotonin receptor 2B signaling with interstitial cell activation and leaflet remodeling in degenerative mitral regurgitation. Kathryn H. Driesbaugh, Emanuela Branchetti, Juan B. Grau, Samuel J. Keeney, Kimberly Glass, Mark A. Oyama, Nancy Rioux, Salma Ayoub, Michael S. Sacks, John Quackenbush, Robert J. Levy, Giovanni Ferrari. J. Molecular & Cellular Cardiol. February 2018;115(2):94-103. Quote: Aims: Mitral valve interstitial cells (MVIC) play an important role in the pathogenesis of degenerative mitral regurgitation (MR) due to mitral valve prolapse (MVP). Numerous clinical studies have observed serotonin (5HT) dysregulation in cardiac valvulopathies; however, the impact of 5HT-mediated signaling on MVIC activation and leaflet remodeling in MVP have been investigated to a limited extent. Here we test the hypothesis that 5HT receptors (5HTRs) signaling contributes to MVP pathophysiology. Methods and results: Diseased human MV leaflets were obtained during cardiac surgery for MVP; normal MV leaflets were obtained from heart transplants. MV RNA was used for microarray analysis of MVP patients versus control, highlighting genes that indicate the involvement of 5HTR pathways and extracellular matrix remodeling in MVP. Human MV leaflets were also studied in vitro and ex vivo with biomechanical testing to assess remodeling in the presence of a 5HTR2B antagonist (LY272015). MVP leaflets from Cavalier King Charles Spaniels were used as a naturally acquired in vivo model of MVP. ... Mitral valve specimens from 4 Cavalier King Charles Spaniels with severe MVP and MR and 4 normal controls were obtained at post-mortem. ... These canine MVP leaflets (N = 5/group) showed 5HTR2B upregulation. This study also utilized CB57.1ML/6 mice in order to determine the effect of Angiotensin II infusion on MV remodeling. Histological analysis showed that MV thickening due to chronic Angiotensin II remodeling is mitigated by a 5HTR2B antagonist (LY272015) but not by 5HTR2A inhibitors. Conclusion: In humans, MVP is associated with an upregulation in 5HTR2B expression and increased 5HT receptor signaling in the leaflets. Antagonism of 5HTR2B mitigates MVIC activation in vitro and MV remodeling in vivo. These observations support the view that 5HTR signaling is involved not only in previously reported 5HT-related valvulopathies, but it is also involved in the pathological remodeling of MVP. Highlights: • Microarray and Network Reconstruction analysis in MVP patients and controls reveals a role for the 5HT signaling pathway in myxomatous mitral valve pathology; • 5HTR2B is upregulated in human MVP leaflets when compared to control as well as in a canine model of myxomatous mitral regurgitation; • A 5HTR2B antagonist (LY 272015) reduces MVICs activation under biomechanical stimulation ex vivo; • LY 272015 prevents Angiotensin II-mediated heart valve thickening in vivo; • We reported for the first time a mechanistic connection between serotonin receptor signaling and one of the most common heart valve diseases, MVP, a disorder affecting millions of patients.

Genome-wide sequencing and quantification of circulating microRNAs for dogs with congestive heart failure secondary to myxomatous mitral valve degeneration. SeungWoo Jung, Amy Bohan. Amer.J. Vet. Res. February 2018;79(2):163-169. Quote: Objective: To characterize expression profiles of circulating microRNAs via genome-wide sequencing for dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve degeneration (MMVD). Animals: 9 healthy client-owned dogs and 8 age-matched client-owned dogs with CHF secondary to MMVD. [None were cavalier King Charles spaniels.] Procedures: Blood samples were collected before administering cardiac medications for the management of CHF. Isolated microRNAs from plasma were classified into microRNA libraries and subjected to next-generation sequencing (NGS) for genome-wide sequencing analysis and quantification of circulating microRNAs. Quantitative reverse transcription PCR (qRT-PCR) assays were used to validate expression profiles of differentially expressed circulating microRNAs identified from NGS analysis of dogs with CHF. Results: 326 microRNAs were identified with NGS analysis. Hierarchical analysis revealed distinct expression patterns of circulating microRNAs between healthy dogs and dogs with CHF. Results of qRT-PCR assays confirmed upregulation of 4 microRNAs (miR-133, miR-1, miR-let-7e, and miR-125) and downregulation of 4 selected microRNAs (miR-30c, miR-128, miR-142, and miR-423). Results of qRT-PCR assays were highly correlated with NGS data and supported the specificity of circulating microRNA expression profiles in dogs with CHF secondary to MMVD. Conclusions & Clinical Relevance: These results suggested that circulating microRNA expression patterns were unique and could serve as molecular biomarkers of CHF in dogs with MMVD.

Effect of benazepril and pimobendan on serum angiotensin-converting enzyme activity in dogs. Jonathan N. King, C. Christinaz, G. Strehlau, J. Hornfeld. Vete. Pharm. & Theraputics. February 2018. DOI: 10.1111/jvp.12475. Quote: To support their combined use, the objective of the study was to evaluate the effects of benazepril and pimobendan on serum angiotensin-converting enzyme (ACE) activity in dogs. A total of 48 healthy beagle dogs were randomized into four groups (n = 12 per group) in a parallel-group design study: A (control, placebo twice daily (BID)); B (0.5–1.0 mg/kg benazepril once daily (SID) in the morning, placebo in the evening); C (0.25–0.5 mg/kg benazepril BID); D (0.25–0.5 mg/kg benazepril and 0.125–0.25 mg/kg pimobendan, both BID). The test items were administered orally for 15 days. Serum ACE activity was measured on days 1 and 15. Groups B, C and D had significantly lower average serum ACE activity compared to baseline and to the control group, on both days 1 and 15. There were no significant differences in average ACE activity between groups B, C and D. Noninferiority of group C to B was demonstrated. In conclusion, 0.25–0.5 mg/kg benazepril administered BID produced noninferior inhibition of serum ACE activity compared to 0.5–1.0 mg/kg benazepril dosed SID. Pimobendan had no significant effect on benazepril's action on serum ACE activity. The results support the use of benazepril BID in dogs and in combination with pimobendan. ... The main limitations of the study are that serum ACE activity does not predict precisely the activity of ACE inhibitors, and the pharmacokinetics and pharmacodynamics of benazepril and pimobendan might be different in clinical cases of CHF compared to healthy beagles. However, no differences in efficacy or safety were detected between BID and SID dosing of benazepril, in combination with pimobendan, in a recent clinical trial in dogs with myxomatous mitral valve disease (King et al., 2018).

Left-Sided Congestive Heart Failure. Jessica McGinnis, Amara Estrada. Vet. Team Brief. January 2018;35-40. Quote: Left-sided congestive heart failure (L-CHF) is a life-threatening condition caused by venous congestion secondary to increased left atrial pressure. This pressure occurs when the left ventricle is unable to adequately fill with or eject blood because of a primary structural or functional cardiac condition. ... Cats and dogs may appear clinically normal in the early compensatory phase of L-CHF. Monitoring sleeping respiratory rates (SRR) at home can help detect early L-CHF in patients with known cardiac disease. A sustained SRR of more than 30 breaths per minute may be indicative of potential decompensated CHF. As the disease progresses and the patient reaches the decompensated phase of L-CHF, pulmonary edema can cause tachypnea and increased inspiratory effort. ... Coughing does not always indicate that a dog with cardiac disease has L-CHF, as small dogs frequently have a paroxysmal-to-sustained cough related to compression of the mainstem bronchus secondary to cardiac enlargement. In these patients, thoracic radiography is needed to establish the diagnosis and guide treatment. ... If clinical signs are not immediately life-threatening, at a minimum, a lateral thoracic radiograph should be obtained. Thoracic radiography is the gold standard for diagnosing pulmonary edema and venous congestion secondary to L-CHF. If the patient is not in distress, a 3-view study with a ventrodorsal or dorsoventral (VD/DV) view and opposite lateral thoracic views is ideal. Characteristic findings of cardiogenic pulmonary edema include increased interstitial-to-alveolar infiltrates of the perihilar and/or caudodorsal lung field in dogs. ... Left atrial enlargement is typically present in both cats and dogs with L-CHF. In dogs, left atrial enlargement typically appears in radiographs as a rounded increased opacity caudal to the carina in the perihilar region on the lateral projection. (See Figure 1A, below.) Generalized cardiomegaly is identified by measuring vertebral heart score (VHS). ... In a well-managed patient naïve to previous cardiac medications, the average survival time with L-CHF is 6 to 12 months. SRR is a valuable parameter for owners to measure at home and, when increased, indicates the need for prompt treatment. Continued follow-up care, including repeat measurement of renal and electrolyte values, thoracic radiography (if indicated), and echocardiography is an important aspect of L-CHF management.

Figure 1A -- Cavalier King Charles Spaniel

 


United States Patent Application Publication Nr. US 2018/0028665 A1. February 2018. Applicant: Luoda Pharma Pty Ltd. Inventors: Nicholas Bova, Stephen Page, Giuseppe Pippia. Quote: The invention relates to a liquid formulation comprising propylene glycol and an effective amount of an inodilator, an angiotensin converting enzyme inhibitor, or a combination of an inodilator and an angiotensin converting enzyme inhibitor and to use of the formulation for treating cardiac disease and/or hypertension. The present invention relates to a liquid formulation, in particular a liquid formulation comprising an inadilator, preferably pimobendan, and/or an angiotensin converting enzyme inhibitor, preferably enalapril or benazepril, for use in treating cardiac disease and/or hypertension in mammals, particularly dogs or cats. ... In a first aspect, there is provided a liquid formulation comprising propylene glycol and an effective amount of an inodilator, an angiotensin converting enzyme inhibitor, or a combination of an inodilator and an angiotensin converting enzyme inhibitor. In a second aspect, there is provided a liquid formulation comprising an effective amount of an inodilator and propylene glycol. In a third aspect, there is provided a liquid formulation comprising an effective amount of an angiotensin converting enzyme inhibitor and propylene glycol. In a fourth aspect, there is provided a liquid formulation comprising propylene glycol and an effective amount of a combination of an inodilator and an angiotensin converting enzyme inhibitor. The formulation may comprise one or more further active agents, such as a diuretic or a calcium channel blocker. In a fifth aspect, there is provided a method of treating cardiac disease and/or hypertension, comprising administering the formulation defined above to a subject in need thereof. ... Another aspect provides a liquid formulation comprising an active agent and propylene glycol, wherein the active agent is selected from the group consisting of an inodilator, an ACE-I, a diuretic and a combination thereof. In an embodiment, the liquid formulation according to this aspect comprises an active agent selected from the group consisting ofpimobendan, enalapril, benazepril, furosemide, hydrochlorothiazide and veterinary and pharmaceutically acceptable salts thereof. ... Example 2: Bioavailability Study: Six adult dogs in good health were selected for inclusion. All dogs underwent a general physical examination (GPE), including weighing prior to the example's commencement. Dogs with a cardiovascular abnormality evident on GPE were not included. Discussion: The objective of the analytical component of this example was to determine the concentration of pimobendan in canine plasma obtained from six adult dogs administered either IVP (oral solution) or RVP (Vetmedin® capsule). The data was required to determine the similarity or difference between IVP and RVP formulations in terms of rate of gastrointestinal absorption of pimobendan. ... The oral solution presents a broader absorption profile; characterised by a slightly lower cmax' slightly longer T max' and a slightly larger AUC than the RVP based on the three dogs examined in each group. Rates of elimination are comparable between groups, but examination of the data at 3 and 4 hours post-treatment indicates that the average pimobendan concentrations of the IVP group are significantly higher than the average of the RVP group. The solution, on average, has achieved an overall higher systemic concentration of pimobendan, for a longer period. This could translate to an improved therapeutic outcome for dogs receiving the solution. Conclusions: This project involved analysis offorty-eight canine plasma samples for pimobendan. The samples were representative of six dogs, three each treated with either IVP (solution) or RVP (Vetmedin® capsule). Plasma samples were collected at designated time points following product administration. An LCMS/MS assay was developed and validated, capable of determining pimobendan in plasma in the range 0.5-50 ng/mL. Analysis of the data generated indicates that oral administration of the IVP can produce plasma concentrations of pimobendan in the treated dogs that are likely to be therapeutic. The rapid uptake of pimobendan is evident following administration of the oral solution. The data generated suggest that in the elimination phase, the systemic concentration of pimobendan from the oral solution is slightly higher, and is retained slightly longer than the RVP.

Effect of benazepril and pimobendan on serum angiotensin-converting enzyme activity in dogs. J. N. King, C. Christinaz, G. Strehlau, J. Hornfeld. Vet. Pharm. & Theraputics. February 2018:1-5. Quote: To support their combined use, the objective of the study was to evaluate the effects of benazepril and pimobendan on serum angiotensin-converting enzyme (ACE) activity in dogs. ... To support the registration of Fortekor Plus®, the primary objective of this study was to compare the efficacy of BID versus SID administration of benazepril. Serum ACE activity was used as the pharmacodynamic endpoint as it is the target enzyme for an ACE inhibitor. ... A total of 48 healthy beagle dogs were randomized into four groups (n = 12 per group) in a parallel-group design study: A (control, placebo twice daily (BID)); B (0.5–1.0 mg/kg benazepril once daily (SID) in the morning, placebo in the evening); C (0.25–0.5 mg/kg benazepril BID); D (0.25–0.5 mg/kg benazepril and 0.125–0.25 mg/kg pimobendan, both BID). The test items were administered orally for 15 days. Serum ACE activity was measured on days 1 and 15. Groups B, C and D had significantly lower average serum ACE activity compared to baseline and to the control group, on both days 1 and 15. There were no significant differences in average ACE activity between groups B, C and D. Noninferiority of group C to B was demonstrated. In conclusion, 0.25–0.5 mg/kg benazepril administered BID produced noninferior inhibition of serum ACE activity compared to 0.5–1.0 mg/kg benazepril dosed SID. Pimobendan had no significant effect on benazepril's action on serum ACE activity. The results support the use of benazepril BID in dogs and in combination with pimobendan.

Pathology and prognosis of canine myxomatous mitral valve disease. Melanie Hezzell. InPractice. March 2018;40:3-6. Quote: Myxomatous mitral valve disease is common in small breed dogs. However, the natural history of the disease is variable, with some dogs experiencing rapid progression to congestive heart failure and cardiac-related death, while other dogs have disease that never progresses to produce clinical signs. ... MMVD is frequently detected at a younger age in the CKCS compared with other breeds. Over half of CKCS are affected by five years of age and almost all CKCS are affected by the time they are 10 years old. ... Figure 5 Treatment is recommended according to the stage of disease progression, so understanding how to make this assessment is important. This article reviews the pathology and natural history of myxomatous mitral valve disease, and provides details of the most commonly used disease staging system. ... Importantly, not all cases of MMVD are progressive and less than 50 per cent of dogs with MMVD will die as a result of their disease. ... VHS is a measure of global heart size, and increases are not specific for left-sided cardiomegaly. The VHS is also not a sensitive way to detect increases in left atrial size; the left atrium contributes little to the VHS measurements due to its caudodorsal position on a lateral radiograph, although this does not preclude a radiographic assessment of left atrial enlargement in these cases (Fig 5, right). Furthermore, in certain breeds, dogs with echocardiographically normal hearts can have a VHS that exceeds the upper limit of the standard reference interval, resulting in the stage B1 dogs being misclassified as stage B2. Such breeds include the CKCS, dachshund, pug, Pomeranian, English bulldog, Boston terrier, boxer and Labrador retriever. Given that CKCS and dachshunds are particularly over-represented, this has clear clinical importance in MMVD. ... Standard echocardiographic measurements of left atrial and ventricular dimensions are fraught with the potential for inaccuracy, as they involve measurements of a nongeometric three-dimensional structure on a two-dimensional image. If the incorrect image plane is chosen (for example, too apical in the ventricle or an oblique rather than a truly transverse plane) these dimensions can be significantly under- or over-estimated, resulting in possible misclassification. Nevertheless, with training and experience, these measurements can be made with good repeatability and reproducibility; echocardiographic staging should be performed by experienced operators.

Simplifying mitral valve disease diagnostics. Nuala Summerfield. InPractice. March 2018;40:7-11. Quote: Myxomatous mitral valve disease (MMVD) in dogs is a slowly progressive disease. Until recently, focus was aimed at the symptomatic phase of the disease, when congestive heart failure (CHF) develops. However, since the publication of the EPIC trial, which showed that treatment with pimobendan delays the onset of CHF, the focus has now shifted onto the early diagnosis of MMVD. This article considers the tests necessary to diagnose MMVD and aims to provide vets with the knowledge and tools to undertake these successfully. ... Following the publication of the EPIC study in 2016, the focus has shifted to diagnosing MMVD earlier in the course of the disease, before the patient shows signs of CHF. ...  Veterinary surgeons are typically more familiar with interpreting thoracic radiographs than cardiac ultrasound images. ... An abnormal VHS is more than 10.5. In dogs with MMVD, an increased VHS strongly suggests cardiac enlargement. ... Many breeds studied individually do fall within the normal VHS range. However, it is important to be aware that a number of breeds normally have VHS values that would suggest cardiomegaly using the original scale. Of the breeds evaluated to date the French and English bulldog, pug, Boston terrier, Pomeranian, CKCS, boxer, Labrador retriever and whippet have been found to have average VHS values that are significantly higher than other dog breeds.  ...  However, with some focused, practical training, the ultrasound images necessary to diagnose and stage MMVD in dogs (as per the EPIC criteria) can be reliably obtained and interpreted in a general practice setting. In the EPIC study, echocardiographic evidence of advanced MMVD was defined as: ... Echocardiographic evidence of left atrial and left ventricular dilatation defined as: Left atrial-to-aortic root ratio (LA:Ao) greater than or equal to 1.6; Bodyweight normalised left ventricular internal diameter in diastole (LVIDDN) greater than or equal to 1.7. ... The normal LA:Ao ratio is less than 1.6 when measured using the short-axis view. So, if your LA:Ao ratio is more than 1.6 this suggests that your patient does indeed have left atrial enlargement.  ... Therefore, diagnosing heart enlargement not only allows you to provide the owner with a prognosis for their dog but also enables you to design an appropriate treatment plan if the dog meets the EPIC study criteria. ... With some focused, practical training, the ultrasound images necessary to diagnose and stage MMVD in dogs (as per the EPIC criteria) can be reliably obtained and interpreted in a general practice setting.

Improving outcomes of myxomatous mitral valve disease in dogs. Adrian Boswood. InPractice. March 2018;40:12-15. Quote: Now that treatment has been shown to slow the onset of clinical signs of myxomatous mitral valve disease (MMVD), recommendations are focusing on diagnosing the condition before clinical signs manifest so that dogs can be maintained free of signs for longer. This article summarises the published evidence and outlines optimal management for dogs at each disease stage. It covers pharmacological and other strategies, with a view to maintaining dogs in the early stages of the disease for as long as possible and effectively managing their clinical signs when they develop. ... Stage B1 disease: ... The current best evidence suggests that there is no benefit to medical management of patients with stage B1 disease. ... Stage B2 disease: ... Three criteria were used to establish cardiac enlargement before a dog was enrolled in the EPIC study: dogs needed to have a normalised left ventricular internal diameter in diastole (LVIDDN) of greater than or equal to 1.7, a left atrial to aortic ratio (LA:Ao) of greater than or equal to 1.6, both shown on echocardiographic evaluation, and a vertebral heart sum (VHS) of more than 10.5, shown on radiographic evaluation. I therefore recommend, as a minimum, that a dog should have undergone an echocardiographic examination and be shown to meet the LVIDDN and LA:Ao criteria before pimobendan therapy is initiated. It is debatable whether dogs should also be shown to have met the radiographic criterion of a VHS of more than 10.5 in addition to the echocardiographic criteria. Due to variability of VHS within breeds, a VHS of more than 10.5 is probably not, as a single measurement, sufficient evidence to warrant therapy; however, it is likely that a dog with a VHS considerably greater than this (for example, more than 11.5) will also have echocardiographic evidence of enlargement. On the basis of the results of the EPIC study I now routinely recommend the use of pimobendan in dogs with preclinical MMVD and evidence of cardiac enlargement (sufficient to meet the EPIC inclusion criteria) at a dose of approximately 0.5 mg/kg/day divided into two doses (0.25 mg/kg twice a day). ... On the basis of a critical reading, I have never believed that the evidence for treatment was sufficiently compelling to warrant treatment and have not recommended the use of ACE inhibitors in dogs with stage B2 disease. There is currently no clear evidence to support the use of other drugs in dogs with stage B2 disease, although there are other ongoing studies that may provide evidence for the benefit of other medications in future. Once treatment with pimobendan has been started it should be continued indefinitely and the dog should be monitored for progression of disease. ... Stage C disease: ... This means there has not been a prospective blinded study which specifically evaluates the effectiveness of the combination of these four commonly used drugs [furosemide, pimobendan, an ACE inhibitor and spironolactone] together. Despite this, most cardiologists (including me) now recommend the administration of four medications for the treatment of stage C MMVD: furosemide, pimobendan, an ACE inhibitor and spironolactone.

Potential Clinical Benefits of D-ribose in Ischemic Cardiovascular Disease. Linda M. Shecterle, Kathleen R. Terry, John A. St. Cyr. Cureus. March 2018;10(3):e2291. Quote: Cardiovascular disease still remains the leading cause of deaths worldwide. Atherosclerosis, the most common type of cardiovascular disease, has continued to progress due to many factors, genetics, and lifestyles. All cells require adequate adenosine triphosphate (ATP) levels to maintain their integrity and function. Myocardial ischemia commonly found in atherosclerosis can produce lower levels of ATP, which affects not only cellular energy, but also alters normal function. D-ribose, a naturally occurring pentose carbohydrate, has been shown to increase cellular energy levels and improve function following ischemia in pre-clinical studies and have demonstrated potential benefits in clinical evaluations. This review paper presents an overview of ischemic cardiovascular disease and the potential role that D-ribose could play in improving myocardial energy levels and function in the area of ischemic cardiovascular diseases.

Prognostic value of echocardiographic indices of left atrial morphology and function in dogs with myxomatous mitral valve disease. Marco Baron Toaldo, Giovanni Romito, Carlo Guglielmini, Alessia Diana, Nazzareno G. Pelle, Barbara Contiero, Mario Cipone. J. Vet. Intern. Med. March 2018; DOI:10.1111/jvim.15093. Quote: Background: The prognostic relevance of left atrial (LA) morphological and functional variables, including those derived from speckle tracking echocardiography (STE), has been little investigated in veterinary medicine. Objectives: ... Therefore, the aims of our study were: (1) to investigate the prognostic value of LA STE variables on survival in dogs with MMVD; and, (2) to compare the usefulness of different echocardiographic variables, particularly those related to LA dimension and function, as predictors of cardiac mortality in dogs with MMVD. ... Animals: One-hundred and fifteen dogs of different breeds with MMVD. [54 mixed breeds; 8 cavalier King Charles spaniels; 7 or fewer dogs of 29 other breeds.] Methods: Prospective cohort study. Conventional morphologic and echo-Doppler variables, LA areas and volumes, and STE-based LA strain analysis were performed in all dogs. A survival analysis was performed to test for the best echocardiographic predictors of cardiac-related death. Results: Most of the tested variables, including all LA STE-derived variables were univariate predictors of cardiac death in Cox proportional hazard analysis. Because of strong correlation between many variables, only left atrium to aorta ratio (LA/Ao>1.7), mitral valve E wave velocity (MV E vel>1.3 m/s), LA maximal volume (LAVmax>3.53 mL/kg), peak atrial longitudinal strain (PALS<30%), and contraction strain index (CSI per 1% increase) were entered in the univariate analysis, and all were predictors of cardiac death. However, only the MV E vel (hazard ratio [HR], 4.45; confidence interval [CI], 1.76-11.24; P<.001) and LAVmax (HR, 2.32; CI, 1.104.89; P=.024) remained statistically significant in the multivariable analysis. Conclusions and Clinical Importance: The assessment of LA dimension and function provides useful prognostic information in dogs with MMVD. Considering all the LA variables, LAVmax appears the strongest predictor of cardiac death, being superior to LA/Ao and STE-derived variables. ... Our findings about the negative prognostic value of LAVmax, but not of LA/Ao, might suggest that the use of linear measurements to predict LA enlargement may underestimate the risk stratification of dogs with MMVD. Although LA/Ao has been proven to predict cardiac-related death in dogs with MMVD, the volumetric approach of measuring the LA seems more effective in predicting mortality.

The cardiovascular assessment skills gap in small animal general veterinary practitioners and identification of methods to reduce this. Anna Elisabeth Beber. Univ. Glasgow MVM(R) thesis. March 2018. Quote: Administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) with cardiomegaly (stage B2 mitral valve disease) has been shown to extend the asymptomatic period by an average of 15 months, and dogs receiving the drug live significantly longer than those receiving a placebo. The identification in general veterinary practice of patients with MMVD who could benefit from this medication relies heavily on the accurate identification of a heart murmur on a physical examination and identification of cardiomegaly, including left atriomegaly, on thoracic radiographs. This study was designed to evaluate the ability of general practitioners to detect changes associated with MMVD on thoracic radiographs. ... Materials and method: Fifteen sets of right lateral (RL) and dorsoventral (DV) thoracic radiographs of Cavalier King Charles Spaniels aged from three years to thirteen years with a systolic murmur of grade 3 intensity or greater were retrospectively selected from examinations performed on dogs attending the University of Glasgow Small Animal Hospital Cardiorespiratory clinic between 2010 and 2017. All dogs had undergone a clinical examination including cardiac auscultation by a board certified veterinary cardiologist (AF and PW) at the time of the radiograph. In all cases, the cause of the murmur was confirmed as myxomatous mitral valve disease (MMVD) using echocardiography. All radiographs were considered of good diagnostic quality and exposed as close to inspiration as possible. ... Whilst practitioners were accurate in their ability to measure a vertebral heart score (VHS), the lack of a clear upper limit for VHS meant that VHS added no significant value in aiding correct diagnosis. ... Assessment two: In this experiment, participants (n = 21) were shown 15 images (7 with no CM, 3 with mild CM and 5 with severe CM) and asked to measure the VHS. These scores were then compared to an independent, experienced assessors score. ... In this study, the range of VHS for patients with no cardiomegaly or left atrial enlargement subjectively and no left atrial enlargement on echocardiography determined by consensus opinion of diplomates was 11.0-11.9v. This is higher than the range suggested by Lamb (Lamb et al., 2001), whose upper limit was 11.1v. Using Lamb’s reference range for the VHS defined by the subjective consensus opinion, 40% of the ‘normal’ Cavalier King Charles Spaniels would have been considered to have cardiomegaly and therefore potentially receiving treatment unnecessarily. Using the vertebral heart score cut off of 10.5v in the EPIC study, all of the ‘normal’ Cavalier King Charles Spaniels in this study (defined by subjective impression consensus opinion) would have been considered to have cardiomegaly and therefore potentially received treatment unnecessarily. ... The consequences of both a false positive detection of cardiomegaly and false negative are undesirable. A false positive could result in a patient receiving pimobendan too soon, which research has suggested could worsen the mitral regurgitation, cause myocardial hypertrophy or acute focal haemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendineae with glycosaminoglycans in the mitral valves of dogs (Tissier et al., 2005; Chetboul et al., 2007). A false negative could mean that the patient would not receive the full benefits of pimobendan. ... Therefore, to ensure that a VHS is of value, the author suggests that large numbers of breed ‘normals’ need to be used to establish a more reliable reference range.

Left atrial deformation and phasic function determined by two-dimensional speckle-tracking echocardiography in dogs with myxomatous mitral valve disease. D. Caivano, M. Rishniw, F. Birettoni, V. Patata, M.E. Giorgi, F. Porciello. J. Vet. Cardiol. April 2018;20(2):102-114. Quote: Introduction: Left atrial (LA) function can provide useful information in dogs with myxomatous mitral valve disease (MMVD). Recently, we have demonstrated the feasibility of measuring LA longitudinal deformation using speckle-tracking echocardiography (STE) to estimate LA function in healthy dogs. Whether LA strain and strain rate variables provide additional information about LA function and clinical cardiac status in dogs with MMVD remains unexplored. Animals: Ninety-six client-owned dogs of different breeds with MMVD were prospectively enrolled. ... 7 were Cavalier King Charles spaniels. ... Methods: LA longitudinal deformation was evaluated in each dog by STE and different STE variables were used to assess LA function. Results: No STE variables differed between American College of Veterinary Internal Medicine Stage B1 and B2 dogs but were lower in Stage C dogs. Peak atrial longitudinal average strain < 27.9%, left-atrial-to-aortic ratio > 2.2 and peak atrial contraction average strain < 7.25% discriminated symptomatic MMVD dogs by receiver operating characteristic analysis with sensitivity and specificity of 100% and 100% (95% confidence interval [CI] 91–100%), 92% (95% CI 78–98%) and 98% (95% CI 87–100%), 100% (95% CI 91–100%) and 95% (95% CI 83–99%), respectively. In 12 dogs with similar left-atrial-to-aortic ratio, peak atrial longitudinal average strain and peak atrial contraction average strain differentiated dogs with subclinical disease from those with congestive heart failure (CHF). Conclusion: Dogs with MMVD in CHF appear to have lower LA longitudinal strain and strain rate variables compared with dogs with subclinical disease. Further studies are needed to establish if our initial findings can provide useful information for the diagnosis, treatment, and prognosis of dogs with MMVD.

Using the Oculocardiac Reflex to Characterize Autonomic Imbalance in a Naturally Occurring Canine Model of Valvular Insufficiency. Brüler, Bruna C; Vieira, Thayane C; Wolf, Marcela; Lucina, Stephany B; Montiani-Ferreira, Fabiano; Sousa, Marlos G. Comparative Med. March 2018. Quote: Congestive heart failure (CHF) is characterized by reduced heart rate variability. Although various methods to achieve parasympathetic withdrawal and sympathetic activation have been documented, stimulation of the vagal nerve (that is, vagal maneuvers) has not often been used to assess the autonomic impairment associated with disease progression in veterinary species. In this study, we investigated cardiac autonomic control in a naturally occurring canine model of mitral insufficiency by means of individual responses to oculocardiac reflex. Indices of heart rate variability were calculated from 5-min ECG tracings obtained before and after ocular compression. After compression, significant increases in the standard deviation of RR intervals, root mean square of the successive differences in RR intervals, and vasovagal tonus index were documented in healthy control animals. In addition, these indices were increased in asymptomatic dogs with remodeled hearts, but no variation occurred in symptomatic animals. Although only the percentage change in vasovagal tonus index differed significantly between controls and diseased dogs, all other parameters showed a tendency to behave the opposite way in the symptomatic group as in the control and asymptomatic groups. Our results document CHF-dependent autonomic dysfunction in a canine model of valve insufficiency.

Development and Evaluation of a Tissue-Engineered Fibrin-based Canine Mitral Valve Three-dimensional Cell Culture System. M.-M. Liu, T. C. Flanagan, S. Jockenhovel, A. Black, C.-C. Lu, A. T. French, D. J. Argyle, B. M. Corcoran. J. Comp. Path. April 2018;160:23-33. Quote: Myxomatous mitral valve disease is the most common cardiac disease of the dog, but examination of the associated cellular and molecular events has relied on the use of cadaveric valve tissue, in which functional studies cannot be undertaken. The aim of this study was to develop a three-dimensional (3D) cell co-culture model as an experimental platform to examine disease pathogenesis. Mitral valve interstitial (VIC) and endothelial (VEC) cells were cultured from normal and diseased canine (VIC only) valves. VICs were embedded in a fibrin-based hydrogel matrix and one surface was lined with VECs. The 3D static cultures (constructs) were examined qualitatively and semiquantitatively by light microscopy, immunofluorescence microscopy and protein immunoblotting. Some constructs were manipulated and the endothelium damaged, and the response examined. The construct gross morphology and histology demonstrated native tissue-like features and comparable expression patterns of cellular (a-smooth muscle actin [SMA] and embryonic smooth muscle myosin heavy chain [SMemb]) and extracellular matrix associated markers (matrix metalloproteinase [MMP]-1 and MMP-3), reminiscent of diseased valves. There were no differences between constructs containing normal valve VICs and VECs (type 1) and those containing diseased valve VICs and normal valve VECs (type 2). Mechanical manipulation and endothelial damage (type 3) tended to decrease a-SMA and SMemb expression, suggesting reversal of VIC activation, but with retention of SMemb+ cells adjacent to the wounded endothelium consistent with response to injury. Fibrin-based 3D mitral valve constructs can be produced using primary cell cultures derived from canine mitral valves, and show a phenotype reminiscent of diseased valves. The constructs demonstrate a response to endothelial damage indicating their utility as experimental platforms.

Evaluation of symptomatic improvements observed by switching to alacepril from other ACE-Inhibitors in dogs with mitral valve regurgitation. Akiko Uemura, Lina Hamabe, Kazumi Shimada, Miki Shimizu, Ryou Tanaka. Thai J. Vet. Med. March 2018;48(1):29-36. Quote: Alacepril is an ACE-inhibitor (ACE-I), which has unique properties including peripheral sympathoinhibitory effect and negative chronotropic effect, and it is suspected to have a superior cough suppressive effect in comparison to other ACE-Is. The purpose of the study was to evaluate whether switching to alacepril from other ACE-Is will alleviate the clinical symptoms of congestive heart failure (CHF) caused by mitral valve regurgitation (MR). The prospective clinical study included 73 client-owned dogs [including 6 cavalier King Charles spaniels] with MR that had been treated with ACE-Is other than alacepril for over a period of one month. ...Of these 73 dogs, only 34 dogs were on ACE-Is only treatments, and the remaining 39 dogs were on combination of drugs including diuretics (furosemide, spironolactone, and azosemide), aminophylline, digoxin, isosorbide mononitrate, pimobendan, and theophylline. As for the ACE-Is, 26 dogs were taking enalapril, 23 dogs were taking benazepril, another 23 dogs were taking temocapril, and only one dog was taking ramipril. ... The ACE-Is were replaced by alacepril and observed for four weeks. Parameters including heart rate (HR), body weight (BW), and general clinical conditions, such as activeness, appetite, responsiveness, and frequency of cough, were recorded before, and at two and four weeks after the switch. Each parameter was then statistically analyzed. Within four weeks of the switch, HR revealed a significant reduction, and clinical symptoms including activeness, appetite, responsiveness, and the frequency of cough showed significant improvements (p<0.001). Under this study condition, switching to alacepril from other ACE-Is has shown to reduce HR, and improve the clinical symptoms of CHF, in particular the frequency of cough. ... The degree of effect of alacepril on the dogs with MR differed depending on the ACE-Is used before the switch. The most significant changes were observed with enalapril and temocapril groups, where significant changes were observed in all parameters, except for the BW in enalapril group and appetite in temocapril group. On the other hand, the frequency of cough was the only parameter that showed significant change in benazepril group. It is also important to note that the frequency of cough was the only parameter that resulted in significant improvement in all three-treatment groups. ... 4 weeks of treatment with alacepril had shifted the number of dogs classified from higher classes to lower classes of ISACHC classification, and overall reduction of murmur intensity was observed.

Congestive Heart Failure in Dogs. Simon Swift. Today's Vet. Pract. J. May-June 2018:25-37. Quote: With a logical treatment approach, congestive heart failure in dogs can be controlled for many months with a good quality of life in most patients. Heart failure in dogs is a syndrome of clinical signs that, although well recognized by clinicians, is difficult to define precisely. It involves the heart’s inability to maintain output sufficient to meet the body’s needs, or to do so at normal filling pressures. Elevated filling pressures can lead to congestion as increased venous pressures cause fluid to leak from the vessels, resulting in congestive heart failure (CHF) in the dog, which moves the patient into stage C. ... For left-sided heart failure, the increased left atrial and pulmonary venous pressures cause fluid to seep into the interstitial spaces and then flood the alveoli with pulmonary edema. Dogs occasionally present with pleural effusion when in CHF, and respiratory effort can increase significantly if this effusion is not drained. ... For example, an 8-year-old Cavalier King Charles spaniel presenting with tachycardia, pulmonary crackles on auscultation, and a several-year history of a left apical systolic murmur with progressively increasing intensity could be considered likely to have developed CHF secondary to degenerative mitral valve disease (DMVD). However, an 8-year-old Cavalier King Charles spaniel with a recently documented quiet murmur that presents with crackles on auscultation, a heart rate of 90 beats/min, and a cough is unlikely to be in CHF.

Clinical findings and survival time in dogs with advanced heart failure. Amelie Beaumier, John E. Rush, Vicky K. Yang, Lisa M. Freeman. J. Vet. Intern. Med. April 2018. DOI: 10.1111/jvim.15126. Quote: Background: Dogs with advanced heart failure are a clinical challenge for veterinarians but there are no studies reporting clinical features and outcome of this population. Hypothesis/Objectives: To describe clinical findings and outcome of dogs with advanced heart failure caused by degenerative mitral valve disease (DMVD). Animals: Fifty-four dogs with advanced heart failure because of DMVD [including 9 cavalier King Charles spaniels (17%)]. Methods: For study purposes, advanced heart failure was defined as recurrence of congestive heart failure signs despite receiving the initially prescribed dose of pimobendan, angiotensin-converting-enzyme inhibitor (ACEI), and furosemide >4 mg/kg/day. Data were collected for the time of diagnosis of Stage C heart failure and time of diagnosis of advanced heart failure. Date of death was recorded. Results: At the diagnosis of advanced heart failure, doses of pimobendan (n=30), furosemide (n=28), ACEI (n=13), and spironolactone (n=4) were increased, with ≥1 new medications added in most dogs. After initial diagnosis of advanced heart failure, 38 (70%) dogs had additional medications adjustments (median=2 [range, 0-27]), with the final total medication number ranging from 2-10 (median=5). Median survival time after diagnosis of advanced heart failure was 281 days (range, 3-885 days). Dogs receiving a furosemide dose >6.70 mg/kg/day had significantly longer median survival times (402 days [range, 3-885 days] versus 129 days [range 9-853 days]; P=.017). Conclusions and Clinical Importance: Dogs with advanced heart failure can have relatively long survival times. Higher furosemide dose and non-hospitalization were associated with longer survival.

Comparing the prevalence of pulmonary hypertension in Cavalier King Charles Spaniels and other breeds in dogs with myxomatous mitral valve disease. Siddharth Sudunagunta, Jo Dukes-McEwan. BSAVA Congress 2018 Proceedings. April 2018;p. 446. Quote: Objectives: To determine if Cavalier King Charles spaniels (CKCS) are more likely to develop pulmonary hypertension (PH) as a result of myxomatous mitral valve disease (MMVD) than dogs of other breeds and also assess whether PH impacts upon survival. A secondary objective was to explore any association between the presence of macroplatelets and PH. Methods: Retrospective review of 187 dogs diagnosed with MMVD identified from electronic patient records, 94 CKCS and 93 non-CKCS. Eligible dogs were >5 years of age, weighed <20 kg and had structural cardiac changes due to MMVD on echocardiography (nodular thickening of the mitral valve, dilated left atrium and ventricle) with or without congestive heart failure (CHF). Data retrieved were analysed for the presence of PH (based on tricuspid regurgitation velocity >2.8 m/s), CHF, selected echocardiographic variables and macroplatelets. Survival analysis was also performed, on both cardiac and all-cause mortality. Results: 71/94 CKCS and 52/93 non-CKCS developed PH (p=0.005). 57/94 CKCS and 45/93 non-CKCS were in left-sided CHF (p=0.093). PH was associated with a greater likelihood of CHF (p<0.001) and death (both cardiac (p<0.001) and all-cause mortality (p=0.011)). CKCS were more likely to experience cardiac death than non-CKCS (p=0.004). Macroplatelets were not associated with PH development (p=0.376). Conclusions: CKCS were more likely than non-CKCS to develop PH due to MMVD in this study population. Further investigations are required to determine the reason for this. Macroplatelets were not associated with the development of PH. (See also the June 2019 article of this abstract.)

Calculation of Left Ventricular Diastolic Time Constant (TAU) in Dogs with Mitral Regurgitation Using Continuous-Wave Doppler. Chaoyang Wen, Jing Sun, Chunzhi Fan, Jianping Dou. Ultrasound in Med. & Biol. May 2018. DOI:10.1016/j.ultrasmedbio.2018.03.023. Quote: The left ventricular diastolic time constant (Tau) cannot be practically measured non-invasively. Thus, the aim of this study was to investigate a new method for the evaluation of Tau using continuous-wave (CW) Doppler in dogs with mitral regurgitation. Guided by ultrasound, we created 12 beagle models of mitral regurgitation and acute ischemic left ventricular diastolic dysfunction. Raw audio signals of the CW Doppler spectra were collected, and new mitral regurgitation Doppler spectra were observed after computer re-processing. The new Doppler spectra contour line was constructed using MATLAB (Version R2009), and two time intervals, t1–t2 and t1–t3, were measured on the descending branch of the mitral regurgitation Doppler spectrum and were substituted into Bai's equation group. The Doppler-derived Tau (Tau-d) was resolved and compared with the simultaneous catheter-derived Tau (Tau-c). No significant difference (p > 0.05) between Tau-d (49.33 ± 18.79 ms) and Tau-c (48.76 ± 17.60 ms) was found. A correlation analysis between Tau-d and Tau-c suggested a strong positive relationship (r = 0.85, p = 0.000). Bland-Altman plots of Tau-d and Tau-c revealed fair agreement. Compared with previous non-invasive approaches, this method is simpler and more accurate. There is a strong positive relationship and fair agreement between Tau-d and Tau-c.

Platelet indices and their association with chronic valvular heart disease in Cavalier King Charles spaniels. Linda J Tong. Murdoch Univ. thesis. May 2018. Quote: Chronic valvular heart disease (CVHD) is common in Cavalier King Charles spaniel (CKCS) Table 4-14.and has the potential to affect platelet activation or function. The present study objective was to determine platelet closure time, mean platelet component (MPC) concentration and platelet component distribution width (PCDW) in dogs with subclinical CVHD, and to assess the factors influencing these variables. A second objective was to assess platelet count, MPC concentration, PCDW, mean platelet volume (MPV), platelet volume distribution width (PDW), plateletcrit (PCT), mean platelet mass (MPM) and platelet mass distribution width (PMDW) in CKCS. Haematological values, closure time, murmur grade and echocardiographic variables were recorded in 89 CKCS. ... A total of 89 CKCS fulfilled the inclusion criteria; 47 were female (34 spayed and 13 entire) and 42 male (38 castrated and 4 entire). ... Murmur grade: A left apical systolic murmur was detected in 51 of 89 CKCS (57%; 95% CI, 46% to 66%). Of the 51 CKCS with a murmur, 24 (47%) were aged 6 years or less. The frequencies of the murmur grades are listed in Table 4.14 and the relationship between age and murmur grade is displayed in Figure 4.9. There was a positive relationship between murmur grade and age. ... Table 4-17.Regurgitant jet size: Mitral valve regurgitation was detected by use of colour-flow Doppler echocardiography in 86 of 89 CKCS. The 3 dogs that had no evidence of MVR were 8 months old, 3 years old, and 4 years old). ... Echocardiographic indices of left heart remodelling: Left atrial enlargement was evident in 22 of 89 CKCS. Four of 89 CKCS had left ventricular enlargement during diastole. Left ventricular enlargement during systole was not detected in any CKCS. ... Canine chronic valvular heart score: The ACVIM canine CVHD scores are summarised below (Table 4.17). As only subclinical cases were included in the present study, no dogs were classified in Stage C or D.

Acute effect of ivabradine on heart rate and myocardial oxygen consumption in dogs with asymptomatic mitral valve degeneration. Pirintr P, Limprasutr V, Saengklub N, Pavinadol P, Yapao N, Limvanicharat N, Kuecharoen H, Kijtawornrat A. Exp Anim. May 2018 doi: 10.1538/expanim.18-0030. Quote: Degenerative mitral valve disease (DMVD) is a common cardiac disease in geriatric dogs characterized by the degeneration of the mitral valve, leading to decreased cardiac output and activation of the sympathetic and renin-angiotensin-aldosterone system. This disease results in an increased resting heart rate (HR) and myocardial oxygen consumption (MVO2). A recent publication demonstrated that dogs with asymptomatic DMVD had a significantly higher HR and systemic blood pressure (BP) than age-matched control dogs. This higher HR will eventually contribute to increased MVO2. This study aimed to determine the effects of a single oral dose of ivabradine on the HR, MVO2 as assessed by the rate-pressure product, and BP in dogs with asymptomatic DMVD. Seven beagles with naturally occurring DMVD were instrumented by the Holter recorder and an oscillometric device to measure electrocardiogram and BP for 24 and 12 h, respectively. Each dog was randomly subjected to receive either placebo or ivabradine (0.5, 1.0 and 2.0 mg/kg). The results revealed that oral administration of ivabradine significantly decreased the HR and rate-pressure product in a dose-dependent manner without adverse effects. The highest dose of 2.0 mg/kg significantly reduced systolic and mean BP. Therefore, the findings imply that a single oral ivabradine administration at a dose of 1.0 mg/kg is suitable for dogs with asymptomatic DMVD to reduce the HR and MVO2 without marked effects on BP. This may potentially make ivabradine promising for management of an elevated HR in DMVD dogs.

Elamipretide restores protein and mRNA expression levels of S100A1 in left ventricular myocardium of dogs with chronic heart failure. RC Gupta, V Singh-Gupta, HN Hani Sabbah. Euro. J. Heart Failure. May 2018;20(S1):150 (p590). Quote: Background: S100A1 is a calcium-binding protein predominantly expressed in cardiac and skeletal muscles and localizes to Z-discs and sarcoplasmic reticulum. S100A1 was shown to play a pivotal role in cardiac contractility. More recently, a novel interaction of S100A1 with mitochondrial F1-ATPase was recognized which affects F1-ATPase activity and cellular ATP production. Cardiomyocytes that overexpress S100A1 exhibit high ATP content whereas knockdown of S100A1 decreases ATP levels. Elamipretide (ELAM), a mitochondria targeting peptide, has been shown to improve cardiac contractility and increase the rate of ATP synthesis in left ventricular (LV) myocardium of dogs with advanced heart failure (HF). This study examined the effects of chronic therapy with ELAM on protein and mRNA levels of S100A1 in LV myocardium of dogs with coronary microembolizations-induced HF (LVEF ˜30%). Methods: LV tissue from 14 HF dogs randomized to 3 months therapy with subcutaneous injections of ELAM (0.5 mg/kg once daily, n = 7) or saline (control, CON, n = 7) and LV tissue from 6 normal (NL) dogs was used. Protein levels of S100A1 were determined in LV tissue extract by Western blotting coupled with chemiluminescence and band intensities expressed in densitometric units (du). mRNA expression of S100A1 normalized to GAPDH was measured in RNA from LV tissue using real-time PCR and was expressed as fold change from NL. Results: Data are shown in the Table. Levels of GAPDH were unchanged among the 3 study groups. mRNA and protein levels of S100A1 were decreased significantly in HF-CON dogs compared to NL dogs. Treatment with ELAM (HF+ELAM) normalized S100A1 mRNA and protein expression. Conclusions: mRNA and protein levels of S100A1 are decreased in LV of HF dogs and are normalized after chronic therapy with ELAM. The finding supports the observations of improved LV function and rate of ATP synthesis after chronic therapy with ELAM.

Increased expression of galectin-3 in the interstitium of left ventricular myocardium of dogs with chronic heart failure. V Singh-Gupta, RC Gupta, HN Hani Sabbah. Euro. J. Heart Failure. May 2018;20(S1):330-331 (p1265). Quote: Background: Accumulation of collagen in the cardiac interstitium termed "reactive interstitial fibrosis (RIF)" occurs in heart failure (HF) with reduced ejection fraction (HFrEF) as well as in HF with preserved EF (HFpEF). This maladaptation leads to increased myocardial stiffness that negatively impacts ventricular filling. RIF also results in poor oxygen diffusion between capillaries and cardiomyocytes leading to cardiomyocyte hypoxia that promotes cellular contractile dysfunction and triggers programmed cell death. The protein galectin-3 (GAL-3) is a member of the lectin family. Increased expression of GAL-3 is implicated in the development of fibrosis in multiple organs including the heart. Elevated levels of GAL-3 are significantly associated with higher risk of death in patients with HF. In this study, we examined whether increased expression of GAL-3 occurs in the LV interstitium of dogs with chronic HF that also manifest increased levels of RIF. Methods: Studies were performed in LV tissue obtained from 7 normal (NL) dogs and 7 dogs with coronary microembolization-induced HF. Frozen LV sections, 6 μm in thickness, were used for fluorescence immunostaining with antibodies against myosin heavy chain and GAL-3. DAPI (4’, 6-diamidino-2-phenylindole) was used to stain nuclei. Confocal images of stained sections were obtained with an Olympus Fluoview FV1000 laser scanning biological microscope. From each section, 4-6 fields, each ˜10 mm2, were randomly selected for laser scanning and subsequently used to calculate the percent area occupied by GAL-3 (%aGAL-3) from each field. The percent area occupied by RIF (%aRIF) was also calculated using frozen sections stained with fluorescein-labeled peanut agglutinin. Results: In NL dogs, the %aRIF was 3.70±0.07 and %aGAL-3 was 2.40±0.45. In dogs with HF, the %aRIF increased significantly to 13.5±0.57 (p < 0.05) and the %aGAL-3 increased significantly to 12.82±1.15 (p < 0.05). Conclusions: The results indicate that in dogs with HF, increased levels of RIF is associated with increased interstitial levels of GAL-3. The findings support the use of this dog model of HF to evaluate the effects of GAL-3 inhibitors for preventing or attenuating RIF that develop during HF.

Interbreed variation in serum serotonin (5-hydroxytryptamine) concentration in healthy dogs. K. Höglund, J. Häggström, S. Hanås, A.-C. Merveille, V. Gouni, M. Wiberg, J. Lundgren Willesen, K.Mc Entee, L. Mejer Sørensen, L. Tiret, E.H. Seppälä. J. Vet. Cardiol. June 2018. DOI: 10.1016/j.jvc.2018.05.002. Quote: Introduction: Serotonin (5-hydroxytryptamine [5-HT]) has several biological functions. In different species, excessive 5-HT has been linked to valvular lesions, similar to those seen in dogs with myxomatous mitral valve disease. Previous studies suggest higher 5-HT in healthy Cavalier King Charles Spaniels (CKCSs), a breed highly affected by myxomatous mitral valve disease, compared to other breeds. Objective: To investigate potential interbreed variation in serum 5-HT in healthy dogs. Animals: 483 healthy dogs of nine breeds aged 1–7 years [including 33 CKCSs]. Methods: Dogs were examined at five European centers. Absence of cardiovascular, organ-related, or systemic diseases was ensured by thorough clinical investigations including echocardiography. Serum was frozen and later analyzed by enzyme-linked immunosorbent assay (ELISA). Results: Median 5-HT concentration was 252.5 (interquartile range = 145.5–390.6) ng/mL. Overall breed difference was found (p<0.0001), and 42% of pairwise breed comparisons were significant. Univariate regression analysis showed association between serum 5-HT concentration and breed, center of examination, storage time, and sex, with higher 5-HT in females. In multiple regression analysis, the final model had an adjusted R2 of 0.27 with breed (p<0.0001), center (p<0.0001), and storage time (p=0.014) remaining significant. Within centers, overall breed differences were found at 3/5 centers (p≤0.028), and pairwise comparisons within those centers showed breed differences in 42% of comparisons. Among the included breeds, Newfoundlands, Belgian Shepherds and CKCSs had highest 5-HT concentrations. Conclusions: Interbreed variation in serum 5-HT concentration was found in healthy dogs aged 1–7 years. These differences should be taken into account when designing clinical studies.

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition: A Translational Study in the Dog and Rabbit. Toru Hashimoto, Grace E. Kim, Richard S. Tunin, Tolulope Adesiyun, Steven Hsu, Ryo Nakagawa, Guangshuo Zhu, Jennifer J. O'Brien, Joseph P. Hendrick, Robert E. Davis, Wei Yao, David Beard, Helen R. Hoxie, Lawrence P. Wennogle, Dong I. Lee, David A. Kass. Circulation. July 2018. DOI: 10.1161/CIRCULATIONAHA.117.030490 Quote: Background: Phosphodiesterase type-1 (PDE1) hydrolyzes cyclic AMP and cGMP and is constitutively expressed in the heart, though cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly express PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs and rabbits, in normal and failing hearts, and explored its regulatory pathways. Methods: Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously ± dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of beta-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left-ventricular myocytes. Results: In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to beta-adrenergic receptor (β-AR) agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbit, β-AR-blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-AR agonism (isoproterenol) or PDE3 inhibition (cilostamide, CIL) increased both. Unlike CIL, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only CIL increased calcium transients. ... The combination of effects in both dog and rabbit results in a rise in cardiac output with negligible changes in cardiac preload and arterial systolic pressure.  ... Conclusions: PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via beta-AR receptors or PDE3 modulation. ITI-214, which has completed Phase I trials, may provide a novel therapy for HF.

A prospective, randomized, double-blind, placebo-controlled pilot study of sacubitril/valsartan (Entresto). Daniel K. Newhard, SeungWoo Jung, Randolph L. Winter, Sue H. Duran. J. Vet. Int. Med. August 2018;doi: 10.1111/jvim.15240. Quote: Background: The effects of sacubitril/valsartan (S/V) on the renin-angiotensin-aldosterone system (RAAS) in dogs with cardiomegaly secondary to myxomatous mitral valve disease (MMVD) are currently unknown. Objectives To determine the pharmacodynamic effects of S/V on the RAAS, natriuretic peptide concentrations, systolic arterial pressure (SAP), tests of renal function, and serum electrolyte concentrations in dogs with cardiomegaly secondary to MMVD. Animals: Thirteen client-owned dogs weighing 4-15 kg with American College of Veterinary Internal Medicine (ACVIM) Stage B2 MMVD. [None were cavalier King Charles spaniels.] Methods: Prospective, randomized, double-blind, placebo-controlled pilot study of S/V in dogs with ACVIM Stage B2 MMVD. Results: Thirteen dogs were recruited: S/V (n=7) and placebo (n=6). The median percentage increase in urinary aldosterone to creatinine ratio (UAldo : C) between day 0 and day 30 was significantly lower in the S/V group (12%; P=.032) as compared with the placebo group (195%). The median percentage decrease of NT-proBNP concentration from day 0 to day 30 was not statistically different between groups (P=.68). No statistical differences were seen in echocardiographic, thoracic radiographic, SAP, or serum biochemical test results measured at any time point between groups. No adverse events were observed for dogs in either group. Conclusion and Clinical Importance: Sacubitril/valsartan may provide a new pharmaceutical method to effectively inhibit the RAAS in dogs with ACVIM Stage B2 MMVD.

Two-dimensional, long-axis echocardiographic ratios for assessment of left atrial and ventricular size in dogs. L.E. Strohm, L.C. Visser, E.H. Chapel, W.T. Drost, J.D. Bonagura. J. Vet. Cardiol. August 2018; doi: 10.1016/j.jvc.2018.07.008. Quote: Introduction: Left ventricular (LV) and left atrial (LA) enlargement affect management and outcome of dogs with cardiac disease. Short-axis, two-dimensional echocardiographic (2DE) images, indexed to the aorta (Ao), are frequently used to identify cardiomegaly. Long-axis images offer complementary views of the left heart. Animals: Eighty healthy dogs [including 2 cavalier King Charles spaniels] and 25 dogs with MMVD [including 3 CKCSs]. Methods: Healthy dogs were prospectively recruited to determine reference intervals (Clinical Laboratory Standards Institute methodology) for long-axis ratios. Measurement variability and repeatability were quantified by intraclass correlation coefficient and coefficient of variation. Mean long-axis ratios from dogs with MMVD were compared with healthy dogs (unpaired t-test). In addition, the proportion of MMVD dogs exceeding the 97.5 percentile by LV/Ao and a conventional, allometric method were compared (McNemar’s test). Results: Two-dimensional echocardiographic long-axis reference intervals were as follows: left ventricular to aortic dimension (LV/Ao) 1.8–2.5; left atrial to aortic dimension (LA/Ao) 1.8–2.4, and left atrial to left ventricular dimension (LA/LV) 0.9–1.1. Intraobserver and interobserver measurement agreement was good-to-excellent (intraclass correlation coefficients ≥0.84), and day-to-day variability was low (coefficient of variations <4%). Left ventricular to aortic dimension, LA/Ao, and LA/LV were significantly greater in canine MMVD compared with healthy dogs (p<0.001). The percentages of MMVD dogs demonstrating LV dilatation by LV/Ao and conventional method were 68% and 36%, respectively (p=0.043, 95% confidence interval for difference 7.9%, 56.1%). ... No attempt was made to determine a specific long-axis ratio that would define the various stages of MMVD. ... Conclusions: Simple 2DE long-axis ratios of LV/Ao, LA/Ao, and LA/LV are repeatable and demonstrate clinical utility for identifying LV and LA enlargement in dogs with MMVD.

Interreader agreement of radiographic left atrial enlargement in dogs and comparison to echocardiographic left atrial assessment. L.Duler, N.L.LeBlanc, S.Cooley, S.Nemanic, K.F.Scollan. J. Vet. Cardiol. August 2018; doi: 10.1016/j.jvc.2018.07.004. Quote: Introduction: Assessing left atrial (LA) size is an integral part of the cardiac evaluation in dogs. Left atrial size is routinely evaluated by thoracic radiographs or echocardiography. Objectives: The objectives of the study were to assess agreement of subjective radiographic left atrial enlargement (LAE) between readers, to compare subjective radiographic LAE with echocardiography, and to assess the accuracy and reliability of commonly used Roentgen signs for LAE. Animals: One hundred one dogs [including 6 cavalier King Charles spaniels] with thoracic radiographs and echocardiography performed on the same day at a veterinary teaching hospital were retrospectively reviewed. Methods: Thoracic radiographs were reviewed by two cardiologists, two radiologists, and two small animal rotating interns. Radiographs were evaluated for the subjective presence and severity of LAE and for seven Roentgen signs. Echocardiographic LA size was evaluated objectively by the left atrial-to-aortic root ratio and LA volume indexed to body weight. Interreader agreement of radiographic LAE evaluation and agreement between radiographic LAE assessment and echocardiographic LAE were assessed by linearly weighted kappa and intraclass correlation coefficient. Results: Interreader agreement for the presence and degree of radiographic LAE ranged from moderate to substantial. The agreement between subjective radiographic LAE and echocardiographic LAE was moderate. Single Roentgen signs had poor to fair correlation with echocardiographic LAE. Conclusions: The present study found that interreader agreement for radiographic classification of LAE was substantial among specialists and moderate for all readers. Subjective, global assessment of radiographic LAE is better than using any single Roentgen sign. ... In conclusion, the results of this study support the hypothesis that interreader agreement for radiographic classification of LAE is strong, even across specialty disciplines and levels of experience. There was variable agreement between readers for application of distinct criteria of LAE and this study indicated two criteria, increased height of the cardiac silhouette and divergence of the principal bronchi, correlated best with echocardiography and had the strongest reliability among observers. Subjective radiographic LAE had only moderate agreement with echocardiographic LAE severity, regardless of objective LA size measure; however, indexed LAV showed stronger agreement than LA:Ao.

Reliability of symmetric dimethylarginine in dogs with myxomatous mitral valve disease as kidney biomarker. Alice Savarese, Monica Probo, Chiara Locatelli, Sergio Aurelio Zanzani, Alessia Libera Gazzonis, Melissa Papa, Paola Giuseppina Brambilla. Open Vet. J. August 2018;8(3):318-324. Quote: The most common cause of heart failure in the canine population is myxomatous mitral valve disease, sometimes complicated by chronic kidney disease. Many studies have been done on the use of symmetric dimethylarginine as biomarker of renal impairment in dogs affected by chronic kidney disease, few studies have examined his reliability as biomarker in dogs affected by heart diseases. Aim of this study was to evaluate symmetric dimethylarginine in dogs affected by mitral valve disease in order to assess his reliability in heart diseases. This was a retrospective case-control study on a clinical population of dogs affected by mitral valve disease (cases) vs healthy dogs (controls). Both groups underwent a complete physical evaluation, echocardiographic examination, complete blood count, biochemical panel, including serum creatinine and urea and urine analysis with protein-to-creatinine ratio. Serum was frozen and sent to IDEXX laboratories for symmetric dimethylarginine determination. General linear model was applied to data. A total number of 24 cases [including two cavalier King Charles spaniels -- 8%] and 7 controls were included. Symmetric dimethylarginine value was in the reference value in the 75% (n=18) of cases, and in the 43% (n=3) of controls. Once set symmetric dimethylarginine as dependent variable, no statistical significant differences were found for each variable considered (breed, age, sex, weight, class of cardiomyopathy, presence/absence of valvular disease, presence/absence of congestive heart failure, pharmacological therapy, creatinine and urea concentration). Blood concentration of SDMA resulted not influenced by the variables mentioned above, so it could be considered a reliable marker of early renal impairment in dogs affected by mitral valve disease. ... In conclusion, our study showed that SDMA is free from correlation with breed, age, sex, weight, presence/absence of MMVD, presence of CHF symptoms and pharmacological therapy as well. SDMA can be actually considered a reliable parameter for evaluation of renal function in dogs affected by MMVD, especially in those patients with a non-advanced stage of disease (ACVIM class B2), for which an early diagnosis of the onset of kidney failure is fundamental in order to plan a diuretic therapy. SDMA repeated measurements over time, as recommended by IRIS guidelines, are necessary (IRIS, 2016), because one determination does not allow us to exclude definitely a later onset of the renal impairment and then to be considered diagnostic in order to highlight a possible onset of CRS.

Effects of the angiotensin-converting enzyme inhibitor alacepril in dogs with mitral valve disease. Hori Y, Nakamura K, Kanno N, Hitomi M, Yamashita Y, Hosaka S, Isayama N, Mimura T. J Vet Med Sci. August 2018;80(8):1212-1218. Quote: Alacepril is a relatively novel angiotensin-converting enzyme inhibitor; however, the safety, tolerance, and efficacy of alacepril in terms of cough suppression in dogs with mitral valve disease (MVD) remain unknown. The aim of this study was to investigate the safety, tolerance, and cough suppression efficacy of alacepril in dogs with MVD. This was a multi-center, prospective study. Forty-two dogs with echocardiographic or radiographic evidence of cardiac enlargement in addition to cough were enrolled [including 4 cavalier King Charles spaniels]. Dogs were treated with alacepril (1.0-3.0 mg/kg/day) for at least 4 weeks. One dog (2.4%) developed complications, including appetite loss, lethargy, and vomiting. Thirty-six dogs were re-evaluated after 4 weeks of treatment. Cough resolved or improved in 20 dogs (55.6%) after treatment. Based on the efficacy of alacepril, the dogs were divided into an effective group (n=20) and an ineffective group (n=16). After treatment, the left ventricular end-diastolic internal diameter corrected for body weight was significantly increased from baseline in the ineffective group but was significantly decreased in the effective group. ... In addition, alacepril reduced LVIDDN in the effective group in the present study. LVIDDN is known as an indicator of cardiac hypertrophy in dogs. ... Univariate binomial logistic regression analyses showed that high atrial natriuretic peptide level, N-terminal pro-B-type natriuretic peptide level, and E wave velocity at baseline were significantly correlated with alacepril inefficacy. Alacepril as treatment for MVD is well tolerated in most dogs, and different conditions of cardiac loading may influence the effect of the drug. Alacepril is expected to improve the quality of life of dogs with early stage MVD.

 Left atrial size and contractile function in healthy dogs and dogs with chronic mitral valve disease. Lilian C. Petrus, Jacqueline R. Castro, Matheus M. Mantovani, André M. Gimenes, Caio N. Duarte3, Guilherme T. Goldfeder, Denise S. Schwartz, Maria Helena M.A. Larsson. Pesquisa Vet. Brasileira. August 2018;38(8):1622-1630. Quote: In humans, left atrial enlargement and reduced contractile functions are associated with adverse cardiovascular events and a poor prognosis in many dilatation of the left atrium occurs with the gradual evolution of chronic mitral valve disease and is well diseases. The left atrium is the most compromised cardiac chamber in dogs with chronic mitral valve disease (CMVD). Therefore, this study aimed to compare the main parameters of left atrial enlargement (left atrium/aorta ratio, left atrial diameter and volume indices) and contractile function (transmitral flow peak velocity A wave and time velocity integral, atrial fraction, and atrial ejection force) at different stages of valve disease, and correlate the left atrial diameter, volume, and contractile function indices with echocardiographic variables predictive of heart failure in dogs (transmitral flow peak velocity E wave, E wave/IVRT ratio, E wave/E´wave ratio, and E wave/A wave ratio). The results showed that progressive characterized by the left atrium/aorta ratio and left atrium volume index. The left atrial diameter and volume indices and left atrium/aorta ratio correlated positively with the transmitral flow peak velocity E wave and E wave/IVRT ratio, which are important indices of diastolic function. The left atrial contractile function indices increased as CMVD evolved. Except for the atrial fraction, the left atrial contractile function indices correlated with the left ventricular filling pressure indices.

Effect of prespecified therapy escalation on plasma NT-proBNP concentrations in dogs with stable congestive heart failure due to myxomatous mitral valve disease. Melanie J. Hezzell, Chloë L. Block, Danielle S. Laughlin, Mark A. Oyama. J. Vet. Int. Med. September 2018;doi: 10.1111/jvim.15228 Quote: Background: Treatment targeted to achieve reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) improves outcomes in human congestive heart failure (CHF) patients. Hypothesis: A pre-specified therapeutic algorithm that increased diuretic or pimobendan usage will reduce plasma NT-proBNP concentrations in dogs with CHF secondary to myxomatous mitral valve disease (MMVD). Animals: Twenty-six dogs with clinically stable CHF secondary to MMVD [including 5 cavalier King Charles spaniels]. Methods: Prospective, controlled before-and-after study. Dogs were examined up to 3 times over 21 days. Treatment was prescribed based on NT-proBNP as follows: <1500 pmol/L at baseline, no treatment adjustment at any point during the study (group 1); ≥1500 pmol/L and creatinine ≤3.0 mg/dL at baseline or SC visits, treatment escalated according to the algorithm (group 2); ≥1500 pmol/L at baseline, no treatment adjustment (group 3). Results: N-terminal pro-B-type natriuretic peptide decreased significantly in group 2 (mean change = −1736 pmol/L (95% CI, −804 to −2668), P <.001) but not in groups 1 or 3 (623 pmol/L [–631 to 1877 pmol/L], P=.14 and 685 pmol/L [–304 to 1068 pmol/L], P=.46, respectively). Serum BUN and creatinine did not change significantly between visit 0 and visit 2 in group 1 (median=23 mg/dL [range 13-32] versus 19 mg/dL [12-38], P=.72 and 1.15 mg/dL [0.70-1.40] versus 0.95 mg/dL [0.70-1.10], P=.10, respectively) or group 2 (28 mg/dL [18-87] versus 43.5 mg/dL [21-160], P=.092 and 1.10 mg/dL [0.90-2.50] versus 1.55 mg/dL [0.90-3.30], P=.062, respectively). Conclusions and Clinical Importance: Use of this treatment escalation algorithm allows effective targeting of treatment for CHF in dogs against an objective criterion.

Comparison of the mitral valve morphologies of Cavalier King Charles Spaniels and dogs of other breeds using 3D transthoracic echocardiography. Giulio Menciotti, Michele Borgarelli, Michael Aherne, Paula Camacho, Jens Häggström, Ingrid Ljungvall, Sunshine M. Lahmers, Jonathan A. Abbott. J.Vet.Int.Med. September 2018;doi: 10.1111/jvim.15252. Quote: Background: Myxomatous mitral valve disease (MMVD) is more prevalent in Cavalier King Charles Spaniels (CKCSs) compared to dogs of other breeds at a given age. Abnormal valvular stress is thought to contribute to the development and progression of MMVD, and a relationship exists between mitral valve (MV) morphology and stress acting on the valve. Objectives: To determine whether the MV morphology of healthy adult CKCSs differs from the morphology of healthy adult dogs of other breeds determined by RT-3DTTE. Animals: Thirty-five healthy CKCSs and 41 healthy dogs of other breeds. Methods: Prospective cross-sectional study. Dogs underwent physical examination, conventional echocardiography, and RT-3DTTE. RT–3DTTE datasets were analyzed using dedicated software for MV morphologic analysis. Morphologic variables were compared between CKCSs and dogs of other breeds. Results: The MV of healthy CKCSs had a smaller annulus height (0.46 ± 0.11 vs. 0.56 ± 0.17; P = .0021), tenting height (0.26 ± 0.12 vs. 0.42 ± 0.18; P < .001), tenting area (0.42 ± 0.15 vs. 0.79 ± 0.34; P < .001), normalized tenting volume (0.09 [0.05–0.13] vs. 0.14 [0.10–0.20]; P < .001), and normalized area of the posterior leaflet (0.57 ± 0.15 vs. 0.66 ± 0.18; P = .016) compared to healthy dogs of other breeds; this results in CKCSs having a flatter MV with reduced tenting, compared to the MV of other breeds. Conclusions and Clinical Importance: These morphologic features could confer a mechanical disadvantage and play a role in the predisposition of CKCSs to the early development of MMVD.

Effects of coenzyme Q10 supplementation on cardiac troponin I level, heart rate variability, and echocardiographic profiles in canine with myxomatous degenerative mitral valve disease: a pilot study. Kittipong Tachampa, Tuchakorn Lertwanakarn, Panupong Atchariyasakchai, Vichayanee Pumpitakkul, Supapatt Kireewan, Chollada Buranakarl. Thai J. Vet. Med. September 2018;48(3):443-452. Quote: The clinical benefits of Coenzyme Q10 (CoQ10) have been well documented in heart failure patients. In veterinary medicine, however, the clinical benefits of CoQ10 have not been well established in dogs with heart diseases. This study aimed to determine the effects of CoQ10 supplementation on 1) preventing myocardial injury 2) cardiac function 3) autonomic balance in dogs with myxomatous degenerative mitral valve disease (MMVD). Thirteen dogs with MMVD at ACVIM stage C were recruited in this study. Dogs were further divided into group I (Body weight [BW] < 6 kg.; n = 7) and group II (BW ≥ 6 kg.; n = 6). Cardiac troponin I (cTnI), echocardiographic examination, and 2 hours of Holter recording were performed on Day 0 and after receiving CoQ10 at 100 mg/dog twice daily for 28 days. CoQ10 caused a reduction of cTnI level in 71% of the dogs. Median cTnI tended to cause tended to decline but not significantly. Systolic function [i.e. fractional shortening (FS) and ejection fraction (EF)] increased significantly by 8 % and 9% (P < 0.05), respectively in group I after CoQ10 supplementation. Other echocardiographic parameters were not altered in either group. HRV analysis revealed no change in autonomic function and balance. cTnI negatively correlated with FS (P < 0.01) and positively correlated with LF/HF ratio (P < 0.05). In conclusion, this study demonstrated the clinical benefits [Systolic function -- fractional shortening and ejection fraction] of CoQ10 supplementation in dogs with MMVD. CoQ10 improves cardiac function in small dogs with MMVD. Finally, supplementation of CoQ10 in dogs should be based on body weight. ... In summary, the clinical benefit after 4 weeks-CoQ10 supplementations in MMVD dogs with the symptom of HF is the improvement of systolic function. CoQ10 did not alter sympathovagal balance in MMVD dogs. The cardio-protective effect of CoQ10 was not observed. Supplementation dose of CoQ10 should be based on the body weight. The large randomized clinical trials are needed to ensure this beneficial effect.

Long-term effects of repeated oral dose of ivabradine on heart rate variability in dogs with asymptomatic degenerative mitral valve disease. Prapawadee Pirintr, Nakkawee Saengklub, Vudhiporn Limprasutr, Anusak Kijtawornrat. Thai J. Vet. Med. September 2018;48(3):423-431. Quote: Degenerative mitral valve disease (DMVD) is the most common acquired cardiac disease in geriatric dogs leading to impaired cardiac autonomic activity and functions. This study aimed to evaluate the heart rate (HR), blood pressure (BP), myocardial oxygen consumption (MVO2) and heart rate variability (HRV) of dogs with DMVD stage B2 in response to long-term treatment with ivabradine, orally. Four beagles with naturally occurring DMVD stage B2 were instrumented with a 24-h Holter recorder to obtain electrocardiography and HRV, an oscillometric device to acquire blood pressure (BP), HR and myocardial oxygen consumption (MVO2) as assessed by rate-pressure product (RPP = HR x Systolic BP). Dogs were given ivabradine (1.0 mg/kg, twice daily, orally) for 3 months. Data were obtained at baseline and every 4 weeks for 12 weeks (M1 = 4 weeks, M2 = 8 weeks, and M3 = 12 weeks) after oral administration of ivabradine. The results revealed that chronic administration of ivabradine significantly decreased HR, BP, and RPP without adverse effects (P < 0.05). All indices of time- and frequency- domain of HRV at M3 were significantly increased when compared with baseline values (P < 0.05). The findings of this study imply that long-term treatment with ivabradine at a dose of 1.0 mg/kg twice daily in dogs with asymptomatic DMVD stage B2 decreased the HR, BP, MVO2 and improves HRV. This makes ivabradine potentially promising for management of elevated HR and impaired HRV in asymptomatic dogs with DMVD stage B2.

 Blood lactate increases with the progression of mitral valve disease in dogs. Jorge Cardoso Silva-Filho, Marlos G. Sousa, Evandro Zacché Pereira, Edna M.G. Ortiz, Rodrigo P. Franco, Fernando A. Rosa Aparecido Antonio Camacho. Pesquisa Veterinária Brasileira. September 2018;38(9):1781-1786. Quote: In dogs with congestive heart failure, the upregulated sympathetic tone causes vasoconstriction that impairs peripheral blood supply, therefore causing the accumulation of lactate. In this prospective cross-sectional study with a longitudinal component, blood lactate was quantified in 10 healthy and 34 myxomatous mitral valve disease (MMVD) dogs to investigate its potential use as a diagnostic and prognostic biomarker. While there were no differences in lactate concentration between control animals and stages B1 (3.31 ± 0.62mmol/L) and B2 (3.32±0.46mmol/L) dogs, significant differences were found between healthy (2.50 ± 0.69mmol/L) and both C (3.99 ± 0.47mmol/L) and D (6.97 ± 1.23mmol/L) animals. When a cut-off of 3.35mmol/L was used, lactate was able to distinguish dogs with normal and remodeled hearts with a sensitivity of 78.2% and specificity of 63.6%. Also, significant correlations existed between lactate and indicators of cardiac remodeling. Finally, animals with blood lactate <3.5mmol/L carried a better prognosis when compared with dogs in which lactate was >5.0mmol/L. Our results suggest that the progression of MMVD results in accumulation of lactate within the bloodstream, which is likely attributable to the impaired peripheral tissue perfusion. In MMVD dogs, blood lactate may be used as a surrogate for cardiac remodeling, and an increased concentration is associated with a worse prognosis regarding the time to evolve into congestive heart failure.

Phytochemical and Pharmacological Activity Profile of Crataegus oxyacantha L. (Hawthorn) - A Cardiotonic Herb. lkay Erdogan Orhan. Current Medicinal Chem. September 2018. Doi: 10.2174/0929867323666160919095519 . Quote: Crataegus oxyacantha L. (syn. C. rhipidophylla Gand.) (Rosac-eae) is one of the two medicinally recognized hawthorn species in European Pharmacopeia. Standardization of the extract prepared from the berry and flowers of the plant is required according to its oli- gomeric procyanidins. C. oxyacantha is well-known for its use in the treatment of various heart problems particularly, including heart failure in cases of declining cardiac performance equivalent to stages I and II of the New York Heart Association classification, angina pecto- ris, hypertension with myocardial insufficiency, mild alterations of cardiac rhythm, and athe- rosclerosis. C. oxyacantha has been reported to exert several other pharmacological activities such as hypotensive, antihyperlipidemic, antihyperglycemic, anxiolytic, immuno-modulatory, and antimutagenic. Oligomeric procyanidins and flavone/flavonol types of flavonoids, which are considered to be the chief groups of active substances, phenolic acids, triterpenes, fatty acids, and sterols are present in the plant. The present review aims mainly to outline car- diotonic effect of C. oxyacantha as well as its brief phytochemistry. Numerous experiments and clinical studies have underlined cardiovascular efficacy of the plant through various mechanisms including positive inotropic and negative chronotropic effects, escalation in coronary blood flow and exercise tolerance, inhibition of the enzymes such as angiotensin- converting enzyme (ACE) and phosphodiesterase, anti-inflammatory and antihyperlipidemic effects, improving status of antioxidant enzymes, etc., which support its cardioactive effi- cacy. The plant possesses several other bioactivities for human health usually concomitant to its rich polyphenolic content.

Diagnostic value of vertebral left atrial size as determined from thoracic radiographs for assessment of left atrial size in dogs with myxomatous mitral valve disease. Elizabeth L. Malcolm, Lance C. Visser, Kathryn L. Phillips, Lynelle R. Johnson. JAMVA. October 2018;253(8):1038-1045. Quote: Objective: To describe vertebral left atrial size (VLAS), a quantitative method to estimate left atrial (LA) size radiographically, and to determine its diagnostic value for prediction of echocardiographic LA enlargement in dogs with myxomatous mitral valve disease (MMVD) of varying severity. Design: Prospective observational study. Animals: 103 client-owned dogs with a left-sided systolic murmur [including 8 cavalier King Charles spaniels]. Procedures: For each dog, 3-view thoracic radiographs were obtained within 24 hours of an echocardiographic examination. The VLAS was measured on right and left lateral thoracic radiographs and compared with the left atrium-to-aortic root ratio acquired from short-axis (LA:AoSx) and long-axis (LA:AoLx) echocardiographic images. ...Visser VLAS Measurement -- Fig 1 First, a line was drawn and measured (in arbitrary units) from the center of the most ventral aspect of the carina to the most caudal aspect of the left atrium where it intersected with the dorsal border of the caudal vena cava. For the purpose of this study, the carina was defined as the radiolucent circular or ovoid structure within the trachea that represented the bifurcation of the left and right mainstem bronchi. Similar to the vertebral heart size method, a second line that was equal in length to the first was drawn beginning at the cranial edge of T4 and extending caudally just ventral and parallel to the vertebral canal (Figure 1). The VLAS was defined as the length of the second line expressed in vertebral-body units to the nearest 0.1 vertebra. ... Left atrial enlargement was defined as an LA:AoLx ≥ 2.6 or LA:AoSx ≥ 1.6. Dogs were allocated to 4 groups on the basis of MMVD severity. Results: Of the 103 dogs, 15 were assigned to the control (no echocardiographic abnormalities), 40 (2 CKCSs) to stage B1 (hemodynamically irrelevant MMVD), 26 (2 CKCSs) to B2 (hemodynamically relevant MMVD), and 22 (4 CKCSs) to C-D (MMVD with congestive heart failure) groups, respectively. Median VLAS, LA:AoSx, and LA:AoLx for the stage B2 and C-D groups were significantly greater than the corresponding medians for the control and stage B1 groups. There was a moderate positive correlation between VLAS and both LA:AoSx and LA:AoLx. Receiver operating characteristic analyses revealed that a VLAS ≥ 2.3 vertebrae was a useful predictor of LA enlargement. Intraobserver and interobserver agreements for VLAS measurements were high. Conclusions & Clinical Relevance: Results indicated VLAS was a repeatable and useful radiographic measurement for prediction of LA enlargement in dogs with MMVD. ... Results of the present study indicated that there was a significant positive correlation between VLAS and both LA:AoSx and LA:AoLx, and VLAS cutoffs of 2.3 to 2.5 vertebrae were associated with an LA:AoSx ≥ 1.6 and LA:AoLx ≥ 2.6 (or both). Thus, a VLAS ≥ 2.3 vertebrae can be used as a radiographic indicator of LA enlargement, and dogs with a VLAS ≥ 2.3 vertebrae likely have hemodynamically important MMVD. ... Results of the present study indicated that VLAS was an accurate predictor of LA enlargement in a large and diverse population of dogs with MMVD of varying severity. There was a moderate positive correlation between VLAS and echocardiographic estimates of LA size by linear measurement methods in both the long (LA:AoLx) and short (LA:AoSx) axes. Results also indicated that VLAS was a readily repeatable measurement, with a high level of agreement among measurements obtained by the same individual on multiple occasions as well as by multiple individuals.

Evaluation of the inhibitory effects of telmisartan on drug-induced renin-angiotensin-aldosterone system activation in normal dogs. M.Konta, M.Nagakawa, A.Sakatani, R.Akabane, Y.Miyagawa, N.Takemura. J. Vet. Cardiol. October 2018;20(5):376-383. Quote: Introduction: This study examined whether the angiotensin II receptor blocker telmisartan had inhibitory effects on drug-induced renin-angiotensin-aldosterone system (RAAS) activation in normal dogs. Animals: Five healthy laboratory beagles were used in this study. Methods: Each dog received amlodipine (0.5 mg/kg, q12h, PO) alone for 14 days. Starting on the next day, animals received both amlodipine and telmisartan (1.0 mg/kg, q24h, PO) for 84 days. Systolic blood pressure, heart rate, plasma biochemical variables (blood urea nitrogen, creatinine, and electrolytes), plasma renin activity, and 24-h urinary aldosterone elimination (U-Aldo) were measured before amlodipine administration; at day 0; and at days 1, 7, 14, 28, 56, and 84 of telmisartan treatment. Results: Telmisartan was associated with significant decreases in systolic blood pressure on day 56 (p=0.046), whereas heart rate did not significantly change during this treatment (p=0.061). Plasma renin activity was significantly increased on days 1, 7, 28, 56, and 84 during telmisartan administration (all p=0.04). No change in median U-Aldo was detected following telmisartan administration (p=0.241). When U-Aldo was evaluated in individual animals, two dogs displayed evidence of aldosterone breakthrough. Conclusions: Telmisartan administration did not suppress RAAS activation. The appearance of aldosterone breakthrough supports the incomplete blockade of RAAS activation.

The effects of submaximal exercise training on cardiovascular functions and physical capacity in dogs with myxomatous mitral valve disease. Saikaew Sutayatram, Chollada Buranakarl, Anusak Kijtawornrat, Kumpanart Soontornvipart, Pakit Boonpala, Prapawadee Pirintr. Thai J. Vet. Med. October 2018;48(3):433-441. Quote: Myxomatous mitral valve disease (MMVD), an important disease in senile small breed dogs, leads to deterioration of cardiovascular function and impairment of functional capacity resulting in poor quality of life. Submaximal treadmill running has been used as both cardiovascular training and testing worldwide in humans and recently in animals. The objectives of this study were to examine the effects of submaximal endurance training (ET) by treadmill running on safety, adverse events, cardiovascular adaptations, hematology, functional capacity, and the feasibility of submaximal treadmill running test and 6-minute walk test (6-MWT) in dogs with MMVD. Six adult beagle dogs with MMVD, stage B1 according to the American College of Veterinary Internal Medicine (ACVIM) guideline, were examined before the study, at weeks 4 and 8 of the ET. The cardiovascular functions assessed by echocardiography and electrocardiography, systolic blood pressure, hematology and blood chemistry profiles, and functional capacity were determined. All dogs completed all tests and ET sessions without clinical complication. ET resulted in significant improvement in physical capacity measured by submaximal treadmill running test and 6-MWT, while cardiac function parameters were not altered. Moreover, serum creatinine was significantly decreased. In conclusion, ET and submaximal exercise tests are clinically feasible. The ET can improve physical capacity in dogs with MMVD, stage B1. Therefore, supervised moderate ET and submaximal exercise tests should be incorporated in MMVD management. ... In conclusion, supervised or moderate regular exercise that is within the individual physical capacity should be performed in subclinical MMVD dogs and dogs with low routine physical activity, in order to preserve or improve physical capacity and quality of life. Also, submaximal treadmill running test and 6-MWT can be incorporated in MR management. More caution should be placed in the animals with severe cardiovascular disease and with other health problems that contradict to intense exercise.

Assessment of left atrial function in dogs with myxomatous mitral valve disease by biplane simpson’s method. M.R. Coelho, R.A.L. Muzzi, C.B. Abreu, T. Schulien, L.A.L. Muzzi, L.E.D. Oliveira, M. Cherem. Arq. Bras. Med. Vet. Zootec. October 2018;70(5):1349-1354. Quote: The relationship between the diameter of the left atrium (LA) and aorta (Ao) is considered as a prognostic factor in chronic mitral valve disease. As the left atrium is a three-dimensional structure, methods based on measurement of the chamber volume can be more accurate than linear methods.The aim of this study was to assess the feasibility of measuring LA volume with 2D echocardiography using the biplane modified Simpson (SIMP) method in 33 dogs with various classes of myxomatous mitral valve disease (MMVD), as well as to present values of LA function using the atrial diastolic and systolic volume indices (ADVI and ASVI), cardiac index (ACI) and atrial ejection fraction (AEF). We observed agreement among the LA/Ao ratio and the atrial volume indices (ADVI and ASVI) and the ACI, suggesting that the values of the variables increase as the LA/Ao ratio increases due to atrial remodeling that accompanies MMVD progression. The data demonstrated a good assessment of atrial function, allowing a better understanding of LA's role in the pathophysiology of MMVD.

Iron status of dogs with myxomatous mitral valve disease. A. Savarese, M. Probo, C. Locatelli, A.L. Gazzonis, S.A. Zanzani, G. Traini, T. Vitiello, P.G. Brambilla. Pollish J. Vet. Sci. October 2018;21(3):507-515. Quote: In humans, iron deficiency represents a relevant occurrence in heart failure (HF), with or without anaemia, and is associated with the worst outcome. Moreover, chronic kidney disease (CKD) is a well-known comorbidity of HF and is strongly associated with the risk of developing anaemia. The most common cause of HF in dogs is myxomatous mitral valve disease (MMVD). To the best of our knowledge, no studies have examined the iron status in dogs with HF, with and without CKD. The aim of this retrospective study was to evaluate the iron status in dogs affected by MMVD and how strong is the relation with HF. The retrospective study included 54 dogs with complete case records, echocardiography and laboratory analyses. Iron status was evaluated by measuring serum iron concentration (SIC), unsaturated iron binding capacity (UIBC), total iron binding capacity (TIBC), and percentage of saturation (%SAT). The prevalence of dogs showing low serum iron concentration (SIC) was 18% in the whole population, 33% in symptomatic patients, 100% in dogs with acute decompensated HF. No significant differences in SIC, UIBC, TIBC and %SAT median values were found among dogs classified in different ACVIM (American College of Veterinary Internal Medicine) classes, between symptomatic and non-symptomatic patients, and among IRIS (International Renal Interest Society) classes. Azotemic and non-azotemic patients presented a significant difference in SIC mean values (p=0.02). Generalised linear model (GLM) revealed that dogs with low SIC were at higher risk of being included in a higher ACVIM class (OR=6.383, p-value=0.014). Log-rank analysis showed shorter survival in dogs with low SIC (p=0.020), multivariate Cox analysis revealed that only HF symptoms can affect survival.

Prognostic factors in dogs with presumed degenerative mitral valve disease attending primary-care veterinary practices in the United Kingdom. M. J. Mattin, A. Boswood, D. B. Church, D. C. Brodbelt. J. Vet. Int. Med. October 2018. DOI: 10.1111/jvim.15251. Quote: Background: Prognostic risk factors were identified for dogs with degenerative mitral valve disease (DMVD) monitored by veterinary cardiologists. The value of these measurements has not been determined in the wider primary care setting. Objectives: To evaluate whether plasma cardiac biomarkers and data obtained from routine history-taking and physical examination are predictive of survival in dogs with DMVD attending primary care practice. Animals: Eight-hundred and ninety-three dogs [316 cavalier King Charles spaniels -- 35.9%] with a presumptive diagnosis of DMVD recruited from 79 primary care veterinary practices in the United Kingdom. Methods: Prospective cohort study. Primary care veterinary practitioners recorded clinical data. Plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) were measured at presentation. Cox regression models evaluated associations between risk factor variables and hazard of death (all-cause mortality and cardiac-related death). Flexible parametric models generated predicted survival probabilities for dogs with different combinations of prognostic risk factor variable values. Results: Dogs with higher NT-proBNP and cTnI concentrations, higher heart rates, older dogs, females, and those reported to be exercise intolerant, dyspneic, and diagnosed with selected comorbidities had an increased hazard of death due to any cause. Dogs with higher concentrations of plasma biomarkers, higher heart rates, and heart murmur intensities, those with exercise intolerance and those receiving potent diuretics had a higher hazard of cardiac-related death. Conclusions and Clinical Importance: Cardiac biomarkers and key clinical findings identified in this study can help primary care veterinary practitioners identify dogs with DMVD that are at highest risk of death. KEYWORDS canine, cardiac biomarker, epidemiology.

ACVIM consensus statement: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. Mark J. Acierno, Scott Brown, Amanda E. Coleman, Rosanne E. Jepson, Mark Papich, Rebecca L. Stepien, Harriet M. Syme. J. Vet. Intern. Med. November 2018;32(6):1803-1822. Quote: An update to the 2007 American College of Veterinary Internal Medicine (ACVIM) consensus statement on the identification, evaluation, and management of systemic hypertension in dogs and cats was presented at the 2017 ACVIM Forum in National Harbor, MD. The updated consensus statement is presented here. The consensus statement aims to provide guidance on appropriate diagnosis and treatment of hypertension in dogs and cats.

 Assessment of plasma lactate and core-peripheral temperature gradient in association with stages of naturally occurring myxomatous mitral valve disease in dogs. Felipe B. Soares, Gláucia B. Pereira-Neto, Rodrigo C. Rabelo. J. Vet. Emerg. & Crit. Care. November 2018; doi: 10.1111/vec.12771. Quote: Objective – To evaluate plasma lactate concentrations and core-peripheral temperature gradients as perfusion parameters in dogs with heart failure caused by myxomatous mitral valve disease (MMVD) and to determine whether the above perfusion parameters are correlated with disease stages. Design – Prospective observational study. Setting – University teaching hospital. Animals – After excluding 129 dogs because of exclusion criteria, 7 dogs with heart failure classified as stage B2 and 10 dogs classified as stage C according to the American Heart Association (AHA)/American College of Cardiology (ACC) were included in the study. Six dogs without MMVD were evaluated as the control group. Interventions – None. Measurements and Main Results – Among the evaluated parameters, the plasma lactate concentrations were increased in stage C (median 3.70 mmol/L [33.3 mg/dL], interquartile range (IQR) 0.72 mmol/L [6.5 mg/dL]) compared with those in the control (median 2.80 mmol/L [25.2 mg/dL], IQR 0.8 mmol/L [7.2 mg/dL]; P = 0.024) and stage B2 groups (median 2.70 mmol/L [24.3 mg/dL], IQR 1.8 mmol/L [16.2 mg/dL]; P = 0.045). Significant differences were not observed in the core-peripheral temperature gradients among the control, stage B2, and stage C dogs. Conclusions – Dogs with structural heart disease as a result of MMVD may have occult tissue hypoperfusion in stage C that is demonstrated by hyperlactatemia.

Comparative M-mode Echocardiographic Study of Male and Female Dogs with Degenerative Mitral Valve Disease. Atanas Pankov. Tradition & Mocenity in Vet. Med. November 2018;4(1). Quote: Via the M-mode echocardiographic study of 20 dogs, without and with pulmonary edema, various statistically significant differences were obtained in dogs separated by gender and showed the different response of the myocardium to the volume loading of the male and female dogs with MVD. ... Male dogs with MVD and without pulmonary edema: 6 (Bichon frise – 1, Pinscher – 1, Dachshund – 2, Yorkshire terrier – 1 and mixed breed – 1); male dogs with MVD and with pulmonary edema: 8 (Cavalier King Charles – 1, Pekingese – 1, mixed breed dogs – 6); female dogs with MVD and without pulmonary edema: 3 (Shih Tzu – 1 , Maltese – 1, Poodle – 1); female dogs with MVD and with pulmonary edema: 3 (Dachshund – 1, Pekingese – 1 and mixed breed dog – 1). ...  In males the remodeling is directed towards thickening of the heart walls and the development of hipercontactility as the heart disease progresses. We found the complete opposite in female dogs - the progression of MVD is associated with thinning of IVS and decreasing of its contractility. These differences between males and females in the left ventricular remodeling with the progression of MVD may require different treatment regimens. The lack of significant difference in the sizes LVFWd/Aom and LVFWs/Aom in male and female dogs, creates a model for semi remodeling. In our opinion, this model of remodeling is a result of the lack of support of the free wall which is provided to the septum by the blood pressure in the right ventricle. Thus, the increased sympathetic stimulation in dogs with pulmonary edema exerts its influence more strongly on the interventricular septum with respect to its contractility. The lack of support for the free left ventricle wall causes the increased volume load to counteract to the sympathetic stimulation, and thus not allowing it to effect its contractility. ... The echocardiographic M-mode study showed that when dividing the dogs by gender in DMVD studies, we obtained statistically significant differences for more left ventricular dimensions in male dogs as the disease progresses. When separating the dogs with MVD by gender, we identified a different miocardial response of males and females to volume overload. It is possible that such a different myocardial reactivity in this disease is associated with the choice of different treatment regimens in male and female dogs.

Is treatment with pimobendan associated with an increased risk of arrhythmias in dogs with heart disease? S. Hillyer, M. Hezzell, E. Place. Vet. Rec. December 2018. DOI:10.1136/vr.k5167 Quote: Pimobendan is a positive inotrope and balanced vasodilator via its actions as a calcium sensitiser and phosphodiesterase III inhibitor, respectively.1 There is strong evidence for its use in the treatment of dogs with congestive heart failure (CHF), with multiple clinical trials demonstrating a resultant increase in survival time.2-5 However, the use of pimobendan for treatment of heart disease in people has been associated with increased risk of arrhythmias.6 This effect is attributed to the racemic nature of pimobendan resulting in D and L chiral enantiomers, with the L-optical isomer having a significantly greater calcium sensitising effect.7-9 There is limited data available regarding any effect of treatment with pimobendan on the risk of arrhythmias in dogs. The aim of this article is to analyse the available data to determine whether evidenced-based conclusions can be drawn. ... While adverse events were noted and reported the [EPIC] study did not specifically investigate the incidence of arrhythmias; therefore it is possible that their presence were missed. Additionally, the summary of adverse events reported does not specifically list ‘arrhythmia’ and instead lists ‘tachycardia’ and further, a large proportion of the adverse events are categorised as ‘other’ (124/196). ... Furthermore, the study was designed to investigate the effect of pimobendan on the time to CHF not arrhythmias. However, auscultation performed throughout the study might have detected the occurrence of arrhythmias, and adverse events related to arrhythmias are not reported.

Breed characteristics in cardiac reverse remodeling and left ventricular systolic function after mitral valve repair in dogs. H. Takano, K. Takamura, K. Mamada, M. Uechi. 28th ECVIM-CA Congress. J. Vet. Int. Med. December 2018; doi: 0.1111/jvim.15372; pg. 10;ESVC-O-8. Quote: Mitral valve repair (MVR) can be considered as a treatment option for severe myxomatous mitral valve disease in dogs, and significant cardiac reverse remodeling (CRR) after a repair has been reported. Although predisposed breeds and the breed-specific progression of this disease have been investigated, the breed characteristics and the outcome of cardiac reverse remodeling for MVR remain unclear. We hypothesized that there is a difference in breed characteristics in CRR for MVR, and some insights for suitable surgical timing can be obtained. The consecutive medical records of 117 dogs that underwent MVR between November 2016 and July 2017 at JASMINE Veterinary Cardiovascular Medical Center were reviewed. ... The dogs were divided into three groups — Cavalier King Charles Spaniels (CKCSs), Chihuahuas, and all dogs — and parameters were compared amongst the groups. A total of 99 dogs were included in the analysis, after the exclusion of 1 dogs that died before the 1-month postoperative review, 6 dogs with missing data, and 2 dogs that underwent secondary surgery. The overall survival rate 1 month after surgery was 91.5%. In multiple comparison analysis, the CKCSs were significantly younger, had higher body weight, preoperative VHS, postoperative normalized left ventricular end-diastolic and end-systolic diameters, and had lower postoperative FS compared amongst the groups. Although the pre- and postoperative number of cardiac medications in the CKCSs tended to be high, no significant difference was observed amongst the groups. Although the heart failure classification did not differ amongst the groups, the CKCSs were significantly younger than the dogs in the other groups. Therefore, the progression of mitral regurgitation is considered to have occurred at an earlier age in the CKCSs and this finding is consistent with previous reports. Stronger postoperative irreversible cardiac dilation and systolic dysfunction observed in the CKCSs amongst the groups, with a similar reduction of regurgitation could be explained by severe myocardial remodeling, and these findings might be hard to detect preoperatively because of regurgitation. These results suggest that MVR should be recommended earlier for CKCSs compared with other breeds to minimize LV systolic dysfunction and dilation after surgery.

