Mitral Valve Disease and the Cavalier King Charles Spaniel

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Mitral Valve Disease and Cavalier King Charles Spaniels

IN SHORT: | What It Is | Diagnosis | Symptoms & Treatment | Breeders' Responsibilities

In Short:

Heart mitral valve disease (MVD) is the leading cause of death of Cavalier King Charles spaniels throughout the world. MVD is a polygenetic disease which afflicts over half of all Cavaliers by age 5 years and nearly all Cavaliers by age 10 years, should they survive that long.

What It Is

MVD is a degeneration of the heart's mitral valve, one of four sets of valves in a dog's heart. As the mitral valve degenerates, the valve no longer fully closes after each pumping action, allowing some blood to flow backwards through them from the ventricle back into the atrium. As the condition worsens, more and more blood is able to backflow through the valve. In the final stages, the valve’s struts sometimes break, causing the valve to collapse completely. MVD results in congestive heart failure in the CKCS.

Mitral valve disease is the most common heart disorder in older dogs of all breeds, affecting more than a third of all dogs over 10 years of age. However, in the Cavalier King Charles spaniel, the prevalence of MVD is about 20 times that of other breeds. Also in Cavaliers, the onset of the disease typically is much earlier in the life of the dog. It has been reported that, once diagnosed, mitral valve disease is much more rapid in Cavaliers than in other breeds, possibly reaching a life-threatening stage within as little as 1 to 3 years, rather than the average 3 to 5 years. More...

Diagnosis

All Cavaliers should be screened for heart murmurs once a year beginning at age 1 year. Once MVD is detected, its progression can be monitored with stethoscopic examinations (auscultations), x-rays, echocardiograms, and color Doppler echocardiograms. If a heart murmur is detected, it should be confirmed in 3 to 6 months. If it still is detected, the dog is considered probable for MVD. More...

Symptoms & Treatment

The progression of mitral valve disease can be rapid or slow. In most Cavaliers, the disease shows a gradual progression in the loudness of the murmur and to more serious symptoms, in as little as 2 years after first detecting the murmur. Drugs may help to minimize the symptoms, but eventually the drugs may be unable to control them. The drugs prescribed for Cavaliers with MVD can sometimes have severe adverse side effects, and blood chemistry should be done routinely to monitor their effects upon the kidneys, liver, and other internal organs. Severe symptoms of MVD in some Cavaliers will appear more quickly, although previously having been stable. The ultimate consequence of the disease is heart failure. More...

Breeders' Responsibilities

Due to the pervasiveness of MVD in the breed worldwide, Cavalier King Charles spaniels under the age of five years should not be bred (with one limited exception -- see MVD Breeding Protocol). Also, no Cavalier should be bred after age five years if it developed an MVD murmur before the age of five years. Any littermates of breeding stock having early-onset MVD (mitral valve murmurs before age 5 years) should be taken into very serious consideration. All CKCS breeding stock should be examined by board certified veterinary cardiologists at least annually and cleared by the veterinary specialists for MVD, the closer the examination to the breeding the better. It is recommended that all Cavaliers, breeding stock or not, be examined annually by board certified veterinary cardiologists after age one year. See the current list of health clinics for upcoming cardiologist examinations.

Related Links:

MVD Breeding Protocol

List of Board Certified Veterinary Cardiologists

Questions for Breeders

Canine Health Testing Clinics

Two MVD support groups are Yahoo! Group: MVD in Cavaliers and Karlin Lillington's CavalierTalk: SM and MVD Cavaliers Forum.

One Cavalier's daily blog about her life with MVD: Darcy's Daily Blog Darcy died at age 6 years on June 27, 2006.

See additional Related Links below.

Donate to The Darcy Fund

In Depth:

CavalierHealth.org Copyright © 2004 Blenheim Company Degenerative mitral valve disease (MVD) -- also called cardiac valve disease (CVD) and medically known as endocardiosis, atrioventricular valve endocardiosis, chronic degenerative valvular disease, chronic valvular disease, chronic mitral valve insufficiency, myxomatous atrioventricular degeneration, chronic valvular fibrosis, acquired mitral regurgitation or insufficiency, and mitral valve defect -- is the leading cause of death of Cavaliers. It is a polygenetic acquired heart disease which afflicts over half of all Cavalier King Charles spaniels by age 5 years and nearly all Cavaliers by age 10 years, should they survive that long.

Veterinary cardiologists began compiling statistics on Cavaliers with MVD murmurs in the United Kingdom in 1990. Since then, cardiologists have examined the hearts of many thousands of Cavalier King Charles spaniels at health clinics held by CKCS breed clubs in the UK, Canada, the USA, and elsewhere. From the data they have compiled, they have found that the percentage of CKCSs which develop MVD murmurs increases at a rate of about 10% per year. So, roughly 10% of Cavaliers by age one year have MVD murmurs, and 20% aged between one and two years have murmurs, and so on for each age level. Specifically, the statistics show that more than half of all Cavaliers aged five years have murmurs, and it is the very rare Cavalier at age ten years which does not have, at the very least, a low grade MVD murmur.

What It Is

Mitral valve disease is a uniquely serious, life-shortening problem for Cavalier King Charles spaniels and is their leading cause of death. MVD is the most common heart disorder in older dogs of all breeds, affecting more than a third of all dogs over 10 years of age. Several smaller breeds of dogs typically are predisposed to suffer from MVD. However, in most all breeds, MVD does not result in heart failure, causing death, because MVD does not develop early in a dog's life, and does not progress rapidly.

In the Cavalier King Charles spaniel, statistics have shown that the prevalence of MVD is about 20 times that of other breeds of dog. Also in Cavaliers, the onset of the disease typically is much earlier in the life of the dog, with over half of all CKCSs having developing MVD by their fifth birthday, as noted above. For most breeds, MVD is an old-age disease, and the age of onset is between 10 and 15 years of age.

It has been reported that, once diagnosed, MVD is much more rapid in Cavaliers than in other breeds, possibly reaching a life-threatening stage within as little as 1 to 3 years, rather than the average 3 to 5 years. Studies of Cavaliers have concluded that it has an hereditary basis and is "polygenetic", meaning that more than one gene can be the cause.

MVD is a degeneration and fibrosis of the heart's mitral valve, one of four sets of valves in a canine's (and a human's) heart. It is the valve which is designed to prevent the backflow of blood from the left ventricle into the left atrium. It consists of a set of double flaps, called "leaflets", that open and close like a set of one-way doors at appropriate times during each heart beat. Normal mitral valve leaflets are comprised of three layers of tissue (atrialis, fibrosa, and spongiosa) and are very thin and nearly transparent. They are connected by tendons (chordae tendineae) to the muscles of the left ventricle.

Blood flows through the pulmonary veins from the lungs into the left atrium, one of the chambers of the heart. The mitral valve is located between the left atrium and the left ventricle, another chamber in the heart. The valve's action is governed by the movement of blood as it is pumped from the atrium and into the ventricle. The leaflets of the mitral valve are controlled by the tendons, which serve as thin "struts" shaped much like the chords of a parachute.

