Mitral Valve Disease and Cavalier King Charles Spaniels

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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...

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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.

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IN DEPTH:

Degenerative mitral valve disease (MVD)* is the leading cause of death of Cavaliers. It is a highly-heritable, polygenetic acquired heart disease which, statistics show, 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.
* MVD is 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.

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.

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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. (In the photo at right, LA is the heart's left atrium, LV is the left ventricle, and in-between, the opening of the mitral valve shows thickened, shortened leaflets which no longer fully close.) 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.

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Diagnosis

Cavaliers should be screened for heart murmurs annually, beginning at age one year. 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.

 

Ask the cardiologist to use this standardized report form. A list of upcoming heart testing examination clinics is on our Health Clinic webpage.
 

 

In a 2009 "Consensus Statement" published by a panel of the board certified veterinary cardiologists of the American College of Veterinary Internal Medicine (ACVIM), they state:

"Consensus recommendations:

"Small breed dogs, including breeds with known predisposition to develop CVHD [chronic valvular heart disease] (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.

"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."

-- 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) (see illustration "C" at right), 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 (see illustration "D" at right).

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-- 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.

The radiograph image at the right shows an enlarged left atrium in a dog's heart, caused by MVD.

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-- 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 echo image at right shows a dog's heart with MVD. LA-left atrium; LV-left ventricle; MV-mitral valve, septal leaflet. Note the thickened free end of the mitral valve leaflet at the left of the valve.

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.

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-- 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. In particular, BNP is secreted by the left ventricle in response to heart wall stretching or stress.  

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 thestudy. In a later study, reported in 2005, Drs. William E. Herndon, Justine A. Lee, Kenneth J. Drobatz, and 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 Drs. 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.

Three trademarked names for NT-proBNP tests are "Canine CardioCare" (Veterinary Diagnostics Institute), and "Canine VetSign CardioSCREEN" (Guildhay Ltd.), and "Cardiopet proBNP" (IDEXX Laboratories). 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."

More recently, in a May 2008 report by Drs. Mark A. Oyama, Philip R. Fox, John E. Rush, Elizabeth A. Rozanski, and Michael B. Lesser of 119 dogs, they found that "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." They concluded that, "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." And that, "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."

In a May 2009 report from Sweden, the researchers concluded: "Plasma concentrations of the natriuretic peptides measured at re-examination could predict progression in regurgitant jet size."

Nevertheless, 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. But it does not yet appear that BNP testing is an any earlier warning system for MVD than auscultation.

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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 an April 2010 research article, Swedish cardiologists reported finding that Cavaliers' left heart chambers increased in size rapidly only during the last year before the onset of congestive heart failure.

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.

Studies are being conducted into possibly slowing the progression of MVD. These studies, discussed in greater depth below at Drugs to Slow the Progression of MVD, involve the testing of medications.

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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.

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Treatment

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.

Studies are being conducted into possibly reducing the progression of MVD.  They are discussed below at Drugs to Slow the Progression of MVD.

Also, in 2008 in at least one pre-med research paper, the author suggests that injecting bone marrow stromal cells into the heart of a Cavalier King Charles spaniel may stimulate stem cells to regenerate heart muscle and repair damage to the valve tissues.

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.

In a 2009 "Consensus Statement" published by a panel of the board certified veterinary cardiologists of the ACVIM, they create a new classification of stages of MVD.  They state:

"The new system describes 4 basic stages of heart disease and failure:

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)'

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.

Stage B1 refers to asymptomatic patients that have no radiographic or echocardiographic evidence of cardiac remodeling in response to CVHD.

Stage B2 refers to asymptomatic patients that have hemodynamically significant valve regurgitation, as evidenced by radiographic or echocardiographic findings of left-sided heart enlargement.

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).

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."

-- mild murmur (Stage B1)

A Cavalier with early mitral valve disease has a mild murmur but otherwise is symptom-free (asymptomatic). This dog would be at Stage B1 of the ACVIM's 2009 Consensus Statement.  Cardiologists refer to this as the pre-clinical stage. 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], ramipril [Altace, Tritace, Vasoto]) 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.

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-- moderate MVD (Stage B2)

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. This is a Stage B2 dog, according to the 2009 ACVIM Consensus Statement.

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 the kidney by activating the renin-angiotensin aldosterone system (RAAS), as well as the 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.