 Epidemiological, clinical, echocardiographic features and prognosis of dogs with a thrilling murmur related to degenerative mitral valve disease: 374 cases (2006-2017). C. Poissonnier, M. Klam, E. Trehiou-Sechi, V. Arqued-Soubeyran, J.L. Pouchelon, R. Tissier, L. Desquilbet, V. Chetboul. 28th ECVIM-CA Congress. J. Vet. Int. Med. December 2018; doi: 0.1111/jvim.15372; pg. 52;ESVC-P-11. Quote: Degenerative mitral valve disease (DMVD) is the most common acquired heart disease in small-breed dogs, resulting in poor apposition of the mitral valve (MV) leaflets during systole. This leads to MV regurgitation, which is clinically detected as a left apical systolic heart murmur, the intensity of which is classically classified according to a 6-grade scheme. Past studies have shown that an increase in heart murmur intensity over time is associated with worsening of DMVD lesions, with thrilling murmurs (TM, i.e., of grade V/VI and VI/VI) associated with more severe disease. The objectives of this retrospective study were to characterize the epidemiological, clinical, and echocardiographic features of dogs with TM related to DMVD, and to identify parameters associated with survival. ... The study population consisted of 374 dogs (median age at detection of TM=10.7 years [IQR=8.6-12.5], male-to-female ratio=1.8). The most represented breeds were Cavalier King Charles Spaniel, Yorkshire Terrier, Poodle and Chihuahua. ... According to the ACVIM classification, 24%(82/338) were in stage B2, 61% (207/338) in stage C and 7% (22/338) in stage D. Chordae tendineae rupture was identified in 75% (254/338) of the included dogs, severe pulmonary hypertension (systolic pulmonary arterial pressure >75 mmHg) in 27% (90/337), and tachyarrhythmias in 46% (157/338). Regurgitation fraction (RF), assessed using the PISA method, was >30% for all dogs (median value=70%[IQR=59-76]), which is consistent with moderate to severe MV regurgitation. Among the 265/338 dogs for which a follow-up was available, 173/265 (65%) died. 68% (118/173) of deaths were cardiac in origin (CD) with a median time to CD of 25.1 months after diagnosis [IQR=8.3-52.7]. Univariate analyses revealed that RF>70%, left atrium to aorta ratio≥1.5 at end-diastole, left ventricular dilation, ACVIM stages, presence of arrhythmias, and collapse were significantly associated with time to CD. Dogs from ACVIM stage B had a median time to decompensation of 15.9 months [IQR=8.2-45.0], and a median time to CD of 42.9 months [IQR=19.1-56.1] versus 17.8 [IQR=5.4-38.4] for dogs from stage C and D. In conclusion, this study confirms that dogs with TM related to DMVD, including dogs from ACVIM stage B, usually have a severe form of the disease, with a majority of dogs presenting with chordae tendineae rupture, pulmonary hypertension, and severe MV regurgitation.

A radiographic measurement of left atrial size in dogs. Xavier Sánchez Salguero, David Prandi, Francisco Llabrés-Díaz, Edgar Garcia Manzanilla, Claudio Bussadori. Irish Vet. J. December 2018;71:25. Quote: Background: The dimensions of the left atrium in cases with mitral regurgitation are an indirect measurement of its severity. The objective of this study was to evaluate the value of a new radiographic measurement, the radiographic left atrial dimension (RLAD), for detecting left atrial enlargement (LAE) in dogs. Thirty one dogs without LAE [including one cavalier King Charles spaniel] and 46 dogs with LAE [none were cavaliers] were recruited in a prospective fashion. Reference left atrium dimension was measured by standard left atrium to aorta ratio (LA/Ao) by 2D echocardiography. LAE was considered if LA/Ao > 1.6. Left atrium dimension was then quantified on lateral radiographs by measuring RLAD. Vertebral heart size (VHS) was measured and RLAD was obtained by drawing a line bisecting the 90 degrees angle defined by the long and short cardiac axes lines of the VHS, up to the dorsal edge of the left atrium and comparing its length to T4’s vertebral body length. The correlation of VHS and RLAD methods with LA/Ao was estimated, as well as their sensitivity and specificity for detecting LAE. Receiver Operating Characteristic (ROC) curves were used to estimate the optimal decision criteria for each method. Results: A positive correlation was observed between RLAD and LA/Ao (r = 0.82). RLAD’s sensitivity and specificity for detecting LAE when evaluated at the optimal cut-off value, 1.8 vertebrae, were 93.5 and 96.8% respectively. RLAD showed high reproducibility and repeatability. Conclusion: RLAD appears to be a clinically useful radiographic measurement for evaluating left atrial dimensions. RLAD would provide clinicians with a simple and cost-effective tool for evaluating and monitoring LAE.

Plasma humanin as a prognostic biomarker for canine myxomatous mitral valve disease: a comparison with plasma NT-proBNP. K. Mangkhang, V. Punyapornwithaya, P. Tankaew, W. Pongkan, N. Chattipakorn, C. Boonyapakorn. Polish H. Vet. Sci. December 2018;21(4):673-680. Quote: Myxomatous mitral valve disease (MMVD) is a cardiac condition commonly found in older dogs. The disease process can lead to heart failure (HF). In HF, an increase of reactive oxygen species (ROS) and abnormal mitochondrial activity, as well as apoptosis, have been reported. Humanin (HN) is a polypeptide that has a cardioprotective effect against apoptosis and oxidative stress. The purposes of this study were (1) to investigate the potential role of plasma HN as a cardiac biomarker to predict disease progression of MMVD, and (2) to compare plasma HN concentrations with plasma NT-pro BNP concentrations. Thirty-one dogs were included in the study. The dogs were separated into four groups: Group 1 was healthy dogs (n = 8), Group 2 was MMVD class B (n = 8), Group 3 was MMVD class C (n = 8), and Group 4 was MMVD class D (n = 7). All dogs were given a physical examination, thoracic radiography, echocardiography, and samples of their blood were collected for hematology and blood chemistry analysis. Levels of plasma HN and plasma NT-proBNP were also investigated. The results showed that plasma HN levels were lower in the dogs with MMVD and that lower plasma HN levels were associated with greater severity of MMVD-induced HF. It was possible to observe changes in plasma HN levels at a less severe disease stage than plasma NT-proBNP in dogs with MMVD. These findings suggest that a decreased plasma HN level can be used as a biomarker to identify dogs with MMVD-induced HF.

Diagnose und Klassifizierung eines Patienten mit Mitralklappenerkrankung. (Diagnosis and classification of a patient with mitral valve disease). Ralph Wendt, Jan-Gerd Kresken, Michael Deinert. kleintier konkret. 2018; DOI: 10.1055/a-0740-4069. Quote: Chronic degenerative mitral valve disease (DMVD) is the most common acquired heart disease in the dog. This is a chronic one myxomatous degeneration of the mitral valve, which is a thickening of the valve and causes incomplete closure of the valve leaflets during systole. The result is mitral valve regurgitation. The chronic degenerative mitral valve disease comes especially with representatives of small breeds of dogs often before, but it is now in the literature as well described in larger breed dogs. This reflects reflect the experiences of the authors. The older the dog is the more likely mitral valve degeneration becomes to be determined. The severity and progression of the disease will vary strong: Long periods without drug therapyare possible. Despite the creeping progression, it can the correct therapy long phases with a high Enabling quality of life. With the left heart failure and the subsequent right heart failure after pulmonary hypertension (PAH, pulmonary arterial hypertension) the disease has reached the terminal stage.

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2019

A pilot study investigating circulating trimethylamine N-oxide and its precursors in dogs with degenerative mitral valve disease with or without congestive heart failure. Emily T. Karlin, John E. Rush, Lisa M. Freeman. J. Vet. Intern. Med. January 2019; doi: 10.1111/jvim.15347. Quote: Background: Pathophysiologic mechanisms for the development and progression of degenerative mitral valve disease (DMVD) remain elusive. Increased concentrations of circulating trimethylamine N-oxide (TMAO) and its precursors choline and l-carnitine are associated with the presence and severity of heart disease in people. Objectives: To determine if differences exist in plasma concentrations of TMAO, choline, or l-carnitine among dogs with DMVD and congestive heart failure (CHF), dogs with asymptomatic DMVD, and healthy control dogs. Animals: Thirty client‐owned dogs: 10 dogs with CHF secondary to DMVD [including one cavalier King Charles spaniel], 10 dogs with asymptomatic DMVD [including 3 CKCSs], and 10 healthy control dogs. Methods: A pilot cross-sectional study in which echocardiography was performed and fasting plasma concentrations of TMAO, choline, and l-carnitine (total and fractions) were measured. Results: TMAO, total l-carnitine, carnitine esters, and carnitine esters to free carnitine ratio (E/F ratio) were significantly higher in dogs with CHF compared to those with asymptomatic DMVD. TMAO, choline, total l-carnitine, carnitine esters, free carnitine, and E/F ratio were significantly higher in dogs with CHF compared to healthy controls. Conclusions and Clinical Importance: Dogs with CHF secondary to DMVD had higher concentrations of TMAO compared to both asymptomatic DMVD dogs and healthy controls. Larger prospective studies are warranted to determine if TMAO plays a role in the development or progression of DMVD or CHF. ... Despite these limitations, our results showed that circulating concentrations of TMAO and its precursors, choline and L-carnitine, are higher in dogs with DMVD/CHF compared to healthy dogs, and concentrations of TMAO and L-carnitine are higher in dogs with DMVD/ CHF compared to those with asymptomatic DMVD. It remains unknown whether increased concentrations of TMAO, choline, and L-carnitine represent a cause or effect of either DMVD or CHF. Therefore, future research on interactions between diet and the GI microbiota is warranted to determine whether TMAO plays a potential role in the development or progression of DMVD or CHF or if it is merely a result of these conditions.

Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization. Guillermo López-Lluch, Jesús del Pozo-Cruz, Ana Sánchez-Cuesta, Ana Belén Cortés-Rodríguez, Plácido Navas. Nutrition. January 2019; doi:10.1016/j.nut.2018.05.020. Quote: Objectives: Bioavailability of supplements with coenzyme Q10 (CoQ10) in humans seems to depend on the excipients of formulations and on physiological characteristics of the individuals. The aim of this study was to determine which factors presented in CoQ10 supplements affect the different response to CoQ10 in humans. Methods: We tested seven different supplement formulations containing 100 mg of CoQ10 in 14 young, healthy individuals. Bioavailability was measured as area under the curve of plasma CoQ10 levels over 48 h after ingestion of a single dose. Measurements were repeated in the same group of 14 volunteers in a double-blind crossover design with a minimum of 4 wk washout between intakes. Results: Bioavailability of the formulations showed large differences that were statistically significant. The two best absorbable formulations were soft-gel capsules containing ubiquinone (oxidized CoQ10) or ubiquinol (reduced CoQ10). The matrix used to dissolve CoQ10 and the proportion and addition of preservatives such as vitamin C affected the bioavailability of CoQ10. Although control measurements documented that all formulations contained 100 mg of either CoQ10 or ubiquinol, some of the participants showed high and others lower capacity to reach high increase of CoQ10 in blood, indicating the participation of individual unknown physiological factors. Conclusion: This study highlights the importance of individually adapted selection of best formulations to reach the highest bioavailability of CoQ10 in humans.

Association between atrial fibrillation and right-sided manifestations of congestive heart failure in dogs with degenerative mitral valve disease or dilated cardiomyopathy. Jessica Ward, Wendy Ware, Austin Viall. J. Vet. Cardio. February 2019;21(1):18-27. Quote: Introduction: To determine whether dogs with atrial fibrillation (AF) are more likely to develop right-sided manifestations of congestive heart failure (R-CHF) than dogs without AF. Animals: Two hundred twenty dogs diagnosed with congestive heart failure (CHF) secondary to degenerative mitral valve disease (DMVD, n = 155) [19 cavalier King Charles spaniels] or dilated cardiomyopathy (DCM, n = 65) at a referral institution. Methods: Medical records were reviewed to extract relevant clinical and echocardiographic data. Results: Fifty dogs had AF at the time of CHF diagnosis, including 17/155 (11.0%) dogs with DMVD and 33/65 (50.8%) dogs with DCM. Sixty dogs had R-CHF evidenced by cavitary effusions. Among DMVD dogs, R-CHF occurred in 13/17 (76.5%) dogs with AF compared with 10/138 (7.2%) dogs without AF; among DCM dogs, R-CHF occurred in 24/33 (72.7%) dogs with AF compared with 13/32 (40.6%) dogs without AF. Dogs with AF were more likely to manifest R-CHF signs than dogs without AF (p < 0.0001 for DMVD; p = 0.0125 for DC). The presence of AF, diagnosis of DCM, and moderate to severe tricuspid regurgitation were associated with R-CHF in multivariate analysis. AF was the strongest predictor of R-CHF (odds ratio, 14.44; 95% confidence interval, 5.75–36.26). Conclusions: Dogs with AF are more likely to manifest R-CHF than dogs without AF. Cavitary effusions are an expected finding in approximately three-quarters of dogs with AF and CHF secondary to either DCM or DMVD.

Comparison between real-time 3-dimensional and 2-dimensional biplane echocardiographic assessment of left atrial volumes in dogs with myxomatous mitral valve disease. Anna Tidholm, Anna Bodegård-Westling, Katja Höglund, Jens Häggström, Ingrid Ljungvall. J. Vet. Int. Med. January 2019; doi: 10.1111/jvim.15408. Quote: Background: Assessment of left atrial (LA) size is important in medical decision making and prognostication in dogs with myxomatous mitral valve disease (MMVD). Real-time 3-dimensional (RT3DE) and 2-dimensional echocardiographic (2DE) methods may be used to assess LA size. Objectives: To compare measured LA volumes obtained by RT3DE with those calculated by biplane Simpson's modified method of discs (SMOD) and the area-length method (ALM) using the same RT3DE acquisition with the same timing. Animals: One hundred twenty-one privately owned dogs [24 cavalier King Charles spaniels] with naturally occurring MMVD. Methods: Prospective observational study comparing LA volumes indexed to body weight using RT3DE and 2DE-based biplane SMOD and ALM. Agreement between methods was evaluated using Bland-Altman plots and linear regression analyses. Results: Estimations of LA volume using SMOD or ALM did not show good agreement with RT3DE-derived measurements. Absolute differences between methods increased with increasing LA volume, but SMOD underestimated whereas ALM overestimated calculated volumes compared to RT3DE-derived measurements. The difference in LA volume between RT3DE and the biplane methods showed a systematic underestimation of 7% for SMOD and a systematic overestimation of 24% for ALM. Comparison of LA volumes obtained by SMOD and ALM did not show good agreement. The ALM yielded 30% larger LA volumes compared to SMOD. Conclusion and Clinical Importance: In comparison with RT3DE, SMOD systematically underestimated whereas ALM systematically overestimated LA volumes in dogs with MMVD. Because the systematic difference between RT3DE and SMOD was only 7%, SMOD might be considered the method of choice. ... In conclusion, neither of the 2 biplane estimations of LA volumes corrected for BW using SMOD or ALM showed good agreement with RT3DE-generated LA volumes obtained from the same acquisition. The absolute differences between methods increased with increasing size of LA, but the percentage differences were reasonably constant over the range of LA sizes of dogs included in the study. The systematic difference of % between RT3DE and SMOD probably is of little consequence in the clinical setting, whereas the 24% difference between RT3DE and ALM and the 30% difference between SMOD and ALM presumably are of more clinical importance. The 2 2DE-based methods should not be used interchangeably because good agreement between methods was not found.

Coughing in dogs: what is the evidence for and against a cardiac cough? L. Ferasin, C. Linney. J. Sm. Anim. Pract. January 2019;doi: 10.1111/jsap.12976. Quote: “Cardiac cough” is defined as a cough that is associated with cardiac disease, but not necessarily congestive heart failure. It is important to emphasise that while cough and heart disease often occur at the same time, they are not necessarily linked and cough may be secondary to another disease process. ... Cardiomegaly with marked left atrial (LA) dilation and main stem bronchus compression is often cited as a possible cause of “cardiac cough” but it has been shown that LA dilation and LA pressure alone may not be sufficient to cause cough secondary to bronchial compression without concurrent underlying tracheobronchial disease. ... Therefore, the explanation that cough is caused by cardiomegaly and concomitant airway abnormalities, rather than pulmonary oedema, appeared to be supported also by these results. ... Concomitant cardiomegaly and airway disease represents the most important morbidity factors leading to coughing in dogs with MMVD and, since airway disease is more commonly observed in small geriatric dogs, it can be speculated that cardiomegaly is more likely a cause of cough in patients with preexisting airway disease than in young individuals with a healthy respiratory system (Ferasin et al. 2013). ... For smaller dogs, in which mitral valve disease is more prevalent, there is also an increased risk of lower airway disease, and the combination of these together is considered a likely cause of “cardiac cough.” In contrast, progressive cardiomegaly may eventually lead to mechanical compression of the bronchial tree and trachea, either because of global cardiomegaly or isolated LA dilation, causing activation of cough receptors and therefore coughing. In this particular situation, it is important to consider that the mechanism may be unrelated to pulmonary oedema. ... Cough should no longer be considered a major clinical sign attributable to pulmonary oedema, since lethargy, e ercise intolerance and tachypnoea/dyspnoea are much more specific signs of left-sided CHF. ... In conclusion, cough in the absence of tachypnoea and/or dyspnoea should lead the clinician to consider that it is most likely a feature of primary respiratory disease rather than a cardiac disease.

Cardiorenal and endocrine effects of synthetic canine BNP1-32 in dogs with compensated congestive heart failure caused by myxomatous mitral valve disease. Mariko Yata, Hans S. Kooistra, Niek J. Beijerink. J. Vet. Intern. Med. January 2019; doi: 10.1111/jvim.15416. Quote: Background: The effects of synthetic brain natriuretic peptide (BNP1-32) on cardiorenal and renin angiotensin aldosterone system in dogs with naturally occurring congestive heart failure (CHF) are unknown. Objectives: To evaluate the cardiorenal and endocrine effects of SC administered synthetic canine BNP1-32, with or without furosemide, in dogs with CHF caused by myxomatous mitral valve disease (MMVD). Animals: Seven client-owned male dogs [including two cavalier King Charles spaniels] with compensated American College of Veterinary Internal Medicine stage C CHF caused by MMVD on chronic treatment with furosemide, benazepril, and pimobendan. Methods: A single-dose, crossover, pilot study. Each dog received a dose of BNP1-32 (5 μg/kg), furosemide (2 mg/kg), and both BNP1-32/furosemide (5 μg/kg and 2 mg/kg, respectively) SC with a 2-week washout period among each treatment. Between- and within-treatment effects were evaluated using linear mixed modeling with restricted maximum likelihood estimation and evaluation of least square differences. Results: Rapid aborption of BNP1-32 and a corresponding rise in urinary cyclic guanosine monophosphate excretion was observed at 1-2 hours after any treatment containing BNP1-32 (P <.05). However, BNP1-32 did not influence measured cardiorenal variables. Plasma aldosterone concentrations were below quantifiable levels in majority of the samples. Conclusions and Clinical Importance: No beneficial cardiorenal effects were detected. ... These findings suggest peripheral natriuretic peptide resistance and raise further questions regarding the role of BNP1-32 in both the pathophysiology and treatment of CHF in dogs with MMVD. ... It is possible that dogs with chronic CHF have a reduction in natriuretic peptide responsiveness.

Effects of high-dose alacepril on left atrial pressure and central aortic pressure in awake dogs with mitral valve regurgitation. Seijirow Goya, Tomoki Wada, Kazumi Shimada, Daiki Hirao, Ryou Tanaka. Vet. J. January 2019;245(1):7-11. Quote: The purpose of this study was to clarify how alacepril in amounts greater than those recommended on the product labeling approved by drug regulatory agencies affects left atrial pressure (LAP) and central aortic pressure in dogs with experimentally induced mitral valve regurgitation (MR). Six healthy Beagle dogs were surgically induced for MR and received alacepril at either 1.5 mg/kg/12-h (3.0 mg/kg/day) or 3.0 mg/kg/12-h (6.0 mg/kg/day) per one administration for seven days. After a four-week washout period, another dosage was administrated as a crossover study. Dogs were randomised to receive 3.0 mg/kg/day or 6.0 mg/kg/day first. LAP and central systolic (SAP), mean (MAP), and diastolic (DAP) aortic pressure were measured for 24-h before and during the administration of alacepril. The earliest decreases in SAP, MAP, and DAP with 6.0 mg/ kg/day were observed on days 4, 4, and 5, respectively. With 3.0 mg/kg/day, the earliest decrease in DAP was observed on day 7. The maximum LAP was decreased on days 5 and 7 with 6.0 mg/kg/day. The mean LAP was decreased on day 7 with 6.0 mg/kg/day. In conclusion, the administration of alacepril at 6.0 mg/kg/day reduced the LAP and central aortic pressure within several days.

Breed-specific reference ranges for standard echocardiographic measurements in salukis. S. Giraut, J. Häggström, L. L. E. Koskinen, H. Lohi, M. Wiberg. J. Sm. Anim. Pract. January 2019; doi: 10.1111/jsap.12975. Quote: Well-established echocardiographic diagnostic criteria are important for the identification and early diagnosis of cardiac disease in dogs (Dukes-McEwan et al. 2003, Meurs 2010, Chetboul & Tissier 2012, Birkegård et al. 2016, Wess et al. 2017). Many common echocardiographic variables are presumed to be influenced by breed, and breed-specific reference ranges are likely to be more accurate than ranges generated from dogs of all-breeds (Bavegems et al. 2007, Wess et al. 2010, Stephenson et al. 2012, Misbach et al. 2014, Dickson et al. 2016). In salukis, a larger left ventricle (LV) might be the result of cardiac disease, such as myxomatous mitral valve disease or dilated cardiomyopathy (DCM), causing volume overload, but might also be an example of athletic heart typical for sighthounds (Page et al. 1993, Della Torre et al. 2000, Cornell et al. 2004, Bavegems et al. 2007, Seckerdieck et al. 2015).

Cardiac Arrhythmias in Dogs with Mitral Regurgitation due to Myxomatous Mitral Valve Disease. Hadi Alihosseini, Ekrem Çağatay Çolakoğlu, Ali Evren Haydardedeoğlu, Doğukan Özen, Arif Kurtdede. Erciyes Üniv. Vet. Fak. Derg. January 2019;16(2):98-102. Quote: Cardiac remodeling in dogs with mitral regurgitation (MR) may stimulate several supraventricular arrhythmi-as. The purpose of this study was to point out the potential of cardiac arrhythmias related to remodeling in dogs with MR. The study was carried out in 30 client-owned dogs [including 9 Cavalier King Charles spaniels] with the signs of myxomatous mitral valve disease (MMVD). Routine clinical applications including cardiac examination, blood analyses and imaging procedures were performed. The inclusion criterion was the presence of left apical heart murmur. While group 1 (n:10) was defined as mild MR with regurgitant jet occupying less than 20% of the left atrial area, group 2 (n:10) was defined as moderate MR with regurgi-tant jet occupying between 20-40% of the left atrial area. Group 3 (n:10) was also defined as severe MR with regurgi-tant jet occupying more than 40% of the left atrial area. ECG variables were recorded by a 6-lead ECG machine. Ar-rhythmias in dogs with MMVD included Sinus Tachycardia (n:11, 37%), Sinus Arrhythmia (n:10, 33%), Supraventricular Premature Complex (n:4, 13%), Atrial Fibrillation (n:4, 13%), Tachycardia-Bradycardia Syndrome (n:2, 6%), 2nd Degree Atrioventricular Block (n:2, 6%), Left Bundle Branch Block (n:1, 3%) and Sinus Pause (n:1, 3%). No significant associa-tion were found between the presence of cardiac arrhythmias and the severity of MR groups (p>0.05). In conclusion, cardiac remodeling in dogs with MR can induce several supraventricular arrhythmias. Although we could not find signif-icant correlations between the presence of cardiac arrhythmias and the severity of MR groups, further studies with larger case series are required.

Effect of atorvastatin on oxidative stress and inflammation markers in myxomatous mitral valve disease in dogs: A comparison of subclinical and clinical stages. Patchaya Thassakorn, Papras Patchanee, Wanpitak Pongkan, Nipon Chattipakorn, Chavalit Boonyapakorn. J. Vet. Pharm. & Therapeutics. January 2019;42(5):1-10. Quote: Myxomatous mitral valve disease (MMVD) is the most common acquired cardiac disorder found in dogs. The disease process can lead to heart failure (HF) and has been found to be associated with oxidative stress and inflammation. Statins exert antioxidant and anti-inflammatory effects in human HF patients. However, the beneficial effects of statins in MMVD dogs are still unclear. ... Our hypothesis was that atorvastatin administration is associated with a decrease in a marker of oxidative stress, a pro-inflammatory cytokine and improvements in heart size and other echocardiographic indices of cardiac function in dogs with MMVD. ... Thirty MMVD dogs [none were cavalier King Charles spaniels] were enrolled in the study and were divided into two groups: MMVD without HF dogs (n = 15) and MMVD with HF dogs (n = 15). Atorvastatin (8 mg kg−1 day−1) was administered orally to all dogs for 4 weeks. All dogs underwent physical examination and cardiac examination at the beginning and end of the experiment, including baseline values for hematology, blood chemistry profile, lipid profile, N-terminal pro B-type natriuretic peptide, oxidative stress marker (8-isoprostane), and inflammatory marker (tumor necrosis factor alpha). The results showed that atorvastatin reduced plasma cholesterol levels in both groups. In addition, plasma concentrations of 8-isoprostane, tumor necrosis factor alpha, and N-terminal pro B-type natriuretic peptide were significantly lower after atorvastatin administration, but only in MMVD dogs in the HF group. Atorvastatin found to be associated with possible antioxidant and inflammatory effects in dogs with HF secondary to MMVD. ... Our studies provide interesting results that suggest that atorvastatin in naturally MMVD induced-HF dogs might reduce some markers of oxidative stress and systemic inflammation as well as decrease NT-proBNP levels. However, further study is needed to confirm the beneficial effects of atorvastatin on MMVD dogs, and investigate whether this translates to a clinical benefit especially designs using placebo controlled randomized clinical trials. ... The potential benefits of statins in dogs with HF merits further investigation in larger, placebo-controlled studies.

CT-based anatomical features of large airway and heart volume in dogs of different body size. T.Uehara, K.Orito, Y.Fujii. Vet. J. April 2019;246(1):21-26. Quote: Differences in the prevalence and clinical signs of cardiopulmonary diseases in dogs of different body sizes have been reported. It was hypothesized that the anatomical features of the heart and large airways varies by body size in dogs and might influence clinical manifestations of cardiopulmonary disease. The purpose of this study was to compare various anatomical features of the thoracic organs (heart, trachea, etc.) in dogs according to body size using computed tomography (CT) images. Dogs without clinically significant heart and lung disease (n = 226) [including 2 cavalier King Charles spaniels] that underwent CT were divided into three groups on the basis of bodyweight: small (<7 kg), medium (7–20 kg), and large (>20 kg). The following parameters were calculated from CT images using OsiriX and compared among groups: relative heart volume (heart volume/thoracic volume), relative distance from mainstem bronchi to vertebra (distance from mainstem bronchi to vertebra/heart length), longitudinal/transverse diameter ratio of trachea, and angle of bronchus. Small dogs had larger hearts relative to their thorax, a shorter distance from the heart to the vertebra, and laterally-elongated oval-shaped tracheas, compared to medium and/or large dogs. These differences in anatomical features according to body size may potentially contribute to different clinical manifestations when the heart is enlarged. ... The results of our study supported the hypothesis that anatomical features of the heart and large airways are influenced by body size. The two main anatomical features related to the heart investigated were the relative heart volume and relative DMBV [distance from mainstem bronchi to vertebra]. A significant difference in the relative heart volume was found between small/medium and large dogs, and the smaller the dog, the larger the heart volume relative to that of the thoracic cavity. The results of this study also indicated that smaller body size was associated with shorter distance from the mainstem bronchi to the dorsal side of the vertebra, relative to the size of the heart. Although dog breed significantly influenced the results, bodyweight was independently associated with relative heart volume and relative DMBV. An early clinical finding in dogs with degenerative mitral valve disease was left atrial enlargement. These anatomical characteristics in small dogs i.e. relatively large heart and short distance from the mainstem bronchi to the vertebra, might compress mainstem bronchi when the left atrium is enlarged, thus triggering coughing, a common clinical sign of this disease. ... Highlights: • Small dogs had a larger heart volume than large dogs. • The distance from the mainstem bronchi to the vertebra was short in small dogs. • Small dogs had oval-shaped trachea compared to large dogs.

Vertebral heart size in healthy Australian cattle dog. Marilia Gabriela Luciani, Jéssica Aline Withoeft, Helena Mondardo Cardoso Pissetti, Livia Pasini de Souza, Marina Silvestre Sombrio, Eloisa Carla Bach, Wilfried Mai, Thiago Rinaldi Müller. Anat. Histol. Embryol. February 2019; doi: 10.1111/ahe.12434 Quote: The vertebral heart score or size (VHS) measurement is routinely used to provide a more objective measurement of cardiomegaly in dogs. However, breed or body conformation can influence the VHS. ... Therefore, reference ranges for different breeds (or for different thoracic conformations) need to be established. ... To assess the specific VHS for the Australian Cattle Dog, left-to-right lateral, right-to-left lateral, dorsoventral and ventrodorsal thoracic radiographs from 20 individuals free from cardiac and pulmonary disease were obtained. The mean VHS was significantly higher in Australian Cattle Dog (10.5 ± 0.4 vertebrae), when compared with the average VHS for 100 normal dogs of different breeds that had been initially published (9.7 ± 0.5 vertebrae). This emphasizes the importance of breed-specific VHS ranges. In our study group of normal Australian Cattle Dogs, the mean VHS was 10.5 ± 0.5 vertebrae (mean ±SD) on right lateral and 10.3 ± 0.5 vertebrae on left lateral radiographs. The VHS on right lateral views was significantly larger than on left lateral views. The VHS was 10.5 ± 0.6 vertebrae on dorsoventral and 11.1 ± 0.6 vertebrae on ventrodorsal radiographs. The VHS on ventrodorsal views was significantly larger than on dorsoventral views. ... In conclusion, this study documents the normal VHS features of a group of healthy non-active Australian Cattle Dog. The mean VHS in this breed is higher than the initial reference range published in 1995, which emphasizes the importance of breed-specific VHS when assessing radiographs for cardiac disease. There were mean VHS differences related to positioning, but there was no VHS variation related to sex or body weight. These data may be useful in the diagnosis of cardiac diseases that affect the Australian Cattle Dog.

Use of measurements from thoracic radiographs to identify high mean left atrium pressure in dogs with myxomatous mitral valve disease. Flavio Shigueru Jojima, Stephany Buba Lucina, Alexandre Leseur Santos, Marlos Gonçalves Sousa, Tilde Rodrigues Froes. Semina: Ciências Agrárias. January 2019;40(1):191-202. Quote: The aim of this study was to estimate echocardiographic elevated mean left atrium pressure (MLAP) based on measurements from thoracic radiographs and to determine a cut-off value for each radiographic measurement that suggests a high MLAP. A retrospective cross-sectional study was performed to include cases admitted from January 2015 to December 2016. Thoracic radiographic examinations from 93 dogs [none were cavalier King Charles spaniels] with and without a high MLAP were included. Specific measurements were made from thoracic radiographs and compared with echocardiographic variables known to indicate high MLAP. This comparison was used to generate equations that allowed the estimation of echocardiographic surrogates from the radiographic measurements. The values indicative of high MLAP were obtained using a regression curve. Formulas that indicated high MLAP were generated using a number of radiographic measurements. Positive echocardiographic findings of high MLAP were used as the gold standard. These formulas helped to predict high MLAP in myxomatous mitral valve disease (MMVD) without the need for echocardiographic examination. The best formula was left atrium (LA):aorta (Ao)echo = 0.03×(vertebral heart score,VHS) + 0.14×(LA) + 0.27×(LA:caudal vena cava (CVC)rad). Values ≥ 12.2v for VHS, ≥ 4.5cm for LA, ≥ 3.3 for LA:Aorad and ≥ 3.2 for LA:CVCrad suggested high MLAP. Thus, we propose equations, based on measurements from thoracic radiographs, to identify high MLAP. Simple radiographic thoracic measurements, such as LA:CVCrad, can be used to define overload and a high MLAP in dogs with MMVD.

Echocardiographic indices and severity of mitral regurgitation in dogs with preclinical degenerative mitral valve disease. Éva Larouche-Lebel, Kerry A. Loughran, Mark A. Oyama. J. Vet. Intern. Med. February 2019; DOI: 10.1111/jvim.15461 Quote: Background: Describing severity of mitral regurgitation (MR) in dogs with degenerative mitral valve disease (DMVD) is challenging. Hypothesis/Objectives: Mitral regurgitant fraction (RF), effective regurgitant orifice area (EROA), and the ratio of mitral regurgitant to aortic flow (QMR:QAo) can be calculated from routine echocardiographic measurements and provide additional information regarding MR severity. Animals: Fifty-seven dogs with preclinical DMVD including 36 without and 21 with cardiomegaly [breeds not identified except 1 bull terrrier]. Methods: Prospective observational study. Dogs were classified into 2 groups based on specific LV and atrial sizes that have been previously identified as important in the clinical evolution of DMVD [citing the EPIC Study parameters]. Dogs in Group 1 included dogs that failed to meet either or both of the following criteria: LVIDdN ≥1.7 or LA:Ao ≥1.6. Group 2 included dogs that met both of the criteria: LVIDdN ≥1.7 and LA:Ao ≥1.6. ... The expected relationships among RF, EROA, and QMR:QAo and 1‐dimensional measurements including left atrium to aortic root diameter ratio (LA:Ao) and normalized left ventricular internal dimension at end-diastole (LVIDdN) were mathematically derived and calculated using echocardiographic data from the study population. Nonlinear goodness of fit was determined by calculation of the root mean standard error. The correlations between 1-dimensional and multidimensional indices were analyzed using receiver operating characteristic curves. Results: The relationships among RF, EROA, QMR:QAo, and both LA:Ao and LVIDdN were curvilinear, and the multidimensional indices differentiated MR of variable severity. By contrast, 1-dimensional measurements were insensitive to MR severity until RF equaled or exceeded 50%. Regurgitant fraction ≥50%, EROA to body surface area ≥0.347 and QMR:QAo ≥0.79 were strongly associated with LA:Ao ≥1.6 and LVIDdN ≥1.7. ... Thus, an important finding of the current study is that calculation of RF enhances characterization of MR severity in the population of dogs with relatively normal left heart diameters in a way 1-dimensional measurements cannot. Second, multidimensional indices are more closely related to the pathophysiology of disease and expected to more holistically reflect MR severity than chamber diameter. The pathophysiology of DMVD is directly related to volume (ie, VOL MR) and volume per unit time (ie, flow or QMR:QAo) as opposed to 1-dimensional cardiac chamber dimensions. ... Finally, simple 1-dimensional measures, such as LV diastolic diameter, fail to account for systolic function, LVVs, or FSV, all of which affect MR VOL. Thus, 1-dimensional measurements of cardiac chamber diameter are a crude estimation of MR severity that lie far removed from the principal determinants of MR VOL as opposed to multidimensional indices such as RF, EROA, or QMR:QAo. ... Our study used a simple volumetric method to calculate indices of MR severity. ... The strengths of volumetric methods are their relative ease of use, lack of reliance on color flow Doppler, and applicability in cases of multiple or eccentric MR jets, which are common in dogs with DMVD. Despite the simplicity of the current method, RF showed good discrimination of the study cohort. ... Conclusions and Clinical Importance: Regurgitant fraction, EROA, and QMR:QAo quantify MR severity in dogs with preclinical DMVD in a manner that 1‐dimensional measurements do not. ... The study was observational in nature and longitudinal studies are needed to relate RF with the timeline of disease progression.

Factors associated with disease progression in dogs with presumed preclinical degenerative mitral valve disease attending primary care veterinary practices in the United Kingdom. Madeleine J. Mattin, David C. Brodbelt, David B. Church, Adrian Boswood. J. Vet. Intern. Med. March 2019;33(2):445-454. Quote: Background: Factors associated with disease progression in dogs with preclinical (stage B) degenerative mitral valve disease (DMVD) have not been evaluated previously in primary care veterinary practice. Objectives: To evaluate whether plasma cardiac biomarkers, clinical signs, and physical examination findings are associated with clinical progression (reaching the composite endpoint of initiation of treatment with a potent diuretic or cardiac death) in dogs presumed to have stage B DMVD. Animals: Six-hundred and eighty-four dogs diagnosed with DMVD recruited from 73 primary care practices in the United Kingdom. ... The breed most frequently recruited was the Cavalier King Charles Spaniel (CKCS; n = 231, 33.9%). ... Dogs were not receiving potent diuretics at recruitment. Methods: Prospective cohort study design. Primary care veterinarians recorded the presence or absence of clinical signs and physical examination findings. Baseline plasma N-terminal pro Btype natriuretic peptide (NT-proBNP) and cardiac troponin I were measured. Cox regression models measured associations between risk factor variables and clinical progression. Flexible parametric models generated predicted probabilities of reaching the composite endpoint for dogs with different combinations of prognostic risk factor variables. Results: Plasma NT-proBNP, heart rate, heart murmur intensity, presence of a cough, being a Cavalier King Charles Spaniel, and being prescribed pimobendan were associated with clinical progression to initiation of treatment with a potent diuretic or cardiac-related death. ... Cavalier King Charles Spaniels had a higher hazard of starting diuretic treatment or experiencing cardiac-related death compared with a category including all other breeds. This observation may be a result of breed differences in disease progression. Alternatively, knowledge of breed predispositions for DMVD might influence the likelihood of dog owners seeking veterinary care or veterinarians prescribing CHF treatment for symptomatic CKCSs compared to other breeds showing similar clinical signs. ... In our study, dogs with heart murmur intensities grade III or above had a higher hazard of clinical progression than those with softer murmurs. ... Conclusions and Clinical Importance: Dogs with stage B DMVD identified as having a high risk of disease progression might benefit from more frequent monitoring or further diagnostic evaluation. The prognostic factors identified could facilitate risk stratification of dogs presenting with preclinical DMVD.

The prevalence of pulmonary hypertension in Cavalier King Charles spaniels compared with other breeds with myxomatous mitral valve disease. S.Sudunagunta, D.Green, R.Christley, J.Dukes-McEwan. J. Vet. Cardiol. June 2019;23(1):21-31. Quote: Introduction: Pulmonary hypertension (PH) is a common consequence of myxomatous mitral valve disease (MMVD). Cavalier King Charles spaniels (CKCS) are frequently affected with MMVD and appear to have different disease progression compared to other dogs. This study aimed to determine if CKCS are more likely to develop PH as a result of MMVD than dogs of other breeds. A secondary aim was to explore whether breed or PH impacted survival. Animals: A total of 187 dogs diagnosed with MMVD, 94 CKCS and 93 non-CKCS [28 different breeds plus cross-breeds], were included in this study. [Only dogs in ACVIM Stages B2, C, or D were included in this study; Stage B1 dogs were excluded.] Methods: This is a retrospective review of dogs with MMVD. Data were analyzed for presence of PH, congestive heart failure (CHF) and echocardiographic variables including the ratio between mitral E wave velocity (E vel) and isovolumic relaxation time (E/IVRT) and were compared between CKCS/non-CKCS and dogs with/without PH. Survival analysis was also performed. Results: American College of Veterinary Internal Medicine (ACVIM) stage (p < 0.001), CKCS (p = 0.005), left atrium-to-aortic ratio (LA/Ao) (p < 0.001), E vel (p < 0.001) and log10(E/IVRT) (p < 0.001) were significant at the univariate level for PH development. At the multivariate level, only ACVIM stage remained significant (p = 0.044), suggesting that worsening MMVD was the predominant determinant of PH development in this study. Pulmonary hypertension was associated with greater likelihood of CHF (p < 0.001) and death (both cardiac [p < 0.001] and all-cause mortality [p = 0.011]). Cavalier King Charles spaniels were more likely to experience cardiac death than non-CKCS (p = 0.004). Conclusions: In this study, development of PH was associated with worse MMVD, according to ACVIM stage. (See also, an April 2018 abstract of this article.)

The renin-angiotensin-aldosterone system and its suppression. Marisa K. Ames, Clarke E. Atkins, Bertram Pitt. J. Vet. Intern. Med. February 2019; doi: 10.1111/jvim.15454 Quote: Chronic activation of the renin-angiotensin-aldosterone system (RAAS) promotes and perpetuates the syndromes of congestive heart failure, systemic hypertension, and chronic kidney disease. Excessive circulating and tissue angiotensin II (AngII) and aldosterone levels lead to a pro-fibrotic, -inflammatory, and -hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Understanding of the role of the RAAS's in this abnormal pathologic remodeling has grown over the past few decades and numerous medical therapies aimed at suppressing the RAAS have been developed. Despite this, morbidity from these diseases remains high. Continued investigation into the complexities of the RAAS should help clinicians modulate (suppress or enhance) components of this system and improve quality of life and survival. This review focuses on updates in our understanding of the RAAS and the pathophysiology of AngII and aldosterone excess, reviewing what is known about its suppression in cardiovascular and renal diseases, especially in the cat and dog. ... Recently, a single nucleotide polymorphism in intron 16 of the ACE gene in a group of 31 dogs (including 10 CKCS) has been described. (See this October 2017 article.) The ACE activity in dogs with the polymorphism was significantly lower than those without, yet both groups had significant suppression of ACE activity after 2 weeks of ACEI treatment. Six of the 10 CKCS carried the polymorphism, which provides support to the concept, held by some, that the RAAS of the CKCS may not truly represent the species as a whole. Further study is necessary to determine whether differences in RAAS phenotypes impact the response to RAAS suppressive treatment and the natural history of cardiac disease in this breed.

Involvement of Serotonin in a Canine Model of Mitral Valve Prolapse: a Complex Genetic Approach. Brian Williams, Steven G. Friedenberg, Kathryn M. Meurs. J. Amer. Coll. Cardiol. March 2019;73(9) Supp. 1:957. Quote: Background: In humans, mitral valve prolapse (MVP) is a common heritable condition. Dogs serve as a spontaneous animal model of familial MVP, with several breeds genetically predisposed. As in humans, previous studies have suggested that canine MVP may be polygenic and may be associated with alterations in the serotonin pathway. We hypothesized that genetic variants in the serotonin receptor signaling (SRS) pathway would be associated with the development of MVP in dogs and add insight into this complex familial disease. Methods: DNA was isolated from blood samples from 51 dogs with MVP and whole genome sequencing was performed. Variant calls were made using a bioinformatics pipeline and filtered to retain rare variants in the control population. Variants were separated into four categories: high, moderate, low & modifier (high, low impact) per Variant Effect Prediction classification. Data was analyzed in a stepwise manner, beginning with a search for a single variant shared across all dogs in the SRS pathway, followed by a search for a shared gene and /or gene family in the SRS pathway, and concluding with a search for variants found within all dogs in the SRS pathway. Results: No high, moderate, or high impact modifying variants in canine genes orthologous to the human genes known to be associated with the SRS pathway were shared in all dogs used for this study. 57% of dogs had a high impact variant in the SRS pathway, but not in the same location, gene, or gene family. The ADCY gene family represented 81% of high impact variants. No other gene or gene families represented more than 10% of high impact mutations. All dogs had &gt; 1 low impact or low impact modifier variant in the SRS pathway. Conclusion: High impact variants were inconsistently identified in the SRS pathway in this canine model. No single high impact variant, gene, or gene family accounted for all dogs. Although serotonin may play a role in MVP development, it may not be the primary genetic cause of the disease. Further studies will use this canine MVP model genetic data to assess additional pathways in a systemic approach.

Effect of Pimobendan on physical fitness, lactate and sonographic parameters in dogs with preclinical mitral valve disease without cardiomegaly. Nayeli Iwanuk, Leona Wall, Ingo Nolte, Katja Rumstedt, Anna Pilgram, Maximiliane Sehn, Jan-Peter Bach. Univ. Vet. Med. Hannover. March 2019. Quote: Pimobendan has gained enormous importance in the treatment of mitral valve disease in dogs. The current ACVIM consensus statement recommends a treatment for dogs with symptomatic disease. Boswood et al. observed that dogs with mitral valve disease stage CHIEF B2 also benefit from therapy with Pimobendan. To investigate whether these dogs also benefit from a therapy with Pimobendan, 21 dogs [including one cavalier King Charles spaniel] with mitral valve disease CHIEF [ACVIM Stage] B1 underwent a standardized submaximal exercise test on a treadmill. Dogs were divided double-blinded and randomized into two groups, one receiving Pimobendan and the other placebo. At the first visit and at every follow-up appointment (on days 90 and 180), covered distance on the treadmill, heart rate during the complete exercise test and lactate before and after running were measured. In addition to this, a questionnaire was completed by the dogs’ owners and all dogs had a cardiographic examination to detect any changes and to observe, if there was progression of the disease. On day 180, two dogs from the Placebo-group developed cardiomegaly, but no dog from the Pimobendan-group. There were no differences at any point between the Pimobendan-group and the placebo-group regarding covered distance and heart rate. On day 180 the increase of lactate after exercise was significant lower than in the placebo-group. The increase in the Pimobendan-group on day 180 was lower than on day 90. Most of the dog owners from the Pimobendan-group declared that their dogs were more active on day 90 (7/11) and on day 180 (9/11), while most dog owners from the Placebo-group saw no changes regarding the activity on day 90 (8/10) and day 180 (6/10). It can be concluded that the results of this study indicate, that dogs with mitral valve disease CHIEF B1 might benefit from a therapy with Pimobendan.

ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. Bruce W. Keene, Clarke E. Atkins, John D. Bonagura, ,Philip R. Fox, Jens Häggström, Virginia Luis Fuentes, Mark A. Oyama, John E. Rush, Rebecca Stepien, Masami Uechi. J. Vet. Intern. Med.  May 2019;33(3):1127-1140. Quote: This report, issued by the ACVIM Specialty of Cardiology consensus panel, revises guidelines for the diagnosis and treatment of myxomatous mitral valve disease (MMVD, also known as endocardiosis and degenerative or chronic valvular heart disease) in dogs, originally published in 2009. Updates were made to diagnostic, as well as medical, surgical, and dietary treatment recommendations. ... Stage B identifies dogs with structural heart disease (eg, the typical murmur of mitral valve regurgitation, accompanied by some typical valve pathology, is present), but that have never developed clinical signs caused by heart failure. In a change from the 2009 recommendations, strong evidence now supports initiating treatment to delay the onset of clinical signs of heart failure in a subset of stage B patients with more advanced cardiac morphologic changes (outlined below). Stage B1 describes asymptomatic dogs that have no radiographic or echocardiographic evidence of cardiac remodeling in response to their MMVD, as well as those in which remodeling changes are present, but not severe enough to meet current clinical trial criteria that have been used to determine that initiating treatment is warranted. ... Treatment is not recommended in these dogs because at this early stage of disease, progression to heart failure is uncertain, unlikely to occur within the recommended evaluation interval, and there is no evidence that medication is effective at this stage. To summarize: No drug or dietary treatment is recommended. Reevaluation by echocardiography is suggested (or radiography if echocardiography is unavailable) in 6-12 months, depending on the imaging results (some panelists recommend more frequent follow‐up in large dogs). ... Stage B2 refers to asymptomatic dogs that have more advanced mitral valve regurgitation that is hemodynamically severe and long‐standing enough to have caused radiographic and echocardiographic findings of left atrial and ventricular enlargement that meet clinical trial criteria used to identify dogs that clearly should benefit from initiating pharmacologic treatment to delay the onset of heart failure. ... Stage B2 criteria for heart enlargement identify dogs that are likely to benefit substantially from treatment before the onset of clinical signs of heart failure: • murmur intensity ≥3/6; • echocardiographic LA:Ao ratio in the right-sided short axis view in early diastole ≥1.6 (Figure 1)45; • left ventricular internal diameter in diastole, normalized for body weight (LVIDDN) ≥1.7 ; • breed-adjusted radiographic vertebral heart score (VHS) >10.5. ecommendations for treatment of Stage B2: Pimobendan is recommended at a dosage of 0.25-0.3mg/kg PO q12h.

Insights on the canine mitral valve in the course of myxomatous mitral valve disease. Sonia C Orozco, Martha Olivera-Angel, Pedro Vargas-Pinto. Med. Zootec. April 2019;14(1):25-41. Quote:  Myxomatous mitral valve disease (MMVD) is the most common heart alteration in dogs. A vast extent of research has been focused on echocardiographic tissue Doppler and strain indices and the medical treatment of this condition, which are beyond the scope of this article. This review intends to include less known information of the mitral valve, acknowledge the American College of Veterinary Internal Medicine (ACVIM) consensus on MMVD and state different surgical approaches and devices, all valuable information for small animal clinicians and cardiologists. Also, during the last decade studies have been oriented towards to understand valve’s mechanical structure and function, genes involved in the etiology and molecular signaling pathways. Advances have been made in understanding the mitral valve, but more assessment and efforts are needed in this specific area. 

Cardiac theraputics: artioventricular valve disease. Sonya Gordon. BSAVA Congress Proceedings 2019. April 2019. Pg 162. Quote: Stage B2 is characterized by heart enlargement and based on the results of the EPIC study, pimobendan is recommended if the degree of heart enlargement is sufficient in magnitude.

Can VHS predict EPIC echo inclusion criteria? Sonya Gordon. Proceedings of Vet. Cardio. Society. April 2019. Quote: Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disease in the dog and can lead to progressive cardiac chamber enlargement and resultant congestive heart failure (CHF) in approximately one third of this population. Cardiomegaly secondary to MMVD is a known risk factor for development of CHF and the EPIC Trial reported that pimobendan significantly delayed the time to onset of CHF in these dogs. In addition, the new ACVIM MMVD consensus statement, as presented, has made a strong recommendation for initiation of pimobendan in dogs with Stage B2 MMVD; where stage B2 is defined as the EPIC echocardiographic inclusion criteria. The EPIC Trial had three cardiac size inclusion criteria, two echocardiographic (LVIDDN > 1.7 and LA:Ao ratio [2D Swedish] >1.6) and one radiographic (VHS > 10.5). However, echocardiography is not always readily available and therefore there is interest in how to identify dogs with Stage B2 MMVD in the absence of echocardiography. Factors that may be useful include; murmur grade, VHS, and breed. Several reports and publications have suggested a VHS > 11.5 may be predictive of EPIC echocardiographic inclusion criteria (now ACVIM Stage B2) in dogs with MMVD, however this cutoff is based on small sample sizes, or was made based on inferences from other publications.

The effect of heart disease on red cell mass. Madeleine Stein, Jenny Wilshaw, Nicola Lotter, Adrian Boswood. BSAVA Congress Proceedings 2019. April 2019. Pg 449. Quote: Objectives: This study aims to demonstrate whether a link exists between increasing severity of heart disease and red blood cell count in dogs with Myxomatous mitral valve disease. Mehods: Data were obtained from 426 dogs enrolled in a longitudinal study from first opinion practices based in London between 2004 and 2017. PCV [packed cell volume] was compared between dogs at different American College of Veterinary Internal Medicine (ACVIM) stages of disease and factors related to changes in PCV were evaluated including; age, sex, breed, total protein, blood urea nitrogen, the left atrial to aortic root ratio and the normalised left ventricular internal diameter (LVIDDN). Results: One-way ANOVA showed a significant difference (p < 0.001) between all four ACVIM stages. Dogs in stage B2 (41.12 ± 6.15, p < 0.001) had a significantly lower PCV than all other stages (A: 46.14 ± 4.97, p < 0.001, B1: 43.44 ± 5.80, p = 0.012, C: 43.98 ±4.57, p = 0.048). The results additionally demonstrated that the mean PCV of dogs in stage A was the greatest and differed significantly from both stage B1 (p = 0.007) and B2 (p < 0.001). A multivariable linear regression analysis revealed that patient age (–0.154 ± 0.111, p = 0.006), ACVIM stage (–0.122 ± 0.496, p = 0.40), LVIDDN (–0.160 ± 1.122, p = 0.008) and breed (0.471 ± 0.661, p = 0.001) all had a significant and independent effect on PCV. Statement (Conclusions): There is a link between mitral valve disease and red blood cell count in dogs, which differs from human disease. A decrease in red blood cell count is seen with diseased progression until patients enter congestive heart failure when there is an increase.

Correlation between NT-proBNP and lipase levels according to the severity of chronic mitral valve disease in dogs. Jun-Seok Park, Jae-Hong Park, Kyoung-Won Seo, Kun-Ho Song. J. Vet. Sci. July 2019;20(4):e43. Quote: Chronic mitral valve disease (CMVD) is the most common cardiovascular disease in dogs, causing decreased cardiac output that results in poor tissue perfusion and tissue damage to kidneys, pancreas, and other organs. The purpose of this study was to evaluate the relationships between heart disease severity and N-terminal pro B-type natriuretic peptide (NT-proBNP) and lipase in dogs with CMVD, as well as to evaluate longitudinal changes in these values. A total of 84 dogs participated in this 2015 to 2017 study. [None were cavalier King Charles spaniels.] Serum values of NT-proBNP and lipase were analyzed; radiography was used to measure the vertebral heart score and assess various echocardiographic values. NT-proBNP showed a strong positive correlation with increasing stage of heart disease; lipase showed a mild positive correlation with heart disease stage. When the three values (NT-proBNP, lipase and month) were continuously measured at 6-month intervals, all showed a correlation with the increasing length of the disease.

Urine 5-hydroxyindoleacetic acid in Cavalier King Charles spaniels with preclinical myxomatous mitral valve disease. L.B.Christiansen, S.E.Cremer, A. Helander, Tine Madsen, M.J. Reimann, J.E. Møller, K. Höglund, I. Ljungvall, J. Häggström, L. Høier Olsen. Vet. J. August 2019;250(1):26-43. Quote: Higher concentrations of circulating serotonin have been reported in Cavalier King Charles spaniels (CKCS) compared to other dog breeds. The CKCS is also a breed highly predisposed to myxomatous mitral valve disease (MMVD). The aim of this study was to determine urine concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite and excretion product of serotonin, in a population of CKCS with preclinical MMVD, and to evaluate whether urine 5-HIAA concentrations were associated with MMVD severity, dog characteristics, setting for urine sampling, platelet count, and serotonin concentration in serum and platelet-poor plasma (PPP). The study population consisted of 40 privately-owned CKCS (23 females; 17 males) with and without preclinical MMVD as follows: American College of Veterinary Internal Medicine (ACVIM) group A (n=11), ACVIM group B1 (n=21) and ACVIM group B2 (n=8). ... CKCS were classified into clinical disease severity groups according to the American College of Veterinary Internal Medicine (ACVIM) guidelines. In brief, CKCS with no auscultatory murmur and/or normal echocardiogram (MR < 20%) were classified as ACVIM group A, while CKCS with a characteristic left apical systolic mitral regurgitation murmur and/or a MR ≥ 20% were classified as ACVIM group B1 if no remodelling of the heart was evident, or ACVIM group B2 if remodelling of LA (LA/Ao ≥ 1.6) and left ventricle (LVIDDN ≥ 1.7) were detected. ... Urine 5-HIAA concentrations were not significantly associated with preclinical MMVD disease, platelet count or circulating concentrations of serotonin (in serum and PPP; P>0.05). Females had higher 5-HIAA concentrations than males in morning urine collected at home (females, 3.1 [2.9-3.7] µmol/mmol creatinine [median and quartiles]; males, 1.7 [1.2-2.2] µmol/mmol creatinine; P=0.0002) and urine collected at the clinic (females, 3.5 [3.1-3.9] µmol/mmol creatinine; males, 1.6 [1.3-2.1] µmol/mmol creatinine; P<0.0001). Five-HIAA concentrations in urine collected at home and at the clinic were significantly associated (P=0.0004; r=0.73), and higher concentrations were found in urine collected at the clinic (P=0.013). Urine 5-HIAA concentration was influenced by sex and setting of urine sampling. Urine 5-HIAA concentration was not associated with MMVD severity or circulating concentrations of serotonin in CKCS with preclinical disease. Highlights: •Urine 5-hydroxyindoleacetic acid (5-HIAA) concentrations predict progression of cardiac disease in some human conditions. •Urine 5-HIAA was measured in cavalier King Charles spaniels (CKCS) with preclinical myxomatous mitral valve disease (MMVD). •Urine 5-HIAA concentrations were higher in clinic-collected samples than in morning, home-collected samples. •Female CKCS showed higher urine 5-HIAA concentrations than male dogs. •Urine 5-HIAA concentrations were not associated with disease severity in CKCS with preclinical MMVD. (See also this January 2017 abstract.)

Effect of Pimobendan on NT-proBNP and c troponin I before and after a submaximal exercise test in dogs with preclinical mitral valve disease without cardiomegaly – a randomised, double-blinded trial. Nayeli Iwanuk, Ingo Nolte, Leona Wall, Maximiliane Sehn, Jonathan Raue, Anna Pilgram, Katja Rumstedt, Jan-Peter Bach. BMC Vet. Res. December 2019;15:237. Quote: Background: Exercise testing in conjunction with measurement of cardiac biomarkers NT-proBNP and cTnI is a useful tool for monitoring the effect of treatment on cardiac patients. Administering Pimobendan in dogs with degenerative mitral valve disease (DMVD) and cardiomegaly results in delaying the onset of clinical symptoms and prolonging life. Its effect in dogs with DMVD without cardiomegaly has not been well examined. The aim of the current study was to investigate the effect of administering Pimobendan in dogs with DMVD without cardiomegaly using exercise testing in conjunction with measuring cardiac biomarkers in addition to echocardiography. Twenty-one dogs [including one cavalier King Charles spaniel] with asymptomatic DMVD without echocardiographic signs of cardiomegaly participated in a randomised, double-blinded trial. ... Dogs had to be free of signs of congestive heart failure and cardiomegaly had to be excluded by assessing the LA/Ao ratio (Ratio of diameters of left atrium and aortic root ≤1.6) and LVIDDN (diastolic diameter of left ventricle ≤1.7) by echocardiography. ...Dogs with raised LA/Ao ratio and raised LVIDDN were excluded from the study. If only one parameter was above the reference range, dogs were eligible to participate in the study. ... Two dogs in the Pimobendan-group and two dogs in the control-group showed slightly increased LVIDDN-values at the initial examination. ... Dogs were divided into a Pimobendan-group (n = 11) and a placebo-group (n = 10) in a double-blinded study design and underwent a standardised submaximal exercise test (SSET). One dog in the Pimobendan-group was retrospectively removed from the study after being diagnosed with Leishmaniosis. Cardiac biomarkers NT-proBNP and cTnI were measured before and after exercise. Follow-up appointments were performed at days 90 and 180. Results: Dogs in the Pimobendan-group had significantly lower post-exercise NT-proBNP-levels after being administered Pimobendan than at the beginning of the study. They also had lower pre- and post-exercise-NTproBNP-levels than those dogs in the placebo-group. There was neither a significant difference regarding the measured cTnI levels nor an increase in cTnI between the groups at any time. ... In contrast to the study of Chetboul et al. (2007), in which myocardial damage was reported, cTnI was not influenced by Pimobendan in the present study. This indicates that there were no structural cardiac lesions after administering Pimobendan in dogs with early stage mitral valve disease. Furthermore, no increase in regurgitation was observed by the echocardiographic examinations during the 180-day treatment. ... Conclusions: Pimobendan lowers NT-proBNP in dogs with presymptomatic mitral valve disease without cardiomegaly before and after submaximal exercise. This indicates a reduction in cardiac wall stress. If dogs with asymptomatic DMVD without cardiomegaly benefit from treatment with Pimobendan (for example, through a longer survival time) warrants further investigation.

Echocardiographic quantitation of left heart size and function in 122 healthy dogs: A prospective study proposing reference intervals and assessing repeatability. Lance C. Visser, Marisa M. Ciccozzi, Daniel J. Sintov, Ashley N. Sharpe. J. Vet. Intern. Med. July 2019; doi: 10.1111/jvim.15562. Quote: Background: Broadly applicable reference intervals (RIs) for measurements of left atrial (LA) and left ventricular (LV) size and function generated prospectively using statistically appropriate methods are limited. Objectives: To generate body size‐independent RIs for linear, area, and volume measurements of LA size and LV size and function. Animals: Healthy adult dogs (n = 122) of variable size and somatotype [none were cavalier King Charles spaniels]. Methods: Prospective study. All dogs underwent an echocardiogram performed by the same examiner. Effects of body weight, sex, age, and heart rate were evaluated by regression and correlation analyses. Scaling exponents and prediction intervals were generated for linear measurements using the allometric equation. After normalization to body weight, 95% RIs were determined using nonparametric methods with 2.5 and 97.5 percentiles serving as the lower and upper limits (each with 90% confidence intervals), respectively. Results: Linear LA and LV measurements were strongly correlated (R2 ≥ 0.79) with body weight. Scaling exponents were close to the expected 1/3 (0.299‐0.392). Prediction intervals for linear measurements of LV chamber size were considerably narrower than previously reported. Weak correlations (r = −0.42 to −0.50) among LV fractional shortening, fractional area change, and ejection fraction and body weight were identified. ... Compared to a previous study evaluating LA/Ao2DE, Sx in multiple breeds (median, 1.31; maximum, 1.59), our results (median, 1.42; maximum, 1.70) were again similar but slightly larger. ... No other meaningful relationships were identified between the measurements and sex, age, and heart rate. Conclusions and Clinical Importance: Body size‐independent RIs for several linear, area, and volume measurements of LA and LV size and function were generated prospectively from a large and diverse reference population and are available for clinical use.

Clinical and laboratory findings and survival time associated with cardiac cachexia in dogs with congestive heart failure. Deanna L. Ineson, Lisa M. Freeman, John E. Rush. J. Vet. Intern. Med. July 2019; doi: 10.1111/jvim.15566 Quote: Background: Cardiac cachexia, loss of muscle mass associated with congestive heart failure (CHF), is associated with increased morbidity and shorter survival times in people, but an association between cardiac cachexia and survival has not been reported in dogs. Objectives: To determine the prevalence of cachexia and its associations with clinical, laboratory, and survival data in dogs with CHF. Animals: Two hundred sixty-nine dogs with CHF [218 of them with DMVD - degenerative mitral valve disease; including 20 cavalier King Charles spaniels]. Methods: Retrospective cohort study. Cachexia was defined by 1 of 2 definitions: (1) mild, moderate, or severe muscle loss or (2) weight loss of ≥5% in 12 months or less. Variables were compared between dogs with and without cachexia. Results: One hundred thirty of 269 dogs (48.3%) had cardiac cachexia based on muscle loss, whereas 67 of 159 dogs (42.1%) with pre‐evaluation body weights had cachexia based on weight loss. Dogs with cachexia (based on muscle loss) were significantly older (P = .05), more likely to have a cardiac arrhythmia (P = .02), had higher chloride concentrations (P = .04), and had a lower body condition score (P <.001), hematocrit (P = .006), hemoglobin (P = .006), and albumin (P = .004) concentrations. On multivariable analysis, cachexia (P = .05), clinically important tachyarrhythmias (P <.001), azotemia (P <.001), and being under- or overweight (both P = .003) were associated with shorter survival times. ... Results of this study showed that dogs with CHF because of DMVD or DCM that had cachexia, defined as having loss of muscle on a MCS [muscle condition score], had a significantly shorter survival time compared with dogs without cachexia. ... Causes for shorter survival times in people and dogs with cardiac cachexia are unknown but might be caused by loss of cardiac muscle, impaired metabolism, or reduced immune function. Additionally, in dogs, reduced quality of life, reduced food intake, and weakness, often associated with cardiac cachexia, are important factors in the decision to euthanize dogs with CHF which could result in shorter survival times. Low BCS [body condition score] at diagnosis was an independent risk factor for death. ... Of note, although both BCS and MCS were predictors of death in this study, only 4.5% of dogs were underweight whereas 48.3% of dogs had muscle loss. This distinction is important because BCS and MCS are not the same. Body condition score assesses fat stores, whereas MCS is an assessment of muscle mass. Dogs can be overweight or obese but still have muscle loss (83.3% of dogs with a low BCS had muscle loss but 56.7% of ideal weight dogs and 30.3% of overweight dogs also had muscle loss) whereas conversely, dogs can be thin but have normal MCS (2 of 12 thin dogs [16.7%] in the current study did not have muscle loss). Therefore, it is critical to measure both BCS and MCS, along with body weight, in all dogs. ... In addition to low BCS being associated with a shorter survival time, dogs that were overweight or obese (BCS >5/9) also had a shorter survival time compared to those with a BCS = 4-5/9 at the time of diagnosis of CHF. ... Conclusions and Clinical Importance: Cardiac cachexia in common in dogs with CHF and is associated with significantly shorter survival. This emphasizes the importance of preventing, diagnosing, and treating muscle loss in dogs with CHF.

Evaluation of canine 2D cell cultures as models of myxomatous mitral valve degeneration. Karen Tan, Greg Markby, Rhona Muirhead, Rachel Blake, Lisa Bergeron, Greg Fici, Kim Summers, Vicky Macrae, Brendan Corcoran. PLoS ONE. August 2019;14(8):eo221126. Quote: We have shown it is feasible to induce, in a TGFβ1 concentration-dependent manner, EndoMT and activated myofibroblast phenotype in normal canine VECs [valve endothelial cells] and VICs [valve interstitial cells] respectively, and to reverse naturally-occurring disease phenotype in canine mitral valve VICs. We identified TGFβ1 as the main driver of disease phenotype, and that inhibition of TGFβ can completely inhibit VIC activation. We did not identify any significant contribution of 5HT, but our data indicate that any changes in 5HT signalling were likely to be TGFβ1-mediated. Simple cell culture systems, using a low serum protocol, can partially model MMVD and more sophisticated culture methods can now be developed to achieve greater approximation to the gene and protein changes seen in disease.

Serial measurements of cardiac troponin I in heart failure secondary to canine mitral valve disease. I-Ping Chan, San-Yu Wu, Chao-Chin Chang, Wen-Ying Chen. Vet. Rec. August 2019; doi: 10.1136/ vetrec-2018-105265. Quote: Serial measurements of cardiac troponin I (cTnI) levels are considered to be better predictors of cardiac death than single-time-point analyses in human medicine. We hypothesised that cTnI levels could reflect the severity of myxomatous mitral valve disease (MMVD), and that serial changes in the cTnI level had a prognostic value in dogs with congestive heart failure (CHF) secondary to MMVD. Seventy-six dogs were initially enrolled and classified by the American College of Veterinary Internal Medicine (ACVIM) staging system. ... If dogs with MMVD had at least two of the following criteria: vertebral heart score (VHS) above 10.5, normalised left ventricular internal dimension at end-diastole (LVIDdn) at least 1.7 cm, or the ratio of left atrium and aorta dimensions (LA/Ao) at least 1.6 on thoracic radiography and echocardiography, they were considered to have evidence of cardiac remodelling. Dogs with MMVD but without evidence of cardiac remodelling were classified as stage B1, and dogs with MMVD and with evidence of cardiac remodelling were classified as stage B2. Dogs showing pulmonary oedema on thoracic radiography at admission were classified as stage C. ... The single-timepoint cTnI concentration in these dogs significantly increased with the ACVIM stage. Twenty-seven dogs with CHF subsequently underwent serial measurement of cTnI levels, and the results showed that those who demonstrated a decrease in cTnI levels from the first to the third visit exhibited a higher risk of cardiac death than did those without such changes (P=0.012). We suspect that the downward trend in cTnI levels may be affected by medical treatment for CHF. In conclusion, although cTnI levels could reflect the severity of MMVD to a certain extent, the serial changes may be affected by medical treatment. Therefore, caution should be exercised when cTnI is used for assessment of the prognosis of CHF secondary to MMVD in dogs.

Pharmacokinetic Analysis after Multiple-dose Administration of Coenzyme Q10 in Dogs with Myxomatous Mitral Valve Disease. Liselotte B. Christiansen, Anne Marie Schou-Pedersen, Maria Josefine Reimann, Malene Morsing, Zita Eriksen, Jens Lykkesfeldt, Lisbeth Olsen. J. Vet. Intern. Med. September 2019;doi: 10.1111/jvim.15597;#C32:15. Quote:  Coenzyme Q10 (Q10) is a mitochondrial cofactor and antioxidant, available as dietary supplement and used in dogs with heart disease. Evidence for using Q10 in dogs is limited and dose size and dosing intervals are not well documented. The objective of this study was to obtain pharmacokinetic and tolerability data on a gelatine capsule formulation of Q10 administered to dogs with myxomatous mitral valve disease (MMVD). In a prospective, randomised, single-blinded, placebo-controlled crossover design, 19 Cavalier King Charles spaniels with MMVD ACVIM class B2 (n = 10) or C (n = 9) received 100 mg Q10 (ubiquinone) BID followed by placebo (or vice versa) for three weeks, separated by a 2-week washout period. Plasma concentrations of Q10 were analysed using high-performance liquid chromatography before and after each treatment period and, in five dogs, on five consecutive days following Q10 treatment. The average (±SD) plasma concentration of Q10 at baseline was 1.01 (± 0.36) μg/mL. After supplementation, the average (±SD) plasma concentration increased significantly to 4.42 (±2.76) μg/mL (P < 0.0001). The terminal elimination half-life was estimated to 3 days after the last dose. No dogs experienced adverse reactions or abnormalities on complete blood count and serum biochemistry following Q10 supplementation. In conclusion, Q10 dissolved in vegetable oil is well-tolerated and well-absorbed in dogs with heart disease and treated dogs reached higher plasma concentrations than previously reported in dogs administered with other Q10 formulations.

What can changes in serial measurements tell us about prognosis in myxomatous mitral valve disease? Melanie J. Hezzell. Vet. Rec. September 2019; doi: 10.1136/vr.l5651 Quote: Myxomatous mitral valve disease (MMVD) is the most common acquired heart disease in dogs, representing approximately 75 per cent of cases. MMVD is relatively straightforward to identify on the basis of a typical left apical, systolic heart murmur. However, the disease course varies markedly between affected individuals, with some dogs having static, non-progressive disease, while others may rapidly develop compensatory cardiomegaly and, eventually, congestive heart failure (CHF). Although a diagnosis of heart disease is a source of great concern for many owners, less than half of affected dogs will die as a direct result of MMVD. There would be a clear benefit to owners and clinicians if those dogs likely to experience significant disease progression – the development of cardiomegaly (which might benefit from treatment with pimobendan) and CHF – and, therefore, a shortened life expectancy could be accurately identified. Factors associated with disease progression include higher heart rates, higher murmur intensities, being a Cavalier King Charles spaniel, increased echocardiographic estimates of cardiac filling pressures and history of cough. However, increases in heart size over time are important in the progression of MMVD. Therefore, it seems logical to imagine that tracking the rate of change of measurements in a patient may have greater prognostic value than measurement at a single time point. This is especially true for markers such as circulating NT-proBNP, for which there are significant breed-related differences in measurements in healthy individuals.

Correlação entre a deflexão intrinsecoide, classificação clínica e parâmetros ecocardiográficos em cães com degeneração mixomatosa valvar mitral. [Correlation between intrinsecoid deflection, clinical classification and echocardiographic parameters in dogs with degenerative mitral valve myxomatosis]. D.C. Veiga, G.C. Santos, M.G. Sousa. Arquivo Brasileiro de Medicina Veterinária e Zootecnia. September 2019;71(5):1506-1512. Quote: The mitral valve myxomatous degeneration (DMVM) is usually diagnosed by echocardiography, however, electrocardiogram (ECG) may suggest specific alterations and aid diagnosis and treatment. Intrinsicoid deflection (DI) is a simple ECG measure that represents the onset of ventricular depolarization and may indicate the presence of overload and hypertrophy in the left ventricle. The objective of this study is to compare previous data on clinical condition and echocardiogram of dogs with mitral endocardiosis and the value of the intrinsicoid deflection from ECG to obtain a concordance relation. The archives of 45 previously examined dogs in the clinical routine of HV-UFPR were selected. The statistic showed a significant difference in groups B1, B2 and C in leads D2, D3, aVF, rV, V2 and V4 (P< 0,05), which allowed to classify them according to the DI size, and this result corresponded to the consensus classification of mitral endocardiosis in dogs at these stages. It was concluded that there is a gradual increase in the value of DI as DMVM progresses, especially in stages B1, B2 and C, associated with left ventricular overload and hypertrophy, so this parameter can be used to classify the disease.

Norwich terriers possess a greater vertebral heart scale than the canine reference value. Colin J. Taylor, Bradley T. Simon, Bryden J. Stanley, Grace P. Lai, Kelley M. Thieman Mankin. Vet.Rad. & Ultra. October 2019;doi: 10.1111/vru.12813. Quote: Previous studies have demonstrated evidence that normal reference ranges for radiographic vertebral heart scale values can vary among dog breeds. The purpose of this retrospective, observational study was to determine whether the normal vertebral heart scale values published by Buchanan and Bücheler for lateral radiographs are applicable to the Norwich terrier. Secondary objectives were to determine if clinical signs of respiratory disease, age, sex, weight, body condition score, recumbency, or thoracic depth-to-width ratio had any influence on vertebral heart scale measurements in this breed. The electronic medical record systems of two universities were reviewed and Norwich terriers were included in the study if they had orthogonal thoracic radiographs performed and no historical or radiographic evidence of cardiopulmonary disease. A vertebral heart scale was calculated for each patient. Sixty-one client-owned, Norwich terrier dogs with no clinical signs of cardiovascular disease were evaluated. The vertebral heart scale for Norwich terriers without evidence of cardiac disease (10.6 ± 0.6) was found to be significantly greater than the canine reference value of 9.7 ± 0.5 initially established by Buchanan and Bücheler. No significant correlation was found between clinical signs of respiratory disease, sex, age, thoracic depth-to-width ratio or lateral recumbency, and vertebral heart scale. Norwich terriers with a body condition score ≥6 had a significantly higher vertebral heart scale than those with a body condition score ≤5. Breed-specific ranges and body condition scores need to be considered when interpreting vertebral heart scale values for Norwich terriers.

Effect of pimobendan on physical fitness, lactate and echocardiographic parameters in dogs with preclinical mitral valve disease without cardiomegaly. Nayeli Iwanuk, Leona Wall, Ingo Nolte, Jonathan Raue, Katja Rumstedt, Anna Pilgram, Maximiliane Sehn, Karl Rohn, Jan-Peter Bach. PLoS ONE. October 2019;14(10):e0223164. Quote: Pimobendan has gained enormous importance in the treatment of mitral valve disease in dogs. The current consensus statement of the American College of Veterinary Internal Medicine (ACVIM) recommends a treatment for dogs with symptomatic disease and dogs with asymptomatic disease with radiographic and echocardiographic signs of cardiomegaly. To investigate whether these dogs also benefit from a therapy with pimobendan, 21 dogs with mitral valve disease ACVIM B1 [including one cavalier King Charles spaniel] underwent a standardized submaximal exercise test on a treadmill. ... Dogs with mitral valve disease Stage ACVIM B1 (presymptomatic disease without signs of cardiomegaly or congestive heart failure) were eligible for participation in the study. Dogs had to have a typical heart murmur, valvular lesions on the mitral valve and mitral regurgitation identified through echocardiographic examination. They were required to have no signs of congestive heart failure or left atrial or ventricular enlargement. Left atrial and ventricular size were assessed by the ratio of diameters of left atrium and aortic root (LA/Ao ratio, ≤ 1.6) and the diastolic diameter of left ventricle (LVIDDn, ≤1.7) during echocardiographic examination. ... The vertebral heart score (VHS) had to be within the reference range for the examined breed, but was only analyzed if an x-ray picture was available. ... In this double-blinded and randomized study, the animals were divided into two groups, one receiving pimobendan and the other a placebo. At the first visit and at every follow-up appointment (at days 90 and 180), heart rate during the complete exercise test and lactate before and after running were measured. In addition to this, a questionnaire was completed by the dogs’ owners and all dogs were given an echocardiographic examination to detect any changes and to observe if the disease had progressed. Due to the diagnosis of leishmaniosis, one dog in the pimobendan group was retrospectively removed from the study so that 20 dogs were included for statistical analysis. No differences were observed at any time between the pimobendan-group and the placebo-group regarding heart rate. At day 180, the increase in lactate after exercise was significantly lower than in the placebo-group. The increase in the pimobendan-group at day 180 was lower than at day 90. Most of the dog owners from the pimobendan-group declared that their dogs were more active at day 90 (6/10) and at day 180 (8/10), while most dog owners from the placebo-group observed no changes regarding activity at day 90 (8/10) and day 180 (6/10). It can be concluded that the results of this study indicate that some dogs with mitral valve disease ACVIM B1 might benefit from a therapy with pimobendan.

Left atrial anteroposterior diameter in dogs: reference interval, allometric scaling, and agreement with the left atrial-to-aortic root ratio. Federica Marchesotti, Tommaso Vezzosi, Rosalba Tognetti, Francesca Marchetti, Valentina Patata, Barbara Contiero, Eric Zini, Oriol Domenech. J. Vet. Med. Sci. October 2019; doi: 10.1292/jvms.19-0240. Quote: Left atrial enlargement (LAE) is a well-known negative prognostic factor in dogs with myxomatous mitral valve disease (MMVD). Left atrial-to-aortic root ratio (LA/Ao) is the most commonly used method to evaluate left atrial (LA) size in dogs, while the left atrial anteroposterior diameter (LAD) has been proposed as an additional measurement of LA size in different species. The aim of this study was to establish a normal reference range of LAD normalized to body weight (LADn) in dogs using allometric scales, and to evaluate the agreement between LADn and LA/Ao in the detection of LAE in dogs with MMVD. This was a retrospective, multicenter, observational study. We included 330 healthy dogs [64 different breeds, including 6 cavalier King Charles spaniels, plus 37 mixed breed dogs], [90 dogs with MMVD, of 23 different breeds, including 7 CKCSs] 30 dogs with MMVD in ACVIM stage B1, 30 dogs in ACVIM stage B2, and 30 dogs in ACVIM stage C. ... Normal LA dimension was defined as an LA/Ao ratio < 1.6, ... According to the LA/Ao, LAE was defined as a LA/Ao ≥ 1.6. ... The reference range for the LAD, depending on body weight, was between 16.91 mm and 49.68 mm. The reference range for the LADn in healthy dogs was between 10.49 and 15.72. LADn was significantly greater in dogs with MMVD compared to healthy dogs, and a significant difference in LADn was noted between different ACVIM stages (P<0.001). The most accurate cut-off value of LADn to differentiate between dogs in groups B2 and C was 20.3 (sensitivity, 83.3%; specificity, 83.3%). There was a misclassification rate of 37% between LADn and LA/Ao in the detection of LAE in group B1. This study provides a normal reference range for LAD in dogs, which can be used as an additional tool to assess LAE in dogs with MMVD. ... We only included 5 breeds in the evaluation of breed influence on LAD values. However, based on this preliminary analysis, it is reasonable to believe that breed does not significantly affect LADn. Further studies may be necessary to better establish if breed-specific reference values are necessary considering differences in type of breed, size, and conformation of the thorax.

Table 1

Retrospective study of the association between neutering status and changes secondary to degenerative mitral valve disease. Ana Margarida Ribeiro da Silva. University of Lisbon. Veterinary masters degree dissertation. October 2019. Quote: Myxomatous mitral valve disease is the most common cardiovascular disease reported in dogs. Although many patients may remain asymptomatic, some of them progress to left-sided congestive heart failure and develop clinical signs. Little has yet been published regarding the possible influence of the neutering status on changes secondary to myxomatous mitral valve disease. This study aims to assess a possible correlation between neutering status and myxomatous mitral valve disease. A retrospective study was conducted and included all the cases diagnosed with myxomatous mitral valve disease, consulted at the Cardiology service of the University of Liverpool. To help assess the association between neutering status and cardiac remodelling, dogs were categorized into four groups: FE (female entire), FN (female neutered), ME (male entire) and MN (male neutered). Retrospective review of echocardiographic data, signalment, and underlying diseases were performed. Echocardiographic measurements were made through offline analysis. Echocardiographic measurements were then compared between groups. Five hundred and eighty-two dogs (n = 582) [of 51 breeds plus cross-breeds] were included [176 (30.4%) were cavalier King Charles spaniels]: female entire (n = 24), female neutered (n = 235), male entire (n = 115) and male neutered (n = 208). Left ventricular internal diameter at end diastole (LVIDd), left atrial dimension to the aortic root diameter (LA:Ao) and left atrium maximal dimension to the aortic root dimension (LAmax:Ao) were significantly different between ME and MN, with ME dogs presenting higher mean values for LVIDd and higher median LA:Ao and LAmax:Ao measurements. Left ventricular internal diameter at end systole (LVIDs) was not significantly different between ME and MN. There were no significant differences between FE and FN groups. This study shows that neutering status may influence the development of myxomatous mitral valve disease in male dogs and that entire male dogs could be at higher risk of developing cardiac remodelling secondary to myxomatous mitral valve disease. On the other hand, neutering status doesn’t seem to have an influence on disease progression in female dogs.

Two-dimensional echocardiographic left-atrial-to-aortic ratio in healthy adult dogs: a re-examination of reference intervals. Mark Rishniw, Domenico Caivano, David Dickson, Liva Vatne, Jo Harris, Jose Novo Matos. J. Vet. Cardiol. November 2019;doi: 10.1016/j.jvc.2019.11.001. Quote: Introduction: Left-atrial-to-aortic ratios (LA:Ao) provide a body-weight independent estimate of left atrial size. However, reference intervals were established with small sample populations, and for only single points in the cardiac cycle. More robust reference intervals are warranted. Animals 238 apparently healthy adult dogs [27 different breeds plus 52 dogs of mixed breeds; 5 cavalier King Charles spaniels (2%)]. Materials and Methods: LA:Ao measurements were obtained at 3 points in the cardiac cycle – maximal dimension, at the closing of the aortic valve (or just before opening of the mitral valve) (LA:AoMAX); minimal dimension, at the onset of the QRS complex (LA:AoMIN) and at the onset of atrial systole (LA:AoP). LA:AoMAX was obtained from right parasternal short and long axis views, LA:AoMIN and LA:AoP were obtained from the right parasternal short axis view. Dogs were excluded from analyses of reference intervals if weight-based left atrial and left ventricular diastolic dimensions exceeded reference interval limits. Effects of breed and bodyweight on LA:Ao measurements were examined. Results: Upper LA:Ao reference limits mostly agreed with previously published limits, although 10% of dogs had LA:AoMAX in the short-axis view exceeding 1.6 [upper limit at 90% confidence interval was 1.76]. These dogs had smaller aortae than expected for their bodyweight, and included mostly boxers and English setters. Reference limits for LA:AoMIN and LA:AoP were smaller than those for LA:AoMAX in either view. No LA:Ao measurements were associated with bodyweight. Conclusions: Reference limits were either confirmed or established for the common two-dimensional methods of assessing relative left atrial size in healthy dogs. Clinicians should use caution when diagnosing mild left atrial enlargement in certain dog breeds, and should examine the weight-based aortic dimensions in such cases.... Our finding that LA:AoMAX, obtained from the right parasternal short-axis view, might exceed 1.6 in approximately 10% of dogs has clinical implications. Several studies have used reference limits of 1.5 or 1.6 when determining left atrial enlargement. This would tend to increase the number of dogs falsely identified as having mild left atrial enlargement. ... Our study suggests that the previous upper reference limit for two-dimensionally measured LA:AoMAX of 1.6, obtained from the right parasternal short-axis view, is reasonable, but might slightly underestimate the true range, resulting in misdiagnosis of some healthy dogs with LA:AoMAX slightly exceeding this limit as having left atrial enlargement. In our current study, approximately 10% of apparently healthy dogs exceeded this limit. Our study augments previous research by providing reference limits for LA:Ao measurements obtained during different points in the cardiac cycle, provides more robust data for left atrial dimension indexed to the weight-based aortic dimension (wLA), and provides novel data for the left atrial dimensions indexed to bodyweight. We identified at least two breeds in which the LA:Ao measurements exceeded traditional reference limits in a moderate proportion of the individuals: boxers and English setters. Therefore, clinicians should perhaps interpret LA:Ao measurements cautiously when examining individuals of these breeds. Whether similar issues exist with breeds absent from our study, or represented by too few individuals (e.g. Beagles), remains to be determined.

Treatment of Congestive Heart Failure with Intravenous Nitroglycerin in Three Dogs with Degenerative Valvular Disease. Ron Achiel, Andy Carver, Robert A. Sanders. JAAHA. November 2019; doi: 10.5326/JAAHA-MS-6730. Quote: We described the use of IV nitroglycerin as adjunctive therapy in three canine patients [all chihuahuas] with left congestive heart failure secondary to degenerative mitral valve disease. All three dogs were admitted for signs of respiratory distress and all were determined to be in left congestive heart failure by history, exam findings, thoracic radiographs, and echocardiography. In addition to standard therapy for left congestive heart failure, IV nitroglycerin was administered as a constant rate infusion at a dose of 1–6 mcg/kg/min. ... As a result of the severity of clinical signs in these three dogs, more aggressive preload and afterload reduction was considered necessary, but nitroprusside was prohibitively expensive for the owners. Based on the available experimental data, IV-NTG was considered an appropriate alternative. The dose of IV-NTG selected was based on previous experimental studies where the doses ranged from 0.3 to 40 mcg/kg/min.17,18 IV-NTG infusion was initiated at a low dose of 1 mcg/kg/min and titrated up by the attending clinician based on the patient’s clinical status. No clinically significant adverse events attributed to IV-NTG were noted in these cases, and the respiratory status of all patients improved during nitroglycerin administration. ... This is the first reported use of IV nitroglycerin in clinical veterinary patients. Further studies are warranted to investigate the safety, efficacy, and optimal dosing of IV nitroglycerin infusions in dogs with left congestive heart failure.

Comparison between the effects of torsemide and furosemide on the renin-angiotensin-aldosterone system of normal dogs. Brianna M. Potter, Marisa K. Ames, Ann Hess, Marko Poglitsch. J. Vet. Cardiol. November 2019; doi: 10.1016/j.jvc.2019.11.003. Quote: Introduction / Objectives: We hypothesized that torsemide and furosemide, at approximately equipotent dosages (similar diuresis), would have comparable effects on the circulating renin-angiotensin-aldosterone system. Animals, Materials and Methods: Six, healthy, middle-aged, male Beagles were randomized to receive torsemide (0.1 mg/kg PO q 12 h), furosemide (2.0 mg/kg PO q 12 h), or placebo for ten days during three separate periods, separated by a ten-day washout period, in a crossover design. Blood was collected on days one, five, and nine and 24-hour urine collection ended on days two, six, and ten. After repeated measures analysis and Bonferonni correction, variables with an adjusted p < 0.05 were investigated further, using Tukey’s method. Results: Twenty-four hour urine production differed significantly between the diuretics only on day ten, with torsemide causing a 38% greater diuresis than furosemide. There was, however, no significant difference in average three-day diuresis. There were no significant differences between diuretics in the 24-hour urinary excretion of sodium, chloride, or potassium, though furosemide caused less kaliuresis [excretion of potassium in the urine] than torsemide. Serum renin, angiotensin II, and aldosterone and the urine aldosterone-to-creatinine ratio were significantly increased in the diuretic groups, as compared to placebo on days five/six and nine/ten. There were no significant differences in these values between diuretics. ... A recent monograph shows an increasing relative potency (from approximately ten to twenty times) as the dosage of torsemide increases. In that monograph, when torsemide was dosed at 0.2 mg/kg once daily, it was about ten times more potent than furosemide. The results of our study support that, when torsemide is given at a dosage of 0.1 mg/kg q 12 h, the potency factor is closer to 20x, implying that frequency of dosing affects this potency relationship. ... Creatinine and blood urea nitrogen concentrations rose comparably in the diuretic groups, remaining within reference intervals in all dogs. Conclusions: At approximately equipotent dosages (20:1), torsemide and furosemide produced comparable renin-angiotensin-aldosterone system activation. Torsemide’s similar potassium excretion profile to furosemide decreases support for a hypothesized mineralocorticoid-receptor blocking capability.

Survival of activated myofibroblasts in canine myxomatous mitral valve disease and the role of apoptosis. Rachel R.Blake, Greg R. Markby, Geoff J. Culshaw, Yolanda Martinez-Pereira, Chi-Chien Lu, Brendan M.Corcoran. Res. Vet. Sci. February 2020;128(1):99-106. Quote: Myxomatous mitral valve disease (MMVD) is the single most important acquired cardiovascular disease of the dog. Much is known about the cellular changes and the contribution of activated myofibroblasts (valve interstitial cells (aVICs) to the valve extra-cellular matrix remodelling characteristic of the disease. However, little is known on how aVIC survival might contribute to disease pathogenesis. This study examined the temporal (disease severity-dependent) and spatial distribution of aVICs in MMVD valves, the expression of a range of apoptosis-related genes in cultured VICs from both normal (quiescent VIC (qVIC) and diseased (aVIC) valves, and the differential effects of doxorubicin treatment, as a trigger of apoptosis, on expression of the same genes.... A selection of valves [from euthanased dogs] were then processed for immunostaining (n=4 per grade; combination of elderly Cavalier King Charles Spaniels, elderly mixed breed dogs and young adult mixed breed dogs and beagles) or for valve interstitial cell culture (n= 11; combination of mixed breed dogs and beagles). ... Activated myofibroblasts were identified in normal valves at the valve base only (the area closest to the annulus), and then became more numerous and apparent along the valve length as the disease progressed, with evidence of cell survival at the valve base. There were no significant differences in basal gene expression comparing qVICs and aVICs for CASP3, FAS, BID, BAX, BCL2, CASP8, DDIAS, XIAP and BIRC5. After doxorubicin treatment (2mM) for 8h there was significant difference (P<.05) in the expression of BID, BCL2, DDIAS, and CASP8, but when assessed for interactions using a mixed model ANOVA only CASP8 was significantly different because of treatment (P<.05). These data suggest aVIC survival in MMVD valves may be a consequence of heightened resistance of aVICs to apoptosis, but would require confirmation examining expression of the relevant proteins progression. Highlights: • Activated myofibroblasts are persistent in myxomatous mitral valve disease (MMVD). • Apoptosis gene expression are comparable in normal and diseased mitral valve VICs. • Doxorubicin induces differential expression of apoptotic genes in normal and diseased VICs. • CASP8 expression is significantly different in diseased VICs treated with doxorubicin. • Activated myofibroblast persistence in MMVD may be due to resistance to apoptosis. (Read our review of this article, here.)

Heart to spine measurements to detect left atrial enlargement in dogs with mitral insufficiency. Xavier Sánchez Salguero, David Prandi, Francisco Llabrés-Díaz, Edgar G. Manzanilla, Llorenç Badiella, Claudio Bussadori. Irish Vet. J. November 2019; doi: 10.1186/s13620-019-0152-6. Quote: Background: Radiography is useful to determine left atrial (LA) size when echocardiography is not available. Recently, the authors have described Radiographic Left Atrial Dimension (RLAD) as a new radiographicmeasurement to assess LA size. [See this December 2018 article.] The objective of this study was to assess the clinical usefulness of 2 new radiographic measurements to detect and quantify left atrial enlargement (LAE) compared to RLAD and using left atrium to aortic root (LA/Ao) ratio as gold standard. These new measurements, bronchus-to-spine (Br-Spine) and RLAD-to-spine (RLAD-Spine) may be more precise in cases were LA boundaries are not well defined. Fifty dogs [including one cavalier King Charles spaniel], 25 with and 25 without LAE were recruited. Reference LA/Ao ratio was assessed by 2D echocardiography and LAE was considered if LA/Ao > 1.6. Br-spine was measured as a straight vertical line from the main stem bronchus to theventral border of the vertebra situated immediately dorsal to the heart base. RLAD-Spine was measured from RLAD endpoint perpendicularly to spine. The correlation of RLAD, Br-Spine and RLAD-Spine methods with LA/Ao andtheir sensitivity and specificity for detecting LAE were calculated. Receiver Operating Characteristic (ROC) curves were used to estimate the optimal cut-off for each method. Results: Correlations between Br-Spine, RLAD-Spine, RLAD and LA/Ao ratio were−0.66,−0.76 and 0.89 respectively (P< 0.001). Sensitivity at the optimal cut-off values for detecting LAE were 32.0, 64.0 and 96.0%, respectively. Specificity was 96.0% in all cases. Conclusion: Br-Spine and RLAD-Spine were less sensitive radiographic measurements than RLAD in detecting LAEin dogs. Both Br-Spine and RLAD-Spine may not be good alternatives to RLAD.

Dietary intervention reduces left atrial enlargement in dogs with early preclinical myxomatous mitral valve disease: a blinded randomized controlled study in 36 dogs. Qinghong Li, Allison Heaney, Natalie Langenfeld-McCoy, Brittany Vester Boler, Dorothy P. Laflamme. BMC Vet. Res. November 2019;15:425. Quote: Background: Myxomatous mitral valve disease (MMVD), the most common naturally-occurring heart disease in dogs, is associated with alterations in energy metabolism, oxidative stress and inflammation. Energy deprivation plays a causal role in the development of heart failure. This study was designed to determine if a cardiac protection blend (CPB) of nutrients containing medium-chain triglycerides [MCTs] as an alternative energy source, fish oil to reduce inflammation, antioxidants, and other key nutrients important to cardiac health and function could slow or prevent MMVD progression. Nineteen dogs with early stage MMVD [17 Beagles and 2 miniature Schnauzers] and 17 breed-, age-, and sex-matched healthy dogs [15 Beagles and 2 miniature Schnauzers] were enrolled for a 6-month blinded, placebo-controlled study. Dogs in each cardiac health group were randomly assigned to either control diet (CON) or CPB-supplemented diet [MCTs; longchain omega-3 fatty acids; lysine and methionine (carnitine precursors); vitamin E (an antioxidant); magnesium; and taurine]. Echocardiography was performed at baseline, 3 months and 6 months. Results: No changes were found in healthy dogs. While MMVD-CON dogs had an average 10% increase over baseline in left atrial diameter (LAD) and left atrial to aortic root ratio (LA/Ao) at 6 months, MMVD-CPB dogs showed 3% decreases, resulting significant diet by time interactions (P=0.037, P=0.005, respectively). More MMVD-CON dogs progressed from stage B1 to B2 during the study. A positive correlation was found between 6-month changes in LAD and blood pressures in MMVD-CPB dogs (systolic: P=0.050, diastolic: P=0.035) but not MMVD-CON dogs. Conclusions: Our results demonstrated efficacy of CPB-based dietary intervention in reducing LA size and mitral regurgitation, and in slowing or preventing the progression of early MMVD in dogs.

Pulmonary hypertension in Cavalier King Charles spaniels. Mark Rishniw. Advances in Sm. Anim. Med. & Surg. December 2019;32(12):3-4. Quote: Review of "The prevalence of pulmonary hypertension in Cavalier King Charles spaniels compared with other breeds with myxomatous mitral valve disease." ... Although the authors struggled to state that their hypothesis was wrong, the data clearly show that the only thing predictive of PH in dogs with MMVD is the severity of the valve disease, and that being a CKCS does not increase your risk of having PH. In other words, the more severe the valve disease, regardless of breed, the higher chance the dog has PH because of the valve disease. The authors initially present the data suggesting that a higher proportion of CKCS had PH than non-CKCS dogs. However, this simply reflects the fact that the CKCS in their study simply were “worse off” at presentation than the non- CKCS dogs. The logistic regression analysis demonstrated this to be the case—once the authors accounted for disease severity, breed was no longer relevant. The authors also report an overall percentage of dogs presenting with PH secondary to mitral valve disease. They suggest that some 65 to 70% of dogs with MMVD disease in their study had PH. However, clinicians should not believe this number as reflective of the real-world situation. First, the authors selected dogs in which a tricuspid regurgitation jet could be measured. It is possible that this biased the population towards selecting dogs with elevated pulmonary artery pressures. Second, the authors used a very low threshold tricuspid regurgitation value (2.8 m/s) to identify PHn. This would necessarily increase the number of false-positive cases (dogs that are identified as having PH but are actually normotensive). Finally, the authors did not differentiate between degrees of PH. Clinicians know and expect some PH with more severe MMVD. If this hypertension is “appropriate” and mild, it is clinically inconsequential and can be ignored. Only “inappropriate” and more severe hypertension concerns us and might warrant intervention. Therefore, clinicians should recognize that PH can occur in dogs with MMVD, and that CKCS are no more “prone” to developing this type of PH than other breeds. With more severe MMVD, clinicians should always consider assessing whether PH exists and whether it warrants therapeutic intervention.

Cardiac cachexia is an independent predictor of survival in dogs with heart failure.  Deanna L. Ineson, Lisa M. Freeman, John E. Rush. J. Cachexia, Sarcopenia and Muscle. December 2019;10:1384 (1-15). Quote:  Background: Heart disease affects 10–15% of all pet dogs and can result in heart failure, which is often associated with cardiac cachexia (defined as loss of muscle). In humans, cardiac cachexia is associated with shorter survival, but this has not been reported in dogs. Therefore, the aim of this study was to evaluate the effect of cardiac cachexia on survival in dogs with heart failure. Methods: Dogs with heart failure (Stage C or D) due to naturally occurring myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM) and evaluated between 2015 and 2018 were eligible. Medical records data recorded included body weight, body condition score (BCS), and muscle condition score (MCS). Cachexia was defined as any muscle loss using the validated World Small Animal Veterinary Association scoring system of normal muscle condition or mild, moderate, or severe muscle loss. Results: Median age of the dogs (n = 269) was 11.0 years (range, 1.8–17.1 years); 54% were male. Mean body weight was 7.9 kg (range, 2.1–82.0 kg). Only 12 dogs were underweight (4.5%), 157 were ideal weight (58.6%), and 99 were overweight (36.9%). Cachexia was present in 48.3% of dogs: mild muscle loss: 101/269 (37.6%), moderate muscle loss: 22/269 (8.2%), and severe muscle loss: 7/269 (2.6%). Dogs with cachexia had a median survival time from onset of heart failure of 233 days (range, 0–1200 days) compared to dogs without cachexia (321 days, range 1–1264 days; P = 0.036). On multivariable analysis, cachexia, presence of arrhythmia or azotaemia, and being under‐ or overweight were independent risk factors for shorter survival time. Conclusions: Cardiac cachexia was present in nearly half of all dogs with heart failure and was associated with a shorter survival time.