As the diseased mitral valve degenerates, myxomatous transformation, the development of excess connective tissue that thickens the spongiosa and separates collagen bundles in the fibrosa, causes the valve to lose its flexibility, its leaflets thickening and shortening, its fibers stiffening, and its chordae tendineae elongating. The leaflets no longer fully close after each pumping action, allowing blood to jet backwards through them from the ventricle back into the atrium. As the condition worsens, advanced lesions cause the leaflets to fold, invert, and displace toward the left atrium. More and more blood is able to backflow through the valve, causing both the left atrium and the left ventricle to enlarge. In the final stages, the valve’s chordae tendineae sometimes rupture, and if they are major chords, causing the valve to collapse completely.

Apart from the mitral valve itself, the disease has severe consequences for the rest of the heart and the lungs. The increased pressure in the left atrium decreases blood flow from the lungs to the heart, resulting in congestion in the pulmonary veins, ultimately causing fluid, called pulmonary edema, to leak out of the capillaries into the pleural cavity of the lungs. As the left atrium enlarges, cardiac output declines. The decrease in output forces the body to compensate by activating angiotensin-converting enzyme (ACE) to excessive levels, forming angiotensin II, which causes the veins and arteries to constrict. Angiotensin II also releases aldosterone, resulting in sodium and water retention. The left atrium enlarges first, followed by an enlarged left ventricle and the pulmonary veins. The heart enlargement may cause a tear in the left atrium, which usually results in immediate stoppage of blood flow.

Diagnosis

-- auscultation (stethoscope)

The earliest indications of MVD are outwardly invisible and silent and can only be observed by echocardiography (ultrasound scanning). The first indication is the excessive bulging of the mitral valve leaflets into the left atrium, which is called mitral valve prolapse (MVP), followed by thickening of the leaflets, and then by the presence of a soft whistling sound, called a "murmur", which can be heard by a veterinarian using a stethoscope, which is called auscultation. The murmur sound is caused by the turbulent flow of blood jetting backwards through the damaged leaflets of the mitral valve into the left ventricle, increasing pressure in the left atrium.

Grades of Mitral Valve Disease Murmurs

Mitral valve murmurs are graded from the mildest and least audible, Grade 1, to the loudest and most turbulent, Grade 6. Most Cavalier King Charles spaniels show a gradual progression in the loudness of the MVD murmur. The loudness of the murmur usually indicates the severity of the valve leak.

Grade 1 (I): A Grade 1 murmur can be heard with a stethoscope in a quiet room.

Grade 2 (II): A Grade 2 can be consistently heard with the stethoscope.

Grade 3 (III): Grade 3 murmurs are louder and are heard as soon as the stethoscope is applied.

Grade 4 (IV): Grade 4s are quite loud, and the vibration can be felt with fingertips without a stethoscope.

Grade 5 (V): A Grade 5 murmur is louder, with a precordial "thrill".

Grade 6 (VI): The Grade 6 is so loud it can be heard with the stethoscope removed from the chest, or even without using the stethoscope.

Cavaliers should be screened for heart murmurs annually, beginning at age one year. Ask the cardiologist to use this standardized report form. A list of upcoming heart testing examination clinics is on our Health Clinic webpage. Once mitral valve disease is detected, its progression can be monitored with stethoscopic examinations (auscultations), x-rays, echocardiograms, and color Doppler echocardiograms. If a heart murmur is first detected by a general practice veterinarian, it should be confirmed within 3 to 6 months by a specialist, preferably a board certified veterinary cardiologist. If it still is detected, the dog is considered probable for MVD.

-- x-rays (radiography)

Radiography (x-ray) is used to determine if the heart is enlarged (particularly the left atrium and left ventricle), if the veins from the lungs to the heart are distended, or if fluid is beginning to develop in the lungs. Once MVD is diagnosed, annual x-rays are very useful in charting the progression of the disease. Mild to moderate heart enlargement indicates moderate progression, with the heart compensating for the effects of mitral valve disease by enlarging. When moderate to severe heart enlargement develops, early clinical signs such as coughing would be expected. Severe heart enlargement indicates impending congestive heart failure.

-- ultrasound (echocardiography)

Echocardiography (ultrasound scanning) is a beam of ultra-high frequency sound directed at the heart, and is used to evaluate heart size, function, and valve appearance. Echo scans can demonstrate the thickened valve leaflets and their abnormal movement, such as prolapse (MVP). The color Doppler can evaluate the direction and velocity of blood flow, quantifying blood leakage. It can be used to distinguish MVD from benign murmurs in ambiguous cases. The Doppler may detect leakage before it is audible as a murmur. However, trivial regurgitation of blood through the mitral valve may be present in as many as 50% of normal dogs. In such cases, however, there is no MVP or valve thickening present.

For Cavaliers' hearts, it is recommended that ultrasound scanning be conducted by specialists, preferably board certified veterinary cardiologists.

-- natriuretic peptides tests (ANP and BNP)

There has been some research into attempting to diagnose MVD in dogs by measuring plasma concentrations of the natriuretic peptides: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Natriuretic peptides are hormones manufactured and secreted by areas of the heart. A test of natriuretic peptides measures the quantity of the natriuretic peptides in the dog's blood. Elevated levels of these natriuretic peptides in the blood may be directly related to heart defects, and natriuretic peptides in the blood become elevated only after the heart has to pump harder to compensate for the disorder.

A 2003 study (conducted by Drs. Kristin A. MacDonald, Mark D. Kittleson, Coralie Munro, and Philip Kass of the University of California at Davis) has shown a positive correlation between BNP and heart disease and congestive heart failure (CHF) in dogs. In that study, BNP increased with the progressively increased severity of mitral valve disease and CHF. For every 10-pg/mL increase in BNP, the 2003 study's dogs' mortality rate increased approximately 44% over the four months of the study. In a later study, reported in 2005, Drs. William E. Herndon, Justine A. Lee, Kenneth J. Drobatz, Matthew J. Ryan concluded that "With further investigation, this new BNP assay may someday provide a widely available noninvasive diagnostic test with rapid turnaround time to help diagnose and/or treat heart disease and congestive heart failure in the dog."

However, in earlier studies (1994 and 1997) conducted by Dr. Jens Häggström, Kjerstin Hansson, Clarence Kvart, and others, the researchers have suggested that BNP levels in Cavaliers with mitral regurgitation did not rise as dramatically as in humans, and that N-terminal (NT)-proANP (NT-proANP) may better reflect the severity of mitral regurgitation in Cavalier King Charles spaniels than NT-proBNP tests.

Two trademarked names for NT-proBNP tests are "Canine CardioCare" (Veterinary Diagnostics Institute) and "Canine VetSign CardioSCREEN" (Guildhay Ltd.). There have been studies showing the effectiveness of these types of tests for dogs suffering from asymptomatic occult dilated cardiomyopathy (DCM), which is not the same disorder as MVD and is not known to be a genetic problem for Cavalier King Charles spaniels.

Whichever test (NT-proBNP or NT-proANP) is found to be more accurate for detecting MVD, it is believed by some researchers that the test may be useful in assisting examining veterinarians in deciding whether or not detected heart murmurs are innocent or are pathologic in nature. However, in a 2007 study of 54 CKCSs by Drs. Tarnow, Pedersen, Kvart, and others from Denmark and Sweden, they found that "Natriuretic peptides are elevated in Cavalier King Charles spaniels with congestive heart failure but not in dogs with clinically inapparent mitral valve disease."

