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 usi