Left atrial volume assessment in 160 Cavalier King Charles Spaniels with and without degenerative mitral valve disease (2017-2019). C. Poissonnier, P. Foulex, M.P. Alvarado, E. Trehiou-Sechi, V. Saponaro, P. Passavin, S. Ghazal, S. Lefort, L. Desquilbet, V. Chetboul. 29th ECVIM-CA Congress. J. Vet. Int. Med. December 2019; doi: 10.1111/jvim.15658; pg. 69;ESVC-P-11. Quote: Degenerative mitral valve disease (DMVD) is the most common acquired heart disease in small-sized dogs with a high predisposition of the Cavalier King Charles Spaniel (CKC) breed. Echocardiographic assessment of the disease is based on the evaluation of atrial and ventricular dimensions, with left atrial (LA) diameter measurement being one of the strongest predictors of clinical outcome. The LA diameter is usually evaluated on the right parasternal transaortic short-axis view and compared to the aortic (Ao) diameter (LA:Ao ratio). However, LA dilation can develop in medio-lateral, cranio-caudal, or ventro-dorsal directions. Therefore, the LA:Ao ratio may not be reliable for the early detection of LA dilation. Measurements of LA volumes have been recently recommended in the dog using monoplane and biplane Simpson's modified methods of discs (SMOD) and area-length methods (ALM). The objectives of this prospective study were therefore to 1) compare different echocardiographic methods in evaluating LA volume in a large population of CKCs and 2) to assess LA volume according to DMVD severity. The study population consisted in 160 CKCs either healthy or affected by DMVD (median weight = 9.15 kg [interquartile range (IQR) = 7.8-10.3], male-to-female ratio = 0.95). According to the ACVIM classification, 28/160 dogs (17.5%) had no identifiable DMVD lesions (stage A), 86/160 (53.8%) and 22/160 (13.8%) were in stages B1 and B2, respectively, 23/160 (14.3%) had past or current congestive heart failure (CHF, stage C), and 1/160 (0.6%) had refractory CHF (stage D). Dogs for which mitral regurgitation (MR) was adequate for quantification by the Proximal Isovelocity Surface Area method (n = 107) had a median regurgitation fraction (RF) of 38% [23-55]. The monoplane SMOD and ALM using the left apical 4-chamber view overestimated LA volume by comparison with the biplane ALM (+2.6% and + 10.8%, respectively), and the monoplane ALM overestimated LA volume in comparison with the monoplane SMOD (+8.3%). Left atrial volumes significantly increased with ACVIM stages. Among B1 dogs, end-systolic LA volume assessed by the biplane ALM was significantly lower in dogs with mild MR (RF<30%, median volume = 0.75 mL/kg [IQR = 0.59-0.90]) than for dogs with higher MR (RF≥30%, median volume = 1.39 mL/kg [IQR = 0.96-1.56]; P < 0.01). In conclusion, this study demonstrates the importance of LA volume measurement in CKCs with DMVD, especially among B1 DMVD dogs. These results suggest that a category of B1 dogs (with RF > 30%) actually show LA dilation, which is however not apparent using the LA:Ao ratio calculation, thus potentially leading to a misdiagnosis between DMVD B1 and B2 stages.

Effect of pimobendan on left atrial function in dogs with preclinical myxomatous mitral valve disease. Fabio Sarcinella, Joao Neves, Thomas W. Maddox, Hannah M. Hodgkiss-Geere, Elizabeth F. Bode, Joanna Dukes-McEwan. Open Vet. J. December 2019;9(4):375-383. Quote: Background: Left atrial (LA) function is an important determinant of the left ventricular (LV) filling, playing a key role in maintaining optimal cardiac performance. Pimobendan is a phosphodiesterase III inhibitor with positive inotropic and vasodilator effects. The present study aims to investigate the effects of pimobendan on LA function in dogs with stage B2 myxomatous mitral valve disease (MMVD). Aim: The aim of this investigation was to study the effects of pimobendan on LA function in dogs with preclinical MMVD. Methods: Twenty-seven dogs [including 15 Cavalier King Charles Spaniels -- 55.6%] with stage B2 MMVD were retrospectively included. ... Dogs that had undergone echo and were coded as stage B2 ... based on the echocardiographic criteria proposed by the EPIC study (short-axis early diastolic left atrial-to-aortic diameter ratio (LA/Ao)≥ 1.6 and M-mode left ventricular internal diameter normalized for body weight (LVIDDN) ≥ 1.7), and that a repeat echocardiographic study was performed within 6 months from initiation of pimobendan. ... LA function was assessed before and 1–6 months following pimobendan initiation. For each dog, two-dimensional (2D) echocardiography was performed to assess LA diameter and volume for each phase of the LA cycle and to assess complete, passive, and active LA function. Pulsed-wave tissue Doppler imaging (TDI) of the left ventricular longitudinal myocardial velocity associated with atrial contraction (A’), both at the level of the interventricular septum and the LV free wall, was also used as an indicator of LA function. Results: There were no significant differences in any of the left atrial variables pre- and posttreatment. Conclusion: Echocardiographic estimates of LA function by 2D diameters and volumes and TDI A’ in dogs with MMVD do not change after treatment with pimobendan. ... While there was no demonstrable improvement in LA size and function, it is important to note that there was also a lack of negative changes in LA function and dimension which may also support a beneficial effect of pimobendan in delaying the progression of the disease, although a maximum of 6 months interval maybe too a short time interval to expect significant progression of this condition. (Read our review of this article, here.)

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2020

DELay of appearance of sYmptoms of canine degenerative mitral valve disease treated with spironolactone and benazepril: The DELAY study. M. Borgarelli, L. Ferasin, K. Lamb, C. Bussadori, D. Chiavegato, G. D’Agnolo, F. Migliorini, M. Poggi, R.A. Santilli, E. Guillot,C. Garelli-Paar, R. Toschi Corneliani, F. Farina, A. Zani, M. Dirven, P. Smets, C. Guglielmini, P. Oliveira, M. DiMarcello, F. Porciello, S. Crosara, P. Ciaramella, D. Piantedosi, S. Smith, S. Vannini, E. Dall’Aglio, P. Savarino, C. Quintavalla, M. Patteson, J. Silva, C. Locatelli, M. Baron Toaldo. J. Vet. Cardio. January 2020; doi: 10.1016/j.jvc.2019.12.002. Quote: Introduction: Efficacy of renin-angiotensin-aldosterone system (RAAS) blockade using angiotensin converting enzyme inhibitors (ACEi) in dogs with preclinical myxomatous mitral valve disease (MMVD) is controversial. Hypothesis: Administration of spironolactone (2-4 mg q 24 h) and benazepril (0.25-0.5 mg q 24 h) in dogs with preclinical MMVD, not receiving any other cardiac medications, delays the onset of heart failure (HF) and cardiac-related death. Moreover, it reduces the progression of the disease as indicated by echocardiographic parameters and level of cardiac biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI). Animals: 184 dogs [34 cavalier King Charles spaniels - 19%] with pre-clinical MMVD and left atrium to aortic root ratio (LA:Ao) >1.6 and normalized left ventricular end-diastolic diameter (LVEDDn) >1.7. Methods: Prospective, randomized, multicenter, single-blinded, placebo-controlled study. Primary outcome variable was time to onset of first occurrence of HF or cardiac death. Secondary endpoints included effect of treatment on progression of the disease based on echocardiographic and radiographic parameters, as well as variations of NT-proBNP and cTn-I concentrations. Results: The median time to primary end-point was 902 days (95% confidence interval (CI) 682-NA) for the treatment group and 1139 days (95% CI 732-not available) for the control group (p=0.45). Vertebral heart score (p=0.05), LA:Ao (p<0.001), LVEDDn (p<0.001), trans-mitral E peak velocity (p=0.011), and NT-proBNP (p=0.037) were lower at the end of study in the treatment group. Conclusions: This study failed in demonstrating that combined administration of spironolactone and benazepril delays onset of HF in dogs with preclinical MMVD. However, such treatment induces beneficial effects on cardiac remodeling and these results could be of clinical relevance. (Read our review of this article, here.)

Multiple retrospective analysis of survival and evaluation of cardiac death predictors in a population of dogs affected by degenerative mitral valve disease in ACVIM class C treated with different therapeutic protocols. Mara Bagardi, Chiara Locatelli, Annamaria Zanaboni, Alberto Galizzi, Dario Malchiodi, Paola G. Brambilla. BioRxiv. January 2020; doi: 10.1101/2020.01.13.904102. Quote: Clinical records of dogs with spontaneous degenerative mitral valve disease (DMVD) with clinical signs related to congestive heart failure (CHF) that had been recruited during routine clinical practice, between 2001 and 2018 at the Cardiology Unit of the Veterinary Teaching Hospital (University of Milan) were included in this retrospective cohort study. ... In this study all genders, weights and breeds were included, except for Cavalier King Charles Spaniel. ... Baseline echocardiographic data were evaluated. Median survival times (MSTs) were calculated. Data on therapeutic treatment, ISACHC or ACVIM classes were reviewed based on the inclusion period and type of endpoint (i.e. cardiac death or death for other causes). The main goal of this data review was to retrospectively evaluate 259 clinical records of subjects belonging to ACVIM C class examined between 2001 to 2018 together with the 202 examined between 2010 to 2018. ... The aim of this retrospective study was to investigate the MST of dogs affected by DMVD belonging ACVIM class C and treated with different combinations of drugs. In addition, the effects of the different therapeutic protocols on the MST and the prognostic values of the echocardiographic data were evaluated. ... The MSTs of these subjects was 531 d (2001-2018) and 335.5 d (2010-2018), respectively. Univariate survival regression analysis for subjects included from 2010 to 2018 showed the following variables as being significantly related to cardiac death (CD): LA/Ao ratio (HR 2.754, p=0.000), E wave (HR 2.961, p=0.000), E/A ratio (HR 1.372, p=0.000), EDVI (HR 1.007, p=0.000), ESVI (HR 1.012, p=0.026), Allo(d) (HR 4.018, p=0.000) and Allo(s) (HR 2.674, p=0.049), age (HR 1.006, p=0.009) and PH severity (HR=1.309, p=0.012). Multivariate analysis, adjusted for age, showed that the only variable that determined a statistically significant difference in MST was PH severity (HR 1.334, p=0.033). The type of therapeutic treatment within this class was not significant for the MST of the subjects. (See also the March 2021 version of this study.)

Evaluation of atrial natriuretic peptide and cardiac troponin I concentrations for assessment of disease severity in dogs with naturally occurring mitral valve disease. Yasutomo Hori, Masayuki Iguchi, Atsushi Hirakawa, Zenta Kamiya, Shigeki Yamano, Toshiki Ibaragi, Noriko Isayama, Yohei Yamashita, Naoki Iwasa, Haruki Inaba, Yasuhiro Heishima, Masashi Yuki. JAVMA. February 2020;256(3):340-348. Quote: Objective: To evaluate and compare the clinical usefulness of plasma atrial natriuretic peptide (ANP) and cardiac troponin-I (cTnI) concentrations for assessment of disease severity in dogs with naturally occurring mitral valve disease (MVD). Animals: 316 dogs [of 21 breeds and 17 mixed-breeds] with MVD [including 41 Cavalier King Charles Spaniels (13%)] and 40 [15 breeds and 3 mixed-breeds] healthy control dogs [including one CKCS]. Procedures: Each dog underwent a physical examination and echocardiographic and thoracic radiographic assessments. Blood samples were obtained and processed for measurement of plasma ANP and cTnI concentrations. Dogs with MVD were categorized into 3 groups (stages B1 [no clinical signs or evidence of cardiac enlargement], B2 [no clinical signs with evidence of cardiac enlargement], and C [history of congestive heart failure and pulmonary edema]) on the basis of American College of Veterinary Internal Medicine guidelines. ... Briefly, dogs without clinical signs of cardiac disease and an LA:Ao < 1.7 or LVIDDn < 1.7 cm/kg0.294 were assigned to stage B1. Dogs without clinical signs of cardiac disease and an LA:Ao ≥ 1.7 and LVIDDn ≥ 1.7 cm/kg0.294 were assigned to stage B2. ... Dogs in stage B2 (n = 102) had no clinical signs of cardiac disease and an LA:Ao ≥ 1.7 or LVIDDn ≥ 1.7 cm/kg0.294. ... Receiver operating characteristic curve analysis was used to evaluate the accuracy of plasma ANP and cTnI concentrations for assessment of MVD severity. Results: Plasma ANP and cTnI concentrations increased as disease severity increased. Median plasma ANP concentrations for all 3 MVD groups and median plasma cTnI concentrations for the stage B2 and C groups were significantly greater than the corresponding concentrations for the control group. Plasma ANP concentration, but not cTnI concentration, appeared to be useful for detection of dogs with subclinical (stages B1 and B2) MVD, whereas both concentrations appeared useful for detection of dogs with stage C MVD. Conclusions and Clinical Relevance: Results indicated that plasma ANP and cTnI concentrations should not be used independently to diagnose MVD but can be used to assess MVD severity and supplement echocardiographic findings. (Read our review of this article, here.)

Angiotensin-Converting Enzyme Inhibitors and Cardiac Disease: Have They Had Their Day? Mark Rishniw. Advances in Sm. Anim. Med. & Surg. February 2020;33(2):1-3. Quote: The first randomized clinical trials of ACE-I in dogs were ... funded by the manufacturer of enalapril, Merial. The first of these studies, IMPROVE (Invasive Multicenter PROspective Veterinary Evaluation of enalapril) ... even if we take the tabulated data at face value, it becomes immediately clear that the majority of benefit, if one existed, occurred in the DCM group, not the MMVD group. ... The IMPROVE study was coupled with the COVE study (COntrolled clinical eValuation of Enalapril). ... Again, examination of Tables 7 and 8 in that article showed that almost all statistically relevant improvement occurred in dogs with DCM, not MMVD. ... The LIVE (Long-term Investigation of Veterinary Enalapril) study completed the initial enalapril “trilogy” studies funded by Merial. This study examined the long-term survival of dogs with either MMVD or DCM, again randomized to receive either enalapril or placebo. ... The published results suggested that dogs with MMVD, but not DCM, survived longer or had stable CHF longer if receiving enalapril. However, subsequent investigations of the data showed that when the study was presented some 4 years prior to publication, the exact opposite had been observed—in other words, the dogs with DCM receiving enalapril did better than those on placebo. The drug had no effect on outcomes in dogs with MMVD. ... In retrospect, it became clear that the veterinary community was hoodwinked into believing that ACE-I were the medical cure for CHF dogs because of corporate marketing decisions. ... The SVEP (Scandinavian Veterinary Enalapril Prevention) trial, randomized Cavalier King Charles Spaniels with subclinical MMVD to receive either enalapril or placebo. Dogs were followed until they developed CHF or died from a cardiac cause. The study showed that enalapril had absolutely no effect on preventing development of CHF in this group of dogs. ... Consequently, the VETPROOF (Veterinary Enalapril Trial to Prove Reduction in Onset of heart Failure) study was undertaken. This study enrolled dogs of various breeds, randomized to enalapril or placebo. Again, despite the authors’ best efforts, the drug failed to demonstrate a benefit in delaying the onset of CHF or cardiac death. ... So, what does all this mean? My interpretation of all this literature suggests that ACE-I have no place in managing mitral valve disease, whether in dogs with CHF or dogs with subclinical disease. ... If ACE-I have any role in managing heart disease, it is restricted to dogs with DCM (either subclinical or with CHF). However, whether the benefit of ACE-I in dogs with DCM persists in the era of pimobendan remains unknown. It is possible that pimobendan provides all the benefit that one will likely see and that ACE-I have no additional effect. It might be time to move ACE-I into the same pile as theophylline and digoxin when it comes to managing progression of disease or stabilizing CHF. (Read our review of this article, here.)

Evaluation of left atrial function in asymptomatic dogs with chronic myxomatous mitral valve disease: two-dimensional feature-tracking echocardiography and Simpson’s monoplanar methods. Pesquisa Vet. Brasil. Mariana R. Coelho, Ruthnea A.L. Muzzi, Elaine M.S. Dorneles, Guilherme G. Pereira, Rosa M. Cabral, Leonardo A.L. Muzzi, Claudine B. Abreu, Luiz E.D. Oliveira. February 2020;40(3):188-196. Quote: The present study evaluated the volume and function of the left atrium by two-dimensional echocardiographic feature-tracking imaging (2D-FTI) and Simpson’s monoplanar modeling in dogs with asymptomatic degenerative mitral valve disease (DMVD). The study consisted of 80 dogs that were divided into the following three groups: Group 1, 21 dogs (A); Group 2, 30 dogs (B1) and Group 3, 29 dogs (B2). The variable strain (contraction phase) was significantly lower in Group 3 than in Group 1 (12.92±4.54 x 16.69±5.74, p=0.014), and significant differences in the contraction strain index (CSI) were observed between all of the groups that were evaluated (1 = 46.82±8.10, 2 = 39.88±8.03, 3 = 35.25±5.64, p<0.0001). The atrial diastolic volume index (AdVi) that was measured by 2D-FTI was significantly higher in Group 3 than in Group 1 (1.31±0.95 x 0.96±0.31, p=0.038), and the atrial cardiac index (ACI) was also higher in Group 3 than in Group 1 (102.38±80.18 x 78.19±33.38, p=0.030). Atrial function was assessed by Simpson’s monoplanar method, which demonstrated an increase in the left atrial systolic volume, while the contractile function decreased with an increasing disease severity (Group 1 0.21±0.06; Group 2 0.25±0.06; Group 3 0.32±0.08, p<0.0001). The intraobserver and interobserver assessments showed low to moderate variability; most of the values for the coefficient of variation for the variables that were analysed with each method were below 25%. Thus, DMVD was determined to cause an alteration in atrial function, especially in the contraction phase, and even in asymptomatic animals, and the methods of 2D-FTI echocardiography and Simpson’s monoplanar evaluation are sensitive and early methods for the detection of left atrial dysfunction.

Comparative Pathology of Human and Canine Myxomatous Mitral Valve Degeneration: 5HT and TGF-β Mechanisms. Mark A. Oyama, W. Chad Elliott, Kerry A. Loughran, Alexander P. Kossar, Estibaliz Castillero, Robert J. Levy, Giovanni Ferrari. Cardio. Pathol. May 2020;46:107196. Quote: Myxomatous mitral valve degeneration (MMVD) is a leading cause of valve repair or replacement secondary to the production of mitral regurgitation, cardiac enlargement, systolic dysfunction, and heart failure. The pathophysiology of MMVD is complex and incompletely understood, but key features include activation and transformation of mitral valve (MV) valvular interstitial cells (VICs) into an active phenotype leading to remodeling of the extracellular matrix and compromise of the structural components of the MV leaflets. Uncovering the mechanisms behind these events offers the potential for therapies to prevent, delay, or reverse MMVD. One such mechanism involves the neurotransmitter serotonin (5HT), which has been linked to development of valvulopathy in a variety of settings, including valvulopathy induced by serotonergic drugs, 5HT-producing carcinoid tumors and development of valvulopathy in laboratory animals exposed to high levels of 5HT. Similar to humans, the domestic dog also experiences naturally-occurring MMVD, and in some breeds of dogs, the lifetime prevalence of MMVD reaches 100%. In dogs, MMVD has been associated with high serum 5HT, increased expression of 5HT-receptors, autocrine production of 5HT within the MV leaflets, and down regulation of 5HT clearance mechanisms. One pathway closely associated with 5HT involves transforming growth factor beta (TGF-β) and the two pathways share a common ability to activate MV VICs in both humans and dogs. Understanding the role of 5HT and TGF-β in MMVD gives rise to potential therapies, such as 5HT receptor (5HT-R) antagonists. The main purposes of this review are to highlight the commonalities between MMVD in humans and dogs, with specific regards to 5HT and TGF-β, and to champion the dog as a relevant and particularly valuable model of human disease that can accelerate development of novel therapies. ... There are potential important interbreed differences: CKCS [cavalier King Charles spaniels], a breed with extremely high prevalence of MMVD, are reported to have particularly increased serum 5HT levels. ... 5HT in platelet rich plasma was higher in healthy CKCS, as well as both CKCS and mixed breed dogs with MMVD vs. healthy mixed breed controls. ... Of interest, the CKCS breed is also associated with an inherited thrombocytopenia and giant platelet disorder affecting approximately half of all CKCS dogs. Scanning electron microscopy of the giant platelets from these dogs revealed the presence of dense granules and other ultrastructural features similar to normal sized platelets. In addition to having macrothrombocytes, the platelet population in CKCS dogs with MMVD also contains at least one flow cytometry scatterplot subpopulation with a higher percentage of surface-bound 5HT-positive expression and activation, but the exact relationship of platelet morphology, ultrastructure, and function to MMVD requires further study. ... The dog, and in particular the CKCS breed, represents a model to further study 5HT and TGF-β mechanisms and to test novel therapies. (Read our review of this article, here.)

ACVIM consensus statement guidelines for the diagnosis, classification, treatment, and monitoring of pulmonary hypertension in dogs. Carol Reinero, Lance C. Visser, Heidi B. Kellihan, Isabelle Masseau, Elizabeth Rozanski, Cécile Clercx, Kurt Williams, Jonathan Abbott, Michele Borgarelli, Brian A. Scansen. J. Vet. Intern. Med. February 2020; doi: 10.1111/jvim.15725. Quote: Pulmonary hypertension (PH), defined by increased pressure within the pulmonary vasculature, is a hemodynamic and pathophysiologic state present in a wide variety of cardiovascular, respiratory, and systemic diseases. The purpose of this consensus statement is to provide a multidisciplinary approach to guidelines for the diagnosis, classification, treatment, and monitoring of PH in dogs. Comprehensive evaluation including consideration of signalment, clinical signs, echocardiographic parameters, and results of other diagnostic tests supports the diagnosis of PH and allows identification of associated underlying conditions. ... Exertional syncope, labored respiration or overt respiratory distress, and exercise intolerance are noteworthy clinical signs frequently directly attributable to PH.  ... In the veterinary medical literature, the degree or severity of PH has been classified as mild, moderate, or severe. These categories are based on the PG derived from TRV (also called the tricuspid regurgitation PG) or estimated systolic PAP. Cutoffs used for these categories (mild, moderate, severe) are arbitrary, and the categories are potentially misleading or flawed. For example, based on the conventional definition of PH (based solely on estimated systolic PAP), a dog with severe PH can be free of clinical signs, whereas a dog with moderate PH could be in rightsided heart failure. Therefore, the panel does not advocate their use. Instead, severity of PH should be based on clinical findings (Table 1) and outcome data from large (prospective) longitudinal studies, which unfortunately are unavailable. ... TABLE 1: Clinical findings suggestive of pulmonary hypertension (PH) in dogs -- Findings strongly suggestive of PH -- Syncope (especially with exertion or activity) without another identifiable cause. ... The panel recognizes the probabilistic approach to diagnosis of PH presents challenges, particularly regarding standardized enrollment in future clinical studies of dogs with suspected PH. Therefore, we propose that the clinical definition of PH should include dogs with intermediate or high probability of PH, and specifically, a tricuspid regurgitation PG cutoff of >46 mm Hg (TRV >3.4 m/s). This roughly equates to what has been conventionally referred to as at least moderate PH. Until there are echocardiographic variables that are repeatable and have acceptable diagnostic accuracy relative to RHC, this cutoff value could be used with an understanding of its limitations. ... Dogs with PH can be classified into the following 6 groups: group 1, pulmonary arterial hypertension; group 2, left heart disease; group 3, respiratory disease/hypoxia; group 4, pulmonary emboli/pulmonary thrombi/pulmonary thromboemboli; group 5, parasitic disease (Dirofilaria and Angiostrongylus); and group 6, disorders that are multifactorial or with unclear mechanisms. The approach to treatment of PH focuses on strategies to decrease the risk of progression, complications, or both, recommendations to target underlying diseases or factors contributing to PH, and PH-specific treatments. ... Treatment strategies for targeting the underlying disease in group 2 patients are centered around identifying and, if possible, reversing the cause of LHD [left-sided heart disease], decreasing postcapillary PH (ie, lowering LA pressure) and, if present, treating heart failure. ... Because dogs with PH secondary to LHD, by definition, have postcapillary PH (with or without pre-PH), the use of phosphodiesterase 5 inhibitors (PDE5i) [e.g., sildenafil (Viagra)] is not recommended as first line treatment. ... A PDE5i should be administered only to dogs free of acute or decompensated LHF (cardiogenic pulmonary edema). Heart failure medications (HFM) and a PDE5i are recommended for dogs with clinical (eg, jugular venous distension, fluid wave on abdominal palpation, or auscultable pleural fluid line) and ultrasonographic (abdominal or pleural effusion without another cause along with RA enlargement, caudal vena caval distension, hepatic venous distension or hepatomegaly) evidence of right-sided heart failure. Addition of a PDE5i may be considered in dogs with exertional syncope without another identifiable cause that have failed to respond to other treatments for preclinical LHD (eg, pimobendan). ... A PDE5i may be considered for dogs with compensated LHF and a high probability of PH (ie, dogs previously diagnosed with LHF and on HFM but that do not currently have pulmonary edema) that develop exertional syncope without another identifiable cause. A thorough diagnostic evaluation is advised to rule out alternative causes of syncope (eg, ECG, ambulatory ECG monitoring, or both to exclude bradyarrhythmias or tachyarrhythmias as potential causes for syncope). ... Dogs with PH should be monitored for improvement, static condition, or progression, and any identified underlying disorder should be addressed and monitored simultaneously. (Read our review of this article, here.)

An Assessment of Vertebral Left Atrial Size in Relation to the Progress of Myxomatous Mitral Valve Disease in Dogs. Sun Hwa Kim, Kyoung Won Seo, Kun Ho Song. J. Vet. Clinics. February 2020; doi: 10.17555/jvc.2020.02.37.1.9. Quote: Left atrial enlargement (LAE) is an important diagnostic factor in dogs with myxomatous mitral valve disease (MMVD). It is associated with the onset of congestive heart failure (CHF). Recently, a new radiographic left atrial measurement called vertebral left atrial size (VLAS) was introduced. This can be considered as a left atrial enlargement above 2.3. It appears to be related to the severity of MMVD. However, serial changes in VLAS in relation to disease progression and improvement in patients have yet to be studied. This study aims to assess the value of VLAS as a left atrial size monitoring indicator by examining correlations with VHS, LA/Ao ratio and LVIDDN, and comparing serial changes in dogs. A total of 126 dogs were studied with their owners’ consent. The dogs were classified into four MMVD groups (Control, B1, B2, C-D) following the ACVIM Guideline by performing a physical examination, radiography and echocardiography. Besides, 24 and 17 dogs were reevaluated to compare values in relation to the progression and improvement of MMVD. VLAS showed significant increase according to the progress of the MMVD stage. This was the same in the Maltese breed group. A strong positive correlation was found between LVIDDN, VHS, LA/Ao ratio, and VLAS. The results of this study found VLAS to be significantly different according to left atrium size, and there was a correlation between disease progression and VLAS levels in each dog. Therefore, VLAS may be used to detect changes in left atrium size as an additional monitoring index of MMVD.

Unilateral diaphragmatic paralysis associated with surgical mitral valve repair in dogs. Kazuya Mamada, Ayaka Chen, Kazuki Takamura, Masaru Murakami, Masami Uechi. J. Vet. Cardiol. March 2020; doi: 10.1016/j.jvc.2020.03.001. Quote: Objectives: Unilateral diaphragmatic paralysis (UDP) due to phrenic nerve injury is a potential complication of thoracic surgery. This study evaluated the prevalence of UDP associated with surgical mitral valve repair (MVR) and its effect on surgical outcomes in dogs. Animals, Materials and Methods: Two hundred ninety-four dogs that underwent MVR were included in the study. ... Chihuahuas were the most common (n=133), followed respectively by Cavalier King Charles Spaniels (n=26), Toy Poodles (n=21), Pomeranians (n=19), Shih Tzus (n=13), Maltese (n=12), Miniature Dachshunds (n=11), other pure breeds (n=29), and mixed breeds (n=20). ... A retrospective review of medical records was performed for dogs surviving surgery. Diagnosis of UDP was based on pre- and post-operative thoracic dorsoventral radiographs. Results: ... Unilateral diaphragmatic paralysis was observed in 86 of the 284 cases; a prevalence of 30%. ... The prevalence of UDP was not related to the lengths of ICU and hospital stay. Recovery from UDP was observed by the time of hospital discharge in 22 of the 86 cases (25%), by one month after surgery in an additional 41 cases (73% total), and by three months after in an additional 22 cases (99% total). ... In-hospital mortality was 10.5% including 10 dogs that did not survive surgery and an additional 21 dogs that died before discharge from the hospital (31/294 dogs). An additional six dogs (2.3%) discharged from the hospital died before 3 months after surgery. Total mortality at 3 months after surgery was 12.6% (37/294 dogs). Twenty-one dogs surviving to the day after surgery died before discharge from the hospital. Unilateral diaphragmatic paralysis was diagnosed in 10 of the 21 dogs that died before hospital discharge [none were cavaliers]. The cause of death was reported as respiratory-failure related in nine and thrombosis-related four (3 dogs had cerebral infarction and one dog had myocardial infarction) of the 21 dogs that died before hospital discharge. Heart failure, arrhythmia, pancreatitis, and septic shock each accounted for one in-hospital death. The cause of death in four dogs was undetermined. ... This study observed that paralysis of the left crus of the diaphragm induced by phrenic nerve injury is relatively common (30%) among small dogs after MVR. ... It is likely that the differences in the surgical approach (i.e., left lateral vs. median sternotomy) and patient size were major factors contributing to the relatively high incidence of postoperative UDP. While UDP was not associated with overall mortality in this group of dogs, it had a profound effect on dogs with pre-existing respiratory disease. Of the nine dogs that died from respiratory complications, eight had UDP accounting for 3% of all dogs that underwent MVR and 38% of the deaths. ... Four of the nine dogs that died of respiratory failure were Chihuahuas. In three of the four dogs, upper airway obstructions were noted on admission or in their respective clinical histories. Pharyngeal airway obstruction has been most commonly observed in brachycephalic dogs, such as the English bulldog, Pug, and Boston Terrier; however, breeds such as the Chihuahua and the Shih Tzu are also predisposed to upper airway disease. These dogs are characterized by skulls that are shortened in the craniocaudal direction, causing excessive soft tissue in the pharynx. ... Two of the Chihuahuas also exhibited tracheal collapse, which can lead to respiratory distress. In dogs without pre-existing respiratory disease/failure, UDP was not a major complicating factor. ... Conclusion: ... The prevalence of UDP induced by phrenic nerve injury 218 leading is high in dogs that have received MVR. In most dogs, phrenic nerve function recovers within 3 months; however, in those with pre-existing respiratory insufficiency, UDP can be a significant complicating factor that may contribute to postoperative morbidity and death. (Read our review of this article, here.)

Temporal changes in clinical and radiographic variables in dogs with preclinical myxomatous mitral valve disease: The EPIC study. Adrian Boswood, Sonya G. Gordon, Jens Häggström, Martin Vanselow, Gerhard Wess, Rebecca L. Stepien, Mark A. Oyama, Bruce W. Keene, John Bonagura, Kristin A. MacDonald, Mark Patteson, Sarah Smith, Philip R. Fox, Karen Sanderson, Richard Woolley, Viktor Szatmári, Pierre Menaut, Whitney M. Church, M. Lynne O'Sullivan, Jean-Philippe Jaudon, Jan-Gerd Kresken, John Rush, Kirstie A. Barrett, Steven L. Rosenthal, Ashley B. Saunders, Ingrid Ljungvall, Michael Deinert, Eric Bomassi, Amara H. Estrada, Maria J. Fernandez Del Palacio, N. Sydney Moise, Jonathan A. Abbott, Yoko Fujii, Alan Spier, Michael W. Luethy, Roberto A. Santilli, Masami Uechi, Anna Tidholm, Christoph Schummer, Philip Watson. J. Ver. Itern. Med. March 2020; doi: 10.1111/jvim.15753. Quote: Background: The Evaluation of pimobendan in dogs with cardiomegaly caused by preclinical myxomatous mitral valve disease (EPIC) study monitored dogs with myxomatous mitral valve disease (MMVD) as they developed congestive heart failure (CHF). Objectives: To describe the changes in clinical and radiographic variables occurring as dogs with MMVD and cardiomegaly develop CHF, compared to similar dogs that do not develop CHF. Animals: 135 dogs [including 62 cavalier King Charles spaniels -- 45.9%] did develop CHF, and 73 dogs [33 cavaliers -- 45.2%] did not develop CHF. Materials and methods: The following variables were evaluated in 2 groups of dogs (dogs that did or did not develop CHF): Heart rate (HR), clinic respiratory rate (RR), home‐measured resting respiratory rate (RRR), rectal temperature (RT), body weight (BW), and vertebral heart sum (VHS). Absolute value and rate of change of each variable were calculated for each day a dog was in study. Daily means were calculated and plotted against time. The onset of CHF or last visit before leaving the study were set as reference time points. Results: The most extreme values and rate of change occurred in variables immediately before onset of CHF. Vertebral heart sum increased earliest. Heart rate, RR, and RRR also increased. Rectal temperature and BW decreased. Increases in RR and RRR were most extreme and occurred immediately before CHF. Conclusions and Clinical Importance: Dogs with MMVD and cardiomegaly experience increases in HR, RR, RRR, and VHS, and decreases in BW and RT as they develop CHF. The variables with highest absolute change and rate of change were RR and RRR. These findings reinforce the value of RR and RRR as indicators of impending or incipient CHF. (See May 2020 Letter to the Editor.) (Read our review of this article, here.)

Use of cardiac sphericity index and manubrium heart scores to assess radiographic cardiac silhouettes in large-and small-breed dogs with and without cardiac disease. Ayman A. Mostafa, Katharine E. Peper, Clifford R. Berry. JAVMA. April 2020; doi: 10.2460/javma.256.8.888. Quote: Objective: To evaluate the usefulness of manubrium heart scores (MHSs) in distinguishing between dogs with and without cardiac disease. Animal: 184 client-owned dogs with (n = 64) [including 4 cavalier King Charles spaniels] and without (120) [including 1 CKCS] cardiac disease. ... Dogs with a VHS [vertebral heart score] <10.9 were considered clinically normal as previously described and included as control dogs. ... Procedures: Medical records, including thoracic radiographic images, of dogs that either had echocardiographically confirmed moderate to severe cardiac disease with cardiomegaly (case dogs) or were healthy and without evidence of cardiac disease (control dogs) were retrospectively reviewed. From right lateral thoracic radiographic images, the lengths of the cardiac short and long axes and the manubrium were measured and cardiac sphericity indices (CSIs), MHSs, and vertebral heart scores were determined. Dogs were grouped on the basis of whether they did or did not have cardiac disease (case dogs vs control dogs), breed size (large-breed dogs vs small-breed dogs), and whether cardiac disease affected the right side of the heart (right-sided cardiac disease) or the left side of heart (left-sided cardiac disease). Results were compared across groups. Results: The mean CSI was greatest in case dogs with right-sided cardiac disease, compared with other groups. In dogs of the present study, a combination of high short-, long-, and overall-MHSs was more suggestive of left-sided cardiac disease, whereas a high short-MHS without high long- and overall-MHSs was more suggestive of right-sided cardiac disease. conclusion & Clinical Relevance: Results indicated that MHSs could be useful, objective values to help assess dogs for potential heart disease, and we recommend that MHSs be added to the diagnostic tools used by veterinarians when screening for heart disease in dogs. ... Nonetheless, echocardiography remains the noninvasive gold standard for assessment of cardiomegaly in dogs. (Read our review of this article, here.)

Disease Severity-Associated Gene Expression in Canine Myxomatous Mitral Valve Disease Is Dominated by TGFβ Signaling. Greg R. Markby, Vicky E. Macrae, Kim M. Summers, Brendan M. Corcoran. Front. Genet. April 2020; doi: 10.3389/fgene.2020.00372. Quote: Myxomatous mitral valve disease (MMVD) is the most common acquired canine cardiovascular disease and shares many similarities with human mitral valvulopathies. While transcriptomic datasets are available for the end-stage disease in both species, there is no information on how gene expression changes as the disease progresses, such that it cannot be stated with certainty if the changes seen in end-stage disease are casual or consequential. In contrast to humans, the disease in dogs can be more readily examined as it progresses, and this allows an opportunity for insight into disease pathogenesis relevant to both species. The aim of this study was to identify changes in valve gene expression as canine MMVD advances over an entire life-time, from normal (grade 0) to severely affected (grade 4), and differences in gene expression comparing normal and disease areas of the same valve. ... The whole valve cohort included 11 different breeds with 10 females and 20 males, and at least one female in each of the grades. All cavalier King Charles spaniels (n = 8 [27%]) had either grade 3 or 4 disease. ... Transcriptomic profiling identified 1002 differentially expressed genes (DEGs) across all four disease grades when compared with normal valves with the greatest number of DEGs in grade 3 (673) and grade 4 (507). DEGs were associated with a large number of gene families, including genes encoding cytoskeletal filaments, peptidases, extra-cellular matrix (ECM) proteins, chemokines and integrins. Gene enrichment analysis identified significant grade-dependent changes in gene clustering, with clusters trending both up and down as disease progressed. Significant grade-dependent changes in hallmark disease gene expression intensity were identified, including ACTA2, HTR2B, MMP12, and CDKN2A. Gene Ontology terms were dominated by terms for ECM and inflammation with TGFβ1, TNF, IFGN identified as the top up-stream regulators in both whole and dissected diseased valve samples. These data show that while disease progression in MMVD is associated with increasing numbers of DEGs, TGFβ appears to be the dominant signaling pathway controlling pathogenesis irrespective of disease severity. ... However, TGFβ1 appears to have the strongest associations with the disease. The baseline gene expression of TGFβ1 was approximately 10 fold that for TNF and IFNg. In addition, cultured VICs have been shown to secrete much higher levels of TGFb1 than TNF and IFNg, and TGFβ1 is secreted at a significantly higher levels in activated VICs compared to quiescent cells. ... In conclusion, despite differences in the total number of DEGs identified as canine MMVD pathology progresses over a lifetime, disease initiation, and progression appears to be primarily dependent on changes in TGFβ signaling. This is the first description of the temporal and spatial expression of gene changes associated with naturally occurring myxomatous degeneration in any species. Other signaling pathways likely contribute to disease pathogenesis over time, with some becoming involved only at the stage of advanced disease. The factors that trigger the development of valve myxomatous degeneration are still unknown, but aberrant TGFβ signaling appears to initiate and perpetuate the valve pathology characteristic of this disease in the dog. Studies are now required to identify the important down-stream components of the TGFβ signaling pathway implicated in myxomatous degeneration. (Read our review of this article, here.)

Comparison of fluoroscopic cardiovascular measurements from healthy dogs obtained at end-diastole and end-systole. C.S. Brown, L.R. Johnson, L.C. Visser, J.C. Chan, R.E. Pollard. J. Vet. Cardiol. June 2020; doi: 10.1016/j.jvc.2020.02.004. Quote: Introduction: Quantitative measurements are commonly implemented to objectively evaluate heart size in dogs. However, recent studies suggest that the phase of cardiac cycle can impact vertebral heart score, thereby potentially influencing clinical management. This study used fluoroscopy to assess the impact of the cardiac cycle on quantitative cardiovascular measurements in healthy dogs of various breeds. Animals, materials, and methods: This was a prospective study. Multiple cardiac and respiratory cycles were recorded fluoroscopically. Peak inspiratory end-systole and end-diastole frames were captured from 49 dogs in right lateral recumbency. Vertebral heart score (VHS), cardiothoracic ratio (CTR), vertebral left atrial size (VLAS), and caudal vena cava diameter ratio (CVCDR) measurements were performed. Mean cardiac measurements were compared between cardiac cycle phases, and the impact of body condition score (BCS), weight, thoracic conformation, sex, and age was evaluated. Results: Cardiac cycle had a significant impact on VHS (mean difference: 0.36 ± 0.14 vertebral units between systole and diastole) and CTR (mean difference: 2.2 ± 1.2% between systole and diastol). Cardiac cycle had no significant impact on VLAS or CVCDR. Increasing BCS significantly increased variation between systole and diastole in CTR measurements. Conclusions: The cardiac cycle has a significant effect on VHS and CTR but does not impact VLAS or CVCDR. These findings should be taken into consideration during clinical use of these measurements, especially if a patient is being monitored for cardiac changes over time via serial radiographs. (Read our review of this article, here.)

Comparative transcriptomic profiling of myxomatous mitral valve disease in the Cavalier King Charles Spaniel. Brendan Corcoran, Greg Markby, Vicky Macrae, Kim Summers. BMC Vet. Res. April 2020; doi: 10.21203/rs.3.rs-23508/v3. Quote: Background. Almost all elderly dogs develop myxomatous mitral valve disease by the end of their life, but the Cavalier King Charles Spaniel (CKCS) has a heightened susceptibility, frequently resulting in death at a young age and suggesting that there is a genetic component to the condition in this breed. Transcriptional profiling can reveal the impact of genetic variation through differences in gene expression levels. The aim of this study was to determine whether expression patterns were different in mitral valves showing myxomatous degeneration from CKCS dogs compared to valves from non-CKCS dogs. Results. Gene expression patterns in three groups of canine valves resulted in distinct separation of normal valves, diseased valves from CKCS and diseased valves from other breeds; the latter were more similar to the normal valves than were the valves from CKCS. Gene expression patterns in diseased valves from CKCS dogs were quite different from those in the valves from other dogs, both affected and normal. Patterns in all diseased valves (from CKCS and other breeds) were also somewhat different from normal non-diseased samples. Analysis of differentially expressed genes showed enrichment in GO terms relating to cardiac development and function and to calcium signalling canonical pathway in the genes down-regulated in the diseased valves from CKCS, compared to normal valves and to diseased valves from other breeds. F2 (prothrombin) (CKCS diseased valves compared to normal) and MEF2C pathway activation (CKCS diseased valves compared to non-CKCS diseased valves) had the strongest association with the gene changes. A large number of genes that were differentially expressed in the CKCS diseased valves compared with normal valves and diseased valves from other breeds were associated with cardiomyocytes including CASQ2, TNNI3 and RYR2. Conclusion. Transcriptomic profiling identified gene expression changes in CKCS diseased valves that were not present in age and disease severity-matched non-CKCS valves. These genes are associated with cardiomyocytes, coagulation and extra-cellular matrix remodelling. Identification of genes that vary in the CKCS will allow exploration of genetic variation to understand the aetiology of the disease in this breed, and ultimately development of breeding strategies to eliminate this disease from the breed. (Read our review of this article, here.)

Intermittent mitral regurgitation in Cavalier King Charles spaniels: Short-term progression and influence of stress tests. M. J. Reimann, J. E. Møller, J. Häggström, L. L. B. Åkerström, T. Martinussen, L. H. Olsen. Vet. J. April 2020; doi: 10.1016/j.tvjl.2020.105457. Quote: In young Cavalier King Charles spaniels (CKCS), intermittent mitral regurgitation (iMR; defined as moderate to severe mitral regurgitation [MR] in a small proportion of heartbeats), has been associated with an increased risk of cardiac death due to myxomatous mitral valve disease (MMVD). It is associated with increased R-R interval variability [the time elapsing between two consecutive R waves in the electrocardiogram]. Little is known about response to physiological factors and whether iMR is a precursor for developing significant MR. The aim of this study was to determine the effect of stress testing on the presence of iMR and heart rate, and short-term (1-2 year) progression of MR in CKCS with and without iMR. ... We hypothesized that: (1) stress tests would reduce the presence of iMRs; (2) stress tests would result in a smaller increase in heart rate in CKCS with iMR compared to CKSC without iMR; and (3) a higher proportion of CKCS with iMR would develop more severe disease (constant MR≥20%) than CKCS without iMR within 1-2 years. ... In total, 52 CKCS were included. Substudy 1 enrolled six dogs with iMR and 11 dogs without iMR. Substudy 2 enrolled 14 dogs with iMR and 28 dogs without iMR. Substudy 1 prospectively assessed the influence of stress testing on the presence of iMR and heart rate. Substudy 2 retrospectively evaluated short-term progression of iMR. During stress testing, iMR disappeared in 50% of CKCS and no iMR was recorded at mean heart rates >150 beats/min. Heart rate response did not differ between CKCS with or without iMR. CKCS with iMR did not have a higher odds of MR progression compared to controls. ... Change of MR direction may be another explanation for reduction of iMR in response to an increased heart rate. ... When performing an echocardiographic examination, it is important to bear in mind the possible effect of an increased heart rate. In CKCS with increased heart rates (especially if they are above 150 bpm), it may be of value, to assess the MR more thoroughly and wait for a normal heart rate (preferably below 150bpm, if possible). Likewise, these findings should be kept in mind when auscultating dogs with increased heart rates. Intermittent heart murmurs are possible to auscultate, but may not be possible to identify in dogs with increased heart rates. In essence, iMR may easily be overlooked in stressed CKCS, which may be especially important in relation to breeding scheme examinations when screening young CKCS for breeding purposes. ... The last part of the study assessed short-term progression (1-2 years) of iMR. We were not able to demonstrate higher odds of progression to a more severe disease group (constant MR≥20% vs. MR<20%) within 1-2 years among CKCS with iMR compared to control CKCS. This is in contrast to a recent study indicating a higher risk of cardiac death later in life in CKCS with iMR at an early age compared to CKCS with MR<20% (Reimann et al., 2017b). Hence, it is possible that a longer period of time or larger sample size would have increased the difference between the two groups. ... Conclusions: In 50% of the CKCS with iMR, stress tests reduced the presence of iMR and no iMR was recorded at mean heart rates above 150 bpm. Furthermore, the increase in heart rate as a response to stress tests was similar for CKCS with and without iMR. This study did not demonstrate higher odds for CKCS with iMR compared to controls for progression to a more severe disease stage (constant MR≥20% vs. MR<20%). It is important not to overlook iMR in stressed CKCS with early disease; the importance of this finding is yet to be fully understood. (Read our review of this article, here.)

Association between neutering status and cardiac changes secondary to myxomatous mitral valve disease. Ana Margarida Silva, Elizabeth Bode, Joanna Dukes-McEwan, Jorge Prieto-Ramos, Rodolfo Oliveira Leal. BSAVA Congress 2020. April 2020. doi: 10.22233/9781910443774.50.4 Quote: Objectives: To determine if neutering status affects cardiac remodeling in male and female dogs with myxomatous mitral valve disease (MMVD). Methods: A retrospective study was conducted including 582 dogs who were diagnosed with MMVD between January 2008 and December 2016. Dogs were categorized into four groups: female entire, female neutered, male entire and male neutered. Transthoracic two-dimensional echocardiographic studies were performed by board-certified (ECVIM or ACVIM) cardiologists or cardiology residents under their supervision. For each dog four echocardiographic measurements were retrieved: left atrial dimension to aortic root diameter in diastole (LA:Ao), left atrium maximal dimension to the aortic root dimension in systole (LAmax:Ao) and left ventricular internal dimension at end diastole (LVIDd-N) and left ventricular internal dimension at end systole (LVIDs-N), which were normalized for body weight by allometric scaling. Echocardiographic measurements were compared between female entire vs female neutered and male entire vs male neutered. Results: Male entire dogs had higher mean LVIDd (p = 0.045) values and median LA:Ao (p = 0.031) and LAmax:Ao (p = 0.002) compared to male neutered dogs. On the other hand, LVIDs was not significantly different (p = 0.070). No significant differences were found between female entire and female neutered dogs. Statement (conclusions): This study shows that male entire dogs may have a higher risk of developing cardiac remodeling secondary to MMVD. It was suggested that testosterone could potentiate the extracellular matrix alterations characteristic of MMVD. Further studies are needed to detail this hypothesis. (Read our review of this article, here.)

Use of radiographic measurements to diagnose stage B2 preclinical myxomatous mitral valve disease in dogs. Rebecca L. Stepien, Mariola B. Rak, Lauren M. Blume. JAVMA. May 2020; doi: 10.2460/javma.256.10.1129. Quote: Objective: To investigate the usefulness of radiographic measures of the left atrium and ventricle as surrogates for echocardiographic criteria in identifying dogs with stage B2 preclinical myxomatous mitral valve disease (MMVD). Animals: 56 client-owned dogs with preclinical mitral regurgitation attributed to MMVD examined between April 19, 2016, and November 22, 2017. [No breeds were identified in the article.] Procedures: Medical records were retrospectively searched, and data collected included age, body weight, heart murmur grade, and echocardiographic and radiographic measurements. Dogs were grouped according to whether they did (case dogs) or did not (control dogs) meet echocardiographic criteria used to identify dogs with stage B2 MMVD. Measurements for lateral thoracic radiographic variables normalized to vertebral body units (VBUs) were obtained, and results were analyzed to identify variables that could best discriminate between case and control dogs. Results: Three radiographic variables of left atrial size (vertebral left atrial size [VLAS], left atrial width, and the combined variable of VLAS + left atrial width) most accurately distinguished control dogs from case dogs, and the VLAS was the simplest and fastest to perform in a clinical setting. The optimal cutoff for VLAS was 2.5 VBUs (sensitivity, 70%; specificity, 84%; and likelihood ratio, 4.38), with VLAS ≥ 2.5 VBUs for case dogs. The maximum specificity cutoff for VLAS was 3.0 VBUs (sensitivity, 40%; specificity, 96%; and likelihood ratio, 10.0), with VLAS ≥ 3.0 VBUs for case dogs. Conclusions and Clinical Relevance: Results indicated that when echocardiography is unavailable, radiographic VLAS ≥ 3 VBUs could be used with minimal risk of false-positive diagnosis of stage B2 MMVD in dogs. (Read our review of this article, here.)

Effect of expiratory phase for radiographic detection of left heart enlargement in dogs with mitral regurgitation. Saran Chhoey, Sang-Kwon Lee, Hyejin Je, Jin-Woo Jung, Youjung Jang, Jihye Choi. Vet. Radiol. Ultrasound. May 2020; doi: 10.1111/vru.12850. Quote: Radiography is a standard diagnostic test for characterizing left heart enlargement in dogs however limited information is available on the effects of respiratory phases. This prospective and retrospective method comparison study investigated the respiratory effect on the size and shape of the left heart in dogs to determine the usefulness of expiratory radiographs to detect enlargements in the left atrium (LA) and left ventricle (LV). Thoracic radiographs taken at full inspiration and expiration were evaluated in 20 normal beagles and 100 dogs diagnosed with mitral regurgitation (MR). Vertebral heart score (VHS), vertebral left atrial size, elevation of the carina, and dorsal bulging of LA on lateral view and lateral bulging of the left auricular appendage and LV on ventrodorsal view were assessed. In normal dogs, therewere no significant differences in the evaluative factors between inspiration and expiration. In dogs with MR, VHS did not change according to respiration. However, bulging of the LA, left auricular appendage, and LV had sharp margin during expiration compared with inspiration. The expiratory radiographic finding of LA bulging had a higher correlation with the LA to aorta ratio compared with LA bulging in the inspiratory radiography. Using a LA to aorta echocardiographic ratio greater than 1.5 as the gold standard, the radiographic sensitivity for LA enlargement was higher during expiration than inspiration. These findings of our study indicated that expiratory radiography can be helpful to support the detection of left heart enlargement, although it can overestimate LA enlargement in dogs with MR. (Read our review of this article, here.)

Letter to the editor regarding Temporal changes in clinical and radiographic variables in dogs with preclinical myxomatous mitral valve disease: The EPIC study. Mark D. Kittleson. J. Vet. Intern. Med. May 2020; doi: 10.1111/jvim.15815 Dear Editor, I was pleased to see more data generated from the EPIC (evaluation of pimobendan in dogs with cardiomegaly caused by preclinical myxo- matous mitral valve disease) trial (see “Temporal changes in clinical and radiographic variables in dogs with preclinical myxomatous mitral valve disease: The EPIC study” J Vet Intern Med. 2020 Mar 22. doi: 10. 1111/jvim.15753). As a comment, I have a slightly different interpre- tation of the data regarding resting respiratory rate (RRR) in this paper. The investigators in this study based on the diagnosis of left heart failure (pulmonary edema) on clinical and radiographic signs at the time a dog was presented by the owner to the investigator. This means clinical signs had to be severe enough for the owner to notice them and pulmonary edema had to be severe enough to be apparent radiographically. In figure 3D, if one makes the logical assumption that the increase in RRR was caused by pulmonary edema, it seems clear to me that the dogs that were subsequently diagnosed with left heart failure had mild pulmonary edema for several weeks before their tachypnea and dyspnea becoming severe enough for the owner to notice a problem. Since I was the first to start by RRR and sleeping RR (SRR) in 1998 I may be biased, but I believe these data clearly show that RRR/SRR is a more sensitive means of identifying pulmonary edema (left heart failure), presumably mild edema, in dogs with severe mitral regurgitation than are thoracic radiographs and clinical signs, such as tachypnea and dyspnea, that are severe enough to be appar- ent to an owner. As such, in my opinion, an elevated RRR is not evi- dence of impending or incipient left heart failure but instead is the first clinical evidence that a dog is in left heart failure. Mark D. Kittleson (See March 2020 article.) (Read our review of this article, here.)

Diuretics and heart failure: 10 things you need to know. Alex Laver, Dave Dickson. InPractice. May 2020; doi: 10.1136/inp.m1683 Quote: Background: Diuretics are the cornerstone of heart failure therapy in veterinary medicine, yet their use can cause confusion and concern in practice. To gather material for this article, the authors asked their peers what they most wanted to know about the diagnosis and treatment of congestive heart failure (CHF). Aim of the article: This article aims to answer some of the most common questions about the use of diuretics in the treatment of CHF. (Read our review of this article, here.)

Monitoring congestive heart failure. Melanie Hezzell. InPractice. May 2020; doi: 10.1136/inp.m1684 Quote: Background: Congestive heart failure (CHF) is a clinical syndrome that is commonly encountered in small animal practice. It is characterised by the accumulation of fluid as a result of severe heart disease. This fluid accumulation manifests as pulmonary oedema in left-sided CHF and as cavitary effusions (pleural, pericardial and ascites) in right-sided CHF. The clinical consequences of both CHF itself and its medical management can have a significant impact on a patient’s welfare; appropriate monitoring is therefore crucial to maintaining a good quality of life. Aim of the article: This article reviews the goals of monitoring CHF and discusses the methods available in veterinary practice.

Survival characteristics and prognostic importance of echocardiographic measurements of right heart size and function in dogs with pulmonary hypertension. Lance C. Visser, James E. Wood, Lynelle R. Johnson. J. Vet. Intern. Med. June 2020; doi: 10.1111/jvim.15826. Quote: Background: The clinical relevance of echocardiographic measurements of right heart size and function in dogs with pulmonary hypertension (PH) is unknown. Objective: To determine if echocardiographic measurements of right heart size and right ventricular (RV) function are associated with survival times in dogs with PH. Animals: Eighty-two client-owned dogs[including 5 cavalier King Charles spaniels]. Methods: Retrospective study where data from medical records and baseline echocardiographic examinations were collected and measured in a standardized manner. Owners or primary veterinarians were contacted for outcome data. ... Classification of PH Dogs were classified with PH secondary to LHD if they had LHD (eg, MMVD) and unequivocal echocardiographic left atrial enlargement2 according to two different measurements of left atrial size: (1) left atrial-to-aortic root dimension (LA/Ao)>1.7 and (2) left atrial dimension (LAD) normalized to bodyweight>1.6. ... Results: Enlargement of the right atrium (88%), RV (69%), and pulmonary artery (72%) was common. One-third of the cases had reduced RV function quantified by two-dimensional echocardiography-derived tricuspid annular plane systolic excursion (TAPSE). Decreased TAPSE was significantly (P = .008) more common in dogs with PH not secondary to left heart disease (LHD; 43%) compared to dogs with PH secondary to LHD (14%) but median survival times (182, 95% confidence interval [CI] = 39-309 versus 298, 95% CI = 85-314 days, respectively) were not significantly different (P = .78). Right atrial area (hazard ratio [HR] = 2.72, 95% CI = 1.58-4.70), TAPSE < 3.23 mm/kg0.284 (HR = 2.19, 95% CI = 1.28-3.74), and right heart failure (HR = 2.05, 95% CI = 1.18-3.57) were independently associated with shorter survival time (P ≤ .04). Conclusions and Clinical Importance: Right atrial area, RV function (TAPSE < 3.23 mm/kg0.284), and right heart failure offer clinically relevant prognostic information in dogs with PH. Results support the quantitative assessment of right heart size and function in dogs with PH. (Read our review of this article, here.)

Whole genome sequencing to explore genetic risk factors in canine myxomatous mitral valve disease. Melanie Hezzell, Marsha Wallace, Jenny Wilshaw, Stephen Hare, Nicholas Timpson, Adrian Boswood, Lucy Davison. 2020 ACVIM Forum. June 2020. J. Vet. Intern. Med. Doi: 10.1111/jvim.15903.  Quote: Canine myxomatous mitral valve disease (MMVD) is the most common acquired cardiac disease in dogs, with cavalier King Charles spaniel (CKCS) being particularly overrepresented. Almost all CKCS >10 years of age are affected, suggesting that genetic risk factors may be ‘fixed’ in this breed. MMVD is believed to be a polygenic trait, and previous genetic work in canine MMVD has employed a casecontrol design within individual breeds. However, this design precludes the identification of disease-associated variants that are ‘fixed’ within high risk breeds and may result in only minimal genetic differences between cases and controls being identified. The aim of the present study was to identify new canine MMVD genes as potential future targets for prevention or treatment of disease. This was achieved by applying a new model for identification of genetic risk variants in complex disease, using whole genome sequencing (WGS) of breeds at relatively high and low risk of disease. Additionally, genetic differences between CKCS with early-onset MMVD that died due to congestive heart failure (group C) and CKCS with late-onset MMVD that died due to non-cardiac disease (group NC) were explored. Whole genome sequencing (WGS) at 30X coverage was undertaken on 12 CKCS, 6 in group C and 6 in group NC. Results were compared with WGS from 48 non-CKCS breed dogs, mainly sequenced as part of the Canine Diabetes Genetics Partnership initiative. DNA was extracted from blood samples that were surplus to requirements for clinical purposes. A custom bioinformatics pipeline was used to call, annotate and prioritise variants for follow-up, based on the Genome Analysis ToolKit, using CanFam3.1 as a reference. Variants were prioritised according to a range of criteria, including their alternate allele frequency (by breed or disease severity status), predicted impact on gene function, or location near a region with a plausible role in cardiac disease. In CKCS, 1993 breed-unique high or moderate impact variants were identified, 1393 of which were present in more than one CKCS, and 43 of which were found exclusively in group C. A total of 103 variants of high or moderate impact were identified in or near genes with a plausible role in cardiac disease and at a high frequency in all CKCS. A further 539 similar variants of potential cardiac relevance were at a higher frequency in group C compared to group NC. A follow-up genotyping study is in progress using a larger cohort and more breeds. This work demonstrates that WGS offers a promising route for investigation of complex diseases where genetic risk may be fixed within a breed. (Read our review of this article, here.)

 Evaluation of radiographic predictors of left heart enlargement in dogs. Lance C. Visser, Laetitia Duler, Kristina Jackson.  2020 ACVIM Forum. June 2020. J. Vet. Intern. Med. Doi: 10.1111/jvim.15903.  Quote:  We sought to determine the diagnostic accuracy of vertebral left atrial size (VLAS), vertebral heart size (VHS), and radiologists' assessment for predicting left atrial enlargement (radLAE) in a large population of dogs with and without echocardiographic left atrial enlargement (echoLAE). Dogs that had an echocardiogram and thoracic radiographs performed within 24 hours were consecutively enrolled provided they did not have pericardial effusion or a cardiac mass. Echocardiographic left atrial enlargement was defined by a left atrium to aortic ratio acquired from short-axis (LA/AoSx) and long-axis (LA/AoLx) >1.68 and >2.54, respectively. Radiographic assessments were blinded to echocardiographic assessments and vice versa. Cutoffs for VLAS and VHS were generated using receiver operating characteristic analyses. Logistic regression was utilized to identify associations with echoLAE. One-hundred eighty-three dogs were enrolled. Dogs were diagnosed with myxomatous mitral valve disease (56%; 35 stage B1, 35 stage B2, and 33 stage C/D), other cardiovascular diseases (25%) or no cardiovascular disease (19%). Prevalence of EchoLAE was 63%. Optimal cutoffs for VLAS (>2.3 vertebrae; sensitivity [Sn] 88.9%; specificity [Sp] 73.3%) and VHS (>11.1 vertebrae; Sn = 74.6%; Sp = 75.8%) were generated and compared with radLAE (yes/no). Vertebral left atrial size >2.3 (area under the curve [AUC] = 0.81) was more accurate than VHS >11.1 (AUC = 0.75) and radLAE (AUC = 0.76) for predicting echoLAE. Vertebral left atrial size >2.3 and radLAE (both P < .001) were independently associated with echoLAE but VHS >11.1 was not (P = .054). Vertebral left atrial size is a useful radiographic measurement for predicting echoLAE, particularly if echocardiography or a radiologist's assessment are unavailable. (See also this January 2021 article.)

Use of vertebral left atrial size for staging of dogs with myxomatous valve disease. Shoma Mikawa, Masayoshi Nagakawa, Haruka Ogi, Ryota Akabane, Yukari Koyama, Atsushi Sakatani, Mizuki Ogawa, Hirosumi Miyakawa, Jin Shigemoto, Tsuyoshi Tokuriki, Noriko Toda, Yuichi Miyagawa, Naoyuki Takemura. J. Vet. Cardiol. June 2020; doi: 10.1016/j.jvc.2020.06.001. Quote: Introduction/Objectives: The American College of Veterinary Internal Medicine (ACVIM) guidelines suggest that pimobendan should be initiated in dogs which meet all criteria of stage B2 myxomatous mitral valve disease (MMVD): murmur intensity ≥ 3/6, left atrial-to-aortic ratio (LA:Ao) ≥ 1.6, normalized left ventricular internal diameter in diastole (LVIDDN) ≥ 1.7, and vertebral heart size > 10.5. Recently, a new radiographic index for left atrial enlargement, vertebral left atrial size (VLAS), was proposed ... as a useful radiographic measurement for the detection of left atrial enlargement in dogs with MMVD. Vertebral left atrial size is the distance between the ventral border of the carina and the point where left atrium intersects with the dorsal border of the caudal vena cava, expressed in vertebral body units. ... The objective of the present study was to evaluate whether VLAS is useful in staging MMVD and if it can distinguish between ACVIM Stages B1 and B2. Animals: Ninety-seven client-owned dogs [9 cavalier King Charles spaniels] with MMVD were evaluated and classified as ACVIM stage B1, B2, or C-D. Methods: The echocardiographs and radiographs of all the dogs were retrospectively evaluated to obtain LA:Ao, LVIDDN, and VLAS values. The data were analyzed to assess the correlation between these measurements and VLAS, and the optimal cutoff value of VLAS was determined. Results: A VLAS cutoff value of 2.6 provided the greatest diagnostic accuracy for identification of dogs with ACVIM Stage B2 MMVD (AUC, 0.96; sensitivity, 95%; specificity, 84%). A VLAS ≥ 2.5 exhibited the highest sensitivity (sensitivity, 100%; specificity, 78%), and a VLAS ≥ 3.1 exhibited the highest specificity (sensitivity, 47%; specificity, 100%). Conclusions: Vertebral left atrial size is a helpful index for monitoring MMVD using radiography. A VLAS cutoff value of 2.5 could be used to identify dogs that may benefit from echocardiography to determine if they have reached ACVIM Stage B2. ... Based on the prevalence of Stage B2 in this study, if pimobendan was administered to all dogs with a VLAS ≥ 2.6, ten Stage B1 dogs would receive this medication. In addition, one Stage B2 dog would not receive pimobendan. This means that a total of 11 dogs (17%) would be managed inappropriately as currently outlined by the ACVIM consensus guidelines. Therefore, it is not recommended to determine pimobendan initiation based on VLAS measurement only. ... Therefore, we propose that a VLAS cutoff value of 2.5 should be used to recommend echocardiography in order to identify whether MMVD in Stage B1 dogs has progressed to ACVIM Stage B2. All dogs included in the present study had previously been diagnosed with MMVD. Consequently, dogs not yet diagnosed with MMVD should have echocardiography performed regardless of the VLAS value. (Read our review of this article, here.)

Radiographic vertebral left atrial size: A reference interval study in healthy adult dogs. Tommaso Vezzosi, Caterina Puccinelli, Rosalba Tognetti, Tina Pelligra, Simonetta Citi. Vet. Radiol. & Ultra. July 2020; doi: 10.1111/vru.12896. Quote: Thoracic radiography is a useful technique for the evaluation of cardiac dimensions, especially when echo-cardiography is not possible. The vertebral left atrial size (VLAS) has recently been proposed as a new radiographic method for quantifying left atrial dimensions in dogs. The aims of this retrospective, reference interval, observational study were to describe values for VLAS in a group of healthy adult dogs and to compare intraobserver and interobserver agreement for VLAS versus vertebral heart score (VHS) methods. Thoracic radiographs of 80 healthy adult dogs were evaluated [of 25 different breeds and 17 mixed breeds, including 1 cavalier King Charles spaniel; the most of one breed were 23 Chihuahuas]. Normal left atrial size was determined based on an echocardiographic left atrial‐to‐aorta ratio < 1.6. The VLAS and vertebral heart score values were measured from right lateral radiographs. The correlations between VLAS, the vertebral heart score, and the left atrial-to-aorta ratio were evaluated. The effects of body weight, sex, and age were also tested using regression analyses. The median value of VLAS were 1.9, with a reference interval of 1.4-2.2. A positive correlation was found between VLAS and vertebral heart score values. No effect of body weight, sex, and age on VLAS was detected. Excellent intraobserver and interobserver agreements were found for both VLAS and vertebral heart score methods (intraclass correlation coefficients ≥ 0.91). Findings from this sample of healthy dogs indicated that VLAS is a repeatable radiographic method for quantifying left atrial size. ... [N]o brachycephalic “screw-tailed” breeds (eg, English Bulldog, French Bulldog, Pug, Boston terrier) were included. These breeds present a typical barrel-shaped thoracic conformation in comparison to other dogs, and a greater occurrence of thoracic vertebral body anomalies that could alter the measurement of vertebral-based methods. The reference interval for VLAS determined in this study may thus not be applicable to brachycephalic dogs. ... Further studies are warranted to evaluate this measure in clinically affected dogs. (Read our review of this article, here.)

Reproducibility of echocardiographic indices of left atrial size in dogs with subclinical myxomatous mitral valve disease. Weihow Hsue, Lance C. Visser. J. Vet. Intern. Med. July 2020; doi: 10.1111/jvim.15850. Quote: Background: Reliability of echocardiographic measurements of left atrial (LA) size, an important marker of disease severity, has not been reported in dogs with myxomatous mitral valve disease (MMVD). Objectives: To define and compare reliability of left atrial dimension/diameter (LAD), LAD indexed to aortic valve diameter (LAD/AoD), left atrium-to-aortic root ratio (LA/Ao), left atrial volume acquired from a right parasternal long-axis (LAVRPLx), and left apical view (LAVLAP) in dogs with subclinical MMVD. Animals: Nine dogs [including 2 cavalier King Charles spaniels] with subclinical MMVD. Methods: Prospective reproducibility study. Dogs underwent 12 echocardiographic examinations by 2 operators on the mornings and afternoons of 3 nonconsecutive days within 1 week. Reliability (measurement variability) was quantified using coefficients of variation (CV) and 95% repeatability/reproducibility coefficients (95% RC). A mixed-model analysis of variance (ANOVA) was used to determine if time of day, day, and operator were significant sources of variability for each index. Results: Linear measurements (LAD, LAD/AoD, and LA/Ao) exhibited less within-day, between-day, and interoperator variability (CVs, 3.9%-12.5%) than did volume estimate measurements (LAVRPLx and LAVLAP; CVs, 11.8%-17.9%). Of the linear measurements, LA/Ao exhibited greater variability (CVs, 9.9%-12.5%) compared to LAD and LAD/AoD (CVs, 3.9%-4.9%). ... However, potential limitations of this method [the LA-to-aortic root ratio (LA/Ao)] include incorporating a pulmonary vein in the LA measurement, lack of consistency of timing of the measurements within the cardiac cycle, and defining the path of aortic root measurement relative to valve sinuses. ... Of the linear measurements, LA/Ao exhibited higher variability compared to LAD and LAD/AoD, which were similar. ... When the effects of time (within‐day and between-day) and operator were evaluated as sources of variability for each of the 5 indices of LA size, only LA/Ao was shown to be significantly impacted by operator. ... When comparing LA/Ao to a directly comparable metric within our study—LAD/AoD (both require 2 linear measurements; 1 of the LA and 1 of the aorta)—LA/Ao was considerably less reproducible. ... When comparing LA/Ao to a directly comparable metric within our study—LAD/AoD (both require 2 linear measurements; 1 of the LA and 1 of the aorta)—LA/Ao was considerably less reproducible. ... Our interoperator reproducibility assessment (Table 2 and Figure 1) indicates considerable bias and only moderate correlation and agreement for LA/Ao compared to minimal bias and strong correlations and agreement for the other LA size indices evaluated. ... Operator was a significant source of variability for LA/Ao, but not for any of the other indices. ... Conclusions and Clinical Importance: Compared to other linear measurements, LA/Ao was the least reproducible and most dependent on operator. The 95% RC for each LA size index are provided to help identify clinically relevant changes (beyond intraoperator or interoperator variability) during serial echocardiographic examinations of dogs with subclinical MMVD. (Read our review of this article, here.)

Echocardiographic parameters for the assessment of congestive heart failure in dogs with myxomatous mitral valve disease and moderate to severe mitral regurgitation. K.R.S. Morgan, G. Monteith, S. Raheb, M. Colpitts, S. Fonfara. Vet. J. July 2020; doi: 10.1016/j.tvjl.2020.105518. Quote: The objective of this study was to evaluate the influence of congestive heart failure (CHF) on echocardiographic variables in dogs with moderate or severe mitral valve regurgitation (MR) secondary to myxomatous mitral valve disease (MMVD). The secondary objective was to investigate the preliminary use of left ventricular early inflow-outflow index (LVEIO) and L-waves as indicators of CHF. Forty-five dogs [including 8 cavalier King Charles spaniels, the breed with the most dogs in this study] with moderate or severe MR without (n = 23) or with (n = 22) CHF were retrospectively included. Echocardiographic variables of elevated left ventricular (LV) filling pressures and cardiac function, LVEIO and the presence of L-waves were obtained and statistically compared between the two groups. On general linear model analysis, mitral inflow peak E-wave velocity, E:A ratio, ratio of E to isovolumic relaxation time (IVRT) and LVEIO were increased, while left atrium (LA) fractional shortening was reduced, in dogs with CHF. Peak E-wave velocity, peak A-wave velocity, E:A ratio, LA minimum diameter, LA diameter before the P-wave, LA fractional shortening and LVEIO were found to be predictive of CHF. The absence of L-waves indicated a reduced risk of CHF. Several echocardiographic variables may be useful in identifying elevated LV filling pressures, consistent with CHF, in dogs with moderate and severe MR. LVEIO and L-waves might be of interest as clinical and prognostic markers in dogs with MMVD and require further investigation. ... Our results demonstrate that LVEIO might be useful as predictive value for CHF in MMVD. The absence L-waves indicated a reduced risk for CHF. Similar to previous studies, we found an increase of peak E-wave velocity, E:A, and E:IVRT, with reduced LA fractional shortening and peak A-wave velocity in dogs with MMVD and CHF. Mitral inflow peak Ewave velocity, peak A-wave velocity, E:A, LA diameter before P-wave, LA minimum diameter, and LA fractional shortening were predictive of CHF in dogs with MMVD with moderate to severe MR on logistic regression and ROC analysis. This included an LVEIO >13.26, a peak E-wave velocity value of >153 cm/s, an E:A ratio >1.85 and LA fractional shortening of <19.5%. (Read our review of this article, here.)

Utility of radiographic measurements to predict echocardiographic left heart enlargement in dogs with preclinical myxomatous mitral valve disease. Megan H. Poad, Timothy J. Manzi, Mark A. Oyama, Anna R. Gelzer. J. Vet. Intern. Med. July 2020; doi: 10.1111/jvim.15854. Quote: Background: Evaluation of left heart size helps determine disease severity in dogs with myxomatous mitral valve disease (MMVD). Hypothesis/Objectives: Determine the ability of radiographic vertebral heart size (VHS) and vertebral left atrial size (VLAS) to predict LHE[ECHO] in dogs with preclinical MMVD. ... The primary objective of this study was to evaluate the ability of VHS and VLAS to predict echocardiographic criteria for left heart enlargement (LHE[ECHO]) in dogs with preclinical MMVD. We hypothesized that radiographic measurements would predict LHE[ECHO] and would help determine severity of disease in dogs with preclinical MMVD. We aimed to identify clinically relevant values of VHS, VLAS, and sum of VHS + VLAS that predicted presence and absence of LHE[ECHO]. ... Animals: Seventy client-owned dogs with MMVD and no historical or present clinical or radiographic evidence of congestive heart failure (CHF) [including 12 cavalier King Charles spaniels]. ... Dogs were divided into 2 groups based on whether or not echocardiographic criteria for left heart enlargement (LHEECHO), namely LVIDDN ≥1.7 and LA:Ao ≥1.6, were met. Dogs in group 1 failed to meet either or both LHEECHO criteria. Dogs in Group 2 met both LHEECHO criteria. ... Methods: Retrospective cross-sectional study of dogs with same-day echocardiography and thoracic radiography. Receiver-operating characteristic (ROC) curves were used to assess the ability of VHS, VLAS, and VHS + VLAS to discern dogs with and without LHE[ECHO], and clinically relevant cutpoints for these radiographic measurements were selected. Results: The ability of VHS and VHS + VLAS to predict LHE[ECHO] was moderate, and performance of VLAS and VHS + VLAS was not different from that of VHS alone. A VHS cutpoint of >10.8 had sensitivity = 91.1% (76.3%-98.1%) and specificity = 69.4% (51.9%-83.7%) for predicting LHE[ECHO]. A cutpoint of >11.7 had sensitivity = 32.4% (17.4%-50.5%) and specificity = 97.2% (85.5%-99.9%) for predicting LHE[ECHO]. Thirty (43%) of the 70 dogs had a VHS value of 10.9 to 11.7. ... In summary, the radiographic VHS is clinically useful in identifying LHE[ECHO] in dogs with preclinical MMVD, but is limited by a substantial proportion of dogs with indeterminate VHS values. Radiographic measures of LA size such as VLAS possessed low correlation to echocardiographic LA size and did not significantly contribute to detection of LHE[ECHO] in comparison to use of VHS alone in dogs with preclinical MMVD. (Read our review of this article, here.)

Mitral valve annuloplasty and chordal replacement in dogs. Masashi Mizuno, Masami Uechi. J. Vet. Cardio. Med. August 2020. DOI: 10.24647/jvcm.4.1_1. Quote: Optimal timing for mitral valve repair surgery for asymptomatic patients with mitral valve prolapse and severe mitral valve regurgitation has become a topic of study in both humans and dogs. The results of these investigations have led to improvements in perioperative management, including anesthesia and cardiopulmonary bypass, and the skill of surgeons. Mitral valve repair has been established as one of gold standard surgical method for mitral valve disease. Surgical procedures have advanced and surgical indications have expanded with the development of the artificial mitral annulus ring and replacement of the chordae tendineae using artificial materials. High survival rates can be expected in dogs if the appropriate surgery is performed. ... Septal leaflet repair: In dogs, the prolapsed leaflets are not routinely resected, instead, the regurgitation is controlled by placing multiple artificial chordae tendineae (i.e., using ePTFE sutures) from the papillary muscle to the free margin of the septal leaflet. ... In dogs, however, it is often necessary to place 4 to 8 pairs of artificial chordae tendineae for the septal leaflet due to the progressive nature of the disease, which it is often associated with generalized septal leaflet prolapse or chordae tendineae rupture. In dogs, prolapsed septal leaflets are not excised because they are too small to modify using plastic surgery techniques. However, there are cases where cleft is observed in the septal leaflet. In such a case, annuloplasty and chordal replacement alone are not sufficient to reduce regurgitation as regurgitation from the cleft remains. Therefore, leaflet clefts are repaired using continuous or a simple interrupted suture technique. The edges of the cleft tend to become thicker and more retracted over time, and it is preferable to cut one edge before suturing. However, in most cases, the leaflets are too small to be resected. ... Mural leaflet repair: ... In dogs, the size of the mural leaflet is not sufficiently large to perform mural leaflet repair but most often requires replacement of one or two pairs of artificial chordal tendineae, or repairing leaflet cleft. ... Mitral annuloplasty: ... In MVR, apart from chordal replacement for the prolapsed leaflet, the restoration of the mitral annulus to a normal shape is crucial. A prosthetic annulus known as “the ring” is often used for annuloplasty. ... Dogs might be more susceptible to thrombus formation upon exposure to prosthetics than humans. Uechi then demonstrated improved postoperative survival rate using continuous suture method with ePTFE sutures. It is necessary to reduce the risk for complications, especially thrombosis, by limiting the intra-cardiac blood exposure to artificial surfaces. ... Optimal timing for mitral valve repair: ... The short-term postoperative outcomes in dogs with MR after MVR demonstrated no difference in survival rate between stages. This suggests that the optimal timing for MVR for dogs does not depend on the stage of disease. ... Therefore, stage B2 dogs become potential candidate only if MVR was performed at the centers demonstrating evidence of acceptably low complication rates and effective, durable results. ... Post-surgical complications: Mitral valve replacement was not offered to every case due to its difficulties in managing thrombosis. In MVR using the ePTFE strip,approximately 10% of dogs experienced complications considered to be postoperative thrombosis. Recently, however, the incidence of thrombosis in annuloplasty by mitral annuloplasty using continuous suture with ePTFE sutures has decreased to approximately 5%. While low molecular weight heparin and antiplatelet therapy appears to be necessary to reduce the incidence of thrombosis, it may be important to avoid exposure of the heart vessels to prosthetic devices. Aside from thrombosis, hematoma of the left ventricular wall is also one of the critical postsurgical complication. Left intraventricular hematoma usually occurs after spontaneous rebeating of the heart following aortic declamping. Hematoma may cause premature ventricular contraction, low blood pressure and, in some cases it can lead to death. Although the cause remains unknown, it is reasonable to suspect that ventricular extra systoles and the persistence of hypotension after MVR are caused by left intraventricular hematoma. In left intraventricular hematoma with a significant decrease in blood pressure, left ventricular function can be recovered by reopening the heart and making an incision in the hematoma to reduce its size. Hematomas that do not affect blood pressure shrink in several days to several weeks. Thrombosis and hematoma are relatively common complications, and other complications include respiratory failure, anemia,and renal failure. ... As the number of mitral valve repair procedures increases, it will be necessary to evaluate the progression of degenerative lesions and the longterm durability of the procedures. Furthermore, as mitral valve repair becomes more common and accessible in more facilities, high levels of expertise and proficiency among veterinary care practitioners will be required. (Read our review of this article, here.)

Efficacy of oral torasemide in dogs with degenerative mitral valve disease and new onset congestive heart failure: The CARPODIEM study. Beatrice Besche, Thomas Blondel, Emilie Guillot, Catherine Garelli‐Paar, Mark A. Oyama. J. Vet. Intern. Med. August 2020; doi: 10.1111/jvim.15864. Quote: Background: Torasemide is a potent loop diuretic with potential to treat congestive heart failure (CHF) in dogs. Objective: Evaluate the efficacy and safety of torasemide compared to furosemide in dogs with first occurrence of CHF caused by degenerative mitral valve disease (DMVD). Animals: Three hundred and nineteen dogs [including 52 cavalier King Charles spaniels (16.3%)] with new onset CHF attributable to DMVD. Methods: Double‐blinded randomized noninferiority study of PO torasemide vs furosemide in addition to standard CHF treatment. The primary efficacy criterion was decreased pulmonary edema and cough and no worsening of dyspnea or exercise tolerance at day 14. Secondary endpoints included clinical response at day 84 and time to death, euthanasia, or premature study withdrawal for cardiac reasons. Results: Torasemide q24h (n = 161) was non-inferior to furosemide q12h (n = 158); percentage of dogs meeting primary efficacy criterion at day 14 was similar between groups (torasemide, 74.4% vs. furosemide, 73.5%. Efficacy at day 84 showed similar results. Dogs receiving torasemide had a longer time to endpoint and were less than half as likely to experience death, euthanasia, or premature study withdrawal than dogs receiving furosemide at any time during the study. Conclusion and Clinical importance: Torasemide was noninferior to furosemide as first line PO treatment for new onset CHF caused by DMVD. Torasemide significantly decreased risk of cardiac‐related death or premature study withdrawal for cardiac reasons compared to furosemide. [Funded by Ceva Santé Animale, manufacturer of torasemide.] (Read our review of this article, here.)

The chromogranin A-derived peptides catestatin and vasostatin in dogs with myxomatous mitral valve disease. Katja Höglund, Jens Häggström, Odd Viking Höglund, Mats Stridsberg, Anna Tidholm, Ingrid Ljungvall. Acta Vet. Scandina. August 2020; doi: 10.1186/s13028-020-00541-3. Quote: Background: The protein chromogranin A (CgA) is stored and co-released with catecholamines from the stimulated adrenal glands. Increased plasma concentrations of CgA have been shown in people with heart disease. The aim of the study was to investigate whether plasma concentrations of the CgA-derived biologically active peptides catestatin and vasostatin were associated with the severity of myxomatous mitral valve disease (MMVD) in dogs and to assess potential associations between these blood variables and dog characteristics, echocardiographic variables, heart rate (HR), blood pressure (BP) and plasma N-terminal-proBNP (NT-proBNP) concentration. Sixty-seven privately owned dogs with or without MMVD were included. The dogs underwent physical examination, blood pressure measurement, blood sample collection, and echocardiographic examination. ... Estimation of MMVD severity was based on obtained LA/Ao ratio and MR jet size, and dogs were classified as follows: Healthy (LA/Ao < 1.5 and non to minimal MR jet), mild (LA/Ao ≤ 1.5 and MR jet < 30%), moderate (LA/Ao < 1.8 and MR jet ≤ 50%), and severe (LA/Ao ≥ 1.8 and MR jet > 50%) MMVD. ... Plasma concentrations of catestatin and vasostatin were analyzed using radioimmunoassay. Results: Catestatin concentration decreased with increasing left atrial and ventricular size and increased with increasing systolic and diastolic blood pressures. Regression analyses showed no significant associations for vasostatin. No differences in plasma concentrations of catestatin or vasostatin were found between the disease severity groups used in the study. Conclusions: In the present dog population, the catestatin concentration showed weak negative associations with left atrial and ventricular sizes, both of which are known to increase with increasing severity of MMVD. Furthermore, the catestatin concentration showed weak positive associations with blood pressure. (Read our review of this article, here.)

Pilot study: Application of artificial intelligence for detecting left atrial enlargement on canine thoracic radiographs. Shen Li, Zigui Wang, Lance C. Visser, Erik R. Wisner, Hao Cheng. Vet. Radiol. Ultrasound. August 2020; doi: 10.1111/vru.12901. Quote: Although deep learning has been explored extensively for computer-aided medical imaging diagnosis in human medicine, very little has been done in veterinary medicine. The goal of this retrospective, pilot project was to apply the deep learning artificial intelligence technique using thoracic radiographs for detection of canine left atrial enlargement and compare results with those of veterinary radiologist interpretations. Seven hundred ninety-two right lateral radiographs from canine patients with thoracic radiographs and contemporaneous echocardiograms were used to train, validate, and test a convolutional neural network algorithm. The accuracy, sensitivity, and specificity for determination of left atrial enlargement were then compared with those of board-certified veterinary radiologists as recorded on radiology reports. The accuracy, sensitivity, and specificity were 82.71%, 68.42%, and 87.09%, respectively, using an accuracy driven variant of the convolutional neural network algorithm and 79.01%, 73.68%, and 80.64%, respectively, using a sensitivity driven variant. By comparison, accuracy, sensitivity, and specificity achieved by board-certified veterinary radiologists was 82.71%, 68.42%, and 87.09%, respectively. Although overall accuracy of the accuracy driven convolutional neural network algorithm and veterinary radiologists was identical, concordance between the two approaches was 85.19%. This study documents proof-of-concept for application of deep learning techniques for computer-aided diagnosis in veterinary medicine.

Echocardiographic Evaluation of the Mitral Valve in Cavalier King Charles Spaniels. Mara Bagardi, Arianna Bionda, Chiara Locatelli, Matteo Cortellari, Stefano Frattini, Alessio Negro1, Paola Crepaldi, Paola Giuseppina Brambilla. Animals. August 2020; doi: doi:10.3390/ani10091454. Quote: This prospective cross-sectional study aimed to: (1) characterize echocardiographic features of mitral valve in MMVD affected Cavalier King Charles Spaniels (CKCS), focusing on dogs classified as American College of Veterinary Internal Medicine (ACVIM) class B1; (2) compare echocardiographic data in ACVIM B1 dogs divided on the basis of age at time of MMVD diagnosis, in order to understand if different aged subjects had different echocardiographic patterns. Length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet, mitral valve prolapse, diameters of the mitral valve annulus in diastole (MVAd) and systole (MVAs) of 90 CKCS in different ACVIM classes, 64 of which in class B1, were measured. ... Ninety CKCS were included; 28 dogs belonged to private owners and 62 to eight different breeders. ... Eighty-one (90%) dogs were affected by MMVD. The subjects were classified as follows: nine (10%) in ACVIM class A, 64 (71%) in class B1, 11 (12%) in class B2, six in class C/D (7%). In 59% of included dogs a heart murmur was detected at auscultation. ... in 44% of B1 subjects, a heart murmur was not audible. In 76% of dogs without a heart murmur, there was an echocardiographic diagnosis of MMVD. ... The prevalence of MMVD in our population was 90%. ... Patients aged over 7 years were all affected, but the disease was also diagnosed in very young dogs (50% of those under 2 years of age, all classified as ACVIM B1). ... Weight was positively related to ACVIM class. ... In 59% of the dogs, it was possible to hear a heart murmur during auscultation. Despite the association between murmur intensity and ACVIM class, the auscultation was not an eligible method for discriminating between A and B1 subjects. These data underline the importance of performing echocardiographic screening, especially in this breed. In support of this, it should be noted that the selection protocols put in place inseveral countries proved to be ineffective when based only on auscultatory findings, while, when taking into account the echocardiographic data, the results were more promising. ... Valvular measurements were indexed to body weight using Wesselowski’s scaling exponents. The presence of heart murmur did not discriminate between A and B1 classes. Heart enlargement was more frequent in males. Within class B1, older subjects showed significantly higher values of AMVA, AMVW, MVAd, MVAs and lower sphericity index (SI). ... Regarding ACVIM class B1 dogs, the diameter of the mitral valve annulus in systole and diastole, as well as the thickness and area of the anterior mitral valve leaflet and the sphericity of the left ventricle, are greater in patients with MMVD diagnosed atan advanced age. ... Since many CKCS with MMVD have no murmur and their mitral valve has peculiarities, a specifically designed echocardiographic screening should be realized. In addition, different aged B1 dogs have different echocardiographic patterns that may imply different genetic and prognostic profiles. (Read our review of this article, here.)

Prevalence of Pulmonary Hypertension in Dogs with Degenerative Mitral Valve Disease. S. Hamsa Yamini, K. Jeyaraja, M. Chandrasekhar, S.Kavitha. Indian J. Anim. Res. August 2020; doi: 10.18805/ijar.B-3704. Quote: The study was conducted to record the various clinical, electrocardiographic, radiographic and echocardiographic changes in dogs with Pulmonary Hypertension (PH) due to mitral valve disease (MVD). Among the MVD, dogs 15.5 per cent, 8.7 per cent and 4.8 per cent had mild PH, moderate PH and severe PH respectively. A highly significant increase in tricuspid regurgitation velocity (>2.5 mm/Hg), tricuspid regurgitation peak gradient (>25 mm Hg), was recorded in dogs with mild, moderate and severe PH due to MVD when compared to their disease control. A highly significant increase in of MPA/Ao (>0.8) ratio was recorded in dogs with various degree of PH (mild, moderate and severe) when compared with dogs without PH. According to the severity tricuspid regurgitation flow pattern in the right atrium during systole was recorded in all these dogs. In dogs with MVD, moderate to severe PH worsens outcome. ... Tricuspid regurgitation can be used as standard noninvasive echocardiographic parameter used for diagnosing the Pulmonary hypertension and assessing the severity of pulmonary hypertension secondary to MVD. It adversely affects the quality of life and worsens outcome in dogs with MVD.

Symmetric dimethylarginine in dogs with myxomatous mitral valve disease at various stages of disease severity. Carlotta Valente, Carlo Guglielmini, Oriol Domenech, Barbara Contiero, Eric Zini, Helen Poser. PLoS ONE. September 2020;15(9): e0238440. Quote: Symmetric dimethylarginine (SDMA) is a serum biomarker of renal damage in dogs. Moreover, SDMA concentration is an independent predictor of development of severe heart failure (HF) in humans with cardiac disease. This study evaluates whether the serum concentration of SDMA in dogs with myxomatous mitral valve disease (MMVD) is influenced by the severity of heart disease, pulmonary hypertension (PH) and treatment of HF. A total of 99 client-owned dogs [including 3 cavalier King Charles spaniels, 50 mongrels, and 46 of 25 other breeds] were included in this retrospective case-control study; 78 dogs were affected by MMVD [incuding the 3 CKCSs] and classified according to the American College of Veterinary Internal Medicine (ACVIM) guidelines, and 21 were healthy controls. ... For each dog, history, physical examination, complete blood count, biochemical profile, thoracic radiography, 6-lead standard electrocardiogram and trans-thoracic echocardiography were available. Comparisons were performed between groups of dogs belonging to different ACVIM stages and between dogs with and without PH. ... The severity of the MMVD was assessed according to ACVIM guidelines. In particular, asymptomatic dogs without radiographic or echocardiographic evidence of cardiac remodeling were considered to be in stage B1; asymptomatic dogs with signs of cardiac remodeling [i.e., cardiomegaly with left atrium (LA) and/or left ventricle (LV) enlargement] were considered to be in stage B2; symptomatic dogs in which at least one episode of pulmonary edema and/or pleural effusion due to HF had occurred were considered to be in stage C, while symptomatic dogs with end-stage disease and refractory to standard therapies were considered to be in stage D. ... Left ventricular enlargement was considered for values of N-LVIDd ≥ 1.7. The left atrium (LA) to aorta (Ao) ratio was determined using the right parasternal short axis view at the heart base level as previously described  and LA enlargement was noted when LA/Ao ≥ 1.6. ... The results of this study failed to demonstrate a significant increase in SDMA concentration with the progression of the disease stage in dogs with MMVD. ... The median SDMA concentration was neither significantly different among groups of dogs in different disease stages, nor among dogs with MMVD, nor between those with [14.5 μg/dl (10.5–18.8)] and without PH [13 μg/dl (9–17.2)]. The concentration of SDMA did not differ between dogs when considering the combined effect of the ACVIM group and cardiac treatment. Furthermore, no correlation was found between SDMA concentration and radiographic and echocardiographic parameters associated with increased MMVD severity. In conclusion, the results of this study failed to demonstrate that renal function, evaluated by measuring serum SDMA concentration, is significantly impaired in dogs with MMVD. Although some dogs in the ACVIM Stages] C+D group of MMVD had an increased concentration of the variables used to identify renal dysfunction, this was most likely due to pre-renal azotemia instead of representing a feature of the CRS [cardiorenal syndrome] described in humans.

Pharmacokinetics of Repeated Oral Dosing with Coenzyme Q10 in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease. Liselotte B. Christiansen, Malene K. Morsing, Maria Josefine Reimann, Torben Martinussen, Zita Birlie, Anne Marie V. Schou-Pedersen, Jens Lykkesfeldt, Lisbeth H. Olsen. Antioxidants. September 2020;9(9):827-840. Quote: Coenzyme Q10 (Q10) is a mitochondrial cofactor and an antioxidant with the potential to combat oxidative stress in heart failure. This study aims to determine the pharmacokinetics of repeated oral dosing of Q10 in Cavalier King Charles Spaniels (CKCS) with spontaneous myxomatous mitral valve disease (MMVD) and to evaluate echocardiographic parameters, circulating cardiac biomarkers, and quality of life (QoL) after treatment. The study is a randomized, placebo-controlled, single-blinded crossover study. Nineteen CKCS with MMVD were randomized to receive 100 mg Q10 (ubiquinone) bi-daily for three weeks, then placebo (or in reverse order). Clinical examination, blood sampling, echocardiography, and QoL assessment were performed before and after each treatment phase. Q10 plasma concentrations were determined in plasma using a validated high-performance liquid chromatography method using electrochemical detection (HPLC-ECD). Eighteen CKCS were included in the analyses. Total plasma concentration of Q10 increased significantly from baseline (median, 0.92 µg/mL; interquartile range (IQR), 0.70–1.26) to after treatment (median, 3.51 µg/mL; IQR, 2.30–6.88). Thirteen dogs reached the threshold of a total plasma Q10 concentration of ≥2.0 µg/mL. The average half-life (T1/2) of Q10 was 2.95 days (IQR, 1.75–4.02). ... Several formulations of Q10 are on the market, but dose recommendations to dogs are based on an anecdotal background. In this placebo-controlled clinical trial, we investigated plasma concentrations of Q10 in CKCS with severe MMVD before and after three weeks supplementation with Q10. The solubilized formulation of Q10 was well tolerated in all dogs. The primary endpoint of the total Q10 plasma concentration of ≥ 2.0 µg/mL was reached in 13 out of 16 dogs. A 3-week period of treatment with Q10 did not significantly improve echocardiographic indices of MMVD severity, circulating cardiac biomarkers, or owner perceived QoL compared to placebo. Pharmacokinetic analyses resulted in an estimated terminal T1/2 of 2.95 days. Our results are relevant when considering treatment dose and dose interval of Q10 in dogs and for the planning of future clinical trials of longer duration. ... In conclusion, we show that a gelatin capsule formulation of solubilized Q10 is well tolerated in CKCS with MMVD and is absorbed into the circulation without adverse reactions. There were, however, inter-individual variations in the plasma concentrations with this formulation of Q10 similarly to findings in humans. A dosage of 200 mg/day for three weeks of Q10 does not appear to change the clinical severity of MMVD or QoL in CKCS. The estimated T1/2 of 2.95 days may suggest that every other day treatment in dogs may suffice to keep circulating concentrations of Q10 2.0 g/mL in dogs. The variation in Q10 plasma concentrations observed among the CKCS suggests initiation of studies investigating the physiological factors determining intestinal absorption of Q10, including dosing and feeding regimens. ...Ultimately, investigation of long-term use of Q10 in dogs with MMVD and heart diseases of other etiologies are therefore relevant—preferably with dosing tailored in accordance with laboratory testing of Q10 plasma concentrations. (Read our review of this article, here.)

Efficacy of adding ramipril (VAsotop) to the combination of furosemide (Lasix) and pimobendan (VEtmedin) in dogs with mitral valve degeneration: The VALVE trial. Gerhard Wess, Jan‐Gerd Kresken, Ralph Wendt, Juliane Gaugele, Markus Killich, Lisa Keller, Julia Simak, Peter Holler, Alexander Bauer, Helmut Küchenhof, Tony Glaus. J. Vet. Intern. Med. September 2020; doi: 10.1111/jvim.15863. Quote: Background: Triple therapy (TT) consisting of furosemide, pimobendan, and an angiotensin‐converting enzyme inhibitor (ACEI) frequently is recommended for the treatment of congestive heart failure (CHF) attributable to myxomatous mitral valve disease (MMVD). However, the effect of adding an ACEI to the combination of pimobendan and furosemide (dual therapy [DT]) so far has not been evaluated prospectively. Hypothesis: Triple therapy will extend survival time compared to DT in dogs with CHF secondary to MMVD. Animals: Client-owned dogs presented with the first episode of CHF caused by MMVD. Methods: Prospective, single-blinded, randomized multicenter study. One-hundred and fifty-eight dogs [8 cavalier King Charles spaniels] were recruited and prospectively randomized to receive either DT (furosemide and pimobendan) or TT (furosemide, pimobendan, and ramipril). The primary endpoint was a composite of cardiac death, euthanasia for heart failure, or treatment failure. Results: Seventy-seven dogs were randomized to receive DT [4 CKCSs] and 79 to receive TT [4 CKCSs]. Two dogs were excluded from analysis. The primary endpoint was reached by 136 dogs (87%; 66 dogs, DT; 70 dogs, TT). Median time to reach the primary endpoint for all dogs in the study was 214 days (95% confidence interval [CI], 168-259 days). Median time to reach the primary endpoint was not significantly different between the DT group (227 days; interquartile range [IQR], 103-636 days) compared with TT group (186 days; IQR, 72-453 days). ... Our inclusion criteria followed those of the QUEST study, and therefore the LA/Ao ratio had to be > 1.5. However, this cutoff would not likely prove a moderate or marked degree of mitral regurgitation typical of advanced MMVD. Likewise, the lower IQR of the LA/Ao ratio in our study was 2.0, consistent with advanced disease. ... Conclusions and Clinical Importance: ... In conclusion, the addition of an ACEI to pimobendan and a diuretic, as recommended in the ACVIM guidelines for the treatment of chronic stage C MMVD, did not have a significant effect on survival time in dogs with CHF caused by MMVD. Therefore, recommending TT as standard treatment for such dogs does not seem justified. (Read our review of this article, here.)

Acute effects of intravenous pimobendan administration in dog models of chronic precapillary pulmonary hypertension. Tomoya Morita, Kensuke Nakamura, Tatsuyuki Osuga, Sei Kawamoto, Shingo Miki, Kazuyoshi Sasaoka, Mitsuyoshi Takiguchi. J. Vet. Cardiol. September 2020; doi: 10.1016/j.jvc.2020.09.003. Quote: Introduction: Pulmonary hypertension (PH) is a progressive and potentially life-threatening disease. Several drugs are used for the treatment of precapillary PH dogs. Pimobendan is an inotropic drug with phosphodiesterase 3 inhibitory and calcium sensitizing effects. Pimobendan administration improved right ventricular (RV) function and lowered pulmonary arterial pressure in some human patients with precapillary PH. However, the efficacy of pimobendan in dogs with precapillary PH is unknown. Animals, Material and Methods: An implantable port device was percutaneously placed in the cranial vena cava of five laboratory beagles. Chronic embolic precapillary PH was induced via the repeated injection of microspheres every 1-2 days. Microspheres injection was continued until systolic pulmonary arterial pressure reached 50 mmHg. Right heart catheterization and echocardiography were performed at baseline and after injections of placebo and pimobendan (0.15 mg/kg). Results: Repeated injections of microspheres caused an increase in pulmonary vascular resistance, a decrease in stroke volume, RV dilation, left ventricular (LV) and RV dysfunction, and RV dyssynchrony as assessed using echocardiography. Compared to placebo, pimobendan improved LV and RV function based on LV Tei index from 0.48 to 0.38 and RV Tei index from 0.76 to 0.61, as well as stroke volume index from 29.4 to 36.7 ml/m2, respectively. Conclusions: In dog models of chronic PH, intravenous pimobendan effectively improved RV and LV function and increased stroke volume. However, pimobendan administration did not decrease pulmonary arterial pressure or produce hypotension.