Therefore, pending further research results, it appears that veterinary cardiologists and other cardio-specialists should be quite capable of detecting mitral valve prolapse (MVP) murmurs and distinguishing between them and flow murmurs or other innocent varieties of heart murmurs. Since BNP in the blood becomes elevated only after the heart has to pump harder to compensate for the disorder, the question then is: When does the heart start working so hard that BNP levels start to go up?

In the Cavalier King Charles spaniel's version of heart defects -- mitral valve disease due to deteriorating valve flaps -- there are no immediate external symptoms. It is not yet clear from research studies thus far, as to whether the heart becomes labored enough to produce increased levels of BNP before auscultation is able to detect the murmurs from minimal backflow of blood leaking through the mitral valve flaps. Advocates of BNP testing do represent that that studies of BNP and cardiomyopathy show that BNP is elevated before the onset of signs and murmur. In a soon-to-be-published study by U.K. Dr. Adrian Boswood, he reports that the degree of elevation of NT-proBNP was proportionately greater in the dogs with dilated cardiomyopathy than in those with mitral valve disease. But it does not yet appear that BNP testing is an any earlier warning system for MVD than auscultation.

Progression

The progression of mitral valve disease can be rapid or slow. Some Cavaliers develop a mild murmur without any more serious symptoms for many years. If the progression is slow enough, the dogs may die of other causes before their hearts reach failure. This is the usual pattern of MVD in most other breeds affected with it.

In the Cavalier King Charles spaniel, some cardiologists have found prognostic value from the degree of mitral valve prolapse, the thickness of the leaflets, and whether ruptured tendinous chords are observed on the echocardiogram.

In most CKCSs, the disease shows a gradual progression in the loudness of the murmur and to more serious symptoms, in as little as 2 years after first detecting the murmur. Drugs may help to minimize the symptoms, but eventually the drugs may be unable to control them. Severe symptoms in some Cavaliers will appear more quickly, although previously having been stable. If the tendinous chords rupture, and the valve leaflets cannot continue to open and close with each heart beat, death could be almost immediate.

Symptoms

As MVD progresses, early symptoms which may occur are exercise intolerance, breathlessness, productive coughing, a distended abdomen, weight loss, and fainting. Breathlessness is a most common sign, starting as excessive panting on exercise. As breathing difficulties become more severe, the dog may sit or stand, holding its elbows away from the chest, and it may be reluctant to sit down.

As greater quantities of blood leak through the damaged mitral valve from the left ventricle back into the left atrium of the heart, the atrium gradually begins to swell and enlarge -- called myocardial remodeling -- to accommodate the overload of blood, and there is a reduction in the ability of the ventricle to provide sufficient blood to meet the demands of the rest of the body. The heart then has to pump harder and faster, to meet those demands.

Also, due to the increasing lack of blood being pumped throughout the body, non-essential blood vessels begin to shut down, to conserve blood flow for vital organs, such as the brain and the heart itself, and reducing the flow to the skin and the kidneys. This causes the skin to pale and the kidneys to retain fluids in the circulation, because the circulation identifies the low cardiac output as dehydration. The excess fluid retention results in further stretching of the heart and greater mitral valve leakage, and the retained fluid, called ascites, is squeezed into other body tissues, the liver, chest, and peritoneal cavity of the abdomen.

The shut-down of the distant blood vessels also has the effect of causing the left ventricle to beat against a higher resistance, causing another increase in mitral valve leakage.

The enlarged size of the heart fills the voids in the chest cavity and causes pressure on the main airway -- the left main bronchus, resulting in a dry, hacking cough and breathlessness. It may even cause the trachea to collapse.* Also, the overload of blood in the left atrium creates increased pressure back into the pulmonary veins, which drain into the left atrium from the lungs. When a critical pressure is reached, flooding of the lungs can occur, with pulmonary edema.

* Trachea collapse also may be due to Brachycephalic airway obstruction syndrome (BAOS).

Cavaliers with murmurs of between Grade 3 and Grade 6 may display episodic weakness of the hindquarters, ataxia, or collapse, which is called presyncope, or combined with loss of consciousness, which is called syncope, due to a sudden decline in blood flow to the brain. See Syncope for a discussion of this disorder and its causes.

A loss of appetite, resulting in possibly severe weight loss (called cardiac cachexia), particularly of muscle mass, is another symptom of advanced MVD.

The ultimate consequence of mitral valve disease is heart failure. The median survival period for dogs once they develop severe congestive heart failure (CHF) due to MVD is approximately seven months, with 75% of the dogs dead by one year. For dogs with less severe CHF, the median survival period is one year, with 75% of the dogs dead by 21 months. However, the CKCS has a more accelerated version of MVD, and they typically progress more rapidly to heart failure.

Treatment

CavalierHealth.org Copyright © 2004 Blenheim Company It is unrealistic to try to cure canine mitral valve disease. Replacement of the defective mitral valve is available in veterinary medicine. For example, Colorado State University's James L. Voss Veterinary Teaching Hospital has such a surgical program under the direction of Dr. E. Christopher Orton, whose cardiac surgery team has been replacing canines' heart valves since 1997. However, surgical replacement usually is cost-prohibitive and would require that the dog's renal system and other vital organs be in ideal condition. Therefore, MVD typically is treated by managing heart failure. The goals of the veterinary cardiologist are to improve the dog's quality of life and to increase the length of its life.

The veterinarian tries to eliminate or reduce signs of fluid accumulation and congestion, and to maintain adequate cardiac output in order to provide needed blood flow. The degree of treatment will depend upon the stage of the disease. Early MVD is not treated in the same way as advanced MVD.

Preventative Vitamins and Supplements?

No medications or food supplements are known to prevent the onset of MVD. However, some supplements may defer the time of onset (although there is no scientific proof that they do so), including:

Vitamin C (300 to 400 mg. daily)

Vitamin E -- Tocopherol (100 I.U. daily)

CoQ10 (30 mg. daily)

Fish oils high in Omegas 3 and 6 -- such as wild salmon oil -- (about 400 mg. daily)

-- mild murmur

A Cavalier with early mitral valve disease has a mild murmur but otherwise is symptom-free (asymptomatic). There may be minimal enlargement of the heart, as shown by x-ray or ultrasound scan. At this stage, there is no need for treatment, but heart size should be monitored by x-rays every 6 to 12 months. Overweight dogs should be put on a weight-reducing diet. Low salt diets have been suggested, to help reduce water retention. It would be prudent to avoid extreme exertion.

Also, the above-described supplements (vitamins C and E and CoQ10 and fish oils) should be considered after MVD murmurs are detected, along with Bio-Cardio, a Thorne Veterinary Products multi-vitamin, mineral, and herbal extract supplement (which includes Vitamin E, selenium, magnesium, potassium, L-Carnitine, L-Taurine, coenzyme Q-10, dimethylglycine [DMG], Hawthorne extract, desiccated bovine heart, and Siberian genseng extract). Standard Process, Inc., which offers nutritional whole food supplements, has veterinary formulas to support heart function, including Canine Cardiac Support, and human-grade supplements, including Cardio-Plus, Cardiotrophin PMG, Cataplex E, and Vasculin. D'Arcy Naturals, which offers herbal supplements, has a veterinary formula called Cardio-Support to aid heart function and blood circulation. Flavonex is a salvia and gingko extract herbal supplement made by Health Concerns. Vitamins and food supplements such as these may be prescribed for all stages of mitral valve disease. Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is holistically trained. A search webpage for finding holistic veterinarians in the United States is located at www.holisticvetlist.com.