In a 2009 study report which did not include CKCSs, veterinary cardiologists observed a three-fold increase in RAAS activity using furosemide.  Their conclusion was that "furosemide 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."

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], ramipril [Altace, Tritace, Vasotop]) 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.

In a 2010 European study, spironolactone (Aldactone, Prilactone), an aldosterone antagonist, when added to conventional cardiac therapy (such as an ACE inhibitor, plus furosemide and digoxin if needed) decreases the risk of reaching the primary endpoint (ie, cardiac-related death, euthanasia, or severe worsening) in dogs with moderate to severe mitral regurgitation caused by MVD.

However, spironolactone, 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 urea (AC Carbamide) by Standard Process, and 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.

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.   

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-- severe MVD (Stage C)

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. This is a Stage C dog, according to the 2009 ACVIM Consensus Statement. 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, often 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."

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 (Stage D)

Follows the Pimobendan box just below.

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-- end stage of MVD (Stage D)

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, other drugs, and even pimobendan, no longer are able to remove enough of the fluids and increase the supplies of blood and oxygen to the heart. This is a Stage D dog under the 2009 ACVIM Consensus Statement.

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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-- drugs to slow the progression of MVD

Two studies are being conducted to find medications directed at the pathology of mitral valve disease and which may slow the progression of MVD.

--- seratonin blockers

One of the two studies involves blocking the Cavalier's excessive production of seratonin. Research thus far has suggested that: (a) seratonin (5HT) activates growth activity in canine mitral valves; (b) dogs with MVD have more seratonin receptors in their valve cells than other dogs; (c) mitral valve cells have the capacity to make their own seratonin; and (d) Cavaliers also have a higher level of seratonin in their bloodstream.

Researchers are exploring the possibility that if seratonin levels can be reduced, by blocking the receptors in the mitral valves, then the progression of the deterioration of the valves and their leaflets can be slowed.  One existing drug, approved for use by humans in Europe, is being tested on dogs with MVD to determine its effectiveness in reducing the level of seratonin and slowing the progression of MVD in Cavaliers.

These drugs may include ketanserin, a 5HT-R2A receptor blocker, or GR55562, a 5HT-R1B receptor blocker, based upon suggestions made by Dr. Mark Oyama in his January 2010 report.

See more information under Current Research below.

--- beta blockers

The other study involves a beta blocker intended to slow the progression of MVD.  This study is being conducted at veterinary schools and some cardiology clinics throughout the United States.  The researchers need participating dogs.  See details below.

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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.

Read about Dr. Orton's current research below. Dr. Orton may be reached by telephone at 970-297-1250, and e-mail at chris.orton@ColoState.edu

4PITTSBURGH, PA: Research physicians at the University of Pittsburgh have conducted experimental mitral valve repairs on dogs, using radiofrequency ablation (RFA).  The RFA energy is applied to the deteriorating valve flaps and chords, resulting in controlled damage which has the affect of qualitatively reducing the leaflet surface and the chordal length.  The researchers found that the result of the application of RFA was to reduce the mitral regurgitation by statistically significant amounts.  Read the details below.

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

4FUJISAWA, JAPAN: Drs. M Nishida, M Uechi, T Mizukoshi, T Ebisawa, M Mizuno, T Mizuno, K Harada, M Fujiwara, N Nakayama of Nihon University, Fujisawa, Japan, have been conducting "mitral valve plasty" surgery on Cavalier King Charles spaniels and other small dogs since 2006. Mitral valve plasty involves suture repairs to the mitral valve leaflets and includes the insertion of artificial chords made of a polymer, expanded polytetrafluoroethylene (e-PTFE). They report in a 2009 journal article, "Mitral Valve Plasty in 11 Cavalier King Charles Spaniels", that "these results suggest that mitral valve plasty is beneficial in CKCS with MVD."

While two of their CKCS patients died during the post-operative study due to complications, and three were diagnosed with syringomyelia, the researchers found that among the nine survivors, "at 1 and 3 months after surgery, the left atrial to aortic root diameter ratio ... and the plasma atrial natriuretic peptide level ... were lower than those before surgery ... There were also significant improvements in the number of prescribed cardiovascular drugs 1 month after surgery ... and in the cardiac murmur grade ... ."