Left ventricular M-mode prediction intervals in 7651 dogs: Population-wide and selected breed-specific values. Lilith Carla Esser, Martin Borkovec, Alexander Bauer, Jens Häggström, Gerhard Wess. J. Vet. Intern. Med. October 2020; doi: 10.1111/jvim.15914. Quote: Background: Echocardiography is a common method to measure heart size in dogs. The heart dimensions are influenced by body weight (BW) and potentially by breed. Objectives: To establish BW-dependent prediction intervals (PIs) of the left ventricular (LV) linear dimensions in a population of dogs of many breeds in multicenter environment, and to identify breeds deviating from these intervals. Dogs: Seven thousand six hundred and fifty‐one [7,651] dogs [including 94 cavalier King Charles spaniels -- 0.012%]. Methods: Retrospectively, data from heart screens conducted between 2009 and 2016 were included. Cardiac dimensional PIs were generated using allometric scaling including all nonsighthound dogs and values were compared to previously published PIs. The values measured in dogs of respective breeds, including sighthounds, were then compared to the overall nonsighthound PIs to identify deviant breeds. The interobserver-variability of the measurements was determined using the explained residual variance. Results: Prediction intervals for the nonsighthound dogs were in agreement with previously published cardiac PIs, although the upper limits of the generated PIs of our study were slightly below those currently applied (except the interventricular septum in systole and the left ventricular free wall in diastole below 10.0 kg and 15.0 kg, respectively). Values measured in the nonsighthound breed Newfoundland deviated for most dimensions. Most of the sighthound breeds analyzed had greater cardiac dimensions, with the exception of the Irish Wolfhound. Conclusion and Importance: Findings of our study reinforces the value of BW-dependent PIs for cardiac dimensions in dogs and suggest that these PIs are valid for most nonsighthound breeds, but not the sighthound breeds. (Read our review of this article, here.)

Prevalence and risk factors for atrial fibrillation in dogs with myxomatous mitral valve disease. Carlo Guglielmini, Marlos Goncalves Sousa, Marco Baron Toaldo, Carlotta Valente, Vinicius Bentivoglio, Chiara Mazzoldi, Ilaria Bergamin, Michele Drigo, Helen Poser. J. Vet. Intern. Med. October 2020; doi: 10.1111/jvim.15927. Quote: Background: Atrial fibrillation (AF) is a common supraventricular arrhythmia more frequently observed in large breed dogs. Objectives: Estimate the prevalence of AF in dogs with myxomatous mitral valve disease (MMVD) and identify risk factors for developing AF. Animals: A total of 2194 client-owned dogs with MMVD [including 51 cavalier King Charles spaniels -- 2.3%], including 1280, 588, 290, and 36 dogs in ACVIM stages B1, B2, C, and D, respectively. Methods: Retrospective, cross-sectional study. The medical databases of 3 veterinary teaching hospitals were reviewed. Inclusion criteria were a diagnosis of MMVD after complete cardiovascular evaluation and cardiac rhythm assessment using routine 2-minute ECG or good quality ECG tracing during echocardiographic examination. Results: Atrial fibrillation was diagnosed in 59 dogs with a prevalence of 2.7%. Univariate analysis showed that mixed breed, male sex, advanced ACVIM stage, left atrial and ventricular enlargement, fractional shortening (FS), and presence of pulmonary hypertension were significantly associated with development of AF. According to 2 multivariable models, the left atrium (LA)-to-aorta ratio, early trans-mitral velocity, body weight, and FS and LA, advanced ACVIM stage, and FS were significant predictors of AF for models 1 and 2, respectively. Conclusions and Clinical Importance: Atrial fibrillation is an uncommon complication of MMVD and is significantly associated with the more advanced stage of the disease, increased LA dimension and body weight, and decreased FS. (Read our review of this article, here.)

A dose-ranging study of coenzyme Q10 in dogs with myxomatous mitral valve disease. Natalia Druzhaeva, Aleksandra Domanjko Petric, Gabrijela Tavcar-Kalcher, Janja Babic, Alenka Nemec Svete. J. Vet. Intern. Med. October 2020; 2020 ACVIM Forum ePoster Abstract C32; doi: 10.1111/jvim.15904. Quote: Coenzyme Q10 (CoQ10) supplementation improves left ventricular systolic function in advanced heart failure human patients. According to human studies, at least a 3-fold rise of basal plasma CoQ10 concentration is needed to achieve the biological effects of CoQ10 supplementation. Our goal was to determine the dose sufficient to achieve a 3-fold increase in CoQ10 plasma concentration in dogs with congestive heart failure (CHF) due to myxomatous mitral valve disease (MMVD). In a randomized, double-blinded, placebo-controlled study 19 client-owned dogs with MMVD and CHF were allocated to 3 groups, receiving water-soluble CoQ10 in a daily dose either 100 mg (6 dogs), 200 mg (6 dogs) or placebo (7 dogs), divided twice daily, for two weeks as an addition to cardiac therapy. Twelve healthy dogs not receiving CoQ10 were also included. Blood was drawn five times in MMVD patients (basal, 4 hours, one and two weeks after the beginning of supplementation and one week after the last dose) and once in healthy dogs. Liquid chromatography-tandem mass spectrometry was used to measure plasma CoQ10 concentration. We found no significant difference in basal CoQ10 concentration among groups of patients and healthy dogs (Kruskal-Wallis test). After two weeks, CoQ10 concentration was significantly higher in both CoQ10 groups compared to their basal concentrations (Wilcoxon test; P < 0.05) and compared to the placebo group (Kruskal-Wallis test). A dose of 100 mg resulted in 1.7-4.7-fold and a dose of 200 mg in a 3.2-6.8-fold increase of plasma CoQ10 concentration. One week after the last dose, CoQ10 concentration decreased in both groups; however, in the 200 mg group, it remained significantly higher in comparison to basal concentration. We found no plasma CoQ10 deficiency in our cardiac patients. A daily dose of 200 mg resulted in at least a 3-fold increase of plasma CoQ10 concentration in all patients and might be used in supplementation studies in canine CHF patients. (Read our review of this article, here.)

Prevalence of mitral regurgitation in Cavalier King Charles Spaniels with no or low-grade murmurs. G. Menciotti, A. Franchini, H. Jeong, J. Abbott, S. Lahmers, M. Borgarelli. J. Vet. Intern. Med. October 2020; doi: 10.1111/jvim.15924; 30th ECVIM-CA Congress, ESVC-O-4, September 2020. Quote: Cavalier King Charles Spaniels (CKCSs) have a higher prevalence of myxomatous valvular degeneration (MMVD) compared to similarly aged dogs of other breeds. In this study, we report the prevalence and severity of mitral regurgitation (MR) (defined as presence of MR every cardiac cycle in at least one echocardiographic view), in CKCSs that have no or low-grade murmurs. CKCSs were screened as part of another study. Eligible dogs were older than 1 year of age, without concomitant cardiac disease, or heart murmurs >2/6. All dogs underwent cardiac auscultation and if a murmur ≤2/6 was heard, or there was no murmur, an echocardiogram was performed. The severity of MR was subjectively assessed by color Doppler echocardiography as trivial, trace, mild, moderate, or severe. 138 dogs were examined. On screening examination, murmur distribution was as follows: 95 = no murmur, 5 = 1/6, 20 = 2/6, 16 = 3/6, and 2 = 4/6. 120 CKCSs met inclusion criteria, 119 tolerated echocardiography and two of these had small, inaudible patent arterial ducts. MR severity distribution in the remaining 117 CKCSs was as follows: 40 = no MR, 4 = trivial, 6 = trace, 64 = mild, 3 = moderate. Intensity of murmur was significantly associated with severity of MR and age. 79% (37) of dogs older than 5 years of age and 94% (16) of dogs older than 7 years of age had more than trivial MR despite no or low-grade murmurs. 55 (59%) CKCSs with no murmur had more than trivial MR. In conclusion, we report a high prevalence of echocardiographically detected MR in CKCSs with no or low-grade murmurs. (Read our review of this article, here.)

Polymorphisms in the serotonin transporter gene do not associate with myxomatous mitral valve disease or circulating serotonin levels in Cavalier King Charles Spaniels. M. J. Reimann, K. Meurs, M. Fredholm, L. B. Christiansen, S. E. Cremer, J. E. Møller, J. Häggström, J. Lykkesfeldt, L. H. Olsen. J. Vet. Intern. Med. October 2020; doi: 10.1111/jvim.15924; 30th ECVIM-CA Congress, ESVC-O-5, September 2020. Quote: The neurotransmitter serotonin has an impact on valvular degeneration and function, and alterations in serotonin signaling have been reported in dogs with myxomatous mitral valve disease (MMVD). In Maltese dogs, three single nucleotide polymorphisms (SNPs) in the serotonin transporter (SERT) gene have been suggested to associate with MMVD. The aim of this study was to investigate if MMVD severity and/or serum serotonin concentrations are associated with the SERT polymorphisms in Cavalier King Charles Spaniels (CKCS). Furthermore, ELISA and HPLC measurements of serum serotonin were compared. The study included 72 CKCS (42 females and 30 males; 7.8 [4.8;10.0] years prospectively enrolled and parentally unrelated, allocated in the following American College of Veterinary Internal Medicine (ACVIM) groups: A (n = 19), B1 (n = 20), B2 (n = 20), C (n = 13). TaqMan genotyping assays were designed for the following polymorphisms: c.814insG; c.1192delT; c.1323A/G in the SERT gene. Serum serotonin concentration was determined using ELISA and HPLC. Multivariable regression analysis was used to assess the influence of genotype, ACVIM group, sex and age on serum serotonin concentration. Spearman correlation, paired t-test and difference plot were used to compare serotonin ELISA and HPLC measurements. Taqman analyses revealed no polymorphisms in any of the selected locations of the SERT gene in the CKCS. ACVIM group, age and sex did not influence serum serotonin concentration except for males (432.5 [358.2;535.2] mg/mL), who had higher serum serotonin concentrations, measured by HPLC analysis, compared to females (342.7 (250.7-454.3) mg/mL). Serum serotonin concentration measured by ELISA correlated with HPLC measurements but was lower (mean difference = -22.00). The difference was independent of serum serotonin concentration. In conclusion, the selected SERT SNPs associated with MMVD in Maltese dogs were not found in CKCS dogs and are therefore unlikely to impact MMVD pathophysiology or serum serotonin concentration in this breed. ELISA and HPLC serum serotonin measurements indicated good correlation but ELISA underestimated serotonin concentrations (constant systematic error) compared to HPLC. (Read our review of this article, here.)

Correlation between radiographic vertebral heart size and vertebral left atrial size and echocardiographic measurements of left heart size in Cavalier King Charles Spaniels with preclinical myxomatous mitral valve disease. S. Wesselowski, S. Gordon, A. B. Saunders, R.C. Fries, K. T. Sykes, J.P. Vitt, B. G. Boutet, S. Kadotani, K. Cusack, B. W. Janacek, J. P. Stack, S. Hubert, C. M. Stoner. J. Vet. Intern. Med. October 2020; doi: 10.1111/jvim.15924; 30th ECVIM-CA Congress, ESVC-O-7, September 2020. Quote: Thoracic radiographs are often utilized as a screening tool to assess heart size in dogs, with vertebral heart size (VHS) and vertebral left atrial size (VLAS) reported as objective measurements of global heart size and left atrial size, respectively. Cavalier King Charles Spaniels (CKCS) are predisposed to developing myxomatous mitral valve disease (MMVD), with radiographs frequently used to screen for evidence of left-sided cardiomegaly secondary to MMVD. Normal VHS in CKCS (10.8 +/- 0.5) is reportedly higher than non-breed-specific cut-offs (9.7 +/- 0.5). Breed-specific VLAS cut-offs have not been reported in CKCS. If available, use of breed-specific radiographic cut-offs is recommended by the 2019 ACVIM MMVD consensus statement. The objective of this study was to determine how echocardiographic measurements of left ventricular and left atrial size correlate to VHS and VLAS in preclinical CKCS not receiving cardiac medications. Two-hundred and thirty asymptomatic CKCS were prospectively enrolled and staged according to the 2019 ACVIM MMVD consensus statement after undergoing a standard echocardiogram. There were 14 CKCS in Stage A, 169 in Stage B1 (22 of which had echocardiographic left ventricular or left atrial enlargement but not both) and 44 in stage B2. A right lateral thoracic radiograph was obtained for measurement of VHS and VLAS in all dogs. Spearman rank-order correlation coefficients (rs) were calculated to determine the strength of associations between echocardiographic and radiographic measurements. The VHS was positively, but not strongly, correlated with normalized left ventricular internal diameter at end-diastole (LVIDdN) (rs = 0.59; CI:0.49-0.67; P < 0.0001), left atrial to aortic root ratio (LA:Ao) (rs = 0.52; CI: 0.40-0.61) and left atrial volume indexed to body weight (LA Vol/BW) (rs = 0.60; CI:0.50-0.68). The VLAS was positively and weakly correlated with LVIDdN (rs = 0.40; CI:0.28-0.51), LA:Ao (rs = 0.41; CI:0.29-.51) and LA Vol/BW (rs = 0.43; CI:0.31-0.53). Correlation between VHS and a combination of LVIDdN+LA:Ao (rs = 0.59; CI:0.49-0.7; P < 0.0001) and LVIDdN+LA Vol/BW (rs = 0.60; CI:0.50-0.28) were also explored given the global nature of the VHS measurement, with correlations found to be similar to those derived from individual echocardiographic variables. These findings suggest that in CKCS, neither VHS nor VLAS correlate strongly with selected echocardiographic measurements of left ventricular or left atrial size. The lack of strong correlation between VHS and VLAS to the echocardiographic measurements of interest for MMVD staging may impact the performance of thoracic radiographs as a screening tool in CKCS. (Read our review of this article, here.)

Myxomatous mitral valve disease in Cavalier King Charles Spaniels: a clinical and genetic study. M. Bagardi, A. Bionda, C. Locatelli, M. Cortellari, S. Frattini, A. Negro, P. Crepaldi, P.G. Brambilla. J. Vet. Intern. Med. October 2020; doi: 10.1111/jvim.15924; 30th ECVIM-CA Congress, ESVC-P-1, September 2020. Quote: Cavalier King Charles Spaniels (CKCSs) show a genetic predisposition to myxomatous mitral valve disease (MMVD) development, even at an early age. It is estimated that 50% of CKCSs before 6-7 years of age and almost 100% over 11 years are interested by MMVD, against 14% in other breeds. The aim of this study was to characterize the clinical and echocardiographic features of healthy and MMVD affected CKCSs, through the description of MV morphology, prolapse and annulus. A cohort of 90 healthy and affected by MMVD at different stages (B1, B2, C) CKCSs was analyzed and phenotypic, pedigree and echocardiographic parameters were recorded. Log10 body weight indexed length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet, prolapse, diameters of the mitral valve annulus in diastole (MVAd) and systole (MVAs) and sphericity index (SI) were measured. In the whole sample AMVL was significatively longer in class B2 than class A and B1 and in class C than B1; AMVW and AMVA were higher in classes B2 and C than A and B1. LA/Ao, MVAd,MVAs and left ventricle longitudinal end-diastolic diameter were higher in males. MVAd was significantly higher in neutered-females than in intact-females. Subjects in class B1 were classified in age-related classes: under 3 y (group 1, 15.6%), between 3 and 6 y (group 2, 46.9%) and over 6 y (group 3, 37.5%). AMVW and AMVA were greater in group 3 than 1. MVAd and MVAs were higher in group 3 compared to 2. SI was lower in group 3 than. A subset of 34 CKCSs, non-relatives in direct line, was genotyped with Canine 230K SNP BeadChips to evaluate genomic regions of interest useful to distinguish between case and control groups of dogs. The first study was created according to age and ACVIM classification, the second to auscultation findings. These analyses highlighted, beside known regions on CFA 4-17 and 13-14, new regions of interest on several chromosomes (CFA 2-11-14-19-21-25). Although further investigations of the genes are needed, these results may contribute to disentangle the complexity of the etiopathogenic mechanism involved in early development and rapid progression of MMVD in CKCSs. Essential will be the follow up of the subjects in class B1 which will allow us to uniquely characterize the association between the genetics and the ventricular and valvular echocardiographic characteristics. (See this companion study.)

Left atrial volume assessment and survival in 160 Cavalier King Charles spaniels with or without degenerative mitral valve disease (2017-2019). C. Poissonnier, P. Foulex, M.P. Alvarado, E. Trehiou-Sechi, V. Saponaro, P. Passavin, L. Desquilbet, V. Chetboul. J. Vet. Intern. Med. October 2020; doi: 10.1111/jvim.15924; 30th ECVIM-CA Congress, ESVC-P-3, September 2020. Quote: Degenerative mitral valve disease (DMVD) is the most common acquired canine heart disease, with a high predisposition of the Cavalier King Charles Spaniel (CKC) breed. Echocardiographic evaluation of canine DMVD includes measurement of left atrial (LA) size, which is one of the strongest prognostic factors for survival or disease worsening. The LA size is usually assessed using a linear measurement from a two-dimensional image, and then indexed to the aortic diameter (left atrium-to-aortic ratio, LA:Ao). As LA enlargement can happen in various directions, quantification of LA volumes (LAV) using the biplane Simpson’s method of discs (SMOD) and area-length method has recently been suggested. A previous study on DMVD demonstrated that a category of asymptomatic DMVD CKCs without apparent cardiac remodeling (B1 dogs, ACVIM 2009 guidelines) actually shows LA dilation, as detected by LAV calculation despite LA:Ao values within reference range. The aims of this prospective study were therefore: 1) to investigate the predictive value of selected clinical and echocardiographic variables, including LAV (biplane SMOD), regarding cardiac-related death (CD) in CKCs with DMVD, and 2) to assess among ACVIM B1 CKCs the association between these variables and the time to congestive heart failure (CHF), i.e., radiographically confirmed pulmonary edema. The study sample consisted of 160 CKCs (132 with DMVD and 28 healthy ACVIM stage A), prospectively recruited (2017-2019). No ACVIM stage A dog died during the study period. Among the 92/132 DMVD CKCs for which a follow-up was available, 34/92 (37%) died, with CD in 29/34 (85%) dogs. Median time to CD was 32.3 months [CI95% = 28.5;NC]. Univariate Cox proportional hazard analysis among DMVD CKCs revealed that age, ACVIM stage, murmur grade, regurgitation fraction (RF) assessed by the PISA method, systolic pulmonary arterial pressure (SPAP) > 50 mmHg, minimal heart rate > 100 bpm, end-diastolic LA:Ao≥1.0, end-systolic LA:Ao≥1.6, and endsystolic LAV > 0.90 mL/kg were significantly associated with shorter time to CD. Furthermore, among the 56 ACVIM B1 dogs, 11 (20%) developed CHF during follow-up. Time to CHF was significantly shorter for dogs with end-systolic LAV > 0.90 mL/kg, as well as for dogs with RF > 30%. In conclusion, these results suggest that end-systolic LAV, LA:Ao, RF, and SPAP are associated with CD in DMVD CKCs. This study also confirms the practical interest of quantifying mitral regurgitation and LAV in ACVIM B1 dogs, in which both variables are associated with time to the first CHF event despite LA:Ao values within reference ranges.

A Genomic Study of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels. Arianna Bionda, Matteo Cortellari, Mara Bagardi, Stefano Frattini, Alessio Negro, Chiara Locatelli, Paola Giuseppina Brambilla, Paola Crepaldi. Animals. October 2020;10(10):1895. Quote: Cavalier King Charles spaniels (CKCSs) show the earliest onset and the highest incidence of myxomatous mitral valve disease (MMVD). Previous studies have suggested a polygenic inheritance of the disease in this breed and revealed an association with regions on canine chromosomes 13 and 14. Following clinical and echocardiographic examinations, 33 not-directly-related CKCSs were selected and classified as cases (n = 16) if MMVD was present before 5 years of age or as controls (n = 17) if no or very mild MMVD was present after 5 years of age. DNA was extracted from whole blood and genotyped with a Canine 230K SNP BeadChip instrument. Cases and controls were compared with three complementary genomic analyses (Wright’s fixation index—FST, cross-population extended haplotype homozygosity—XP-EHH, and runs of homozygosity—ROH) to identify differences in terms of heterozygosity and regions of homozygosity. The top 1% single-nucleotide polymorphisms (SNPs) were selected and mapped, and the genes were thoroughly investigated. Ten consensus genes were found localized on chromosomes 3-11-14-19, partially confirming previous studies. The HEPACAM2, CDK6, and FAH genes, related to the transforming growth factor β (TGF-β) pathway and heart development, also emerged in the ROH analysis. In conclusion, this work expands the knowledge of the genetic basis of MMVD by identifying genes involved in the early onset of MMVD in CKCSs. (See this companion study.)

Short-term effects of sildenafil in the treatment of dogs with pulmonary hypertension secondary to degenerative mitral valve disease. Karun Saetang, Sirilak Disatian Surachetpong. Vet. World. October 2020; doi: 10.14202/vetworld. 2020.2260-2268. Quote: Background and Aim: Pulmonary hypertension (PH) is a common complication of degenerative mitral valve disease (DMVD). Sildenafil, a phosphodiesterase-5 inhibitor, has effects in reducing pulmonary arterial pressure by selectively dilating pulmonary vessels. The study aimed to evaluate the effects of sildenafil in combination with conventional therapy in dogs with PH caused by DMVD. Materials and Methods: Fourteen dogs diagnosed with PH secondary to DMVD Stage C on conventional therapy were randomly assigned to placebo (n=7) and sildenafil (n=7) groups. On day 0, the recruited dogs underwent physical examinations, clinical score assessments, electrocardiography, systolic blood pressure measurements, blood collection, thoracic radiography, and echocardiography for baseline. The dogs then received a combination of conventional therapy with sildenafil or placebo every 8 h for 1 week. On day 7, all dogs underwent the baseline evaluations again. Results: The sildenafil group experienced a significant decrease in estimated systolic pulmonary artery pressure (sPAP) (p=0.043) from day 0 to day 7. Moreover, the total clinical scores were decreased in dogs treated with sildenafil relative to those who received the placebo (p=0.007); however, the lung scores were not different between before and after treatment with sildenafil. Conclusion: Sildenafil had a synergistic effect with conventional therapy in reducing the estimated sPAP and clinical scores in dogs with PH secondary to DMVD.

Comparison of Thoracic Radiographs with Echocardiography in the Interpretation of Cardiac Chamber Enlargement in Dogs with Severe Left-Sided Cardiomegaly. Elodie Huguet, Federico Grosso, Whitney Lamb, Meg Sleeper, James Colee, Clifford Berry. American College of Veterinary Radiology abstract #26. November 2020. Quote: Qualitative assessment of individual cardiac chamber enlargement on thoracic radiographs was assessed using echocardiography as the gold standard in non-sedated dogs. Using this method, the presence of severe left-sided cardiomegaly was hypothesized to contribute to the false identification of right-sided cardiomegaly on thoracic radiographs. 175 dogs with three view thoracic radiographs were retrospectively included if echocardiography was done within 24 hours and no rescue therapy was provided in the interim. All radiographic studies were reviewed by two groups of five board-certified radiologists with greater and less than 10 years of experience for classification of cardiac chamber enlargement as normal or mildly, moderately or severely enlarged. The agreement, sensitivity and specificity of the radiologists' interpretation of cardiac chamber size on thoracic radiographs and quantitative echocardiographic measurements were evaluated. A total of 147 cases (mixed breed dog [n=42; 28.6%], Chihuahua [n=27; 18.4%] and cavalier King Charles spaniel [n=17; 11.6%]) had complete data available for analysis. Intragroup agreement was moderate for the evaluation of left atrial enlargement and slight to fair for all other cardiac chambers. Between the mode of the radiologists’ responses in the two groups and the echocardiographic measurements, there was slight agreement for all cardiac chambers with higher scores reported using echocardiography. When moderate to severe left-sided cardiomgegaly was identified on echocardiography, the sensitivity, specificity and accuracy of radiographs was low, identifying a small subset of dogs with radiographic evidence of right-sided cardiomegaly in the absence of corresponding right-sided cardiomegaly on echocardiography. Therefore, thoracic radiographs should be used with caution for the evaluation of cardiac chamber enlargement, particularly in the presence of severe left-sided cardiomegaly.

Echocardiograpny, Chap. 8 of Small Animal Diagnostic Ultrasound (Fourth Edition), Johsn D. Bonagura, Virginia Luis Fuentes. Elsevier. October 2020;230-354e12. Quote: Echocardiography is widely used for the noninvasive evaluation of cardiac diseases in dogs and cats. Cardiac ultrasonography (US) studies complement auscultation, electrocardiography, thoracic radiography, and clinical laboratory testing. A properly conducted two-dimensional (2D) echocardiogram (echo), complemented by motion (M)-mode and Doppler studies, represents the noninvasive standard for the diagnosis and staging of most congenital and acquired heart diseases. This chapter introduces the principles and practice of echocardiography and offers specific guidelines for establishing a cardiac diagnosis and prognosis based on US findings. Because echocardiography often guides cardiac therapy, some pertinent aspects of clinical management are also summarized in this chapter. ... Echocardiography should be placed in a clinical context. It is not a substitute for a careful history and physical examination. ... Furthermore, an individual capable of integrating information from all sources, including the history, physical examination, and laboratory studies, should ultimately direct patient management. ... Many echocardiographic measurements can change by 10% or more because of biologic variability, differences in operator technique, and interobserver factors when measuring images. ... Normal values for dogs and cats are affected not only by species but also significantly by body weight, breed, physiologic variation, plasma volume status, heart rate and rhythm, and measurement errors. ... Accepting these uncertainties in the veterinary landscape, the authors use a multifaceted approach for measuring chamber sizes, identifying cardiomegaly, and assessing ventricular function. These recommendations include: (1) subjective assessment; (2) use of simple ratios that relate chamber sizes to one or more aortic measurements; (3) reference (prediction) values indexed to bodyweight by allometry; and (4) breed-specific normal ranges, when available. ... Because no standardizations or accepted guidelines are in place currently, a variety of different diameters, areas, and ratios have been advocated to quantify LA size.

Interobserver variability of radiographic methods for the evaluation of left atrial size in dogs. Mara Bagardi, Martina Manfredi, Davide D. Zani, Paola G. Brambilla, Chiara Locatelli. Vet. Radiol Ultrasound. November 2020; doi: 10.1111/vru.12930. Quote: The objectives of this retrospective, observer agreement study were to (a) test variability of radiographic left atrial dimension (RLAD) and vertebral left atrial size (VLAS) measurements among observers with different levels of expertise in thoracic radiology and cardiology, (b) assess whether one method is better than the other in detecting left atrial enlargement (LAE), and (c) assess the agreement among RLAD, VLAS, and American College of Veterinary Internal Medicine (ACVIM) classes. ... Compared with echocardiography, thoracic radiography is widely available and cost-effective. However, radiographic assessment of LA size could be primarily subjective and prone to error. ... Seventy-four dogs [including 15 cavalier King Charles spaniels (20.3%) and 3 English setters (4.1%)] (eight healthy and 66 with mitral valve disease) with thoracic radiographs and echocardiography performed on the same day were reviewed. Thirty showed echocardiographic LAE. ... Dogs with MMVD were allocated to one of four classes in accordance with ACVIM guidelines: the healthy group was free of echocardiographic abnormalities; the stage B1 group had MMVD, LA/Ao < 1.6, and LVIDaN < 1.7; the stage B2 group had MMVD, LA/Ao ≥ 1.6 and LVIDaN ≥ 1.7 without evidence of previous (compensated) or concurrent (decompensated) CHF; and stage C-D group had MMVD and evidence of compensated or decompensated CHF. ... Dogs were assigned to one of two groups according to the absence or presence of LAE defined by 2D echocardiography as LA/Ao ≥ 1.6. ... Left atrial dimension was quantified using RLAD and VLAS by six different operators with three levels of clinical experience in veterinary cardiology/radiology. Vertebral heart score and fourth thoracic vertebra (T4) were also measured. Differences in T4, vertebral heart score (VHS), RLAD, and VLAS measurements were found among six operators and among the three levels of clinical expertise as well as between veterinary cardiology readers and veterinary radiology readers. The area under the receiver operating characteristic (AUC) curve for VHS showed good performances for all observers and level and type of expertise; the AUC for RLAD and VLAS was suboptimal only for the radiology student. Our RLAD and VLAS cutoffs (1.9 and 2.43 v, respectively) were better related to qualitative radiographic than quantitative echocardiographic LAE evaluation. Radiographic LA dimension and VLAS showed an increase proportional to the worsening of the ACVIM class. ... The mean VHS value obtained in this study for normal dogs was 10.7 ± 0.65 v, which is slightly above the suggested upper limit for normal heart size in most breeds. ... The use of breed-specific VHS values is needed for the VHS method to have a higher specificity for normal heart size. In this study, due to breed variability of subjects, it was not possible to apply a breed-specific VHS value. ... In conclusion, results of the present study indicate that new radiographic measurements RLAD and VLAS demonstrated high sensitivity and specificity for detecting LAE with a moderate/strong correlation with LA/Ao ratio and especially with qualitative radiographic LAE evaluation in dogs affected byMMVD at different ACVIM stages. Thoracic radiographs and evaluation of LA dimension are a simple and cost-effective tool that can be used when echocardiography is not available, also by low experienced practitioners. Better performances are associated with increased clinical expertise and background.

Effect of angiotensin receptor blockers and angiotensin converting enzyme 2 on plasma equilibrium angiotensin peptide concentrations in dogs with heart disease. Éva Larouche-Lebel, Kerry A. Loughran, Terry Huh, Mark A. Oyama. J. Vet. Intern. Med. December 2020; doi: 10.1111/jvim.16025. Quote: Background: The pathophysiology of heart failure involves maladaptive angiotensin peptides (APs) and enzymes, including angiotensin 2 (AT2) and angiotensin converting enzyme (ACE), as well as recently described alternative components, such as angiotensin 1-7 (Ang1-7) and angiotensin converting enzyme 2 (ACE2). The relative effects of different neurohormonal-targeting drugs on balance of APs in dogs with heart disease are unknown. Hypothesis/Objectives: Plasma AP concentrations differ in dogs receiving angiotensin converting enzyme inhibitors (ACEIs) vs angiotensin receptor blockers (ARBs) and recombinant human ACE2 (rhACE2) will further increase these differences. Animals: Eight dogs with degenerative mitral valve disease (DMVD) [including 2 cavalier King Charles spaniels (25%)]. Methods: Prospective open-label trial. Equilibrium concentrations of APs from plasma during PO ACEI treatment and then after 14 days of PO ARB treatment using telmisartan were measured using liquid chromatography-tandem mass spectroscopy before and after in vitro incubation with rhACE2. Results: Concentration of Ang1 7 was increased during ARB treatment (Ang1-7: 443 pg/mL; 95% confidence interval [CI] = 247-794 pg/mL) vs ACEI (Ang1 7: 182 pg/mL; 95% CI = 66.2-503 pg/mL; P = .01). Incubation with rhACE2 decreased traditional APs while increasing beneficial alternative APs, and Ang1-7 was significantly higher in the ARB + rhACE2 (880 pg/mL; 95% CI = 560-1383 pg/mL) vs ACEI + rhACE2 (455 pg/mL; 95% CI = 188-1104 pg/mL; P = .03) group. The most favorable theoretical AP profile was achieved in the ARB + rhACE2 group. Conclusions and Clinical Importance: The AP profile during telmisartan treatment is associated with higher plasma Ang1-7 as compared with during ACEI. This favorable shift is potentiated in vitro by combination of ARB + rhACE2. These data support potential AP-targeting strategies and drugs in dogs with DMVD.

Peptide barcodes in dogs with pulmonary hypertension secondary to mitral valve disease using MALDI-TOF MS and LC-MS/MS. Nattapon Riengvirodkij, Sittiruk Roytrakul, Janthima Jaresitthikunchai, Narumon Phaonakrop, Sawanya Charoenlappanich, Walasinee Sakcamduang. Research Square. December 2020; doi: 10.21203/rs.3.rs-135232/v1. Quote: Background: Pulmonary hypertension (PH) is an important complication in dogs with cardiorespiratory diseases. The most common underlying disease of PH has been described to be mitral valve disease (MVD), which is the most frequent acquired heart disease found in dogs. Doppler echocardiography is generally used in routine practice for identifying PH; however, there are several limitations to this method in practical use. Matrix-assisted laser desorption/ionization time-of-ight mass spectrometry (MALDI-TOF MS) is a technique that can characterize specic patterns of peptide mass called peptide barcodes from various samples. In addition, in combination with liquid chromatography tandem mass spectrometry (LCMS/MS), potential peptide sequences associated with specic conditions could be identied. The present study aimed to use MALDI-TOF coupled with LC-MS/MS to characterize specic peptide barcodes and potential peptide candidates in serum samples from healthy dogs (normal control), dogs with MVD stage B (MVD B) (asymptomatic stage), MVD stage C (MVD C) (symptomatic stage), MVD stage B with PH (MVD B PH) and MVD stage C with PH (MVD C PH).[None of the dogs were cavalier King Charles spaniels.] Results: Discrete clusters of the 5 sample groups were identied by 3D plot analysis. Peptide barcodes also revealed differences in peptide patterns among the 5 groups. Six amino acid sequences of peptide candidates at 1,225.60, 1,363.85, 1,688.71, 1789.52, 2020.21 and 2156.42 Da were identied as part of the proteins CLCN1, CLUL1, EDNRA, PTEN, SLC39A7, and CLN6, respectively. The network interactions between these discovered proteins and common cardiovascular drugs were also investigated. Conclusion: The present study revealed distinct clusters and different peptide barcodes for the MVD B, MVD C, MVD B PH, MVD C PH and normal control groups using MALDI-TOF MS. These results demonstrate that MALDITOF MS has promise as a technique for diagnosing dogs affected by asymptomatic and symptomatic stages of MVD with and without PH. Additionally, with MALDI-TOF MS in combination with LC-MS/MS, potential peptide candidates related to diseases were also identied. Further studies are required to identify peptide barcodes in dogs with other diseases to create peptide barcode databases in veterinary medicine before using this method as a novel diagnostic tool in the future.

Preliminary Outcome of a Novel Edge-to-Edge Closure Device to Manage Mitral Regurgitation in Dogs. Sebastiaan A Van Nimwegen, Gareth Edward Zeiler, Jing Li. Front. Vet. Sci. December 2020; doi: 10.3389/fvets.2020.597879. Quote: Background: Veterinary management of mitral valve regurgitation due to mxyomatous valve disease in dogs is limited to medical treatments, which only postpones the onset of congestive heart failure or alleviates clinical symptoms. Most surgical procedures to manage this condition in humans require cardiopulmonary bypass and have a high risk of complications. Animals: Eight dogs [3 miniature poodles, 2 Pomeranians, and 3 mix-breeds] with naturally occurring mitral valve regurgitation. Methods: Prospective observational study. All dogs were treated with a novel edge-to-edge transcatheter device named ValveClamp. ... In short, the apex of the heart was exposed via a 5–8-cm intercostal minithoracotomy incision at the left 5th intercostal space near the sternum. A purse-string suture of 2-0 polypropylene monofilament (Jinghuan, Shanghai, China) was placed in the cardiac apex, which encircled a stab incision through which a 14F sheath (APT Medical Tech, Hunan, China) was passed into the left ventricle. The ValveClamp mitral valve ValveClamprepair system was passed through the sheath and used to guide the sheath across the mitral valve and into the left atrium. The distal part of the clamp was released into the left atrium and positioned under transesophageal or direct epicardial echocardiographic guidance. The catheter was then partially withdrawn so that the proximal half of the clamp was released into the left ventricle. The two halves of the clamp were then tightened, capturing the mitral leaflets between them. [See diagram at right.] If the valves were not sufficiently well-trapped the clamp arms were released and the process was repeated. Once the valve flaps were adequately secured, the guide was released and removed, leaving the clamp in situ. The size of the clamp was selected based on the mitral valve annulus diameter of each animal. Type I (14 mm) clamps were selected for dogs with mitral valve annulus diameter <20 mm, and Type II (16 mm) clamps for 20–30 mm. ... The total surgical procedural time and total catheterization time were recorded. Echocardiographic variables measured pre- and post-procedure were compared using Wilcoxin-signed rank test with a P<0.05 considered significant. Data were expressed as median and interquartile range and absolute numbers and percentages. Results: The procedural success rate was 100% and all the dogs survived without complications. The median (interquartile range) total surgical procedural time was 86.5 (76–96.2) minutes and catheterization time was 23.5 (22–33.8) minutes. Echocardio-graphy revealed a significant reduction in mitral regurgitation severity in all dogs following the procedure based on both a reduced mitral regurgitant maximum jet area and a reduced mitral regurgitant maximum jet area to left atrial area. ... No major complications have been reported in any of the dogs to date, with a mean follow-up time of 124 days since surgery (range from 100 to 141 days). ... The procedure to implant the ValveClamp device is technically more straightforward and appears to be prone to fewer intraoperative complications [than the ePTFE chordal implantation technique involves transapical delivery of ePTFE artificial cords that are anchored to the affected valve leaflets and secured to an ePTFE pledget on the epicardium]. The 100% survival rate and rapid recovery of dogs following this procedure are highly encouraging. However, the post-operative period for all dogs presented here is still relatively short and longer follow-up is required to demonstrate long-term benefits before the widespread adoption of the procedure is recommended. ... Limitations of the study include the short follow-up and the fact that outcomes are limited to observation of clinical parameters. None of the dogs died or were euthanized and, therefore, the security of the clamp device on the valves and its effect on the valve leaflets could not be evaluated post-mortem. Furthermore, the dogs included in this study were limited to dogs with mitral regurgitation but no clinical signs and minimal, if any, chamber enlargement (stage B1 MMVD). The efficacy of this device still needs to be further tested on patients with varying stages of MMVD. ... In conclusion, the edge-to-edge valve closure using the ValveClamp mitral valve system is easy to perform and is highly effective at reducing the severity of mitral regurgitation. The system has good potential to be used in clinical practice on canine MMVD patients, although more data needs to be collected to prove its long-term safety and efficacy.

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2021

Factors affecting the urinary aldosterone-to-creatinine ratio in healthy dogs and dogs with naturally occurring myxomatous mitral valve disease. Alberto Galizzi, Mara Bagardi, Angelica Stranieri, Anna Maria Zanaboni, Dario Malchiodi, Vitaliano Borromeo, Paola Giuseppina Brambilla, Chiara Locatelli. BMC Vet. REs. January 2021; doi: 10.1186/s12917-020-02716-6. Quote: Background: Chronic renin-angiotensin-aldosterone system (RAAS) activation in course of heart diseases contributes to cardiac remodeling and heart failure. Myxomatous mitral valve disease (MMVD) is characterized by different stages of severity and trend of RAAS activity during the course of the disease is still uncertain. The urinary aldosterone-to-creatinine ratio (UAldo:C) has been proven to reflect RAAS activation in dogs and might be a useful marker in monitoring therapy and disease progression, but data about this parameter need to be expanded. The objective of this study was to evaluate the UAldo:C in healthy dogs and dogs with naturally occurring MMVD, and to investigate the relationships between this parameter and clinical, echocardiographic and laboratory variables. Results: The study population consisted of 149 dogs [27 cavalier King Charles spaniels (18%)]: 49 healthy [6 CKCSs (12%)] and 100 MMVD dogs (45 stage B1 [8 CKCSs (17.8%)], 13 stage B2 [6 CKCSs (46%)] and 42 stage C [7 CKCSs (16.7%)]). Urinary aldosterone-to-creatinine ratio was not significantly different among healthy and MMVD dogs of any stages. Breed, sex and age showed a significant impact on UAldo:C. In particular, Chihuahua and Cavalier King Charles spaniel showed significantly higher UAldo:C than other breeds, as well as intact females than other genders. In stage C dogs, UAldo:C appeared to be increased by spironolactone and was positively associated with furosemide dose. Aldosterone breakthrough (ABT) appeared to occur in 36% (8/22) of stage C dogs not receiving spironolactone. A significant positive association between UAldo:C and left atrium-to-aortic root ratio (LA/Ao) was found. Conclusions: Individual factors such as breed, sex and age appeared to influence UAldo:C, and therapy seemed to add further variability. In the light of these results, comparing the UAldo:C of a single patient with a population-based reference value might lead to wrong interpretations and an individual monitoring should be considered. The prevalence of ABT in the present study (36%) was in line with those previously reported. However, due to the high individual variability of UAldo:C found in the study, even this result should be re-evaluated in the setting of an individual longitudinal approach. The positive association between UAldo:C and LA/Ao supports the mutual relationship between RAAS and cardiac remodeling.

Evaluation of radiographic predictors of left heart enlargement in dogs with known or suspected cardiovascular disease. Laetitia Duler, Lance C. Visser, Kristina N. Jackson, Kathryn L. Phillips, Rachel E. Pollard, Mason W. Wanamaker. Vet. Radiol. & Ultra. January 2021; doi: 10.1111/vru.12949. Quote: Radiographic assessment of heart size is important for clinical management of dogs with cardiovascular disease (CVDz). We sought to compare the ability of vertebral heart size (VHS), vertebral left atrial size (VLAS), and radiologists’ assessment of left atrial size (RadLAE) to predict echocardiographic left atrial size (EchoLAE), an important marker of left heart disease severity. We also compared the ability of VHS and VLAS to predict echocardiographic criteria for ACVIM stage B2 (EchoB2) in dogs with myxomatous mitral valve disease (MMVD). This prospective observational study enrolled 183 dogs with known or suspected CVDz that had an echocardiographic examination and thoracic radiographs obtained within 24 h. ... The majority of dogs (77%, n = 141) had a cardiac murmur. Slightly more than half (56%, n = 103) were diagnosed with MMVD (n = 38 with ACVIM stage B1, n = 32 with ACVIM B2, n = 33 with ACVIM stage C or D). ... Thirty dogs with cardiovascular disease (16%) had radiographic evidence of pulmonary edema. Sixty-two dogs (34%) had EchoLAE. ... Echo-cardiographic LA enlargement (EchoLAE - yes) was defined by a LAD/AoD_Lx >2.54 and a LA/Ao_Sx >1.68. ... "Increased VHS” was defined using published breed-specific VHS reference intervals, if available. If unavailable or a mixed-breed, normal VHS was considered to be ≤10.7 vertebrae. Normal VLAS was considered tobe ≤2.3 vertebrae. ... Dogs diagnosed with MMVD were staged according to the ACVIM consensus recommendations. For study purposes, dogs with subclinical MMVD (ie, dogs with MMVD that had not experienced heart failure) with a body weight <20 kg were subclassified as EchoB2 if they met the echocardiographic criteria for ACVIM stage B2 (ie, EchoB2 – yes), if LA/Ao_Sx ≥1.6 and LVIDdN ≥1.7 and EchoB2 - no, if LA/Ao_Sx <1.6 and LVIDdN <1.7. ... When using EchoLAE as the criterion standard, the false positive rate for VLAS >2.3 vertebrae was 26% and the false negative rate was 10%. For increased VHS, the false positive rate was 40% and the false negative rate was 16%. The false positive rate for RadLAE was 39% and the false negative rate was 6%. ... Within the subset of dogs with subclinical MMVD, diagnostic accuracy of VLAS and VHS for predicting EchoB2 were not significantly different. The optimal cutoffs identified to predict EchoB2 for VLAS and VHS were >2.5 and >11.1 vertebrae, respectively. Importantly, the VLAS and VHS cutoffs identified with maximum specificity (ie, fewest false positives) for predicting EchoB2, which is associated with life-long treatment decisions, were >2.8 and >12.0 vertebrae, respectively. Multiple logistic regression showed that VLAS, and not VHS, was independently associated with EchoB2. ... Our data suggest that in a dog with suspected cardiovascular disease, if VLAS is increased above normal (ie, >2.3 vertebrae) clinicians can be reasonably confident the LA is enlarged. Conversely, if VHS is increased (using breed-specific cutoffs or VHS >10.7 if mixed-breed), there is approximately a 40% chance the LA is not enlarged (false negative). ... To be certain, however, an echocardiographic examination remains the clinical gold standard. ... Based on the results of our study and others, we believe it is reasonable to conclude that both VLAS and VHS are clinically useful for clinical staging of dogs with known or highly suspected subclinical MMVD. Vertebral heart size >11.7-12.25 suggest EchoB2 is very likely. ... In practice, radiologists might qualify LA enlargement with terms such as mild, moderate, or severe. We contend that these qualifiers are subjective and likely mean different things to different people thus presenting significant challenges. ... Lastly, our chosen criteria for EchoLAE is not a gold standard for assessment of LA size/volume. This should not be overlooked. For example, our EchoLAE criteria are likely less sensitive for detecting LA enlargement compared to a gold standard three-dimensional volumetric imaging technique (eg, cardiac magnetic resonance). The 2 linear measurement ratios of LA size are standard practice in our hospital and represent what impacts decision-making in a more clinically relevant manner. In conclusion, VLAS is a clinically useful radiographic measurement to quantify LA size in dogs with known or suspected cardiovascular disease. Our results confirm it is a more specific indicator of a LA enlargement compared to VHS. These results might help clinicians explain clinical signs and assess risk (or lack thereof) for left heart failure in symptomatic dogs. Further research on the clinical utility of VLAS for predicting heart failure in symptomatic dogs and in other specific clinical scenarios are needed. Both VLAS and VHS can aid clinical staging and therefore life-long treatment decisions in dogs with subclinical MMVD when an echocardiographic examination is not performed. (See also this 2020 abstract.)

Echocardiographic estimation of left ventricular-arterial coupling in dogs with myxomatous mitral valve disease. Tatsuyuki Osuga, Tomoya Morita, Noboru Sasaki, Keitaro Morishita, Hiroshi Ohta, Mitsuyoshi Takiguchi. J. Vet. Intern. Med. January 2021; doi: 10.1111/jvim.16028. Quote: Background: The interaction between the left ventricle and systemic arterial systems is termed left ventricular-arterial coupling (VAC). It is related to the pump efficiency of the left ventricle, and the deterioration of VAC plays an important role in the pathophysiology of various heart diseases. ... The effective arterial elastance (Ea) to left ventricular (LV) end-systolic elastance (Ees) ratio (Ea/Ees) is an index of the interaction between LV and systemic arterial systems, left ventricular-arterial coupling (VAC). The Ea is an index of total arterial load of the LV, whereas Ees is an index of LV systolic function. In humans, inappropriate VAC based on increased Ea/Ees estimated using echocardiography is associated with more advanced heart disease severity. Hypothesis: Our aim was to determine the VAC status estimated by echocardiography in dogs with MMVD. Our hypothesis was that inappropriate VAC assessed by echocardiographic estimation of Ea/Ees would be associated with advanced disease severity in dogs with myxomatous mitral valve disease (MMVD). ... Animals: Ninety MMVD dogs and 61 healthy dogs. [No cavalier King Charles spaniels were identified.]. Methods: Prospective cross-sectional study. The MMVD dogs were classified into stages B1, B2, or C according to [2019] American College of Veterinary Internal Medicine guidelines. Effective arterial elastance was echocardiographically estimated using the formula: mean blood pressure/(forward stroke volume/body weight). End-systolic elastance was echocardiographically estimated using the formula: mean blood pressure/(LV end‐systolic volume/body weight). The ratio Ea/Ees was calculated. ... [W]e did not perform cardiac catherization for left ventricular pressure-volume loop analysis, the gold standard for the determination of Ees and Ea. ... Results: The ratio Ea/Ees was higher in stage B2 dogs than in healthy dogs and dogs stage B1, and higher in stage C dogs than in healthy dogs and dogs in the other 2 stages. Multivariable logistic regression analysis showed that Ea/Ees and the peak velocity of early diastolic transmitral flow to isovolumic relaxation time ratio were independent predictors of stage C among echocardiographic indices in MMVD dogs. ... Our results show that inappropriate VAC indicated by an increase in echocardiographically estimated Ea/Ees is associated with advanced disease severity in dogs with MMVD. The increase in Ea/Ees in stage B2 mainly was associated with the decrease in Ees, suggesting that left ventricular systolic dysfunction mainly contributed to inappropriate VAC in this stage. On the other hand, the increase in Ea/Ees in stage C was associated with both the decrease in Ees and increase in Ea, suggesting that both left ventricular systolic dysfunction and increase in the total arterial load of the left ventricle contributed to inappropriate VAC in this stage. Our study is the first to estimate VAC using echocardiography in dogs clinically affected by MMVD. ... The results on Ea in our study suggest that the total arterial load of the left ventricle increases in stage C, leading to more inappropriate VAC in stage C when compared with stage B2. ... Conclusions and Clinical Importance: ... In conclusion, inappropriate VAC assessed by echocardiographic estimation of Ea/Ees is associated with advanced disease severity in dogs with MMVD. Inappropriate VAC indicated by the increase in Ea/Ees was mainly associated with decreases in Ees in stage B2, and was associated with both a decrease in Ees and an increase in Ea in stage C. Multivariable logistic regression analysis showed that Ea/Ees was an independent predictor of stage C in dogs with MMVD among the various echocardiographic indices evaluated.

Two radiographic methods for assessing left atrial enlargement and cardiac remodeling in dogs with myxomatous mitral valve disease. T. Vezzosi, C. Puccinelli, S. Citi, R. Tognetti. J. Vet. Cardiol. January 2021; doi: 10.1016/j.jvc.2021.01.002. Quote: Introduction: Two radiographic measures of the left atrial (LA) size, the vertebral left atrial size (VLAS) and the radiographic left atrial dimension (RLAD), have been described in dogs. The aim of this study was to determine their feasibility and diagnostic value in the prediction of LA enlargement and clinical stage in dogs with myxomatous mitral valve disease (MMVD). Animals: 111 client-owned dogs affected by MMVD [including 10 (9%) cavalier King Charles spaniels]. Methods: Retrospective study. In each dog, VLAS, RLAD, vertebral heart score (VHS) and left atrium-to-aorta-ratio (LA/Ao) were measured. The correlation between VLAS, RLAD and LA/Ao was evaluated. The diagnostic accuracy of VLAS and RLAD was assessed for the detection of LA enlargement and clinical staging using the receiver operating characteristic curve analysis. Results: A positive correlation was observed between VLAS, RLAS and LA/Ao. Both VLAS and RLAD showed high diagnostic accuracy in the detection of LA enlargement. In the stage B, the RLAD performed better that VLAS and VHS in the detection of dogs fulfilling the echocardiographic criteria for stage B2. .. The higher feasibility of VLAS in comparison to RLAD can be explained by the fact that the identification of the landmarks for the measurement of VLAS (ie.e the carina and the point of intersection between the most caudal aspect of the LA and the dorsal border of the caudal vena cava) are more easily identifiable than the dorsal margin of the LA, which represents one of the landmarks for measuring the RLAD. The presence of cardiogenic pulmonary edema, with perihiar and/or dorso-caudal diatribution, may obscure the dorsal margin of the LA. Furthermore, the dorsal margin of the LA can overlap with the other anatomical structures with radiopacity of soft tissues (such as the aorta and pulmonary vessels of the caudal lung lobes) and/or ribs, making clear identification more difficult. ... In cases in which neither the VLAS nor the RLAD are measurable, the VHS remains the main objective method to radiographically assess cardiac enlargement. ... The best cutoff of RLAD to detect LA enlargement was 1.8 in our study ... and a RLAD ≥ 2.0 was the best predictor of moderate-to-severe LA enlargement. Regarding VLAS, our results showed that the best cutoff to detect LA enlargement ws 2.2 ... A VLAS ≥ 2.4 was the best predictor of moderate-to-severe LA enlargement. In our study, the RLAD showed a higher diagnostic accuracy in detecting LA enlargement than the VLAS. A possible explanation is that LA mainly enlarges in a dorso-caudal direction, with secondary dorsal displacement of the tracheal bifurcation on latero-lateral chest radiographs. The RLAD probably better highlights this geometrical pattern of LA enlargement in comparison to VLAS. Regarding the utility of VLAS and RLAD in the staging of dogs with MMVD, both methods showed a good diagnostic accuracy for the prediction of the ACVIM stage in asymptomatic dogs (i.e. B1 versus B2). ... Our results are in line with two recent studies agreeing that the optimal cutoff of VLAS in the prediction of the B2 stage is 2.5. However, our results showed that the RLAD (cutoff 1.8) performs better than VLAS in the distinction between B1 and B2 cases. ... In our study the best cutoff of VHS in predicting dogs fulfilling the echocardiographic criteria for stage B2 was 10.7. ... Conclusions: VLAS and RLAD represent useful radiological tools for the detection of LA enlargement in dogs with MMVD. In asymptomatic dogs, the RLAD performs better than VLAS and VHS in the prediction of those fulfilling the echocardiographic criteria for stage B2.

Depleted Myocardial Coenzyme Q10 in Cavalier King Charles Spaniels with Congestive Heart Failure Due to Myxomatous Mitral Valve Disease. Liselotte B. Christiansen, Maria J. Reimann, Anne Marie V. Schou-Pedersen, Steen Larsen, Jens Lykkesfeldt, Lisbeth H. Olsen. Antioxidants. January 2021;10:161; doi: 10.3390/antiox10020161. Quote: Congestive heart failure (CHF) has been associated with depleted myocardial coenzyme Q10 (Q10) concentrations in human patients. The aim of this study was to investigate associations between myocardial Q10 concentrations and myxomatous mitral valve disease (MMVD) severity in dogs. Furthermore, citrate synthase (CS) activity was analysed to determine if a reduction in myocardial Q10 was associated with mitochondrial depletion in the myocardium. Thirty Cavalier King Charles spaniels (CKCS) in MMVD stages B1 (n = 11), B2 (n = 5) and C (n = 14) according to the American College of Veterinary Internal Medicine (ACVIM) guidelines and 10 control (CON) dogs of other breeds were included. Myocardial Q10 concentration was analysed in left ventricular tissue samples using HPLC-ECD. CKCS with congestive heart failure (CHF; group C) had significantly reduced Q10 concentrations (median, 1.54 µg/mg; IQR, 1.36–1.94), compared to B1 (2.76 µg/mg; 2.10–4.81), B2 (3.85 µg/mg; 3.13–4.46) and CON dogs (2.8 µg/mg; 1.64–4.88). CS activity was comparable between disease groups. In conclusion, dogs with CHF due to MMVD had reduced myocardial Q10 concentrations. Studies evaluating antioxidant defense mechanisms as a therapeutic target for treatment of CHF in dogs are warranted.

Letter to the editor regarding “Efficacy of adding ramipril (VAsotop) to the combination of furosemide (Lasix) and pimobendan (VEtmedin) in dogs with mitral valve degeneration: The VALVE trial”. Clarke Atkins, Bruce Keene, Teresa C. DeFrancesco, Sandra Tou, Valérie Chetboul, Étienne Côté, Stephen Ettinger, Robert L. Hamlin, Jonathan P. Mochel, Jean‐Louis Pouchelon, Rebecca L. Stepien. J. Vet. Intern. Med. January 2021; doi: 10.1111/jvim.16035. Quote: While agreeing with the [VALVE Trial] authors that this question has merit, we share several comments and questions regarding applicability of their study results to current practice. ... Although unknowable by the authors at the time of the VALVE trial design, other studies completed during the 10-year duration of the VALVE trial have demonstrated significant benefit from greater, longer, and more broad-spectrum RAAS suppression (eg, higher or q12h ACEI dosing and mineralocorticoid antagonist [MRA] inclusion) in treating proteinuria and CHF. ... Although the VALVE results are surprising and interesting, a conclusion that they obviate the need for ACEI treatment in the management of CHF from MMVD is not justified. We believe this study to be hypothesis generating, rather than pivotal. A larger study, employing methodology that provides evidence of more complete RAAS inhibition with contemporary adjunctive heart failure treatment is needed to provide pivotal data upon which to guide practice. (See VALVE Trial authors' response to this letter, below.)

Response to letter to the editor regarding “Efficacy of adding ramipril (VAsotop) to the combination of furosemide (Lasix) and pimobendan (VEtmedin) in dogs with mitral valve degeneration: The VALVE trial”. Gerhard Wess, Tony Glaus. J. Vet. Intern. Med. January 2021; doi: 10.1111/jvim.16033. Quote: The goal of the VALVE trial was to answer whether adding ACEI to furosemide plus pimobendan would improve outcome, and most VALVE coauthors had already been involved in the QUEST trial. To be consistent and credible, the authors largely adopted the QUEST trial's study protocol with some differences. In both the QUEST and the VALVE trials, the following features were identical: (a) dogs had to be in an advanced stage of MMVD with pulmonary edema objectively present on thoracic radiographs; (b) the study was not placebo-controlled, but the study authors were blinded to the treatment as the drugs were provided to the clients using a provider; (c) treatment failure was defined as decompensation despite the use of very high doses of furosemide. This dosage had been set at 12 mg/kg/d in the QUEST trial and at 15 mg/kg/d in the VALVE trial. Admittedly, these are very high dosages. Nevertheless, this was the definition of treatment failure in these respective studies. ... [T]he VALVE trial is a large, prospective, randomized, multicenter study with a very high event rate that did not show any survival benefit with respect to the use of an ACEI in dogs with advanced MMVD. Therefore, given the data available today, we cannot in good faith recommend adding an ACEI to the basic treatment consisting of furosemide and pimobendan in dogs with MMVD in ACVIM stage C. (See letter to the editor, above.)

Diagnosis of Isolated Cleft of the Anterior Mitral Leaflet in a Dog: A Case Study Using Real-Time Three- Dimensional Echocardiography. Ryuji Araki, Koji Iwanaga, Kazunori Ueda, Mitsuhiro Isaka. Case Rpts. in Vet. Med. January 2021; doi: 10.1155/2021/6610526. Quote: The occurrence of ICAML [isolated cleft of the anterior mitral leaflet] in canines is rare and has only been reported once. Thus, the present case is a very rare clinical case. ... We aimed to determine the usefulness of a diagnostic technique using 3-DE in a 2-year-old Cavalier King Charles Spaniel with ICAML that exhibited mild mitral valve regurgitation. ICAML was initially assessed by transthoracic two-dimensional echocardiography. A diagnosis of congenital mitral regurgitation due to ICAML and understanding of the morphological structure of the valve was established based on the 3-DE findings. ... The patient was a 2-year-old castrated male Cavalier King Charles Spaniel that weighed 8.2 kg. The patient had a left ventricular systolic murmur confirmed at another hospital at 4 months of age. MR was confirmed using color-flow Doppler instead of two-dimensional echocardiography (2- DE). The patient was diagnosed with MR due to mitral valve dysplasia. ... MR was observed on a left parasternal long-axis view using color-flow Doppler echocardiography. A cleft of the anterior leaflet of the mitral valve was observed from the left ventricular shor-taxis view at the level of the mitral valve. ... To obtain a detailed view of the mitral morphology, real-time threedimensional (3-D) echocardiography (3-DE) was performed using a 4v probe. It directly showed the 3-D structure of the mitral valve cleft (MVC) in multiple views, revealing the position, shape, longitudinal diameter, and width, as well as the spatial position between the chordae tendineae surrounding the MVC and the aortic valve. The examination also revealed a maximum diameter of 2.1 cm, a maximum of crack by cleft width of 0.8 cm, and a V shape (Figure 3). ... The examinations led to a diagnosis of congenital MR due to ICAML. Although organic cardiac abnormality was observed, there was no heart enlargement (mitral valve disease was classified as Stage B1 per the American College of Veterinary Internal Medicine classification). Following discussion with the owner, treatment with oral temocapril hydrochloride and pimobendan, as prescribed from other hospitals, was continued. The symptoms related to the cardiac condition remained unchanged and did not worsen without treatment until the dog died of lymphocytic leukemia. ... It is rare for ICAMLs to be diagnosed as an isolated finding in dogs. ICAML is assumed to be a partial defect of the endocardial bed. ... Our patient did not show dynamic left ventricular outflow stenosis due to the cleft; however, symptoms could be worsened in the presence of acquired factors such as myxoma-like degeneration. Further studies involving careful follow-up with surgical treatment are required.

Predictors of reoccurrence of congestive signs within 180 days after successful treatment of the first episode of congestive heart failure in dogs with myxomatous mitral valve disease. Alessandra Franchini, Jonathan A. Abbott, William Tyrrel, Steven Rosenthal, Sunshine Lahmers, Giulio Menciotti, Serena Crosara, Jens Häggström, Michele Borgarelli. J. Vet. Cardiol. February 2021; doi:10.1016/j.jvc.2020.11.005. Quote: Introduction: Myxomatous mitral valve disease (MMVD) is the most common cause of left-sided congestive heart failure in dogs. We sought to identify predictors of first reoccurrence of congestive signs (CS) within 180 days in dogs with MMVD and clinically stable heart failure. Animals: A total of 445 dogs affected by stable American College of Veterinary Internal Medicine (ACVIM)-Stage C MMVD were included [including 37 (8%) cavalier King Charles spaniels], 106 in the reoccurrence group (RG) and 339 in no reoccurrence group (NRG). Patients were considered "stable" if medical treatment had been unchanged for at least 4 weeks since the first identification of CS. Methods: Medical records of dogs with stable ACVIM-Stage C MMVD included in a registry of dogs affected by MMVD were reviewed. Follow-up was required for inclusion in this investigation. Logistic regression was used to identify clinical and echocardiographic variables that independently predict first reoccurrence of CS. Results: Baseline [at the enrolment of the 445 dogs in stable ACVIM Stage C MMVD] left atrial-aortic ratio (OR: 1.89, 1.10-3.54), left ventricular internal diameter at end-diastole (LVIDd_N) (OR: 2.84, 90% CI: 1.41-5.77), peak velocity of early diastolic transmitral flow (OR: 1.81, 90% CI: 1.10- 3.00) and furosemide daily dosage (OR: 1.19, 90% CI: 1.04-1.37) were associated with reoccurrence of CS in univariable analyses. The LVIDd_N remained significant in the multivariable analysis, but the area under the receiver operator characteristic curve was 0.57. Conclusion: This study failed to identify accurate predictors of reoccurrence of CS. However, dogs with larger value of LVIDd_N are more likely to have reoccurrence of CS within 180 days.

Two-dimensional echocardiographic measures of left ventricular dimensions agree with M-mode measurements in dogs. M. Rishniw, A. Corda, F. Spina, D. Caivano. J. Vet. Cardiol. February 2021; doi: 10.1016/j.jvc.2020.12.001. Quote: Introduction: Clinicians measure left ventricular dimensions in dogs from both M-mode and two-dimensional images. Little information currently exists as to whether these two methods provide measurements similar enough to be interchangeable. Animals: The animals included in this study are 206 client-owned dogs: 68 healthy, 105 with myxomatous mitral valve disease, 33 with other cardiac or extracardiac disease. Materials and methods: Investigators measured left ventricular diastolic and systolic dimensions from archived M-mode and two-dimensional images obtained from the right parasternal short-axis view. Agreement between the pairs of measurements was examined using limits of agreement (Bland-Altman) plots. Results: Left ventricular diastolic dimensions showed no fixed or proportional bias but did show heteroscedasticity. Ninety-five percent limits of agreement for normalized differences approximated ±10%; 95% of the absolute differences for any pair of measurements were <3.9 mm regardless of bodyweight and <2.7 mm for dogs <15 kg. Left ventricular systolic dimensions showed slight proportional bias, with two-dimensional measurements being progressively larger than M-mode measurements as ventricular size increased. Ninety-five percent limits of agreement for normalized differences approximated ±20%; 95% of the absolute differences for any pair of measurements were <4.6 mm regardless of bodyweight and <3.5 mm for dogs <15 kg. Mitral valve disease did not appreciably affect these findings. Conclusions: Left ventricular internal dimensions in dogs with and without cardiac disease measured from two-dimensional right parasternal short-axis images are interchangeable with those measured from M-mode images using the same view.

Analysis of mitral valve morphology in dogs undergoing mitral valve repair with three-dimensional transesophageal echocardiography. T. Mizuno, A. Chen, K. Mamada, A. Takahashi, S. Uchida, M. Uechi. J. Vet. Cardiol. April 2021 doi: 10.1016/j.jvc.2021.01.004. Quote: Introduction: Information about real-time three-dimensional (3D) transesophageal echocardiography (TEE) for the evaluation of canine mitral valve morphology is lacking in veterinary medicine. Objectives: To evaluate the feasibility of 3D TEE for the evaluation of canine mitral valves and whether there was a difference in mitral valve morphology between American College of Veterinary Internal Medicine (ACVIM) stages. Animals: Thirty-one dogs were evaluated, including nine dogs classified as ACVIM stage B2, 15 as stage C, and seven as stage D. Materials and methods: Three-dimensional TEE was performed after anesthetic induction for mitral valve surgery, and the 3D geometry of the mitral valve apparatus was measured. Results: The intraclass correlation coefficient was good in both inter- and intraobserver analyses of the 3D measurements of mitral valve annulus geometry and excellent in both inter- and intraobserver analyses in the 3D measurements of mitral valve annular and leaflet sizes. Annulus height to commissural width ratio of stage D dogs showed significantly lower values than B2 dogs (B2: 14.2% [9.1–20.5%]; C: 10.6% [6.5–24.1%]; D: 9.5% [4.7–13.8%]). The aortic–mitral angle of stages C and D were significantly flatter than stage B2 (B2: 122.32 ± 9.39; C: 133.66 ± 8.43; D: 140.70 ± 10.70). Conclusions: Real-time 3D echocardiography using TEE is a feasible method to evaluate the morphology of the mitral valve in dogs. The saddle shape of the mitral annulus and aortic–mitral angle were flatter in stage D. Further studies are required to understand the pathology of mitral valve disease in dogs.

The effect of myxomatous mitral valve disease severity on packed cell volume in dogs. J. Wilshaw, M. Stein, N. Lotter, J. Elliott, A. Boswood. J. Sm. Anim. Pract. February 2021; doi: 10.1111/jsap.13308. Quote: Objectives: The aim of this study was to examine whether associations between disease severity and packed cell volume exist in dogs with myxomatous mitral valve disease. Materials and Methods: ... Data from 289 dogs were available for analysis, providing results from a total of 1465 visits. Amongst these data, 12.7% (n=186) of visits were from dogs in stage A, 64.4% (n=944) in stage B1, 10.0% (n=147) in stage B2 and 10.3% (n=151) in stage C. A small number of dogs (2.5%, n=37) had not been staged at the time of examination and had insufficient data available to complete this retrospectively. Cavalier King Charles Spaniels formed the majority breed having been assessed on 43.1% (n=631) of visits. ... American College of Veterinary Internal Medicine stage and echocardiographic measurements were entered in separate multivariable linear mixed effects models with packed cell volume as the dependent variable. Age, breed, sex, weight and blood urea nitrogen concentrations were additionally tested in these analyses to control for patient characteristics. Results: Packed cell volume (% whole blood) in stages B1 and B2 (B1: 42.62 ±0.27; B2: 41.77± 0.42) was lower than stage A (44.57 ±0.53). In stage C, packed cell volume was greater than both preclinical stages (C: 43.84 ±0.46). When the administration of loop diuretics was included in statistical models, packed cell volume was inversely related to normalised left ventricular internal diameters (β: −2.37; 95% confidence intervals: −3.49, −1.25). Clinical Significance: Dogs with myxomatous mitral valve disease may develop reductions in packed cell volume as their disease progresses. Although this finding was statistically significant at a population level, it should be noted that the differences described are relatively small. This, along with other causes of variation in packed cell volume, means that changes would be challenging to appreciate within individual patients. Plasma volume depletion following diuretic administration may explain why findings differed in stage C.

Radiographic quantification of left atrial size in dogs with myxomatous mitral valve disease. Christopher Lam, Brad J. Gavaghan, Fiona E. Meyers. J. Vet. Intern. Med. February 2021; doi: 10.1111/jvim.16073. Quote: Background: In the absence of echocardiography, identification of cardiomegaly via thoracic radiography is a necessary criterion for classification of disease severity in dogs with myxomatous mitral valve disease (MMVD). Objective: Modified-vertebral left atrial size (M-VLAS) facilitates objective radiographic assessment of the left atrium (LA) in 2 dimensions and identifies LA enlargement more accurately than existing methods. Animals: Sixty-four dogs with various stages of MMVD [including 12 cavalier King Charles spaniels (18.8%)] and 6 control healthy dogs. ... Within the stage B1 group (11 females and 11 males), there were ... 4 Cavalier King Charles Spaniels (CKCS) [18%] ... . Stage B2 dogs (8 females and 13 males) consisted of ... 6 CKCS [28.6%] ... . Within the stage C group (7 females and 14 males), there were ... 2 CKCS [9.5%]... . ... Methods: Retrospective case–control study. Medical records were searched for dogs with varying severity of MMVD. ... The original VLAS method aimed to quantify LA size radiographically based on a single-dimensional measurement that roughly represented the transverse diameter of the LA body. Yet, LA functional anatomy and geometry is complex, with the left atrium described as a cylinder with an almost fixed head and distensible walls attached to a piston (ie, mitral annulus). The process of LA remodeling is equally complex and non-uniform. Recognizing the limitations of only using a single 2D lateral radiograph to quantify the complex LA anatomy, the M-VLAS method aimed to complement the existing VLAS method with an additional aspect of measurement, incorporating the dorsoventral dimension of the LA chamber. The goal was to capture dogs with LA remodeling secondary to MMVD that would have otherwise been missed by the VLAS method given its potential limitations as a single-dimensional measurement. [See Figure 1, below]. ... Modified-vertebral left atrial size, vertebral left atrial size (VLAS), vertebral heart size (VHS), and radiographic left atrial dimension (RLAD) were measured from thoracic radiographs and compared with echocardiographically derived measurements. Results: Positive correlation to LA/Ao was identified for M‐VLAS, VLAS, RLAD, and VHS. Receiver operating characteristic analyzes provided an area under the curve of 0.97 (95% CI, 0.94-1.00) for M‐VLAS, which was superior to VHS (0.90, 95% CI, 0.94-1.00) in identifying dogs with LA/Ao ≥1.6. A cut-off value of ≥3.4 vertebrae using M-VLAS provided 92.7% sensitivity and 93.1% specificity in predicting LA enlargement. Conclusions and clinical importance: M-VLAS, which is superior to VHS, offers an accurate and repeatable way to radiographically identify LA enlargement in dogs with MMVD.

Figure 1: Measurements of M-VLAS, VLAS, VHS, and RLAD demonstrated on the same right lateral inspiratory radiograph of a dog with stage B2 MMVD. All methods take their respective measurements from the cranial edge of the T4 vertebral body extending caudally, parallel to the vertebral column, rounded to the nearest 0.1 vertebrae. A. MVLAS — an initial line (yellow) — is drawn from the centre of the most ventral aspect of the carina to the intersection between the most caudal aspect of the left atrium and the dorsal border of the caudal vena cava. A second additional line (red) is then drawn from the most distal border of the left atrium towards the first line, intersecting it perpendicularly. Two separate straight lines corresponding to the lengths of the first 2 lines (yellow + red) were then drawn from the cranial edge of the T4 vertebral body extending in a caudal direction, ventral and parallel to the vertebral canal. The M-VLAS for this dog is 2.2+1.4 = 3.6 vertebrae (v). (Note: the first value being the VLAS.) B. Vertebral left atrial size (VLAS = 2.2v)—yellow line C. Vertebral heart score (VHS = 5.7+4.6 = 10.3v), vertical axis—thick white line; horizontal axis—thin white line. D. Radiographic left atrial dimension (RLAD = 2.0v)—dashed white lines represent the VHS vertical and horizontal axes, constituting the foundation for the RLAD measurement (green line), which bisects the VHS intersection. M-VLAS Figure 1

Accuracy of history, physical examination, cardiac biomarkers, and biochemical variables in identifying dogs with stage B2 degenerative mitral valve disease. Jenny Wilshaw, Steven L. Rosenthal, Gerhard Wess, Dave Dickson, Luca Bevilacqua, Emily Dutton, Michael Deinert, Ricardo Abrantes, Ingo Schneider, Mark A. Oyama, Sonya G. Gordon, Jonathan Elliott, Dong Xia, Adrian Boswood. J. Vet. Intern. Med. February 2021; doi: 10.1111/jvim.16083. Quote: Background: Treatment is indicated in dogs with preclinical degenerative mitral valve disease (DMVD) and cardiomegaly (stage B2). ... Stage B2 was defined as an LA:Ao ≥1.6 and LVIDDN ≥1.7. Dogs that did not meet both of these criteria were classified as stage B1. ... Of the 361 dogs receiving treatment with pimobendan, only 56.51% (n = 204) met the criteria for stage B2 disease. ... This is best diagnosed using echocardiography; however, relying upon this limits access to accurate diagnosis. Objectives: To evaluate whether cardiac biomarker concentrations can be used alongside other clinical data to identify stage B2 dogs. Animals: Client-owned dogs (n = 1887) [including 478 (25.33%) cavalier King Charles spaniels] with preclinical DMVD prospectively sampled in Germany, the United Kingdom, and the United States. Methods: Dogs that met inclusion criteria and were not receiving pimobendan (n = 1245) were used for model development. ... The most common breed evaluated was the Cavalier King Charles Spaniel (n = 292, 27.07%) ... Explanatory (multivariable logistic regression) and predictive models were developed using clinical observations, biochemistry, and cardiac biomarker concentrations, with echocardiographically confirmed stage B2 disease as the outcome. Receiver operating characteristic curves assessed the ability to identify stage B2 dogs. Results: Age, appetite, serum alanine aminotransferase activity, body condition, serum creatinine concentration, murmur intensity, and plasma N-terminal propeptide of B-type natriuretic peptide (NT-proBNP) concentration were independently associated with the likelihood of being stage B2. The discriminatory ability of this explanatory model was superior to NT-proBNP or the vertebral heart score alone. A predictive logistic regression model could identify the probability of being stage B2. Conclusion and Clinical Importance: Our findings indicate accessible measurements could be used to screen dogs with preclinical DMVD. Encouraging at-risk dogs to seek further evaluation could result in a greater proportion of cases being appropriately managed. ... This study found that variables from different aspects of a dog's examination could be used in combination to assess the likelihood of being stage B2. A predictive model that analyses a dog's appetite, BCS [body condition score], creatinine concentration, murmur intensity, and NT-proBNP concentration could be presented as an app for use in primary-care practice. This has potential as a screening test and might provide an informed way to allocate client and practice resources. The correct application of this prediction model could improve outcomes for dogs with preclinical DMVD.

Echocardiographic reference intervals for volumetric measurements of the left ventricle using the Simpson's method of discs in 1331 dogs. Gerhard Wess, Alexander Bauer, Antonia Kopp. J. Vet. Intern. Med. March 2021; doi: 10.1111/jvim.16089. Quote: Background: Echocardiographic measurements play an important role in detecting cardiac enlargement and assessing cardiac function. In human cardiology, M-mode measurements have been widely replaced by volumetric measurements of the left ventricle (LV) using Simpson's method of disc (SMOD). In veterinary cardiology, more large-scale studies are necessary to generate reference intervals (RIs) for SMOD LV volume measurements. ... Veterinary cardiologists face the problem of dealing with many different breeds and therefore a wide range of different body and BWs. To diagnose cardiac enlargement or, less commonly, to evaluate if a heart is volume underloaded, it is necessary to compare the obtained measurements to RIs. The optimal situation would be to have breed-specific RIs, generated from a large healthy population. ... Objective: To generate body size independent RIs for LV volume measurements in dogs. Animals: A total of 1331 dogs were enrolled in the study. ... Healthy adult dogs (n = 1331) of variable size and somatotype. ... The population consisted of 128 different breeds and many mixed breeds [including 16 cavalier King Charles spaniels (0.01%)]. Methods: Prospective study. The SMOD was measured from the right parasternal long axis and the left apical 4-chamber view in clinically healthy dogs. The SMOD measurements were normalized to various allometric scales (kg, kg2/3, or kg1/3). RIs for LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) using SMOD were estimated as prediction intervals of both a linear and an additive regression model. Additionally, after normalization to body weight, 95% RIs were determined using nonparametric methods with 2.5 and 97.5 percentiles serving as the lower and upper limits. Separate analyses were performed for 120 sighthound breeds and 1211 other breeds. Results: Echocardiographic LV volumes correlated best with weight in kilograms. The additive model proved to be more flexible and accurate than the other 2 methods to generate RIs. Separate RIs for sighthound and all other breeds are provided. ... Breed-specific RIs still are important for selected breeds, but the numbers of individuals in our study were not high enough to establish such RIs. ... Conclusions and Clinical Importance: Body size and breed-independent RIs for LV volume measurements using SMOD were generated prospectively from a large and diverse population of dogs and are available for clinical use.

Left atrial decompression as a palliative minimally invasive treatment for congestive heart failure caused by myxomatous mitral valve disease in dogs: 17 cases (2018–2019). Justin W. Allen, Kevin L. Phipps, Anthony A. Llamas, Kirstie A. Barrett. J. Amer. Vet. Med. Assn. March 2021; doi: 10.2460/javma.258.6.638. Quote: Objective: To determine whether left atrial decompression (LAD) would reduce left atrial pressure (LAP) in dogs with advanced myxomatous mitral valve disease (MMVD) and left-sided congestive heart failure (CHF) and to describe the LAD procedure and hemodynamic alterations and complications. Animals: 17 dogs with advanced MMVD and left-sided CHF that underwent LAD [including 3 (17.65%) cavalier King Charles spaniels]. Procedures: The medical record database was retrospectively reviewed for all LAD procedures attempted in dogs with MMVD and left-sided CHF between October 2018 and June 2019. Data were collected regarding signalment (age, breed, weight, and sex), clinical signs, treatment, physical examination findings, and diagnostic testing before and after LAD. Procedural data were also collected including approach, technique, hemodynamic data, complications, and outcome. Results: 18 LAD procedures performed in 17 patients were identified. Dogs ranged in age from 7.5 to 16 years old (median, 11 years) and ranged in body weight from 2.9 to 11.6 kg (6.4 to 25.5 lb) with a median body weight of 7.0 kg (15.4 lb). Minimally invasive creation of an atrial septal defect for the purpose of LAD was successful in all dogs without any intraoperative deaths. Before LAD, mean LAP was elevated and ranged from 8 to 32 mm Hg with a median value of 14 mm Hg (reference value, < 10 mm Hg). Following LAD, there was a significant decrease in mean LAP (median decrease of 6 mm Hg [range, 1 to 15 mm Hg]). Survival time following LAD ranged from 0 to 478 days (median, 195 days). Conclusions and Clinica Relevance: For dogs with advanced MMVD and left-sided CHF, LAD resulted in an immediate and substantial reduction in LAP.

Effect of spironolactone and benazepril on furosemide‐induced diuresis and renin‐angiotensin-aldosterone system activation in normal dogs. Darcy Adin, Clarke Atkins, Gabrielle Wallace, Allison Klein. J. Vet. Intern. Med. March 2021; doi: 10.1111/jvim.16097. Quote: Background: Diuretic braking during furosemide continuous rate infusion (FCRI) curtails urine production. Hypothesis: Renin-angiotensin-aldosterone system (RAAS) activation mediates braking, and RAAS inhibition will increase urine production. Animals: ... Study dogs were clinically healthy, intact [purpose-bred] males, consisting of 8 hound dogs and 2 beagles. ... Methods: Dogs receive- placebo, benazepril, or benazepril and spironolactone PO for 3 days before a 5-hour FCRI (0.66 mg/kg/h) in a 3-way, randomized, blinded, cross-over design. Body weight (BW), serum creatinine concentration (sCr), serum electrolyte concentrations, PCV, and total protein concentration were measured before PO medications, at hours 0 and 5 of FCRI, and at hour 24. During the FCRI, water intake, urine output, urine creatinine concentration, and urine electrolyte concentrations were measured hourly. Selected RAAS components were measured before and after FCRI. Variables were compared among time points and treatments. Results: Diuretic braking and urine production were not different among treatments. Loss of BW, hemoconcentration, and decreased serum chloride concentration occurred during FCRI with incomplete recovery at hour 24 for all treatments. Although unchanged during FCRI, sCr increased and serum sodium concentration decreased at hour 24 for all treatments. Plasma aldosterone and angiotensin-II concentrations increased significantly at hour 5 for all treatments, despite suppressed angiotensin-converting enzyme activity during benazepril background treatment. Conclusions: The neurohormonal profile during FCRI supports RAAS mediation of diuretic braking in this model. Background treatment with benazepril with or without spironolactone did not mitigate braking, but was well tolerated. Delayed changes in sCr and serum sodium concentration and incomplete recovery of hydration indicators caused by furosemide hold implications for clinical patients.

Accuracy of echocardiographically estimated pulmonary artery pressure in dogs with myxomatous mitral valve disease. Giulio Menciotti, Jonathan A. Abbott, Michael Aherne, Sunshine M. Lahmers, Michele Borgarelli. J. Vet. Cardiol. March, 2021; doi: 10.1016/j.jvc.2021.03.003. Quote: Introduction: Echocardiographically identified pulmonary hypertension is an independent predictor of poor outcome in dogs affected by myxomatous valvular degeneration (MMVD). Systolic pulmonary arterial pressure is routinely estimated based on its relationship with the Doppler determined velocity of tricuspid regurgitation as defined by the simplified Bernoulli equation (sPAP_D). Experimental studies suggest that the method is imperfect, but its accuracy in dogs with MMVD is not known. Animals: Twenty dogs affected by MMVD that had cardiac remodeling and measurable tricuspid regurgitation [including 4 (20%) cavalier King Charles spaniels]. ... Stage B2 was defined as echocardiographic evidence of left atrial and left ventricular enlargement in absence of clinical signs or pulmonary infiltrates compatible with congestive heart failure. Left atrial enlargement was defined as a ratio between left atrial diameter to aortic root diameter >1.5, using the “Swedish Method”. Left ventricular enlargement was defined as M-Mode derived left ventricular end-diastolic diameter exceeding the 97.5 percentile of the prediction interval based on allometric scaling of the measurement. Dogs were classified as affected by MMVD Stage C if cardiogenic pulmonary edema had in the past resulted from MMVD, as assessed by either thoracic radiographs interpreted by a board-certified radiologist, a board-certified cardiologist, a referring veterinarian, or if clinical signs such as cough and/or resting tachypnea and/or dyspnea improved after administration of furosemide. ... Methods: A flow-directed thermodilution monitoring catheter was percutaneously placed in the right external jugular vein and advanced to the main pulmonary artery. Pulmonary arterial systolic pressure was recorded (sPAP_C). A second operator contemporaneously acquired tricuspid regurgitant velocity spectra to calculate sPAP_D. Each operator was blinded to the result of the other technique. Results: Technical difficulties prevented analysis of catheterization data in two dogs. Eighteen measurement pairs were therefore used for comparison of sPAP_C and sPAP_D through correlation and Bland-Altman analysis. A statistically significant bias between sPAP_C and sPAP_D (mean difference = 0.5 mmHg; Confidence interval: -6.5 mmHg, +7.5 mmHg) was not detected. The interval of agreement between the techniques was wide (-27.3 mmHg, +28.2 mmHg). A significant linear association between the two techniques was not identified. Conclusion: Echocardiographically estimated pulmonary artery pressure poorly agrees with sPAP_C measurement in dogs affected by MMVD and cardiac remodeling with or without previously diagnosed congestive heart failure. In these dogs, sPAP_D could under- or over-estimate sPAP_C by more than 20 mmHg, and therefore caution should be used when interpreting sPAP_D. ... In conclusion, this study showed that Doppler echocardiographic estimates of PAP are inaccurate and limits of agreement are widely separated when compared to invasively measured PAP in dogs affected by MMVD ACVIM stage B2 and C stable in their treatment regimen. This study supports the recommendations provided in the most recent guidelines published in veterinary and human medicine, in which it is specified that a non-invasive diagnosis of PHT should not rely merely on TR velocities. Furthermore, a common sedation protocol used for patients with cardiac disease significantly reduces Doppler estimates of PAP, therefore the effect of sedation on this variable should be taken into account when performing clinical evaluations.

Clinical and Echocardiographic Findings in an Aged Population of Cavalier King Charles Spaniels. Jorge Prieto Ramos, Andrea Corda, Simon Swift, Laura Sader, Gabriel De La Fuente Oliver, Brendan Corcoran, Kim M. Summers, Anne T. French. Animals. March 2021; doi: 10.3390/ani11040949. Quote: Myxomatous mitral valve disease (MMVD) is the most common cardiac disease in dogs. It varies from dogs without clinical signs to those developing left-sided congestive heart failure, leading to death. Cavalier King Charles Spaniels (CKCSs) are particularly susceptible to MMVD. We hypothesised that within the elderly CKCS population, there is a sub-cohort of MMVD-affected dogs that do not have cardiac remodelling. The objectives of the present study were (i) to determine the prevalence and the degree of cardiac remodelling associated with MMVD; and (ii) assess the effect of age, gender, and body weight on echocardiographic status in a population of aged CKCSs. A total of 126 CKCSs ≥ 8 years old were prospectively included. They all had a physical and echocardiographic examination. A systolic murmur was detected in 89% of dogs; the presence of clinical signs was reported in 19% of them; and echocardiographic evidence of MMVD was described in 100%. ... Left atrium to Ao ratio (LA/Ao) was calculated and recorded. Cardiac remodelling was defined as echocardiographic findings of LA and/or LV enlargement secondary to chronic MMVD. The LA was considered dilated if the LA/Ao ≥ 1.6. The LV was considered dilated in diastole when LVIDdN was ≥1.73, and in systole when LVIDsN was ≥1.14. ... Presence of clinical signs was reported in 24 dogs (19%). Owner-reported clinical signs were cough (n = 21; 16.7%) and exercise intolerance (n = 9; 7.1%). ... A systolic murmur was detected in 112 dogs (89%), 11 dogs (9%) did not present a murmur, and in 3 dogs (2%) the presence or absence of a murmur was not recorded. The murmur intensity and point of maximum intensity (PMI) was recorded in 109 of 112 dogs with murmurs. ... Intensity of left apical murmurs was scored as grade 1 (n = 7; 6%), grade 2 (n = 24; 21%), grade 3 (n = 26; 23%), grade 4 (n = 37; 33%), grade 5 (n = 9; 8%), and grade 6 (n = 1; 1%). ... On echocardiographic examination. all 126 CKCSs (100%) were diagnosed with MMVD; 123 of them (98%) had both MR and TR. Mitral valve prolapse was evidenced in 111 dogs (88%); classified as mild in 91 (82%) and severe in 20 (18%) dogs. Fifty-six dogs (44.4%) had heart chamber sizes within normal limits, and in three of these, the owners reported clinical signs commonly seen with MMVD (cough n = 2, exercise intolerance n = 1), with one dog being treated with pimobendan. ... Nine out of 56 dogs (16%) without cardiac remodelling did not have murmur on cardiac auscultation. Cardiac remodelling was present in 70 (55.6%) dogs. ... This study showed that despite the 100% prevalence of MMVD in this population of aged CKCSs, a relatively large proportion (44%) showed an absence of cardiac remodelling, indicating that a proportion of elderly CKCSs with confirmed MMVD do not undergo advanced stages of this pathology. This could be because the form of MMVD affecting CKCS at a young age, for which strong heritability has been demonstrated, is more aggressive and leads to death in young subjects, while a sub-cohort of dogs are affected by milder disease, more similar to that affecting all elderly dogs regardless of breed, which allows them to live longer. Identification of genetic and pathophysiologic mechanisms that lead to delayed progression of the disease may warrant future studies in order to reduce the clinical impact of the condition in this breed.

Randomized, double-blinded, controlled trial of the effects of coenzyme Q10 supplementation on plasma coenzyme Q10 concentration in dogs with myxomatous mitral valve disease. Natalia Druzhaeva, Aleksandra Domanjko Petrič, Gabrijela Tavčar-Kalcher, Janja Babič, Alenka Nemec Svete. April 2021; doi: 10.2460/ajvr.82.4.280. Quote: Objective: To determine the dose of coenzyme Q10 (CoQ10) needed to achieve at least a 3-fold increase in plasma CoQ10 concentration in dogs with myxomatous mitral valve disease (MMVD) and congestive heart failure (CHF). Animals: 18 dogs with CHF due to MMVD [including one cavalier King Charles spaniel] and 12 healthy dogs. Procedures: In a randomized, double-blinded, controlled trial, dogs with MMVD were given 50 or 100 mg of water-soluble CoQ10 (ubiquinone; total daily dose, 100 mg [n = 5] or 200 mg [6]) or a placebo (7), PO, twice a day for 2 weeks in addition to regular cardiac treatment. Plasma CoQ10 concentration was measured in dogs with MMVD before (baseline) and at various time points after supplementation began and in healthy dogs once. Concentrations were compared among and within groups. Results: No significant difference in median baseline plasma CoQ10 concentration was detected between healthy dogs and dogs with MMVD. Fold increases in plasma CoQ10 concentrations ranged from 1.7 to 4.7 and 3.2 to 6.8 for individual dogs in the 100-mg and 200-mg groups, respectively. The change in plasma CoQ10 concentration after supplementation began was significantly higher than in the placebo group at 4 hours and 1 and 2 weeks for dogs in the 200-mg group and at 1 and 2 weeks for dogs in the 100-mg group. Conclusions & Clinical Relevance: A daily CoQ10 dose of 200 mg was sufficient to achieve at least a 3-fold increase in plasma CoQ10 concentration and may be used in CoQ10 supplementation studies involving dogs with CHF due to MMVD.

Study of the correlation between a radiographic size and two echocardiographic sizes in dogs with myxomatous mitral valve degeneration. Atanas Pankov. Trad. & Modernity in Vet. Med. March 2021;6(1):30-33. Quote: In dogs with myxomatous mitral valve degeneration, the correlation between the radiographic left atrial dimension RLAD and two echocardiographic sizes has been examined. The dogs without pulmonary edema showed a low degree of correlation between RLAD and the linearly indexed left atrial size LA/Ao, and a high degree of correlation between RLAD and the linearly indexed diastolic size of the left ventricle LVD-d/Ao. The dogs with pulmonary edema showed no correlation between RLAD and the two echocardiographic sizes. ... The lack of reliability for all the results obtained in the study, despite the established correla-tions, is due, according to us, to the small number of dogs that were included in the study. ... Conclusion: (1) The established linear correlation in dogs with MMVD without pulmonary edema between the radiographic size RLAD and the echocardiographic sizes LA/Ao and LVD-d/Ao indicates that the size RLAD may be useful to veterinarian doctors for the well-reasoned appointment of echocardiographic and other additional examinations. The lack of reliability of our results, however, indicates that this statement should be verified via more dogs with MMVD. (2) The established lack of linear correlation in dogs with MMVD with pulmonary edema between the radiographic size RLAD and the echocardiographic sizes LA/Ao and LVD-d/Ao indicates that a more radiographically distinct dorsal border for the size RLAD should be sought.

Multiple retrospective analysis of survival and evaluation of cardiac death predictors in a population of dogs affected by degenerative mitral valve disease in ACVIM class C treated with different therapeutic protocols. M. Bagardi, C. Locatelli, A. Zanaboni, A. Galizzi, D. Malchiodi, P. G. Brambilla. Polish J. Vet. Sci. March 2021; doi: 10.24425/pjvs.2021.136799. Quote: Clinical records of dogs with spontaneous degenerative mitral valve disease (DMVD) with clinical signs related to congestive heart failure (CHF) recruited during routine clinical practice between 2001 and 2018 at the Cardiology Unit of the Veterinary Teaching Hospital (University of Milan) were included in this retrospective cohort study. ... In this study all genders, weights and breeds were included, except for the cavalier King Charles Spaniel. ... 259 clinical records fulfilled the inclusion criteria and were thus included. ... Baseline echocardiographic data were evaluated. ... Table 1: LA/Ao minimum 1.30; maximum 4.40. ... Median survival time (MST) was calculated. Data on therapeutic treatment, ISACHC (International Small Animal Cardiac Health Council) or ACVIM (American College of Veterinary Internal Medicine) classes were reviewed based on the inclusion period and type of endpoint (i.e. cardiac death or death for other causes). A univocal classification was needed, and the patients classified in ISACHC classes II, IIIa and IIIb, visited before 2009, were reallocated to ACVIM class C. The main goal of this data review was to retrospectively evaluate 259 clinical records of subjects belonging to ACVIM C class examined between 2001 to 2018 and 202 dogs examined between 2010 to 2018. In this way, in the second group, the bias of the reclassification was avoided. The MST (median survival time) of these subjects was 531 d (2001-2018) and 335.5 d (2010-2018), respectively. Univariate survival regression analysis for subjects included from 2010 to 2018 showed as significantly related to cardiac death (CD): left atrium to aorta ratio (LA/Ao) (HR 2.754), E wave (HR 2.961), E/A ratio (HR 1.372), end-diastolic (HR 1.007) (EDVI) and end-systolic (HR 1.012) (ESVI) volume indexes, allometric diastolic (HR 4.018) (LVIDdN) and systolic (HR 2.674) (LVIDsN) left ventricular internal diameters, age (HR 1.006) and pulmonary hypertension severity (HR=1.309) (PH). ... The multivariate analysis showed that only LA/Ao led to a statistically significant difference in MST, and significantly increased (2.5 times) the risk of CD. ... The increase in LA/Ao ratio and E-wave values corresponds to an increased risk of CD. ... Adjusting for age, the PH [pulmonary hyperension] severity was shown to be a risk of factor for CD. ... The type of therapeutic treatment within this class was not significant for the MST of the subjects. (See also the January 2020 version of this study.)

Red Cell Distribution Width Has a Negative Prognostic Role in Dogs with Myxomatous Mitral Valve Disease. Carlo Guglielmini, Chiara Martina Valentini, Barbara Contiero, Carlotta Valente, Helen Poser. Animals. March 2021; doi: 10.3390/ani11030778. Quote: Red cell distribution width (RDW) is a quantitative measurement of anisocytosis. This hematological parameter is an important prognostic biomarker for different cardiovascular disorders in humans but its influence on survival has been poorly investigated in dogs with cardiovascular disease. The RDW and various clinical, complete blood count, serum biochemical and echocardiographic variables were retrospectively investigated in 146 client-owned dogs with myxomatous mitral valve disease (MMVD) at various disease stages, with or without concurrent diseases and treatment. Laboratory variables, including RDW, urea, and white blood cell (WBC), in addition to the echocardiographic variable left atrium to aorta ratio were found to be independent predictors of all-cause mortality at six months in a multivariable Cox proportional hazards regression model. In particular, the hazard ratio of RDW was 1.203 (95% confidence interval = 1.045–1.384; p = 0.010). The negative effect of increased RDW on outcome was confirmed using Kaplan–Meier curve analysis. The results of this study indicate that RDW acted as an independent predictor of negative outcome in dogs with MMVD.

Evaluation of bronchial narrowing in coughing dogs with heart murmurs using computed tomography. Matthieu Lebastard, Kevin Le Boedec, Mark Howes, Stephen Joslyn, Jodi S. Matheson, Robert T. O'Brien. J. Vet. Intern. Med. April 2021; doi: 10.1111/jvim.16115. Quote: Background: The origin of cough in dogs with heart murmurs is controversial, because the cough could be primary cardiac (eg, pulmonary edema, bronchi compression by left-sided cardiomegaly) or respiratory (eg, bronchomalacia, other bronchial or bronchiolar disease, interstitial lung disease) in origin. Hypothesis/Objectives: To study the association between left atrium (LA) dilatation and cardiomegaly and bronchial narrowing in coughing dogs with heart murmurs using computed tomography (CT). Animals: Twenty-one client-owned coughing dogs with heart murmurs [including 2 cavalier King Charles spaniels (9.5%)] and 14 historical control dogs. Methods: Dogs with cough and murmur were prospectively recruited over 4 months. Cervical and thoracic radiography, echocardiography, and thoracic CT were performed in enrolled dogs. Control dogs, with no disease on thoracic CT and no records of heart murmur and coughing, were gathered from the institution's computerized database. Degree of bronchial narrowing was assessed using the bronchial-to-aorta (Ao) ratio, measured by 3 radiologists blinded to the clinical findings. After identifying bronchi that were significantly narrowed in dogs with murmur compared to controls, the relationship between degree of narrowing and LA/Ao ratio (measured echocardiographically) and vertebral heart scale (VHS) measured radiographically was studied in dogs with murmur using mixed-effects regression. ... Cardiac diseases diagnosed from echocardiogram included 17 (81%) dogs with MMVD (2/17 [12%] stage B1, 5/17 [29%] stage B2, 9/17 [53%] stage C, and 1/17 [6%] stage D), 3 (14%) with dilated cardiomyopathy, and 1 (5%) with mitral dysplasia. Median LA/Ao ratio measured by echocardiography was 2.0 (range, 1.5-3.5). Three dogs (14%) had a LA/Ao ratio < 1.6. ... Result: Significant narrowing was identified for all left-sided bronchi and the right principal, middle, and caudal bronchi in the coughing dogs, compared with controls. Increasing LA size and VHS were significantly inversely associated with diameter for all left-sided and right-sided bronchi indicated above. Conclusion and Clinical Importance: Results indicate an association between LA enlargement and cardiomegaly and bronchial narrowing and support heart size-associated exacerbation of cough in dogs with murmurs. (See, also, Letter regarding “Evaluation of bronchial narrowing in coughing dogs with heart murmurs using computed tomography” and Response to letter regarding “Evaluation of bronchial narrowing in coughing dogs with heart murmurs using computed tomography”.)