A 2002 study, sponsored by a drug manufacturer and involving 124 dogs of several breeds, suggests that dogs with only mild MVD murmurs and some enlargement of the heart but which otherwise are symptomless be prescribed angiotensin converting enzyme (ACE) inhibitors (enalapril maleate [Enacard, Vasotec], benazepril [Lotensin, Fortekor], imidapril [Tanatril]) as therapy to postpone or prevent congestive heart failure. (See below for discussion of ACE inhibitors' adverse side effects.) However, a 2002 Scandinavian study of 229 asymptomatic Cavalier King Charles spaniels with mild MVD murmurs has shown that the such application of ACE inhibitors had no significant affect upon the time from the initiation of ACE inhibitor therapy to heart failure.

Other drugs being used by some veterinary cardiologists are carvedilol (Coreg), and Bisoprolol, both non-selective beta-and alpha-blockers with anti-oxidant effects which reduce the heart's rate and the force of its contraction, thereby reducing the work of the heart. Carvedilol and Bisoprolol also cause the arteries to relax and the blood pressure to drop. Some cardiologists have begun to administer low doses of carvedilol and Bisoprolol early in the disease process, with the aim of causing MVD to progress at a slower rate than dogs not taking the medication. A less expensive alternative beta-blocker is atenolol (Tenormin, Tenoretic). However, atenolol lacks the vasodilatory and antioxidant properties of carvedilol.

Finally, pimobendan (Vetmedin), which has been prescribed for dogs with severe MVD, such as congestive heart failure, is the subject to research for treatment of dogs in the early stage of MVD. See the "A Few Words About Pimobendan" box below.

-- moderate MVD

Moderate MVD is indicated by a louder murmur, increased breathlessness on occasions, occasional dry, hacking coughing, and moderate to severe enlargement of the heart on x-rays or scan, with some fluid present in the lungs. At this stage, reducing exercise will help to reduce the heart's workload.

Treatment will be necessary at this stage, usually in a tablet form. Since a dog with moderate MVD begins to retain fluid and salt, drugs which prevent fluid retention, or which increase fluid elimination, may be used. Diuretics (furosemide [such as Lasix, Diuride, Frudix, Frusemide] and hydrochlorothiazide [Dyazide]), which are drugs which cause the kidneys to excrete more fluid than normal, may be used to remove fluid from the lungs. Side effects would be that the dog is thirstier than normal, and increased urination. Furosemide can severely affect kidney, liver, and other bodily functions, and so the kidneys and liver should be evaluated before starting furosemide and should be monitored every three months thereafter.

Medications approved to treat humans with congestive heart failure, such as the aquaretic (vasopressin receptor anatagonist = vaptans), (tolvaptan), are being empirically considered as alternatives to diuretics such as furosemide.

An ACE inhibitor (enalapril maleate [Enacard, Vasotec], benazepril [Lotensin, Fortekor]) usually also will be prescribed. ACE inhibitors block the angiotensin converting enzyme, which is necessary to produce a substance that causes blood vessels to tighten. So, ACE inhibitors serve to relax the blood vessels, thereby lowering the blood pressure and increasing the supply of blood and oxygen to the heart. The result is that they tend to blunt the enlargement of the heart and slow the progression of heart failure.

In a 2007 U.S. study of 124 dogs, the researchers concluded that enalapril "modestly delays the onset of congestive heart failure in dogs with moderate to severe mitral regurgitation."

Recent studies have concluded that diuretics such as furosemide should be used only combined with ACE inhibitors -- which also prevent fluid retention -- so that the diuretic dosage may be sharply reduced to avoid the worst of its negative side effects. Researchers have found that extensive use of diuretics alone may contribute to renal dysfunction by activating the renin-angiotensin aldosterone system (RAAS) , as well as dehydration, azotemia, and hypokalemia.

However, another increasingly popular diuretic in treating MVD patients, spironolactone (Aldactone) -- which is known as a potassium-sparing diuretic because, unlike some other diuretics, it does not cause the loss of potassium -- reportedly may lead to excessively high, life-threatening levels of potassium in the dog's blood, particularly when combined with ACE inhibitors. Some veterinary cardiologists recommend that potassium levels be carefully monitored when using spironolactone in combination with ACE inhibitors by drawing blood at regular intervals until it is evident that the potassium level is or is not going to be a problem.

Carvedilol (Coreg), and Bisoprolol, also are being prescribed for moderate MVD. They are non-selective beta-and alpha-blockers with anti-oxidant effects which reduce the heart's rate and the force of its contraction, thereby reducing the work of the heart.

Natural diuretics include Wu Ling San and Alisma, both traditional Chinese herbal medicines (TCM). Other Chinese herbal alternatives include Salvia Shou Wu, a Seven Forests patented supplement which consists of Salvia extract, and several other herbs and flowers. Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is holistically trained in TCM. A search webpage for finding holistic veterinarians in the United States is located at www.holisticvetlist.com.

ACE Inhibitors -- More Pluses Or Minuses?

ACE inhibitors may have serious side effects. They can cause severe renal insufficiency, and the kidneys should be monitored carefully when using these drugs. Benazepril (Lotensin, Fortekor) is reported to be slightly less harsh on the kidneys than is enalapril maleate (Enacard, Vasotec). Also, ACE inhibitors traditionally are used for the treatment of high blood pressure. However, not all veterinary cardiologists check a Cavalier's blood pressure before prescribing the drug. Unless the dog's blood pressure is high, the use of an ACE inhibiting drug could dangerously lower its blood pressure.

The use of ACE inhibitors combined with extreme salt (sodium) restriction may contribute to renal dysfunction by activating the renin-angiotensin aldosterone system (RAAS). Therefore, some cardiologists recommend only moderate salt restricted diets when prescribing ACE inhibitors.

Other side effects include the accumulation of toxins which can damage the liver, anorexia or loss of appetite, vomiting, azotemia, and the development of a dry cough due to the accumulation of bradykinin. Since a dry, hacking cough is a frequent symptom of progressing MVD, this side effect of the drug could be confused with the worsening of the disease.

Pimobendan (Vetmedin), which has been prescribed for dogs with severe MVD, such as congestive heart failure, may be a new alternative to ACE inhibitors for dogs with only moderate MVD, based upon a 2006 study comparing the two medications. See the "A Few Words About Pimobendan" box below.

A natural supplement as an alternative to ACE inhibitors is a combination of active fish petides, including LKPNM, from the bonito fish (Sarda orientalis), such as Vasotensin, manufactured by Metagenics, Inc.

-- severe MVD

Severe MVD normally involves a murmur that has become much louder. However, the murmur can become more difficult to hear, if the heart's deterioration has been sudden. So a Grade 6 murmur later could be downgraded to a Grade 5, but that would not mean an improvement in the dog's condition. Also, the dog will have difficulty breathing while at rest, and may not be able to tolerate even minimal exercise. Pressure in the left atrium can be relieved by diuretics and drugs which lower the pressure in the veins, called venodilators. Diuretics should be given by injection in severe cases. ACE inhibitors also have venodilating effects.