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    

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Current Research

4July 2010: NC State's veterinary college seeks dogs with mild heart murmurs for activity study. The school's press release states: "Does your dog have a heart murmur? If so, he may be eligible for a new study of heart disease! We are enrolling dogs with early heart disease into a clinical trial to measure their activity at home. We will record their activity with a small device (the size of a quarter) that is attached to their collar. Activity will be recorded before, and during treatment with a medication used to treat heart disease. Requirements: The study will require an outpatient appointment with the cardiology service at the Veterinary Teaching Hospital. Your dog will then wear the collar/activity recording device for two weeks, then for another two weeks after twice-daily medication is started. Benefits to you: The study will pay $300 towards the cost of an evaluation by the cardiology service and the cost of the medication. The evaluation includes an extensive health screening. By comparing your pet’s activity before and after addition of the medication, and by comparing activity with that of a similar dog without heart disease, we hope to be able to measure any increase in your pet’s activity and vigor when treated with the medication." Contact Andrea Thomson, telephone 513-513-6854, email cvm_cprl@ncsu.edu

4May 2010: Dr. Sarah Blott issues her first report on using estimation of breeding values (EBVs). She writes in her May 2010 article:

"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."

4April 2010: Univ. of Pennsylvania MVD researchers need blood samples for gene study. The researchers are seeking to identify gene variation, and to verify it as the actual cause of MVD in the breed. Dr. Paula Henthorn asks for blood samples from Cavaliers in these categories:

4CKCS with Grade 3 or louder murmur (by cardiologist) at age 5 years or younger.

4CKCS with no murmur (by cardiologist) at age 9 years or older.

4Older dogs which currently have a murmur but were cardiac clear at 9 years of age can be enrolled as long as a copy of the clearance at 9 years of age (or greater) is available.

If possible, they would also like a copy of the pedigree, but it is not necessary for enrollment. Click here for further information and the enrollment form.

If you are interested in making a financial donation to this research project, please send a check written to “Trustees of the University of Pennsylvania” with “Cavalier heart fund” in the memo to Dr. Paula Henthorn, Veterinary Hospital – Room 4033, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104-6010; email: cmichel@vet.upenn.edu; telephone 215-898-8894; fax 215-573-2162. Donations are tax deductible. See also the September 2007 entry below for additional information about this research project.

4March 2010: UK researchers report early-onset MVD is "highly heritable" in Cavaliers.  Drs. Tom Lewis, Simon Swift, John A. Woolliams, and Sarah Blott also found that "selection against the disease should be successful."  See report summary.

4March 2010: Swedish MVD researchers find Cavaliers' most rapid heart enlargement only in last year before congestive heart failure. Drs. Clarence Kvart,  Jens Häggström, and others studied 24 Cavalier King Charles spaniels with MVD for the rate of change of their heart size before congestive heart failure.  They found in their research journal article that "The left heart chambers increase in size rapidly only in the last year before the onset of congestive heart failure."

4March 2010:  Two recent studies examine connection between cardiac troponin I (cTnI) concentrations and severity of MVD. In a UK study soon to be published in The Veterinary Journal, 120 dogs, including Cavaliers, were enrolled, and in a Swedish study in the Journal of Veterinary Internal Medicine, 81 dogs, including 67 CKCSs, were studied. Both groups observed that increases in cTnI concentrations in dogs with poor prognoses, and both also concluded that cTnI has potential in assessing the prognosis and severity of MVD and enlargement of the heart. Both reports also recommend more detailed future studies.

4January 2010: Dr. Mark Oyama summarizes research into the possible roles of serotonin (5HT) and transforming growth factor-b in transforming valvular interstitial cells (VIC) into a more active myofibroblast, which is an important component of MVD in Cavaliers.  See his "insights".  Also check out his September 2009 entry, below. Dr. Oyama also suggests that ketaerin, a 5HT-R2A receptor blocker, or GR55562, a 5HT-R1B receptor blocker, may be effective in dealing with serotonin's affect on dogs' mitral valves.

4December 2009: Research physicians at the University of Pittsburgh conduct experimental mitral valve repairs on dogs, using radiofrequency ablation (RFA).  The RFA energy is applied to the deteriorating valve flaps and chords, resulting in controlled damage which has the affect of qualitatively reducing the leaflet surface and the chordal length.  The researchers found that the result of the application of RFA was to reduce the mitral regurgitation by statistically significant amounts.  Read the details below.