Diagnosis of Myxomatous Mitral Valve Disease (MMVD) in Aged Dogs. K. Satish Kumar, V. V. V. Amruth Kumar. Indian J. of Anim. Res. April 2021; doi: 10.18805/IJAR.B-4403. Quote: Background: Aging is a biological process, which affects many body systems and increases susceptibility to disease that is associated with a reduction in immune response, a decline in cognitive function and a diminished functional reserve of the cardiovascular, pulmonary and renal systems. Diseases of heart or cardiovascular system represents a major component of geriatric medicine among which, myxomatous mitral valve disease is more common among geriatric dogs. The present study is keeping on record about the diagnosis of myxomatous mitral valve disease in geriatric dogs in and around Hyderabad, Telangana state.Methods: A total of 1695 geriatric dogs presented to various clinics including university veterinary clinical complex of Hyderabad, Telangana state during 2015 to 2020 were considered for this study. After confirming that they were free from any other systemic disease, small size breed dogs above 9 years with the history of exercise intolerance, dyspnoea and cough were selected. ... About 30 percent of presented dogs were also reported as insomniac, were completely standing to sitting on hind legs for short periods, without sleep for more than 24-36 hrs. ... Coughing which is predominant in these cases might be a result of pressure on the left mainstem bronchus caused by left atrial enlargement, rather than a result of pulmonary edema. Lethargy and reduced physical activity could be due to diminished oxygen delivery to the tissues associated with reduced cardiac output. ... Diagnostic protocol included, auscultation, chest x-ray and 2d-echocardiography to confirm mitral valve degeneration. Result: Myxomatous mitral valve disease was diagnosed in 427/695 geriatric dogs (61.43%) and were showing hyperechoeic thick mitral valve leaflets with kinking and prolapse. ... Dilatation of left atrium or left atrial/auricle bulge, elevation of trachea and pulmonary congestion with a mean vertebral heart score (VHS) 12.2, were the significant radiographic abnormalities of valvular disease geriatric patients. ... Further, echocardiography also revealed dilated left atrium and ventricle, hyperkinesis of interventricular septum, mitral valve degeneration and rupture of chordae tendineae with valvular regurgitation. ... Significant findings also include, dilatation of left atrium (2.10±1.28 cm) that was measured by left atrium and aorta ratio and dilated left ventricular end diastolic (56.58 ± 2.87 mm) and end systolic diameter (41.50 ± 1.86 mm) with increased fractional shortening (48.80 ± 2.40 mm), as shown in the Table 1. ... In the present study, MMVD was diagnosed in 65% of geriatric small sized breed. Thickening, prolapsed, flial appearance, rupture of chordae tendineae, increased left ventricular end diastolic and systolic dimensions along with increased shortened fraction were the significant echocardiographic features among present study.

Echocardiographic mitral valve association with morphometric measurements in Cavalier King Charles Spaniels via Inverse Probability Weighting analysis. Mara Bagardi, Sara Ghilardi, Chiara Locatelli, Arianna Bionda, Michele Polli, Claudio M. Bussadori, Fabio M. Colombo, Laura Pazzagli, Paola G. Brambilla. BioRxiv. April 2021; doi: 10.1101/2021.04.15.439951. Quote: Development and progression of myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS) are difficult to predict. Identification at a young age of dogs with a morphotype associated with more severe mitral disease is desirable. The aims of this study were to: 1) describe the physical, morphometric, and echocardiographic features of MMVD affected Cavalier King Charles Spaniels (CKCS) in American College of Veterinary Internal Medicine (ACVIM) class B1; 2) evaluate the influence of morphometric physical measurements on murmur intensity, mitral valve prolapse (MVP), regurgitant jet size and indexed mitral valve and annulus measurements. Fifty-two MMVD affected CKCS in ACVIM class B1 were included ... belonging to different lineages and breeders ... with asymptomatic MMVD and no cardiac enlargement. ... To be included in the study, dogs must have no evidence of left atrial and left ventricle dilatation, defined as a left atrial-to-aortic root ratio (LA/Ao) ≥ 1.6 on a 2-dimensional echocardiography, and as left ventricular normalized dimensions in diastole (LVIDad) ≥ 1.7. ... This is a prospective clinical cross-sectional study. Morphometric measurements, which included body, thorax, and the head sizing of each dog, have been investigated to establish the association with heart murmur intensity, valvular and annular echocardiographic measurements, MVP and regurgitant jet size using inverse probability weighting (IPW) analyses to adjust for confounding. The IPW analyses showed that when head length and nose length decreased, dogs had more severe regurgitant jet size. Furthermore, subjects with more pronounced head stop angle had thicker anterior mitral valve leaflets. A brachycephalic morphotype, with dogs more similar to King Charles Spaniel breed in cephalic morphology, is associated with a more severe regurgitant jet size and with valvular characteristics related to worse forms of MMVD. ... Regarding mitral valve and mitral annulus measurements, subjects with more barrel-shaped thorax and shorter nose had shorter and thicker anterior mitral valve leaflets and greater mitral valve annulus in systole and diastole. This means that a brachycephalic morphotype, with dogs much more similar to King Charles Spaniel breed in cephalic morphology, is correlated with a more severe jet size and with valvular characteristics related to worse forms of MMVD and this may be counterproductive in view of the selected reproduction for MMVD. Studying of the B1 subjects’ follow-up and the results of this study would allow for a better understanding of the morphological aspects more often associated with the more severe and/or faster evolution of the disease in the CKCS. This, together with clinical and echocardiographic characterization, could be used as part of a screening program for CKCS defining early selection criteria for the exclusion of a subject from reproduction.

Metabolomics Analysis Reveals Deranged Energy Metabolism and Amino Acid Metabolic Reprogramming in Dogs With Myxomatous Mitral Valve Disease. Qinghong Li, Éva Larouche‐Lebel, Kerry A. Loughran, Terry P. Huh, Jan S. Suchodolski, Mark A. Oyama. J. Amer. Heart Assn. April 2021; doi: 10.1161/JAHA.120.018923 Quote: Background: Myxomatous mitral valve disease (MMVD), a naturally occurring heart disease, affects 10% to 15% of the canine population. Canine MMVD shares many similarities with human MMVD. Untargeted metabolomics was performed to identify changes in metabolic pathways and biomarkers with potential clinical utilities. Methods and Results: Serum samples from 27 healthy, 22 stage B1, 18 stage B2 preclinical MMVD dogs, and 17 MMVD dogs with a history of congestive heart failure (CHF) were analyzed. Linear regression analysis identified 173 known metabolites whose concentrations were different among the 4 groups (adjusted P<0.05), of which 40% belonged to amino acid super pathways, while 30% were lipids. More than 50% of significant metabolites were correlated with left atrial diameter but not left ventricular dimension. Acylcarnitines, tricarboxylic acid cycle intermediates, and creatine accumulated in proportion to MMVD severity. α‐Ketobutyrate and ketone bodies were increased as MMVD advanced. Nicotinamide, a key substrate of the main nicotinamide adenine dinucleotide (NAD+) salvage pathway, was decreased, while quinolinate of the de novo NAD+ biosynthesis was increased in CHF dogs versus healthy dogs. 3‐Methylhistidine, marker for myofibrillar protein degradation, was higher in CHF dogs than non‐CHF dogs. Trimethylamine N‐oxide (TMAO) and TMAO–producing precursors, including carnitine, phosphatidylcholine, betaine, and trimethyllysine, were increased in CHF dogs versus non‐CHF dogs. Elevated levels of uremic toxins, including guanidino compounds, TMAO, and urea, were observed in CHF dogs. Pathway analysis highlighted the importance of bioenergetics and amino acid metabolism in canine MMVD. Conclusions: Our study revealed altered energy metabolism, amino acid metabolic programming, and reduced renal function in the development of MMVD and CHF. Complex interplays along the heart‐kidney‐gut axis were implicated.

Gut Dysbiosis and Its Associations with Gut Microbiota-Derived Metabolites in Dogs with Myxomatous Mitral Valve Disease. Qinghong Li, Eva Larouche-Lebel, Kerry A. Loughran, Terry P. Huh, Jan S. Suchodolski, Mark A. Oyama. mSystems. April 2021; doi: 10.1128/mSystems .00111-21. Quote: Gut dysbiosis and gut microbiota-derived metabolites, including bile acid (BA), short-chain fatty acid, and trimethylamine N-oxide (TMAO), are associated with cardiovascular disease. Canine myxomatous mitral valve disease (MMVD) is a model for human MMVD. The aim of the study is to evaluate gut microbial dysbiosis and its relationship with gut-produced metabolites in dogs with MMVD. Fecal samples from 92 privately owned dogs, including 17 healthy, 23 and 27 asymptomatic MMVD dogs without (stage B1) and with (stage B2) secondary cardiac enlargement, respectively, and 25 MMVD dogs with history of congestive heart failure (stage C or D), were analyzed by 16S rRNA sequencing. Alpha and beta diversities were different between healthy and MMVD dogs. The average dysbiosis indexes were -1.48, -0.6, 0.01, and 1.47 for healthy, B1, B2, and C/D dogs, respectively. Dysbiosis index was negatively correlated with Clostridium hiranonis. Escherichia coli, capable of trimethylamine production in the gut, had an increased abundance and may be responsible for the increased circulating TMAO levels in stage B2 and C/D MMVD dogs. Primary and secondary BAs showed opposite associations with C. hiranonis, a key BA converter. Secondary BAs appeared to promote the growth of Fusobacterium and Faecalibacterium but inhibit that of E. coli Multivariate analysis revealed significant but weak associations between gut microbiota and several circulating metabolites, including short-chain acylcarnitines and TMAO. Importance: Our study expands the current "gut hypothesis" to include gut dysbiosis at the preclinical stage, prior to the onset of heart failure. Gut dysbiosis index increases in proportion to the severity of myxomatous mitral valve disease (MMVD) and is inversely associated with Clostridium hiranonis, a key bile acid (BA) converter in the gut. Secondary BAs appear to promote the growth of beneficial bacteria but inhibit that of harmful ones. An intricate interplay between gut microbiota, gut microbiota-produced metabolites, and MMVD pathophysiological progression is implicated.

Open-heart techniques and mitral valve plasty for mitral regurgitation in toy- and small-breed dogs: A review. Isamu Kanemoto, Kippei Mihara, Keiichi Sato. Open Vet. J. March 2021; doi: 10.4314/ovj.v11i1.4. Quote: In human medicine, in the past, open-heart techniques for low-bodyweight children and newborn babies with congenital heart disease were more difficult than high-bodyweight adults. In toy- and small-breed dogs with mitral regurgitation (MR), an acquired heart disease, these techniques are more difficult to perform than for congenital heart diseases in young medium-sized or large dogs because of old age and low body weight. Therefore, improved open-heart techniques and mitral valve surgery for severe MR in older toy- and small-breed dogs are essential. Through our surface-cooling hypothermia (sHT) studies, we designed a new, improved open-heart method, namely, “the low-flow cardiopulmonary bypass (CPB) combined with deep sHT in toy- and small-breed dogs (Japan method)”; sHT was later replaced by blood-cooling hypothermia (bHT). At the same time, we devised a new, improved mitral valve plasty (MVP) applicable to severe MR, instead of mitral valve replacement, in toy- and small-breed dogs. This MVP technique was combined with artificial chordal reconstruction, semi-circular suture annuloplasty (AP), and direct scallop-suture valvuloplasty. These MVP techniques are simple, durable, and lead to good long-term quality of life in toy- and small-breed dogs. This review highlights the benefits of our improved CPB and MVP techniques (Japan method) for severe MR in toy-and small-breed dogs, which have led to a high success rate for MVP in severe clinical MR cases in Japan. It may further contribute to the development of more robust techniques for MR in toy- and small-breed dogs. This also represents the first comprehensive review of the history of open-heart surgery, CPB techniques, and MVP methods for MR in toy- and small-breed dogs. ... This is the first comprehensive review about the history of open-heart surgery, CPB techniques, and MVP methods for MR in toy- and small-breed dogs. 1. We first studied sHT as an open-heart method in a small dog. Using this sHT, we succeeded in the first clinical case of MVP for MR in a small dog. 2. We then applied the deep sHT method combined with the CPB method in a small dog, sHT has been replaced with slow bHT. At present, we could improve the CPB technique to permit open heart surgery with over 2 hours of ACC time. As a result, we have been able to apply CPB techniques to complex congenital cardiac diseases other than MR in toy- and small-breed dogs. 3. At the sam time, we developed MVP techniques suitable for treating MR in toy- and small-breed dogs. Our recommended MVP techniques include ACR, semi-circular SAP, and direct SSVP. Our MVP techniques make it possible to repair severe MR, which was previously indicated for MVR, in small dogs. 4. As of now, we have performed MVP on 102 cases in our hospital, using our open-heart techniques and improved on MVP methods during the 9 months from January 2020 to September 2020, with 98 dogs successfully discharged from the hospital (a success rate of 96.1%) in toy- and small-breed dogs. 5. In Japan, Kanemoto et al. (2010, 2017b, 2017c), Mihara et al. (2017, 2018), Uechi (2012), Uechi et al. (2012), and other cardiac surgeons performed our improved CPB techniques and MVP methods and have achieved high success rates for MVP in toy- and small-breed dogs. However, in other countries, cardiac surgeons using the usual CPB techniques and MVP methods have achieved low success rates for MVP or ceased to perform MVP in small dogs, although they succeeded in some MVP procedures in medium-sized or large dogs. It appears that our “Japan methods” of CPB and MVP are better suited for severe MR in toy- and small-breed dogs. 6. In the future, we hope to establish highly safe open-heart techniques and high-quality MVP methods in toy- and small-breed dogs. 7. Limitation of the review: This review was about open-heart techniques and MVP for MR in toy- and small-breed dogs. Therefore, some applicable CPB techniques and MVP method in medium-size or large dogs were omitted from this review.

Impact of selected individual dog traits on echocardiographic parameters obtained in 1-dimensional (M-mode) and 2-dimensional (2D) imaging. Szpinda, Oktawia; Parzeniecka-Jaworska, Marta; Jank, Michał; Garncarz, Magdalena; Czopowicz, Michał. Canadian J. Vet. Res. April 2021;85(2):112-118. Quote: The popularity and availability of echocardiography in veterinary practice for companion animals have substantially increased in recent years. The results obtained during the procedure are compared to reference values established for the general dog population or to standards developed for a specific dog breed. The aim of this study was to determine whether individual dog traits, such as body weight, chest structure, and level of physical activity and performance, affect the reference values for echocardiographic parameters. Published reference values for echocardiographic examination parameters for 32 dog breeds were analyzed and the relationship between individual echocardiographic parameters and body weight, chest structure, and level of physical activity and performance was then statistically analyzed. [134 cavalier King Charles spaniels were included in one study.] It was found that echocardiographic parameters are affected by the dog’s weight and physical activity. There was no significant relationship between heart size and chest structure. ... It is important to establish echocardiographic values for individual dog breeds, not only for primary measurements such as left ventricular dimension or left atrial dimension, but also for secondary measurements. ... After echocardiographic examination and measurements, it is not clear whether obtained results should be compared to the reference values set according to the patient’s current, too high or low body weight, or to their ideal body weight. As this issue has not been clarified, more research is needed to answer this question and determine whether echocardiographic parameters in obese dogs can be compared to the norms for their breed. ... Due to the wide variety of dog breeds and inhomogeneous research groups, echocardiographic measurements should be established individually for each breed based on a population study. This will allow for a more accurate interpretation of the results obtained in the echocardiographic examination and lead to earlier diagnosis of heart disease. ... The great variety of dog breeds means that echocardiographic findings should be individually interpreted rather than establishing reference ranges for each breed in population studies. This will allow for a more accurate interpretation of the results obtained in the echocardiographic examination and consequently lead to earlier diagnosis of changes in myocardial morphology.

The Longitudinal Outcome Of Canine (K9) myxomatous mitral valve disease (LOOK-Mitral registry); Baseline characteristics. Alessandra Franchini, Michele Borgarelli, Jonathan A. Abbott, Giulio Menciotti, Serena Crosara, Jens Häggström, Sunshine Lahmers, Steven Rosenthal, William Tyrrell. J. Vet. Cardiol. April 2021; doi: 10.1016/j.jvc.2021.04.005. Quote: Introduction: The Longitudinal Outcome Of Canine (K9) myxomatous mitral valve disease registry (LOOK-Mitral registry) was established with the main purpose of prospectively collecting clinical and diagnostic data from a large population of dogs affected by MMVD. ... This study was intended to describe the baseline characteristics of dogs in the LOOK-mitral registry. Animals: Dogs with echocardiographic evidence of MMVD were prospectively enrolled by thirteen referral centers ... during the 3 years study period. ... Dogs were subsequently classified with respect to the ACVIM stages of MMVD: Stage-B1 was defined by the absence of echocardiographic enlargement of the left atrium (LA) and left ventricle. Stage-B2 was defined by MMVD associated with echocardiographic evidence of both LA and left ventricular enlargement (left atrium to aortic ratio (LA:Ao) ≥ 1.6 and left ventricular internal diameter normalized in diastole (LVIDd_N) ≥ 1.7), but absence of current or historical clinical signs of congestive heart failure (CHF) ... with mild to moderate LA enlargement (LA:Ao ≥ 1.6 and < 2) and dogs with severe LA enlargement (LA:Ao ≥ 2). ... Stage-C was defined by the presence of current or past clinical signs and/or radiographic evidence of CHF. Clinical signs of CHF were defined as tachypnea, dyspnea, and/or cough that resolved by normalization of the resting respiratory rate (RR) and respiratory efforts with medical treatment with furosemide, together with any combination of pimobendan, an angiotensin-converting enzyme inhibitor, or spironolactone. Moreover, dogs in which furosemide was prescribed by the specialist based on clinical and echocardiographic findings were also included in ACVIM Stage-C. ... Tachypnea was defined as a resting RR greater than 36 breaths per minute, while dyspnea was defined by the appearance of difficult or labored breathing. ... Results: A total of 6,102 dogs [of 190 breeds] with MMVD were included [including 491 cavalier King Charles spaniels (8%)]. Median age was 10 years (1-19 years), and mixed breed was the most common breed (n= 1,360, 22%)[; the CKCS was the most common purebred breed]. Concomitant diseases were reported in 2,459 dogs with chronic respiratory diseases occurring most frequently (14%), followed by presence of azotemia (6%) and orthopedic diseases (5%). Regarding disease severity, 65% of dogs were in ACVIM Stage-B1, 15% in Stage-B2, and 20% in Stage-C. Dogs in Stage-B1 were younger than dogs in other stages. ... CKCSs were younger than other most common breeds. Moreover, when only dogs in ACVIM Stage-C were considered, CKCSs were younger (median age: 9 years, range: 6-13 years) than some of the other most common breeds. ... Murmur intensity, heart rate during physical examination and radiographic vertebral heart score were positively associated with the stage. Dogs in Stage-C were more likely to have tachypnea, dyspnea, cough, syncopal episodes and tachyarrhythmias compared to dogs in Stage-B1 and B2. ... Thoracic radiographs of 1,666 (28%) dogs were obtained. ... The VHS was positively associated with the stage of the disease. Cardiomegaly was radiographically detected in 117 dogs (33%) with a normal LA:Ao and LVIDd_N. Moreover, 21% (n=46) of the dogs with echocardiographic mild to moderate LA enlargement and an LVIDd_N ≥ 1.7, and 14% (n=44) of dogs with severe LA enlargement and an LVIDd_N ≥ 1.7 had a normal VHS. ... Our results showed a positive correlation between VHS and LA:Ao as well as between VHS and LVIDd_N, the latter being an echocardiographic measure that is commonly used to assess the degree of left ventricular dilation. However, our findings also showed that cardiomegaly was identified by VHS in 33% of the dogs with normal echocardiographic LA and left ventricle chamber dimensions. ... Echocardiographic indices of left atrial and ventricular size were positively correlated with ACVIM stage. Interestingly, 4% of dogs that weighed <20 kg had an increased normalized end-systolic left ventricle internal diameter (>1.26). ... An early onset of the disease has been reported in CKCSs, and our results are in agreement with what was previously reported. ... However, when only dogs in Stage-C were considered, CKCSs were younger when compared with some of the other 20 most common breeds in our study. This might suggest that CKCSs might develop CHF at a younger age. ... The prevalence of PH [pulmonary hypertension] in our population was 36%. ... 58% of dogs in Stage-C had PH. ... In this study, arrhythmias were reported in 9% of the dogs suggesting that rhythm disorders are relatively uncommon in our population. ... Our results showed that the majority, but not all dogs with soft murmurs, are in Stage-B1, suggesting that soft murmurs are usually indicative of an early stage of MMVD. ... Conclusions: This study contributes to a better understanding of the clinical characteristics of dogs affected by MMVD and provides new findings that may be of clinical relevance.

Reference intervals for transthoracic echocardiography in the American Staffordshire Terrier. Tommaso Vezzosi, Roberto Ghinello, Paolo Ferrari, Francesco Porciello. J. Vet. Med. Sci. April 2021; doi: 10.1292/jvms.20-0622. Quote: This study reports the echocardiographic reference intervals in the American Staffordshire Terrier (AST). The echocardiographic variables obtained in 57 healthy adult AST were compared with published data from the general canine population and other breeds. In the AST, the left ventricular volumes were lower than values reported in Boxers and Dobermans, but higher than in small breeds. ... The mean value of LVIDDn in the present study (1.62) was significantly higher than values previously reported in a range  of different breeds (1.53). ... Regarding echocardiographic variables, the mean LVIDDn in our AST population was significantly higher than values reported in a range of canine breeds. ... Table 1: LVIDDn: Mean: 1.64; Lower RI: 1.27; Upper RI: 1.87. ... Regarding the LA/Ao, the upper reference limit in our AST population was 1.75, with 6/57 (10%) dogs with a LA/Ao >1.6. ... Table 1: LA/Ao: Mean: 1.39; Lower RI: 1.00; Upper RI: 1.75. ... The LA/Ao is the most widely used echocardiographic index to evaluate left atrial dimension in dogs, and several studies have used the upper reference limit of 1.6 to define left atrial enlargement. However, our results are in line with a study demonstrating that in around 10% of dogs, in particular in Boxers and Beagles, a small aortic root is present, which leads to an increase in the LA/Ao up to an upper reference limit of 1.73. ... The reference intervals presented in this study are clinically useful for an accurate echocardiographic interpretation and screening in the AST. ... In conclusion, this is the first study providing echocardiographic reference intervals in healthy adult ASTs. This breed tends to have smaller ventricular volumes, lower SI and higher EF than Boxers and Dobermans and than the general canine population. In addition, the AST shows a smaller aortic annulus and an increased aortic flow velocity. These breed-specific echocardiographic features should be taken into consideration for an accurate echocardiographic interpretation and screening in the AST.

The Mitral INsufficiency Echocardiographic score: A severity classification of myxomatous mitral valve disease in dogs. Tommaso Vezzosi, Giovanni Grosso, Rosalba Tognetti, Valentina Meucci, Valentina Patata, Federica Marchesotti, Oriol Domenech. J. Vet. Intern. Med. May 2021; doi: 10.1111/jvim.16131. MINE Tables 1 & 2Quote: Background: There is no commonly shared severity score for myxomatous mitral valve disease (MMVD) based on routinely acquired echocardiographic variables. Hypothesis/Objectives: To propose an easy‐to‐use echocardiographic classification of severity of MMVD in dogs. Animals: Five hundred and sixty dogs with MMVD [including 69 (12.32%) cavalier King Charles spaniels]. Methods: This was a retrospective, multicenter, observational study. The proposed Mitral INsufficiency Echocardiographic (MINE) score was based on 4 echocardiographic variables: left atrium-to-aorta ratio, left ventricular end-diastolic diameter normalized for body weight, fractional shortening, and E-wave transmitral peak velocity. Specific echocardiographic cutoffs were defined based on previous prognostic studies on MMVD, and severity scores were assigned as follows: mild (score: 4-5), moderate (score: 6-7), severe (score: 8-12), late stage (score: 13-14). Results: Median survival time was significantly different between the proposed severi ty classes: mild (2344 days, 95% confidence interval [CI] 1877-2810 days), moderate (1882 days, 95% CI 1341-2434 days), severe (623 days, 95% CI 432-710  days), and late stage (157 days, 95% CI 53-257 days). A MINE score >8 was predictive of cardiac death (area under the curve = 0.85; sensitivity 87%, specificity 73%). In the multivariable analysis, all the echocardiographic variables of the MINE score were independent predictors of death because of heart disease. Conclusions and Clinical Importance: The MINE score is a new easy‐to‐use echocardiographic classification of severity of MMVD, which has been proven to be clinically effective as it is associated with survival. This classification provides prognostic information and could be useful for an objective echocardiographic assessment of MMVD.

Echocardiographic parameters in 50 healthy English Bulldog: Preliminary Reference Intervals. Valentina Patata, Tommaso Vezzosi, Federica Marchesotti, Oriol Domenech. J. Vet. Cardiol. May 2021; doi: 10.1016/j.jvc.2021.04.010. Quote: Introduction/Objectives: To provide echocardiographic reference intervals for English Bulldogs (EB) and to assess if age, sex, body weight (BW) and heart rate have an influence on echocardiographic variables. Animals: We prospectively enrolled client-owned EB that were considered healthy based on unremarkable history, normal physical examination, six-lead electrocardiography and transthoracic echocardiography. Materials and Methods: Breed-related reference intervals were provided, and associations between age, sex, BW and heart rate and echocardiographic variables were tested using a multivariate analysis. Allometric scales were generated for echocardiographic variables showing correlation with BW. Moreover, echocardiographic variables obtained in our population of EB and previous published reference ranges were compared. Results: Echocardiographic reference intervals were generated from 50 healthy adult EB. According to the multivariate analysis, left atrial diameter, left ventricular internal end diastolic diameter, aortic valve annulus and pulmonary valve annulus resulted influenced by BW, and reference intervals were generated using allometric scales. Our study suggests that EB tend to have a smaller aortic root and sphericity index if compared to other breeds. In addition, EB seem to have smaller indexed left ventricular volumes and higher left ventricular ejection fraction than Boxers and Dobermann. ... One reason for this difference could be the breed-specific cardiac morphology and geometry of the EB, which based on our results have a more rounded heart compared with other breeds. ... In our sample of EB, the LA:Ao ratio in the short axis plane exceeded the previous upper reference limit of <1.6 in a significant number of dogs (12%). ... Furthermore, our results suggest that EB tend to have a small Ao compared to the general population of dogs with a mean weight-indexed aorta of 0.82. This might be the reason for the increased LA:Ao ratio, because if we considered left atrial dimension our population of EB presented a weight-indexed left atrium under the previously reported upper limit of 1.56. Moreover, mean normalized LAD in our population of EB is in line with mean value of a general population of dogs, thus supporting our hypothesis that left atrium enlargement cannot be the reason for the increased LA:Ao ratio. ... Conclusion: Preliminary reference intervals in the EB are reported, which might be helpful for accurate echocardiographic interpretation and screening purposes in this breed. ... Further studies are needed to evaluate the result of the present study in a larger cohort of dogs. ... Further studies comparing indexed cardiac dimensions and geometry among canine breeds with different thoracic somatotype may be useful.

The predictive value of clinical, radiographic, echocardiographic variables and cardiac biomarkers for assessing risk of the onset of heart failure or cardiac death in dogs with preclinical myxomatous mitral valve disease enrolled in the DELAY study. M. Borgarelli, L. Ferasin, K. Lamb, D. Chiavegato, C. Bussadori, G. D’Agnolo, F. Migliorini, M. Poggi, R.A. Santilli, E. Guillot, C. Garelli-Paar, R. Toschi Corneliani, F. Farina, A. Zani, M. Dirven, P. Smets, C. Guglielmini, P. Oliveira, M. DiMarcello, F. Porciello, S. Crosara, P. Ciaramella, D. Piantedosi, S. Smith, S. Vannini, E. Dall’Aglio, P. Savarino, C. Quintavalla, M. Patteson, J. Silva, C. Locatelli, M. Baron Toaldo. J. Vet. Cardiol. May 2021; doi: 10.1016/ j.jvc.2021.04.009. Quote: Objectives: To identify the predictive value on time to onset of heart failure (HF) or cardiac death of clinical, radiographic and echocardiographic variables, as well as cardiac biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and cardiac troponin I in dogs with preclinical myxomatous mitral valve disease (MMVD). Animals: One-hundred sixty eight dogs [of 18 different breeds, including 34 cavalier King Charles spaniels (20%), the highest number among purebreds] with pre-clinical MMVD and left atrium to aortic root ratio (LA:Ao) ≥1.6 and normalized left ventricular end-diastolic diameter (LVEDDn) ≥1.7. Methods: Prospective, randomized, multicenter, single-blinded, placebo-controlled study. Clinical, radiographic, echocardiographic variables and plasma cardiac biomarkers concentrations, were compared at different time points. Using receiving operating curves analysis, best cut off for selected variables were identified and the risk to develop the study end-point at six-months intervals was calculated. Results: ... This study demonstrates that NT-proBNP and some selected echocardiographic variables can predict the risk for first onset of HF or cardiac death in dogs with preclinical MMVD and cardiac remodeling. ... In this study NT-proBNP plasma concentrations > 1.500 ρmol/L represented the best predictor for reaching the predefined composite endpoint. ... In our study the optimal cut off values to identify dogs with an increased risk for progression of the disease were 2.1 for LA:Ao and 1.9 for LVEDDn. ... Therefore, the cutoff values reported in this current study identify dogs with significant cardiac enlargement and therefore that may have a higher risk of developing HF or die for their cardiac disease. ... In the current study, transmitral inflow E peak velocity higher than 1 m/sec was an independent predictor for progression to a primary endpoint. This cut off value was higher than normal values observed in normal dogs of similar age. ... In this study, the best predictor model for identifying dogs with increased risk of reaching the composite endpoint was a composite of NT-proBNP concentrations, LA:Ao ratio and E peak velocity. Normalized left ventricular end-diastolic diameter was not included in this statistical model due to its strong correlation to the left atrial enlargement. However, it is of interest to notice that LVEDDn was a variable associated with an increased hazard at 6 months after inclusion in the study. ... Left atrial to aortic root ratio > 2.1, normalized left ventricular end-diastolic diameter > 1.9 early transmitral peak velocity (E peak) > 1 m/sec and NT-proBNP > 1500 ρmol/L were associated with increased risk of HF or cardiac death. The best fit model to predict the risk to reach the end-point was represented by the plasma NT-proBNP concentrations adjusted for LA:Ao and E peak. Conclusions: Logistic and survival models including echocardiographic variables and NT-proBNP can be used to identify dogs with preclinical MMVD at higher risk to develop HF or cardiac death.

Clinical efficacy of a benazepril and spironolactone combination in dogs with congestive heart failure due to myxomatous mitral valve disease: The BEnazepril Spironolactone STudy (BESST). Melissa Coffman, Emilie Guillot, Thomas Blondel, Catherine Garelli-Paar, Shuo Feng, Susanne Heartsill, Clarke E. Atkins. J. Vet. Intern. Med. May 2021; doi: 10.1111/jvim.16155. Quote: Background: The renin-angiotensin-aldosterone system (RAAS), when chronically activated, is harmful and RAAS-suppressive drugs are beneficial in the treatment of congestive heart failure (CHF). Mineralocorticoid receptor antagonists are widely used in the treatment of CHF in people. Hypothesis/Objectives: To determine if a mineralocorticoid receptor antagonist (spironolactone) is beneficial and safe in CHF due to myxomatous mitral valve disease (MMVD) of varying severity, we hypothesized that, when combined with furosemide, a combination product (S+BNZ) containing the ACE inhibitor (ACE-I), benazepril, and spironolactone, would be superior to benazepril alone. Animals: Five hundred and sixty-nine client-owned dogs [including 40 cavalier King Charles spaniels (7.0%)], with MMVD and CHF (ACVIM Stage C) of ≤10-days' duration. Methods: after initial stabilization, dogs were randomized into a positive-controlled, double-blind, multicenter trial, to receive furosemide plus S+BNZ or furosemide plus benazepril. The primary outcome variable was the percentage of dogs reaching cardiac endpoint before Day 360. Cardiac endpoint was defined as cardiac death or euthanasia, recurrence of pulmonary edema, necessity for nonauthorized cardiac drug(s) or a furosemide dosage >8 mg/kg/d. Results: A significantly lower percentage of dogs treated with S+BNZ reached the primary outcome variable by Day 360 (OR = 0.56; 95% CI, 0.32-0.98) and risk of dying or worsening from cardiac causes, was significantly reduced (HR = 0.73; 95% CI = 0.59-0.89) vs benazepril alone. Adverse events, potentially associated with treatment, were rare and equal between groups. Conclusion and Clinical Importance: The combination of S+BNZ is effective, safe, and superior to benazepril alone, when used with furosemide for the management of mild, moderate or severe CHF caused by MMVD in dogs.

An echocardiographic study of breed-specific reference ranges in healthy French Bulldogs. Murat Vurucu, Gencay Ekinci, Vehbi Gunes. Vet. Radiol. Unltrasound. May 2021; doi: 10.1111/vru.12997. Quote: Echocardiography is a standard diagnostic tool for assessment of cardiac functions and cardiovascular diseases in dogs, however published echocardiographic measurements have varied widely based on dog breeds. ... Reference values obtained from breed-specific echocardiographic studies have been reported to have a significant difference compared to the general population of healthy different dog breeds. Therefore, breed-specific echocardiographic reference ranges may be more helpful in avoiding the misinterpretation of echocardiographic findings. During an evaluation without considering the breed-specific echocardiographic reference values, a normal heart structure and/or measurement could end up being falsely interpreted as either large or small or increased or decreased when compared to the general non-breed-specific reference ranges. These misinterpretations could lead to a misdiagnosis or an underdiagnosis of an underlying cardiac problem resulting in unnecessary/wrong treatment and/or no treatment. ... The objective of this prospective reference interval study was to provide breed-specific echocardiographic values for healthy French Bulldogs. A total of 42 healthy French Bulldogs of both sexes (23 females and 19 males) were sampled. Furthermore, measurements for a control group (n = 16) were also conducted in four other dog breeds (Cocker Spaniel [n = 2], Cavalier King Charles Spaniel [n = 4], Terrier [n = 5], and Crossbreed [n = 5]). Standard M-mode, two-dimensional (2D), pulse wave (PW) Doppler, and tissue Doppler imaging (TDI) echocardiographic measurements were obtained from healthy French Bulldogs. The M-mode echocardiographic data obtained from French Bulldogs were compared to the data obtained from the control group. The left ventricular internal dimension at end-diastole (LVIDd; cm)/body surface area (BSA) (m2) ratio for the study group was 3.35/0.53 = 6.32. Left ventricular measurements for French bulldogs and internal dimension at end-systole (21.23 ± 3.50 mm) and at end-diastole (33.50 ± 4.12 mm) were found to be significantly higher compared to control group values (left ventricular internal dimension at end-systole [LVIDs]; 17.46±2.85mm,LVIDd; 27.16± 4.20 mm, respectively). A significantly positive correlation in the French Bulldog group was noted between body weight andM-mode measurements (EPSS, IVSd, IVSs, LVIDd, LVIDs, and LVPWd). ... In our study, the LVIDd (cm)/body surface area (BSA) (m2) ratios for French Bulldogs (3.35/0.53 = 6.32) were found to be higher than the values reported for other breeds in previous studies, such as Boxers (4.34), Doberman Pinschers (4.29), English Pointers (5.47), Golden Retrievers (4.46), Irish Wolfhounds (2.99), Afghan Hounds (5.19), and Great Danes (3.38). The findings of this study suggest that French Bulldogs have a different cardiac M-mode measurement than other breeds. French bulldogs had a greater systolic and diastolic left ventricular volume than the control group. As a result, values reported in this study could be used as specific reference ranges in French Bulldogs. ... An echocardiographic evaluation of French Bulldogs based on general or different dog breed population reference ranges may result in misdiagnosis (such as an early phase of dilated cardiomyopathy or heart failure) because this breed has a different chest structure, cardiac silhouette, and left ventricular internal dimensions compared to other breeds. ... Normal heart sizes and shapes show substantial variation based on dog breed. Breed-specific reference ranges should be taken into consideration when evaluating the heart.

Regurgitant Fraction in Dogs with Mitral Regurgitation: Method Comparison, Effects of Pimobendan, and Reproducibility. Lance C. Visser, Riley E. Ellis-Reis, Weihow Hsue. 2021 ACVIM Forum. June 2021; C07. Quote: We sought to determine echocardiographic regurgitant fraction (RF) using Simpson’s method of disks (RF_SMOD) to estimate total stroke volume (TSV) in a large number of dogs with myxomatous mitral valve disease (MMVD) and compare it to RF using M-mode to estimate TSV (RF_M-mode). We also sought to evaluate the effect of pimobendan on RF and the reproducibility of RF. Eighty-one dogs with MMVD were prospectively enrolled and underwent an echocardiographic examination. Ten dogs underwent a second echocardiographic examination after receiving pimobendan 0.3 mg/kg PO q12h for 7-10 days. Nine dogs underwent six echocardiographic examinations by two operators on three nonconsecutive days within one week for reproducibility analysis. The relationship between left atrial size (LA/Ao) and RF_SMOD was determined using regression analysis. Agreement between RF_SMOD and RF_M-mode was evaluated using Bland-Altman’s method. Wilcoxon’s test was used to compare RF before and after pimobendan. Reproducibility was quantified with reproducibility coefficients (RC). Dogs with stage B1 (n=30), B2 (n=38), and heart failure (n=13) were enrolled. RF_SMOD exhibited a curvilinear relationship with LA/Ao (R2=0.60). ... I have the LA/Ao of 1.6, one of the EPIC criteria, for a reference line here. ... There is a subset of dogs [12 out of 56 (21.4%)] with regurgitant fraction of at least 30%, and some of them over 50%, considered severe in humans, with LA/Ao's less than 1.6.] ... RF_SMOD versus RF_M-mode revealed a mean (SD) bias of -8.0 (12.0)% with significant proportional bias. Pimobendan caused a significant decrease in RF_SMOD and RF_M-mode (median IQR percent changes of -25.8 [-36.8, -15.6] and -37.6 [-47.2, -33.2]%, respectively). Between-day intraoperator and between-operator RCs for RF_SMOD were 19.1% and 24.6%, respectively, and for RF_M-mode were 24.8% and 28.0%, respectively. RF_SMOD might aid the echocardiographic assessment of MMVD and should be considered for multifactorial approaches to determine disease severity.

Syringomyelia and Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels. Maiken B.T. Bach, C.L. Stougaard, M.S. Thofner, M.J. Reimann, U. Westrup, J. Koch, M. Fredholm, T. Martinussen, M.Berendt, L.H. Olsen. 2021 ACVIM Forum. June 2021; C12. Quote: Cavalier King Charles spaniels (CKCS) are genetically predisposed to both syringomyelia (SM) and myxomatous mitral valve disease (MMVD). This study investigated if a possible association between the occurrence of the two diseases exists. This combined retrospective and prospective study running 2007-2015 included 55 CKCS: Forty-one dogs with syrinx identified with MRI, defined by a hypointense area in T1 > 2mm in width, and 14 controls ( > 5 years of age) with no syrinx on MRI. Of dogs with SM, 19 dogs were asymptomatic while 22 were symptomatic. Echocardiography ( > 4 years of age) were performed in all dogs. A possible association between syringomyelia and MMVD disease severity (left ventricle internal diameter in diastole (LVIDD), LVIDD normalized to bodyweight (LVIDDN) and left atrium to aortic ration (LA:Ao)) was tested using multivariable linear regression analysis adjusting for sex and age. There was no significant difference in LVIDD, LVIDDN and LA:Ao (median [IQR]) between CKCS with SM (28.20 [27.0–30.80], 1.50 [1.40–1.60], 1.20 [1.10–1.40]) and CKCS without SM (28.90 [27.15–36.75], 1.55 [1.43–1.83], 1.30 [1.20–1.80]). Yet, LVIDD, LVIDDN and LA:Ao were smaller in CKCS with symptomatic SM (27.20 [25.85–28.80], 1.45 [1.30–1.50] and 1.20 [1.10–1.28]) compared to CKCS with asymptomatic SM (30.80 [28.40–38.40] p < 0.001, 1.60 [1.50–1.90] p < 0.001, 1.40 [1.20–1.75]). We found no overall association between MMVD and SM. Dogs affected with symptomatic SM had less severe MMVD compared to dogs with asymptomatic SM indicating it is important to be aware of both diseases when breeding CKCS.

Differentiating Preclinical Myxomatous Mitral Valve Disease Stages Using Electrocardiography in Cavalier King Charles Spaniels. Brian G. Barnett, S. Gordon, S. Wesselowski, A. Saunders, R. Fries, K.T. Sykes, J. Vitt, b. Boutet, S. Kadotani, K. Cusack, B. Janacek, J. Stack, S. Hubert, C. Stoner. 2021 ACVIM Forum. June 2021; C13. Quote: The diagnostic utility of electrocardiography (ECG) and heart rate variability (HRV) variables to differentiate Stage A and Stage B1 from Stage B2, as defined by the 2019 ACVIM MMVD consensus statement has not been evaluated in Cavalier King Charles Spaniels (CKCS). The goal of this study was to evaluate diagnostic utility of a variety of ECG-derived variables alone and in combination to differentiate Stage A and Stage B1 from Stage B2 MMVD in CKCS. Two-hundred and twenty-seven apparently healthy CKCS that were not receiving any cardiac medications were prospectively recruited. Dogs were staged with auscultation and echocardiography: Stage A (N = 14; 6.2%), Stage B1 (N = 169; 74.4%), Stage B2 (N = 44; 19.4%). As part of the study, a 30-second resting right lateral six-lead ECG was performed and analyzed off-line using IDEXX CardioPet. Measured variables included; P wave duration (ms), P wave amplitude (mV), PR interval (ms), R wave peak time (ms), QRS duration (ms), R wave amplitude (mV), QT interval (ms). Twenty sequential RR intervals were used to calculate average heart rate (HR) and vasovagal tonus index (VVTI) to assess HRV. Additionally, QRS+P duration (ms), a novel ECG variable, was calculated. Receiver operating characteristic (ROC) curves were constructed for each variable to determine their discriminatory utility. The area under the curve (AUC) was < 0.6 for P and R amplitude, PR and QT interval, R wave peak time, HR and VVTI, demonstrating poor discrimination. The AUC for P and QRS duration was 0.742 and 0.759 respectively, demonstrating fair discrimination. The AUC for QRS+P duration was 0.812 (standard error = 0.037; 95% confidence interval = 0.750 - 0.884; p < 0.0001), demonstrating good discrimination. A cut-off of 79 ms for QRS+P duration had good specificity (85%) and fair sensitivity (59%) for identification of Stage B2, suggesting it may be useful to rule-out Stage B2 in CKCS with preclinical MMVD with a false negative rate of 10%. However, the false positive rate remains high at 51%. Subsequent decision tree analysis using P (< 40 ms) and QRS (< 39 ms) in series reduced the false negative rate to 6% but the false positive rate remained high at 42%. These data suggest that P and QRS durations combined as P+QRS or in series may represent a good screening test to rule-out Stage B2 MMVD in CKCS with preclinical MMVD with a negative predictive value 90-94%.

Resolution of Congestive Heart Failure in Dogs with Myxomatous Mitral Valve Disease. Tung Hsueh, I-Ping Chan. 2021 ACVIM Forum. June 2021; C19. Quote: Myxomatous mitral valve disease (MMVD) is one of the causes of congestive heart failure (CHF) in small-breed dogs. Based on our clinical observations, few dogs with CHF secondary to MMVD are stable to the extent that the dose of diuretic can be lowered, tapered, or stopped. Therefore, this study aimed to investigate the differences between dogs with MMVD that showed resolution of CHF and those that died due to cardiac causes. Electronic medical records of dogs with a new diagnosis of MMVD from October 2012 to December 2020 were retrospectively reviewed. Dogs that were diagnosed with pulmonary edema at admission, and for whom the dose of diuretic could be lowered (furosemide not exceeding 3 mg/kg/day), tapered, or stopped for at least one year without recurrent pulmonary edema were included. Of the 1,223 MMVD cases, 8 (8/1223, 0.65%) met the inclusion criteria and were allocated to the resolved group (5 Maltese, 2 toy poodles, and 1 schnauzer). Breed- and sex-matched controls, which were also diagnosed with CHF secondary to MMVD and ultimately died of cardiac reasons, were allocated to the progressive group (5 Maltese, 2 toy poodles, and 1 schnauzer). This was a retrospective case-control study. Breed, sex, age, body weight, vertebral heart size, vertebral left atrial size, normalized left ventricular internal dimension in systole and diastole, left ventricular fractional shortening, mitral E/A, mitral E/E’, normalized left atrial dimension, left atrium to aorta ratio (2D and M-mode), variables representing left atrial functions, and the presence of a flailed mitral valve and pulmonary hypertension were compared between the two groups. All variables showed no statistically significant difference between the two groups. In the resolved group, more than half of the patients (5/8, 62.5%) had other systemic diseases that required tapering of diuretic therapy; two were diagnosed with Cushing’s disease and one each had proteinuria, chronic kidney disease, and urinary obstruction. Of the remaining three dogs, without evidence of other systemic diseases, two were still under follow-up, and the dose of diuretics was unchanged for 1079 and 1035 days. Diuretic therapy had been stopped in the third dog 779 days after the first admission. None of them showed evidence of pulmonary hypertension at the first admission, and all of them showed decreased left atrium and left ventricle size upon re-evaluation by echocardiography (ranging from 255 to 910 days after the first admission). For dogs with MMVD and CHF, the occurrence of other systemic diseases that could alter the hydration status may lead to the resolution of CHF signs, followed by the modification of diuretic therapy. This emphasizes the importance of regular follow-up in dogs with MMVD and CHF. For unknown reasons, few cases without other identifiable systemic disease can be stable for a long time. The reason why only very few dogs with MMVD and CHF need lowering or cessation of diuretic therapy warrants further study.

Contribution of Chronic Kidney Disease to the Progression of Myxomatous Mitral Valve Disease in Dogs. Jeong-Sook Oh, Dohee Lee, Taesik Yun, Yoonhoi Koo, Yeon Chae, Dongwoo Chang, Byeong-Teck Kang, Mhan-Pyo Yang, Hakhyn Kim. 2021 ACVIM Forum. June 2021; C23. Quote: In veterinary medicine, the understanding of the interation between renal and cardiovascular system is increasing, but it has not yet been completely elucidated. Therefore, in this study, we aimed to investigate the cardiorenal system in dogs by evaluating chronic kidney disease (CKD) as a risk factor for the progression of myxomatous mitral valve disease (MMVD). The medical records of 63 dogs diagnosed with MMVD stage B1, B2, or C, according to the guidelines of the American College of Veterinary Internal Medicine, were retrospectively reviewed. The progression of MMVD was examined 6 months after the first diagnosis, and the mortality rate was recorded. The indicators for the progression of MMVD and mortality rate were compared between the dogs with only MMVD (MMVD group) and the dogs with both CKD and MMVD (concurrent group). In MMVD stages B2 and C, change in vertebral heart score was significantly greater in the concurrent group than in the MMVD group. In all stages of MMVD, the concurrent group showed a greater change in left ventricular end-diastolic diameter normalized for body weight than the MMVD group. However, no significant differences were found in the progression of murmur grade and left atrium/aorta ratio between the two groups. The mortality of the concurrent group was significantly higher than that of the MMVD group. These results provide an insight into the relationship between CKD and MMVD, and suggest the potential role of CKD as a risk factor for the progression of canine MMVD.

Genetics of canine myxomatous mitral valve disease. M. J. O’Brien, N. J. Beijerink, C. M. Wade. Anim. Genet. May 2021; doi: 10.1111/age.13082. Quote: Myxomatous mitral valve disease (MMVD) is the most common heart disease and cause of cardiac death in domestic dogs. MMVD is characterised by slow progressive myxomatous degeneration from the tips of the mitral valves onwards with subsequent mitral valve regurgitation, and left atrial and ventricular dilatation. Although the disease usually has a long asymptomatic period, in dogs with severe disease, mortality is typically secondary to left-sided congestive heart failure. Although it is not uncommon for dogs to survive long enough in the asymptomatic period to die from unrelated causes; a proportion of dogs rapidly advance into congestive heart failure. Heightened prevalence in certain breeds, such as the Cavalier King Charles Spaniel, has indicated that MMVD is under a genetic influence. The genetic characterisation of the factors that underlie the difference in progression of disease is of strong interest to those concerned with dog longevity and welfare. Advanced genomic technologies have the potential to provide information that may impact treatment, prevalence, or severity of MMVD through the elucidation of pathogenic mechanisms and the detection of predisposing genetic loci of major effect. Here we describe briefly the clinical nature of the disorder and consider the physiological mechanisms that might impact its occurrence in the domestic dog. Using results from comparative genomics we suggest possible genetic approaches for identifying genetic risk factors within breeds. The Cavalier King Charles Spaniel breed represents a robust resource for uncovering the genetic basis of MMVD.

Use of whole genome analysis to identify shared genomic variants across breeds in canine mitral valve disease. Brian Williams, Steven G. Friedenberg, Bruce W. Keene, Sandy P. Tou, Teresa C. DeFrancesco, Kathryn M. Meurs. Human Genetics. June 2021; doi: 10.1007/s00439-021-02297-w. Quote: Familial mitral valve prolapse in human beings has been associated with several genetic variants; however, in most cases, a known variant has not been identified. Dogs also have a naturally occurring form of familial mitral valve disease (MMVD) with similarities to the human disease. A shared genetic background and clinical phenotype of this disease in some dog breeds has indicated that the disease may share a common genetic cause. ... The objective of this study was to utilize DNA from 50 affected dogs from five different dog breeds in a whole genome sequencing approach to identify shared genetic variants across and within breeds that could be associated with the development of MMVD. ... We evaluated DNA from 50 affected dogs from five different dog breeds in a whole genome sequencing approach to identify shared variants across and within breeds that could be associated with MMVD. No single causative genetic mutation was found from the 50 dogs with MMVD. Ten variants were identified in 37/50 dogs around and within the MED13L gene. These variants were no longer associated with MMVD when evaluated with a larger cohort including both affected and unaffected dogs. No high/moderate impact variants were identified in 10/10 miniature poodles, one was identified in 10/10 Yorkshire Terriers and 10/10 dachshunds, respectively, 14 were identified in 10/10 Miniature schnauzers, and 19 in 10/10 CKCS. Only one of these could be associated with the cardiac valve (Chr12:36801705, COL12A1; CKCS) but when evaluated in an additional 100 affected CKCS the variant was only identified in 84/100 affected dogs, perhaps indicating genetic heterogeneity in this disease. ... Although we did not find a specific shared variant in CKCS with MMVD, the transcriptomic profile of CKCS MMVD mitral valves has been shown to be different than non-CKCS MMVD valves demonstrating some breed specific differences. ... Our findings indicate that development of MMVD in the dog may be related to a combination of genetic and environmental factors that impact specific molecular pathways rather than a single shared genetic variant across or within breeds. ... In conclusion, no single causative genetic mutation was found in all 50 dogs with MMVD. We did identify a small number of intergenic and intronic variants in a large number of dogs that were located around and within the MED13L gene. However, we were unable to identify a specific molecular impact of these variants on the gene product and the variants were no longer associated with MMVD when evaluated with other small breed dogs that were thought to be unaffected. Given the complexity of the exact phenotyping of this disease which can be impacted by late and variable onset of disease and possibly incomplete penetrance, these variants should not be completely disregarded and further study is warranted. Development of MMVD in the dog may be related to a combination of genetic and environmental factors that impact specific molecular pathways.  

Heart rate variability and quality of life in dogs with mitral valve disease treated with metoprolol. Tamyris Beluque, Aparecido Antonio Camacho, Roberto Navarrete Ampuero, Jaislane Bastos Braz, Murillo Daparé Kirnew, Raphaela Arantes Marques Canola, Elizabeth Carvalho, Marlos Gonçalves Sousa. Brazilian J. Vet. Med. June 2021; doi: 10.29374/2527-2179.bjvm003020. Quote: Mitral valve disease (MVD) is a progressive disease that can reduce cardiac output. Activation of the sympathetic autonomic nervous system is one of the body’s first responses in order to maintain cardiac output, but may have deleterious effects on the cardiovascular system. This study investigated the effect of metoprolol on heart rate variability and quality of life in dogs with severe MVD (stage C, according to the guidelines of the American College of Veterinary Internal Medicine). Eight dogs between nine and thirteen years of age were enrolled [including one cavalier King Charles spaniel] and screening tests such as complete blood count, serum biochemistry profile, systolic blood pressure, thoracic radiographs, electrocardiogram, echocardiogram and long-term electrocardiography (24 hours) were performed. The patients were treated with enalapril, furosemide, spironolactone, and pimobendan until considered clinically stable, and metoprolol was then added to the therapy. One month later, all animals were re-assessed. Owners responded to a questionnaire about their dog’s quality of life before and after beta-blocker therapy. The value for pNN50 (percentage difference between adjacent N-N intervals more than 50 ms) was significantly higher (P=0.039) after treatment with metoprolol, indicating higher heart rate variability as indicated by the increased parasympathetic component. Furthermore, quality of life was improved in 30% of patients after metoprolol was initiated. The results suggest that treatment with beta-blockers in dogs with stage C MVD may yield additional benefits in comparison to standard CHF treatment. ... Our study demonstrated that 30 days of metoprolol associated with at least 2 months of classic treatment for severe mitral valve disease improved quality of life and cardiac autonomic function in dogs.

Peripheral blood lymphocyte subtypes in dogs with different stages of myxomatous mitral valve disease. Natalia Druzhaeva, Alenka Nemec Svete, Alojz Ihan, Katka Pohar, Aleksandra Domanjko Petrič. J. Vet. Intern. Med. July 2021; doi: 10.1111/jvim.16207. Quote: Background: Data on alterations in peripheral blood lymphocyte (PBL) subtypes in dogs with myxomatous mitral valve disease (MMVD) is lacking. Objectives: To investigate PBL subtypes and their correlation with parameters of inflammation and MMVD progression markers in dogs with different stages of MMVD. Animals: Seventy-eight client-owned dogs: 65 with MMVD (American College of Veterinary Internal Medicine [ACVIM] classification stages B2, C, and D) [including 19 cavalier King Charles spaniels (29%)] and 13 healthy controls. Methods: Prospective cross-sectional study. Complete cardiac assessment, flow cytometry (T lymphocytes [CD3+], their subtypes [CD3+CD4+, CD3+CD8+, CD3+CD4+CD8+, CD3+CD4−CD8−], and B lymphocytes [CD45+CD21+]) and measurement of N-terminal pro B-type natriuretic peptide, cardiac troponin I, and C-reactive protein concentrations were performed. Results: The percentage of CD3+CD4+ lymphocytes was significantly lower in stable ACVIM C patients and unstable ACVIM C and D patients, the percentage of CD3+CD8+ lymphocytes was significantly higher in stable ACVIM C patients and unstable ACVIM C and D patients, CD3+CD8+ lymphocyte concentration was significantly higher in unstable ACVIM C and D patients, and the CD3+CD4+/CD3+CD8+ ratio was significantly lower in stable ACVIM C patients and unstable ACVIM C and D patients compared with healthy controls. Conclusions and Clinical Importance: The percentages of CD3+CD4+ and CD3+CD8+ PBL and CD4+/CD8+ ratio were altered in MMVD dogs with congestive heart failure (ACVIM C, D), but not in ACVIM B2, suggesting involvement of these PBL subtypes in the pathogenesis of congestive heart failure in dogs with MMVD.

Prevalence of an angiotensin-converting enzyme gene variant in dogs. D. B. Adin, C. E. Atkins, S. G. Friedenberg, J. A. Stern, K. M. Meurs. Canine Med. & Genetics. July 2021; doi: 10.1186/s40575-021-00105-2. Quote: Background; Genetic differences in the angiotensin converting enzyme (ACE) have been shown to affect the way dogs respond to ACE-inhibitors, a class of medication which is used to treat dogs with heart disease. Dogs that have a genetic mutation of the ACE gene show less benefit with ACE-inhibitor medications than dogs without the mutation, ... because the degree of aldosterone breakthrough with ACE-inhibitor therapy is greater in variant positive dogs compared to variant negative dogs, but the prevalence of the variant is not known. ... The purpose of this study was to determine ACE gene variant-positive prevalence in a population of 497 dogs of different breeds. Results: ... The overall variant-positive prevalence in this population of 497 dogs was 31%. The variant was overrepresented in Irish Wolfhounds (prevalence 95%), Dachshunds (prevalence 90%), Cavalier King Charles Spaniels (prevalence 85%), Great Danes (prevalence 84%), and Bull Mastiffs (prevalence 58%). Irish Wolfhounds were more likely than other breeds to have 2 copies of the mutation (homozygous) than 1 copy of the mutation (heterozygous). The clinical importance of high ACE gene variant-positive prevalence in some breeds will require additional studies because some breeds are predisposed to heart disease, for which treatment with ACE-inhibitor medication might be recommended.

Protective effects of omega-3 fatty acids in dogs with myxomatous mitral valve disease stages B2 and C. Priscilla Regina Nasciutti, Aline Tavares Moraes, Thaiz Krawczyk Santos, Karine Kelly Gonçalves Queiroz, Ana Paula Araŭjo Costa, Andressa Rodrigues Amara, Rodrigo Fernando Gomes Olivindo, Cristiana Ferreira Fonseca Pontieri, Juliana Toloi Jeremias, Thiago Henrique Annibale Vendramini, Marcio Antonio Brunetto, Rosângela de Oliveira Alves Carvalho. PLoS ONE. July 2021; doi: 10.1371/journal.pone.0254887. Quote: Myxomatous mitral valve disease (MMVD) is characterized by thickening of the valve leaflets and omega-3 (ω-3) supplementation has been associated with modulation of blood pressure (BP) and heart rate, improvement of doppler echocardiographic indices, antiarrhythmic, anti-inflammatory and anti-dislipidemic effects in dogs and humans, although prospective studies of it single use are still absent in the veterinary literature. The objective of this study was to evaluate the influence of ω-3 supplementation in dogs with MMVD. Twenty-nine dogs [none were cavalier King Charles spaniels] were followed quarterly for 12 months by clinical evaluation, arterial blood pressure, electrocardiography, doppler echocardiography, thoracic radiography and laboratory tests including inflammatory mediators and cardiac biomarker blood concentrations. The dogs were classified in stages B2 and C, according to the classification proposed by ACVIM 2019. They were randomly assigned to either ω-3 group (ω-3G) or control group (CG). ... The ω-3G composed of 16 dogs ... Among those, 9 classified in stage B2 and 7 in stage C and received dry food for cardiac dogs supplemented with ω-3 in the average doses of 54.2mg/kg EPA and 40.65mg/kg DHA. The ingestion of ω-3 reduced the chance of developing arrhythmias by 2.96 times. The vertebral heart size (VHS) measurements were higher in the control group. ... Dogs that died during the study showed clinical signs of cardiac insufficiency before death and the evaluation of the progression of MMVD within the groups showed higher percentage of control dogs that evolved from asymptomatic to CHF and death. In contrast, in the ω-3 group most of them remained asymptomatic throughout the evaluation period, and those who died had already developed CHF when they were included in the study. Patients included in stage C have had at least one episode of CHF and were, therefore, in a more advanced stage of the disease. In conclusion, at the dosages used in this study, ω-3 dietary supplementation reduces the volumetric overload, has antiarrhythmic effect and keeps dogs with B2 and C stages of MMVD in milder stages of the disease. ... Dietary supplementation with ω-3 fatty acids contributes to more favourably Doppler echocardiographic measurements, such as normalized LVD, and reduces the VHS measures. NTproBNP dosages, associated with normalized LVD averages suggest a lower volumetric overload in the ω-3G dogs. Thus, showing a contribution to the control of volumetric overload and, consequently, CHF.

Interpretation of cardiac chamber size on canine thoracic radiographs is limited and may result in the false identification of right-sided cardiomegaly in the presence of severe left-sided cardiomegaly. Elodie E. Huguet, Federico Vilaplana Grosso, Whitney R. Lamb, Margaret M. Sleeper, John Mattoon, Nathan Nelson, James Brown, Bennett Deddens, Hock Gan Heng, Stephanie Knapp, Maureen Levesque, Rudy Rivas, James C. Colee, Clifford R. Berry. Vet. Radiol. & Ultrasound. July 2021; doi: 10.1111/vru.13006. Quote: Qualitative assessment of individual cardiac chamber enlargement on thoracic radiographs was assessed using echocardiography as the gold standard in dogs. ... For all [echocardiographic] calculations, cardiac chamber enlargement was graded as mild if up to 10% enlarged, moderate if 11-39% enlarged, and severe if greater than 40% enlarged in correlation to the weight-corrected calculations. [165 dogs were identified with degenerative mitral valve disease (94.3%) and were categorized in Stage B1 (5 dogs), Stage B2 (54 dogs), Stage C (82 dogs), or Stage D (24 dogs).] ... Using this method, the presence of severe left-sided cardiomegaly was hypothesized to contribute to the false identification of right-sided cardiomegaly on radiographs. 175 dogs [including 17 cavalier King Charles spaniels (9.7%)] with three-view thoracic radiographs were retrospectively included in this diagnostic accuracy study if echocardiography was done within 24 h, and no rescue therapy was provided in the interim. All radiographic studies were reviewed by two groups of five board-certified veterinary radiologists with greater and less than 10 years of experience for grading of cardiac chamber enlargement as normal or mildly, moderately, or severely enlarged. The agreement, sensitivity, and specificity of the radiologists’ interpretation of cardiac chamber size on thoracic radiographs to measured echocardiographic grades were evaluated. A total of 147 cases had complete echocardiographic data available for analysis. Intragroup agreement was moderate for the evaluation of left atrial enlargement and slight to fair for all other cardiac chambers. ... In opposition to the proposed hypothesis, the subjective grading of cardiac chamber size on thoracic radiographs underestimated and poorly agreed with echocardiographic grades, supporting the use of echocardiography over radiography for the characterization of cardiac chamber enlargement. When comparing the radiologists' responses in the two groups to the echocardiographic grades, there was slight agreement for all cardiac chambers with higher grades reported using echocardiography, meaning that thoracic radiographs underestimated the degree of cardiac chamber enlargement. ... Between the mode of the radiologists’ responses in the two groups and the echocardiographic grades, there was slight agreement for all cardiac chambers with higher severity grades reported using echocardiography. When moderate to severe left-sided cardiomegaly was identified on echocardiography, the sensitivity, specificity, and accuracy of radiographs were low, identifying dogs with radiographic evidence of right-sided cardiomegaly in the absence of corresponding right-sided cardiomegaly on echocardiography. Therefore, thoracic radiographs should be used with caution for the evaluation of cardiac chamber enlargement, particularly in the presence of severe left-sided cardiomegaly.

Short-Term Effects of Sacubitril/valsartan on Echocardiographic Parameters in Dogs With Symptomatic Myxomatous Mitral Valve Disease. Nakkawee Saengklub, Prapawadee Pirintr, Thanida Nampimoon, Anusak Kijtawornrat, Narongsak Chaiyabutr. Front. Vet. Sci. July 2021; doi: 10.3389/fvets.2021.700230. Quote: Background and Objective: is an angiotensin receptor-neprilysin inhibitor that works by inhibiting the neprilysin enzyme as well as blocking angiotensin receptors. The benefits of using SV in congestive heart failure patients has been demonstrated in several clinical trials; however, limited data are available for dogs with heart failure. The aim of this study was to investigate the short-term effects of SV in comparison with ramipril in the standard therapy of symptomatic dogs suffering from myxomatous mitral valve disease (MMVD). Methods: In this prospective, randomized, single-blind study, 21 dogs with MMVD stage C ... Pomeranian (9), Shih-Tzu (5), Maltese (2), Poodle (2), Chihuahua (2), and Beagle (1) ... were randomly assigned to received SV (20 mg/kg orally twice a day) [11 dogs] or ramipril (0.125 mg/kg, orally once a day) [10 dogs] in addition to pimobendan and furosemide. ... Since there is no recommended dose for SV in dogs, a dose finding pharmacodynamic study was conducted. The MMVD dogs with ACVIM stage B1 and B2 were used to evaluate the effect of SV on BP as well as HR and RPP. Based on our results, SV at a dose of 20 mg/kg twice a day was chosen for the main study since the changes in SBP and RPP were more consistent when given to these dogs than other groups (i.e., 5 and 10mg/kg). ... Echocardiography, electrocardiography, blood pressure, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and urinary aldosterone per creatinine ratio were obtained at baseline (D0) and at follow-up (4 weeks). Results: When comparing the percent change from baseline between groups, the left atrium to aortic root ratio (LA/Ao) and left ventricular internal diameter diastole normalized to body weight (LVIDDN) were significantly reduced in the SV group. The end-diastolic volume index (EDVI), end-systolic volume index (ESVI), and stroke volume were lower in the SV group. No changes were observed between groups for NTproBNP, blood pressure, ECG parameters, and urinary aldosterone per creatinine ratio. ... In conclusion, SV is effective at lowering LA/Ao, LVIDDN, EDVI, ESVI, and SV in dogs with naturally occurring symptomatic MMVD stage C, which indicated reverse myocardial remodeling. In addition, the short-term effects of SV in these populations were well-tolerated and they did not show any alteration in hematology, blood chemistry profiles, BP, and ECG parameters. ... Conclusion: The current study suggested that the short-term effects of SV can reverse myocardial remodeling, as inferred from several echocardiographic indices (i.e., the reduction in LA/Ao, LVIDDN, EDVI and ESVI) in dogs with MMVD stage C. These findings would support the use of SV in clinically symptomatic heart failure in dogs.

A retrospective study of 14 dogs with advanced heart failure treated with loop diuretics and hydrochlorothiazide. Koji Iwanaga, Ryuji Araki, Mitsuhiro Isaka. Open Vet. J. July 2021; doi: 10.5455/OVJ.2021.v11.i3.2. Quote: Background: The use of thiazide diuretics is recommended in the American College of Veterinary Internal Medicine guidelines for advanced heart failure due to mitral insufficiency (MI) in dogs. However, there are no large-scale reports of the use of thiazide diuretics in dogs with advanced heart failure. Aim: This retrospective study evaluated the therapeutic effect of concomitant hydrochlorothiazide (HTCZ) with loop diuretics in dogs with heart failure. Methods: The study included 14 dogs [including 1 cavalier King Charles spaniel (7%)] diagnosed with advanced pulmonary edema with MI at two facilities. In all cases, high-dose loop diuretics (torsemide; 0.78–4 mg/kg/day) did not improve pulmonary edema. ... The dogs had been previously treated with loop diuretics ... high-dose loop diuretics (torsemide; 0.78–4 mg/kg/day) ... however, they did not respond to the treatment. The criteria for resistance to loop diuretics in this study were assessed based on the following criteria: no reduction in cardiac load and no change in renal function even though the loop diuretics were administered at the maximum doses. ... The results of the echocardiography and renal function tests before and after the administration of HTCZ (0.2–0.84 mg/kg/day) in addition to torsemide were statistically compared. Results: The echocardiographic data demonstrated significant improvement in relation to cardiac stress; left atrium to the aorta ratio, normalized left ventricular internal dimension in diastole, and E wave velocity (m/s) after HTCZ administration. However, blood urea nitrogen and creatinine levels increased, and potassium levels decreased, indicating a decline in renal function following HTCZ administration. Conclusion: This study suggests that the administration of HTCZ in combination with loop diuretics may be beneficial during advanced heart failure due to MI in dogs. The results can also be extended to patients who are resistant to loop diuretics, resulting in the improvement of cardiac function. However, as the combination of HTCZ and loop diuretics can deteriorate renal function, caution should be exercised prior to making recommendations regarding its use, and renal function should be monitored.

Prediction of clinically important acquired cardiac disease without an echocardiogram in large breed dogs using a combination of clinical, radiographic and electrocardiographic variables. S. Wesselowski, S.G. Gordon, N. Meddaugh, A.B. Saunders, J. Häggström, K. Cusack, B.W. Janacek, D.J. Matthews. J. Vet. Cardiol. August 2021; doi: 10.1016/j.jvc.2021.07.003. Quote: Introduction: Large breed (LB) dogs develop dilated cardiomyopathy (DCM) and myxomatous mitral valve disease (MMVD). Echocardiography is required for definitive diagnosis but not always available. Our objective was to assess clinical utility of thoracic radiographs alone, and in combination with physical examination and electrocardiography findings, for prediction of clinically important DCM or MMVD ... in the absence of an echocardiogram in a large population of LB dogs. For both objectives, clinically important disease was defined as disease meeting a threshold for initiation of medical treatment. ... Animals: Four hundred fifty-five client owned dogs ≥20 kg with concurrent thoracic radiographs and echocardiogram. ... Across the entire population, dogs from 50 breeds were represented in addition to mixed breed dogs. The most commonly represented breeds overall were DP [Doberman Pinschers] (n=83), Labrador Retriever (n=82), Boxer (n=69), Golden Retriever ( 299 n=19), mixed breed (n=19), Great Dane (n=17), American Pit Bull Terrier (n=17) and German Shepherd (n=15). ... The most commonly represented breeds in the combined [mitral valve disease] PC-MMVD and C-MMVD groups were Labrador Retriever (n=8; 13.6%), Golden Retriever (n=6; 10.2%), and Border Collie (n=5; 8.5%) with 26 total breeds represented. ... Materials and Methods: Medical records were reviewed and stored thoracic radiographs and echocardiographic images were measured to classify dogs as normal heart size (NHS), preclinical DCM, clinical DCM, preclinical MMVD (with cardiomegaly), clinical MMVD, or equivocal. Dogs with preclinical MMVD without cardiomegaly were classified as NHS [normal heart size]. ... In non-Doberman Pinscher dogs, normalized left ventricular internal diameter at end-diastole (LVIDdN) was defined as normal if <1.85. ... Normal 2D short axis LA:Ao was defined as ≤1.6, with Boxers considered normal if ≤1.73. ... Vertebral heart size (VHS) and vertebral left atrial size (VLAS) were measured. Receiver operating characteristic curves and prediction models were derived. Results: Prevalence of MMVD (39.3%) was higher than prevalence of DCM (24.8%), though most MMVD dogs (67.0%) lacked cardiomegaly and were classified as NHS for analysis. ... Of note, 67.0% dogs with MMVD in this population had echocardiographic evidence of MMVD but no secondary heart enlargement, indicating that an early and clinically less important stage of this disease was most common. ... In this LB population of dogs, VHS was positively, but not strongly, correlated with LVIDdN. Similarly, VLAS was positively, but not strongly correlated with LVIDdN. Compared to dogs with preclinical disease (PC-DCM + PC-MMVD), dogs with clinical disease (C369 DCM + C-MMVD) had a significantly larger LVIDdN and LA:Ao measurement. ... Area under the curve (AUC) for VHS to discriminate between NHS versus clinical DCM/MMVD or versus preclinical DCM/MMVD was 0.861 and 0.712, respectively, while for VLAS it was 0.891 and 0.722, respectively. Predictive models incorporating physical examination and electrocardiography findings in addition to VHS/VLAS increased AUC to 0.978 (NHS vs clinical DCM/MMVD) and 0.829 (NHS vs preclinical DCM/MMVD). Conclusions: Thoracic radiographs were useful for predicting clinically important DCM or MMVD in LB dogs, with improved discriminatory ability when physical examination abnormalities and arrhythmias were accounted for. ... [T]horacic radiographs should always be the first diagnostic test of choice. ... Within this population, for a dog with clinical signs that could be consistent with CHF, a VLAS <2.0 and a VHS <10.5 was associated with a 99.1% and 96.9% chance of having a normally sized heart, respectively, suggesting CHF would be very unlikely. On the other hand, a similar dog with a VLAS ≥2.8 or a VHS ≥12.3 had an 89.7% and 89.2% chance of being abnormal, respectively, and was very likely to have underlying cardiac disease. Dogs with preclinical disease in this population were harder to identify with as much confidence, though a VLAS <2.0 and a VHS <10.5 still suggested an 86.2% and 87.9% chance of having a normally sized heart, while a VLAS ≥2.8 or a VHS ≥12.3 both suggested a 73.3% chance of being abnormal and could reasonably prompt a recommendation for echocardiography to confirm whether disease is present.

Role of Two-Dimensional Speckle Tracking Echocardiography in Early Detection of Left Ventricular Dysfunction in Dogs. Lina Hamabe, Ahmed S. Mandour, Kazumi Shimada, Akiko Uemura, Zeki Yilmaz, Kentaro Nagaoka, Ryou Tanaka. Animals. August 2021; doi: 10.3390/xxxxx. Quote: Two-dimensional speckle tracking echocardiography (2D-STE) is an advanced echocardi-ographic technique based on deformation imaging, which allows comprehensive evaluation of the myocardial function. Clinical application of 2D-STE holds great potential for its ability to provide valuable information on both global and regional myocardial function and to quantify cardiac rotation and synchronicity, which are not readily possible with the conventional echocardiography. It has gained growing importance especially in the human medicine for the past decade, and its application include assessment of myocardial function, detection of subclinical myocardial dysfunc-tion and as prognostic indicators. This review aims to illustrate the fundamental concepts of deformation analysis and an overview of the current understanding of this technique, and its clinical application in the field of veterinary medicine, with focus on early detection of left ventricular (LV) dysfunction in dogs. ... Smith et al. evaluated asymptomatic dogs with Stage B2 MMVD using 2D-STE. In comparison to the control group, Stage B2 group had significantly higher HR, greater LV size and systolic function including both radial and circumferential strains, and was unable to identify LV dysfunction. Zois et al. observed similar results with increased strains, SRs and twist in dogs with congestive heart failure (CHF) in comparison to dogs with no or minimal MR, and these parameters increased with severity of MMVD which suggest augmented LV function. However, longitudinal and radial strains and longitudinal SR showed curvilinear relationships with left atrial-to-aortic ratio (LA/Ao), illustrating a decrease in LV function in dogs with CHF with severe left atrial enlargement. These studies were unable to demonstrate LV dysfunction prior to the onset of clinical signs of CHF, and the hyperdynamic values of strain analysis may reflect a compensatory mechanism important for the preservation of LV function.

Retrospective evaluation of a dose-dependent effect of angiotensin-converting enzyme inhibitors on long-term outcome in dogs with cardiac disease. Jessica L. Ward, Yen-Yu Chou, Lingnan Yuan, Karin S. Dorman, Jonathan P. Mochel. J. Vet. Intern. Med. August 2021; doi: 10.1111/jvim.16236. Quote: Background: Angiotensin-converting enzyme inhibitors (ACEIs) are commonly prescribed in dogs, but the ideal dosage is unknown. Hypothesis/Objectives: In dogs with cardiac disease, a dose-response relationship exists for ACEIs with respect to long-term outcome. Animals: One hundred forty-four dogs with cardiac disease, 63 with current or prior congestive heart failure. ... The most commonly represented breed [was] Cavalier King Charles spaniel (13) [9%] ... Methods: Retrospective medical record review. Cox proportional hazards models were used to determine variables associated with 2-year survival or survival from first-onset congestive heart failure (CHF). Results: Median initial ACEI dosage was 0.84 (interquartile range [IQR], 0.56-0.98) mg/kg/day, and 108/144 (75%) of dogs received q12h [twice-daily] dosing. No clinically relevant changes in renal function test results, serum electrolyte concentrations, or blood pressure occurred between initial prescription of ACEI and first reevaluation (median, 14 days later). In univariable analysis, higher ACEI dose was associated with increased survival from first-onset CHF, and within the subgroup of dogs in CHF at the time of ACEI prescription, higher ACEI dose was associated with improved survival at 2 years. In multivariable analysis, q12h dose frequency of ACEI (hazard ratio [HR], 0.30; 95% CI, 0.10-0.88) and higher serum potassium concentration at visit 1 (HR, 0.39; 95% CI, 0.16-0.97) were predictive of 2-year survival. The ACEIs were well-tolerated, with only 8/144 (5.6%) dogs having ACEI dose decreased or discontinued because of adverse effects. Conclusions and Clinical Importance: Twice daily dose frequency might optimize the cardioprotective benefit of ACEIs. ... Our retrospective study indicated an association between ACEI dose frequency and long-term outcome in a sample of dogs with cardiac disease. ... These results suggest that the clinical benefit of ACEI might be dose-dependent, with q12h dosing conferring superior cardioprotection. ... Our findings could provide a potential explanation for the failure of previous clinical trials to demonstrate long-term benefit in dogs with cardiac disease when utilizing ACEI dosages of 0.25-0.5 mg/kg q24h. .... Importantly, our study could not differentiate the effects of ACEI dose vs frequency on long-term outcomes. Substantial overlap existed between total daily dose and dose frequency in our study such that all dogs receiving low-dose ACEIs (<0.5 mg/kg/day) were receiving q24h dosing. It is therefore impossible to determine whether the survival benefit found in our study was associated with higher ACEI dose, q12h dose frequency, or both. Indeed, total daily dose was a more consistent predictor of survival than was dose frequency in univariable analysis, whereas dose frequency was significant in multivariable analysis. ... Our results suggest that q12h ACEI dosing might be associated with improved long-term survival compared to q24h dose frequency. Administration of ACEI at a median dose of 0.84 mg/kg/day was well-tolerated in this large group of dogs with cardiac disease. These findings provide a potential explanation for the failure of clinical trials to identify a clinical benefit of ACEI in dogs with cardiovascular disease, because all such previous trials have utilized ACEI dosages <0.5 mg/kg q24h. Additional PK/PD and prospective clinical studies will be needed to determine the ideal dosage of ACEIs to optimize RAAS suppression and cardioprotective benefit in dogs.

Peptide barcodes in dogs affected by mitral valve disease with and without pulmonary hypertension using MALDI-TOF MS and LC-MS/MS. Nattapon Riengvirodkij, Sittiruk Roytrakul, Janthima Jaresitthikunchai, Narumon Phaonakrop, Sawanya Charoenlappanich, Walasinee Sakcamduang. PLoS ONE. August 2021; doi: 10.1371/journal.pone.0255611. Quote: Mitral valve disease (MVD) is an important and most frequently acquired heart disease found in dogs. MVD is classified into different stages according to its severity. There is a challenge in differentiation between asymptomatic and symptomatic stages of the MVD. Moreover, pulmonary hypertension (PH) is a common complication in dogs affected by MVD. In clinical practice, there are also some limitations to identify PH. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a technique that can characterize specific patterns of peptide mass called peptide barcodes from various samples. Besides, in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS), potential peptide sequences associated with specific conditions could be identified. The present study aimed to use MALDI-TOF coupled with LC-MS/MS to characterize specific peptide barcodes and potential peptide candidates in serum samples from healthy dogs, dogs with MVD stage B (MVD B, asymptomatic stage), MVD stage C (MVD C, symptomatic stage), MVD stage B with PH (MVD B PH), and MVD stage C with PH (MVD C PH). Discrete clusters of the 5 sample groups were identified by 3D plot analysis. Peptide barcodes also revealed differences in peptide patterns among the 5 groups. Six amino acid sequences of peptide candidates at 1,225.60, 1,363.85, 1,688.71, 1789.52, 2020.21, and 2156.42 Da were identified as part of the proteins CLCN1, CLUL1, EDNRA, PTEN, SLC39A7, and CLN6, respectively. The network interactions between these discovered proteins and common cardiovascular drugs were also investigated. These results demonstrate that MALDI-TOF MS has promise as an optional technique for diagnosing dogs affected by asymptomatic and symptomatic stages of MVD with and without PH. Further studies are required to identify peptide barcodes in dogs with other diseases to create peptide barcode databases in veterinary medicine before using this method as a novel diagnostic tool in the future.

Echocardiographic evaluation of deformity and enlargement of the canine mitral valve annulus associated with myxomatous degenerative mitral valve disease. K. Mihara, I. Kanemoto, K. Sato, Y. Yasuhira, I. Watanabe, K. Misumi. J. Vet. Cardiol. August 2021; doi: 10.1016/j.jvc.2021.08.002. Quote: Introduction/Objectives: Quantitative evaluation of the morphology of the mitral valve annulus (MVA) in dogs with myxomatous mitral valve disease (MMVD) may improve the techniques of mitral valve plasty. This study aimed to compare the MVA morphology on echocardiography in normal dogs versus dogs with MMVD, and to compare the echocardiographic and intra-operative measurements of the MVA in dogs with MMVD. Animals, Materials and Methods: The study population comprised 59 healthy dogs (control group) and 371 dogs with MMVD (MMVD group). [Breeds were not identified. the MMVD group dogs all had undergone mitral valve plasty (surgery) following measurements of the MVA.] The anterior-posterior (APD) and transversal diameters (TD) of the MVA and the aortic annulus diameter (AAD) were measured by echocardiography to calculate the mitral valve flattening ratio (F), mitral annulus area (MAA), mitral annulus circumference (MAC), contraction ratio of the MAA (CRMAA) and aortic annulus area (AAA). In the MMVD group, the mitral annulus diameter (MAD) was macroscopically measured during mitral valve plasty. Areas and lengths were divided by the body surface area (BSA) and √BSA, respectively, for comparative analyses. Results: The systolic and diastolic APD/√BSA, TD/√BSA, MAA/BSA converted to a natural logarithm (Ln(MAA/BSA)), and MAC/√BSA were significantly higher in the MMVD group than the control group, whereas F values and CRMAA were significantly lower. Neither the AAD/√BSA nor the Ln(AAA/BSA) significantly differed between groups. In the MMVD group, diastolic MAC/√BSA and MAA/BSA correlated significantly with the MAD/√BSA. Conclusions: The MVA is larger and rounder in dogs with MMVD than controls. Two-dimensional echocardiographic measures of MAA and MAC correlate well with intraoperative measures of MAD. ... In the present study, two-dimensional echocardiography revealed that the MVA morphology differed between dogs with MMVD and control dogs. In the control dogs, the MVA was elliptical and was rounder during the diastolic phase than the systolic phase.

The effects of activity, body weight, sex and age on echocardiographic values in English setter dogs. Liva Vatne, David Dickson, Anna Tidholm, Domenico Caivano, Mark Rishniw. J. Vet. Cardiol. August 2021; doi: 10.1016/j.jvc.2021.08.003. Quote: Background: Breed specific reference intervals improve echocardiographic interpretation and thereby reduce misdiagnoses, especially in athletic breeds. Objectives: To examine transthoracic echocardiographic values in healthy adult English setter dogs and determine the effects of activity, body weight, sex and age on these values. Animals, Materials and Methods: One hundred and one adult English setter dogs, recruited from local veterinary clinics and from the Norwegian English setter club, underwent routine transthoracic echocardiography. The population was stratified into two groups based on reported level of activity. The effects of activity level, body weight, sex and age on echocardiographic variables were examined. ... Dogs with a trace of inaudible atrioventricular valve regurgitation, defined as colour jet not exceeding 15% of atrial area, were included. ... Results were compared to published data from other breeds and from a pre-existing species-wide allometric model. Results: Of the 100 dogs between 19 months and ten years of age included in the study, 72 were reported as very active, 28 as less active. Echocardiographic intervals were calculated for body-size-independent echocardiographic variables. The upper limits of the intervals for left-atrial-to-aortic ratios [LA:Ao = 1.8] and normalised left ventricular volumes [LVIDdN = 2.1] exceeded those of various, previously published studies of other breeds. Normalised left ventricular dimensions exceeded published allometric 95th percentile upper reference values in 13% of dogs in diastole and 32% of dogs in systole. More active dogs had larger cardiac dimensions than less active dogs, however activity level did not predict echocardiographic variables when included in a multiple regression model. Conclusions: The study provides breed specific transthoracic echocardiographic values for English setter dogs, thereby contributing to improve diagnostic assessment of cardiac health in this breed.

Pharmacodynamics and Pharmacokinetics of Injectable Pimobendan and Its Metabolite, O-Desmethyl-Pimobendan, in Healthy Dogs. Poonavit Pichayapaiboon, Lalida Tantisuwat, Pakit Boonpala, Nakkawee Saengklub, Tussapon Toonyarattanasoonthorn, Phisit Khemawoot, Anusak Kijtawornrat. Front. Vet. Sci. August 2021; doi: 10.3389/fvets.2021.656902. Quote: Objectives: This study was designed to thoroughly evaluate the effects of bolus pimobendan at a dose of 0.15 mg/kg on cardiac functions, hemodynamics, and electrocardiographic parameters together with the pharmacokinetic profile of pimobendan and its active metabolite, o-desmethyl-pimobendan (ODMP), in anesthetized dogs. Methods: Nine beagle dogs were anesthetized and instrumented to obtain left ventricular pressures, aortic pressures, cardiac outputs, right atrial pressures, pulmonary arterial pressures, pulmonary capillary wedge pressures, electrocardiograms. After baseline data were collected, dogs were given a single bolus of pimobendan, and the pharmacodynamic parameters were obtained at 10, 20, 30, 60, and 120 min. Meanwhile, the venous blood was collected at baseline and 2, 5, 10, 20, 30, 60, 120, 180, 360, and 1,440 min after administration for the determination of pharmacokinetic parameters. Results: Compared with baseline measurements, the left ventricular inotropic indices significantly increased in response to intravenous pimobendan, as inferred from the maximum rate of rise in the left ventricular pressure and the contractility index. Conversely, the left ventricular lusitropic parameters significantly decreased, as inferred from the maximum rate of fall in the left ventricular pressure and the left ventricular relaxation time constant. Significant increases were also noted in cardiac output and systolic blood pressure. Decreases were observed in the systemic vascular resistance, pulmonary vascular resistance, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure. The heart rate increased, but the PQ interval decreased. There was no arrhythmia during the observed period (2 h). The mean maximum plasma concentration (in μg/L) for ODMP was 30.0 ± 8.8. Pimobendan exerted large volume of distribution ~9 L/kg. Conclusions: Intravenous pimobendan at the recommended dose for dogs increased cardiac contraction and cardiac output, accelerated cardiac relaxation but decreased both vascular resistances. These mechanisms support the use of injectable pimobendan in acute heart failure.

Database Development and Statistical Analysis of Survival in a Clinical and Historical Coort of Dogs Affected by Myxomatous Mitral Valve Disease Treated With Different Therapeutic Protocols Using Causal Inference Techniques. Mara Bagardi, Valentina Palermo, Chiara Locatelli, Fabio Maria Colombo, Laura Pazzagli, Paola Giuseppina Brambilla. Research Square. August 2021; doi: 10.21203/rs.3.rs-794366/v1. Quote: The aim of this work was to retrospectively evaluate the influence of different therapeutic protocols (loop diuretics, ACE-inhibitors, spironolactone +/- pimobendan) on the survival time (ST) of dogs with myxomatous mitral valve disease at different stages using an Inverse Probability Weighting (IPW) analysis. An IPW method was used to minimize confounding and IPW weighted time-repeated logistic model wasused to approximate survival curves (SCs) and calculate survival differences. Subjects were allocated into cases (CA) and controls (CO). Dogs in American College of Veterinary Internal Medicine (ACVIM) B2 class treated with pimobendan (+/- ACE-inhibitors) were selected for the CA group, as well assymptomatic patients (ACVIM class C) threated with triple (furosemide, ACE-inhibitor, pimobendan) or quadruple (furosemide, ACE-inhibitor, pimobendan and spironolactone) therapy. ... The population included 398 subjects affected by MMVD, 236 (59.30%) were classified as CA and 162 (40.70%) as CO. ... [P]ure breeds included 25 (6.28%) Poodles, 25 (6.28%) Yorkshire Terriers, 22 (5.53%) Cavalier King Charles Spaniels, 17 (4.27%) Shih-tzu, 17 (4.27%) Dachshunds, 13 (3.27%) Chihuahuas, 10 (2.51%) Maltese dogs, 10 (2.51%) Pinscher and other breeds in lower percentage. ... The CO group included ACVIM class B2 dogs not treated with any medication and ACVIM C dogs treated with a combination of furosemide and ACE-inhibitor/spironolactone without pimobendan. The SC of the CA group crossed the CO group at 1634 days. The difference between the two SCs at the time of maximum survival difference in favour of the CO group was 11.3% (CI 1.7%–20.9%) (significant), in favour of the CA group was 3.9% (CI -8.6%–16.4%) (not significant), and at the mean ST was 3.6% (CI-8.5%–15.7%) (not significant) in favour of the CA group. For times greater than 1634 days the survival was in favour of the CA group, there were no statistically significant differences in survival in favour of the CA group in this clinical population.

The genetic consequences of dog breed formation — Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels. Erik Axelsson, Ingrid Ljungvall, Priyasma Bhoumik, Laura Bas Conn, Eva Muren, Åsa Ohlsson, Lisbeth Høier Olsen, Karolina Engdahl, Ragnvi Hagman, Jeanette Hanson, Dmytro Kryvokhyzha, Mats Pettersson, Olivier Grenet, Jonathan Moggs, Alberto Del Rio-Espinola, Christian Epe, Bruce Taillon, Nilesh Tawari, Shrinivas Mane, Troy Hawkins, Åke Hedhammar, Philippe Gruet, Jens Häggström, Kerstin Lindblad-Toh. PLoS Genet. September 2021; doi: 10.1371/journal.pgen.1009726. Quote: Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. ... Here we generate whole genome resequencing data from 20 individuals from each of eight common dog breeds to investigate if levels of mutational load differ between breeds. We estimate that dogs from the most heavily bottlenecked breed investigated here — cavalier King Charles spaniel (cKCs) — carry 6–13% more derived, potentially deleterious alleles, than other dog breeds investigated here at sites displaying high sequence conservation. This represents the first clear documentation of a continued accumulation of mutational load during dog breed formation indicating that the breeding process may have been associated with an increased overall disease burden. ... We have no simple explanation to this observation but speculate that the intensity and duration of the bottleneck(s) leading to breed formation may have been extreme in cKCs relative to in most other breeds. This hypothesis is consistent with previous array-based analyses in which cKCs rank among the ~10 least variable breeds out of 80 analysed and combinations of both long-range linkage disequilibrium and extensive runs of homozygosity in cKCs indicate that both older population contractions and recent inbreeding may indeed have been pronounced. ... We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heart-derived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity. ... NEBL encodes two proteins; i) a nebulin like protein (Nebulette) that is abundantly expressed in cardiac muscle where it binds to actin and interacts with thin filaments and Z-line associated proteins, and hence may be involved in cardiac myofibril assembly; and ii) LIM-nebulette coding for a widely expressed dynamic focal adhesion protein that has been shown to increase the rate of attachment and spreading of fibroblasts on fibronectin coated surfaces. ... We find that individuals belonging to the breed affected by the most intense breeding — cavalier King Charles spaniel (cKCs) — carry more harmful variants than other breeds, indicating that past breeding practices may have increased the overall levels of harmful genetic variation in dogs. The most common disease in cKCs is myxomatous mitral valve disease (MMVD). To identify variants linked to this disease we next characterize mutations that are common in cKCs, but rare in other breeds, and then investigate if these mutations can predict MMVD in dachshunds. We find that variants that regulate the expression of the gene NEBL in papillary muscles may increase the risk of the disease, indicating that loss of papillary muscle integrity could contribute to the development of MMVD. ... cKCs carry significantly fewer segregating sites and is less heterozygous than any of the other breeds, a pattern that is consistent across all categories of variants. In line with a more extreme bottleneck during the history of cKCs, linkage disequilibrium extends over longer distances and more regions are homozygous in cKCs relative to in other breeds. ... We have no simple explanation to this observation but speculate that the intensity and duration of the bottleneck(s) leading to breed formation may have been extreme in cKCs relative to in most other breeds. ... The accumulation of derived potentially deleterious alleles in cKCs reflects the consequences of processes that have been ongoing during the last 200–300 years of strictly controlled breeding, but that may have started earlier given that most breeds compared here belong to separate breed groups that likely started to diverge several hundred years earlier. ... Historical records suggest that small spaniel-type dogs have existed for at least 1,000 years and hint at a history involving serial bottlenecks. Small spaniels were popular at royal courts throughout Europe and Asia for several hundred years and the appearance of cKCs in particular is very similar to toy spaniels kept by the royal Stuart family (rulers of Scotland, England and Ireland), including King Charles II (1630–1685). Over time a brachycephalic variety of these spaniels became the dominating type, but eventually the old, more long-nosed type was restored by a small breeding initiative starting in the 1920’s. This rescued variety however suffered a serious decline in numbers during the second world war before becoming recognized as a breed of its own (cKCs) in 1945. ... We next hypothesized that one or several of the many high frequency-derived alleles in cKCs are likely to contribute to the exceptionally high risk of developing MMVD in this breed and asked whether the sequencing data generated here could be used to identify potential MMVD risk variants. ... To conclude, independent of the dominating effect of disease mutations, we demonstrate the first unequivocal example of an increase in mutational load as a consequence of dog breed formation. Although this effect is most evident in one of the most heavily bottlenecked breeds (cKCs) known, we find no simple relationship between overall levels of genetic variation and additive load among the eight breeds analysed here. ... In conclusion, we analysed eight dog breeds and identified an increased mutational load in the cKCs breed, which is highly bottlenecked. This breed has a high frequency of MMVD. Looking for derived alleles of high frequency specifically in this breed, we identified four highly conserved variants in protein coding genes that may relate to MMVD as well as several candidate regulatory variants near the NEBL gene. We find that some of these NEBL variants are associated with MMVD in dachshund and may be affecting gene expression in multiple relevant heart cell types and thus probably affect heart function. These results merit further validation in separate cohorts.

Influence of Morphometry on Echocardiographic Measurements in Cavalier King Charles Spaniels: An Inverse Probability Weighting Analysis. Mara Bagardi, Sara Ghilardi, Chiara Locatelli, Arianna Bionda, Michele Polli, Claudio M. Bussadori, Fabio M. Colombo, Laura Pazzagli, Paola G. Brambilla. Vet. Sci. September 2021; doi: 10.3390/vetsci8100205. Quote: The development and progression of myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS) are difficult to predict. Thus, the identification of dogs with a morphotype associated with more severe mitral disease at a young age is desirable. The aims of this study were to: (1) describe the physical, morphometric, and echocardiographic features of class B1 MMVD-affected Cavalier King Charles Spaniels (CKCS) according to the American College of Veterinary Internal Medicine (ACVIM) guidelines; (2) evaluate the influence of morphometric physical measurements on murmur intensity, mitral valve prolapse (MVP), regurgitant jet size, and indexed mitral valve and annulus measurements. Fifty-two MMVD-affected CKCS were included in the ACVIM class B1. ... To be included in the study, dogs must have had no evidence of left atrial and left ventricle enlargement, defined as a left atrial-to-aortic root ratio (LA/Ao) ≥ 1.6 on 2-dimensional echocardiography, and as leftventricular normalized dimensions in diastole (LVIDad) ≥ 1.7, respectively. ... [D]ogs younger than one year of age (n = 2) were also excluded. ... Clinical and echocardiographic examinations were completed by a specific morphometric evaluation that included the assessment of the ENCI standard coat color type (Blenheim, ruby, tricolor, and black and tan) and the measurement of the body, thorax, and head of each dog. All the morphometric measurements taken, as well as their reference points, are outlined in Table 1. Body size and cephalic, thoracic, and volume indexes were also calculated. ... This is a prospective clinical cross-sectional study. Morphometric measurements, which included the body, thorax, and head sizes of each dog, were investigated to establish the association with heart murmur intensity, valvular and annular echocardiographic measurements, MVP, and regurgitant jet size, using inverse probability weighting (IPW) analyses to adjust for confounding. ... In 26 dogs (50%), no murmurs were found. Soft murmurs (1) were present in 20 dogs (38.5%), whereas in 6 dogs (11.5%) the murmurs were of moderate/loud intensity (2). With reference to the 26 dogs with undetectable murmurs, 25 had MVP (19 mild and 6 moderate) and 19 had MR (13 trivial, 3 trace, and 3 mild). Of these 26 subjects, 18 dogs presented with MVP and MR, 1 had MR only, and 7 had MVP only. However, 51 (98.1%) of the 52 subjects included had MVP. The sphericity index was lower than 1.65 in 48 (92.3%) subjects. ... The identification of the phenotypic characteristics associated with more severe forms of MMVD could be useful for establishing breeding selection programs aimed at reducing the prevalence of the disease in this breed. ... The authors observed that subjects with a shorter head are more likely to have a higher jet size. Furthermore, subjects with a shorter body and nose length have a greater heart-murmur intensity. Thus, given all the results discussed, CKCS that have a shorter nose and head, and a more barrel-shaped thorax, are likely to have valvular characteristics related to more severe forms of MMVD than are those dogs with longer and narrower skulls and bodies. According to these results, the breeding of subjects with a cranial morphology tending toward brachycephalism (wider and shorter head) may be counterproductive in view of the selected reproduction for MMVD, although additional studies are needed to confirm the authors’ findings. ... In the CKCS included in the present study, MVP had an epidemiology resembling that known for MVP in humans and dachshunds. In fact, MVP severity was significantly positively associated with measures of the degree of MMVD (e.g., jet size, leaflet length, and murmur intensity). ... In particular, the most interesting result obtained is that subjects with a shorter head were associated with a higher jet size, while subjects with a shorter body and nose length had a greater heart murmur intensity. Regarding mitral valve and mitral annulus measurements, subjects with a more barrel-shaped thorax and a shorter nose had shorter and thicker anterior mitral valve leaflets and a greater mitral valve annulus in the systole and diastole. This suggests that a brachycephalic morphotype, with dogs that are much more similar to the King Charles Spaniel breed regarding cephalic morphology, is correlated with a more severe jet size and with valvular characteristics related to more severe forms of MMVD; this may be counterproductive in view of the selected reproduction for MMVD.