Reducing pressure in the arteries can make it easier for the heart to pump. ACE inhibitors reduce arterial pressure, as do arteriolardilators (hydrazaline [Apresoline], pimobendan, sodium nitroprusside). In advanced heart failure, the heart muscle may become weakened so that it does not contract properly. Digoxin (Lanoxin), a cardiac glycoside extracted from the foxglove plant (digitalis), may be used to improve heart muscle strength to help the heart contract more strongly. Pimobendan (Vetmedin) reportedly eases the resistance in the circulatory system by dilating blood vessels, and improves the efficiency with which the heart can function as a pump, thereby both improving cardiovascular function and the blood flow to major organs.

Also, sildenafil (Viagra) (a/k/a sildenifil) a phosphodiesterase (PDI) 5 inhibitor, is being prescribed to lower pulmonary hypertension by some cardiologists for dogs with congestive heart failure, particularly in combination with pimobendan. In an April 2006 French study report, tadalafil (Cialis®), a long-acting PDI-5 inhibitor, belonging to the same family as sildenafil, has been shown to have decreased systolic pulmonary arterial pressure significantly. However, research by Dr. Rosemary A Henik, of the University of Wisconsin-Madison, has indicated that pulmonary venous hypertension due to left heart disease, is managed best with "afterload" reduction, and not sildenafil. More recently, a 2007 study by Drs. Joao S. Orvalho, William P. Thomas, and P. H. Kass found that "these data suggest that oral tadalafil, when added to conventional heart failure therapy, decreases the pulmonary artery pressure in this group of dogs."

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A Few Words About Pimobendan (Vetmedin®)

Cavalier King Charles spaniels suffering from mitral valve disease (MVD) received a dose of really good news in April 2007, when the U.S. Food and Drug Administration approved the use of pimobendan to treat dogs suffering from congestive heart failure (CHF), a particularly common disorder in Cavaliers. (See FDA Approval Report.)

Pimobendan (Vetmedin®) is a relatively new heart drug that has been shown to improve the quality of life for dogs suffering from CHF due to MVD. Pimobendan is a benzimidazole pyridazinone derivative and is classified as an inodilator (a calcium sensitizer and phosphodiesterase I11 inhibitor and a positive inotrope and arteriovenous dilator) which reportedly eases the resistance in the circulatory system by dilating blood vessels.

Often, the Cavalier in the late stage of congestive heart failure suffers from a progressive deterioration of the quality of its life, which is due to the combination of an inability to comfortably keep the dog free from fluid congestion in its heart, lungs, and abdominal cavity, together with enlarged heart chambers, lethargy, collapse, and deterioration of its kidney and/or liver functions. Eventually diuretics, ACE inhibitors, and other drugs no longer are able to remove enough of the fluids and increase the supplies of blood and oxygen to the heart. At that point, often the owner elects euthanasia, rather than to allow the dog to continue to suffer.

Pimobendan now may be called to the rescue. In addition to dilating the blood vessels like ACE inhibitors do, pimobendan increases the strength with which the heart muscle contracts, which improves the heart’s efficiency to function as a pump, and increases the blood flow to major organs. It even has been shown, in some studies, to actually reduce the amount of backflow of blood through the mitral valve and reverse the enlargement of the heart chambers. And, it may be administered safely with diuretics, ACE inhibitors, and digoxin. The FDA report states that pimobendan “is indicated for use with concurrent therapy for congestive heart failure (e.g., furosemide, etc.) as appropriate on a case-by-case basis.” Furosemide is a diuretic.

Remarkably, pimobendan also has been shown to have fewer severe side effects than its main rival drugs, the ACE inhibitors benazepril (brand names Lotensin, Fortekor) and enalapril maleate (brand names Enacard, Vasotec). See ACE Inhibitors -- More Pluses Or Minuses?

CAUTION

Before prescribing pimobendan, cardiologists may require an echocardiogram to measure the heart's contractibility. This precautionary test is recommended, because a negative effect reportedly has been instances of pimobendan improving the heart’s pumping ability and contractibility to the extent that the mitral valve's major chordae tendineae have been overworked and have actually ruptured, causing immediate death. Therefore, the drug should not be prescribed for dogs whose hearts have remained strong despite the MVD. Cavalier owners should never self-prescribe pimobendan for their dogs suffering from mitral valve disease.

Owners also should be wary of general practice veterinarians prescribing pimobendan without first consulting with a cardiologist about performing an echocardiogram to resolve the contractibility issue. Also, pimobendan should not be prescribed by a non-cardiologist for CKCSs which are not in congestive heart failure (CHF). Researchers have reported severe adverse cardiac effects upon pimobendan-treated dogs not in CHF, including increased blood backflow through the valve, heart enlargement, and deterioration of the chordae tendinae. We have found, now that pimobendan is available to the general practice veterinarians, that many of them are prescribing it without taking the precautions which would be instinctive to cardiologists and internal medicine specialists.

Pimobendan was developed by Boehringer Ingelheim GmbH, a German pharmaceutical company, and is marketed under the registered brand name “Vetmedin”. In Europe and elsewhere apart from the United States, it has been studied since the late 1980s and prescribed by veterinarians since the 1990s. During recent studies by American veterinary cardiologists, pimobendan’s availability in the United States has been strictly controlled, and it has become a popular item on the underground drug market and on international Internet websites. Overseas shipments reportedly had been delayed by U.S. Customs agents at ports, and concerns had arisen that versions offered on Internet sites may be not be authentic.

With FDA approval, pimobendan should become more readily available in the United States, if not at lower prices. As long as Boehringer Ingelheim holds its patent (expires March 2013) and the FDA’s grant of marketing exclusivity in the U.S. (expires May 2012), it should not be expected to be sold as a reduced price generic drug.

Several veterinary research studies of pimobendan have been published recently, leading up to the FDA’s report. In studies of dogs with mitral regurgitation, it has shown improved survival, heart and respiratory rate, and left atrial size, without evidence of arrhythmogenesis. It has been compared favorably with ramipril in a March 2005 study report. In a March/April 2006 study report, Texas A&M University Drs. Sonya G. Gordon, Matthew W. Miller, and Ashley B. Saunders find that "pimobendan is safe, well tolerated, and leads to enhanced quality of life in dogs with CHF secondary to...chronic valvular disease when used in combination with furosemide or other conventional therapies (e.g., angiotensin-converting enzyme inhibitors, digoxin)" and that "ongoing studies are evaluating its effects on mortality associated with chronic valvular disease." See Veterinary Resources for citations.

Pimobendan also may begin to be considered for Cavaliers in the early stages of MVD. However, great caution should be taken when considering treating any dog suffering only from mild, asymptomatic MVD. There is evidence from recent studies that treatment with pimobendan of dogs not in CHF may accelerate the symptoms of MVD, including increased regurgitation of blood through the mitral valve, deterioration of the chordae tendinea, and enlargement of the left side of the heart. See the 2007 study "Increased Mitral Valve Regurgitation and Myocardial Hypertrophy in Two Dogs With Long-Term Pimobendan Therapy" below, and the 2005 study "Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study", below. To the contrary, however, in a 2007 study, "Evaluation of Pimobendan in the Treatment of Early Mitral Valve Disease", the researchers concluded from their study of 26 dogs that their "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." They concluded, however, that more data are needed to further assess their findings. A positive inotropic effect means that the drug increases the strength with which the heart muscle contracts.