4November 2009: ACVIM's "Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease".  A panel of board certified veterinary cardiologists have published a "Consensus Statement, classifying the stages of MVD and the recommended treatment at each stage.

4September 2009: The Serotonin Concentration Studies Continue. "Healthy CKCS dogs had significantly higher serum [serotonin] 5HT concentrations than other healthy dogs predisposed to DMVD [degenerative mitral valve disease]," concludes the University of Pennsylvania team studying serontonin's connection to mitral valve disease (see the January 2009 Current Research entry below) in its report to be published in the November/December 2009 issue of the Journal of Veterinary Internal Medicine. They also found that "Dogs with DMVD had significantly higher serum 5HT concentrations when compared with large breed control dogs."

4August 2009: Researchers need dogs with Grade 3 heart murmurs. HECTOR Study: Free screening tests -- a consultation ,an echocardiogram, chest radiographs, blood sample analysis and ECG -- are included. At several veterinary schools, the University of Pennsylvania's Veterinary Hospital (VHUP), in Philadelphia, PA, Washington State University's veterinary medicine's cardiology department, in Pullman, WA, the University of Missouri's veterinary medicine teaching hospital, in Columbia, MO, North Carolina State University's veterinary medicine cardiology department in Raleigh, NC, Cornell University's veterinary medicine cardiology department in Ithaca, NY, and Texas A&M University's (TAMU) veterinary medicine's cardiology department, in College Stations, TX, as well as the Animal Medical Center in New York City, and the MedVet Medical and Cancer Center for Pets in Worthington, Ohio, are recruiting dogs for a study evaluating a beta-blocker to treat heart disease due to MVD. All breeds are eligible. The dogs must have at least a Grade 3 murmur, be at least a year old, and have never had any clinical signs of heart disease of any kind.

Dogs included in the study will receive a beta-blocker or placebo, and will be required to return for rechecks four times the first year and twice yearly each year after. The study's title is “Clinical Evaluation of the Efficacy and Safety of a Beta-blocker Medication used to Treat Heart Disease due to Chronic Valvular Heart Disease”.

The beta-blocker being tested is not one of the ones commonly being prescribed and is administered in liquid form. The researchers hope to have up to 400 dogs participate in the study, over up to a four year period.  The study is sponsored by Bayer Animal Health.

Contacts:

The UPenn study in Philadelphia is being led by Dr. Mark A. Oyama. For more information, please contact Dana Durso by email or telephone 215-573-6553.

The Washington State U study in Pullman is led by Dr. Kate Meurs.  Email her or Becky Connors or call 509-335-6038.

The U. of Missouri study in Columbia is led by Dr. Deborah Fine.  You may contact her by email, or Ed Durham, or call 573-882-7821.

North Carolina State Univ. study in Raleigh contact is Allison Klein. Email her or call 919-513-6325.

Cornell University study in Ithaca contact is Dr. Syndey Moise. Email her or call 607-253-3081.

TAMU's study in College Station contact is led by Dr. Sonya Gale Gordon.  You may contact Kathy Glaze by email or call 979-845-2351.

The Animal Medical Center study in New York City is Dr. Philip Fox.  You may email him or contact him at telephone 212-329-8606.

The MedVet study in Ohio is being led by Dr. Linda Lehmkuhl. For more information, please contact her or Dr. Ann Bancroft by email or telephone, 614-431-4405.

4June 2009: Japan Surgeons Report Successful Repairs to CKCS Mitral Valves. Nihon University veterinary surgeons have been conducting "mitral valve plasty" surgery on Cavalier King Charles spaniels and other small dogs since 2006. Mitral valve plasty involves suture repairs to the mitral valve leaflets and includes the insertion of artificial chords made of a polymer, expanded polytetrafluoroethylene (e-PTFE). They report in a 2009 journal article, "Mitral Valve Plasty in 11 Cavalier King Charles Spaniels", that "these results suggest that mitral valve plasty is beneficial in CKCS with MVD."

While two of their CKCS patients died during the post-operative study due to complications, and three were diagnosed with syringomyelia, the researchers found that among the nine survivors, "at 1 and 3 months after surgery, the left atrial to aortic root diameter ratio ... and the plasma atrial natriuretic peptide level ... were lower than those before surgery ... There were also significant improvements in the number of prescribed cardiovascular drugs 1 month after surgery ... and in the cardiac murmur grade ... ."