The effect of treatment with pimobendan in dogs with preclinical mitral valve disease – a placebo-controlled double-blinded crossover study. Stephanie Klein, Ingo Nolte, Katja Rumstedt, Maximiliane Sehn, Jonathan Friedemann Raue, Franziska Weiner, Julia Sophie Treese, Martin Beyerbach, Jan-Peter Bach. BMC Vet. Res. September 2021; doi: 10.1186/s12917-021-03014-5. Quote: Background: Pimobendan is a widely used medication for the treatment of dogs with congestive heart failure (CHF) and preclinical degenerative mitral valve disease (DMVD) with cardiomegaly. The benefit of a treatment in dogs with preclinical DMVD but without cardiomegaly has not yet been elucidated. Some positive effects concerning life quality and a decrease in cardiac biomarkers could be verified. This study aimed to further investigate these results using a placebo-controlled double-blinded crossover design. Out of a total of 15 dogs, eight were allocated to sequence-group AB, in which dogs received pimobendan (A) during the first treatment period and placebo (B) during the second period. Accordingly, sequence-group BA was treated first with placebo followed by pimobendan. Each treatment period lasted six months and included a baseline investigation and follow-ups after 90 and 180 days. The investigations included a questionnaire completed by the owners, echocardiographic examination, and measurements of NT-proBNP, cTnI and lactate before and after a standardised submaximal exercise test. Results: NT-proBNP values decreased significantly during the treatment period with pimobendan, and the postexercise increase was attenuated at day 180. No significant treatment effects could be verified for cTnI and lactate, neither pre- nor post-exercise. Left ventricular size decreased under treatment, whereas no significant changes in left atrial size were detected. The owners described their dogs under treatment with pimobendan as being more active at day 90 (11/15) and day 180 (12/15). Those animals treated with placebo were described as being more active at day 90 (2/15) and day 180 (5/15). Conclusions: Pimobendan had reducing effects on the concentrations of pre- and post-exercise cardiac biomarkers and the size of the left ventricle in dogs with DMVD ACVIM B1. Exercise testing in addition to an assessment of cardiac biomarkers might improve the decision when to initiate pimobendan treatment in dogs with DMVD.

Plasmatic Dimethylarginines in Dogs With Myxomatous Mitral Valve Disease. Carlotta Valente, Carlo Guglielmini, Marco Baron Toaldo, Giovanni Romito,Carlo Artusi, Laura Brugnolo, Barbara Contiero, Helen Poser. Front. Vet. Sci. September 2021; doi: 10.3389/fvets.2021.738898. Quote: Plasmatic dimethylarginines, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are considered biomarkers of endothelial and renal dysfunction, respectively, in humans. We hypothesize that plasmatic concentration of dimethylarginines in dogs with myxomatous mitral valve disease (MMVD) is influenced by heart disease stage. Eighty-five client-owned dogs with MMVD [including 9 (9.3%) Cavalier King Charles Spaniels], including 39, 19, and 27 dogs in ACVIM stages B1 [6 (15.4%) CKCSs], B2 [3 (15.8%) CKCSs], and C+D, respectively, and a control group of 11 clinically healthy dogs were enrolled. A prospective, multicentric, case-control study was performed. Each dog underwent a complete clinical examination, arterial blood pressure measurement, thoracic radiography, six-lead standard electrocardiogram, transthoracic echocardiography, CBC, biochemical profile, and urinalysis. Plasmatic concentration of dimethylarginines was determined through high-performance liquid chromatography coupled with tandem mass spectrometry. Median ADMA was significantly increased in dogs of group C+D (2.5 μmol/L [2.1–3.0]) compared to those of group B1 (1.8 μmol/L [1.6–2.3]) and healthy dogs (1.9 μmol/L [1.7–2.3]). Median SDMA was significantly increased in dogs of group C+D (0.7 μmol/L [0.5–0.9]) compared to those of groups B1 (0.4 μmol/L [0.3–0.5]), B2 (0.4 μmol/L [0.3–0.6]), and the control group (0.4 μmol/L [0.35–0.45]). ... The L-arginine/ADMA was significantly lower in dogs with decompensated MMVD compared to those of group B1 and clinically healthy controls. This finding is in contrast with the results of a previous study in which no significant difference was found for L-arginine/ADMA in 43 Cavalier King Charles Spaniels with MMVD at various stages, classified according to a mitral regurgitation quantitative score. However, that study found decreased flow mediated dilation, a reference diagnostic method to identify endothelial dysfunction in humans. Different results from this study and that of Moesgaard et al. are likely due to differences in number and type of enrolled dogs, various breeds vs. a unique breed, and method of MMVD classification. ... Based on a previous study, ADMA could be influenced by breed. Specifically, in that study, Pointers showed increased concentrations of ADMA compared to Cairn Terriers and Cavalier King Charles Spaniels. However, it should also be noted that ADMA concentrations were evaluated exclusively in healthy dogs and only in the three aforesaid breeds. Of note, no Pointer was included in our study. Therefore, further data are needed to conclusively clarify a potential breed effect on ADMA concentration. In the final multivariable analysis, ADMA and SDMA were significantly associated with left atrium to aorta ratio, and creatinine, respectively. Increased plasmatic concentrations of dimethylarginines suggest a possible role as biomarkers of disease severity in dogs with decompensated MMVD.

Polymorphisms in the serotonin transporter gene and circulating concentrations of neurotransmitters in Cavalier King Charles Spaniels with myxomatous mitral valve disease. Maria J. Reimann, Merete Fredholm, Signe E. Cremer, Liselotte B. Christiansen, Kathryn M. Meurs, Jacob E. Møller, Jens Häggström, Jens Lykkesfeldt, Lisbeth H. Olsen. J. Vet. Intern. Med. October 2021; doi: 10.1111/jvim.16277. Quote: Background: The neurotransmitter serotonin (5-HT) affects valvular degeneration and dogs with myxomatous mitral valve disease (MMVD) exhibit alterations in 5-HT signaling. In Maltese dogs, 3 single nucleotide polymorphisms (SNPs) in the 5-HT transporter (SERT) gene are suggested to associate with MMVD. Hypothesis/Objectives: ... The aim of the present study was to take such an approach in Cavalier King Charles Spaniels (CKCS) and to investigate if SERT polymorphisms previously identified in Maltese dogs arepresent and associated with serum 5-HT concentration, MMVD severity or both. ... Additionally, investigate the association between selected clinical and hematologic variables and serum 5-HT and assess the correlation between HPLC and ELISA measurements of serum 5-HT. Animals: Seventy-one CKCS (42 females and 29 males; 7.8 [4.7;9.9] years (median [Q1;Q3])) in different MMVD stages. ... Severity of MMVD was classified as MMVD stages modified from American College of Veterinary Internal Medicine consensus statement guidelines as follows: stage A modified (stage Am), CKCS with no auscultatory heart murmur and no or minimal MR (MR <20%); stage B1, CKCS with auscultatory heart murmur or MR ≥20% and echocardiographic evidence of MMVD but no cardiac enlargement; stage B2, CKCS with current or previous echocardiographic evidence of cardiac enlargement but no current or previous clinical signs of CHF; stage C, CKCS with CHF. Thus, the MMVD stage Am included dogs with mild structural disorder of the heart (MR <20%) because such minimal MRs have been demonstrated not necessarily to have clinical or prognostic significance for MMVD in CKCS. Cardiac enlargement was defined as LA/Ao ≥1.6 and left ventricular end-diastolic diameter normalized to bodyweight ≥1.7. In addition to presence of MR, the diagnosis of MMVD was based on the presence of mitral valve thickening, prolapse or both. The diagnosis of CHF was based on a history of MMVD, previous or current clinical signs of CHF (eg, cough, dyspnea, tachypnea, nocturnal restlessness, and exercise intolerance), echocardiographic changes compatible with severe MMVD and response to diuretic treatment. Thoracic radiographs were not included in the examination. ... The final population of 71 CKCS were allocated to the following MMVD stages: stage Am (n = 19), stage B1 (n = 22), stage B2 (n = 17) and stage C (n = 13). Three CKCS (MMVD stage C: n = 1; MMVD stage B2: n = 2) treated with pimobendan were classified as having cardiac enlargement despite having LA/Ao < 1.6, LVIDDN <1.7 or both because it had been demonstrated at previous echocardiographic examinations before onset of cardiac therapy. ... Methods: This prospective study used TaqMan genotyping assays to assess SERT gene polymorphisms. Neurotransmitter concentrations were assessed by HPLC and ELISA. Results: TaqMan analyses identified none of the selected SERT polymorphisms in any of the CKCS examined. Serum 5-HT was associated with platelet count (P < .001) but not MMVD severity, age or medical therapy and did not correlate with serum concentration of the 5-HT metabolite, 5-hydroxyindoleacetic acid. The ELISA serum 5-HT correlated with HPLC measurements (ρ = .87; P < .0001) but was lower (mean difference = −22 ng/mL; P = .02) independent of serum 5-HT concentration (P = .2). Conclusions and Clinical Importance: Selected SERT SNPs associated with MMVD in Maltese dogs were not found in CKCS and only platelet count influenced serum 5-HT concentration. These SNPs are unlikely to be associated with MMVD pathophysiology or serum 5-HT concentration in CKCS. HPLC and ELISA serum 5-HT demonstrated good correlation but ELISA systematically underestimated 5-HT.

The Instability of the Lipid-Soluble Antioxidant Ubiquinol: Part 2–Dog Studies. William V. Judy. Integrative Med. October 2021;20(5):26-30. Quote: Background: Coenzyme Q10 is one of the most widely sold nutritional supplements in the United States. Coenzyme Q10 is available in both its oxidized form (ubiquinone) and its reduced form (ubiquinol). The predominant marketing of Coenzyme Q10 to physicians and patients asserts that the ubiquinol form of Coenzyme Q10 has superior absorption to the ubiquinone form. This study has been designed to compare and contrast the stability and absorption of ubiquinol supplements, as well as the claims made for ubiquinol compared with ubiquinone. Ubiquinol, the reduced state of Coenzyme Q10, is commercially available as a nutritional supplement; however, ubiquinol, by its nature as an electron donor, is much less stable than ubiquinone, the oxidized state of Coenzyme Q10. The absorption, bioavailability and efficacy of ubiquinol products has been much less often tested in clinical trials. Consequently, insufficiently documented marketing claims are being made for ubiquinol supplements. Methods: In Part 1 of this report on the instability of the lipid-soluble antioxidant ubiquinol, SIBR Research presented data from lab studies showing that oral ubiquinol is likely to be oxidized to ubiquinone and absorbed as ubiquinone. In this Part 2, SIBR Research conducted a study of the transfer and absorption of orally ingested ubiquinol in large dogs. Results: In the dog studies, the percentage of ubiquinol converted to ubiquinone increased as the capsule contents passed through the stomach and small intestines and into the lymph system. Conclusions: The dog studies demonstrate that oral ubiquinol in commercial nutritional supplements is not stable in the gastrointestinal tract of large dogs. Based on these results, it seems likely that in humans also, most of the ubiquinol from capsules will be oxidized to ubiquinone in the acid profile between the stomach and the small intestines, where there is a wide range of acidity. The ubiquinol from the supplement will be absorbed in the ubiquinone state and will pass into the lymph system as ubiquinone, where it will be reduced back to ubiquinol. It will pass from the lymph system into the blood circulation as ubiquinol. ... The in vitro studies reported in Part 1 of this article showed that between 76% and 84% of the ubiquinol in 13 commercially-available ubiquinol supplements is oxidized to ubiquinone in pH solutions, simulating the pH in the stomach and in the small intestines. The low pH in the gastric juice is characterized by the presence of many free hydrogen ions, and the somewhat elevated pH in the small intestines is characterized by the presence of many free hydroxyl ions. Ubiquinol acts as an electron donor in the gastric and small intestine juices; accordingly, the ubiquinol from supplement capsules is converted to ubiquinone, the oxidized form of Coenzyme Q10. In the dog study, the measurements of the relative percentages of ubiquinol and ubiquinone at various stages show that the ingested ubiquinol is largely oxidized to ubiquinone before it reaches the enterocytes. When it passes from the enterocytes into the lymph system, it is converted back to ubiquinol, and it is predominantly as ubiquinol that it enters the blood circulation.

Prognostic value of left ventricular-arterial coupling estimated using echocardiography in dogs with myxomatous mitral valve disease. Tatsuyuki Osuga, Tomoya Morita, Noboru Sasaki, Keitaro Morishita, Hiroshi Ohta, Mitsuyoshi Takiguchi. J. Vet. Intern. Med. November 2021; doi: 10.1111/jvim.16290. Quote: Background: The interaction between the left ventricle (LV) and systemic arterial systems, known as left ventricular-arterial coupling (VAC), has been evaluated based on the effective arterial elastance (Ea) to LV end-systolic elastance (Ees) ratio (Ea/Ees). The Ea reflects the total arterial load of LV, whereas Ees reflects the LV systolic function. A recent study found that inappropriate VAC based on increased Ea/Ees estimated by echocardiography is associated with advanced disease severity in dogs with myxomatous mitral valve disease (MMVD). Hypothesis: Inappropriate VAC assessed by echocardiographic estimation of Ea/Ees is associated with a worse prognosis in dogs with MMVD. Animals: Eighty-nine dogs with MMVD ... including 35 dogs in stage B1, 30 dogs in stage B2, and 24 dogs in stage C, were enrolled in the study. ... The most commonly represented breed was Chihuahua (n = 27), followed by Pomeranian (n = 9), Toy Poodle (n = 8), Cavalier King Charles Spaniel (n = 8), Maltese (n = 7), Miniature Dachshund (n = 6), and Shih tzu (n = 6).. Methods: Prospective cohort study. Dogs underwent echocardiographic examinations at enrollment. The Ea was estimated using the formula: mean blood pressure/(forward stroke volume/body weight). The Ees was estimated using the formula: mean blood pressure/(LV end-systolic volume/body weight). The Ea/Ees was calculated. Results: By end of study, 22 dogs died of cardiac-related causes with 67 dogs censored. Dogs with increased Ea/Ees (Ea/Ees >0.34; median survival time, 527 days; 95% confidence interval [CI], 322 days-not determinable) had a shorter survival time (P < .0001) than those without increased Ea/Ees (Ea/Ees ≤0.34; median survival time, >1112 days; 95% CI, not determinable). Multivariate Cox proportional hazard analysis showed that Ea/Ees, body weight, peak systolic mitral annular velocity, and the peak early diastolic transmitral velocity-to-peak early diastolic mitral annular velocity ratio were independent predictors of cardiac-related death among echocardiographic indices. Conclusions and Clinical Importance: Inappropriate VAC assessed based on echocardiographically-estimated Ea/Ees is associated with a worse prognosis in dogs with MMVD.

Circulating miRNAs as potential biomarkers of early myxomatous mitral valve disease in Cavalier King Charles Spaniels. M. Bagardi, S. Ghilardi, V. Zamarian, C. Locatelli, A. Galizzi, G. S. Cozzoli, C. Lecchi, P. G. Brambilla. ESVC-O-1. J. Vet. Intern. Med. November 2021; doi: 10.1111/jvim.16289. Quote: MicroRNAs (miRNAs) are small non-coding RNAs, identified as posttranscriptional regulators of gene expression, both in physiologic and pathologic conditions that meet diagnostic and prognostic expectancies as biomarkers of MMVD. In this study, we quantified the expression of 5 circulating miRNAs as being involved in MMVD in the plasma (left-over samples) of CKCS classified as ACVIM classes A (healthy) and B1 (affected by MMVD, asymptomatic and without cardiac remodelling). Forty-four CKCS were included in the study: 11 A, 11 B1 younger than 3 years, 11 B1 between 3 and 7 years, and 11 B1 older than 7 years. ... The comparative analysis demonstrated that the concentrations of circulating miR128-3p and miR-30b were significantly greater in B1<3y and B1>7y as compared with A. The age of the subjects did not affect miRNAs' expression. ROC curves showed that miR-30b and miR-128-3p can discriminate between A and B1 under 3 years CKCS, and between A and B1 over 7 years CKCS. Combining two miRNAs, namely miR-30b and miR- 128-3p, in a panel increased the efficiency of distinguishing between A and B1 over 7 years CKCS. The expression of miR-30b and miR-128-3p allows to discriminate ACVIM A and young B1 (< 3 years) CKCS, in most cases without heart murmurs. These miRNAs may be candidates as novel biomarkers in the disease characterization and may provide the basis for further investigations in the follow-up of the examined subjects, aimed to the characterization of the evolution of the disease in the CKCS.

Use of physical examination, electrocardiography, radiography and biomarkers to predict stage B2 myxomatous mitral valve disease in preclinical Cavalier King Charles Spaniels. S. Wesselowski, S. Gordon, A. Saunders, R. C. Fries, K. T. Sykes, J. Vitt, B. Boutet, S. Kadotani, J. Stack, J. Häggström. ESVC-O-2. J. Vet. Intern. Med. November 2021; doi: 10.1111/jvim.16289. Quote: The objective of this study was to develop predictive models to identify the best combination of history, physical examination and diagnostic tests to predict ACVIM Stage B2 MMVD in the absence of an echocardiogram in CKCS [Cavakier King Charles Spaniels]. Two-hundred and thirty [230] preclinical CKCS were prospectively enrolled. Dogs were staged by echocardiography using 2019 ACVIM MMVD consensus guidelines. Dogs underwent: physical examination, right lateral thoracic radiograph with vertebral heart size and left atrial size measurements (VHS, VLAS), systemic blood pressure measurement, 30-second electrocardiogram (ECG), and blood sampling to assess N-terminal pro B-type natriuretic peptide (NTproBNP), ultrasensitive cardiac troponin I, and a renal panel including symmetric dimethylarginine (SDMA). There were 185(80.4%) CKCS in Stage A or B1 and 45(19.6%) in stage B2. ... Six variables were retained in the final model including (in order of significance): NTproBNP, VHS, P+QRS duration, murmur grade, ECG average heart rate. ... Discriminatory ability to identify Stage B2 was improved using variables derived from a combination of diagnostics compared to any variable alone. 

Platelet aggregation response to pimobendan in Cavalier King Charles Spaniels with myxomatous mitral valve disease. M. J. Reimann, D. N. Faisst, M. Knold, K. Meurs, S. E. Cremer, J. E. Møller, I. Ljungvall, J. Häggström, L. H. Olsen. ESVC-O-19. J. Vet. Intern. Med. November 2021; doi: 10.1111/jvim.16289. Quote: Pimobendan is recommended for treatment of certain stages of canine myxomatous mitral valve disease (MMVD). The beneficial effect of pimobendan is mainly thought to be a result of the inotropic and vasodilatory properties. Interestingly, at high concentrations, an inhibitory effect on canine blood platelets has been described ex vivo using whole blood impedance aggregometry and thromboelastography. This study aimed to determine the ex vivo effect of pimobendan on adenosine diphosphate (ADP)-induced platelet aggregation response at therapeutic (0.03μM [micromolars -- one millionth of a molar, a substance concentration measurement) and high (10μM) concentrations using optical aggregometry; considered gold standard for platelet function assessment. Secondary aims were to investigate if the effect of pimobendan on platelets was influenced by age, sex, severity of MMVD, haematocrit and platelet count. A total of 41 privately-owned Cavalier King Charles Spaniels (CKCS) were prospectively enrolled and grouped based on ACVIM consensus guidelines: Stage A (n=9), stage B1 (n=22) and stage B2 (n=10). None of the dogs received cardiac treatment. Aggregation response was assessed in platelet rich plasma using optical aggregometry. Area under the curve (AUC), maximal aggregation (Amax) and aggregation velocity (Vel) were included as measures of platelet aggregation response. Pimobendan significantly inhibited platelet aggregation response (AUC, Amax and Vel) at a concentration of 10 μM but not at 0.03 μM. Age but not sex, severity of MMVD, haematocrit or platelet count was associated with the effect of pimobendan. In conclusion, this study confirmed an inhibitory effect of pimobendan at a high concentration on platelets in CKCS, but not at the therapeutic concentration. The effect of pimobendan was influenced by age only. Further studies are warranted to determine the platelet effects of the active pimobendan metabolite (UD-CG 212), a more potent phosphodiesterase inhibitor, in dogs.

Presumptive and reversible left ventricular systolic dysfunction secondary to chloramphenicol administration in a dog. Sarah E. Hoff, Allison K. Masters, Melissa A. Tropf, James O. Noxon, Darren J. Berger. Vet. Rec. November 2021; doi: 10.1002/vrc2.228. Quote: A 6-year-old neutered male 35 kg Staffordshire terrier dog was presented for evaluation of interdigital furunculosis. Culture from lesions revealed meticillin-resistant Staphylococcus pseudintermedius, with susceptibility to only amikacin, chloramphenicol and vancomycin. Chloramphenicol was administered at a dose of 1500 mg per os (PO) q8h (42 mg/kg) for a total of 52 days. On Day 52 of treatment, a new mid-systolic click was appreciated on cardiothoracic auscultation that prompted cardiac evaluation. Echocardiogram revealed mild mitral valve prolapse with no mitral valve regurgitation and mild left ventricular systolic dysfunction in multiple indices. [LVIDdN = 1.23.] Chloramphenicol was discontinued, and a recheck echocardiogram performed 63 days later showed persistent mild mitral valve prolapse and resolution of the left ventricular systolic dysfunction. [LVIDdN = 1.29.] Reversible left ventricular systolic dysfunction should be considered a potential complication associated with chloramphenicol therapy, and suggests chloramphenicol may need to be used with caution in canine patients with underlying cardiac disease.

Breed-specific vertebral heart score, vertebral left atrial size, and radiographic left atrial dimension in Cavalier King Charles Spaniels: Reference interval study. Mara Bagardi, Chiara Locatelli, Martina Manfredi, Jessica Bassi, Carlotta Spediacci, Sara Ghilardi, Davide D. Zani, Paola G. Brambilla. Vet. Radiol. Ultrasound. November 2021; doi: 10.1111/vru.13036. Quote: Cavalier King Charles Spaniels (CKCS) are predisposed to developing myxomatous mitral valve disease (MMVD), with radiographs frequently used to screen for evidence of left-sided cardiomegaly secondary to MMVD. Vertebral heart size (VHS), vertebral left atrial size (VLAS), modified VLAS (M-VLAS), and radiographic left atrial dimension (RLAD) are reported as objective measurements of global heart size and left atrial size. Normal VHS in CKCS (10.6 ± 0.5) is reportedly higher than the non-breed-specific value (9.7±0.5). Breed-specific VLAS, M-VLAS, and RLAD cut-offs have not been reported in CKCS. The aim of this prospective reference interval study was to describe the VHS, VLAS, M-VLAS, and RLAD values for 30 clinically healthy adult CKCS. Inclusion criteria were unremarkable physical examination, normal echocardiography, and thoracic radiographs without malposition/ abnormalities. There were 22 female and eight male dogs. Ages ranged from 1 to 6 years. The VHS mean value in our sample was 10.08 ± 0.56 (95% range, 9.87-10.29). This was significantly greater than a previously published general canine reference value of 9.7 ± 0.5 and significantly less than a previously published CKCS breed-specific value of 10.6 ± 0.5. Mean VLAS, M-VLAS, and the RLAD values in our study were 1.79 ± 0.3 (95% range, 1.68-1.9), 2.23 ± 0.44 (95% range, 2.06-2.39), and 1.2 ± 0.34 (95% range, 1.07-1.33), respectively. These were significantly less than previously published reference interval values. The VHS, M-VLAS, and the RLAD were not affected by sex, body weight, or BCS; whereas the VLAS was moderately affected by body weight. ... Overall population LA/Ao_Sx: 1.20 ± 0.17, Females 1.22 ± 0.16, Males 1.07 ± 0.11. Overall population LVIDDN 1.30 ± 0.16, Females 1.28 ± 0.16, Males 1.33 ± 0.18. ... Findings from this study can be used as background for future thoracic radiographic assessments in CKCS.

Dobutamine infusion without pericardiocentesis as a treatment for cardiac tamponade due to left atrial rupture in a dog. Noriko Isayama, Yusuke Uchimura, Erika Maeda. Vet. Rec. November 2021; doi: 10.1002/vrc2.237. Quote: We describe the successful management of an obstructive shock case caused by cardiac tamponade following atrial rupture. The dog was an 11-year-old female chihuahua with a 1-year history of mitral valve insufficiency. During a radiographic examination, the dog collapsed. We diagnosed a case of obstructive shock caused by cardiac tamponadefollowing left atrial rupture, secondary to mitral valve regurgitation. After administration of atropine and dobutamine, the blood pressure stabilised. The dog regained consciousness and was discharged 96 hours post collapse. The use of dobutamine should be considered in selected obstructive shock cases and may reduce the high mortality rate associated with atrial rupture.

Assessment of heart rate turbulence in dogs with myxomatous mitral valve disease. Julio P. dos Santos, Stephany B. Lucina, Bruna N. da Costa, Karla L. C. Olaguivel, Giovana L. R. Tuleski, Marlos G. Sousa. Open Vet. J. November 2021; doi: 10.5455/OVJ.2021.v11.i4.13. Quote: Background: Myxomatous mitral valve degeneration (MMVD) is the most common heart disease affecting small dogs, it reduces cardiac output resulting in compensatory adaptation of the autonomic nervous system. Chronically it leads to reduced heart rate variability (HRV) which is an accurate marker for autonomic balance. More than two decades ago in human medicine an indicator of autonomic balance that happens after a premature ventricular beat, it was described as heart rate turbulence (HRT). In humans with ischaemic heart disease the absence of HRT has proven to be a more accurate and an independent indicator of mortality than known HRV parameters. Currently there are very few studies of HRT in dogs and it is still not tested in small dogs within different stages of myxomatous mitral valve disease. Aim: The aim of this study was to assess the HRT indicators, onset and slope, in small dogs with myxomatous mitral valve disease and to statistically test it. Methods: Dogs under 25 kg had electrocardiogram and echocardiography performed and, in some patients, holter monitoring was carried out. Data was divided into groups B1, B2, C and D for mean comparison with ANOVA and Tukey test. In addition, Receiver Operating Characteristic (ROC) curve for differentiating among symptomatic and asymptomatic dogs and for differentiating between remodeled and non-remodeled hearts. The Pearson was executed after correlations of turbulence onset (TO) and turbulence slope (TS) with commonly used echocardiographic parameters. Results: Variance analyses held significant differences in TO and TS between stages B1 from stages C and D, while B2 held similarity to the other groups. In the Receiver Operating Curve(ROC) was found a very good AUC for differentiating among symptomatic and asymptomatic dogs and remodeled and non-remodeled dogs. Few echocardiography parameters held weak correlation with TO while others held weak to moderate correlation with TS. Conclusion: In dogs with MMVD and without other diseases, heart rate turbulence is a feasible indicator for autonomic balance. Our result suggests HRT changes as the MMVD progresses and CHF is present. More studies with HRT are needed. The number of VPCs may be the strongest limitation for the technique.

Angiotensin-converting enzyme inhibitors in preclinical myxomatous mitral valve disease in dogs: systematic review and meta-analysis. P. Donati, A. Tarducci, R. Zanatta, N. Verdier, G. Belerenian, I. Cordero, C. Villalta, J. Franco, L. Tarragona. J. Sm. Anim. Pract. December 2021; doi: 10.1111/jsap.13461. Quote: To determine the efficacy and adverse events of the administration of angiotensin-converting enzyme inhibitors for the management of preclinical myxomatous mitral valve disease in dogs. A comprehensive search using Pubmed/MEDLINE, LILACS and CAB abstracts databases was performed. Randomised clinical trials that assessed efficacy and adverse events of angiotensin-converting enzyme inhibitors for the management of preclinical myxomatous mitral valve disease in dogs were included. Certainty of evidence was rated using GRADE methods. Four randomised clinical trials were included. While safe, angiotensin-converting enzyme inhibitors administration to dogs with myxomatous mitral valve disease and cardiomegaly results in little to no difference in the risk of development congestive heart failure (high certainty of evidence; relative risk: 1.03; 95% confidence interval: 0.87 to 1.23) and may result in little to no difference in cardiovascular-related (low certainty of evidence; relative risk: 1.01; 95% confidence interval: 0.54 to 1.89) and all-cause mortality (low certainty of evidence; relative risk: 0.93; 95% confidence interval: 0.63 to 1.36). Administration of angiotensin-converting enzyme inhibitors to dogs with myxomatous mitral valve disease without cardiomegaly may result in a reduced risk of congestive heart failure development. However, the range in which the actual effect for this outcome may be, the “margin of error,” indicates it might also increase the risk of congestive heart failure development (low certainty of evidence; relative risk: 0.86; 95% confidence interval: 0.54 to 1.35). Administration of angiotensin-converting enzyme inhibitors to dogs with preclinical myxomatous mitral valve disease and cardiomegaly results in little to no difference in the risk of the development of congestive heart failure and may result in little to no difference in cardiovascular-related and all-cause mortality. The certainty of evidence of the efficacy of angiotensin-converting enzyme inhibitors administration to dogs without cardiomegaly was low.

The Instability of the Lipid-Soluble Antioxidant Ubiquinol: Part 3 - Misleading Marketing Claims. William V Judy. Integr. Med. December 2021;20(6):24-28. Quote: Background: A lack of understanding of the processes involved in the absorption and transfer of the ubiquinol form of Coenzyme Q10 has led to a situation in which incorrect marketing claims are being made for the absorption of ubiquinol supplements, possibly misleading physicians and patients in the selection of a Coenzyme Q10 supplement for heart health benefits. In clinical trials, the ubiquinone form of Coenzyme Q10 has been associated with significantly improved symptoms and survival in patients with heart failure and significantly improved heart function and reduced cardiovascular mortality in community-living senior citizens. The ubiquinone form is the more stable and more extensively researched form. The ubiquinol form is unstable by virtue of being an electron donor that is easily oxidized to the ubiquinone form. Nevertheless, insufficiently documented marketing claims are being made for ubiquinol supplements. Methods: To investigate whether or not oral ubiquinol from supplements is absorbed in the ubiquinol form or ubiquinone form, our labs conducted 2 studies of the instability of ubiquinol supplements: a lab study of 13 ubiquinol products sold in the United States and an in vivo study of ubiquinol absorption in large dogs. Results: In the lab study, 76% to 84% of the oral ubiquinol in the nutritional supplements was oxidized to ubiquinone at body temperature in an 8.2 pH solution simulating small intestinal juice. That is to say, much of the oral ubiquinol had been converted to ubiquinone in the sort of pH environment that it would encounter prior to absorption. In a similar fashion, the percentage of ubiquinol converted to ubiquinone increased as the capsule contents passed through the stomach and small intestines of the study dogs. Conclusions: Based on the data from the lab study and the large dog study, we concluded that ubiquinol in commercial nutritional supplements will most likely be oxidized to ubiquinone before it reaches the absorption cells and that the Coenzyme Q10 in the ubiquinol supplements will be absorbed predominantly in the ubiquinone state, transfer into the lymph nodes predominantly in the ubiquinone state and be reduced back to ubiquinol in the lymphatic system.

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2022

Cardiovascular Disease in Companion Animals Dog, Cat and Horse, 2d ed. Wendy A. Ware , John D. Bonagura. CRC Press. January 2022.

Management of Chronic Congestive Heart Failure Caused by Myxomatous Mitral Valve Disease in Dogs: A Narrative Review from 1970 to 2020. Mara Bagardi, Viola Zamboni, Chiara Locatelli, Alberto Galizzi, Sara Ghilardi, Paola G. Brambilla. Animals. 2022; doi: 10.3390/ani12020209. Quote: The treatment of chronic congestive heart failure (CHF), secondary to myxomatous mitral valve disease (MMVD) in dogs, has considerably changed in the last fifty years. An analysis of the literature concerning the therapy of chronic CHF in dogs affected by MMVD is not available, and it is needed. Narrative reviews (NRs) are aimed at identifying and summarizing what has been previously published, avoiding duplications, and seeking new study areas that have not yet been addressed. The most accessible open-access databases, PubMed, Embase, and Google Scholar, were chosen, and the searching time frame was set in five decades, from 1970 to 2020. The 384 selected studies were classified into categories depending on the aim of the study, the population target, the pathogenesis of MMVD (natural/induced), and the resulting CHF. Over the years, the types of studies have increased considerably in veterinary medicine. In particular, there have been 43 (24.29%) clinical trials, 41 (23.16%) randomized controlled trials, 10 (5.65%) cross-over trials, 40 (22.60%) reviews, 5 (2.82%) comparative studies, 17 (9.60%) case-control studies, 2 (1.13%) cohort studies, 2 (1.13%) experimental studies, 2 (1.13%) questionnaires, 6 (3.40%) case-reports, 7 (3,95%) retrospective studies, and 2 (1,13%) guidelines. The experimental studies on dogs with an induced form of the disease were less numerous (49–27.68%) than the studies on dogs affected by spontaneous MMVD (128–72.32%). The therapy of chronic CHF in dogs has considerably changed in the last fifty years: in the last century, some of the currently prescribed drugs did not exist yet, while others had different indications.

Successful mitral repair in dogs by mitral annuloplasty using Hegar dilator: two case reports. Won-Jong Lee, Junyoung Kim, Chang-Hwan Moon, TaeHeum Eom, DongJu Son, Seungmin Lee, Haebeom Lee, Seong-Mok Jeong, Dae-Hyun Kim. J. Vet, Sci. January 2022; doi: 10.4142/jvs.21192. Quote: Mitral regurgitation (MR) is the most common heart disease in small-breed dogs. Mitral repair, which comprise artificial chorda tendineae implantation and mitral annuloplasty, has become the mainstay of treatment in the veterinary field.  We report on two small dogs [Maltese] who underwent mitral repair surgery for MR. A Hegar dilator was used during mitral annuloplasty for accurate and reproducible surgery. In both cases, mitral regurgitant flow almost disappeared after surgery, and clinical signs improved. The treatment regimen was terminated 3 months after the surgery. We concluded that using a Hegar dilator may facilitate mitral valve repair surgery.

Unusual case of pleural effusion caused by amlodipine in a dog with systemic hypertension. Hee-Won Jang, Su-Min Park, Seo-young Hwang, Kyuyong Kang, Mincheol Choi, Ju-Hyun An, Hyung-Kyu Chae, Ye-In Oh, Hwa-Young Youn. J. Vet. Intern. Med. February 2022; doi: 10.1002/vms3.727. Quote: Objective: The aim of this report is to document the case of a dog that developed pleural effusion as a potential side-effect to the administration of a high-dose of amlodipine. Case summary: A Yorkshire terrier dog (13-year-old, castrated male, 4.5 kg) presented with severe systemic hypertension (>200 mmHg), hyperkalaemia, and acute pancreatitis. The dog had hyperadrenocorticism [Cusing's disease], chronic valvular heart disease [myxomatous mitral valve degeneration ACVIM stage B1 with a heart murmur (grade 4/6)], chronic kidney disease [IRIS stage 2], and cerebellar infarction as underlying diseases. Additionally, the dog had laboured breathing and tachypnoea during hospitalization. Screening examinations revealed a pleural effusion [build-up of excess fluid between the layers of the pleura outside the lungs] (pure transudate) for which hypoalbuminemia and thromboembolismwere ruled out as the causes. ... [O]n day 11 ... the dose of amlodipine was reduced from 0.4 mg/kg PO q12h to 0.3 mg/kg PO q12h. Twenty-four hours after reducing the dose of amlodipine, laboured breathing was not observed. On day 16, pleural effusion was not identified on thoracic radiographs despite continuing the reduced dose of amlodipine. Thoracic radiography was rechecked on day 23, and pleural effusion was still not found. Therefore, the cause of the pleural effusion was suspected to be an adverse drug event in response to amlodipine. ... Conclusions: Pleural effusion resolved within 24 h of reducing the dosage of amlodipine. Hence, the dog was diagnosed with amlodipine-induced pleural effusion. ... This is the first report of suspected high dose amlodipine-induced pleural effusion in a dog. As the dosage of amlodipine was reduced, the pleural effusion improved and was effusion-free until 4 months as we monitored. If pleural effusion occurs in a patient who has been administered a high-dose of amlodipine, the possibility of an amlodipine related adverse drug event should be considered.

The Longitudinal Outcome Of Canine (K9) myxomatous mitral valve disease (LOOK-Mitral) registry: baseline treatment characteristics. Alessandra Franchini, Michele Borgarelli, Jonathan A.Abbott, Giulio Menciotti, Serena Crosara, Jens Häggström, Sunshine Lahmers, Steven Rosenthal, William Tyrrell. J. Vet. Cardiol. February 2022; doi: 10.1016/j.jvc.2022.02.001. Quote: Objectives: To describe the medical treatment prescribed or modified by veterinary cardiologists at the enrollment visit in dogs included in The Longitudinal Outcome of Canine (K9) myxomatous mitral valve disease (MMVD) registry (LOOK-mitral registry) and to evaluate the influence of the EPIC trial and other selected variables on cardiologist prescription habits. Animals: The medical records of 6,102 dogs enrolled in the LOOK_mitral registry between 2015 and 2018 were retrospectively reviewed and 6,016 dogs were included. ... Of these dogs, 3,891 were in Stage-B1 (65%), 889 in Stage-B2 (15%), and 1,236 Stage-C (20%). Mixed breed dog was the most commonly represented breed (n=1,239, 20%), followed by Cavalier King Charles Spaniel (n=491, 8%) and Chihuahua (n=483, 8%). ... Results: Medical treatment was prescribed by a cardiologist to 2,599 dogs (15% Stage-B1, 90% Stage-B2 and to all dogs in Stage-C). Angiotensin converting enzyme inhibitors (Ace-i) were the treatment most commonly prescribed for dogs in Stage-B1 (n=352, 9%). ... The result of this study showed that a medical treatment for MMVD was started by the referring veterinarian in 16% of the dogs. However, in 88% of these dogs, the medical treatment was discontinued or modified by the cardiologist. ... Among the 3,891 dogs in Stage-B1, 1,180 dogs (30%) had evidence of either LA or LV enlargement. In particular, 217 dogs (5%) had only LA enlargement while 963 dogs (25%) had only LV enlargement. ... Five-hundred-eighty-eight dogs [15%] in this [Stage B1] group had evidence of PH [pulmonary hypertension]. ... Stage-B2 dogs: A total of 797 dogs out of the 889 in this stage were receiving a medical treatment (90%). ... Pulmonary hypertension was diagnosed in 265 dogs in this stage [B2] (30%). ... Stage-C dogs: ... Pulmonary hypertension was diagnosed in 714 dogs in this stage [C] (58%). ... The combination of pimobendan and an Ace-i was the most common treatment in Stage-B2 dogs (n=367, 41%). Furosemide, an Ace-i, and pimobendan was the most common cardiac medical treatment prescribed for ACVIM Stage-C dogs (n=704, 57%). Within each stage, dogs with larger left atrial and left ventricular dimensions were more likely to receive Ace-i, pimobendan or spironolactone. There was a four-fold increase in pimobendan prescription in Stage-B2 dogs after the publication of the epic trial. Moreover, a 15% reduction in Ace-i prescription and a 30% reduction in spironolactone prescription occurred after EPIC. ... In 974 dogs a medical treatment was prescribed by the referring veterinarian. This was not changed (12%), modified (74%) or discontinued (14%) by the cardiologist. Conclusions: The EPIC trial and the echocardiographic assessment of left atrial and ventricular dimensions influence cardiologists’ prescription habits.

A Survey On Dogs With Valvular Disease Flying To Japan For Operation. Arane Takahashi, Sayaka Takeuchi, Ayaka Chen, Masami Uechi. Res. Sq. February 2022; doi: 10.21203/rs.3.rs-1342177/v1. Quote: In small-breed dogs, mitral valve disease is common, which leads to future cardiac failure. Mitral valve repair is an optimal surgical treatment that is currently available in limited veterinary facilities globally because it requires a special surgery team and specific devices. Therefore, some dogs must travel overseas to undergo this surgery. However, a question arises regarding the safety of dogs when traveling by air with a heart disease. We aimed to evaluate the effect of flight journey on dogs with mitral valve disease, including survival rates, symptoms during the trip, laboratory test results, and operational outcomes. All dogs stayed near the owner in the cabin during the flight. The survival rate after the flight was 97.5% in 80 dogs [including 10 cavalier King Charles spaniels (12.5%)]. The surgical survival rates (96.0% and 94.3%) and hospitalization periods (7 days and 7 days) were similar between overseas and domestic dogs. ... On arrival in Japan, four dogs showed severe symptoms related to heart failure. Three dogs were diagnosed with pulmonary edema, and one with left atrial rupture. After receiving treatment, two dogs with pulmonary edema recovered, and two dogs died; thus, the overall survival rate for the inbound journey was 97.5%. The dog that died of pulmonary edema was a 7-year-old Cavalier King Charles Spaniel that flew from eastern USA (total flight hour, 12 h). The dog that died of left atrial rupture was a 9-year-old Maltese that flew from western USA (total flight hour, 11 h). ... Of the 80 dogs in this study, five did not undergo MVR. The reasons were death of two dogs after arrival, unfavorable preoperative screening results, or refusal of consent to surgery by the owner. Three of the 75 dogs that underwent MVR died postoperatively; thus, the surgical survival rate was 96%. In comparison, the surgical survival rate in 629 domestic dogs during the same study period at this facility was 94.3%. The average hospitalization periods were 7.3 days for the overseas dogs and 7.2 days for the domestic dogs. ... This report shows that taking air flights in the cabin may not have a significant effect on dogs with MMVD, on the premise that their overall conditions are stable under cardiac medication. ... The proportion of dogs showing fatal events seems rather low, and this report indicates that dogs with MVD cannot be strongly prohibited from going onboard if MVR is included in the list of treatment options. At the same time, owners considering taking the chance to treat their dogs overseas should be aware of the in-flight symptoms and cardiac events behind them, as reported in some dogs in this study. It is strongly recommended that owners consult their local veterinarians in the short term before getting on board, adhering to the daily medication protocol while traveling, and have a medical check-up shortly after arrival in case their dogs experience any progressive symptoms.

Prospective study of dilated cardiomyopathy in dogs eating nontraditional or traditional diets and in dogs with subclinical cardiac abnormalities. Lisa Freeman, John Rush, Darcy Adin, Kelsey Weeks, Kristen Antoon, Sara Brethel, Suzanne Cunningham, Luis Dos Santos, Renee Girens, Robert Goldberg, Emily Karlin, Darleen Lessard, Katherine Lopez, Camden Rouben, Michelle Vereb, Vicky Yang. J. Vet. Intern. Med. March 2022; doi: 10.1111/jvim.16397. Quote: Background: Recent studies have investigated dogs with presumed diet-associated dilated cardiomyopathy (daDCM), but prospective studies of multiple breeds are needed. Hypothesis/Objectives: To evaluate baseline features and serial changes in echocardiography and cardiac biomarkers in dogs with DCM eating nontraditional diets (NTDs) or traditional diets (TDs), and in dogs with subclinical cardiac abnormalities (SCA) eating NTD. ... months. Baseline diets were categorized as NT if they were grainfree or included pulses or potatoes/sweet potatoes in the top 10 ingredients and T if they were grain-inclusive and had no pulses or potatoes/sweet potatoes in the top 10 ingredients. ... Animals: Sixty dogs with DCM (NTD, n = 51; TDs, n = 9) and 16 dogs with SCA eating NTDs. [None were CKCSs.] ... Dogs with >1+ (mild) mitral regurgitation or obvious thickening of the mitral valve were excluded from this group. [None of t ... Twenty-nine of 51 dogs (57%) in the NTD group and 3/9 dogs (33%) in the TD group survived until the 9-month re-evaluation. ... Methods: Echocardiography, electrocardiography, and measurement of taurine, cardiac troponin I, and N-terminal pro-B-type natriuretic peptide were performed in dogs with DCM or SCA. Diets were changed for all dogs, taurine was supplemented in most, and echocardiography and cardiac biomarkers were reassessed (3, 6, and 9 months). ... In most dogs, taurine supplementation was initiated at the baseline visit. Owners were instructed to administer taurine supplementation until laboratory results were available 2 to 4 weeks later and to continue supplementation if plasma or whole blood taurine concentrations were low or borderline. ... Results: At enrollment, there were few differences between dogs with DCM eating NTDs or TDs; none had low plasma or whole blood taurine concentrations. Improvement in fractional shortening over time was significantly associated with previous consumption of a NTD, even after adjustment for other variables. Median survival time for dogs with DCM was 611 days (range, 2-940 days) for the NTD group and 161 days (range, 12-669 days) for the TD group. Sudden death was the most common cause of death in both diet groups. Dogs with SCA also had significant echocardiographic improvements over time. Conclusions and Clinical Importance: Dogs with DCM or SCA previously eating NTDs had small, yet significant improvements in echocardiographic parameters after diet changes.

Metastatic osteosarcoma tumor thrombus in a Cavalier King Charles Spaniel presenting with dyspnea. Alex Shirlow, Kieran Borgeat, Nicolette Hayward, Emma Scurrell, Jessie Rose Payne. J. Vet. Cardiol. March 2022; doi: 10.1016/j.jvc.2022.03.003. Quote: A six-year-seven-month-old female neutered Cavalier King Charles Spaniel was referred for investigation of progressive dyspnea and hyphema in the right eye with secondary glaucoma. Previous medical history included a high-grade soft tissue spindle cell sarcoma removed from the cranial sternal region one year before. On presentation at the referral hospital, the dog was tachypneic and dyspneic. The heart rhythm was regular and there was a soft left-sided systolic murmur. Echocardiography identified the presence of a mass significantly occluding left heart inflow, with no other lesions identified. Thoracic radiographs documented a localized alveolar pattern within the left caudal lung lobe. The size of the heart and pulmonary vessels were within normal limits, indicating a non-cardiogenic alveolar pattern. Given the clinical presentation of dyspnea and high index of suspicion of intra-cardiac neoplasia, the dog was considered to have a grave prognosis and therefore euthanized. Post-mortem gross and histopathologic examination revealed the presence of a metastatic osteosarcoma tumor thrombus in the left atrium and pulmonary vein, metastatic osteosarcoma infiltrating the myocardium, lungs, the uveal tract of the right eye, and both adrenal glands. Whitney grade II myxomatous changes were noted on the mitral and tricuspid valve leaflets. This report describes an unusual intra-cardiac tumor thrombus in a dog presenting with dyspnea. Cavalier King Charles Spaniels presenting with dyspnea often raise suspicion for myxomatous mitral valve disease. However as demonstrated in this case, other more unusual causes of dyspnea should also be considered in the absence of classic clinical findings.

Circulating miR-30b-5p is upregulated in Cavalier King Charles Spaniels affected by early myxomatous mitral valve disease. Mara Bagardi, Sara Ghilardi, Valentina Zamarian, Fabrizio Ceciliani, Paola G. Brambilla, Cristina Lecchi. bioRxiv. March 2022; doi: 10.1101/2022.03.17.484775. Quote: There is a growing interest in developing new molecular markers of heart disease in young Cavalier King Charles Spaniels affected by myxomatous mitral valve disease. The aim of the study was to measure the abundance of 3 circulating microRNAs and their application as potential biomarkers in the plasma of Cavalier King Charles Spaniels with early asymptomatic myxomatous mitral valve disease. 33 dogs affected by the disease in American College of Veterinary Internal Medicine (ACVIM) stage B1 were divided in three groups (11 younger than 3 years, 11 older than 3 years and younger than 7 years, and 11 older than 7 years), and 11 healthy (ACVIM stage A) Cavalier King Charles Spaniels were included as the control group. This is a prospective cross-sectional study. The abundance of three circulating microRNAs (miR-1-3p, miR30b-5p, and miR-128-3p) was measured by quantitative real-time PCR using TaqMan® probes. ... The comparative analysis demonstrated that one miRNA, namely miR-30b-5p, had a significant differential abundance in the plasma of MMVD-affected dogs compared to the healthy group. ... Diagnostic performance was evaluated by calculating the area under the receiver operating curve (AUC). miR-30b-5p was significantly higher in ACVIM B1 dogs compared to ACVIM A subjects, and the area under the receiver operating curve was 0.79. ... The echocardiographic exam was used to diagnose MMVD. ... Inclusion criteria for dogs in the clinically normal group (ACVIM A) were: no echocardiographic evidence of heart disease, no clinical signs, no abnormalities on results of a complete blood count and biochemical analyses, and no history of medical treatment within the previous 6 months. Inclusion criteria for dogs with MMVD at stage B1 were: echocardiographic evidence of a thickened or prolapsed mitral valve and mitral valve regurgitation, regurgitation, no evidence 113 of left atrial dilatation, defined as a left atrial-to-aortic root ratio (LA/Ao) <1.6 on 2-dimensional echocardiography, and no left ventricle dilation, defined as left ventricular normalized dimensions in diastole (LVIDdN) <1.7. ... According to the age of dogs, the abundance of miR-30b-5p was statistically significantly higher in group B1<3y (2.3 folds, P = 0.034), B1 3-7y (2.2 folds, P = 0.028), and B1>7y (2.7 folds, P = 0.018) than in group A. The area under the receiver operating curves were fair in discriminating between group B1<3y and group A (AUC 0.780), between B1 3-7y and A (AUC 0.78), and good in discriminating between group B1>7y and A (AUC 0.822). miR-30b-5p changed in the plasma of dogs at the asymptomatic stage of disease, particularly at a young age. ... This study identified a biomarker that may have an impact in both implementing preventing programs through genetic selection and in clinical practice. These results confirm that in CKCSs, as already demonstrated in humans, there is a differential expression of miRNAs, suggesting that their expression profiles are distinct for dogs with MMVD compared to healthy dogs. We demonstrated that miR-30b-5p could discriminate among ACVIM stage A CKCSs and ACVIM stage B1 CKCSs younger than 3 years, without heart murmurs, without clinical signs, but with an echocardiographic diagnosis of MMVD. ... Conclusions: The present results lay the basis for a breeding program that will help the CKCS’ breeders in their targeted selection to obtain healthier subjects with a reasonable life expectancy. At the same time, highlighting the risk of the development of the disease at an earlier stage will favour a preventive screening and a mitigating therapeutical approach.

Evaluation of Changes in the Cardiac Function before and after Transcatheter Edge-to-Edge Mitral Valve Repair in Healthy Dogs: Conventional and Novel Echocardiography. Kenta Sasaki, Danfu Ma, Ahmed S. Mandour, Yusuke Ozai, Tomohiko Yoshida, Katsuhiro Matsuura, Aki Takeuchi, Chieh-Jen Cheng, Hussein M. El-Husseiny, Hanan Hendawy, Kazumi Shimada, Lina Hamabe, Akiko Uemura, Ryou Tanaka. Animals. March 2022; doi: 10.3390/ani12010056. Quote: Mitral valve regurgitation is a common canine heart disease. Transcatheter Edge-to-Edge Repair (TEER) is a transcatheter, edge-to-edge mitral repair device that uses a hybrid approach. No detailed information has been published on the hemodynamic effect of TEER on cardiac function. The aim of this report is to provide a longitudinal observation of the cardiac functional changes observed after TEER implantation in normal dogs using traditional, two-dimensional speckle tracking, and color M-mode echocardiographic methods. In the current report, TEER was implanted into ... two female beagles, aged 2 and 2.5 years and weighing 8.6 and 10.3 kg, respectively. These two dogs were healthy, based on physical examinations, hematobiochemical profile, conventional echocardiography, and urinalysis. ... The TEER was guided by a transesophageal echocardiography (TEE) probe in the median longitudinal and transverse views [15]. Heparinized normal saline (100 IU/kg) was administered intravenously after exposing the heart at the left sixth intercostal space via thoracotomy. The pericardium was incised and the apical area leaked. After placing a purse-string on the cardiac apex, the TEER MV repair delivery system was inserted through the cardiac apex first into the left ventricle and then into the left atrium under echocardiographic guidance. The MV was captured, and the TEER was deployed after the clamp position was confirmed (Figure 1). The delivery system was released, and the cardiac apex were sutured by the purse-string. Pericardium, thoracic wall and skin were sutured by 3-0 Prolene, PDS and Nylon, respectively. No medication was given to the dogs during the operation. ... An echocardiographic examination was performed at baseline and weekly postoperative follow-ups were conducted until the fourth week. Successful TEER implantation was achieved with a short operation time (98 and 63 min) in the two dogs. Functional mitral valve regurgitation, elevated E/e’ ratio, elevated radial strain, and stable intraventricular pressure gradients (IVPG) were observed after the operation in the dogs. Mild non progressive mitral valve stenosis was observed in both dogs. ... TEER provides a minimally invasive method for mitral valve repair that warrants further clinical trials in dogs with mitral valve disease to suppress volume overload. The narrowing of the mitral valve, caused by TEER, might be beneficial to MMVD patients. Basal IVPG appears to be a potential index for evaluating postoperative congestion.

Amlodipine decreases mitral regurgitation volume in dogs over 7 days: A study of 24 dogs with myxomatous mitral valve degeneration. Sool Yi Park, Won-Seok Oh, Seunggon Lee. Vet. Rec. April 2022; doi: 10.1002/vro2.33. Quote: Background: Amlodipine, a dihydropyridine calcium-channel blocker, is currently being investigated as a treatment for myxomatous mitral valvular degeneration (MMVD). However, the effects of amlodipine on moderate or severe spontaneous MMVD, based on changes in echocardiographic indices, remain unclear. Animals: Client-owned small-breed dogs (n = 24) with naturally occurring MMVD of the American College of Veterinary Internal Medicine (ACVIM) stage B2 or higher. [Including 11 Maltese, 5 mixed, 2 Pomeranian, and 1 each of 6 other breeds; no cavalier King Charles spaniels.] Methods: Basic dog information including previous medication treatments were recorded. All subjects received amlodipine 0.1 mg/kg, administered per os, twice daily for 7 days, in addition to their existing medication. We measured systolic blood pressure, obtained x-ray, echocardiography, blood test data before and after 1 week of amlodipine administration. Results: Left ventricular end-diastolic internal diameter, left atrial diameter [LAD] and E wave reduced statistically after 1 week of amlodipine treatment. ... LVIDdN, which forms part of the ACVIM MMVD grading criteria, with LVIDD, were decreased by 8% (2.2 mm). LAD and consequently the LA/Ao ratio, was decreased by 6.4% (1.57 mm) (Table 2). The E wave was decreased by 14% (0.18 m/s) (Table 2). ... No adverse effects were reported. ... We could not identify an optimal dosage of amlodipine to reduce LAP [left atrial pressure], without apparent side effects, in this study. It is noteworthy that compared to a previous study, in which 0.2 mg/kg PO twice daily amlodipine showed apparent reduction in LAP, in our study, at half that dose, some 33% of the dogs showed an apparent improvement in LAP. A longer term study comprising a prospective randomised controlled trial based on the 0.1 mg/kg twice daily dose, may confirm that the positive effect on LAP is maintained. The dogs in this study were already receiving furosemide, enalapril or pimobendane, with amlodipine added. Furosemide and enalapril are known to have an impact on systemic arterial pressure, while enalapril may show an interaction with amlodipine with combined administration. As the dogs received varied drugs, the consequent interactions might have exerted an influence on the results of this study. ... Conclusions: These findings suggest that low-dose amlodipine should be considered as treatment for dogs with ACVIM stage B2-C MMVD.

Adjunct ambrisentan therapy had clinical benefits in 5 dogs with sildenafil-refractory pulmonary hypertension. Seijirow Goya, Tomohiko Yoshida, Shigeharu Sennba, Tsuyoshi Uchide, Ryou Tanaka. Can. Vet. J. May 2022;63(5):497-503. Quote: Although sildenafil is used in dogs with severe pulmonary hypertension, they sometimes become resistant and clinical signs deteriorate over time. The objective of this study was to determine the benefits of adjunct ambrisentan therapy in dogs with sildenafil-refractory pulmonary hypertension. In 5 dogs with severe pulmonary hypertension with deteriorating clinical signs despite ongoing sildenafil treatment, adding ambrisentan improved appetite, activity, and respiratory functions. Although peak tricuspid valve regurgitation velocity, as measured by Doppler echocardiography, did not necessarily decrease after ambrisentan administration, there was improved partial pressure of arterial oxygen and the alveolar-arterial oxygen gradient, with no apparent side effects. We concluded that ambrisentan has potential as an adjunct treatment in dogs with pulmonary hypertension that are refractory to sildenafil therapy. Key clinical message: Ambrisentan improved clinical signs in dogs with sildenafil-refractory pulmonary hypertension.

Change of Vertebral Left Atrial Size in Dogs with Preclinical Myxomatous Mitral Valve Disease prior to the Onset of Congestive Heart Failure. Dohee Lee, Taesik Yun, Yoonhoi Koo, Yeon Chae, Dayoung Ku, Dongwoo Chang, Byeong-Teck Kang, Mhan-Pyo Yang, Hakhyun Kim. J. Vet. Cardiol. May 2022; doi: 10.1016/j.jvc.2022.05.003. Quote: Introduction: Objectives: It has been proposed that vertebral left atrial size (VLAS) on thoracic radiographs can be used to assess left atrial enlargement in dogs with myxomatous mitral valve disease (MMVD). However, it remains unclear whether VLAS can be used to distinguish dogs between pre-clinical MMVD that are at a greater risk of developing congestive heart failure (CHF) from those at a lower risk. We investigated this possibility. Animals, Materials and Methods: Forty-one dogs with MMVD were retrospectively classified into one of two groups; a group that developed CHF (group CHF, n = 17) or remained CHF-free (group no-CHF, n = 24). The value of VHS and VLAS at three time points, change in VHS and VLAS at a specific time interval (ΔVHS, ΔVLAS) and rate of change in the values per month (ΔVHS/month, ΔVLAS/month) were compared. Results: At the first visit, there were no significant differences in VLAS between the groups. At the median of 105 (interquartile ranges 83–155) days prior to the onset of CHF (group CHF) or the last visit (group no-CHF), VLAS was significantly higher in group CHF (mean, 2.9; standard deviation ± 0.4) than in group no-CHF (2.6 ± 0.3) (P = 0.028). ΔVLAS/month (area under the curve, 0.91; P < 0.001) showed high diagnostic accuracy in distinguishing which dogs would develop CHF within 180 days and which would not. Conclusions: VLAS and ΔVLAS/month in dogs with pre-clinical MMVD may be useful to identify dogs at risk of developing CHF within the next 180 days.

The Role of Transforming Growth Factor-β Signaling in Myxomatous Mitral Valve Degeneration. Qiyu Tang, Andrew J. McNair, Kanchan Phadwal, Vicky E. Macrae, Brendan M. Corcoran. Front. Cardiovasc. Med. May 2022; doi: 10.3389/fcvm.2022.872288. Quote: Mitral valve prolapse (MVP) due to myxomatous degeneration is one of the most important chronic degenerative cardiovascular diseases in people and dogs. It is a common cause of heart failure leading to significant morbidity and mortality in both species. Human MVP is usually classified into primary or non-syndromic, including Barlow’s Disease (BD), fibro-elastic deficiency (FED) and Filamin-A mutation, and secondary or syndromic forms (typically familial), such as Marfan syndrome (MFS), Ehlers-Danlos syndrome, and Loeys–Dietz syndrome. Despite different etiologies the diseased valves share pathological features consistent with myxomatous degeneration. To reflect this common pathology the condition is often called myxomatous mitral valve degeneration (disease) (MMVD) and this term is universally used to describe the analogous condition in the dog. MMVD in both species is characterized by leaflet thickening and deformity, disorganized extracellular matrix, increased transformation of the quiescent valve interstitial cell (qVICs) to an activated state (aVICs), also known as activated myofibroblasts. Significant alterations in these cellular activities contribute to the initiation and progression of MMVD due to the increased expression of transforming growth factor-β (TGF-β) superfamily cytokines and the dysregulation of the TGF-β signaling pathways. Further understanding the molecular mechanisms of MMVD is needed to identify pharmacological manipulation strategies of the signaling pathway that might regulate VIC differentiation and so control the disease onset and development. This review briefly summarizes current understanding of the histopathology, cellular activities, molecular mechanisms and pathogenesis of MMVD in dogs and humans, and in more detail reviews the evidence for the role of TGF-β. ... Phenotypic transition of qVICs to aVICs induced by dysregulated TGF-β signaling appears to be a key contributor to valve myxomatous degeneration though aberrant matrix remodeling, exerting control through complex canonical and non-canonical signaling pathways interactions and effects, which can conceivably affect the disease phenotype alone or in combinations. To what extent one of these might be a dominant pathway for the diseased is still unknown. Furthermore, what abnormal signaling contributes to the survival and persistence of aVICs in diseased valves remains unanswered. Understanding the mechanisms that control cell persistence in this disease likely will give clues to the pathogenesis and identify potential therapeutic targets in both the dog and human.

Taurine Concentrations in Cavalier King Charles Spaniels: Reference Intervals, Diet, and Mitral Valve Disease Effects. Sonya R. Wesselowski. 2022 ACVIM Forum, ePoster C52. June 2022. Quote: Background: Reference intervals for whole blood (WB) and plasma taurine may be breed-specific. Platelets are rich in taurine and Cavalier King Charles Spaniels (CKCS) are frequently affected by thrombocytopenia and macrothrombocytosis. Additionally, increased plasma taurine concentrations have been reported in some dogs with myxomatous mitral valve disease (MMVD) while decreased concentrations have been reported in some dogs eating diets that do not meet World Small Animal Veterinary Association (WSAVA) guidelines. Hypothesis/Objectives: Determine breed-specific reference intervals for WB and plasma taurine concentrations in CKCS and determine whether taurine concentrations differ across MMVD stages or between CKCS eating diets that meet WSAVA guidelines versus other diets. Animals: Two hundred CKCS. Methods: Asymptomatic CKCS were prospectively recruited. Diet and supplement history was collected. Dogs were staged by echocardiography using MMVD consensus guidelines. Taurine concentrations were measured from deproteinized lithium heparin blood and plasma samples. Results: There were 12 Stage A (6%), 150 Stage B (75%), and 38 Stage B2 (19%) CKCS. Seventy-eight dogs (39%) ate diets meeting WSAVA guidelines and 116 (58%) did not. Taurine concentrations in plasma (P = .444) and WB were not significantly different across MMVD stages or between CKCS eating diets meeting WSAVA guidelines versus other diets. Reference intervals for WB taurine (152-373 µM) and plasma taurine (51-217 µM) concentrations in CKCS were generated. Conclusions and clinical importance: In CKCS, taurine concentrations do not differ significantly based on MMVD stage or diet. (See related entry here.)

Evidence of altered fatty acid metabolism in dogs with naturally occurring valvular heart disease and congestive heart failure. Jenny Wilshaw, A. Boswood, Y. M. Chang, C. J. Sands, S. Camuzeaux, M. R. Lewis, D. Xia, D. J. Connolly. Metabolomics. May 2022; doi: 10.1007/s11306-022-01887-7. Quote: Introduction: Myxomatous mitral valve disease (MMVD) is the most common cardiac condition in adult dogs. The disease progresses over several years and affected dogs may develop congestive heart failure (HF). Research has shown that myocardial metabolism is altered in cardiac disease, leading to a reduction in β-oxidation of fatty acids and an increased dependence upon glycolysis. Objectives: This study aimed to evaluate whether a shift in substrate use occurs in canine patients with MMVD; a naturally occurring model of human disease. Methods: Client-owned dogs were longitudinally evaluated at a research clinic in London, UK and paired serum samples were selected from visits when patients were in ACVIM stage B1: asymptomatic disease without cardiomegaly, and stage C: HF. ... The study population was formed of 30 affected and 10 control dogs. Cavalier King Charles Spaniels comprised 67% (n = 20) of the affected group and 50% (n = 5) of the control group. The affected group otherwise comprised 1 Bichon Frisé, 1 Chihuahua, 1 Cocker Spaniel, 1 Maltese, 2 Shih Tzus, 1 Yorkshire terrier and 3 cross breed dogs. The 5 non-CKCS dogs in the control group were 1 Jack Russell Terrier, 2 Poodles, 1 Pug and 1 Shih Tzu. ... Stage B1 defined preclinical dogs where the left atrial to aortic root ratio (LA:Ao) and the normalised left ventricular internal diameter at end diastole (LVIDDN) fell below 1.50 and 1.85 respectively. A diagnosis of stage C disease was primarily reliant upon radiographic signs of congestive heart failure (HF). ... Table 2(A summary of the clinical characteristics of the affected population at each visit): LA:Ao: Stage B1: 1.17 (1.09 - 1.28); Stage C: 1.72 (1.53-1.97); LVIDDN: Stage B1: 1.60 (1.53-1.73); Stage C: 2.21 (2.03-2.35). ... Dogs that had progressed from ACVIM stage B1 to stage C (HF) were targeted to capture disease progression. Selection criteria were based upon breed, diet, and the availability of stored serum. Cavalier King Charles Spaniels are of interest when studying MMVD because of the breed’s marked predisposition, early disease onset, risk of progression and the degree to which neuroendocrine pathways are activated. A cohort of CKCS were therefore selected to form the majority breed, facilitating between and within breed comparisons (CKCS/ non-CKCS). ... Samples were processed using ultra-performance liquid chromatography mass spectrometry and lipid profiles were compared using mixed effects models with false discovery rate adjustment. The effect of disease stage was evaluated with patient breed entered as a confounder. Features that significantly differed were screened for selection for annotation efforts using reference databases. ... In the affected population, the intensity of 169 features (97 lipid RPC+, 72 lipid RPC-) were found to change significantly with progression to a more advanced stage of heart disease (Supplementary Table 2). In addition, 10 features (5 lipid RPC+, 5 lipid RPC-) differed between CKCS and non CKCS (Supplementary Table 3). Only one feature was associated with the interaction term between disease stage and breed (retention time: 3.4 min, mass-to-charge ratio: 915.53, polarity: RPC-, β: -1.32, Q: < 0.001), indicating that, for this feature, the relationship between its intensity and disease stage was different in each of the two breed groups. ... Results: Dogs in HF had altered concentrations of lipid species belonging to several classes previously associated with cardiovascular disease. Concentrations of certain acylcarnitines, phospholipids and sphingomyelins were increased after individuals had developed HF, whilst some ceramides and lysophosphatidylcholines decreased. Conclusions: The canine metabolome appears to change as MMVD progresses. Findings from this study suggest that in HF myocardial metabolism may be characterised by reduced β-oxidation. This proposed explanation warrants further research.

Mitral Regurgitation Severity Index: A Simple Calculation for Classification and Prognostication? Clarke E. Atkins, Darcy Adin, Thomas Blondell, Emilie Guillot, Michelle Vereb, Jessica Ward. 2022 ACVIM Forum. June 2022. Quote: Background: Prognosis in myxomatous mitral valve disease (MMVD) is variable. Better methods of predicting outcome would aid in communication with individual pet owners and sub-division of research cohorts. The mitral regurgitation severity index (MRSI) was originally developed by VETPROOF (Veterinary Enalapril Trial to Prove Reduction in Onset Of Failure) investigators to predict MMVD outcome. While other promising indices are now available, MRSI is appealing in its simplicity.MRSI Chart This abstract serves as the seminal report of MRSI’s efficacy in prognosticating asymptomatic MMVD. Hypothesis/Objectives: MRSI will predict time to CHF. Animals: 133 dogs with ACVIM Stage B2 MMVD. Methods: VETPROOF entry data from dogs randomized to either enalapril or placebo were retrospectively evaluated. Potentially useful indicators of time to onset of heart failure (CHF), including age, heart rate, and echocardiographically-determined left atrium-to-aortic ratio (LA:Ao), were used to establish MRSI, by the following equation: MRSI = [(Age/10) x (Heart-Rate/120) x (LA:Ao)] x 100. Kaplan-Meier survival curves and Cox proportional hazard analyses were used to evaluate the predictive ability of MRSI for time to CHF (significance, P<0.05). Results: MRSI, stratified at <150, 150–249, and >249 demonstrated significant differences in time to the endpoints, thereby predicting MMVD prognosis. [See chart at right.] Conclusion: MRSI is easily obtained and useful in stratification and prognostication of MMVD. Studies are ongoing to test this index more rigorously in a larger cohort of dogs with MMVD, stage B2 or C. The MRSI could be modified by substituting radiographic determination of LA:Ao, making calculation and utilization of MRSI more practitioner-friendly.

Factors related to survival time in dogs with pulmonary hypertension secondary to degenerative mitral valve disease stage C. Jutamas Udomkiattikul, Noppasorn Kirdratanasak, Panatsada Siritianwanitchakul, Wasaporn Worapunyaanun, Sirilak Disatian Surachetpong. Int'l J. Vet. Sci. & Med. June 2022; doi: 10.1080/23144599.2022.2067630. Quote: Pulmonary hypertension (PH) is a common complication in dogs with degenerative mitral valve disease (DMVD). The aim of this study was to determine the survival time and to determine factors related to the survival time of dogs with PH secondary to DMVD stage C. A retrospective study was conducted in 37 dogs with PH secondary to DMVD stage C to analyse the median survival time and associated factors such as age, sex, breed, body weight, the presence of syncope, heart rate, systolic blood pressure, manifestation of congestive heart failure (CHF), vertebral heart score (VHS), the presence of left or right heart enlargement, probability of PH and medication. Data were analysed using the Log-Rank test and plotted with the Kaplan- Meier curve. The results showed that the median survival time of dogs with PH secondary to DMVD stage C was 368 days, and factors that shortened the median survival time of dogs with PH secondary to DMVD stage C were mixed breeds, VHS > 11.5, the presence of right heart enlargement, ascites and high probability of PH. Factors associated with an increased hazard of death were mixed breed dogs, dogs with right heart enlargement and ascites. These findings may be useful for the prognosis and management of dogs with PH secondary to DMVD stage C.

The ACVIM consensus statement definition of LV enlargement in myxomatous mitral valve disease does not always represent LV enlargement. Mark Rishniw, Donald J. Brown. J. Vet. Cardiol. June 2022; doi: 10.1016/j.jvc.2022.06.004. Quote: Objective: To determine how frequently current criteria for left ventricular enlargement in dogs misclassify healthy dogs as having left ventricular enlargement; to examine the effect of breed on diastolic left ventricular normalized dimensions (LVIDDN); to propose appropriate scaling exponents and reference limits for dogs. ... We hypothesized that the ACVIM Consensus criterion of LVIDDN ≥ 1.7 to define left ventricular enlargement in Stage B dogs is too low, and would classify many normal dogs (and, by extension, dogs with mild mitral valve disease and without echocardiographic evidence of left ventricular enlargement) as having evidence of left ventricular enlargement when none is present. Animals: Echocardiographic data from 1124 healthy adult dogs, including 454 dogs weighing <20 kg. [including 59 cavalier King Charles spaniels (12%)]. Methods: We calculated power regression parameters (allometric scaling), including exponents and proportionality constants, for various subsets of the dogs (all dogs, dogs <20 kg, generic dogs, and individual breeds with >10 observations), and derived upper reference limits for LVIDDN. We determined the proportions of dogs that would be identified as having left ventricular enlargement with each regression model compared to previously published reference limits or guidelines. We then identified breeds failing to conform to generic dog models. Results: The ACVIM-recommended scaling exponent (0.294) and criterion for identifying left ventricular enlargement (1.7) identified >10% of apparently healthy dogs as having left ventricular enlargement, with specific breeds being misclassified up to 50% of the time. ... Five breeds <20 kg had LVIDDN larger than the LVIDDN of “generic” dogs: Cavalier King Charles spaniels, English cocker spaniels, English setters, English springer spaniels, and Whippets. ... The EPIC study employed an essentially arbitrary value of LVIDDN to dogs subsequently randomized to treatment with pimobendan or placebo and showed that dogs with LVIDDN≥1.7 (and LA:Ao≥1.6 and a VHS>10.5V) generally do better with the drug than without. ... The criterion for left ventricular enlargement used by the EPIC investigators for study inclusion has never been critically evaluated as indicative of left ventricular enlargement. The EPIC investigators adopted the scaling exponent from the study by Cornell and colleagues, but used a value for LVIDDN that differed from a more conventional threshold value defining LV enlargement (the 97.5th percentile). ... The LVIDDN limit of 1.7 at a scaling exponent of 0.294 used by the EPIC study investigators (and consequently the criterion adopted by the ACVIM Consensus panel) would effectively classify approximately 10% of healthy dogs as having left ventricular enlargement. ... Therefore, the definition of "left ventricular enlargement", provided by the ACVIM Consensus panel in the most recent guidelines does not necessarily apply to all dogs and could lead clinicians to inappropriately indentify left ventricular enlargement where none exists. Further, our data support the observation of other investigators that certain breeds fail to adhere to previously published allometric models of normalized left ventricular measurements, and likely require breed-specific reference intervals for normalized left ventricular measurements. ... Our observation that a LVIDDN > 1.7 using the traditional scaling exponent of 0.294 does not necessarily represent LV enlargement in healthy dogs suggests that not all the dogs included in the EPIC study had left ventricular enlargement. What the implications are for the ACVIM classification system remains unclear. Using this limit would result in 14% of dogs with normal left ventricles being incorrectly classified as having ventricular remodeling (one of the components for defining Stage B2). Indeed, based on our evaluation, approximately 50% of English Springer Spaniels, 40% of whippets, 23% of English Cocker Spaniels and 10% of Cavalier King Charles Spaniels would be identified as having left ventricular enlargement using an LVIDDN limit of 1.7 at scaling exponents <0.3. ... Importantly, these breeds commonly develop myxomatous mitral valve disease, where clinicians assess cardiomegaly to determine whether the dog being examined warrants medical interventions. ... It must be clear however, that the EPIC study does not provide independent criteria for left ventricular enlargement; nor does it determine whether all included dogs will benefit from the treatment. Nevertheless, these investigators defined left ventricular enlargement in their study as an LVIDDN ≥1.7 and defined cardiomegaly as LVIDDN≥1.7, LA:Ao≥1.6 and VHS>10.5V. The subsequent definition of the Stage B2 classification by the ACVIM Consensus panel based on these EPIC criteria is understandably expedient, but the justification should be considered carefully. We should note, however, that the definition of LV enlargement proposed by both the EPIC trial and, subsequently, by the ACVIM Consensus panel, is not a reference value, but a somewhat arbitrarily chosen threshold for inclusion in the EPIC trial. Therefore, clinicians adhering to these guidelines should be cautious in ascribing LVIDDN that exceed the threshold value of 1.7 as being indicative of LV enlargement. Furthermore, clinicians should note that the ACVIM Stage B2 classification requires enlargement of both the left atrium (to a LA:Ao>1.6) and enlargement of the left ventricle. How many dogs with mild left atrial enlargement, but without LV enlargement, might consequently be misclassified as having cardiomegaly remains unknown. ... Specific breeds (English Springer Spaniels, English Cocker Spaniels, Cavalier King Charles Spaniels, Greyhounds, Whippets, and Scottish Deerhounds) exhibit obvious departure of LVIDDN from expectations for generic dogs that is not due to an aspect of body size characterized by bodyweight. All these breeds have LVIDDN that are, on average, larger than generic dogs of similar size. ... Two options exist to correct for these breeds – either ascribe a more conservative (higher) reference limit that encompasses all breeds, which could fail to identify LV enlargement in a sizeable proportion of conforming breeds or generic dogs, or provide one reference limit for dogs that conform to the generic dog model, and separate reference limits for the non-conforming breeds. ... For example, if a dog has a LVIDDN that consistently oscillates around 1.3 (within 0.1 units), an increase to 1.6 could indicate left ventricular enlargement for that dog, despite being within the population-based reference interval. However, no data currently exist demonstrating that such use of reference change value and intra-individual reference intervals applies to left ventricular dimensions. Furthermore, without establishing individual baseline values for each dog, clinicians cannot identify a change such as described above. Nevertheless, our study cannot determine how many dogs that might ultimately fall within population-based reference intervals might demonstrate left ventricular enlargement. Conclusions: LVIDDN are breed-dependent. ... Our study demonstrates that using the previously reported exponent (0.294) and a prediction limit of 1.7 results in approximately 17% of healthy dogs (and up to 50% of dogs of specific breeds) being classified as having left ventricular enlargement. Specific breeds fail to conform to the allometric scaling model of generic dogs, and have LVIDDN values that exceed those for the generic population of similar bodyweight. Finally, the scaling exponents defining left ventricular enlargement in dogs approach the isometric scaling exponent of 0.333, which might most conveniently allow calculations of reference limits for different groups of dogs, particularly where the range of body size is limited. Non-conforming breeds likely require breed-specific reference intervals for LVIDDN to correctly identify left ventricular enlargement.

The Outcome of Surgical Mitral Valve Repair with Loop-in-Loop Technique in Dogs with Different Stage Myxomatous Mitral Valve Disease. K. Matsuura, T. Yoshida, S. Yamada, Yuki Aboshi, H. Yotsuida, Y. Yaginuma, M. Hasegawa. J. Vet. Cardiol. June 2022; doi: 10.1016/j.jvc.2022.06.001. Quote: Objectives: Surgical mitral valve repair is a possible option for dogs with myxomatous mitral valve disease (MMVD). However, information on surgical results and postoperative echocardiography is limited. ... The loop-in-loop technique was used to adjust the height of each mitral leaflet. The expanded polytetrafluoroethylene (ePTFE) loop anchor with a single small loop was made of a double-armed ePTFE suture and a small ePTFE pledget. Primary loop anchors (2 total) were fixed on the anterior and posterior papillary muscles respectively, with another ePTFE pledget. Next, a new CV-6 suture was passed through the primary loop sutured on the affected leaflet as a secondary loop, to adjust the length of the neochord (Fig.1 below). The number of secondary loops depended on the status of the prolapsed area. In all cases, a modified DeVega semi-circular suture annuloplasty was subsequently performed using CV-6 or CV-5 sutures with small ePTFE pledgets. Finally, a saline test was conducted to confirm the quality of the valve function. In cases where any inappropriate length of the neochord was recognized, the secondary loop was cut and/or added as appropriate. The recorded number of neochord on each papillary muscle was also reviewed. ... This study aimed to verify the stage-specific surgical results of mitral valve repair and postoperative echocardiographic changes for two years following surgery. Animals: Adult dogs (n = 55)[2 cavalier King Charles spaniels (3.6%)] treated with surgical mitral valve repair using the loop-in-loop technique were included in this study. ... All dogs that underwent mitral valve repair surgery at VCA Japan Shiraishi Animal Hospital between July 2019 and November 2021 were enrolled in this retrospective study. ... Medical records were retrospectively reviewed. Results: Ninety percent of cases (50/55) survived to discharge, which survival was significantly decreased in MMVD advanced stage dogs, Stage B2 (n = 14): 100%, Stage C (n = 27): 96.2%, and Stage D (n = 14): 71.4%. Significant reductions of overall heart size (vertebral heart score: preoperative 11.4 vs post 1 month 10.2, p < 0.001), left atrium (left atrium to aortic root ratio: preoperative 2.3 vs post 1 month 1.5, p < 0.001) and left ventricle (left ventricular end-diastolic diameter [normalized for bodyweight]: preoperative 2.2 vs post 1 month 1.5, p < 0.001) were documented one month after surgery, showing successful management of mitral regurgitation. All medications for mitral valve disease were discontinued 3 months after surgery. Recurrence of mitral regurgitation was not evident during the two-year follow-up period. Conclusions: Surgical mitral valve repair with the loop-in-loop technique is associated with significant decreases in indices of cardiac size at 1-month post-repair. Disease stage influences operative survival after surgical mitral valve repair. ... The present study described stage-specific success rates of mitral valve repair, which was 100% in Stage B2, 96.2% in Stage C, and 71.4 % in Stage D MMVD dogs. Surgical mortality was observed in no dogs with Stage B2 and only one dog with Stage C.

Fig. 1 -- Loop-to-loop

Serum digoxin concentrations in dogs with atrial fibrillation under long term digoxin treatment. Antonella Colella, Serena Digiaro, Marco Fiorentino, Beatrice Greco, Mariateresa Sasanelli, Paola Paradies. Open Vet. J. June 2022; doi: 10.5455/OVJ.2022.v12.i3.9. Quote: Background: Atrial fibrillation (AF) is the most common arrhythmia in dogs, most frequently diagnosed as chronic AF associated with a structural heart disease. The therapeutic strategy, in these cases, is based on the heart rate control and digoxin is one of the most used drugs. Aim: The aim of this work was to study the serum digoxin concentration changes in dogs with AF under long-term treatment with digoxin. Furthermore, the remission of clinical signs and the correlation between digoxinemia and other clinical and laboratory variables were retrospectively evaluated. Methods: The prospective study was conducted on seven large breed dogs from the time of reaching the definitive digoxin dosage. Digoxinemia was determined at month: 1, 3, 6, 9, 12, then twice a year. A post hoc statistical analysis investigated the influence of selected clinical and laboratory variables on the risk to develop spikes in digoxinemia. Clinical data, heart rate, digoxin dosage (mg/m2), and digoxinemia (ng/ml) at all available follow-ups were retrospectively evaluated from the medical records of 17 further dogs and a linear regression analysis was performed on the whole data set. The relation between the time of remission of AF clinical signs and variables was also investigated. Results: An unexpected increase in digoxin serum concentration was recorded in three dogs after one year monitoring, in absence of digoxin dosage changes. No statistical significance of all the studied variables on the risk to develop spikes of digoxinemia was registered. Two dogs, reaching digoxinemia 4.46 and 5.24 ng/ml, showed symptoms that reversed after digoxin withdrawal. From retrospective data, 88% of dogs reached complete reverse of AF clinical signs in 2.1 months from digoxin treatment starting, regardless of digoxin initial dosage, digoxinemia, and heart rate. Conclusion: Digoxin in monotherapy remain a good option to treat AF in dogs, anyway digoxin toxicity could emerge during long-term therapy, similarly to what happen in human medicine. Life-threatening spikes of digoxinemia could occur, especially after 1-year treatment with digoxin. It is very important that practitioners be aware of this possibility and encourage the owners to monitor digoxinemia during long-term treatment to avoid dangerous and toxic effects.

Combination of the Modified Loop Technique and De Vega Annuloplasty in Dogs with Mitral Regurgitation. Takuma Aoki, Takashi Miyamoto, Naoyuki Fukamachi, Seiya Niimi, Yao Jingya, Yoshito Wakao. Animals. June 2022; doi: 10.3390/ani12131653. Quote: Background: Detailed surgical techniques for treating canine mitral regurgitation have not been previously reported. Method: This case series included six consecutive client-owned dogs with mitral regurgitation. All dogs underwent a combined protocol, including the modified loop technique and De Vega annuloplasty (MODEL surgery), in 2021. ... In humans, this procedure includes chordal replacement using expanded polytetrafluoroethylene (ePTFE) sutures for elongated or ruptured chordae tendineae (CT), ring annuloplasty using a prosthetic valve ring for an enlarged mitral annulus, and valve leaflet resection for an elongated leaflet. ... The ePTFE suture is an ideal artificial CT; however, it is slippery and challenging to ligate at the targeted length. In addition, the correct length of artificial CT in dogs has not been determined, except in our experimental study. In mitral annuloplasty, a prosthetic valve ring is used in humans; however, to date, no prosthetic valve ring has been manufactured for dogs. Therefore, surgeons perform purse-string suturing (De Vega annuloplasty) in the mitral annulus under visual inspection based on their own experience. Valve leaflet resection is an important procedure in humans but is not performed in dogs because the valve leaflets are fragile, and the sutured site might tear. ... The advantages of this method are that it is simple and easy, and there is no obstruction of the blood inflow from the LA to the ventricle, unlike in the case of an artificial ring. Another advantage is that it maintains the natural flexibility of the mitral valve annulus, unlike the artificial ring method. ... Thus, canine mitral valve repair is performed with chordal replacement using artificial CT and mitral annuloplasty with purse-string sutures. However, detailed indications for canine mitral valve repair have not been previously determined, and a subjective assessment is performed by surgeons based on their individual experience. Therefore, surgical outcomes depend on the skills of the surgeon. Artificial loops covering 80% of the length of the strut chordae tendineae were used for chordal replacement. Mitral annuloplasty was subjectively performed, targeting the circumference of the septal leaflet. Results: The breeds were Chihuahua-mixed breed, Spitz, Pomeranian, Cavalier King Charles Spaniel [16.67%], and Chihuahua, with average ages and weights of 11.4 ± 2.3 years and 5.49 ± 2.98 kg, respectively. The aortic cross-clamp, pumping, and surgery times were 64.0 ± 7.5 min, 168.5 ± 39.1 min, and 321.0 ± 53.1 min, respectively. After MODEL surgery, left atrial-to-aortic ratios significantly decreased from 2.20 ± 0.18 to 1.26 ± 0.22 (p < 0.01), and left ventricular end-diastolic internal diameter normalized to body weight significantly decreased from 2.03 ± 0.26 to 1.48 ± 0.20 (p < 0.01). In all cases, the clinical signs disappeared or improved significantly. Conclusions: MODEL surgery increased mitral valve coaptation, normalized heart sizes, and significantly improved clinical signs in dogs with mitral regurgitation.

Pro-Inflammatory and Immunological Profile of Dogs with Myxomatous Mitral Valve Disease. Diego Piantedosi, Nadia Musco, Anna Teresa Palatucci, Flavia Carriero, Valentina Rubino, Francesco Pizzo, Saad Nasir, Giuseppe Molinaro, Giuseppina Ruggiero, Giuseppe Terrazzano, Pietro Lombardi, Laura Cortese. Vet. Sci. June 2022; doi: 10.3390/vetsci9070326. Quote: Myxomatous mitral valve disease (MMVD) is a very frequently acquired cardiac disease in dog breeds and is responsible for congestive heart failure (CHF). The involvement of the immune system and pro-inflammatory cytokines in dogs with CHF due to mitral valve disease has not yet been extensively investigated. Here, we investigate the role of pro-inflammatory cytokines and the dysfunction of the immune system in dogs with different stages of severity through the blood assessment of CD4+FoxP3+regulatory T cells (Treg) cells, leptin, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 pro-inflammatory cytokines, and immunological and echocardiographic parameters. A total of 36 cardiopathic dogs, 14 females and 22 males, with MMVD were included [including 7 cavalier King Charles spaniels (19.5%)]. Mean age and body weight (BW) at the time of enrollment were 10.7 ± 2.77 years and 10.9 ± 6.69 kg, respectively. For the comparison of the pro-inflammatory and immunological parameters, two groups of healthy dogs were also established. Control group 1 consisted of young animals (n. 11; 6 females and 5 males), whose age and mean weight were 4.1 ± 0.82 years and 13.8 ± 4.30 kg, respectively. Control group 2 consisted of elderly dogs (n. 12; 6 females and 6 males), whose age and BW were 9.6 ± 0.98 years and 14.8 ± 6.15 kg, respectively. Of particular interest, an increase in Treg cells was observed in the cohort of MMVD dogs, as compared to the healthy dogs, as Treg cells are involved in the maintenance of peripheral tolerance, and they are involved in etiopathogenetic and pathophysiological mechanisms in the dog. On the other hand, TNF-α, IL-1β, and IL-6 significantly increased according to the severity of the disease in MMVD dogs. Furthermore, the positive correlation between IL-6 and the left ventricle diastolic volume suggests that inflammatory activation may be involved in cardiac remodeling associated with the progressive volumetric overload in MMVD.

Prediction of Stage B2 Mitral Valve Disease in Cavaliers with Longitudinal Follow-Up. Sonya R. Wesselowski, Sonya G. Gordon. 2022 ACVIM Forum. June 2022. Quote: This session will discuss the utility of breed-specific cut-offs and prediction models aimed at identifying stage B2 MMVD [myxomatous mitral valve disease] in preclinical CKCS [cavalier King Charles spaniels] in the absence of an echocardiogram using a variety of combinations of physical examination/ signalment, electrocardiography (ECG), radiography, and biomarker variables. These cut-offs and prediction models were developed from a large, prospectively collected dataset of 226 CKCS. Enrolled CKCS were classified based on echocardiography as stage A, B1, or B2 according to the EPIC study inclusion criteria/2019 ACVIM MMVD consensus guidelines. Accordingly, stage B2 was defined as LA to aortic (Ao) ratio ≥1.6 and left ventricular internal dimension in diastole normalized for body weight (LVIDDN) ≥1.7. CKCS with echocardiographic confirmation of MMVD that failed to meet or exceed the echocardiographic heart size criteria used for identification of stage B2 were defined as stage B1. Stage A CKCS had no evidence of MMVD based on echocardiography. Cut-offs were identified for a subset of individual variables, including VHS, vertebral left atrial size (VLAS), P+QRS duration, and NTproBNP. Physical examination/signalment, objective radiographic measurements (VHS, VLAS), and blood test (SDMA, creatinine, blood urea nitrogen, NTproBNP, ultrasensitive cardiac troponin I) variables were explored as clusters to identify significant variables by cluster that were carried forward into the final models. Each testing modality was considered a separate cluster (four clusters in total). N-terminal pro B-type natriuretic peptide and VHS had the best discriminatory ability as individual diagnostic tests to differentiate stage A and B1 from stage B2, with an area under the curve (AUC) of 0.855 and 0.843, respectively. An NT-proBNP ≥1138 pmol/L or a VHS ≥11.5 had high specificity for predicting stage B2 (90.1% and 90.6%, respectively). Prediction models incorporating variables from multiple tests had better discriminatory ability than single tests. The four-test prediction model had an AUC of 0.971. Three- and two-test models had AUCs ranging between 0.925– 0.959 and 0.895–0.949, respectively. In summary, both NT-proBNP and VHS have good utility for predicting stage B2 MMVD in CKCS as individual tests. Prediction models for stage B2 MMVD in CKCS incorporating variables from more than one testing modality have superior discriminatory ability. This highlights the value of a more comprehensive approach to staging, using a variety of combinations of readily available diagnostic tests to identify dogs that would most benefit from confirmatory echocardiography, or alternatively, to establish a diagnosis of stage B2 with acceptable clinical accuracy if echocardiography is not available. These data also emphasize positive impact of breed-specific approaches on overall accuracy.

Reference Values of M-mode Echocardiographic Parameter in Adult Toy Breed Dogs. Noriko Isayama, Yusuke Uchimura, Kenta Sasaki, Erika Maeda, Toshihisa Takahashi, Megumi Watanabe. Front. Vet. Sci. June 2022; doi: 10.3389/fvets.2022.918457. Quote: Introduction: Myxomatous mitral valve disease (MMVD) is one of the most common heart diseases in dogs, and there is a dearth of reports that have investigated reference values for left ventricular end-diastolic internal diameter corrected for body weight (LVIDDN) exclusively in toy breeds. Animals: Eighty-six client-owned healthy dogs weighing <5 kg, including Toy Poodles, Chihuahuas, Yorkshire Terriers, Papillon, and other small breeds or small mixed breeds (mixed breed, Pomeranian, dachshund, Shih Tzu, and Maltese). In this retrospective single-center study, data were collected from dogs attending clinic for annual checkup between April 2014 and March 2021. Materials and methods: Experienced echocardiographers performed transthoracic echocardiography, with reference ranges established using healthy dogs. Measurements of body weight (BW), heart rate, and several echocardiographic variables were obtained. The association between BW and echocardiographic parameters was assessed by linear regression analyses. M-mode measurements were obtained and normalized using equations developed from the regression analyses. Results: The LVIDDN value for 95% of dogs weighing <5 kg was achieved by dividing the M-mode measurement by BW raised to the power 0.332. The upper limit of the prediction interval for breeds weighing <5 kg was much lower than the value currently applied. ... Taking all 86 dogs into account, when we calculated LVIDDN as measured LVIDD/BW0.294, according to the ACVIM consensus statement, the median LVIDDN value was 1.3215 and the mean value was 1.3204, the observed minimum and maximum were 0.9214 and 1.6072, respectively, while in the first and third quartiles, the values were 1.2472 and 1.4140, respectively. Notably, none of these values approached 1.7, the threshold value proposed previously, and was clinically followed by the ACVIM consensus statement. A natural corollary of this observation is that since the normal range for dogs <5 kg is <1.7, the possibility is high that by the time these toy breed dogs start receiving treatment, according to the current guidelines of diagnosis criteria of stage B2 of MMVD, they already reach a very advanced stage of the disease. Previous reports, including the EPIC study, focused mainly on dogs with BW >4 kg, and the diagnostic criteria for toy breed dogs remain mostly unexplored. Therefore, along with diagnostic criteria, we should consider starting treatment as B2 for dogs weighing <5 kg with an LVIDDN of ≥1.6. ... Instead of the current threshold of LVIDDN ≥1.7, we propose a value of ≥1.6 to be included in the B2 criterion of the ACVIM consensus statement and guide clinicians in deciding when to start treatment of mitral valve disease in small breed dogs for small breed dogs. ... The results of our study will guide clinicians in deciding when to start treatment for MMVD in small breed dogs.

Evaluation of new and old biomarkers in dogs with degenerative mitral valve disease. Stephanie Klein, Ingo Nolte, José Luis Granados-Soler, Philipp Lietz, Maximiliane Sehn, Jonathan Friedemann Raue, Karl Rohn, Eva-Maria Packeiser, Jan-Peter Bach. BMC Vet. Res. July 2022; doi: 10.1186/s12917-022-03343-z. Quote: Background: Dogs with degenerative mitral valve disease are commonly presented to small animal clinicians. Diagnosis, clinical staging, and therapeutic design are based on a combination of clinical examination, radiography, and echocardiography. To support diagnosis and clinical monitoring, a multi-marker-based approach would be conceivable. The aim of this study was to investigate the suitability of Galectin-3 and interleukin-1 receptor-like 1 protein (ST2) in dogs with degenerative mitral valve disease in accordance with N-terminal-prohormone-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI). For this purpose, serum concentrations of Galectin-3 and ST2 of 64 dogs [4 cavalier King Charles spaniels (6.3%)] with different stages of mitral valve disease and 21 dogs without cardiac disease were analyzed at the first examination and six months later. Echocardiography, blood cell count and clinical chemistry were performed and established biomarkers NT-proBNP and cTnI were measured additionally. Differences in the biomarker concentrations between all groups at both timepoints and the change in biomarker concentrations from first to second evaluation was investigated. Furthermore, correlations of each biomarker, between biomarkers and echocardiographic measurements, were calculated. Finally, the receiver-operating characteristic curve and the area under the curve analysis were performed to differentiate between disease stages and controls. Results: Serum concentrations of Galectin-3 and ST2 were not statistically different between canine patients in the respective stages of mitral valve disease or in comparison to dogs in the control group at any timepoint. A significant increase in ST2 concentrations from the baseline to the follow-up examination was observed in dogs classified as stage B1 and the control group. The concentrations of NT-proBNP and cTnI in stage C dogs were significantly increased in comparison to the other groups. ... In conclusion, the results of the present study provide evidence that the new biomarkers Galectin-3 and ST2 are both measurable biomarkers in the canine patient. However, neither for Galectin-3 nor for ST2, significant differences in serum concentrations between the different dogs with or without DMVD, and across clinical stages of DMVD were found. Thus, it might indicate that they are unsuitable for diagnosing and staging canine DMVD patients. On the other hand, as results of the current study suggest, serial measurements of ST2 might be helpful for monitoring the disease progression, response to treatment, and could be a valid approach in conjunction to survival analysis. As the results concerning Galectin-3 concentrations from the current study and former studies are discordant, the usefulness of Galectin-3 in heart disease should be further investigated. In agreement with previous reports, the diagnostic value of NT-proBNP and cTnI for detecting dogs with severe DMVD was confirmed. Reliable differentiation between the different preclinical stages of DMVD was not possible in our study with any of the examined biomarkers. Furthermore, the identification of other meaningful cardiac biomarkers for canine cardiac patients and the development of a multimarker strategy for diagnosing and staging DMVD, and individual treatment modifications in dogs are worth pursuing and should be continued, though our results indicate that ST2 and Galectin-3 may be of limited value to achieve this goal.

Evaluation of endothelial cell-specific molecule-1 as a biomarker of glycocalyx damage in canine myxomatous mitral valve disease. Hee‑Jeong Hong, Ye‑In Oh, Su‑Min Park, Ju‑Hyun An, Tae‑Hee Kim, Hyung‑Kyu Chae, Kyoung‑won Seo, Hwa‑Young Youn. BMC Vet. Res. July 2022; doi: 10.1186/s12917-022-03344-y. Quote: Background: Endothelial cell-specific molecule-1 (ESM-1) has emerged as a potential biomarker for cardiovascular disease in humans. Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs, and we hypothesized that MMVD causes chronic inflammation that increases susceptibility to endothelial glycocalyx (eGCX) damage. ... and that eGCX could be an index of worsening and progression of heart failure. ... In this study, we evaluated the relationship between eGCX damage and MMVD in dogs, using serum ESM-1 concentrations. The correlation between ESM-1 concentration and other factors such as vital signs, echocardiographic parameters, medication, and underlying diseases was also estimated. ... In this study, we measured the concentration of ESM-1 in a group of dogs with MMVD and evaluated factors affecting eGCX damage. Results: Sixty-four dogs (control, n = 6; MMVD, n = 58) were enrolled in this study. There was no significant difference in serum ESM-1 concentrations among the MMVD stages. The serum ESM-1 concentration was significantly higher in the death group than in the alive group in MMVD dogs. In five dogs with MMVD, serum ESM-1 concentrations tended to decrease when the cardiac drug (pimobendan, furosemide, and digoxin) dose was increased. Conclusions: In cases where MMVD progressed to decompensated heart failure with clinical symptoms and resulted in death, the concentration of serum ESM-1 increased significantly. Therefore, ESM-1 could be utilized as a new potential negative prognostic factor in patients with MMVD.