Dogs with CHF treated with pimobendan also have been found to live longer. In a July 2006 Swedish study of 76 dogs with acquired atrioventricular valvular disease, sponsored by Boehringer Ingelheim, the manufacturer of Vetmedin, which is pimobendan's brand name, researchers report that dogs treated with benazepril hydrochloride, an ACE inhibitor, lived an average of 128 days, while those treated with pimobendan lived an average of 415 days, a difference between four months and thirteen months. The study reportedly also found that within seven days of treatment with pimobendan, over half of the dogs were symptom free. Most of the dogs were treated concurrently with furosemide.

To the contrary, in an October 2006 report, University of Georgia internal medicine specialists Drs. Justin D. Thomason and Clay Calvert conclude that pimobendan may benefit dogs with congestive heart failure secondary to dilated cardiomyopathy or valvular insufficiency, only when used in conjunction with other cardiac drugs, such as ACE inhibitors.

Possible negative side effects of pimobendan include ventricular arrhythmias, particularly in dogs previously diagnosed with that disorder. However, in a 2007 study by Canadian Drs. M. Lynne O'Sullivan, Michael R. O'Grady, and C. Walker, which included eight Cavaliers out of 23 dogs, they concluded that "Pimobendan did not result in an increase in frequency of ventricular arrhythmias in comparison to benazepril."

In addition to the natural alternatives to diuretics and ACE inhibitors described above, natural supplements which may help to strengthen and energize the heart of a dog with severe MVD include D-Ribose, also known as alpha-D-ribofuranoside, which reportedly improves ventilatory efficiency in patients with congestive heart failure (CHF).

-- end stage of MVD

General nutrition is very important. Cavaliers at this advanced stage may suffer severe weight loss, called progressive cardiac cachexia, and they should be fed any palliative food to maintain muscle mass. Cardiologists may prescribe an appetite stimulant, such as mirtazapine (Remeron) or meclizine (Antivert, Bonine, Dramamine II, Driminate II). A good general health supplement for older dogs in congestive heart failure is N, N-Dimethylglycine (DMG). Vetri-DMG is a pure DMG product offered by Vetri-Science Laboratories of Vermont (www.vetriscience.com). DMG is said to support the immune system, promote oxygen utilization, improve cardiovascular function, support liver function, and support ocular health.

Dogs with severe flooding of the lungs should not be exerted in any way. Some cardiologists may prescribe a bronchial dialator, such as aminophylline, oxtriphylline, or theophylline (Corvental), which are human grade prescription medications which relax and open air passages in the lungs, making breathing easier. The onset of acute pulmonary edema requires immediate recognition and therapy, including oxygen treatment, in order to save the dog's life. (See the Darcy's Daily Blog entry dated 8/25/06 for details of symptoms requiring oxygen treatment.) Retained fluids (ascites), which fill the peritoneal cavity of the abdomen, may be removed periodically by aspiration with a hypodermic needle (abdominocentesis).

At this stage of deterioration, inability to breathe, and suffering, the owner may elect euthanasia, rather than to allow the dog to continue to suffer.

Some cardiologists recommend that dogs with advanced mitral valve disease not be vaccinated with the usual serums, including rabies, because of possible adverse reactions which might accelerate damage to the dogs' hearts. In such cases, the veterinarians will write letters to the county licensing authorities which require periodic vaccinations, and in many instances, the counties will accept the cardiologists' letters and excuse the dogs from having to be vaccinated. There is a large body of research, much of which may be found on the Internet, on the questions of vaccinosis and other health problems attributed to annual or other periodic vaccinations, particularly immune-mediated disorders.

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Canine Heart Valve Replacement & Repair Surgery

4FT. COLLINS, CO: Dr. E. Christopher Orton of the James L. Voss Veterinary Teaching Hospital at Colorado State University (CSU) in Ft. Collins, Colorado, heads an animal cardiac surgery program which reportedly has consistently and successfully completed life-saving, open-heart surgeries on canines. Dr. Orton and his surgical team have performed over 100 open-heart surgeries since1991 and began replacing heart valves in 1997.

Valve surgery requires a team of six to eight people, additional staff in the critical care unit, and intensive monitoring of the dog before, during, and immediately after surgery, which limits the team's ability to conduct surgeries to only a few per month. The team replaces the defective valve with an artificial heart valve made from bovine pericardial tissue or with a mechanical valve prosthesis. The surgical procedure typically lasts about five hours, during which the new valve is placed in the dog's heart while its blood circulates through a heart-lung machine; then its heart is re-started, after which the dog is monitored in the surgical suite for two hours. The patient then is placed in the hospital's intensive care unit, where it is closely monitored for the next 72 hours.

The dog has to be monitored carefully for several months after it is discharged from the surgical unit. The surgery offers the dog the possibility of a lifelong cure, as long as the prosthetic valve continues to function well and does not develop complications, such as blood clots or tissue rejection. Dr. Orton's reports on his team's studies are cited below in Veterinary Resources. See 2004 MVD Surgery Report and 2005 MVD Surgery Report.

Dr. Orton may be reached by telephone at 970-297-1250, and e-mail at corton@ColoState.edu or chris.orton@ColoState.edu

4COLLEGE STATION, TX: Dr. David A. Nelson of the Small Animal Medicine and Surgery Center at Texas A&M's College of Veterinary Medicine leads a similar veterinary surgical team which specializes in canine open heart surgery, including mitral valve repair. The surgical center is a part of the Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices. It is researching effective ways to repair the valves, rather than replace them, in smaller dogs.

Dr. Nelson advises that, to be eligible for surgery, the dog's heart function must still be preserved. Dogs that have reached the end point of a lengthy cardiac disease cycle are not considered as candidates. The total number of cases performed is still too low to offer any probability of success. There are still great risks involved, and each dog's case is different. A normal healthy young dog could likely undergo and recover from cardiac surgery without complication. One that is older, with cardiac disease or other organ involvement, presents a much more difficult challenge.

All candidates are referred by veterinarians, who will make the first contact to with the Texas A&M surgical team and send pertinent medical information that allows the team to make an initial determination. A cardiac work-up examination of the dog then is scheduled. The work-up may be scheduled in connection with a tentative surgery date. However, only after the work-up and consultation with the team is a final decision made as to recommend surgery.

A modest amount of mitral valve leakage may continue following the successful surgical mitral valve repair. Changing the disease from a rapidly progressive one to a static, manageable situation is considered a very acceptable result. Following surgery, the dog may remain on some cardiac medications.

The costs of surgery and aftercare is determined on a case by case basis. A current range of costs is from $5,000.00 to $10,000.00 or higher. Higher costs usually are due to increased intensive care unit charges. The team will make an accurate estimate after the dog's cardiac work-up examination. Due to the nature and expense of the service, the surgical center requires a deposit of $4,500.00 prior to surgery. Conventional types of credit cards are acceptable.

Dr. Nelson may be reached by telephone at 979-845-2351 and email dnelson@cvm.tamu.edu The surgical team's website is http://kndn.com/cv/

4LONDON, ENGLAND, UK: Heart surgeon Dan Brockman (BVSc, CVR, CSAO, MRCVS, Diplomate ACVS/ECVS) at the Royal Veterinary College, University of London, in England, has begun a animal cardiac surgery program, which includes open-heart mitral valve surgeries on canines. He has consulted with Dr. Orton at Colorado State University, and the two surgeons have been working together to advance heart surgeries in the UK.