Effects of Coenzyme Q10 Supplementation on Oxidative Stress Markers, Inflammatory Markers, Lymphocyte Subpopulations, and Clinical Status in Dogs with Myxomatous Mitral Valve Disease. Natalia Druzhaeva, Alenka Nemec Svete, Gabrijela Tavčar-Kalcher, Janja Babič, Alojz Ihan, Katka Pohar, Uroš Krapež, Aleksandra Domanjko Petrič. Antioxidants. July 2022; doi: 10.3390/antiox11081427. Quote: Scarce data exist on the effects of coenzyme Q10 (CoQ10) supplementation in dogs with myxomatous mitral valve disease (MMVD). The purpose of this study was to investigate the effect of CoQ10 supplementation on oxidative stress markers (glutathione peroxidase, F2-isoprostanes), markers of inflammation (tumor necrosis factor-α, TNF soluble receptor II, leucocytes, and their subtypes), lymphocyte subpopulations (T helper and cytotoxic T lymphocytes, including activated T lymphocytes, and B lymphocytes), and echocardiographic and clinical parameters in dogs with MMVD. In this randomized, controlled, double-blind, longitudinal study, 43 MMVD dogs [including 16 (37%) cavalier King Charles spaniels] in stages ACVIM (American College of Veterinary Internal Medicine classification) B2 and ACVIM C and D (congestive heart failure (CHF)) received water-soluble coenzyme Q10 [ubiquinone] (100 mg twice daily) or placebo for 3 months, and 12 non-supplemented healthy dogs served as controls. All parameters were measured before and after supplementation in MMVD dogs and once in healthy dogs. CoQ10 supplementation had a positive impact on neutrophil percentage, lymphocyte percentage, and lymphocyte concentration in our cohort of dogs with CHF (ACVIM C and D). ... After the three-month supplementation period, plasma CoQ10 concentrations were significantly higher in the CoQ10-supplemented group than in the placebo-supplemented group in ACVIM B2 and CHF dogs. No other parameters differed significantly in either patient group. ... A daily dose of 200 mg of CoQ10 (given as 100 mg twice per day) was well-tolerated and significantly increased plasma CoQ10 concentration in both CoQ10-supplemented groups (ACVIM B2 and CHF) in comparison to their basal concentrations and to the concentration of plasma CoQ10 measured in corresponding placebo groups. ... In both patient groups, ACVIM B2 and CHF, a significantly higher change (increase) in plasma CoQ10 concentration was observed in the CoQ10-supplemented groups compared with the change in this parameter in the corresponding placebo groups. ... No significant adverse effects were noticed during the study. Short-lived diarrhea which did not require treatment was noted in 3 out of 23 dogs receiving CoQ10 and in 4 out of 20 dogs receiving placebo during the study period. ... The positive effect of CoQ10 supplementation may be the result of CoQ10’s anti-inflammatory properties. ... Our study is the first to report the possible benefits of oral CoQ10 supplementation in combating inflammation in dogs with CHF. ... No positive effects of CoQ10 supplementation on echocardiographic parameters were detected in our study. ... [I]n both groups of our MMVD patients (ACVIM B2 and CHF), plasma CoQ10 concentration was significantly higher in comparison to that in healthy dogs. ... Of all parameters assessed, only neutrophil percentage and lymphocyte percentage and concentration were positively affected by supplementation, which may indicate the anti-inflammatory role of CoQ10 in systemic inflammation in dogs with CHF due to MMVD. Studies with a longer supplementation period and a larger number of dogs or studies examining the effect of CoQ10 on survival are warranted. ... Conclusion: CoQ10 as an oral supplement may have benefits in terms of decreasing inflammation in dogs with MMVD and CHF.

Dose-response of benazepril on biomarkers of the classical and alternative pathways of the reninangiotensin-aldosterone system in dogs. Samantha Sotillo, Jessica L. Ward, Emilie Guillot, Oliver Domenig, Lingnan Yuan, Joseph S. Smith, Vojtech Gabriel, Chelsea A. Iennarella-Servantez, Jonathan P. Mochel. Res. Square. July 2022; doi: 10.21203/rs.3.rs-1858200/v1. Quote: Angiotensin-converting enzyme inhibitors (ACEI) such as benazepril are commonly prescribed in both humans and dogs with heart disease to mitigate the renin-angiotensin-aldosterone system (RAAS); however, the dose-dependent effects of benazepril on comprehensive RAAS components remain unknown. In this study, nine purpose-bred healthy dogs received three different dosages of oral benazepril (0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg) in a randomized crossover design following induction of RAAS activation by consuming a low-sodium diet ... (Hill's Prescription Diet h/d; 17 mg sodium per 100kcal, 0.08% sodium on a dry matter basis) at 23:00 PM once daily for five days to attain a steady activation of RAAS. ... Blood samples were collected at serial time intervals after benazepril dosing to measure plasma benazeprilat (active metabolite of benazepril) and serum RAAS biomarkers. Blood pressure and echocardiogram were performed at baseline and after each benazepril administration. Time-weighted averages for RAAS biomarkers for 12 hours post-dose and hemodynamic variables were compared between dosing groups using Wilcoxon rank-sum testing. Compared to the lowest dosage of benazepril (0.125 mg/kg), the highest dosage (0.5 mg/kg) resulted in lower time-weighted average values of angiotensin (Ang) II (-38%, P = 0.004), Ang1-5 (-53%, P = 0.001), ACE-S (surrogate for ACE activity; -59%, P = 0.0002), and ALT-S (surrogate for alternative RAAS activity; -22%, P = 0.004), and higher values of AngI (+ 78%, P = 0.014) and PRA-S (surrogate for plasma renin activity; +58%, P = 0.040). There were no relevant differences between dosing groups for blood pressure or echocardiographic variables. Knowledge of dose-dependent alterations in biomarkers of the classical and alternative RAAS pathways could help inform clinical trials for dosage optimization in both dogs and humans.

Cardiac MRI may not detect myocardial ischemia and fibrosis in dogs with cardiomegaly secondary to myxomatous mitral valve disease. William A. Clark, Randolph L. Winter, Turi K. Aarnes, Eric M. Green, Katarzyna Mikrut, Patrick Ruz, Daniel Addison, Jaylyn D. Rhinehart, Karsten E. Schober, Harry T. Friel. Am J, Vet. Res. August 2022; doi: 10.2460/ajvr.22.05.0076. Quote: Objective: ... (1) to determine whether cardiac MRI could be used to detect myocardial ischemia and fibrosis in healthy dogs and dogs with cardiomegaly secondary to naturally acquired MMVD [myxomatous mitral valve disease] and (2) to investigate whether circulating biomarker concentrations could be used as predictors of myocardial changes identified on cardiac MRI. We hypothesized that myocardial ischemia and fibrosis would be present in some dogs with MMVD, that serum cTnI concentrations would be high in dogs with myocardial ischemia, and that serum galectin-3 concentrations would be high in dogs with myocardial fibrosis. ... Animals: 6 dogs [including 4 cavalier King Charles spaniels] (67%) with cardiomegaly secondary to naturally occurring stage B2 MMVD being treated only with pimobendan with or without enalapril and 6 control dogs with no cardiac disease. All dogs were ≥5 years old with no systemic illness. Procedures: Serum cardiac troponin I and concentrations were measured, and dogs were anesthetized for cardiac MRI with ECG-triggered acquisition of native T1- and T2-weighted images. Gadolinium contrast was administered to evaluate myocardial perfusion and late gadolinium enhancement (LGE). Mean T1 and T2 values and regions of LGE were measured with dedicated software. Extracellular volume (ECV) was estimated on the basis of Hct and T1 values of myocardium and surrounding blood. Subjective analysis for myocardial perfusion deficits was performed. Results: Dogs with MMVD had significantly higher cardiac troponin I concentrations than control dogs, but galectin-3 concentrations did not differ between groups. Myocardial fibrosis was detected in 4 dogs with MMVD and 3 control dogs; no dogs had obvious myocardial perfusion deficits. Native T1 and T2 values, postcontrast T1 values, and ECV values were not significantly different between groups. ... To our knowledge, no veterinary clinical trial has thus far demonstrated a significant survival benefit when dogs with preclinical MMVD have been treated with angiotensin-converting enzyme inhibitors. The lack of significant differences in myocardial fibrosis between healthy dogs and those with MMVD may explain these historical findings in part. Four dogs with MMVD and 3 control dogs in our study did have evidence of LGE [late gadolinium enhancement], suggesting that focal areas of myocardial fibrosis were present. The interpretation of this finding is challenging. The fact that both groups were represented similarly suggests that dogs with advanced MMVD may not develop focal areas of myocardial fibrosis significantly more often than what may occur during the normal aging process. However, the number of dogs studied here was relatively low, and further investigation is warranted. ... Clinical Relevance: Results suggest that some dogs with cardiomegaly secondary to MMVD may not have clinically relevant myocardial fibrosis.

Echocardiographic measurement of the mitral valve in normal Cavalier King Charles spaniels: repeatability, optimal future study methods, and preliminary reference intervals. Sonya Wesselowski, Ashley B. Saunders, Stephen Werre, Sonya G.Gordon. J. Vet. Cardiol. August 2022; doi: 10.1016/j.jvc.2022.08.001. Quote: Introduction: Objectives: Cavalier King Charles spaniels (CKCS) are ideal candidates for longitudinal study of myxomatous mitral valve disease and stage B1 clinical trials, however optimization of mitral valve (MV) measurement acquisition and repeatability must be better defined to realize this potential. Additionally, breed-specific reference ranges for CKCS MV measurements are lacking. Study objectives were to assess measurement repeatability and define optimal methods for longitudinal study of echocardiographic MV anatomy and to define preliminary, 2-dimensional echocardiographic reference ranges for MV measurements in CKCS. Animals: Forty CKCS between 10-24 months old. Materials and Methods: Pre- and post-sedation 2-dimensional echocardiographic images optimized for the MV were obtained. The length, width and area of the anterior and posterior leaflets and the diameter of the MV annulus at end-diastole and end-systole were measured. Measurement repeatability was assessed using % coefficient of variation and repeatability coefficients. Results: Intraoperator repeatability was best for the operator with previous MV measurement experience, with comparable results for the experienced operator measuring the second operator’s images, mimicking a core echocardiography laboratory setting. Except for MV annulus diameter at end-systole, sedation had no significant effect on any MV measurements, nor did it impact measurement repeatability. Preliminary, breed-specific reference ranges were defined for the population, with CKCS often noted to have larger annular diameter at end-systole than end-diastole. ... The MV apparatus is both a complex structure and a delicate one ..., making measurement of the MV a challenging task. Taking these factors into consideration, the primary objective of this study was to assess the repeatability of MV measurements in CKCS, including the potential impact of sedation on repeatability, and to better define the optimal logistics required to plan a longitudinal MV study in this breed. ... Furthermore, sedation with butorphanol could be used as needed for study participants requiring anxiolysis with no impact on MV measurements with the possible exception of MVAs. ... One of the most challenging aspects of obtaining repeatable MV measurements lies in consistent delineation of MV leaflet boundaries compared to chordal attachment points. The anterior leaflet of the canine MV has an average of 24 chordae tendineae attaching to it while the posterior leaflet has an average of 18. This results in many attachment points where chordae tendineae might be inadvertently measured along with the actual anterior or posterior MV leaflets. ... In the authors opinion, identification of trace MR on a screening echocardiogram should not result in a definitive diagnosis of MMVD in the absence of other anatomic findings, rather that the dog should be 363 longitudinally evaluated to monitor for any evidence of progressive change, receiving an equivocal cardiac screening distinction at worst. ... There is already strong evidence that the presence of moderate or severe MR in CKCS between 1-3 years of age carries an increased risk of cardiac mortality later in life, thus this finding should reasonably prompt removal from the breeding pool. ... Conclusions: Optimal methods for longitudinal study of the MV in CKCS have been proposed, as have 2-dimensional preliminary echocardiographic reference ranges for CKCS MV measurements. The MV annulus in CKCS may differ from other breeds.

Digoxin for atrial fibrillation: good, but not too good: a case report. Gustavo Luiz Gouvêa de Almeida, Marcelo Barbosa de Almeida, Ana Carolina Mendes dos Santos, Ângela Vargas, Sophie Ballot, Elaine Waite Souza. Acta Vet. Brasilica. August 2022; doi: 10.21708/avb.2022.16.3.10837. Quote: Digoxin is a cardiotonic glycoside that is traditionally used for the treatment of heart failure and atrial fibrillation in humans and animals. However, the use of digoxin is still a challenge in clinical practice due to its narrow therapeutic range and its potential interaction with several drugs, which could facilitate the development of toxicity. A 12-year-old Labrador retriever was referred with a clinical diagnosis of heart failure and atrial fibrillation, anorexia, vomiting, and diarrhea. He had been medicated with digoxin, furosemide, lisinopril, and amiodarone. The patient also showed clinical signs of hip osteoarthritis and received firocoxib for four days. He additionally received drugs for gastrointeritis. The electrocardiogram demonstrated atrial fibrillation and signs of digitalis toxicity. Laboratory examination showed a high concentration of plasma digoxin, and 5 days after withdrawal of the drugs, the symptoms disappeared, as did the digitalis effects seen in the previous electrocardiogram. ... The aim of this case presentation was to describe the clinical, laboratory, echocardiographic, and electrocardiographic manifestations of Digitalis toxicity in a dog treated for AF. The focus was on directing clinicians’ attention to the use of digoxin and the value of interpretation of clinical manifestations, laboratory examination, and serial electrocardiograms to identify the presence of Digitalis toxicity. Early suspicion and recognition of Digitalis toxicity are crucial for the proper treatment of this potentially lethal condition.

The leaflet-annulus index in canine myxomatous mitral valve disease. Mitsuhiro Isaka, Shinichi Hisada, Ryuji Araki, Hiroshi Ueno. Res. Vet. Sci. August 2022; doi: 10.1016/j.rvsc.2022.08.004. Quote: Myxomatous mitral valve disease (MMVD) is the most common chronic heart valve disease, leading to the eccentric hypertrophy. Recently, the leaflet-annulus index (LAI), which focuses on the mitral valve apparatus, has been considered a prognostic factor for human mitral regurgitation (MR); however, it has not been reported in veterinary medicine. In the present study, we retrospectively evaluated the LAI in dogs with MMVD. ... Leaflet-annulus index (LAI) is calculated from the AP [anteroposterior] length and the lengths of the anterior and posterior mitral leaflets. ... Eighty-three dogs [including 9 (10.8%) cavalier King Charles spaniels] with MMVD diagnosed using echocardiography were included in this study. The anteroposterior length, anterior and posterior cusp coaptation lengths, LAI, left ventricular end-diastolic internal diameter normalized to body weight (LVIDDN), and left atrium to aorta ratio (LA/Ao) were measured. A significant correlation between the LAI, LVIDDN, and LA/Ao of MR grading, and left ventricle dilation was observed. ... In this study, LAI correlated significantly with LVIDDN and LA/Ao, i.e., the chronic volume overload from MR causes the left ventricle to expand (as the stage increases), which in turn causes the mitral annulus to expand, resulting in FMR [functional mitral regurgitation -- MR occurring due to ventricular remodeling]. These results suggest that LAI is a useful indicator of annular widening; further studies on the measurement method are warranted. ... In conclusion, LAI could help determine annular widening, suggesting the decision of an appropriate for SVR in clinical settings.

Surgical treatment for left atrial rupture due to myxomatous mitral valve disease in three dogs: A case report. Tomohiko Yoshida, Katsuhiro Matsuura, Cheng Chieh-Jen, Yuki Aboshi, Shusaku Yamada, Hideki Yotsuida, Mizuki Hasegawa, Hanan A. Hendawy, Hussein M. El-Husseiny, Yusuke Takahashi, Yuki Oonuma, Youta Yaginuma, Shou Fukuzumi, Ryou Tanaka. Vet. Med. & Sci. August 2022; doi: 10.1002/vms3.915. Quote: Introduction: Myxomatous mitral valve degeneration (MMVD) is an acquired heart disease which sometimes result in pulmonary oedema and left atrial rupture. ... Although left atrial rupture has been reported as a rare consequence of MMVD in dogs, left atrial rupture can cause rapid bleeding and cardiac tamponade, and in some cases sudden death. Sometimes, as a result of left atrial rupture, left atrial pressure may decrease and bleeding may stop. ... In previous reports, left atrial rupture has been non-surgically controlled and its prognosis investigated. ... There is, however, no report concerning surgically treated left atrial rupture and follow-up results. Here we present three cases [all chihuahuas] of left atrial rupture caused by MMVD, in which Mitral valvuloplasty (MVP) was performed. Depending on the site of rupture and pericardial adhesion, the surgical procedure was adjusted to cope with each specific situation. All three cases achieved long-term survival, with complete cessation of cardiac medication. ... Objectives: This report aimed to develop a surgical strategy for a case of left atrial rupture caused by MMVD. Materials and methods: Three dogs were presented at a private hospital for surgical treatment of MMVD. All three dogs had a previous history of left atrial rupture due to MMVD. The left atrium rapture was diagnosed from indicating that characteristics of the drained pericardial effusion consistent with blood. Mitral valvuloplasty was performed in all dogs using an extracorporeal circulation machine, and the surgical procedure was modified according to each case. In cases with severe adhesion between the pericardial and left atrial appendage, suturing of the left atrial appendage was performed strategically. Additionally, in cases with severe hypotension caused by left atrial rupture, cardiopulmonary bypass was started as soon as possible during the surgical procedure. Discussion and Conclusion: Since the haemodynamics of all dogs had improved, and the owner reported no cardiac-related clinical signs, all drugs were withdrawn 3 months after surgery. Since left atrial rupture due to MMVD can cause hypotension, cardiopulmonary bypass should be started as soon as possible during the surgical procedure to maintain the blood pressure and suturing of the left atrial appendage should be performed strategically.

Beraprost Sodium for Pulmonary Hypertension in Dogs: Effect on Hemodynamics and Cardiac Function. Ryohei Suzuki, Yunosuke Yuchi, Takahiro Saito, Yuyo Yasumura, Takahiro Teshima, Hirotaka Matsumoto, Hidekazu Koyama. Animals. August 2022; doi: 10.3390/ani12162078. Quote: Pulmonary hypertension (PH) is a fatal condition that affects many dogs. In humans, PH is often treated with beraprost sodium (BPS). However, the effectiveness of BPS for canine PH has not been established. This study aimed to evaluate the clinical and cardiovascular response of BPS in canine patients with PH of various causes. Sixteen dogs with PH (post-capillary PH, n = 8; pre-capillary PH, n = 8) were included. BPS was continuously administered twice daily at 15 µg/kg. All dogs underwent echocardiography, including speckle-tracking analysis and blood pressure measurement, before and after BPS administration. Continuous BPS administration (range: 13.2–22.0 µg/kg) significantly decreased the pulmonary and systemic vascular impedance and increased left and right ventricular myocardial strain. In dogs with post-capillary PH, BPS administration caused no significant worsening of the left atrial pressure indicators. No side effects of BPS were observed in any dog. BPS also improved cardiac function and pulmonary circulation through pulmonary vasodilation, suggesting that BPS may be an additional treatment option for canine PH of various causes. Particularly, BPS increased left ventricular function and systemic circulation without worsening the left heart loading condition in dogs with post-capillary PH.

Caudal pulmonary artery to vein ratio on radiography can predict pulmonary hypertension in dogs with mitral regurgitation. Sang-Kwon Lee, Jihye Choi. Vet. Radiol. & Ultrasound. September 2022; doi: 10.1111/vru.13145. Quote: Pulmonary hypertension (PH) is an important predictor of poor outcomes in dogs with mitral regurgitation (MR). The feasibility of radiography to predict PH in dogs with MR is unknown. This retrospective, observational, and analytic study aimed to identify a radiographic parameter to predict PH in dogs with MR. A total of 302 dogs diagnosed with MR on echocardiography were enrolled. Medical record and radiographic findings such as the size of the main pulmonary artery, left atrium, left ventricle, and right chamber, and cranial and caudal pulmonary arteries and veins were evaluated according to the presence of PH. The diameters of the cranial and caudal pulmonary vessels were compared to the fourth rib and the ninth rib, respectively, and the ratio of the pulmonary artery to the corresponding vein (CdPA/CdPV) was calculated. Pulmonary hypertension was diagnosed in 77 dogs (25.5%) and the prevalence of PH increased with MR grade. The CdPA/CdPV was significantly higher in the presence of PH. Multivariate analysis showed that the CdPA/CdPV was the only independent radiographic parameter that had a significant association with PH in dogs with MR. The cut-off value of the CdPA/CdPV = 1.10 showed 90.6% specificity and 31.1% sensitivity for detecting PH in dogs with MR. In dogs with MR, PH can be predicted with high specificity when the caudal pulmonary artery is 1.1 times larger than the corresponding vein on radiographs.

Breed-specific values for vertebral heart score (VHS), vertebral left atrial size (VLAS), and radiographic left atrial dimension (RLAD) in pugs without cardiac disease, and their relationship to Brachycephalic Obstructive Airway Syndrome (BOAS). Pia Saskia Wiegel, Rebekka Mach, Ingo Nolte, Fritjof Freise, Charanthorn Levicar, Kristina Merhof, Jan-Peter Bach. PlosOne. September 2022; doi: 10.1371/journal.pone.0274085. Quote: This prospective study aims to establish reference ranges for vertebral heart score (VHS), vertebral left atrial size (VLAS), and radiographic left atrial dimension (RLAD) in pugs. The impact of clinical severity of Brachycephalic Obstructive Airway Syndrome (BOAS), gender, body condition score, and body weight on VHS, VLAS, and RLAD were investigated. Intra- and interobserver correlation was determined. Correlation of radiographic scores to echocardiographic left atrial dimension was inspected. Additionally, for VLAS and RLAD, correlation to VHS was examined. Additionally, an assessment of thoracic and vertebral malformations was performed. Forty-seven privately owned pugs underwent physical examination, echocardiography, and thoracic radiography to determine cardiac health. Thirty-two pugs were eligible for establishing reference ranges for VHS in right lateral radiographs, which was 11.25 ± 0.62 (95% range, 10.1–12.8). Reference ranges for VHS in left lateral, and for VLAS and RLAD in right lateral radiograph were determined in 30 pugs. The VHS in left lateral radiograph was 11.01 ± 0.70 (95% range, 9.4–12.6), VLAS was 1.96 ± 0.38 (95% range, 1.1–2.8), and RLAD was 1.59 ± 0.34 (95% range, 0.7–2.4). ... LA:Ao: 1.32 mean; 0.97 - 1.62 range. ... Clinical severity of BOAS did not show any impact on radiographic measurements. For VLAS, a significant correlation to VHS was detected by all observers. No other variables had a consistent influence on the radiographic scores given by all observers. Interobserver agreement was almost perfect for VHS (0.89 on right lateral and 0.91 on left lateral image), moderate for VLAS (0.49), and fair for RLAD (0.22). More than one third of the entire study population (18 of 47 pugs) showed at least one thoracic cavity or spine abnormality, often leading to considerable changes in vertebral body shape and size.

Preliminary prospective study on the predictive significance of plasma miR-30b-5p through the study of echocardiographic modifications in Cavalier King Charles Spaniels affected by different stages of myxomatous mitral valve disease: the PRIME study. Sara Ghilardi, Cristina Lecchi, Mara Bagardi, Giovanni Romito, Fabio M. Colombo, Michele Polli, Celeste Franco, Paola G. Brambilla. bioRxiv. September 2022; doi: 10.1101/2022.09.05.506710v1. Quote: Specific microRNAs expressions may accurately characterize different stages of canine myxomatous mitral valve disease. This preliminary study aimed to (1) describe the clinical and echocardiographic parameters of Cavalier King Charles Spaniels affected by myxomatous mitral valve disease at different American College of Veterinary Internal Medicine (ACVIM) stages (B1, B2 and C) and healthy control group (ACVIM A), comparing the parameters collected during the first examination (T0) and the end of the follow-up (T1); (2) assess the association between the values of echocardiographic parameters at T1 and the expression profile of miR-30b-5p at T0. Thirty-five Cavalier King Charles Spaniels (median age 4.29 years and median weight 9 Kg) in different ACVIM stages were included (7 A, 19 B1, 6 B2 and 3 C). Inverse probability weighting analysis was performed to estimate the association of the exposure variable (miR-30b-5p) with the outcome variables (clinical and echocardiographic variables). Time was included as variable. The results pointed out that high levels of plasma miR-30b-5p corresponded to lower values of left ventricular end-diastolic diameter normalized for body weight, end-diastolic and end-systolic volumes indexed for body weight, and left atrium-to aortic root ratio. Hence, higher miR-30b-5p expressions were associated with milder forms of mitral valve disease in our study population. In contrast, the results obtained for the intensity of heart murmur, the mitral regurgitation severity, and the Mitral INsufficiency Echocardiographic score) were not statistically significant. A relationship between high abundance of miR-30b-5p and myxomatous mitral valve disease that appear echocardiographically more stable over time has been demonstrated. In conclusion, Cavalier King Charles Spaniels affected by myxomatous mitral valve disease that at the first cardiologic evaluation showed an upregulation of miR-30b-5p are expected to experience lesser variations on their echocardiographic examination between T0 and T1.

Effect of standard-dose and high-dose pimobendan on select indices of renal and cardiac function in dogs with American College of Veterinary Internal Medicine stage B2 myxomatous mitral valve disease. Joanna L. Kaplan, Lance C. Visser, Catherine T. Gunther-Harrington, Eric S. Ontiveros, Luke A. Wittenburg, Carrie A. Palm, Joshua A. Stern. J. Vet. Intern. Med. September 2022; doi: 10.1111/jvim.16537. Quote: Renal dysfunction might complicate clinical management and adversely impact quality of life and outcome in dogs with MMVD. Therefore, it is important to understand how drugs used in the clinical management of MMVD affect renal function. ... In contrast to other drugs used in the management of MMVD (vasodilators, diuretics), pimobendan does not activate the renin angiotensin aldosterone system (RAAS). ... Background: Pimobendan might have favorable effects on renal function but this has not been well-studied in dogs with myxomatous mitral valve disease (MMVD). Objectives: Determine the effects of standard-dose (SD_pimo) and high-dose pimobendan (HD_pimo) on glomerular filtration rate (GFR) and cardiac size and function in dogs with preclinical MMVD. Animals: Thirty nonazotemic dogs with stage B2 MMVD. ... Thirty-one dogs with ACVIM stage B2 MMVD were enrolled in this study. One dog was withdrawn from the study at its owner's request due to perceived behavior changes of aggression toward the owner and ataxia after receiving several doses of the study medication (later determined to be HD_pimo). Thus, 30 dogs completed the study. ... Twelve dogs were enrolled in each pimobendan group [including 3 cavalier King Charles spaniels in the HD-pimo group (25%)] and 6 were enrolled in the placebo group [including 1 CKCS (17%)]. ... No adverse effects, adverse clinical events or clinical signs were reported in any of the dogs that completed the study. ... Methods: Prospective, randomized, double-blinded, placebo-controlled clinical study. Dogs had an echocardiographic examination, assessment of GFR (iohexol clearance), N-terminal probrain natriuretic peptide (NT-proBNP), and quality of life (QOL) score at baseline and 7 to 10 days after placebo (n = 6), SD_pimo 0.2 to 0.3 mg/kg q12 (n = 12), or HD_pimo 0.5 to 0.6 mg/kg q12h (n = 12). Results: ... Results of this study did not support our hypothesis that pimobendan increases GFR (as assessed by iohexol clearance) in nonazotemic dogs with ACVIM stage B2 MMVD. The study did document changes in cardiac chamber size, systolic function and NT-proBNP secondary to both SD_pimo and HD_pimo that are presumed to be beneficial. ... No significant differences in GFR or QOL scores were detected between groups. After HD_pimo, the mean [SD] percent change of NT_proBNP (−46.1 [20.2]%), left atrial volume (LAV; −27.1 [16.9]%), left ventricular end-diastolic volume (EDV; −21.8 [15.0]%), and end-systolic volume (ESV; −55.0 [20.7]%) were significantly different from placebo (0.5 [19.9]%, 1.3 [15.6]%, −0.2 [8.2]%, −7.3 [35.6]%, respectively) but not the percent change after SD_pimo (−36.6 [16.1]%, −22.7 [14.9]%, −16.7 [12.5]%, −41.6 [14.8]%, respectively). After SD_pimo, percent change of NT_proBNP, LAV, EDV, and ESV were significantly different from placebo. Conclusions and Clinical Importance: Results suggest that pimobendan (SD_pimo or HD_pimo) might not affect renal function in nonazotemic dogs with stage B2 MMVD. High-dose pimobendan did not demonstrate advantages over SD_pimo within the constraints of our study. ... Thus, our study supports the hypothesis that any enhanced renal blood flow to due pimobendan's positive effect on cardiac output might be limited by renal arterial vasodilation.

Étude rétrospective clinique, écho-Doppler et pronostique chez 500 chiens atteints de maladie valvulaire dégénérative mitrale avec rupture de cordage (2009–2019). (Retrospective clinical, echo-Doppler and prognostic study in 500 dogs with degenerative mitral valve disease with cord rupture ( 2009–2019)). C. Poissonnier. Revue Vet. Clinical. September 2022; doi: 10.1016/j.anicom.2022.09.005. Quote: Introduction: Degenerative mitral valve disease (MVDM) is the most frequent acquired heart disease in dogs, with small breeds being the most represented. This valvulopathy can be complicated by valve prolapse with rupture of one or more tendinous cords (RDC), which can lead to the onset or deterioration of congestive heart failure (CHF). Different types of cord can be affected and visible on echocardiography: a DRC is said to be primary when the rupture can be observed on several cuts, or secondary when it is only observed on a single cut. Furthermore, a chordal tear can affect the anterior mitral leaflet (AM) or the posterior mitral leaflet (PMF). The objectives of this retrospective study were to describe the epidemiological characteristics ... Material and methods: Were retrospectively included dogs for which an echocardiographic diagnosis of MVDM with RDC had been made between 2009 and 2019. A descriptive statistical analysis of epidemiological, clinical, echocardiographic and Doppler parameters was performed (median, interquartile range [IQR]). A univariate survival analysis (Kaplan Meier) was performed, and exposures associated with survival were sought. ... Results: A total of 500 small format dogs with MVDM with DRC were included. They were mainly old dogs (median (IQR) = 11.2 years [9.0–13.0]), small format (7.0 kg [4.9–9.1]), mainly males (male to female ratio = 2.0). The most represented breed was the Cavalier King Charles (136/500, 27%). Most dogs had functional clinical signs (77%), including cough (61%) and dyspnoea (25%). A grade left apex systolic murmur ... Discussion and conclusion: To our knowledge, this is the first study specifically analyzing the type of CDR during MVDM. The results show that, although the stage of MVDM is more advanced during primary CDR at the time of diagnosis, no statistical association could be identified between cardiac death and the type of cord involved. Interestingly, the median overall survival here is much longer (27 months) than that found in a previous study, published almost 15 years ago. ...

Whole blood and plasma taurine reference intervals in adult Cavalier King Charles Spaniels and correlations between taurine concentration, diet and mitral valve disease. Sonya Wesselowski, Amanda B. Blake, Sonya G. Gordon, Jan S. Suchodolski, Joerg M. Steiner. J.A.V.M.A. September 2022; doi: 10.2460/javma.22.07.0280. Quote: Objective: To determine breed-specific reference intervals for whole blood (WB) and plasma taurine concentrations in adult, overtly healthy Cavalier King Charles Spaniels (CKCSs) and determine whether taurine concentrations differ across preclinical myxomatous mitral valve disease (MMVD) stages or between CKCSs eating diets that meet World Small Animal Veterinary Association (WSAVA) nutritional guidelines versus other diets. Animals: 200 privately owned CKCSs. Procedures: Clinically healthy adult CKCSs were recruited prospectively. Diet and supplement history was collected. Dogs were staged by echocardiography using MMVD consensus guidelines. Taurine concentrations were measured in deproteinized lithium heparin WB and plasma samples with the postcolumn ninhydrin derivatization method on a dedicated amino acid analyzer. Results: There were 12 stage A (6%), 150 stage B1 (75%), and 38 stage B2 (19%) CKCSs. Seventy-eight dogs (39%) were reported by their owners to be eating diets meeting WSAVA nutritional guidelines; 116 (58%) were not. Taurine concentrations in plasma and WB were not significantly different across MMVD stages or between CKCSs eating diets meeting WSAVA nutritional guidelines versus other diets. Reference intervals for WB taurine (152 to 373 µM) and plasma taurine (51 to 217 µM) concentrations in CKCSs were generated. Clinical Relevance: In CKCSs, taurine concentrations do not differ significantly based on preclinical MMVD stage, nor do they differ significantly based on consumption of a diet that does or does not meet WSAVA nutritional guidelines. (See related entry here.)

Methods of Radiographic Measurements of Heart and Left Atrial Size in Dogs with and without Myxomatous Mitral Valve Disease: Intra- and Interobserver Agreement and Practicability of Different Methods. Charanthorn Levicar, Ingo Nolte, José Luis Granados-Soler, Fritjof Freise, Jonathan Friedemann Raue, Jan-Peter Bach. Animals. September 2022; doi: 10.3390/ani12192531. Quote: Dogs suffering from Myxomatous Mitral Valve Disease (MMVD) show a potential heart enlargement, especially in the left atrium, detectable by radiography. Due to digital radiography, different radiographic measurements estimate cardiac size quite uncomplicatedly. The Vertebral Heart Size (VHS), Radiographic Left Atrial Dimension (RLAD), Left Atrial Width (LAWidth), and the Vertebral Left Atrial Size (VLAS) used anatomical landmarks for measuring cardiac size in relation to the vertebral column. This study aimed to compare VHS, RLAD, LAWidth, and VLAS measured in conventional and inverted radiographs by veterinarians with different levels of experience in healthy dogs and dogs with MMVD. The reliability and user-friendliness of these measurements were evaluated, and the staging was compared to the echocardiography staging. A total of 50 unaffected dogs and 150 dogs with MMVD in stages B1, B2, and C were assessed. ... The dogs included represented 69 breeds; mixed breed dogs made up the largest group numerically (n = 35), followed by Dachshund (n = 13), Cavalier King Charles Spaniel (n = 9), Chihuahua (n = 9), Jack Russell Terrier (n = 9), Labrador Retriever (n = 9), and Pug (n = 8). ... In total, 1200 radiographic evaluations were performed based on 200 conventional radiographs and 200 corresponding inverted radiographs by three observers. ... Analyses were performed to compare the measurements’ grading and determine anatomical landmarks with measurement difficulties. Additionally, inter- and intraobserver agreement was assessed using intraclass correlation coefficient, and the agreement between radiographic and echocardiographic staging was compared using the kappa coefficient. The VHS, LAWidth, and VLAS were easier to define than the RLAD. The interobserver agreement was almost perfect for VHS (0.962) and good for the other radiographic measurements (RLAD: 0.778, LAWidth: 0.772, VLAS: 0.858). The VHS assigned the most dogs to the correct stage. However, VHS, RLAD, LAWidth, and VLAS presented an almost perfect intraobserver agreement. The dorsal left atrial margin of the RLAD was the most difficult measurement point to identify. The VHS is the most reproducible radiographic method for measuring the canine heart size and shows the highest agreement with echocardiography. An observer-related influence could be detected for RLAD, LAWidth, and VLAS. ... Considering that VLAS was easier to apply than LAWidth, VHS and VLAS seem the obvious choices for radiographic evaluation of the canine heart in the future. The evaluation of the different radiographic landmarks showed that the dorsal margin of the LA was especially challenging, and the cranial margin of the cardiac silhouette was comparatively easy to identify. In addition to the subjectively more straightforward method of radiographic measurements in conventional radiographs, no differences could be detected between the radiographic methods.

Differences in mitral valve morphology between Cavalier King Charles Spaniels with mild mitral regurgitation and without mitral regurgitation. G. Menciotti, M. Borgarelli, A. Franchini, S.M. Lahmers, H.W. Jeong. 32d ECVIM-CA Congress; ESVC-O-2. September 2022; doi: 10.1111/jvim.16559 (pg 8). Quote: Mitral valve (MV) morphology is an important determinant of leaflet stress which in turn has been implicated in the pathogenesis of the most common canine cardiac disease, myxomatous valvular degeneration (MMVD). Particularly, MMVD is extremely prevalent in Cavalier King Charles Spaniels (CKCS) at a young age. In this study, we used transthoracic three-dimensional echocardiography (3DTTE) to evaluate the MV morphology of CKCS with low-grade murmurs (<3/6) and no more than mild mitral regurgitation (MR). We hypothesized that CKCS with mild MR (MR+), would have a MV of different morphology compared to CKCS without MR (MR-). MR was quantified subjectively by color Doppler evaluation of the MV in all standard echocardiographic planes. Full-volume 4-beat 3DTTE datasets of the MV were acquired during the same examination and analyzed using dedicated software. Eighty dogs were prospectively enrolled; 41 had no murmur, 13 had a grade 1/6 murmur, 26 had a grade 2/6 murmur. The MV of MR+ was significantly different from MR-. Particularly, MR+ had bigger annular diameters, circumference, and area. Both leaflets had larger areas and length in MR+. The angle between both anterior and posterior leaflets and the annulus was reduced in MR+. These findings indicate that CKCS with only mild MR have MV morphological differences compared to CKCS without MR. This further supports previous research suggesting a role of MV morphology in the pathophysiology of MMVD, and further investigation of a causative link is warranted.

 Analysis of pimobendan prescriptions in small breed dogs with myxomatous mitral valve disease using Electronic Health Records in Primary Care Veterinary Practices in the United Kingdom. M. Silva, E. Bode, D. Singleton, M. Hezzell , H. Hodgkiss-Geere. 32d ECVIM-CA Congress; SCH-O-1. September 2022; doi: 10.1111/jvim.16559 (pg 8). Quote: Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disease reported in dogs and is often managed in primarycare veterinary practices. The use of pimobendan in MMVD has been reported to delay the onset of congestive heart failure by 15 months, as described in the EPIC study. This study aimed to determine whether pimobendan prescription increased following market authorization in 2017, describe the population characteristics and use of diagnostic tests reported in electronic health records (EHRs) from UK primary veterinary practices compared to those used in the EPIC study. EHRs describing 2,945,591 consultations (861,814 unique dogs) were gathered (between 22nd November 2013 and 31st December 2018) by the Small Animal Veterinary Surveillance Network (SAVSNET) from 224 veterinary practices. Free-text clinical narratives were manually read to identify first pimobendan prescriptions. Dogs were excluded if in the 6 months prior to the prescription of pimobendan they were: prescribed any medication other than pimobendan, diagnosed with a systemic disease, congenital or acquired cardiac disease, or had a pregnancy diagnosis. Diagnostic tests were categorised as “recommended” if these were advised before pimobendan prescription, and “suggested” if these were not deemed necessary for pimobendan prescription. Annual variation in pimobendan prescriptions were analysed using mixed effects binomial regression models. Pimobendan prescriptions increased in 2018 vs. 2017. 110 dogs met the inclusion criteria. 59 female (53.6%), 51 male (46.4%), 50 Cavalier King Charles spaniels (45.5%), 12 crossbreed (10.9%) and 11 Jack Russell terriers (10%). Recorded murmur grades were as follows: 1 (n=7, 6.4%), 2 (n=21, 19.1%), 3 (n=38, 34.5%), 4 (n=25, 22.7%), 5 (n=16, 14.5%), 6 (n=3, 2.7%). Recorded presenting complaints included cough (n=41, 37.3%), exercise intolerance (n=16, 14.5%), syncope (n=9, 8.2%). Performed and recorded diagnostic tests prior to pimobendan prescription were as follows: echocardiography (n=36, 32.7%), thoracic radiography (n=5, 4.5%), NT-proBNP measurement (n=4, 3.6%), while 6 were referred for further evaluation (5.4%). Recorded recommendations included echocardiography (n=17, 15.4%), thoracic radiography (n=6, 5.4%) and referral (n=5, 4.5%). 7 had echocardiography suggested (6.3%). In 34 dogs, no diagnostic tests were recorded as being offered (30.9%). Considering that the conclusions of the EPIC study are only relevant for dogs with significant cardiac remodelling, most dogs still had pimobendan prescribed without recorded evidence of assessment of cardiomegaly, either by echocardiography or thoracic radiography. Treatment with pimobendan is expensive and prescribing it to patients who might not benefit from it could impose an unnecessary economic burden on the client.

Genetic susceptibility of canine myxomatous mitral valve disease. M. Hezzell, M. Wallace, J. Wilshaw, A. Boswood, L. Davison. 32d ECVIM-CA Congress; SCH-O-1. September 2022; doi: 10.1111/jvim.16559 (pg 14). Quote: Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disease affecting adult dogs, often leading to congestive heart failure (CHF). A genetic component is suggested by strong breed predispositions e.g. Cavalier King Charles Spaniel (CKCS). Novel therapies directed at underlying patho-physiological mechanisms are urgently needed. We hypothesize that a combination of genetic variants contribute to risk of MMVD and CHF in CKCS, and may offer new treatment targets. Some variants may be at high frequency in the breed, and others present at higher frequency in CKCS with earliest onset CHF compared to CKCS with late onset CHF. The aims of this study were to 1) identify genetic variants associated with early onset of CHF in CKCS with MMVD and 2) to explore these variants further in a validation cohort. Archived surplus blood or buffy coat samples from a total of 142 client- owned dogs with MMVD were used for this case-control genotyping study including 121 CKCS. Whole-genome sequencing (WGS) of a discovery cohort of 12 CKCS with MMVD was undertaken at 30X coverage on the Illumina platform. Additional unpublished WGS data was available from 48 dogs across 7 breeds for comparison, as well as data in public databases (e.g. Dog Biomedical Variant Database Consortium). A bespoke bioinformatics workflow based on Genome Analysis Tool Kit (GATK) best practices identified c.2000 variants of potential cardiovascular relevance. These were either high frequency within CKCS compared to other breeds, or at highest frequency in CKCS with earliest-onset CHF. Variants were prioritized further and validated by two rounds of targeted high throughput sequencing based genotyping of additional cohorts. In addition to CKCS, additional dogs with MMVD from 7 further breeds were included in follow up genotyping (1-4 dogs per breed). Additional targeted sequencing genetic data were available from a total of 165 dogs without MMVD across 9 breeds. We identified >100 variants of potential importance in CKCS MMVD and associated CHF. Notably, many significant variants were located in genes and biological pathways with potential for therapeutic intervention, including transcriptional regulation, calcium signaling, cell adhesion, inflammation, and wound healing. Evaluation of the impact on gene and cell function of the genetic variants associated with MMVD and CHF in MMVD is now required. These findings offer novel pathway targets for pharmacological intervention and future precision treatment of MMVD and CHF.

Validation of a focused echocardiographic training program in first opinion practice. David Dickson, Joanne Harris, Chia-Hsuan Chang, Mark Patteson, Melanie J. Hezzell. J. Vet. Intern. Med. October 2022; doi: 10.1111/jvim.16539. Quote: Background: The EPIC study defines criteria, including echocardiographic assessments of left atrial to aortic ratio (LA: Ao) and left ventricular internal diameter in diastole normalized for body weight (LVIDdN), for dogs with preclinical myxomatous mitral valve disease (MMVD) likely to benefit from pimobendan therapy. Access to echocardiography by a cardiologist is not universally available. Hypothesis/Objectives: Completion of a focused echocardiographic training program would result in accurate identification of dogs fulfilling the EPIC criteria by primary care veterinarians (PC). Participants: Six PCs with no previous echocardiographic experience. Methods: Prospective diagnostic test accuracy study. After training, each PC evaluated ≤10 dogs that they believed to have preclinical MMVD. The evaluation was repeated by 1 of 3 cardiology diplomates, blinded to the PC's findings. Agreement between clinical assessments and echocardiographic measurements was assessed. Results: Fifty-seven dogs [including 18 (32%) cavalier King Charles spaniels] were evaluated by PCs; 1 dog was withdrawn because of congestive heart failure. The median time between PC and cardiologist evaluation was 0 days (range, 0-8). One incorrect diagnosis of MMVD was made by a PC (this dog had dilated cardiomyopathy [DCM]); preclinical MMVD was confirmed by the cardiologist in 55 dogs. No difference in LA: Ao (P = .96; CV = 6.9%) was detected between PCs and cardiologists. LVIDdN (1.69 cm/kg0.294 (1.26-2.21) vs 1.73 cm/kg0.294 (1.32-2.73); P = .001; CV = 6.5%), was significantly lower when measured by PCs vs cardiologists. PCs and cardiologists agreed regarding assessment of EPIC criteria in 49/56 dogs (Alpha = .761, 95% confidence interval 0.697-0.922). Conclusions and Clinical Importance: The program effectively trained PCs to accurately assess EPIC criteria in dogs with preclinical MMVD.

Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels. Sophie E. Mead, Niek J. Beijerink, Mitchell O’Brien, Claire M. Wade. Genes. December 2022; doi: 10.3390/genes13122292. Quote: The most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually high prevalence of early-onset MMVD, and thus, potentially greater cardiac morbidity and mortality compared to other breeds. Previous research has suggested that selected candidate risk alleles for MMVD are fixed in CKCSs, including six locations within the Nebulette (NEBL) gene on CFA2. The current study analysed genotypes of 180 Australian CKCSs at the identified risk loci. Of these, 178 were phenotyped for severity of disease by echocardiographic measurements of left atrium to aortic root ratio (LA:Ao) and weight normalised left ventricular end diastolic diameter (LVIDdN). Genotyping array markers correctly predicted the genotype at the risk-variant loci in the CKCS population, and the NEBL1, NEBL2 and NEBL3 variants were observed to be in perfect linkage disequilibrium in this cohort. The CKCS cohort included 6/178 dogs being heterozygous for the protective/wild-type alleles at the NEBL locus. ... Our results find that variation exists at the previously identified MMVD risk loci, and that heterozygous animals at the NEBL1-3 loci have smaller heart sizes, as indicated by LA:Ao and LVIDdN values. ... In agreement with Axelsson et al., this study identifies that of the variants considered, NEBL1-3 are the most physiologically significant. It is expected that the dogs heterozygous for wild-type alleles at these loci will experience reduced risk of mortality as a result of their lower LVIDdN and LA:Ao measurements. ... Mutations in the nebulette gene appear to be associated with heart enlargement, possibly due to a poorer quality cytoskeletal framework of cardiomyocytes. Our results showing smaller heart measurements in dogs exhibiting the wild-type allele at the NEBL variant locations are expected due to the known function of nebulette. ... The mean LA:Ao and LVIDdN scores of these dogs heterozygous at NEBL1-3 variants were significantly smaller, and with significantly lower variance compared to age-matched CKCSs that were homozygous for risk alleles. The lower cardiac measurements in the heterozygous dogs indicate a significantly reduced risk of severe MMVD disease. Our analysis suggests that despite relative fixation of the NEBL risk alleles, healthy reference alleles at NEBL1-3 exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality. ... Once identified, the frequency of these favourable alleles can be increased if the right tools are made available to CKCS breeders. Since heterozygosity for the wild-type NEBL allele seems to reduce MMVD severity, CKCS breeders should plan to increase wild-type allele prevalence into the gene pool. There are two methods to accomplish this. The first is to apply genetic testing to identify registered CKCSs carrying the wild-type NEBL allele. Subsequently, breeders could be selecting for the wild-type allele, not against the derived allele, taking into consideration that selection for the wild-type allele should not reduce the gene pool too much. Second, breeders could introduce animals to the registry via an indexing scheme that enables the introduction of unregistered dogs (potentially of other breeds) carrying the wild-type NEBL allele into the registry system for this breed. While crossbreeding is a viable option for improving heart health in the CKCS, rules across many canine registries currently preclude this approach and such rules will likely take a long time to change. Selection for favourable dominant alleles present in the breed can be applied immediately.

The heart to single vertebra ratio: A new objective method for radiographic assessment of cardiac silhouette size in dogs. Dario Costanza, Adelaide Greco, Diego Piantedosi, Dario Bruzzese, Maria Pia Pasolini, Pierpaolo Coluccia, Erica Castiello, Cláudia Sofia Baptista, Leonardo Meomartino. Vet. Radiol. & Ultrasound. December 2022; doi: 10.1111/vru.13201. Quote: Vertebral heart size (VHS) is widely determined in clinical practice as an objective method to assess the cardiac silhouette dimensions. However, a key limitation is that it is difficult to determine VHS in dogs with vertebral alterations. This retrospective, method comparison, observer agreement study sought to overcome this limitation by using the heart-to-single vertebra ratio (HSVR), by evaluating the level of agreement between VHS and HSVR, as well as the intra- and inter-observer agreement for HSVR. Three independent observers retrospectively evaluated thoracic radiographs obtained over a set time period. Exclusion criteria were the presence of alterations of the thoracic spine and the inability to clearly outline the cardiac silhouette. The lengths of the vertebral bodies, from the fourth to eighth thoracic vertebra, and VHS were measured on each radiograph. The HSVR was calculated by dividing the sum of the cardiac long and short axes by the length of each vertebral body. Eighty dogs of different breeds were included in the final analysis. Lin's concordance correlation coefficients revealed strong correlations between VHS and HSVR (0.91–0.96), and the Bland–Altman plots showed low bias (0.01–0.2) between the methods. The mean absolute errors indicated low average magnitudes of error (0.11–0.28). The intraclass correlation coefficients showed good to excellent inter-observer (0.87–0.92; P = 0.000) and intra-observer (0.87–0.99; P < .001) agreement. In the authors’ opinion, this new method, which is less time consuming and more objective, could offer a valuable alternative to VHS.

Comparison of different radiographic scores with associated echocardiographic measurements and prediction of heart enlargement in dogs with and without myxomatous mitral valve disease. C. Levicar, J.L. Granados-Soler, F. Freise, J.F. Raue, I. Nolte, J.-P. Bach. J. Vet. Cardiol. December 2022; doi: 10.1016/j.jvc.2022.08.004. Quote: Introduction: Staging of myxomatous mitral valve disease (MMVD) requires an echocardiographic examination along with thoracic radiographs. The aims of this study were to calculate mean values for radiographic scores vertebral heart size (VHS), left atrial width (LAWidth), radiographic left atrial dimension (RLAD), and vertebral left atrial size (VLAS) in conventional and grayscale inverted images in healthy dogs and dogs with different stages of MMVD, and to find cutoff values for a stage assignment. Animals: One hundred fifty dogs [of 69 different breeds, including 7 cavalier King Charles spaniels] in different stages of MMVD and 50 unaffected dogs [including 2 CKCSs] were evaluated. A total of 50 patients in each MMVD stage (stages B1, B2, and C according to the ACVIM Consensus Statement) and 50 patients in the control group were included in this study. ...  Methods: Radiographic scores, echocardiographic left atrium-to-aorta ratio and normalized left ventricular internal dimension at end-diastole, and results of a clinical examination were obtained. Analyses were performed to evaluate the correlation between radiographic scores and echocardiographic values, to determine cutoff values for a radiographic stage assignment, and to compare measurements in conventional and inverted radiographs. Results: After excluding breed-specific higher VHS, the means of VHS, LAWidth, RLAD, and VLAS were similar in the control group and stage B1. ... In this study, which was the first to compare all four mentioned radiographic scores, LAWidth showed to have the most diagnostic accuracy in differentiation between stages B1 and B2. ... All radiographic scores increased in stages B2 and C. The cutoff values identifying heart enlargement, and therefore differentiating stages B1 and B2, were 11.0 for VHS, 1.8 for LAWidth, 2.0 for RLAD, and 2.3 for VLAS. Besides RLAD, scores were similar in conventional and inverted radiographs. Conclusion: Cutoff values for the different radiographic scores for stage assignment were calculated. Radiographic cardiac scores using either conventional or inverted grayscale could be a tool to differentiate between different stages of MMVD when echocardiography is unavailable.

Prognostic significance of left cardiac enlargement in dogs with preclinical myxomatous mitral valve disease. G. Grosso, T. Vezzosi, O. Domenech, R. Tognetti. J. Vet. Cardiol. December 2022; DOI: 10.1016/j.jvc.2022.12.004. Quote: Introduction: According to the most recent consensus guidelines on canine myxomatous mitral valve disease (MMVD), dogs with only left atrial enlargement (LAE) or left ventricular enlargement are classified as stage B1. The concomitant presence of LAE and left ventricular enlargement is needed to be classified as stage B2. The primary aim of the study was to evaluate prognosis in stage B1 and stage B2 according to the revised definition. The secondary aim was to assess the prognostic relevance of LAE in stage B1. Animals: Four hundred forty dogs with MMVD ... The most frequently represented breeds were mixed-breed dogs (n=157), then Cavalier King Charles Spaniel (n=60), Dachshund (n=31), Chihuahua (n=30), Poodle (n=27), Jack Russel Terrier (n=16), Yorkshire Terrier (n=15), Pinscher (n=13), Maltese (n=11), Spitz (n=10) and the remaining 70 dogs were of 25 other different breeds. ... 276 in stage B1 and 164 in stage B2. ... According to the 2019 ACVIM classification, 276 dogs were in stage B1 and 164 dog were in stage B2. Regarding the presence of a heart murmur in stage B1, 72% of dogs presented a systolic left apical murmur while the remaining 28% did not present a heart murmur. All stage B2 dogs presented a systolic left apical murmur. Among stage B1, 173 dogs (63%) had no left cardiac enlargement, 73 (26%) had only LAE, and 30 (11%) had only LVE. By definition all B2 dogs presented both LAE and LVE. [left ventricular enlargement]. ... Materials and methods: Retrospective, observational study. The left atrium-to-aorta ratio (LA:Ao) and the left ventricular end-diastolic diameter normalized (LVIDdn) were used to define cardiac dimensions. Long-term outcome was assessed by telephone interviews with owners and referring vets. Both cardiac-related and all-cause mortality were evaluated. Results: ... At the end of the study, 273 dogs (62%) were still alive, and 167 dogs (38%) had died. Regarding causes of death, 72/167 dogs (43%) experienced a cardiac-related death and the remaining 95/167 dogs (57%) died due to non-cardiac-related causes. Among dogs experiencing a cardiac-related death, 23/72 (32%) were in stage B1 and 49/72 (68%) were in stage B2. The main cardiac-related causes of death were: cardiac-related euthanasia in 35/72 dogs (49%), cardiogenic pulmonary edema in 26/72 (36%), and sudden death in 11/72 (15%). Among dogs experiencing a non-cardiac-related death, 53/95 (56%) were in stage B1 and 42/95 (44%) were in stage B2. ... Stage B1 dogs had longer median survival time than stage B2 considering both cardiac-related death (2344 versus 1341 days) and all-cause mortality (1832 versus 855 days). Age, LA:Ao and LVIDdn were independent predictors of cardiac-related death and all-cause mortality. Among stage B1, dogs with LAE lived shorter than those without LAE (1183 versus 1882 days) considering all-cause mortality. Conclusions: Stage B1 dogs lived longer than stage B2 dogs. Among stage B1, LAE had prognostic significance considering all-cause mortality. This finding could add useful prognostic information in the management of preclinical MMVD.

Echocardiographic evaluation of regurgitant fraction in dogs with subclinical myxomatous mitral valve disease: Method comparison, effects of pimobendan, and reproducibility. R. E. Ellis-Reis, L. C. Visser, W. Hsue, A. N. Sharpe, J. L. Kaplan. J. Vet. Cardiol. December 2022; doi: 10.1016/j.jvc.2022.12.002. Quote: Introduction/ Objectives: To evaluate regurgitant fraction (RF) using Simpson's method of discs to estimate total stroke volume (RFSMOD_TSV) and using Motion-mode to estimate total stroke volume (RFM-modeTSV) in dogs with subclinical myxomatous mitral valve disease (MMVD). We also sought to evaluate the effects of pimobendan on RF, and to determine the reproducibility of RFSMOD_TSV and RFM-modeTSV. Animals, materials, and methods: Echocardiography was performed on 57 dogs with MMVD (30 stage B1 and 27 stage B2). Ten dogs received pimobendan for 7–10 days and had a second echocardiogram. Nine dogs underwent six repeated echocardiographic examinations by two operators on three nonconsecutive days within one week for reproducibility analysis. Results: Both RFSMOD_TSV and RFM-modeTSV exhibited a curvilinear relationship with left atrium-to-aortic root ratio. Both RFSMOD_TSV and RFM-modeTSV varied considerably within stage B1 (minimum–maximum: −9.1%–58.2% and −35.7%–66.2%, respectively) and B2 (13.6%–76.2% and 20.1%–85.7%, respectively). Method comparison showed RFSMOD_TSV and RFM-modeTSV were not interchangeable with proportional bias. Pimobendan significantly reduced RFSMOD_TSV (−32.0 ± 23.3%) and RFM-modeTSV (−19.2 ± 10.9%) within the same dog and relative to controls. Good inter-day and between-operator reproducibility was observed for RFSMOD_TSV and RFM-modeTSV based on intraclass correlation coefficients 0.86–0.90 and 0.83–0.90, respectively. Reproducibility coefficients were 19.6–24.1% and 24.1–27.0%, respectively. Conclusions: Use of RF using the total stroke volume method to aid the assessment of dogs with subclinical MMVD might be of clinical value. However, further study is warranted. Based on response to pimobendan and reproducibility analysis, RF SMOD_TSV might be a more reliable technique to quantify RF.

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2023

 Association of Paraoxonase-1 and NT-proBNP with Clinical, Clinico-Pathologic and Echocardiographic Variables in Dogs with Mitral Valve Disease. Diana Rammal, Christos K. Koutinas, Labrini V. Athanasiou, Melpomeni Tangalidi, Camila P. Rubio, José J. Cerón, Androniki Tamvakis, Michael N. Patsikas, Zoe S. Polizopoulou. Vet, Sci. January 2023; doi: 10.3390/vetsci10010033. Quote: The objective of the present study was to measure the concentration of Paraoxonase-1 (PON-1) and N-terminal-prohormone-B-type natriuretic peptide (NT-proBNP), in the serum of dogs with degenerative Mitral Valve Disease (MVD), in order to identify their association with the clinical stage and specific clinico-pathologic and echocardiographic findings. Eighty dogs[including 14 (17.5%) cavalier King Charles spaniels] diagnosed with MVD and staged according to the ACVIM (American College of Veterinary Internal Medicine) consensus statement (B1, B2, C and D), based on their clinical, radiographic, and echocardiographic findings, were included in the study. NT-proBNP was measured only in stage B1 and B2 dogs. ... Clinical Stage of MVD: LA/Ao: Stage B1 (n+31), mean 1.22 (1.1-1.3); Stage B2 (n=30), mean 1.46 (1.4-1.6) ... LVIDdn: Stage B1 mean 1.77 (1.5-1.9); Stage B2 mean 2.07 (1.7-2.2) ... Clinical stage did not have a significant effect on PON-1 concentrations, but NT-proBNP levels were lower in B1 dogs. A significant correlation between PON-1 and total plasma proteins, albumin and white blood cell count was detected, whereas there was no significant correlation between PON-1 and NT-proBNP concentrations.PON-1 showed a significant but weak negative correlation with normalized left ventricular internal diameter at diastole (LVIDdn) and systole (LVIDsn), as well as mitral valve E to A wave velocity ratio (MV E/A), but not with Left Atrial to Aortic root ratio (LA/Ao) or fractional shortening (FS%). PON-1 seems to be an insensitive marker of clinical stage and disease severity in MVD, but can be indicative of some clinico-pathological and echocardiographic changes. NT-proBNP changes are independent of oxidative stress. ... NT-proBNP concentration is significantly higher in stage B2 compared to B1 and is significantly and strongly correlated with echocardiographic parameters of cardiomegaly and congestion.

Mitral valve transcriptome analysis in thirty-four age-matched Cavalier King Charles Spaniels with or without myxomatous mitral valve disease. Maria J. Reimann, Signe Cremer, Liselotte Christiansen, Emil Ibragimov, Fei Gao, Susanna Cirera, Merete Fredholm, Lisbeth H. Olsen, Peter Karlskov-Mortensen. Res. Square January 2023; doi: 10.21203/rs.3.rs-2458329/v1. Quote: We here report the results of a mitral valve transcriptome study designed to identify genes and molecular pathways involved in development of myxomatous mitral valve disease (MMVD) in dogs. The study is focused on a cohort of elderly age-matched dogs (n=34, age ~10 years) from a single breed – Cavalier King Charles Spaniels – with a high incidence of MMVD. The cohort comprises 19 dogs (10♀, 9♂) without MMVD, or with early stages of MMVD [the majority in Stages B1 or B2] and 15 dogs (6♀, 9♂) with congestive heart failure caused by MMVD. I.e. we compare gene expression in breed and age matched groups of dogs, which only differ with respect to severity of disease. ... Privately owned CKCS with no MMVD or different stages of MMVD were recruited at time for elective euthanasia at Department of Veterinary and Animal Sciences, University of Copenhagen. ... [T]he objective of the present study is to identify differentially expressed (DE) genes, which may explain the difference in MMVD progression in two groups of elderly dogs, which resemble each other very closely except for their MMVD status. ... We identify 56 genes, which are differentially expressed between the two groups. In this list of genes, we confirm an enrichment of genes related to the TNFβ signaling pathway, extracellular matrix organization, vascular development, and endothelium damage, which also have been identified in previous studies. ... We primarily found a number of genes upregulated in dogs with no/early MMVD and only a few genes down regulated in this group. Many of the upregulated genes play a central role in mechanisms, which can be considered beneficial for heart maintenance. Hence, a relevant question is, why some dogs (the no/early MMVD dogs) could institute an appropriate response to whatever caused the disease, and why some dogs (the severe MMVD dogs) did not do this? Among the DE genes identified in the present study, ALDH1A2 and RDH10 formed a small high confidence functional network together with the additional interactor CYP26A1. ... Both genes [ALDH1A2 and RDH10] encode proteins, which are predicted to have an effect on the contractile activity of myocardial cells, which in turn may have an effect on valvular performance and hemodynamics across the mitral valve. This may result in shear forces with impact on MMVD progression. ... Hence, we suggest that the observed changes in expression of ALDH1A2 and RDH10 may be a compensatory reaction to MMVD rather than a cause of disease. The interpretation of our results is thus that dogs, which upregulate expression of these two genes, have a better chance of not developing CHF due to MMVD. Why some dogs had an appropriate up regulation of these genes and why some did not, needs to be investigated further. Overall, it must be expected that compensatory mechanisms to disease, including MMVD, are established and managed in an orchestrated way, which in a transcriptome analysis will appear as networks of functionally related genes expressed in a coordinated manner. Hence, it is not surprising that many of the genes in the identified larger networks are involved in mechanisms such as TGFβ-signaling and ECM organization. Abundance of myxomatous effector proteins has previously been shown to increase in response to increased tensile strain on the heart valves. TGFβ-signaling and disturbances in ECM organization have also been suggested as primary causes of MMVD. However, the present results, i.e., the apparent well-orchestrated expression of genes related to these pathways, encourage us to suggest that these pathways were upregulated as a well-regulated compensatory mechanism to MMVD in ~ 10 years old dogs with no/early MMVD. This up-regulation resulted in a more benign development of the disease, i.e., a disease that did not progress into severe MMVD with CHF. On the other hand, the genes with the greatest difference in expression between no/early MMVD and severe MMVD were three genes, MYH1, LOC102724058 and CNTN3, which were not part of the identified gene networks. I.e., they were not part of an orchestrated response to disease but might instead be possible causative agents of disease. ... Based on these observations, we suggest that the primary cause of MMVD in CKCS may be found in a gene coding for one of the heart muscle proteins. However, the conclusion based on the present results is that an appropriate upregulation of MYH1 and downregulation of CNTN3, as a response to a so far unknown causative factor, can protect a dog with MMVD from developing CHF. An alternative conclusion is that an inappropriate downregulation and upregulation of MYH1 and CNTN3, respectively, in CKCS with MMVD may lead to development of CHF.

Electrocardiographic findings in healthy Cavalier King Charles Spaniels, Pugs, and English Bulldogs. Giovanni Romito, Prisca Castagna, Maria Chiara Sabetti, Mario Cipone. J. Am. Vet. Med. Assn. January 2023; doi: 10.2460/javma.22.12.0542. Quote: Objective: To describe the ECG findings in 3 different canine brachycephalic breeds: the Cavalier King Charles Spaniel, the Pug, and the English Bulldog (EB). Animals: 135 healthy dogs (50 Cavalier King Charles Spaniels, 50 Pugs, and 35 EBs). Procedures: Medical records were retrospectively reviewed to identify healthy dogs ≥ 1 year old that had undergone an ECG. The Mann-Whitney U test or the Student t test were used to compare continuous variables between male and female dogs, whereas the χ2 test was used for categorical variables. Spearman correlation coefficients between ECG measurements and age and body weight were also calculated in the case of continuous variables, whereas the Kruskal-Wallis test was used for categorical ones. Results: Electrocardiographic parameters of healthy Cavalier King Charles Spaniels overall fitted with traditional reference intervals cited in textbooks; in contrast, 28% of Pugs and 20% of EBs showed a shift of the QRS-complex mean electrical axis (QRS-MEA). In Pugs and EBs, the mean/median QRS-MEA value was 56° (from 0° to 100°) and 59° (from 20° to 100°), respectively. All axis shifts were left shifts (in Pugs, from 0° to 34°; in EBs, 20° to 39°). Only a few meaningful differences were found when comparing ECG variables between males and females. Similarly, only 1 statistically significant correlation was found between ECG parameters and age and body weight. Clinical relevance: Healthy Pugs and EBs present a trend to a left shift of the QRS-MEA. This should be considered when interpreting ECG tracings in these breeds.

The Thoracic Inlet Heart Size, a New Approach to Radiographic Cardiac Measurement. David Marbella Fernández, Verónica García, Alexis José Santana, José Alberto Montoya-Alonso. Animals. January 2023; doi: 10.3390/ani13030389. Quote: In 1995, the Vertebral Heart Size (VHS) method for measuring the cardiac silhouette on thoracic radiographs was published, becoming a quantifiable and objective reference way of assessing the heart size. Since then, many studies have showed that VHS is influenced by breed variations, vertebral malformations, reference points selection, and short and long axes dimensions conversion into vertebral units. The Thoracic Inlet Heart Size (TIHS) normalizes heart size to body size using the thoracic inlet length. The lengths of the long and short axes of the heart of 144 clinically normal dogs [including one cavalier King Charles spaniel] were measured on right lateral thoracic radiographs. The sum of both measures was indexed to the thoracic inlet length. For comparison, dogs of the most represented breeds in our hospital were selected to measure their heart size using the TIHS protocol. The mean TIHS value for the population studied was 2.86 ± 0.27, and 90% of dogs had a TIHS value of less than 3.25. There was no difference in TIHS between male and female, and between small and large dogs. There was no difference in the TIHS value between Yorkshire Terrier, Chihuahua, and Labrador retriever breeds, and between each of those three breeds and the general population. The TIHS is a simple, straightforward and accurate way to measure heart size.

 Long-term histological effects of high-dose prednisolone administration on the mitral valve in normal Beagle dogs. Sachiyo Tanaka, Shuji Suzuki, Misaki Shimura, Asaka Kawana, Aki Tanaka, Satoshi Soeta, Yasushi Hara. Open Vet. J. February 2023: doi: 10.5455/OVJ.2023.v13.i2.3. Quote: Background: In recent years, left ventricular hypertrophy and cardiac dysfunction have been reported in human and canine patients with hypercortisolism (HAC) and in dogs treated experimentally with high-dose prednisolone. However, to our knowledge, there have been no reports on the effects of hyperglucocorticism (HGC) on the mitral valve (MV). Aim: This study aimed to compare the MV in dogs treated with high-dose prednisolone with that in healthy dogs to investigate the effects of HGC on the MV. Methods: We investigated the effects of HGC on the MV by comparing samples obtained from high-dose glucocorticoid-treated (P) and healthy (C) dogs. The P group included healthy Beagle dogs (n = 6) treated with prednisolone (2 mg/kg, bid, po) for 84 days and the C group included healthy Beagle dogs (n = 6) euthanized for unrelated reasons. The anterior and posterior mitral leaflets (AML and PML, respectively) from both groups were harvested and stained with hematoxylin–eosin, Alcian blue, and Masson trichome. Additionally, adiponectin (ADN) and glucocorticoid receptor immuno-histochemistry were performed. Histological evaluation was performed in the atrialis, spongiosa, fibrosa, and all layers of the proximal, middle, and distal regions of the AML and PML. Results: The proportion of the spongiosa layer thickness to the total thickness was higher in the P than in the C group (proximal and middle AML). However, the proportion of the fibrosa layer thickness to the total thickness was lower in the P than in the C group (middle PML). Areas of acidic sulfated mucosubstance deposition were smaller in the fibrosa layer and all layers (middle AML), while those of collagen deposition were smaller in the spongiosa and total layers (proximal and middle AML), in the P than in the C group. Additionally, ADN expression in the spongiosa layer was higher in the P than in the C group (middle AML). Conclusion: These findings suggest that long-term administration of synthetic glucocorticoids induces histological changes in the MV. These changes may lead to MV dysfunction in dogs with HGC. ... Therefore, prolonged administration of synthetic GCs or the presence of HAC in dogs with chronic valvular disease, the most common cardiac disease in dogs, may further contribute to mechanical abnormalities in the MV.

A Retrospective Study of Radiographic Measurements of Small Breed Dogs with Myxomatous Mitral Valve Degeneration: A New Modified Vertebral Left Atrial Size. Soyon An, Gunha Hwang, Seul Ah Noh, Young-Min Yoon, Hee Chun Lee, Tae Sung Hwang. J. Vet. Clin. February 2023; doi: 10.17555/jvc.2023.40.1.31. Quote: Vertebral left atrial size (VLAS) is an important indicator to predict myxomatous mitral valve degeneration (MMVD) in dogs. When the caudal margin of cardiac silhouette and the dorsal margin of caudal vena cava (CdVC) could not be seen exactly, another way to evaluate VLAS is needed. The objective of this study was to assess whether a new modified VLAS (m-VLAS) could be used as an indicator to predict MMVD in 57 small breed dogs with MMVD. The m-VLAS was also used to classify American College of Veterinary Internal Medicine staging groups and left heart enlargement confirmed with echocardiograph (EchoLHE) groups. The m-VLAS was measured as the distance from the ventral aspect of the carina to the dorsal aspect of the intersection of the cardiac silhouette and the farthest LA caudal margin, not the CdVC, followed by drawing the same line beginning at the cranial edge of T4. Based on VLAS values and m-VLAS values measured for dogs with MMVD, correlations between these values and left heart enlargement groups were then evaluated. There were significant differences in both the VLAS and the m-VLAS between EchoLHE groups. The AUC of the ROC curve of the m-VLAS to detect EchoLHE was higher than that of the VLAS. The optimal cutoff value for the m-VLAS was >2.7, which had a higher specificity (86.84%) than the VLAS specificity (71.05%). This study reveals that a new m-VLAS is a more specific indicator than the VLAS for predicting left side heart enlargement in small breed dogs. Therefore, the m-VLAS can be used as a clinically useful radiographic measurement alternative to or better than the VLAS.

Evaluation of the Corrected QT Interval with Bazett’s Method in Cavalier King Charles Spaniel Dogs with Myxomatous Mitral Valve Disease. Hande Sağoğlu, Remzi Gönül, Lora Koenhemsi, Emine Merve Alan, Suzan Murat, Ashkan Seddigh Nia, Mehmet Erman Or. Macedonian Vet. Rev. March 2023; doi: 10.2478/macvetrev-2023-0014. Quote:
Myxomatous mitral valve disease (MMVD) is one of the most common heart diseases in dogs. The disease progresses faster in Cavalier King Charles Spaniel (CKCS) dogs and occurs at an earlier age. QT interval length reflects abnormalities in ventricular repolarization which may predispose to the formation of fatal arrhythmias such as torsades de pointes. A fast and accurate assessment is therefore essential. The study aimed to examine the changes in QT duration in MMVD cases of CKCS and to calculate the corrected QT durations with Bazett’s formula in various stages of the disease. The study included 20 CKCS dogs of both genders, various ages and weights, and different stages of MMVD (n=6 in B1 stage, n=6 in B2 stage, and n=8 in C stage), and 5 healthy CKCS which were included in the control group. Clinical, radiological, hematological, biochemical, echocardiographic, and electrocardiographic examinations were performed. The corrected QT interval duration in the MMVD group was longer than the control. However, there was no significant difference between B1, B2, and C. It was concluded that the corrected QT interval can give a significant distinction between healthy and MMVD CKCS dogs.

TGF-β-induced PI3K/AKT/mTOR pathway controls myofibroblast differentiation and secretory phenotype of valvular interstitial cells through the modulation of cellular senescence in a naturally occurring in vitro canine model of myxomatous mitral valve disease. Qiyu Tang, Greg R. Markby, Andrew J. MacNair, Keyi Tang, Michal Tkacz, Maciej Parys, Kanchan Phadwal, Vicky E. MacRae, Brendan M. Corcoran. Cell Prolif. March 2023; doi: 10.1111/cpr.13435. Quote: PI3K/AKT/mTOR signalling contributes to several cardiovascular disorders. The aim of this study was to examine the PI3K/AKT/mTOR pathway in myxomatous mitral valve disease (MMVD). Double-immunofluorescence examined expression of PI3K and TGF-β1 in canine valves. Valve interstitial cells (VICs) from [6] healthy or [6] MMVD dogs [including one cavalier King Charles spaniel] were isolated and characterized. Healthy quiescent VICs (qVICs) were treated with TGF-β1 and SC-79 to induce activated myofibroblast phenotypes (aVICs). Diseased valve-derived aVICs were treated with PI3K antagonists and expression of RPS6KB1 (encoding p70 S6K) was modulated using siRNA and gene overexpression. SA-β-gal and TUNEL staining were used to identify cell senescence and apoptosis, and qPCR and ELISA to examine for senescence-associated secretory phenotype. Protein immunoblotting was used to examine expression of phosphorylated and total proteins. TGF-β1 and PI3K are highly expressed in mitral valve tissues. Activation of PI3K/AKT/mTOR and increased expression of TGF-β are found in aVICs. TGF-β transitions qVICs to aVICs by upregulation of PI3K/AKT/mTOR. Antagonism of PI3K/AKT/mTOR reverses aVIC myofibroblast transition by inhibiting senescence and promoting autophagy. Upregulation of mTOR/S6K induces transformation of senescent aVICs, with reduced capacity for apoptosis and autophagy. Selective knockdown of p70 S6K reverses cell transition by attenuating cell senescence, inhibiting apoptosis and improving autophagy. TGF-β-induced PI3K/AKT/mTOR signalling contributes to MMVD pathogenesis and plays crucial roles in the regulation of myofibroblast differentiation, apoptosis,

Echocardiographic parameters in French Bulldogs, Pugs and Boston Terriers with brachycephalic obstructive airways syndrome. M. Brložnik, A. Nemec Svete, V. Erjavec & A. Domanjko Petric. BMC Vet. Res. February 2023; doi: 10.1186/s12917-023-03600-9. Quote: Background: In this prospective study, we hypothesized that dogs with signs of brachycephalic obstructive airway syndrome (BOAS) would show differences in left and right heart echocardiographic parameters compared with brachycephalic dogs without signs of BOAS and non-brachycephalic dogs. Result: We included 57 brachycephalic (30 French Bulldogs, 15 Pugs, and 12 Boston Terriers) and 10 non-brachycephalic control dogs. Brachycephalic dogs had significantly higher ratios of the left atrium to aorta and mitral early wave velocity to early diastolic septal annular velocity; smaller left ventricular (LV) diastolic internal diameter index; and lower tricuspid annular plane systolic excursion index, late diastolic annular velocity of the LV free wall, peak systolic septal annular velocity, late diastolic septal annular velocitiy, and right ventricular global strain than non-brachycephalic dogs. ... French Bulldogs: LA/Ao: 1.56 (1.44-1.60); Pugs: LA/Ao: 1.49 (1.45-1.62); Boston Terriers: LA/Ao: 1.55 (1.50-1.68). ... French Bulldogs with signs of BOAS had a smaller diameter of the left atrium index and right ventricular systolic area index; higher caudal vena cava at inspiration index; and lower caudal vena cava collapsibility index, late diastolic annular velocity of the LV free wall, and peak systolic annular velocity of the interventricular septum than non-brachycephalic dogs. Conclusions: ... The results of this study showed significant differences in echocardiographic parameters between the dogs of the three brachycephalic breeds and non-brachycephalic dogs. In addition, there were significant differences in echocardiographic parameters between dogs with and without signs of BOAS. ... We found significant differences in echocardiographic parameters between dogs of the three brachycephalic breeds and non-brachycephalic dogs, implying that breed-specific echocardiographic reference values should be used in clinical practice. In addition, significant differences were observed between brachycephalic dogs with and without signs of BOAS. The observed echocardiographic differences suggest higher right heart diastolic pressures affecting right heart function in brachycephalic dogs with and without signs of BOAS, and several of the differences are consistent with findings in OSA patients. Most of the changes of the heart morphology and function can be attributed to brachycephaly alone and not to the symptomatic stage.

Proposed thresholds for ordinal echocardiographic estimates of left atrial enlargement in dogs. Mark Rishniw. J. Vet. Cardiol. April 2023; doi: 10.1016/j.jvc.2023.04.003. Quote: Objective: To propose echocardiographic left-atrial-to-aortic ratio (LA:Ao) limits for defining ordinal categories of left atrial (LA) enlargement in dogs. Animals, materials and methods: Right parasternal short-axis echocardiographic images from 33 dogs with various degrees of LA enlargement. Right parasternal short-axis and long-axis echocardiographic measurements from 238 healthy dogs. Images were duplicated and randomized. Duplicate images contained a LA:Ao estimate. Participants categorized the LA in each image into one of four categories: normal, mildly, moderately or severely enlarged. Distributions of categorization were compared between cardiologists and non-cardiologists. Intra-observer intra-study and inter-study agreement was examined. Effect of measurement was evaluated on agreement between participants. A parametric estimate of LA enlargement was calculated for both short-axis and long-axis views. Results: Cardiologists and non-cardiologists provided similar distributions of LA size estimates, and showed similarly high intra-observer agreement (kappa = 0.84). Having a measurement provided with the image increased agreement for categorizing LA as normal or mildly enlarged (P<0.001). Parametric and consensus-based approaches provided similar limits for categorizing left atrial size in the right parasternal short-axis view – normal = LA:Ao<1.6, mildly enlarged = 1.6<LA:Ao<1.9, moderately enlarged = 1.9<LA:Ao<2.3, severely enlarged = LA:Ao≥2.3. A parametric approach for the right parasternal long-axis view provided the following: normal = LA:Ao<2.1, mildly enlarged = 2.1<LA:Ao<2.5, moderately enlarged = 2.5<LA:Ao<2.7, severely enlarged = LA:Ao≥2.7. Conclusions: Participants mostly classified LA sizes into four ordinal categories that corresponded to the aforementioned limits. Clinicians estimating LA size in early diastole can use these limits to increase inter-observer agreement when identifying LA enlargement.

Resolution of congestive heart failure and reverse remodeling in two chihuahuas with flail mitral valve leaflets. Sonya Wesselowski. J. Vet. Cardiol. May 2023; doi: 10.1016/j.jvc.2023.05.002. Quote: Development of a flail mitral valve leaflet secondary to ruptured chordae tendineae in the setting of myxomatous mitral valve disease (MMVD) is a known complication of the disease that often results in severe mitral regurgitation. Two cases are presented in which a flail anterior mitral valve leaflet caused severe mitral regurgitation and led to the development of congestive heart failure (CHF) in male castrated Chihuahuas. Over variable periods of time, repeat cardiac evaluation disclosed reverse left-sided cardiac remodeling and lessened mitral regurgitation that allowed for withdrawal of furosemide in both dogs. ... While both dogs continued to have evidence of a MV flail segment on subsequent echocardiograms, the size of the gap between the anterior and posterior MV leaflets as a result of the flail segment subjectively appeared to decrease over time. ... While rare, improvement in mitral regurgitation severity may occur without surgical intervention, allowing for reverse left-sided cardiac remodeling and discontinuation of furosemide.

A study of the inter- and intra-operator variability on echocardiographic measurements in dogs. Sara Ghilardi, Danitza Pradelli, Rita M. Rizzi, Michele Polli, Mara Bagardi Roberto A. Santilli, Paola G. Brambilla, Claudio M. Bussadori. Res. Sq. May 2023; doi: 10.21203/rs.3.rs-2862744/v1. Quote: Standard transthoracic echocardiography is considered the non-invasive gold standard for the diagnosis of most cardiac diseases. Defining reproducibility, repeatability, and reliability of this exam is imperative to reduce errors in clinical evaluations. The present study aimed at: 1) evaluating the reproducibility and repeatability of 15 echocardiographic parameters in dogs by analyzing measurements obtained from several operators with different levels of experience and comparing them to the ones obtained from two board-certified operators (gold standards - GSs); 2) assessing whether different formative paths have an influence on the variability of the echocardiographic measurements. Fifty-one operators have been included in this study, along with two diplomates of the European College of Veterinary Internal Medicine - Cardiology. Ten dogs were enrolled, 5 Golden Retrievers and 5 Cavalier King Charles Spaniels. ... All the dogs had to be clinically healthy at the time of the echocardiography based on clinical examination, blood analysis and serum chemistry. ... Echocardiographic examination was performed on each dog by one GS and several operators on the same day. Results show that M-mode measurements of the interventricular septum and the left ventricular free wall are the least reliable ones since they show a high deviation from the GS and a poor inter-operator reproducibility. Differently, M-mode-obtained internal diameters of the left ventricle in systole and diastole, and measurements of the aortic annulus and root are the most reliable echocardiographic parameters, demonstrating that all the operators can correctly assess left ventricular systolic function and dilation, and evaluate the aortic valve. Furthermore, a specialist clinical activity, more than the acquired theoretical knowledge, affects the reliability of the echocardiographic examination by reducing the difference from the GS’ measurements. (See, also, this later version, at Vet. Research Communi. June 2023; doi: 10.1007/s11259-023-10154-6)

Proposed limits for ordinal echocardiographic estimates of left atrial enlargement in dogs. M. Rishniw. J. Vet. Cardiol. May 2023; doi: 10.1016/j.jvc.2023.04.003. Quote: Objective: To propose echocardiographic left-atrial-to-aortic ratio (LA:Ao) limits for defining ordinal categories of left atrial (LA) enlargement in dogs. Animals, materials and methods: Right parasternal short-axis echocardiographic images from 33 dogs with various degrees of LA enlargement. Right parasternal short-axis and long-axis echocardiographic measurements from 238 healthy dogs. Images were duplicated and randomized. Duplicate images contained a LA:Ao estimate. ... Seventy-nine respondents participated in the study: 58 Diplomates, 11 candidates and 10 ‘other’ (creating 21 ‘non-Diplomate’ respondents). All respondents provided estimates of the left atrial size category for all 66 images, generating 5,214 individual estimates (2,607 estimates each for measured and unmeasured images). Thirty-six respondents completed the survey a second time after a hiatus of three months. The images examined in the study provided a spectrum of LA:AoRPSA estimates, ranging from 0.8 to 3.1. ... Participants categorized the LA in each image into one of four categories: normal, mildly, moderately or severely enlarged. Distributions of categorization were compared between cardiologists and non-cardiologists. Intra-observer intra-study and inter-study agreement were examined. Effect of measurement was evaluated on agreement between participants. A parametric estimate of LA enlargement was calculated for both short-axis and long-axis views. Results: Cardiologists and non-cardiologists provided similar distributions of LA size estimates, and showed similarly high intra-observer agreement. ... This study proposes limits of LA:Ao, measured from the right parasternal short-axis view at the onset of ventricular diastole (just after closure of the aortic valve) for determining ordinal degrees of left atrial enlargement in dogs. Although the data were generated from healthy dogs and dogs with mitral valve disease, these limits would apply equally for any cardiac disease that affects the left heart in dogs. This study further proposes limits of LA:Ao measured from the right parasternal longaxis view at the onset of ventricular diastole. Based on both the expert opinion approach and parametric approach, I propose the following LA:Ao limits for degrees of enlargement when measured from the right parasternal short-axis view at end-diastole:
Normal <1.6
Mild between 1.6 and 1.9
Moderate between 1.9 and 2.2
Severe >2.2.
... Although these limits are based on a plurality of responses, individual responses varied considerably -- 50% of responses classifying at least 1 image as ‘moderately enlarged’ fell outside 1.9 and 2.2, with some responses being as low as 1.0 and others as high as 3.0 for a classification of ‘moderate’. Similarly, some respondents applied the ‘normal’ category to images with a measured LA: AoRPSA of 2.0; responses of ‘mild enlargement’ described images with LA: AoRPSA that ranged from 1.3 to 2.5. I cannot determine whether respondents made such extreme classifications in error (by selecting the wrong option in the online survey) or if these choices reflect valid estimates of severity. ... This study provides the first critical approach to classifying left atrial enlargement in dogs for atria imaged in the right parasternal short-axis and long-axis views at the onset of ventricular diastole (coincident with closure of the aortic valve or just prior to the opening of the mitral valve). Using these values as a reference standard, investigators could provide similar limits for classifying left atrial enlargement in dogs using other views or other points in the cardiac cycle. These data might help consistently stratify dogs with left atrial enlargement into clinically meaningful populations when considering various management strategies.

Evaluation of the short-term echocardiographic effects of two loop diuretics, furosemide and torsemide, in a group of dogs. Farzaneh Hosseini, Zeinab Mahmoudi Filabadi, Peter B Hill, Morteza Hosseininejad. Vet. Med. & Sci. May 2023; doi: 10.1002/vms3.1129. Quote: Background: Two loop diuretics, torsemide and frusemide, can affect the urinary system and consequently the cardiordiovascular haemodynamics in different ways. Objectives: This study compared a number of echocardiographic parameters and systemic arterial blood pressure (ABP) changes following administration of furosemide or torsemide. Methods: Five shelter dogs underwent transthoracic two-dimensional M-mode echocardiography to obtain the following measurements: left ventricular internal dimension at end-systole (LVIDs), left ventricular internal dimension at end-diastole (LVIDd), fractional shortening (FS), heart rate (HR) and the distance between the mitral valve socket and the ventricle wall (septal to E Point, SEP). Arterial blood pressure was measured using the oscillometric method. Measurements recorded before treatment (baseline data) were compared to those after the dogs received furosemide (5 mg/kg) or torsemide (0.5 mg/kg). Results: Torsemide significantly reduced blood pressure 1 h after administration, but this was not seen with furosemide. Fractional shortening, LVIDd and SEP decreased following both treatments, but there were no significant differences between the treatment groups. Torsemide increased heart rate above that seen in the furosemide groups. Conclusions: The results of this study indicate that 1 h after administration, torsemide increases heart rate and decreases blood pressure when compared to furosemide, but both drugs have similar effects on measured cardiovascular indices.

Mitral Valve Repair Outcomes in Different Dog Breeds. Kentaro Kurogochi; Masami Uechi. ACVIM Forum 2023. June 2023. Quote: Background: Mitral valve repair (MVR) could be a curative treatment for myxomatous mitral valve disease (MMVD) in dogs. Previous reports in medical treatment have suggested that Cavalier King Charles Spaniels (CKCS) might be more susceptible to developing MMVD than other breeds, but the breed-specific characteristics and the long-term outcomes of MVR are unclear. Hypothesis/Objectives: We investigated the differences in cardiac reverse-remodeling and survival for MVR in different breeds. Animals: We retrospectively analyzed the data of dogs with MMVD that underwent MVR from February 2017 to February 2019 at our center. Methods: Based on breeds, dogs were divided into three groups: Chihuahuas, CKCS, and others. Thoracic radiographs and echocardiography were evaluated in the preoperative period and 6, 12, and 36 months post-surgery. Results: Our study included 444 dogs (Chihuahuas=206, CKCS=40, and others=198). CKCS group had significantly higher vertebral heart score, left atrial aortic root ratio, and diastolic left ventricular normalized dimension both pre- and post-surgery. The three-year survival rate for all-cause mortality derived by the Kaplan-Meier curve was not different among the three groups: 75%, 66%, and 67%, respectively. Conclusion and Clinical Importance: Postoperative reverse remodeling might differ, especially in CKCS. Thus, early surgical intervention might be better for improving reverse remodeling in CKCS. However, MVR improves survival in all breeds despite differences in heart size.

Feasibility Clinical Study of Transcatheter Edge-to-Edge Repair in Dogs With the Canine Mitral V-Clamp Device. Brianna M. Potter, E. Christopher Orton, I-Jung Chi, Brian Scansen, Katie Abbott-Johnson, Lance Visser, Ellen Shaub. ACVIM Forum 2023. June 2023. Quote: Background: Transcatheter edge-to-edge mitral valve repair (TEER) has been shown in pivotal studies to be an effective treatment for degenerative mitral regurgitation (MR) in humans. Hypothesis/Objective: Determine feasibility, acute safety, adverse device-related events, early efficacy, and freedom from all-cause and cardiac-related mortality of a canine-specific TEER device (V-Clamp) in dogs with degenerative MR. Animals: Initial inclusion criteria were dogs with stage C or D degenerative MR. During the study, stage B2 dogs were added if they met guidelines for severe MR. Methods: Prospective single-arm single-institution FDA feasibility-type study. TEER was performed via a transapical approach under transesophageal echocardiography and fluoroscopic guidance. Results: Forty dogs were enrolled over a two-year period (12 B2, 26 C, 2 D). Procedural feasibility was 95% based on successful delivery of at least 1 clamp in 38/40 dogs. There were no procedural deaths. Acute procedural safety was 95% based on survival to hospital discharge of 38/40 dogs. Most dogs were discharged by the 2nd day. Adverse device-related event rate was 6.2% based on 3 events (1 single-leaflet detachment, 1 clamp unlock, 1 clamp embolization) in 48 implanted clamps. All 3 events were nonfatal and successfully treated with a second clamp. Regurgitant fraction and volume decreased from 64±12% and 2.4±0.9 mL/kg at baseline to 43±26% (p< 0.0001) and 1.3±1.1 mL/kg (p< 0.0001) at hospital discharge. Freedom from all-cause and cardiac-related mortality at 9 months was 87.4% and 91.1%, respectively. Conclusions: Initial feasibility results support continued development of TEER as a low-risk and effective treatment for degenerative MR in dogs.

Left Atrial Decompression in Dogs With Mitral Valve Disease and Heart Failure: Long Term Outcome. Kevin L. Phipps, Justin Allen, Kirstie Barrett. ACVIM Forum 2023. June 2023. Quote: Background: Left-sided congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD) is associated with significant morbidity and mortality in the canine patient. Left atrial decompression (LAD) has been used to treat severely affected dogs who are failing standard medical therapy for a variety of reasons. No data has been published regarding the long term outcome of dogs who have undergone LAD. Hypothesis/Objectives: The objective of our study was to determine incidence of atrial septal defect closure, frequency of right-sided congestive heart failure, frequency of hospitalizations after LAD, and survival times. Animals: 111 client-owned dogs who were afflicted with ACVIM stage B2 (late), C or D MMVD and underwent LAD. Methods: Retrospective cohort study enrolling patients with MMVD who had LAD performed between October 2018 and September 2021. Primary outcome variable was time to cardiac-related death or euthanasia. Secondary variables were time to right-sided CHF, atrial septal defect closure, and number of hospitalizations for CHF post-LAD. Results: Closure of the iatrogenic atrial septal defect occurred in 22 dogs (20%). Iatrogenic atrial septal defect closure occurred most commonly in defects that were located caudally to the fossa ovalis. Forty dogs (36%) developed right-sided CHF as a sequela to the LAD, which occurred between 1 and 800 days post-operatively. 25/111 (22.5%) patients had hospitalizations within their lifetime post-LAD as a result of cardiac disease. Median survival time post-LAD was 379 days with a range of 1-1282 days. Conclusions and clinical importance: Left atrial decompression was associated with a satisfactory survival time, given the severity of disease in the patient population. Right-sided congestive heart failure is common after the procedure, though onset is variable. Closure of the iatrogenic atrial septal defect is uncommon, and incidence can be minimized by ensuring transseptal puncture occurs within the fossa ovalis.

Effect of a specially formulated diet on progression of heart enlargement in dogs with subclinical degenerative mitral valve disease. Mark A. Oyama, Brian A. Scansen, Adrian Boswood, Guilherme Goldfeder, Steven Rosenthal, Richard Cober, Kendra LaFauci, Ryan C. Friese, Márcia Gomes, Yu-Mei Ruby Chang, Qinghong Li. J. Vet. Intern. Med. July 2023; doi: 10.1111/jvim.16796. Quote: Background: Previous studies in dogs with degenerative mitral valve disease (DMVD) have identified altered myocardial energy metabolism and oxidation, which might contribute to cardiac hypertrophy. Diets rich in medium chain fatty acids and antioxidants are a potential means of treatment. A previous clinical study found significantly smaller left atrial diameter (LAD) and left atrium-to-aorta diameter ratio (LA : Ao) in dogs with subclinical DMVD fed a specially formulated diet ... a custom formulated diet, enriched with antioxidants, MCT, and other metabolic precursors [Purina’s Pro Plan CardioCare kibble dog food] ... vs control diet for 6 months. ... Randomization was performed at the center level by breed (Cavalier King Charles Spaniel [CKCS] vs. non-CKCS) and diet in blocks of 4. The study's test article was a specially formulated dry kibble diet enriched in MCT and antioxidants. ... Hypothesis/Objectives: A specially formulated diet will slow or arrest left heart enlargement in dogs with subclinical DMVD over 365 days. Animals: One hundred twenty-seven dogs with unmedicated subclinical DMVD; 101 dogs in the per protocol cohort. ... The per protocol cohort consisted of 101 dogs, including 46 dogs that received the test diet and 55 dogs that received the control die. Dogs typically were older male dogs of small to medium body size. The most common breed was the CKCS (29/101, [29%]) ... Methods: Randomized double-blinded controlled multicenter clinical trial. Results: The study's primary composite outcome measure was the sum of percentage change in LAD and left ventricular internal dimension at end-diastole (LVIDd) at day 365. In the per protocol cohort, the outcome measure increased by 8.0% (95% confidence interval [CI], 2.9%-13.1%) in dogs receiving the test diet vs 8.8% (95% CI, 5.1%-12.5%) in dogs receiving control diet (P = .79). Neither component of the primary outcome measure was significantly different between groups (LAD, P = .65; LVIDd, P = .92). No difference was found in mitral valve E wave velocity (P = .36) or the proportion of dogs withdrawn from the study because of worsening DMVD and heart enlargement (P = .41). Conclusions and Clinical Importance: Feeding a specially formulated diet for 365 days was not associated with a significantly different rate of change of left heart size in dogs with subclinical DMVD as compared to control.

The effect of taurine supplementation on the renin–angiotensin–aldosterone system of dogs with congestive heart failure. Sara Brethel, Seth Locker, Renee Girens, Paulo Rivera, Kathryn Meurs, Darcy Adin. Sci. Rpts. July 2023; doi: 10.1038/s41598-023-37978-1. Quote: The role of taurine in the treatment of congestive heart failure (CHF) in dogs without systemic deficiency is unexplored. Taurine might have beneficial cardiac effects aside from deficit replacement. We hypothesized that oral taurine supplementation administered to dogs with naturally-occurring CHF would suppress the renin-angiotensin aldosterone system (RAAS). Oral taurine was administered to 14 dogs with stable CHF [including 4 cavalier King Charles spaniels (29%)]. Serum biochemical variables, blood taurine concentrations, and comprehensive analysis of RAAS variables were compared before and 2 weeks after taurine supplementation added to background furosemide and pimobendan therapy for CHF. ... The results of this study were not supportive of a RAAS suppressive effect of oral taurine supplementation for this group of dogs with naturally occurring CHF secondary to mitral valve degeneration. ... Whole blood taurine concentrations increased after supplementation (median 408 nMol/mL, range 248–608 before and median 493 nMol/mL, range 396–690 after; P = .006). Aldosterone to angiotensin II ratio (AA2) was significantly decreased after taurine supplementation (median 1.00, range 0.03–7.05 before and median 0.65, range 0.01–3.63 after; P = .009), but no other RAAS components significantly differed between timepoints. A subset of dogs showed marked decreases in RAAS metabolites after supplementation and these dogs were more likely to have been recently hospitalized for CHF treatment than dogs that did not show marked decreases in classical RAAS metabolites. Overall, taurine only lowered AA2 in this group of dogs, however, response heterogeneity was noted, with some dogs showing RAAS suppression.

Analytical validation, sample stability, and clinical evaluation of a new high-sensitivity cardiac troponin I immunoassay for use in dogs, with comparison to a previous ultrasensitive assay. Sonya Wesselowski, Jonathan Lidbury, Ashley B. Saunders, Sonya G. Gordon, Jan S. Suchodolski, Joerg M. Steiner. PLoS ONE. July 2023; doi: 10.1371/journal.pone.0288801. Quote: Cardiac troponin I (cTnI) is considered the gold standard biomarker for myocardial injury and shows a high degree of homology between humans and dogs. The ADVIA Centaur XP High-Sensitivity Troponin I (AC-cTnI-HS) assay has been validated for use in humans but not dogs. The study objectives were to analytically validate the AC-cTnI-HS assay in dogs, to assess correlation between the AC-cTnI-HS and a previous ADVIA Centaur TnI-Ultra (AC-cTnI-U) assay, to assess cTnI sample storage stability, and to clinically evaluate the AC-cTnI-HS assay in healthy dogs and dogs with cardiac disease. Canine serum samples were used for analytical validation. Intra- and inter-assay variability, dilutional parallelism, and spiking recovery were assessed. Samples from 196 client-owned dogs were evaluated (healthy dogs (n = 39) [including 12 cavalier King Charles spaniels (31.8%)] or dogs with congenital heart disease (n = 54), myxomatous mitral valve disease (n = 68) [including 56 CKCSs (82.4%)], dilated cardiomyopathy (n = 15), or myocarditis (n = 20)). Inter- and intra-assay coefficient of variation (%CV) was between 2.8–41.4% and 3.8–30.2%, respectively, with pools with concentrations >20 pg/mL all having %CVs <10%. The observed to expected ratios for dilutional parallelism and spiking recovery experiments ranged between 92.3 and 266.7.0% and 84.3 and 108%, respectively. A strong correlation between the AC-cTnI-HS and AC-cTnI-U assays was observed (Spearman’s ρ = 0.927), though a proportional bias existed, with AC-cTnI-HS assay concentrations being proportionally lower than AC-cTnI-U assay concentrations. Serum samples stored at -80°C had stable cTnI measurements for up to 2.7 years and after a single freeze-thaw cycle. Healthy dogs and dogs with congenital heart disease had significantly lower cTnI concentrations than dogs in the other three groups. The AC-cTnI-HS assay precisely, reproducibly, and accurately measures cTnI concentrations in dog serum with cTnI concentrations >20 pg/mL.