Mr. Brockman may be reached at The Queen Mother Hospital for Animals, Hawkshead Campus, the Royal Veterinary College, telephone +44 (0)1707 666366, email qmhreception@rvc.ac.uk The website is www.rvc.ac.uk/Hospitals/QMH/Index.cfm

4TOKYO, JAPAN: Drs. Midori Akiyama, Ryou Tanaka, Kohji Maruo, and Yoshihisa Yamane, of the Department of Veterinary Surgery, Tokyo University of Agriculture and Technology, in Tokyo, Japan, have conducted mitral valve repair surgery on at least one small dog, a 6-month-old, 15.6 lb., male Shiba Inu. They write in their 2005 article: 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." See their 2005 journal article. Their clinic is located at Department of Veterinary Surgery, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan; website: www.tuat.ac.jp/index-e.html

See also, a 2007 article by Drs. Koichi Tamura, Mayumi Murakami, and Makoto Washizu on post-mortem examinations of 12 dogs with suture-repaired mitral valve leaflets. Drs. Murakami and Washizu are at the Nippon Veterinary and Animal Science University, Tokyo, Japan, website: www.nvlu.ac.jp/e/index.html

Current Research

4June 2007: Dogs needed for reduced rate Ohio State study to improve ultrasound imaging for diagnosing congestive heart failure: Dr. Karsten E. Schober of the cardiology department at the Ohio State University's College of Veterinary Medicine in Columbus, Ohio is looking for dogs with diagnosed heart disease to be a part of a non-invasive study titled: "Can better imaging predict heart failure?". The researchers seek to utilize cardiac ultrasound to identify and stage congestive heart failure (CHF) in dogs. Dogs with asymptomatic dilated cardiomyopathy (DCM) and degenerative mitral valve disease (MVD) and dogs with CHF caused by MVD or DCM will be enrolled.

Any dog with DCM or MVD -- unless treated with high doses of diuretics and no concurrent systemic disease -- is eligible. Participating dogs would be examined twice at the Ohio State Veterinary Hospital, five to fourteen days apart. During these two visits, the dogs will be given a complete physical examination, chest x-rays, an echocardiogram, blood pressure measurement, and a blood sample drawn. Benefits for dog owners include low cost examinations (50 percent cost reduction for the first visit and free second visit), short scheduling and waiting times, and important contribution to a research study that can improve the health of dogs. The results of this study may help to earlier diagnose CHF, better stratify cardiovascular risk, tailor therapy to specific dog needs, and reduce the exposure of personnel and animals to the ionizing radiation required for repeated thoracic radiography.

Contact: Dr. Schober, telephone 614-292-3551, email schober.4@osu.edu, or Laura Spayd, telephone 614-292-3551. Also visit http://www.vet.ohio-state.edu/2404.htm

4Pathophysiological aspects of early mitral valve diseases in Cavaliers: Dr. Inge Tarnow, at the University of Copenhagen's Department of Animal and Veterinary Basic Sciences, heads a group of specialists studying pathophysiological aspects of early mitral valve disease in Cavaliers, including changes in platelet function, hemostatic changes, and prognostic factors. They currently are performing a large longitudinal study of 100 Cavaliers with examinations (echocardiographic and blood tests) at ages 2, 4, and 8 years.

4DNA to discover genes causing MVD: Dr. Clare Rusbridge at the Stone Lion Veterinary Centre in the UK is coordinating an international group of geneticists and other specialists who are researching DNA samples from a variety of categories of Cavalier King Charles spaniels throughout the world, in an effort to discover the genes causing mitral valve disease. In an April 2006 research update, Ms. Rushbridge reports that "a full genome scan looking for the causal gene/s of syringomyelia and mitral valve disease is underway!" The Cavalier Health Foundation (associated with the Cavalier King Charles Spaniel Club, USA) has contributed a grant to help underwrite this project. Donations are tax deductible. Donate to the Cavalier Health Foundation!

Also participating are Marie Pierre Dube, a genetics epidemiologist at the Montreal Heart Institute, and Dr. Zoha Kibar, the molecular geneticist in charge of fine mapping and identification of the gene(s) defective in MVD and syringomyelia in CKCSs, at Centre for the Study of Brain Diseases, CHUM – Montreal. Dr. Kibar reports in the April 2006 update:

    "Both Syringomyelia and Mitral valve disease are particularly common in the Cavaliers. Such high incidence in a particular breed as compared to other breeds suggests the involvement of genetic factors. The mode of inheritance including the number, identity and relative contribution of the causative genes is not determined yet. The etiology of both conditions could be further complicated by variable penetrance of the various genotypes and the involvement of environmental factors.

    "The first step which is genetic mapping is currently underway. Due to the complex inbreeding in the CKCS, a preliminary genetic analysis was necessary to evaluate the informativeness of the genetic markers and hence the feasibility of a whole genome scan in such breed. Consequently, 10 dogs were selected for genotyping with 122 markers distributed among the 38 autosomes and X chromosome. The markers were found to be sufficiently polymorphic and informative. Next, 200 dogs were selected for a whole genome scan, primarily for Chiari malformation. However with additional phenotypic information on mitral valve disease, it is possible to use the same data to map the gene(s) defective in this disease. The whole genome scan was conducted at the Mammalian genotyping Center at the Marshfield Clinic in Wisconsin, USA. The genotyping data will now be analyzed using both linkage-based and association studies. In the latter, we will be taking advantage of the founder effect demonstrated for both these disorders in the CKCS breed.

    "This strategy involves: 1) genetic mapping of the underlying gene(s), 2) identification of these defective gene(s) using the positional candidate gene approach and characterization of the mutation(s) and 3) initial functional characterization of the protein(s) encoded by the gene(s). This will help better understand the underlying pathogenic mechanisms for better diagnosis, prognosis and clinical management of these devastating conditions. These studies will also help unravel some of the complexity involved in this malformation in humans and in the embryonic development of the affected structures."

4Genomic expression patterns of mitral valve tissues from dogs with MVD: Dr. Mark A. Oyama at the School of Veterinary Medicine, University of Pennsylvania, and Sridar V. Chittur, PhD, Center for Functional Genomics, State University of New York at Albany, have published "Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease" in the August 2006 issue of the American Journal of Veterinary Research. Their conclusion is that "Evaluation of global expression patterns provides a molecular portrait of mitral valve disease, yields insight into the pathophysiologic aspects of DMVD [degenerative mitral valve disease], and identifies intriguing genes and pathways for further study."

4Repairing damaged heart cells by transplanting stem cells: Dr. Oyama also is investigating whether dogs' damaged heart cells can be repaired by transplanting the dogs' own stem cells into their hearts, a procedure called cardiac cellular transplantation.

4June 2007: 3-D echocardiographics and image reconstruction of Cavaliers with MVD: Dr. Mark A. Oyama at the School of Veterinary Medicine, University of Pennsylvania, is leading a team of investigators to determine whether the heart valves of dogs with MVD possess inherently different geometrical characteristics when compared to those of non-affected dogs. They propose using a novel 3-D echocardiographic technique and specialized image reconstruction to visualize the geometry of the valve annulus and valve leaflets in greater detail. They intend to correlate the valve geometry with disease severity, ventricular function and geometry, and conventional 2-D echocardiographic measurements of mitral valve disease.

4 Reduced rate for heart examinations in Philadelphia: In connection with his 3-D echocardiograph study, Dr. Oyama wants to examine Cavaliers of all ages, regardless of whether they have MVD murmurs or not. For a reduced price of $70.00 (instead of the usual $400.00), each dog will be auscultated by a veterinary cardiologist, have an echocardiogram and an electrocardiogram, and a blood sample taken, in Philadelphia at the University of Pennsylvania's School of Veterinary Medicine.

To schedule an appointment for your Cavalier, telephone the school's department of cardiology at 215-898-3331 and ask to speak with Fey or Carolyn. Appointments will be scheduled Monday through Friday before Noon. Please note that this telephone number is only for scheduling and not for fielding questions. If you get voicemail, leave your name and phone number and they will get back to you. If you have any questions about participating in the project, contact Erin Tennyson at telephone 609-468-1577, email erint@vet.upenn.edu

4September 2007: Indentifying DNA markers and altered genes that predispose Cavaliers to develop early-onset MVD: Drs. Margaret M. (Meg) Sleeper, Petra Werner, and James Buchanan, of the University of Pennsylvania's School of Veterinary Medicine, are conducting a genetic analysis of CKCS hearts and blood samples, with the goal to identify DNA markers and altered versions of genes that predispose Cavaliers to develop early-onset mitral valve disease. The inclusion criteria are CKCSs that develop from grade 3 to grade 6 MVD murmurs before the age of 5 years; and their immediate relatives (parents, siblings, and grandparents); and dogs over age 6 years without murmurs. They are obtaining samples consisting of: 3 mls of EDTA blood. For more information about sending blood samples to this project, contact either the ACKCSC trust's Bettina M. Sterling, email Sterlingtoys@aol.com, or Dr. Werner, telephone number 215-898-8894, email cmichel@vet.upenn.edu. An application form is available at www.ackcsc.org/health/CKCS_owner_info_form.pdf

Drs. Sleeper and Buchanan are board certified cardiologists. Dr. Buchanan has contributed over sixteen years of his time to research of MVD in the CKCS. Dr. Werner, who has a doctorate in molecular genetics from the University of Zürich, has been leading a team of researchers at the Center for Comparative Medical Genetics and Section of Medical Genetics at the School of Veterinary Medicine, University of Pennsylvania for the past ten years in developing a genetic map of the canine genome.

The American Cavalier King Charles Spaniel Club's charitable trust's Darcy Fund is helping to underwrite this research, and the ACKCSC trust is actively participating in the project by collecting selected blood samples and pedigrees during health clinics around the United States. Financial donations to support this research project may be made either through the Darcy Fund or by sending checks payable to "Trustees of the University of Pennsylvania", with "Cavalier Heart Fund" in the memo, directly to Dr. Petra Werner, Room 4033, Ryan Veterinary Hospital, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104-6010. Donations are tax deductible. Donate to the Darcy Fund!

4January 2007: Studying cellular changes that occur as the mitral valve deteriorates: Dr. Brendan M. Corcoran and Richard Han of the veterinary school at the University of Edinburgh, in collaboration with University College Galway, are conducting studies of the cell type of Cavaliers afflicted with MVD, including the cellular changes that occur as the mitral valve deteriorates, assessing affected valves for the presence of a variety of markers that identify cell types, and determining if there is increased cell enzymatic activity which could result in valve destruction. The investigating panel suspects that that reason dogs develop MVD is because of a cell type, known as a valvular interstitial cell, which is malfunctioning and failing to produce normal structural components. These components are crucial to maintaining the valves structural rigidity, its shape and function, and to prevent it from leaking.

The study is looking at the structure and appearance of the valve cells using electron microscopy, thereby enabling the researchers to characterize the differences between normal and abnormal cells. The immediate aim of the studies is to prove these cells are abnormal, in what way they are abnormal, and why they are abnormal. In conjunction with that work, they are hope to determine procedures to isolate normal and abnormal cells and investigate the function of the cells in a controlled laboratory environment. See below a reference to Dr. Corcoran's 2004 article, "Identification of surface morphologic changes in the mitral valve leaflets and chordae tendineae of dogs with myxomatous degeneration", in the American Journal of Veterinary Research.

The Scottish study also involves evaluating the changes in the structural elements (collagen and elastin) in the valves, using routine and special stains for light microscopy, and looking at the expression of immunoglobulins in affected dogs. In a February 2006 interim report, the researchers stated that they are "confident that there are recognisable changes in the cell types that are crucial for maintaining healthy valves, and preliminary data suggests this is resulting in altered protein expression by the valve cells." According to the February 2006 interim report, Richard Han is leading two other projects related to the Scottish study. In the first, he is looking into "the structural change in the valve, particularly the spatial arrangement of the matrix, which gives the valves their structural rigidity and which is disorganised in disease." The researchers are using a powerful x-ray technique to investigate this problem.

Also, Mr. Han is leading a second related study, which is of innervation (nerve supply) of the mitral valve. Dr. Corcoran states that, "We know that a derangement of nerve supply has an adverse affect on valve function and we suspect on valve cells. This study is using immuno-histochemistry to map the innervation of the valve in normal and diseased dogs."

In their January 2007 report to the U.K.Cavalier King Charles Spaniel Club, the researchers state that their work is divided into five categories: (1) Immunohistochemical localization and identification of cell types in affected valves; (2) Quantification of cellular changes in diseased valves; (3) Identification of alteration in connective tissue elements and the factors that control these elements; (4) Evaluation of alteration in endothelial cell morphology and function; and (5) Analysis of differential protein and gene expression in diseased valves.

Dr. Corcoran concludes in his January 2007 report that, "We have identified fundamental changes in the valve that were not previously known and we have also identified the nature of change that occurs with disease progression. We have begun to look at the more fundamental changes that occur at the gene expression level and the consequence of changes in gene expression, namely what protein are expressed or absent. Like all research, this project has answered some questions, but has also raised new questions that will need investigation. Historically, we have known very little about the mitral valve disease in either dogs or humans and by its very nature this type of research slowly fills in the gaps in our knowledge hopefully eventually leading to the answer to the question of why does mitral valve disease occur."

Dr. Corcoran next (as of May 2007) is proceeding to investigate the phenomenon of interstitial cell phenotypic change further, using proteomics (two-dimensional gel electrophoresis) to identify potential proteins of interest. He states that, "From these data, in future studies we would use RT-PCR to identify differential gene expressions and identify potential genes of interest." The American Cavalier King Charles Spaniel Club's charitable trust's Darcy Fund, is helping to underwrite Dr. Corcoran's new area of research. Donations are tax deductible. Donate to the Darcy Fund!

Dr. Corcoran may be reached at telephone 0131 650 6070, email Brendan.Corcoran@ed.ac.uk Mr. Han's telephone number is 0131 650 7680.

Mitral Valve Disease Seminars

4May 31, 2008, Laguna Niguel, CA: Dr. Michael Lesser, board certified veterinary cardiologist, speaks on "What's New in Managing Heart Disease", at Darcy Fun Day '08, at Laguna Niguel Regional Park, 28241 La Paz Road, Laguna Niguel, CA 92677. Contact Kim Thornton at kthornton@cox.net for details, or go to webpage http://members.cox.net/cavalierpark/DarcyFUNDay2008.jpg