Radiographic Evaluation of Left Atrial Size in Cavalier King Charles Spaniel Dogs with Mitral Valve Disease. Gonul Remzi, Hande Sağoğlu, Murat Suzan. Macedonian Vet. Rev. July 2023; doi: 10.2478/macvetrev-2023-0023. Quote: Myxomatous mitral valve disease (MMVD) is one of the most common heart diseases in Cavalier King Charles spaniel (CKCS) dogs. The American College of Veterinary Internal Medicine (ACVIM) uses clinical, echocardiographic, and radiographic criteria to diagnose the disease, but measurement of vertebral left atrial size (VLAS) provides a simpler assessment. The aim of this study was to determine VLAS values in MMVD cases of CKCS and to investigate their clinical significance at different MMVD stages. Eighteen CKCS dogs of both sexes, different ages and weights, and different MMVD stages (6 at B1 stage, 6 at B2 stage, and 6 at C stage) were included in the study, as well as 6 healthy CKCS as control group A. We performed clinical, radiological, and echocardiographic examinations. VHS and VLAS values were significantly higher in the MMVD group than in the control group. VLAS showed high diagnostic accuracy in the detection of LA enlargement (area under the curve [AUC]: 0.98, cutoff ≥ 2.25, sensitivity: 88%, specificity: 100%). We also found high positive correlations between the VLAS and other values (LA/Ao, LVIDDn, and VHS). ... As a result of this study in Cavalier King Charles spaniel dogs, a cut-off VLAS value ≥2.25 in dogs with MMVD was found to be a cost-effective, easy-to-use, and reliable method to detect left atrial enlargement and monitor disease. However, the atrial enlargement does not always point in the same direction because of the overall structure of the heart, pulmonary edema, effusion, mass formation, and so on. Considering the limitations of radiographic diagnosis in the presence of additional diseases and the possible inclusion of breed-specific differences, new studies on this topic are needed.

The Thoracic Inlet Length as a Reference Point to Radiographically Assess Cardiac Enlargement in Dogs with Myxomatous Mitral Valve Disease. David Marbella Fernández, Verónica García, Alexis José Santana, José Alberto Montoya-Alonso. Animals. August 2023; doi: 10.3390/ani13162666. Quote: The diagnostic value of the vertebral heart size (VHS) in dogs with mitral valve degeneration (MVD) is compromised when middle thoracic vertebral anomalies are present. The objective of this study was to assess the use of the thoracic inlet heart score (TIHS) to identify left heart enlargement (LHE) secondary to MVD. The cardiac silhouette of 50 clinically healthy dogs [including one cavalier King Charles spaniel] and 106 MVD dogs in different stages was assessed on a right lateral chest radiograph [including two CKCSs in Stage C]. The TIHS and VHS value were calculated for each patient and compared. The TIHS was significantly different between the control dogs and the dogs with MMVD, increasing with disease stage, control 2.91 ± 0.23, Stage B1 2.98 ± 0.36, B2 3.25 ± 0.34, and C 3.53 ± 0.36. A TIHS ≥3.3 showed 69% sensitivity and 81% specificity to identify LHE. The TIHS showed moderate correlation with the VHS, LA/Ao, and LVIDDN 0.59, 0.42, and 0.62, respectively. The intraobserver and interobserver agreement were almost perfect, 0.96, and substantial, 0.73. The TIHS method can be used to identify LHE secondary to MMVD on dogs’ thoracic radiographs. ... The TIHS is a simple method to measure the cardiac silhouette in dogs with and without myxomatous mitral valve disease. A TIHS value >3.3 would suggest cardiac enlargement in a dog with a heart murmur secondary to mitral valve disease, recommending an echocardiography. The TIHS can help clinicians in the staging of MMVD in a general population of dogs, including dogs with midthoracic vertebral anomalies, or when the thoracic vertebral bodies cannot be identified, and of chihuahua dogs, a breed commonly affected by the disease. It could also be used to monitor progression of the disease in a dog already diagnosed.

Differences in Left Ventricular Enlargement Secondary to Chronic Volume Loading Between English Springer Spaniels and Two Similar Sporting Breeds. D. Dickson, E. Bode, C. Linney, E. Dutton, D. Caivano, T. Bispo, J. Harris, M. Rishniw. J. Vet. Cardiol. August 2023; doi: 10.1016/j.jvc.2023.06.001. Quote: Introduction: English springer spaniels have larger, rounder ventricles than most other breeds. How this geometry impacts responses to volume overload remains unknown. We compared left ventricular size between English springer spaniels and two similarly sized sporting breeds (Border collies and Labrador retrievers) in naturally occurring chronic left ventricular volume loading conditions (mitral regurgitation and patent ductus arteriosus [PDA]) to examine whether differences in remodelling responses exist between these breeds. Animals, materials and methods: We searched records for cases of mitral regurgitation and PDA in three breeds. We recorded age, sex, presence of congestive heart failure (CHF), body weight and specific echocardiographic variables. We compared normalised measures of left ventricular size between breeds. Cases with CHF were further examined as a separate group. Results: 191 dogs were included: 110 with degenerative mitral valve disease, 42 with mitral dysplasia and 39 with PDA. One third of all cases had CHF. All measures of left ventricular size were larger in English springer spaniels in mitral regurgitation cases, whereas PDA cases did not differ. English springer spaniels with PDA resulting in CHF had larger systolic dimensions and volumes than similarly affected non-English Springer Spaniel dogs. Conclusions: English springer spaniels have greater left ventricular dimensions when exposed to chronic mitral regurgitation, compared with Border collies and Labrador retrievers, but not when exposed to volume overload from a PDA. English springer spaniels differ in their left ventricular morphology from two other sporting breeds, supporting previous studies that they have a unique cardiac morphotype. ... Our results provide evidence that English springer spaniels develop more pronounced left ventricular eccentric hypertrophy secondary to mitral regurgitation compared with two similarly sized athletic breeds but not in response to PDA. These findings have clinical relevance. Commonly used markers of disease severity such as left ventricular size and function cannot be compared across breeds: for the same degree of mitral regurgitation, English springer spaniels will have proportionally larger ... We found that English springer spaniels develop more pronounced left ventricular eccentric hypertrophy when exposed to chronic mitral regurgitation compared with two similarly sized athletic breeds.

M-Mode Echocardiography in Canine Veterinary Practice: A Comprehensive Review of Left Ventricular Measurements in 44 Different Dog Breeds. Maria Cerbu, Constantin Cerbu, Ionel Papuc. Animals. September 2023; doi: 10.3390/ani13182986. Quote: This review article focuses on the use of canine M-mode in veterinary medicine, specifically in assessing the left ventricle measurements in several breeds. It traces the historical development of echocardiography techniques, including A-mode, B-mode, and motion mode (M-mode), which provide accurate unidimensional records of cardiac structures. This article highlights the significance of M-mode measurements in diagnosing stage B2 of MMVD, where left ventricular end-diastolic internal diameter corrected with body weight (LVIDdN) is essential for identifying cardiac enlargement. It also explains the role of M-mode in diagnosing DCM, outlining criteria such as left ventricular dilatation. The authors emphasize the importance of breed-specific reference values for echocardiographic measurements due to variations in somatotype among dogs. This review provides a comprehensive table summarizing M-mode measurements of the left ventricle for 44 different dog breeds [including 134 cavalier King Charles spnaniels], including interventricular septum thickness, left ventricular internal diameter, and left ventricular posterior wall thickness during systole and diastole. This review’s methodology involves compiling data from various scientific literature sources, providing an extensive tabular representation of M-mode measurements for different breeds, ages, and sexes. Overall, this review highlights the critical role of M-mode echocardiography in diagnosing and managing cardiac diseases in dogs, underscores the importance of breed-specific reference values, and presents a comprehensive summary of M-mode measurements for various dog breeds, aiding both clinicians and researchers. ... To ensure accurate interpretation of echocardiographic examinations in dogs, it is crucial to consider breed-specific reference values. Failing to do so can lead to misinterpretations, falsely indicating heart enlargement or altered activity when compared with general reference ranges, potentially resulting in misdiagnosis and inappropriate treatment.

No impact of polymorphism in the phosphodiesterase 5A gene in Cavalier King Charles Spaniels on pimobendan-induced inhibition of platelet aggregation response. Maria J. Reimann, Daniel N. Faisst, Mads Knold, Kathryn M. Meurs, Joshua A. Stern, Signe E. Cremer, Jacob E. Møller, Ingrid Ljungvall, Jens Häggström, Lisbeth H. Olsen. J. Vet. Intern. Med. September 2023; doi: 10.1111/jvim.16871. Quote: Background: A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs. Hypothesis: PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet-rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results. Animals: Fifty-two privately owned CKCS with no or preclinical MMVD. ... Stage A: CKCS with no auscultatory heart murmur and normal echocardiogram (no or minimal MR [MR < 20%]); stage B1: CKCS with auscultatory heart murmur or MR ≥20% but no cardiac enlargement; stage B2: CKCS with heart murmur ≥3 of 6 and echocardiographic evidence of cardiac enlargement but no current or previous clinical signs of CHF; stage C: CKCS with CHF. Cardiac enlargement was defined as LA/Ao ≥1.6 and LV end-diastolic diameter normalized to body weight (LVIDDN) ≥ 1.7. Thus, the MMVD stage A included dogs with minimal MR, because such minimal valve leakage has little to no clinical or prognostic significance for MMVD in CKCS. ... Methods: Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate-induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography. Results: Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 μM and Vel at 0.03μM. PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response. Conclusions and Clinical Importance: The PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment.

Pharmacokinetics of pimobendan after oral administration to dogs with myxomatous mitral valve disease. Anna K. McManamey, Teresa C. DeFrancesco, Kathryn M. Meurs, Mark G. Papich. J. Vet. Intern. Med. September 2023; doi: 10.1111/jvim.16891. Quote: Background: Pimobendan is an important therapy for dogs with myxomatous mitral valve disease (MMVD). The pharmacokinetics are reported in healthy dogs but not in dogs with heart disease. Hypothesis/Objectives: To determine if dog characteristics such as age, breed, body condition score, ACVIM stage of heart disease or biochemical laboratory value alter the pharmacokinetics of orally administered pimobendan and its metabolite in a cohort of dogs with naturally occurring MMVD. ... The objective of this study was to determine if dog characteristics such as age, breed, body condition score, mg/kg dose, or stage of heart disease alter the pharmacokinetics of orally administered pimobendan. An additional objective of the study was to determine if the pharmacokinetics of pimobendan observed in dogs with heart disease is comparable to that in healthy dogs. Our hypothesis is that the pharmacokinetic properties of pimobendan and its metabolite, O-desmethyl-pimobendan (ODMP), are altered by medication dose, body condition, and ACVIM stage of MMVD. ... The dogs eligible for enrollment were ACVIM Stage B2, C, or D MMVD based on the 2009 ACVIM Consensus Guidelines for the diagnosis and treatment of MMVD. ... Animals: Fifty-seven client-owned dogs [including 14 cavalier King Charles spaniels (24.5%)] with MMVD ACVIM Stage B2, C, or D and administered pimobendan to steady state blood concentrations. Methods: Prospective, observational study. Samples were collected using a sparse-sampling protocol at specific intervals after administration of pimobendan. Plasma pimobendan and the active metabolite (O-desmethyl-pimobendan, ODMP) concentrations were determined via high-pressure liquid chromatography and fluorescence detection. Data was analyzed via a population pharmacokinetic approach and nonlinear mixed effects modeling (NLME). Numerous covariates were examined in the NLME model. ... The most represented breed was Cavalier King Charles Spaniel (CKCS); therefore, this was examined as a categorical covariate as CKCS vs all others. ... Sources of variability examined were dog age, weight, dose, body condition score, stage of heart disease (B2, C, and D; B2 and combined C, D), serum creatinine concentration, serum alkaline phosphatase activity, and breed (CKCS vs other breeds). ... Results: ... Our results showed that the concentrations in plasma were highly variable, and dose was not a significant factor in the absorption or elimination of pimobendan or its metabolite. ... The absorption and elimination half-lives (t1/2) were approximately 1.4 and 1 hour for pimobendan and 1.4 and 1.3 hours for ODMP, respectively. Pharmacokinetic parameters were highly variable, especially the values for pimobendan absorption and elimination rate, and absorption rate of ODMP with coefficients of variation of 147.84%, 64.51% and 64.49%, respectively. No covariate evaluated was a significant source of variability. Conclusions and Clinical Importance: The pharmacokinetic parameters were highly variable among this group of dogs with MMVD. The variability was not associated with the dog's age, body weight or condition score, stage of heart disease, dose, serum creatinine, or alkaline phosphatase. ... In conclusion, the absorption, elimination of pimobendan and its metabolite, ODMP, were highly variable in this cohort of dogs with various stages of naturally occurring MMVD. The source of the variability was not identified.

Development of an artificial intelligence-based method for the diagnosis of the severity of myxomatous mitral valve disease from canine chest radiographs. Carlotta Valente, Marek Wodzinski, Carlo Guglielmini, Helen Poser, David Chiavegato, Alessandro Zotti, Roberto Venturini, Tommaso Banzato. Front. Vet. Sci. September 2023; doi: 10.3389/fvets.2023.1227009. Quote: An algorithm based on artificial intelligence (AI) was developed and tested to classify different stages of myxomatous mitral valve disease (MMVD) from canine thoracic radiographs. The radiographs were selected from the medical databases of two different institutions, considering dogs over 6 years of age that had undergone chest X-ray and echocardiographic examination. Only radiographs clearly showing the cardiac silhouette were considered. ... Cases admitted between July 2012 and December 2022 were included. ... The database consisted of 1,242 (793 from the Veterinary Teaching Hospital and 449 from the Arcella Veterinary Clinic) radiographs in total, including 728 (58.6%) (381 from the Veterinary Teaching Hospital and 347 from the Arcella Veterinary Clinic lateral and 514 (41.4%) (412 from the Veterinary Teaching Hospital and 102 from the Arcella Veterinary Clinic) DV or VD projections. ... The convolutional neural network (CNN) was trained on both the right and left lateral and/or ventro-dorsal or dorso-ventral views. Each dog was classified according to the American College of Veterinary Internal Medicine (ACVIM) guidelines [2019] as stage B1, B2 or C + D. ResNet18 CNN was used as a classification network, and the results were evaluated using confusion matrices, receiver operating characteristic curves, and t-SNE and UMAP projections. The area under the curve (AUC) showed good heart-CNN performance in determining the MMVD stage from the lateral views with an AUC of 0.87, 0.77, and 0.88 for stages B1, B2, and C + D, respectively. ... Interestingly, our model performed better in identifying stage B1 and C + D dogs than stage B2 dogs. ... Even if the overall accuracy of the developed system for the B2 and C + D stages was adequate a significant number of B2 (23.6%) and C + D (6.7%) cases was this misclassified as B1 potentially classifying deseased dogs as healthy. ... Not surprisingly, the worst classification results were obtained for the B2 stage dogs. This can be explained, among other factors, by the greater variability that exists between animals classified in this stage of the disease and animals classified as B1 or C + D. In fact, they range from having a slightly enlarged cardiac silhouette to having a severe cardiomegaly with signs of cardiac remodelling. ... An AI-based algorithm for the automatic staging of dogs affected by MMVD was proposed based on canine thoracic radiographs. This method showed a high accuracy in identifying dogs belonging to stage B1 or C + D stage and a moderate accuracy in the identification of stage B2 dogs.

Use of physical examination, electrocardiography, radiography and biomarkers to predict echocardiographic stage B2 myxomatous mitral valve disease in preclinical Cavalier King Charles Spaniels. Sonya Wesselowski, Sonya G. Gordon, Ryan Fries, Ashley B. Saunders, K.Tess Sykes, Jordan Vitt, Bruno Boutet, Jens Häggström, Saki Kadotani, Jonathan Stack, Brian G. Barnett. J. Vet. Cardiol. October 2023; doi: 10.1016/j.jvc.2023.10.001. Quote: Introduction: Cavalier King Charles Spaniels (CKCS) are predisposed to developing myxomatous mitral valve disease (MMVD). Dogs with stage B2 MMVD benefit from medication. Objectives: To develop 1) breed-specific cut-offs for individual screening tests and 2) predictive models utilizing physical examination (PE), ECG, radiograph, and blood-based biomarker variables in combination, for identification of echocardiographic stage B2 MMVD in preclinical CKCS. Animals: Adult, preclinical CKCS not receiving cardiac medications (N=226). Materials and Methods: Prospective, cross-sectional study. Enrolled CKCS underwent PE, ECG, radiography, Doppler blood pressure measurement, echocardiography and biomarker testing. Dogs were grouped by MMVD Stage using echocardiography only. ... There were 14 CKCS (6.2%) in stage A, 167 (73.9%) in stage B1 and 45 (19.9%) in stage B2. ... There were 27 CKCS categorized as stage B1 that did not have a heart murmur detected on auscultation. Of these 27 dogs, two had moderate MR on their echocardiogram, 12 had mild MR, and 13 had none or trivial MR but had mitral valve remodeling consistent with MMVD such as mitral valve prolapse and/or thickening. In CKCS that were stage B2, 91.1% had a heart murmur that was a grade 4/6 or louder. Twelve stage B1 dogs were noted to have mid-systolic clicks. Additionally, auscultable premature beats were detectable on auscultation in 21.4%, 31.1% and 26.7% of stage A, B1 and B2 dogs, respectively. ... From a history perspective, in this population of 298 preclinical CKCS there were 35 dogs (15.5% of the total population) that had a history of a cough, 13 dogs (5.9%) had a history of breathing difficulty, 4 dogs (1.8%) had a 300 history of abnormal activity level, 3 dogs (1.4%) had a history of having had fainting 301 spells, and 2 dogs (0.9%) had a history of an abnormal appetite. ... Discriminatory ability of individual tests to identify stage B2 was assessed, and prediction models were developed using variables derived from four ‘tests’ (PE, ECG, radiography, biomarkers). Results: ... All tests showed good discriminatory ability to differentiate between echocardiographic stage B2 versus stage A + B1 combined. ... N-terminal pro B-type natriuretic peptide (NT-proBNP) and radiographic vertebral heart size (VHS) had the best discriminatory ability of individual diagnostic tests to differentiate stage A/B1 CKCS from stage B2, with an area under the curve (AUC) of 0.855 and 0.843, respectively. An NT-proBNP ≥ 1138 pmol/L or a VHS ≥ 11.5 had high specificity for predicting stage B2 (90.1% and 90.6%, respectively). ... VHS slightly outperformed VLAS. ... The newer VLAS measurement did not perform as well as VHS in CKCS, though the summation of both VHS and VLAS performed similarly to VHS alone. ... Prediction models incorporating variables from multiple tests had better discriminatory ability than single tests. The 4-test prediction model had an AUC of 0.971. Three and two-test models had AUCs ranging between 0.925-0.959 and 0.895-0.949, respectively. ... On an individual dog level, the data ranges shown in Table 2 highlight the fact that there can be considerable variability amongst CKCS in the same MMVD stage across the investigated diagnostic tests. For example, many CKCS fell below the high specificity stage B2 VHS cut-off of 11.5 but were confirmed to be stage B2 by echocardiography. In addition, there were CKCS that were echocardiographically classified as being in stage A or B1 that met or exceeded this same VHS cut-off of 11.5. These individual cases would have reflected false negative or false positive cases, respectively, if VHS was the sole diagnostic test relied upon and a cut-off of 11.5 was used for prediction of stage B2 status. Reliance on any single diagnostic test inevitably requires compromise on the side of sensitivity or specificity when population-based cut-offs are utilized even in a single breed population. ... Conclusions: Both NT-proBNP and VHS have good utility for predicting echocardiographic stage B2 MMVD in CKCS as individual tests. Prediction models incorporating multiple test variables have superior discriminatory ability. ... To most confidently rule out echocardiographic stage B2 status, however, use of all four diagnostic tests is most ideal based on the four-test model having the highest sensitivity.

TGF-β phospho antibody array identifies altered SMAD2, PI3K/AKT/SMAD, and RAC signaling contribute to the pathogenesis of myxomatous mitral valve disease. Andrew J. McNair, Greg R. Markby, Qiyu Tang, Vicky E. MacRae, Brendan M. Corcoran. Front. Vet. Sci. October 2023; doi: 10.3389/fvets.2023.1202001. Quote: Background: TGFβ signaling appears to contribute to the pathogenesis of myxomatous mitral valve disease (MMVD) in both dogs and humans. However, little is known about the extent of the downstream signaling changes that will then affect cell phenotype and function in both species. Objective: Identify changes in downstream signals in the TGFβ pathway in canine MMVD and examine the effects of antagonism of one significant signal (SMAD2 was selected). Materials and methods: Canine cultures of [n = 6] normal quiescent valve interstitial cells (qVICs) and disease-derived activated myofibroblasts (aVICs) (n = 6 [including one cavalier King Charles spaniel]) were examined for TGFβ signaling protein expression using a commercial antibody array. Significant changes were confirmed, and additional proteins of interest downstream in the TGFβ signaling pathway and markers of cell phenotype were examined (PRAS40, S6K, elF4E IRS-1, αSMA, and VIM), using protein immunoblotting. RT-PCR examined expression of gene markers of VIC activation (ACTA2, TAGLN, and MYH10; encoding the proteins αSMA, SM22, and Smemb, respectively). Attenuation of pSMAD2 in aVICs was examined using a combination of RNA interference technology (siRNA) and the SMAD7 (antagonizes SMAD2) agonist asiaticoside. Results: The antibody array identified significant changes (P < 0.05) in 19 proteins, of which six were phosphorylated (p). There was increased expression of pSMAD2 and pRAC1 and decreased expression of pmTOR, pERK1/2, and pAKT1. Expression of pPRAS40 and pIRS-1 was increased, as was the mTOR downstream transcription factor pS6K, with increased expression of peIF4E in aVICs, indicating negative feedback control of the PI3K/AKT/mTOR pathway. SMAD2 antagonism by siRNA and the SMAD7 agonist asiaticoside decreased detection of pSMAD by at least 50%, significantly decreased expression of the aVIC gene markers ACTA2, TAGLN, and MYH10, and pαSMA, pAKT2, and pERK1, but had no effect on pS6K, pERK2, or pVIM expression in aVICs. SMAD2 antagonism transitioned diseased aVICs to normal qVICs, while maintaining a mesenchymal phenotype (VIM+) while concurrently affecting non-canonical TGFβ signaling. Conclusion: ... Myxomatous mitral valve disease is associated with changes in both the canonical SMAD and several of the non-canonical parts of the TGFβ signaling pathway, particularly PI3K/AKT/mTOR, indicating likely contribution to disease pathogenesis. ... MMVD is associated with changes in both the canonical and non-canonical TGFβ signaling pathway. Antagonism of SMAD2 transitions diseased-activated myofibroblasts back to a normal phenotype, providing data that will inform studies on developing novel therapeutics to treat MMVD in dogs and humans.

Utility of vertebral left atrial size and vertebral heart size to aid detection of congestive heart failure in dogs with respiratory signs. Evan S. Ross, Lance C. Visser, Nicholas Sbardellati, Brianna M. Potter, Alex Ohlendorf, Brian A. Scansen. J. Vet. Intern. Med. October 2023; doi: 10.1111/jvim.16918. Quote: Background: Differentiating cardiogenic vs noncardiogenic causes of respiratory signs can be challenging when echocardiography is unavailable. Radiographic vertebral left atrial size (VLAS) and vertebral heart size (VHS) have been shown to predict echocardiographic left heart size, with VLAS specifically estimating left atrial size. Hypothesis/Objectives: Compare the diagnostic accuracy of VLAS and VHS to predict left-sided congestive heart failure (CHF) in dogs presenting with respiratory signs. Animals: One-hundred fourteen dogs with respiratory signs and radiographic pulmonary abnormalities. Methods: Retrospective cross-sectional study. Dogs had to have an echocardiogram and thoracic radiographs obtained within 24 hours. Diagnosis of CHF was confirmed based on the presence of respiratory signs, cardiac disease, LA enlargement, and cardiogenic pulmonary edema. ... Echocardiographic LA enlargement (EchoLAE) was defined by LA/Ao_Sx >1.68 and LAD/AoD_Lx >2.54. ... Results: Fifty-seven dogs had CHF and 57 did not have CHF. [47 different breeds, including 4 cavalier King Charles spaniels, and 21 mixed breed dogs.] Compared to VHS (area under the curve [AUC] 0.85; 95% confidence interval [CI], 0.77-0.91), VLAS was a significantly (P=.03) more accurate predictor of CHF (AUC, 0.92; 95% CI, 0.85-0.96). Optimal cutoff for VLAS was >2.3 vertebrae (sensitivity, 93.0%; specificity, 82.5%). Murmur grade and VLAS were independently associated with CHF and VHS was not. Increased VHS (54%) was significantly more common than increased VLAS (24%) in dogs without CHF. Results were similar in a subsample of older and smaller dogs. Conclusions and Clinical Importance: When echocardiography is unavailable, VLAS and murmur grade have clinically utility to aid in differentiating cardiogenic from noncardiogenic respiratory signs. These findings might be especially useful to help rule out CHF in dogs with increased VHS that present with respiratory signs.

Efficacy of a mitral regurgitation severity index to predict long-term outcome in dogs with myxomatous mitral valve disease. Michelle Vereb, Clarke E. Atkins, Darcy Adin, Thomas Blondel, Melissa Coffman, Seunggon Lee, Emilie Guillot, Jessica L. Ward. J. Vet. Intern. Med. November 2023; doi: 10.1111/jvim.16923. Quote: Background: Predicting progression of myxomatous mitral valve disease (MMVD) in dogs can be challenging. Hypothesis/Objectives: The mitral regurgitation severity index (MRSI) will predict time to congestive heart failure (CHF) and all-cause death in dogs with MMVD. Animals: Eight hundred sixty-nine client-owned dogs. Methods: Retrospective study pooling data from 4 previous samples including dogs with MMVD stage B2 or C. MRSI was calculated as: (heart rate [HR]/120)  left atrium-to-aorta ratio (LA:Ao)  (age in years/10)  100. Alternative MRSI formulas substituting radiographic measures of left atrial size were also calculated. Cox proportional hazard modeling and time-dependent receiver-operator characteristic curves quantified prognostic performance. Results: For Stage B2 pooled samples, MRSI > 156 was predictive of time to CHF (median 407 vs 1404 days; area under the curve [AUC] 0.68; hazard ratio 3.02 [95% CI 1.9-4.9]; P < .001). MRSI > 173 was predictive of all-cause death (median survival 868 vs 1843 days; AUC 0.64; hazard ratio 4.26 [95% CI 2.4-7.5]; P < .001). MRSI showed superior predictive value compared to the individual variables of HR, LA:Ao, and age. Variations of the MRSI equation substituting radiographic vertebral left atrial size for LA:Ao were also significantly predictive of outcome in stage B2. MRSI was not consistently predictive of outcome in Stage C. Conclusions and Clinical Importance: MRSI was predictive of outcome (onset of CHF and all-cause death) in MMVD Stage B2, demonstrating utility as a useful prognostic tool. Echocardiographic LA:Ao can be effectively replaced by radiographically determined LA size in the MRSI formula.

Mitral valve transcriptome analysis in thirty-four age-matched Cavalier King Charles Spaniels with or without congestive heart failure caused by myxomatous mitral valve disease. Maria J Reimann, Signe Cremer, Liselotte Christiansen, Emil Ibragimov, Fei Gao, Susanna Cirera, Merete Fredholm, Lisbeth H Olsen, Peter Karlskov-Mortensen. Mamm. Genome. November 2023; doi: 10.1007/s00335-023-10024-1. Quote: We here report the results of a mitral valve transcriptome study designed to identify genes and molecular pathways involved in development of congestive heart failure (CHF) following myxomatous mitral valve disease (MMVD) in dogs. The study is focused on a cohort of elderly age-matched dogs (n = 34, age ~ 10 years) from a single breed-Cavalier King Charles Spaniels (CKCS)-with a high incidence of MMVD. The cohort comprises 19 dogs (10♀, 9♂) without MMVD-associated CHF, and 15 dogs (6♀, 9♂) with CHF caused by MMVD; i.e., we compare gene expression in breed and age-matched groups of dogs, which only differ with respect to CHF status. We identify 56 genes, which are differentially expressed between the two groups. In this list of genes, we confirm an enrichment of genes related to the TNFβ-signaling pathway, extracellular matrix organization, vascular development, and endothelium damage, which also have been identified in previous studies. However, the genes with the greatest difference in expression between the two groups are CNTN3 and MYH1. Both genes encode proteins, which are predicted to have an effect on the contractile activity of myocardial cells, which in turn may have an effect on valvular performance and hemodynamics across the mitral valve. This may result in shear forces with impact on MMVD progression.

Lung ultrasound score in dogs and cats: A reliability study. Stefano Oricco1, Daniele Medico, Ilaria Tommasi1, Richard Marcello Bini, Roberto Rabozzi. J. Vet. Intern. Med. November 2023; doi: 10.1111/jvim.16956. Quote: Background: Lung ultrasound (LUS) is a noninvasive tool for examining respiratory distress patients. The lung ultrasound score (LUSS) can be used to quantify and monitor lung aeration loss with good reliability. Hypothesis/Objectives: Assess the reliability of a new LUSS among raters with different levels of experience and determine how well the same raters agree on identifying patterns of LUS abnormalities. Animals: Forty LUS examinations of dogs and cats and 320 videos were reviewed from a digital database. Methods: Retrospective reliability study with post hoc analysis. Protocolized LUS were randomly selected; intrarater and interrater reliability of the LUSS and pattern recognition agreement among 4 raters with different levels of experience in LUS were tested. Results: The intrarater intraclass correlation coefficient (ICC) single measurement, absolute agreement, and 2-way mixed effects model was 0.967 for the high-experience rater (H-Exp), 0.963 and 0.952 for the medium-experience raters (M-Exp-1; M-Exp-2), and 0.950 for the low-experience rater (L-Exp). The interrater ICC average measurement, absolute agreement, and 2-way random effects model among the observers was 0.980. The Fleiss' kappa (k) values showed almost perfect agreement (k = 1) among raters in identifying pleural effusion and translobar tissue-like pattern, strong agreement for Alines (k = 0.881) and B-lines (k = 0.806), moderate agreement (k = 0.693) for subpleural loss of aeration, and weak agreement (k = 0.474) for irregularities of the pleural line. Conclusions and Clinical Importance: Our results indicate excellent intra- and interrater reliability for LUS scoring and pattern identification, providing a foundation for the use of the LUSS in emergency medicine and intensive care.

Development and feasibility of new cardiac measurement method using vertebral heart area ratio in dogs. Jaebeom So, Jiwon Chung, Miseong Je, Kyuyong Kang, Jihye Choi, Junghee Yoon. J. Vet. Med. Sci. November 2023; doi: 10.1292/jvms.23-0078. Quote: The vertebral heart scale (VHS) is the most common method used for the objective evaluation of heart size, however, VHS cannot evaluate the entire heart area. This retrospective study aimed to evaluate the development and feasibility of vertebral heart area ratio (VHAR = heart area/the fourth thoracic vertebra [T4] body area) as a new cardiac measurement method. A total of 125 dogs [none were CKCSs] considered without clinical heart abnormalities in the pre-anesthetic examination, measurements of the VHS and VHAR using thoracic radiography were compared with computed tomography measurements of the vertebral cardiac volume ratio (VCVR = cardiac volume/T4 body volume) and investigate whether the VHAR values differed between observers. The mean cardiac and T4 body volumes were 116.99 ± 108.07 cm3 and 0.92 ± 0.91 cm3, respectively. The mean values of observers 1 and 2 were 9.9 ± 0.7 v (VHS), 42.64 ± 27.94 cm2 (heart area), and 1.37 ± 0.96 cm2 (T4 body area). Intraclass coefficients were the highest for the heart area, followed by the T4 body area and VHS. The VHAR showed a moderate correlation with VHS in observers 1 (r=0.671) and 2 (r=0.633). The VCVR showed a more positive correlation with VHAR (r=0.573) than with VHS (r=0.426). These results indicated that VHAR could be used as a complement to VHS for heart size measurement, and the high degree of observer agreement for the measurements indicated the measurement reproducibility of VHAR.

Self-Reported Utilization of International Guidelines for Staging Dogs with Myxomatous Mitral Valve Degeneration: A Survey among Veterinary Practitioners. Marie D. B. van Staveren, Esther Muis, Viktor Szatmári. Vet. Sci. December 2023; doi: 10.3390/vetsci10120687. Quote: Background: ACVIM developed and published guidelines for staging myxomatous mitral valve degeneration in dogs in 2009. An updated version was published in 2019. The present study aimed to investigate whether these guidelines are actually used by the intended public more than a decade after their first publication. Methods: An online survey was distributed among Dutch and Belgian veterinarians through online channels and mailing lists. Results: Of the 524 responses, only 363 complete surveys were analyzed. The ACVIM guidelines are used by 60% of the respondents. Veterinarians find it more difficult to differentiate stage B1 from B2 in asymptomatic dogs compared to diagnosing stage C. Three-quarters of the respondents would recommend echocardiography for an incidentally detected new murmur with an intensity of 3 out of 6 in an adult dog. Two-thirds of the respondents find coughing a convincing finding for stage C disease. Close to half of the respondents associate a horizontal, dull percussion line with pulmonary edema. For confirming cardiogenic pulmonary edema, 98% of the respondents used thoracic radiographs. Conclusions: Veterinary practitioners might not have the expected training and equipment to be able to apply the guidelines in their practices, especially in the differentiation of stage B1 from stage B2. (See also this February 2024 article.)

Renin-angiotensin-aldosterone and phosphodiesterase system gene polymorphisms associated with congestive heart failure in Cavalier King Charles Spaniels with myxomatous mitral valve disease. MJ Reimann, K Meurs, J Stern, J Møller, T Martinussen, I Ljungvall, J Häggström, LH Olsen. Abstract ESVC-0-3, 33d ECVIM-CA Congress, J. Vet. Int. Med. December 2023; doi: 10.1111/jvim.16930. Quote: Myxomatous mitral valve disease (MMVD) is associated with changes in the renin-angiotensin-aldosterone and phosphodiesterase (PDE) systems. Gene polymorphisms with functional importance in genes involved in both systems have been identified in dogs. The aim of the study was to determine the impact of selected angiotensin converting enzyme (ACE) and PDE5A polymorphisms on presence of congestive heart failure (CHF) due to MMVD in Cavalier King Charles Spaniels (CKCS). In this retrospective study, 107 client-owned CKCS with CHF and 75 control CKCS ≥8 years of age were included. Diagnosis of CHF was based on history of MMVD, previous or current clinical signs of CHF, echocardiographic changes compatible with severe MMVD and response to diuretic treatment. Blood samples were stored for PCR genotyping of selected ACE and PDE5A gene polymorphisms. Odds of having CHF were estimated using logistic regression including ACE and PDE5A gene polymorphisms as explanatory factors. ACE polymorphism positive CKCS had reduced odds for CHF compared to negative wildtype CKCS (heterozygous odds ratio (OR)=0.41, 95% confidence interval (95% CI)=0.19;0.85, P=0.018; homozygous OR=0.40, 95% CI=0.17;0.92, P=0.032) while PDE5A polymorphism positive CKCS had increased odds for CHF compared to negative wildtype CKCS (heterozygous OR=2.89, 95% CI=1.07;8.30, P=0.040; homozygous OR=2.94, 95% CI=1.09;8.40, P=0.037). In conclusion, selected ACE and PDE5A gene polymorphisms were associated with presence of CHF due to MMVD in CKCS. The findings indicate that in CKCS, ACE gene polymorphism might have a protective role while PDE5A gene polymorphism might be disadvantageous in relation to presence of CHF due to MMVD.

A Case Report of a Novel Treatmentfor Mitral Regurgitation in Dogs — A Novel Transcatheter Mitral Valve Repair Device Was Used to Treat Mitral Regurgitation in Dogs. Qingbo Ma, Junjie Wu, Zihan Wang. Asian Vet. Case Studies. December 2023; doi: 10.12677/ACRPVM.2023.124005. Quote: Introduce a new type of transcatheter mitral valve repair device for the treatment of canine myxoma-like mitral valve disease and its therapeutic effect. This case is a stage C case of myxomatous mitral valve disease [Bichon Frize]. The new transcatheter mitral valve repair device was used for treatment. The operation was smooth, the postoperative symptoms improved significantly, the quality of life wasimproved, and the life expectancy increased. ... In conclusion, edge-to-edge valve closure using the Valve Clamp Mitral Valve System is simple to perform and highly effective in reducing the severity of mitral regurgitation, providing a new option for veterinary clinical treatment of MMVD.

Differentially expressed platelet activation-related genes in dogs with stage B2 myxomatous mitral valve disease. Qingqing Zhou, Xiang Cui, Han Zhou, Shuai Guo, Zhimin Wu, Liyang Li, Jinxin Zhang, Wen Feng, Yingfang Guo, Xiaofei Ma, Yu Chen, Changwei Qiu, Ming Xu, Ganzhen Deng. BMC Vet. Res. December 2023; doi: 10.1186/s12917-023-03789-9. Quote: Background: Peripheral blood carries a reservoir of mRNAs that regulate cardiac structure and function potential. Although it is well recognized that the typical symptoms of Myxomatous Mitral Valve Disease (MMVD) stage B2 are long-standing hemodynamic disorder and cardiac structure remodeling caused by mitral regurgitation, the transcriptomic alterations in blood from such dogs are not understood. ... Finally, a discovery cohort (three NC [normal control] and five with MMVD stage B2 Poodles) and a validation cohort (52 NC and 56 with MMVD stageB2 multi-breed canines) were included in the study. ... Results: In the present study, comparative high-throughput transcriptomic profiling of blood was performed from normal control (NC) and naturally-occurring MMVD stage B2 (MMVD) dogs. Using Weighted Gene Co-expression Network Analyses (WGCNA), Gene Ontology (GO), and Kyoto Encyclopedia of Gene and Genomes (KEGG), we identified that the turquoise module was the most highly correlated with echocardiographic features and found 64 differentially expressed genes (DEGs) that were significantly enriched in platelet activation related pathways. Therefore, from the turquoise module, we selected five DEGs (MDM2, ROCK1, RIPK1, SNAP23, and ARHGAP35) that, according to real-time qPCR, exhibited significant enrichment in platelet activation related pathways for validation. The results showed that the blood transcriptional abundance of MDM2, ROCK1, RIPK1, and SNAP23 differed significantly between NC and MMVD dogs. On the other hand, Correlation Analysis revealed that MDM2, ROCK1, RIPK1, and SNAP23 genes negatively regulated the heart structure parameters, and followed the same trend as observed in WGCNA. Conclusion: We screened four platelet activation related genes, MDM2, ROCK1, RIPK1, and SNAP23, which may be considered as the candidate biomarkers for the diagnosis of MMVD stage B2. These findings provided new insights into MMVD pathogenesis. ... In the current study, MDM2 expression was significantly lower in dogs with MMVD stage B2 than in healthy dogs. In addition, the MDM2 mRNA expression was significantly negatively correlated with LA:AO, LVIDDN, and VHS. Overall, these findings suggested that MDM2 may be a promising diagnostic and therapeutic target for MMVD stage B2. Unfortunately, an analysis of platelet count and function was not performed in the current study. Thus, the potential relationship between the significant down-regulation of MDM2 in MMVD and the number and activation status of platelets requires further investigation.

Radiographic Left Atrial Size Measurement of Dogs in Different Mitral Valve Disease Stages with Four Different Methods. David Marbella, José Alberto Montoya-Alonso. Animals. ecember 2023; doi: 10.3390/ani13243835. Quote: The left atrial size increases (LAS) in patients with mitral valve disease (MVD) as the disease progresses. The vertebral left atrial size (VLAS), the modified-vertebral left atrial size (M-VLAS), and the radiographic left atrial dimension (RLAD) are methods reported to assess LAS on dogs’ radiographs. All these methods transform the LAS into vertebral units. The thoracic inlet (TI) has been used as a reliable reference point to measure the cardiac silhouette of dogs with MVD in different stages. The objective of this study was to assess the clinical utility of measuring a dog LAS on right thoracic X-rays using the TI as a reference and determine whether it could differentiate dogs in different MVD stages. LAS was divided by the TI to obtain the thoracic inlet left atrial score (TILAS). This was a retrospective observational study including 135 apparently healthy dogs [one cavalier King Charles spaniel] performed to assess their LAS with four different methods: VLAS, M-VLAS, RLAD, and TILAS. Thirty-six dogs from the general population were selected and compared to 100 dogs in different MVD stages. The TILAS was significantly different between the control dogs and MVD dogs, increasing with the disease stage: control dogs 0.51 ± 0.08, B1 0.57 ± 0.14, B2 0.75 ± 0.13, and C 0.84 ± 0.18. VLAS, M-VLAS, and RLAD also increased as the disease progressed, as shown in previous studies. The TILAS accuracy to distinguish MVD dogs with cardiac enlargement was comparable to VLAS, M-VLAS, and RLAD (AUC 0.91 vs. 0.93, 0.90, and 0.94 respectively). A TILAS > 0.8 can identify dogs with cardiac enlargement secondary to MVD. ... The TILAS method is a simple way to assess the left atrial size in dogs’ thoracic radiographs. A TILAS cutoff < 0.6 means that the patient is less likely to have cardiac enlargement. A cutoff > 0.8 can be used to identify dogs that might need echocardiography for further evaluation. A cutoff > 1 can be used to identify dogs with cardiac enlargement in the absence of echocardiography. VLAS, M-VLAS, and RLAD are reproducible methods to assess the left atrial size by a different observer in a different population. Different reference points can be used to assess the progression of cardiac enlargement on MVD dog X-rays, considering that the only structure that changes its size with time is the cardiac silhouette.

Indicators for pulmonary hypertension in dogs with degenerative mitral valve disease. Pasika Chalermpromma, Sirilak Disatian Surachetpong. Vet. World. December 2023; doi: 10.14202/vetworld.2023.2515-2520. Quote: Background and Aim: Pulmonary hypertension (PH) is a common complication of degenerative mitral valve disease (DMVD) in dogs. This study aimed to determine PH indicators in dogs with stage C DMVD through thoracic radiography and M-mode and 2-dimensional echocardiography. Materials and Methods: A retrospective study of 133 dogs with DMVD stage C was conducted. The patients were divided into two groups: DMVD and DMVD with PH. Characteristics, thoracic radiographic findings, and echocardiographic variables were recorded for analysis. Results: Pulmonary hypertension was diagnosed in 56 dogs, with a prevalence of 42.1%. Univariable logistic regression analysis revealed associations among PH and right-sided heart enlargement, pulmonary artery enlargement, left ventricular size, and percent fractional shortening. Multivariable logistic regression analysis demonstrated that pulmonary artery enlargement (odds ratio [OR]: 5.96; 95% confidence interval [CI]: 1.45-24.54; p = 0.014) and decreased left ventricular size (OR: 0.02; 95%CI: 0.003-0.13; p = 0.001) were significantly associated with PH. The accuracy of predicting PH in dogs at DMVD stage C using pulmonary artery enlargement combined with decreased left ventricular size was moderate (area under the curve [AUC] 0.77; 95%CI: 0.68-0.86). Conclusion: Pulmonary hypertension is common in dogs with DMVD stage C. The presence of pulmonary artery enlargement assessed by radiography and decreased left ventricular size assessed by echocardiography, were associated with PH and may serve as predictors of PH in DMVD stage C. Keywords: canine, degenerative mitral valve disease, pulmonary hypertension.

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2024

Automated echocardiographic left ventricular dimension assessment in dogs using artificial intelligence: Development and validation. Catherine C. Stowell, Valeria Kallassy, Beth Lane, Jonathan Abbott, Kieran Borgeat, David Connolly, Oriol Domenech, Joanna Dukes-McEwan, Luca Ferasin, Josefa Fernández Del Palacio, Chris Linney, Jose Novo Matos, Ilaria Spalla, Nuala Summerfield, Tommaso Vezzosi, James P. Howard, Matthew J. Shun-Shin, Darrel P. Francis, Virginia Luis Fuentes. J. Vet. Intern. Med. February 2024; doi: 10.1111/jvim.17012. Quote: Background: Artificial intelligence (AI) could improve accuracy and reproducibility of echocardiographic measurements in dogs. Hypothesis: A neural network can be trained to measure echocardiographic left ventricular (LV) linear dimensions in dogs. Animals: Training dataset: 1398 frames from 461 canine echocardiograms from a single specialist center [including 39 cavalier King Charles spaniels, the breed with the most participating dogs]. Validation: 50 additional echocardiograms from the same center. Methods: Training dataset: a right parasternal 4-chamber long axis frame from each study, labeled by 1 of 18 echocardiographers, marking anterior and posterior points of the septum and free wall. Validation Dataset: End-diastolic and end-systolic frames from 50 studies, annotated twice (blindly) by 13 experts, producing 26 measurements of each site from each frame. The neural network also made these measurements. We quantified its accuracy as the deviation from the expert consensus, using the individual-expert deviation from consensus as context for acceptable variation. The deviation of the AI measurement away from the expert consensus was assessed on each individual frame and compared with the root-mean-square-variation of the individual expert opinions away from that consensus. Results: For the septum in end-diastole, individual expert opinions deviated by 0.12 cm from the consensus, while the AI deviated by 0.11 cm (P = .61). For LVD, the corresponding values were 0.20 cm for experts and 0.13 cm for AI (P = .65); for the free wall, experts 0.20 cm, AI 0.13 cm (P < .01). In end-systole, there were no differences between individual expert and AI performances. Conclusions and Clinical Importance: An artificial intelligence network can be trained to adequately measure linear LV dimensions, with performance indistinguishable from that of experts.

Factors related to longevity and mortality of dogs in Italy. Mariana Roccaro, Romolo Salini, Marco Pietra, Micaela Sgorbini, Eleonora Gori, Maurizio Dondi, Paolo E. Crisi, Annamaria Conte, Paolo Dalla Villa, Michele Podaliri, Paolo Ciaramella, Cristina Di Palma, Annamaria Passantino, Francesco Porciello, Paola Gianella, Carlo Guglielmini, Giovanni L. Alborali, Sara Rota Nodari, Sonia Sabatelli, Angelo Peli. Preventive Vet. Med. February 2024; doi: 10.1016/j.prevetmed.2024.106155. Quote: Highlights: • The overall median longevity of dogs in Italy was 10.0 years. • Mixed-breed dogs generally lived longer than purebreds. • Dog size was inversely correlated to longevity. • Neutering/spaying appeared to be positively related to longevity. • Neoplasia was the most frequent cause of death, mostly affecting large-sized dogs. Besides its translational value, an improved understanding of dog longevity and mortality is necessary to guide health management decisions, breed selection, and improve dog welfare. In order to analyse the lifespan of dogs in Italy, identify the most common causes of death, and evaluate possible risk factors, anonymised medical records were collected from 9 veterinary teaching hospitals and 2 public health institutions. Data regarding breed, sex, neuter status, age, diagnosis, and mechanism of death were retrieved. Cause of death (COD) was classified by pathophysiologic process (PP) and organ system (OS). Of the 4957 dogs [62 were Cavalier King Charles Spaniels] that died between 2004 and 2020 included in the study, 2920 (59.0%) were purebred, 2293 (46.2%) were female, 3005 (60.6%) were intact, 2883 (58.2%) were euthanised. Overall median longevity was 10.0 years. Median longevity was significantly longer for crossbreds, females, neutered dogs, and small-sized breeds. The breeds with the highest median age at death were the Yorkshire terrier, English cocker spaniel, West Highland white terrier, Italian volpino, and Shih Tzu, whilst the American bulldog, English bulldog, American pit bull terrier, Bernese mountain dog and the Maremma and the Abruzzes sheepdog had the lowest median age at death. The most frequent COD by PP was neoplasia (34.0%), which occurred more frequently in large breeds, namely German shepherd, Labrador retriever and Boxer. Degenerative diseases mostly affected small-sized dogs like Miniature pinscher and Dachshund. ... Degenerative diseases affected mostly the Cavalier King Charles spaniel (51.6%). ... The breeds with the highest relative proportion of cardiovascular causes of death were the Cavalier King Charles spaniel (53.2%) and Chihuahua (33.3%). ... The Cavalier King Charles spaniel and Chihuahua also showed the highest relative proportion of degenerative cardiovascular causes of death. Small and toy breeds are in fact at elevated risk for myxomatous mitral valve disease, i.e., the most commonly diagnosed cardiovascular disease in dogs. ... Regarding the OS involved, diseases of the renal/urinary system were most frequently responsible for COD (15.0%), prevalently degenerative and inflammatory/infectious. Substantial variation in median longevity according to causes of death by PP and OS was observed. These data are relevant for breeders, veterinary practitioners, and owners, to assist breed selection, facilitate early diagnosis, guide choice when purchasing a purebred dog and making health management decisions, and ultimately improve dog welfare.

Relationship between syringomyelia and myxomatous mitral valve disease in Cavalier King Charles spaniels. Maiken B. T. Bach, Camilla L. Stougaard, Maria S. Thøfner, Maria J. Reimann, Ulrik Westrup, Jørgen Koch, Merete Fredholm, Torben Martinussen, Mette Berendt, Lisbeth H. Olsen. J. Vet. Intern. Med. February 2024; doi: 10.1111/jvim.17018. Quote: Background: Syringomyelia (SM) and myxomatous mitral valve disease (MMVD) are highly prevalent in Cavalier King Charles spaniels (CKCS). Cardiac status in CKCS with and without SM is currently unknown. Objectives: To investigate the association between SM and MMVD severity in CKCS and CKCS with SM with and without clinical signs of SM. Animals: . ... The study cohort consisted of 55 CKCS, 40 CKCS with SM and 15 CKCS without SM that had Magnetic Resonance Imaging (MRI) at the University [of Copenhagen, Denmark] Hospital for Companion Animals, Department of Veterinary Clinical Sciences in 2007-2015. ... Over the years, national breeding schemes have been established to reduce the occurrence of MMVD in CKCS, reducing the prevalence of early onset heart murmur in CKCS. At the same time, however, no such breeding restrictions have been established to remove CKCS with early-onset SM from the breeding program, thereby reducing the incidence of SM. The concern that longstanding MMVD-breeding restrictions could potentially influence the prevalence of SM, motivated the present study. Therefore, this study aimed to investigate MMVD in CKCS with and without SM. The secondary aim of this study was to investigate the severity of MMVD in SM affected CKCS with and without clinical signs of SM. ... Methods: A combined retrospective and prospective study. MRI and echocardiography were used to diagnose SM and MMVD, respectively. The association between SM and MMVD severity (left ventricle internal diameter in diastole normalized to bodyweight [LVIDDN] and left atrium to aortic ratio [LA/Ao]) were tested using multivariable linear regression analysis adjusting for sex and age. ... Based on American College of Veterinary Internal Medicine (ACVIM) consensus statement guidelines, the severity of MMVD was staged as follows: Group A, CKCS with no auscultatory heart murmur and normal echocardiogram (no or minimal MR [MR<20%]); group B1, CKCS with an auscultatory heart murmur or MR ≥20% and echocardiographic evidence of MMVD but no cardiac enlargement (LA/Ao<1.6 and LVIDDN<1.7); group B2, CKCS with heart murmur ≥3 of 6 and current or previous echocardiographic evidence of cardiac enlargement (LA/Ao≥1.6 and LVIDDN≥1.7), but without current or previous clinical signs of CHF; group C, CKCS with CHF. Congestive heart failure was defined as a history of MMVD, clinical signs of CHF (eg, cough, dyspnea, tachypnea, nocturnal restlessness, and exercise intolerance), echocardiographic changes compatible with CHF caused by MMVD and response to diuretic treatment. ... In total, 32 of the 55 CKCS were diagnosed with ACVIM MMVD stage B1, 7 with stage B2 and 3 dogs with stage C. ... Results: Overall, no significant difference in LVIDDN and LA/Ao was found between CKCS with or without SM. However, CKCS with symptomatic SM had significantly smaller LVIDDN (1.45 [1.30-1.50]) (median [IQR]) and LA/Ao (1.20 [1.10-1.28]) compared to CKCS with asymptomatic SM (1.60 [1.50-1.90] and 1.40 [1.20-1.75]) as well as CKCS without SM (0.24 [0.03-0.45] and 0.30 [0.05-0.56]) (all P values <.03). Conclusions and Clinical Importance: ... This study investigates the co-occurrence of SM and MMVD. We found no overall association between SM (symptomatic and asymptomatic pooled together) and the severity of MMVD in CKCS, but CKCS with symptomatic SM exhibited smaller left ventricular and left atrial dimensions compared to those with asymptomatic SM and CKCS without SM, suggesting that a complex relationship might exist. However, this study was limited by a relatively small and selected study sample.

Self-Reported Utilization of International (ACVIM Consensus) Guidelines and the Latest Clinical Trial Results on the Treatment of Dogs with Various Stages of Myxomatous Mitral Valve Degeneration: A Survey among Veterinary Practitioners. Marie D. B. van Staveren, Esther Muis, Viktor Szatmári. Animals. February 2024; doi: 10.3390/ani14050772. Quote: Background: Myxomatous mitral valve degeneration is the most common canine heart disease. Several clinical trials have investigated various treatments. The latest recommendations are published in the ACVIM consensus guidelines (2019). Our study aimed to investigate how closely veterinary practitioners apply the treatment recommendations of these guidelines and the latest clinical trials. Methods: An online survey was sent to Dutch and Belgian veterinary practices via digital channels. Results: The data from 363 fully completed surveys were analyzed. For stage B1 disease, 93% recommended, correctly, no treatment. For stage B2 disease, 67% of the respondents recommended starting pimobendan as monotherapy. For chronic treatment of stage C disease, 16 different drug combinations were mentioned, but nobody recommended surgery. Only 48% of the respondents recommended the only evidence-based drug combination: a loop diuretic with pimobendan. A concerning finding was the simultaneous prescription of two loop diuretics, by 19% of the respondents. Conclusions: Treatment recommendations showed an increasing variation with more advanced disease stages from B1 through B2 to C. This reflects the increasing disagreement among the panelists who prepared the ACVIM consensus guidelines. Practitioners of our study seem to practice more evidence-based medicine than veterinary cardiologists, as it was reported in a recent survey-based study. (See also this December 2023 article.)

Pulmonary Hypertension Secondary to Myxomatous Mitral Valve Disease in Dogs: Current Insights into the Histological Manifestation and Its Determining Factors. Arkadiusz Grzeczka, Urszula Pasławska, Szymon Graczyk, Paulina Antosik, Marcin Zawadzki, Robert Pasławski. Appl. Sci. March 2024; doi: 10.3390/app14062577. Quote: Pulmonary venous hypertension (PVH) is caused by deteriorating left ventricular function. The most common cause of PVH in dogs is myxomatous mitral valve degeneration (MMVD). It causes left ventricular volume overload and an increase in left atrial and pulmonary venous pressure (PVH), which leads to pulmonary vascular wall remodeling and contributes to the perpetuation and worsening of PVH. Pulmonary vascular wall remodeling is also characteristic of pulmonary arterial hypertension (PAH). However, the changes in PVH arise secondary to heart failure and vas-cular remodeling progresses as the disease progresses. On the other hand, PAH is a primary disease that can be triggered, for example, by the use of certain drugs. Similar structural changes may suggest the influence of similar pathophysiological mechanisms or the intermediation of similar mediators. Therefore, this article discusses recent and hitherto uncommented findings elucidating the pathophysiology of the processes and influences on the pattern of histological changes observed in pulmonary hypertension secondary to degenerative mitral valve disease. In particular, we focus on the activity of factors such as endothelin, serotonin, and nitric oxide, which are involved in pulmonary vascular wall remodeling in both PVH and PAH.

Volumetric quantification identifies some left atrial dilations undetected by left atrium:aorta ratio measurements: A prospective echocardiographic study in 155 Cavalier King Charles Spaniels with and without degenerative mitral valve disease. Valérie Chetboul, Camille Poissonnier, Pierre Foulex, Maria Paz Alvarado, Émilie Trehiou-Sechi, Vittorio Saponaro, Peggy Passavin, Loïc Desquilbet. PLoS One. March 2024; doi: 10.1371/journal.pone.0300827. eCollection 2024. Quote: Introduction: Degenerative mitral valve disease (DMVD) is the most common canine heart disease with a high predisposition in Cavalier King Charles Spaniels (CKCSs). Mitral regurgitation related to DMVD can lead to left atrial (LA) dilation, which is associated with survival time. Left-atrial-to-aortic (LA:Ao) ratio assessed by two-dimensional echocardiography is commonly used to evaluate LA size. The objectives of this prospective observational study were therefore 1) to compare different echocardiographic methods (i.e., monoplane and biplane Simpson's methods of discs (SMOD) and area-length methods (ALM)) in evaluating LA volume (LAvol) in CKCSs, 2) to assess LA volumes according to DMVD severity and, 3) compare the ability of LAvol and LA:Ao ratio to identify LA enlargement in CKCSs with subclinical DMVD (i.e., American College of Veterinary Internal Medicine (ACVIM) stage B). Materials and methods: 155 CKCSs, either healthy [27 dogs - 17%] or affected by DMVD [128 dogs - 83%], were recruited. Variability and concordance between volumetric methods were evaluated. Values were analyzed according to 2019 ACVIM stages. ... According to the 2019 ACVIM classification, 27/155 dogs (17%) were considered as healthy (stage A), 94/155 (61%) and 15/155 (10%) were in stages B1 and B2, respectively, 19/155 (12%) had past or current CHF, with 18/155 in stage C and only 1 in stage D. ... However, these multibreed echocardiographic ACVIM cut-offs do not correctly fit with the CKCS breed regarding both LA and LV sizes. Therefore, in the present study, CKCS breed-specific reference intervals (instead of the ACVIM multi-breed cut-offs) were used to define LA and LV enlargement, as explained above. Stage B1 included asymptomatic dogs with mitral regurgitation that was not severe enough to meet stage B2 criteria. ... Results: ... In healthy CKCS dogs (ACVIM stage A), the median LA:Ao ratios were ... 1.02 (0.90–1.12) at end-systole. ... Tricuspid regurgitation adequate for TRPG [tricuspid regurgitation pressure gradient] assessment was identified in 145/155 (94%) CKCSs, and pulmonary arterial hypertension (defined as TRPG >46 mmHg) was diagnosed in 22 DMVD dogs: 5/87 (6%) in ACVIM stage B1, 2/14 (14%) in ACVIM stage B2, 15/19 (79%) in ACVIM stages C and D. Four out of the 5 ACVIM DMVD B1 dogs with moderate PAH did not show overt respiratory clinical signs at time of DMVD diagnosis and inclusion. One had history of mild tracheal collapse on previous thoracic radiographs and for the three others, snoring during sleep at home was the sole clinical sign reported by the owners. The other B1 dog was obese with at least a 3-kg overweight. Therefore, pulmonary hypertension for these 5 ACVIM B1 dogs was consistent with at least type 3 PAH according to the ACVIM classification. One ACVIM stage B1 dog with a high TRPG gradient (52 mmHg) underwent a single syncope episode after an intense physical effort. ... All Lin's concordance correlation coefficients regarding intra- and inter-observer variability were considered as very good to excellent. Monoplane methods and ALM produced higher values of LAvol than biplane methods and SMOD, respectively. The upper limit of normal end-systolic LAvol/body weight (LASvol/BW) was defined as 0.90 mL/kg. Left atrial volumes significantly increased with ACVIM stages. Additionally, 37% of stage B1 CKCSs demonstrated LA enlargement using LASvol/BW assessment, with significantly lower LASvol/BW values in dogs with regurgitation fraction ≤30% than in others (p<0.01). ... Regarding LA and LV dilation criteria, there is now scientific evidence that the proposed multibreed echocardiographic ACVIM cut-offs do not perfectly fit for several specific breeds, and the use of breed-specific reference intervals would be more appropriate. As recently demonstrated by Rishniw and Brown, approximately 10% of healthy CKCSs would be misclassified as having LV enlargement using the ACVIM-recommended scaling exponent (0.294) and the cut-off of 1.7 for normalized end-diastolic LV internal diameter. The study published by Misbach et al dedicated to the establishment of echocardiographic reference intervals in a large population of healthy CKCSs also demonstrated the discrepancy between their LV breed-specific reference intervals (assessed according to the Clinical Laboratory and Standard Institute recommendations) and the predictive reference intervals obtained in the same population using Cornell’s formula. ... Regarding LA size, CKCS dogs seem to have smaller end-diastolic and end-systolic LA dimensions than most other breeds. In the present study, LA/Ao ratios were measured at end-diastole and end-systole as respectively described in CKCSs by Misbach et al and Hansson et al. End-diastolic LA:Ao values of our ACVIM stage A CKCS dogs (Table 1) are consistent with reference intervals (lower and upper limits with 90% confidence intervals) from Misbach et al, i.e., 0.54 (0.47–0.56) - 0.93 (0.90–0.94). Similarly end-systolic LA:Ao values of our ACVIM stage A CKCS dogs (Table 1) are consistent with those from Hansson et al who reported relatively low LA:Ao ratios at end-systole on 56 healthy CKCSs, with mean ± SD (range) values of 1.03 ± 0.09 (0.84–1.27). Based on these data, the end-systolic LA:Ao ratio cut-off value of 1.6 proposed by the 2019 consensus ACVIM statement to detect end-systolic LA enlargement in all-breed dogs appears inappropriate (i.e., too high) for CKCSs, with a risk of missing some mild LA dilations. ... The present prospective study demonstrates that no dogs with increased LA:Ao ratios had normal LA volumes. Conversely, a sub-population of ACVIM B1 dogs with normal LA/Ao ratios actually showed LA dilation detected by LA volume calculation, which was not apparent when applying end-diastolic and end-systolic LA:Ao ratios. This confirms that LA volume quantification is more effective to detect LA dilation than linear LA measurements. From a practical point of view, this also suggests that considering linear LA measurements only, may lead to an erroneous left heart evaluation, which will not be the case when using volumetric methods only. The high negative prognostic value of LA enlargement has been demonstrated in DMVD dogs, with LA volume being the strongest predictor of cardiac-related death, highly superior to all other parameters of LA size and function including LA/Ao ratios. Therefore, as in human cardiology, LA volumetric quantification should the method of first choice for assessing LA size particularly to stratify ACVIM stage B dogs. Additionally, the early identification of LA enlargement in stage B dogs is of practical interest, as these dogs at risk for decompensation may benefit from a closer longitudinal follow-up than others. Additionally, among the 31 CKCSs with normal end-systolic LA:Ao ratio but increased LASvol/BW volume (Fig 3), 19/31 (61%) showed increased end-diastolic LV diameter. In other words, these 19 dogs were characterized by mitral valve regurgitation severe enough to have induced both LA and LV dilation (with a median RF value of 38%). Thus, according to the 2019 ACVIM classification, these dogs may actually belong to ACVIM stage B2. ... Conclusion: In CKCSs, LAvol methods are not interchangeable. In ACVIM stage B CKCSs, LAvol quantification is more effective to detect LA enlargement than LA linear measurements.

Pulmonary-vein-to-pulmonary-artery ratio can be utilized to evaluate myxomatous mitral valve disease progression in dogs. Min-Suk Kim, Jiyoung Kim, Min Woong Seo, Chul Park. Amer. J. Vet. Res. April 2024; doi: 10.2460/ajvr.24.01.0004. Quote: Objective: To evaluate the diagnostic value of pulmonary-vein-to-pulmonary-artery ratio (PV:PA) in dogs with myxomatous mitral valve degeneration (MMVD), classified according to the American College of Veterinary Internal Medicine (ACVIM) consensus guidelines. Animals: 80 client-owned dogs with either MMVD (n = 65) or no cardiovascular disease (control group; n = 15) between August 5, 2020, and July 19, 2023. Methods: This is a retrospective study. Dogs with MMVD were classified according to ACVIM consensus guidelines. Echocardiograms, thoracic radiographs, and other measurements needed in this study were reviewed in all dogs. Spearman correlation was used to determine the correlation between the PV:PA and the following variables: vertebral heart size, vertebral left atrial size, left-atrium-to-aorta ratio, normalized left ventricular internal diameter, and peak transmitral early diastolic velocity. Receiver operating characteristic (ROC) curve analysis was used to evaluate the value of PV:PA in distinguishing between stages B1 and B2 and stages B2 and C. Results: All conventional indices showed correlations with PV:PA. The area under the ROC curve (AUC) for stages B1 and B2 was 0.83, and the cutoff value for differentiating stage B2 was 1.52. The AUC for stages B2 and C was 0.81, and the cutoff value for differentiating stage C was 2.09. Clinical Relevance: PV:PA was significantly different between control and the stage B1 group, stage B1 and B2 group, and stage B2 and C group. PV:PA can be an index that can be used in evaluating MMVD dogs.

Comparative Study of Cardiovascular Effects of Selected Pulmonary Vasodilators in Canine Models of Mitral Valve Disease. Yunosuke Yuchi, Ryohei Suzuki, Narumi Ishida, Shuji Satomi, Takahiro Saito, Takahiro Teshima, Hirotaka Matsumoto. Biology. April 2024; doi: 10.3390/biology13050311. Quote: Previous reports have shown that various oral pulmonary vasodilators are effective against canine pulmonary hypertension (PH). However, no studies have compared their hemodynamic effects. We aimed to compare the hemodynamic effects of 15 µg/kg beraprost sodium, 1.0 mg/kg sildenafil, and their combination, in dogs with experimentally induced mitral regurgitation. This experimental crossover study evaluated the hemodynamic and functional effects of oral pulmonary vasodilators by application of right-sided heart catheterization and echocardiography. Beraprost significantly decreased pulmonary and systemic vascular resistance. Additionally, beraprost increased right-ventricular stroke volume and left-ventricular cardiac output without worsening left-heart size and left-atrial pressure. The pulmonary vasodilatory effects of sildenafil were stronger, and its systemic vasodilatory effects were weaker than those of beraprost. However, sildenafil significantly increased the left-ventricular volume, left-atrial pressure indicator, and right-ventricular cardiac output. Combination therapy resulted in the strongest pulmonary and systemic vasodilating effects without worsening the left-heart size and left-atrial pressure indicators. Both beraprost and sildenafil were effective against canine PH; however, sildenafil was associated with the risk of worsening left-heart loading. Combination therapy with beraprost and sildenafil synergistically dilated pulmonary and systemic vessels, indicating a more potent treatment option for severe PH cases.

Left Atrial Volume and Function in Cavalier King Charles Spaniels at Different Acvim Stages. Paolo Savarino, Serena Crosara, Marco Poggi, Stefano Oricco, Veronica Chiavassa, Andrea Degiovanni, Alberto Tarducci. SSRN. May 2024. Quote: This study described the atrial dimension and function in a group of CKCS at different ACVIM stages. We evidenced significant atrial enlargement in dogs in class ACVIM B1 and atrial dysfunction in symptomatic dogs. ... Background - The correct assessment of left atrial size and function is essential to evaluate the severity of degenerative mitral valve disease in dogs. Hypothesis/Objectives - Evaluate left atrial (LA) dimension and function in Cavalier King Charles Spaniel (CKCS) at different ACVIM stages and the accuracy of linear and volumetric indexes to assess LA enlargement. Animals - One hundred and ninety-eight [198] privately owned CKCS. Methods - Multicentric prospective observational cross-sectional study. Dogs underwent an echocardiographic exam for breed screening or cardiac examination. Linear and volumetric echocardiographic LA size and function indexes were compared between classes. Results - Dogs were allocated as follows: 43 in class ACVIM A, 58 ACVIM B1, 55 ACVIM B2, and 42 ACVIM C/D. Only LA anteroposterior diameter normalized on body weight (LADn) and LA P volume (LAVP) differed across all pairwise comparisons. A LADn > 1.39 can differentiate between CKCS in classes A and B1 (Sensitivity .79; Specificity .72; AUC .81). Active LA emptying fraction (aLAEF) was higher in class B1 compared to class A (P = .0008), and then decreased in class C/D compared to class B2 (P = .0021), suggesting the presence of atrial dysfunction in symptomatic dogs. Conclusions and clinical importance - The LADn and LAVP are higher in CKCS in class ACVIM B1 compared to class ACVIM A, suggesting the presence of LA remodeling at the early stages of the disease. Atrial dysfunction is evident in symptomatic dogs. (See also this September 2024 version of this study.)

Retrospective evaluation of the utility of shock index to determine the presence of congestive heart failure in dogs with myxomatous mitral valve disease (2019–2021): 98 cases. Hannah Matson, Efa A. Llewellyn. Vet. Emerg. & Critical Care. May 2024; doi: 10.1111/vec.13379. Quote: Objectives: To calculate the shock index (SI) in dogswithmyxomatous mitral valve disease( MMVD) and to evaluate its use to predict the presence of congestive heart failure (CHF). Design: Retrospective study. Setting: Small animal university veterinary teaching hospital. Animals: Ninety-eight dogs with MMVD [including 17 cavalier King Charles spaniels (17.4%)] and 20 healthy dogs as part of a control group. Interventions: Heart rate (HR) and systolic blood pressure (SBP) were recorded, and SI was calculated by dividing HR by SBP for each dog. Measurements and Main Results: The mean (SD)HR, SBP, and SI were 123/min (32.6), 147mmHg (21.5), and 0.86 (0.3), respectively, for dogs with MMVD and 98/min (20.9), 145 mm Hg (18.7), and 0.68 (0.13), respectively, for control dogs. Dogs with MMVD had a significantly higher HR compared with control dogs, and an elevation in HR was seen as the severity of MMVD increased. Dogs in stage B2 and C/D MMVD had a significantly higher SI value compared with control dogs. SI was significantly higher in dogs in stage C/D MMVD compared with dogs in stage B2 MMVD. Ten of 98 (10%) dogs had an arrhythmia. HR, SBP, and SI were not significantly different between dogs with and without arrhythmias, but significantly more dogs with CHF had an arrhythmia. SI (area under the curve [AUC]: 0.98) and HR (AUC: 0.95) were excellent indicators for the presence of CHF. An optimal SI cutoff value ≥1.1 had 92% sensitivity and 95% specificity for predicting the presence of CHF, and an optimal HRcutoff value of ≥157/min had 92% sensitivity and 93% specificity for the prediction of CHF. Conclusions: When there are compatible clinical signs, SI values ≥1.1 may suggest the presence of CHF in dogs with MMVD.

Myxomatous degenerative mitral valve disease in Chihuahuas. Seiya Nimi. Azabu Univ. School of Vet. Med. July 2024. Quote: Chihuahuas are one of the small breed dogs which are predisposed to myxomatous degenerative mitral valve disease (MMVD), which is an important disease observed in this breed in clinical practice. The etiology of MMVD is not completely understood, making prevention and treatment of the disease difficult. There are more than 50,000 Chihuahuas bred in Japan. Herein, we analyze the early stages of MMVD to clarify the cause of Chihuahuas' predilection for MMVD. An allometric equation for exponential echocardiographic values influenced by body weight was obtained from 47 clinically healthy Chihuahuas to establish and echocardiography reference range for the breed (Study 1). Our results showed a high frequency of trivial mitral regurgitation (MR). Since MMVD is essentially a disease of old age, the fact that MR is observed at a young age suggest the characteristics of MMVD in Chihuahuas. Thereafter, we examined the prevalence and characteristics of MR in young Chihuahuas without a heart murmur. The results showed that a high percentage (86.7%, 26/30) of the Chihuahuas had MR. Additionally, findings suggestive of MMVD, such as mitral valve thickening and deviation to the left atrial side, were observed in 17 and 14 cases, respectively. These results suggest that Chihuahuas have MR from a young age and that even young individuals may develop MMVD. Furthermore, late systolic MR, which occurs only during the late systolic phase, and previously unreported in veterinary medicine, was also observed. This may be a predisposing factor for the high incidence of MMVD observed in this breed. Late systolic MR is different from the usual MR that occurs from early to late systole (full systolic MR). Finally, we examined the association between trivial MR and cardiac biomarkers. ANP and NT-proBNP were measured in 56 samples collected from 28 Chihuahuas with no heart murmur. There was no correlation between the degree of mitral regurgitation and biomarker values. we can thus conclude the following: it is good that cardiac biomarkers are not abnormal values because trivial MR in Chihuahuas is not a target for treatment. Biomarkers can be used as a screening test to consider the need for treatment even in young Chihuahuas. This study provided baseline information for the echocardiographic indices and cardiac biomarkers, which are important clinical evaluation methods for this breed. Notably, our results show that Chihuahuas have trivial MR from a young age, which may be one of the predisposing factors for MMVD.

Cellular senescence – the culprit of MMVD? Michal Tkacz, Brendan Corcoran. BSAVA Companion. August 2024; doi: 10.22233/20412495.0824.18. Quote: The cells that are affected by senescence in this case are valve interstitial cells (VICs), which are specialized fibroblasts located in the mitral valve matrix. They are normally found in a quiescent state and become activated (aVICs) in response to damage to the mitral valve, contributing to life-long valve extracellular matrix (ECM) remodelling. They lay down collagen and other connective tissue substances as needed and subsequently return to a quiescent phenotype or are removed from the valve by programmed cell death (apoptosis). However, this does not occur in diseased valves, where they remain in an activated phenotype and enter the arrested cell cycle in a state known as senescence. Targeting of this cellular senescence has the potential to be a novel medical therapeutic approach to controlling the development of valve pathology. ... stressors. MMVD-induced senescence might be triggered by valve edge trauma from repeated closure, although the exact triggering mechanism is unknown. While senescent cells can no longer divide, they remain metabolically active and release a cocktail of damaging proteins including cytokines, chemokines and ECM products into the valve matrix. This is known as senescence-associated secretory phenotype (SASP) and also induces senescence in other nearby cells. ... A very large class of medications has been produced or identified that target senescent cells. Of particular interest are the food-based flavonoids found in fruits, nuts and vegetables, mainly in those of a dark colour (e.g. red grapes, red apples and pomegranate seeds). This PetSavers-funded student research project examined the effect of senolytic candidate drugs (which eliminate senescent cells) including the flavonoids quercetin and fisetin, as well as dasatinib which has been shown to improve flavonoid effects. Each of these drugs targets different points of the senescent signalling pathway; quercetin inhibits the PI3K-AKT pathway, fisetin is a topoisomerase inhibitor and dasatinib is a tyrosine kinase inhibitor. Our study showed that all three can inhibit senescence in aVICs, but that quercetin is more potent than fisetin, and the effect is more pronounced when quercetin and dasatinib are used together (Figure 1). While this was only examined in cell culture, it is a proof of principle that MMVD-associated cell senescence can be countered, and these findings will inform future studies in clinically affected patients.

Quantification of respiratory sinus arrhythmia in control dogs and in dogs with various severity classes of myxomatous mitral valve disease. Radu A. Baisan, Cătălina A. Turcu, Laura M. Bilboc, Mălina C. Maftei, Vasile Vulpe, Dan G. Ohad. J. Vet. Cardiol. August 2024; doi: 10.1016/j.jvc.2024.08.001. Quote: Introduction/objectives: Loss of respiratory sinus arrhythmia (RSA) is a negative prognostic factor in dogs with myxomatous mitral valve disease (MMVD). The aim of this study was to calculate the percentage (%) of RSA in healthy dogs and dogs in various MMVD classes. Animals, materials and methods: Control and MMVD dogs were prospectively included in the study. Respiratory sinus arrhythmia was calculated from a dual channel electrocardiography and breathing curve recording using the peak-to-trough method from three consecutive breaths, in percent of the average heart rate. Results: One hundred and forty-nine dogs were studied, including 24 control and 125 MMVD dogs divided into ACVIM Classes. An overall %RSA decrease was documented with increasing disease severity up to the Ca class along with a relative %RSA increase in the Cc class. The %RSA magnitude differed between B2 and Ca (P<0.01), and between Ca and Cc (P=0.01) groups, respectively. The %RSA magnitude showed a medium negative correlation with the La:Ao ratio (r2 = -0.568, P < 0.01) and with the E-wave velocity (r2 = 0.561, P < 0.01). Conclusions: A decrease in %RSA was shown with increased disease severity up to acute CHF. Furthermore, dogs receiving cardiac therapy leading to stabilized CHF might restore their ability to exhibit RSA and often reveal a higher %RSA compared to those in acute CHF. These findings can serve as the basis for future risk stratification and carry the potential of proving an additional clinical marker for diagnostic and therapeutic decisions making when managing dogs with MMVD.

The impact of intravenous medetomidine and vatinoxan on echocardiographic evaluation of dogs with stage B1 mitral valve disease. E. Välimäki, H. Leppänen, H. Turunen, M. Raekallio, J. Honkavaara. J. Vet. Cardiol. August 2024; doi: 10.1016/j.jvc.2024.04.003. Quote: Introduction/objective: The purpose of this study was to investigate the echocardiographic effects of intravenous medetomidine and vatinoxan in dogs with stage B1 mitral valve disease. We hypothesised medetomidine-vatinoxan would reduce the need for manual restraint during echocardiography without producing detrimental cardiovascular effects or echocardiographic changes. ... Currently, alpha2-adrenoceptor agonists, such as dexmedetomidine and medetomidine, are commonly used in clinical practice due to their ability to induce dose-dependent, reliable, and profound sedation. The peripheral effects of the alpha2-agonists, however, impair the function of the canine cardiovascular system by increasing vascular resistance and decreasing heart rate and cardiac output. These effects limit their usefulness, especially in patients with mitral valve disease, which is the most common chronic cardiac disease in dogs. They also produce notable echocardiographic and radiographic changes which impair the correct evaluation of the cardiac dimensions and function. ... Animals: Twelve client-owned dogs with stage B1 mitral valve disease. ... Breeds were distributed as follows: four Cavalier King Charles Spaniels, two Dachshunds, and one dog of each: American hairless terrier, miniature poodle, Australian kelpie, Labrador-mixed, miniature pinscher, and border collie. ... Methods: A transthoracic echocardiographic examination was performed before and after sedation with intravenous medetomidine (10 mg/kg) and vatinoxan (200 mg/kg). Vital parameters were also recorded, and the level of sedation was assessed subjectively. The data were analysed with Student’s t-tests with an alpha level of <0.05. ... Conclusion: Intravenous medetomidine and vatinoxan caused only mild hemodynamic changes and could be considered safe and useful for sedating dogs with stage B1 MMVD. Still, the effects on some systolic and diastolic echocardiographic variables were notable, which should be taken into consideration when evaluating echocardiographic results in dogs sedated with medetomidine-vatinoxan.

Development of an artificial intelligence-based algorithm for predicting the severity of myxomatous mitral valve disease from thoracic radiographs by using two grading systems. Carlotta Valente, Marek Wodzinski, Carlo Guglielmini, Helen Poser, David Chiavegato, Alessandro Zotti, Roberto Venturini, Tommaso Banzato. Res. Vet. Sci. August 2024; doi: 10.1016/j.rvsc.2024.105377. Quote: A heart-convolutional neural network (heart-CNN) was designed and tested for the automatic classification of chest radiographs in dogs affected by myxomatous mitral valve disease (MMVD) at different stages of disease severity. A retrospective and multicenter study was conducted. Lateral radiographs of dogs with concomitant X-ray and echocardiographic examination were selected from the internal databases of two institutions. Dogs were classified as healthy, B1, B2, C and D, based on American College of Veterinary Internal Medicine (ACVIM) guidelines, and as healthy, mild, moderate, severe and late stage, based on Mitral INsufficiency Echocardiographic (MINE) score. Heart-CNN performance was evaluated using confusion matrices, receiver operating characteristic curves, and t-SNE and UMAP analysis. The area under the curve (AUC) was 0.88, 0.88, 0.79, 0.89 and 0.84 for healthy and ACVIM stage B1, B2, C and D, respectively. According to the MINE score, the AUC was 0.90, 0.86, 0.71, 0.82 and 0.82 for healthy, mild, moderate, severe and late stage, respectively. The developed algorithm showed good accuracy in predicting MMVD stages based on both classification systems, proving a potentially useful tool in the early diagnosis of canine MMVD. Highlights: • AI automatic evaluation of thoracic radiographs supports diagnosis of heart disease. • Heart-CNN can be a support in the prediction of MMVD stages. • This machine-learning algorithm could improve the cardiological diagnostic process.

Quantification of Mitral Valve Regurgitation in Cavalier King Charles Spaniels and Chihuahuas Using Radius of Proximal Isovelocity Surface Area. Jørgen Koch, Inge V. Engeland, Jakob L. Willesen, Anders S. Schrøder, Caroline H. Gleerup, Maiken B. T. Bach. Animals. September 2024; doi: 10.3390/ani14192805. Quote: Mitral regurgitation (MR) resulting from myxomatous mitral valve disease (MMVD) is a prevalent condition in dogs, particularly smaller breeds like Cavalier King Charles Spaniels (CKCSs) and Chihuahuas (CHHs). An accurate assessment of MR severity is essential for effective treatment and disease monitoring, yet a standardized method has yet to be established. In this retrospective study, we evaluated 124 client-owned dogs diagnosed with MMVD, including 64 CKCSs and 60 CHHs. Dogs were categorized into three stages: asymptomatic (B1), remodeled (B2), and congestive heart failure (CHF, C). The MR severity was quantified using the proximal isovelocity surface area (PISA) method, specifically focusing on the PISA radius (PISA-r). The PISA-r measurements exhibited significant increases across disease stages and demonstrated strong correlations with echocardiographic parameters (ranging from 0.83 to 0.94), including the left atrial size and left ventricular internal diameter. The receiver operating characteristic (ROC) curve analysis revealed the high sensitivity and specificity of PISA-r in classifying disease stages, establishing optimal cut-off values. The method displayed excellent repeatability (interobserver variability: 0.95) and reproducibility (intraobserver variability: 0.97). In conclusion, the PISA method, specifically PISA-r, was reliable for assessing MR severity in dogs with MMVD. By simplifying the diagnosis and management of MR, this research can potentially improve the life and management of MMVD-affected dogs.

Left atrial volume and function in Cavalier King Charles spaniels at different ACVIM stages. Res. Vet. Sci. Paolo Savarino, Serena Crosara, Marco Poggi, Stefano Oricco, Veronica Chiavassa, Andrea Degiovanni, Alberto Tarducci. September 2024; doi: 10.1016/j.rvsc.2024.105428. Quote: Background: The correct assessment of left atrial size and function is essential to evaluate the severity of degenerative mitral valve disease in dogs. Hypothesis/objectives: Evaluate left atrial (LA) dimension and function in Cavalier King Charles Spaniel (CKCS) at different ACVIM stages and the accuracy of linear and volumetric indexes to assess LA enlargement. Animals: One hundred and ninety-eight privately owned CKCS. Methods: Multicentric prospective observational cross-sectional study. Dogs underwent an echocardiographic exam for breed screening or cardiac examination. Linear and volumetric echocardiographic LA size and function indexes were compared between classes. Results: Dogs were allocated as follows: 43 in class ACVIM A, 58 ACVIM B1, 55 ACVIM B2, and 42 ACVIM C/D. Only LA anteroposterior diameter normalized on body weight (LADn) and LA maximal, minimal and P volumes (LAVmax, LAVmin, LAVP) differed across all pairwise comparisons. Active LA emptying fraction (aLAEF) was higher in class B1 compared to class A, and then decreased in class C/D compared to class B2. This suggests an increase in the left atrial active component due to the Frank-Starling mechanism in ACVIM B1 dogs, and the presence of atrial dysfunction in symptomatic dogs. Conclusions and clinical importance: The LADn and LAV are higher in CKCS in class ACVIM B1 compared to class ACVIM A, suggesting the presence of LA remodelling at the early stages of the disease. Atrial dysfunction is evident in symptomatic dogs. (See also this May 2024 version of this study.)

Three-dimensional echocardiographic determinants of the age of onset of myxomatous mitral valve disease in Cavalier King Charles Spaniels dogs. A. Franchini, G. Menciotti, H. Jeong, S. Lahmers, M. Borgarelli. ESVC-O-9; 34th ECVIM-CA Congress, September 2024. J. Vet. Intern. Med. November 2024: doi: 10.1111/jvim.17231. Quote: This study investigated whether mitral valve (MV) morphological variables obtained by three-dimensional transthoracic echocardiography (3DTTE) could predict the age of onset of myxomatous mitral valve disease (MMVD) in healthy Cavalier King Charles Spaniels (CKCSs). CKCSs without echocardiographic evidence of MMVD were prospectively enrolled. Standard echocardiogram and 3DTTE were performed at enrollment and every four months until the development of MMVD or 24 months from enrollment. Dedicated software was used to analyze the 3DTTE datasets and assess MV morphologic variables. Cox's proportional hazard models were used to investigate the effect of 3DTTE MV morphologic variables at enrollment on the time to onset of MMVD. A multivariable model was also created with backward stepwise selection to identify independent predictors of the age of onset of MMVD. MV morphologic variables of 76 CKCSs with median age of 2 (range: 1–3 years) were analyzed. Non-planar angle (NPA) (p<0.001, hazard ratio (HR) 1.05, 95%, confidence interval (CI):1.02–1.09), tenting area (p = 0.001, HR: 0.55, 95% CI: 0.40–0.76), and tenting volume normalized by body weight (nTnV) (p<0.001, HR: 0.81, 95% CI: 0.69–0.94) were significant in the univariable models. NPA (p<0.001, HR: 1.05, 95% CI: 1.02–1.09) and nTnV (p = 0.009, HR: 0.82, 95% CI: 0.71– 0.95) remained significant in the multivariable model. This study demonstrated that some MV variables obtained with 3DTTE predict the early onset of MMVD in healthy CKCSs. Specifically, the lower the value of nTnV, the sooner the onset of MMVD. Therefore, 3DTTE could be used in screening and breeding programs to reduce the prevalence of MMVD in CKCSs.

Assessment of pulmonary veins diameter in cavalier King Charles Spaniels with degenerative mitral valve disease. C. Ferri, J. Besso, H. Gaillot, Y. Ruel, A. Agoulon, C. Bourguignon, C. Mey1, V. Gouni. ESVC-O-10; 34th ECVIM-CA Congress, September 2024. J. Vet. Intern. Med. November 2024: doi: 10.1111/jvim.17231. Quote: In the treatment of dogs with degenerative mitral valve disease (DMVD), diuretics are crucial to prevent life-threatening complications. The optimal time to add diuretics to the treatment is difficult to assess in early stages of left-sided congestive heart failure (CHF). The objectives of this study are to: 1) compare pulmonary vein (PV) diameter in heathy Cavalier King Charles Spaniels (CKCS) with PV diameter in CKCS with DMVD at various stages of the ACVIM classification, 2) correlate PV diameter to several clinical and Doppler echocardiographic parameters, and 3) determine the optimal threshold PV diameter distinguishing between dogs in stage B2 and stage C of the disease. This study includes 100 CKCS: 28 healthy controls and 72 dogs with DMVD. All dogs received a Doppler echocardiographic exam, PV diameter measurement, and 2 orthogonal thoracic radiographs. Dogs were scored as stage A, B1, B2 or C. PV diameter was measured in bidimensional (2D) mode from a left apical view at end systole using the inner edge-to-inner edge method. Three PVs were visible and their diameter recorded as PV1, PV2 and PV3. Inter- and intra-observer coefficients of variation of the measurement of the three veins were <10%. There was no significant correlation between PV2 and body weight in stage A (rho=0.24, p = 0.247); thus, PV2 was used to compare groups. There was no significant difference of PV2 between stage A (n = 28; median, interquartile range; 4.9 mm, 3.9-5.2 mm), and stage B1 (n = 21; 5.1 mm, 4.0-6.0 mm, p = 0.24). There was a significant increase of PV2 between stages B1 and B2 (n = 29; 9.3 mm, 7.3–11.1 mm, p<0.001) and between B2 and C (n = 22, 13.7 mm, 9.9-15.1 mm, p = 0.003). A significant positive correlation was observed between PV2 and the left ventricular internal diameter normalized to body weight, the left atrium-to-aorta ratio, the tricuspid regurgitation gradient, the ejection fraction, the E wave velocity, and the E/A ratio. The optimal PV2 cut-off discriminating between stages B2 and C was set at 12.8 mm (area under the curve, 0.753; 95% CI, 0.61–0.90) with sensitivity of 57% and a specificity of 93%. In conclusion, PV2 diameter is a reproducible echocardiographic parameter, which increases with the progression of DMVD in CKCS. In this breed, it can be used as an additional parameter to identify dogs in early CHF and help in the decision-making process for starting treatment with diuretics.

The 2016 EPIC Study’s and 2019 ACVIM Consensus Statement’s definitions of canine cardiac dilatation due to MMVD (LA/Ao≥1.6 & LVIDDN≥1.7) are unscientific and arbitrary. Rod Russell. ResearchGate. October 2024; doi: 10.13140/RG.2.2.26168.35843. Quote: The species-wide definitions of cardiomegaly due to myxomatous mitral valve disease (MMVD) in both the 2016 EPIC Study and the 2019 ACVIM Consensus Statement are based upon no scientific evidence whatsoever and are unscientific and arbitrary, thereby placing cavalier King Charles spaniels (CKCS), in particular, at grave risk of being under-medicated or overmedicated with pimobendan.

A machine-learning algorithm to grade heart murmurs and stage preclinical myxomatous mitral valve disease in dogs. Andrew McDonald, Jose Novo Matos, Joel Silva, Catheryn Partington, Eve J. Y. Lo, Virginia Luis Fuentes, Lara Barron, Penny Watson, Anurag Agarwal. J. Vet. Intern. Med. October 2024; doi: 10.1111/jvim.17224. Background: The presence and intensity of heart murmurs are sensitive indicators ofseveral cardiac diseases in dogs, particularly myxomatous mitral valve disease (MMVD), but accurate interpretation requires substantial clinical expertise. Objectives: Assess if a machine-learning algorithm can be trained to accurately detect and grade heart murmurs in dogs and detect cardiac disease in electronic stethoscope recordings. Animals: Dogs (n = 756) with and without cardiac disease attending referral centers in the United Kingdom. ... Dogs with a normal heart, other cardiac diseases, congestive heart failure (stage C/D MMVD), or on loop diuretics (furosemide or torasemide) were excluded from this subanalysis. This resulted in a preclinical MMVD sample of 343 cases. Following the previously described method and nomenclature, this dataset was further partitioned into a clean sample (n = 240) and a confounded sample (n = 103). The confounded sample included patients with bodyweight outside of the 2-25 kg range, < 6 years of age, or dogs that were medicated with pimobendan. ... The most common breed was Cavalier King Charles Spaniel (n = 88/343) [25.7%], followed by Chihuahua (n = 55) and Labrador (n = 45). ... Methods: All dogs received full physical and echocardiographic examinations by a cardiologist to grade any murmurs and identify cardiac disease. A recurrent neural network algorithm, originally trained for heart murmur detection in humans, was fine-tuned on a subset of the dog data to predict the cardiologist's murmur grade from the audio recordings. Results: The algorithm detected murmurs of any grade with a sensitivity of 87.9% (95% confidence interval [CI], 83.8%-92.1%) and a specificity of 81.7% (95% CI,72.8%-89.0%). The predicted grade exactly matched the cardiologist's grade in 57.0% of recordings (95% CI, 52.8%-61.0%). The algorithm's prediction of loud or thrilling murmurs effectively differentiated between stage B1 and B2 preclinical MMVD (areaunder the curve [AUC], 0.861; 95% CI, 0.791-0.922), with a sensitivity of 81.4% (95% CI, 68.3%-93.3%) and a specificity of 73.9% (95% CI, 61.5%-84.9%). Conclusion and Clinical Importance: A machine-learning algorithm trained onhumans can be successfully adapted to grade heart murmurs in dogs caused by common cardiac diseases, and assist in differentiating preclinical MMVD. The model is a promising tool to enable accurate, low-cost screening in primary care.

Correlation of serum chloride concentrations with components of the renin-angiotensin-aldosterone system in a dog with congestive heart failure. Cailey Banken, Autumn N. Harris, Rachel Conway, Eduardo J. Benjamin, Robin Shoemaker, Darcy Adin. J. Vet. Intern. Med. October 2024; doi: 10.1111/jvim.17238. Quote: A 7-year-old male castrated Cavalier King Charles Spaniel weighing 8.2 kg was presented to the University of Florida, Small Animal Hospital after being treated by its primary care veterinarian for acute left-sided CHF secondary to severe degenerative mitral valve disease. Before the presentation, over a 24-hour period, the dog received a cumulative dose of 12 mg/kg furosemide (Salix) IV, torsemide (Demadex; 0.15 mg/kg PO twice), pimobendan (Vetmedin; 0.29 mg/kg PO q8h), and oxygen therapy. Because the dog remained clinically affected by unresolved CHF at presentation, it was placed in an oxygen cage for continued diuretic therapy after admission to our hospital. The dog received an additional cumulative dose of 10 mg/kg furosemide administered as a continuous IV infusion over 17 hours in addition to pimobendan (0.3 mg/kg PO q8h), which resolved radiographic and clinical signs of CHF. The dog was then transitioned to PO furosemide (2.4 mg/kg) on the 2nd day of hospitalization. Echocardiography showed severe degenerative mitral valve disease with severe mitral regurgitation, severe left ventricular enlargement, and severe left atrial enlargement. Two small thrombi were noted on the left atrium wall, so the dog was prescribed clopidogrel (Plavix; 2.3 mg/kg PO q24h). The dog developed concurrent suspected pancreatitis, which prompted the initiation of supportive therapy, including nasogastric feeding, ondansetron (Zofran), maropitant citrate (Cerenia), capromorelin (Entyce), buprenorphine (Buprenex), methadone (Mylan), pantoprazole (Protonix), mirtazapine (Remeron), and metoclopramide (Reglan). Because of progressive electrolyte abnormalities, potassium chloride supplementation (0.3 mEq/kg PO q12h) and tolvaptan (Samsca; 1.8 mg/kg PO q12h) were started on Day 4, the PO furosemide was reduced to 1.2 mg/kg q12h, and amlodipine (Norvsac) 0.1 mg/kg q24h was started on Day 5 of hospitalization. Tolvaptan (Samsca) was discontinued after 2 doses because of the development of hematuria which then resolved. The bloodwork values reflected advanced CHF and loop diuretic administration, with varying degrees of azotemia, hyponatremia, hypokalemia, hyperphosphatemia, and alkalosis at most time points. The dog was variably hypochloremic at all time points ([Cl−] ranged from 71.6 to 103.1 mmol/L). The dog improved with supportive therapy and was discharged to home care after 12 days of hospitalization. The dog successfully underwent open heart surgery for mitral valve repair 7 months after presentation. ... During that time, 6 serum samples from different days were analyzed for serum biochemical and renin-angiotensin-aldosterone system components. Serum chloride concentrations (ranging from 71.6 to 103.1 mmol/L) were inversely related to angiotensin I concentrations, aldosterone concentrations, a surrogate marker of renin activity, and a surrogate marker of adrenal responsiveness to angiotensin II. In light of recent studies showing that hypochloremia is associated with advanced heart failure in dogs and is associated with poor outcomes in people, the information from the dog in this report supports exploration of RAAS dysregulation as an underlying mechanism. 

Dose-exposure-response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin-angiotensin-aldosterone system in healthy dogs. Elizabeth Manson, Jessica L. Ward, Maria Merodio, Emilie Guillot, Thomas Blondel, Karin Allenspach, Oliver Domenig, Jonathan P. Mochel. J. Vet. Intern. Med. November 2024; doi: 10.1111/jvim.17255. Quote: Background: Benazepril exhibits a dose-dependent effect on biomarkers of the circulating renin-angiotensin-aldosterone system (RAAS) in dogs. Hypothesis/Objectives: To characterize the dose-exposure-response relationship of a fixed-dose combination product including benazepril and spironolactone (CARDALIS®) on RAAS biomarkers in dogs. Animals: Eighteen purpose-bred healthy beagle dogs. Methods: Three groups of 6 dogs received different doses of CARDALIS® for 14 days following induction of RAAS activation by feeding a low-sodium diet ... (Hill's Prescription h/d Heart Care; 17 mg sodium per 100 kcal, 0.08% sodium on a dry matter basis) to attain a steady activation of RAAS ...: (a) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q24h (label dose); (b) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q12h; or (c) benazepril 0.5 mg/kg + spironolactone 4 mg/kg PO q12h. Blood samples were collected at baseline and serial time intervals after CARDALIS® dosing to measure serum RAAS biomarkers and plasma concentrations of active drug metabolites. Time-weighted averages for serum RAAS biomarkers after CARDALIS® dosing at steady state were compared between dosage groups using Wilcoxon rank-sum testing. Results: Compared to the label dose, the highest dose of CARDALIS® was associated with a 30% decrease in angiotensin II (P = .03), 94% increase in angiotensin 1-7 (P = .03), 71% decrease in surrogate activity of ACE (P = .002), and 116% increase in circulating aldosterone (P = .02). CARDALIS® was well-tolerated at all doses with no clinically relevant changes in renal values or serum electrolytes. Conclusions and Clinical Importance: The combined CARDALIS® product leads to dose-dependent alterations of RAAS metabolites. These results could help inform clinical trials in dogs with heart disease.

Effects of dog cardiac orientation on vertebral heart score measurements in different thoracic types. Suphat Soeratanapant, Somchin Sutthigran, Phasamon Saisawart, Nardtiwa Chaivoravitsakul, Kongthit Horoongruang, Luksamee Limpongsai, Artima Tantarawanich, Chutimon Thanaboonnipat, Kittipong Tachampa, Nan Choisunirachon. Vet. World. November 2024; doi: 10.14202/vetworld.2024.2635-2643. Quote: Background and Aim: Computed tomographic (CT) images can elucidate the variations of cardiac orientation that this information among dog breeds has never been reported. This study aimed to explore the heart orientations of dogs with different thoracic types and study their effects on vertebral heart score (VHS) measurements using CT images. Materials and Methods: Thoracic CT images of 115 mature dogs [including 1 cavalier King Charles spaniel] without thoracic abnormalities were retrospectively examined. The dogs were classified into four groups: Normal Broad, Abnormal Broad, Normal, and Deep. All dogs were also classified based on their heart deviations. The VHSs were evaluated using lateral VHS, dorsal VHS, and adjusted VHS, and all were compared. Results: In the normal broad and abnormal broad groups, the lateral VHS and lateral long-axis dimensions were significantly lower than those obtained from the dorsal and adjusted VHSs. In addition, heart deviations were mostly observed in the normal broad and abnormal broad groups. Nevertheless, little evidence was found in the normal and deep groups. The lateral VHS and lateral long-axis dimensions were significantly reduced by heart deviation more than the dorsal and adjusted VHSs. Conclusion: Cardiac orientations among dog breeds can affect VHSs of lateral projection, especially in the broad thoracic group. Clinical evaluation of the VHS in the broad thoracic dogs should be performed on the dorsal view for more accurate measurement of heart size.

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