 4January 2009: Colorado State Univ. researchers to test drug inhibiting serotonin in mitral valves. Dr. E. Christopher Orton of the of Colorado State University's James L. Voss Veterinary Teaching Hospital and its Animal Heart Center in Ft. Collins, Colorado, and Dr. Sirilak Disatian, have issued a report on their study begun in June 2008, "Autocrine Serotonin and TGF-beta Signaling in Human Myxomatous Mitral Valve", which has been sponsored by the American Heart Association. The researchers have found that serotonin is created locally in heart mitral valves, thereby causing pathologic changes in the valves, resulting in their malfunction.

Serotonin is made by an enzyme called tryptophan hydroxylase 1 (TPH1). Serotonin then goes into the blood stream where it is picked up by platelets which are involved in blood clotting. Orton's group has shown that TPH1 is present in high levels in abnormal mitral valves from both dogs and humans.

Dr. Orton's group is seeking to find what triggers the enzyme in the valve which produces the serotonin. He plans to start a clinical trial on dogs to examine the impact of a drug that inhibits the enzyme that produces serotonin in the heart.

See also June 2008 entry for Dr. Mark Oyama.

4October 2008: UK Kennel Club to Add "Health Plan" to Cavalier King Charles Spaniel Breed Standard. The (UK) Kennel Club announced that it will include a "breed health plan" in the CKCS breed standard, to "ensure that no dog is bred for features that might prevent it from seeing, walking and breathing freely." A meeting to include representatives of the UK's Cavalier club and cardiologists is set for December 1. The club expects to issue the CKSC health plan by early 2009.

The UK club also is asking the UK government to "give it statutory powers to make its established Accredited Breeder Scheme compulsory throughout the country. If successful, this would mean that all breeders who are not part of the scheme and who have not officially confirmed their willingness to follow the health standards set by the Kennel Club would be unable to produce or sell puppies within the law." Additionally, the UK's Cavalier breed club is "now required to adopt the Kennel Club's Code of Ethics, to ensure that their practices fall in line with Kennel Club policy for putting the health and welfare of puppies first. This includes a clause that explicitly forbids the compulsory culling (killing) of healthy puppies." See website www.thekennelclub.org.uk

4September 2008: UK Kennel Club and British Veterinary Association Plan Possible Heart Testing Protocol for Cavalier Breeding Stock. On September 15, 2008, the UK Kennel Club and British Veterinary Association representatives met with representatives of UK Cavalier King Charles spaniel clubs to discuss introducing a heart testing scheme, which would be applied to CKCS and three other breeds. The test results would be published in the Kennel Club's breed registration quarterly supplements and on the progeny's registration certificates. The group plans to meet again in December to consider adopting the scheme.  The UK Kennel Club also is looking at ways by which breeders could access health results of dogs/ bloodlines. This service will be available to breeders and pet owners.

4July 2008: ACVIM Announces "ARCH" -- New Registry of Cardiac Health. The board certified cardiologists of the American College of Veterinary Internal Medicine (ACVIM) have introduced a new registry, ARCH, to certify dogs' hearts are clear of mitral valve disease and other genetic heart disorders. ARCH certifications are issued only by board certified veterinary cardiologists. Look for the ARCH symbol and check out the website.

4June 2008: Serum Serotonin Concentration Is Elevated in CKCSs. University of Pennsylvania Drs. Jason W. Arndt, Mark A. Oyama, and C. A. Reynolds have completed initial research showing that CKCSs have higher levels of serotonin (5-HT) than other breeds which are pre-disposed to MVD. (CKCS, 903.9 [321.5] ng/ml vs. non-CKCS, 536.0 [153.7]; P50.004). The team studied 51 dogs, including 32 Cavaliers, which either were affected with or pre-disposed to MVD (CKCSs as a breed are pre-disposed to MVD), plus 28 control dogs. They report: "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. ... 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."

Meanwhile, at Colorado State University, Dr. E. Christopher Orton of the of CSU's James L. Voss Veterinary Teaching Hospital and its Animal Heart Center in Ft. Collins, Colorado, has started a study, "Autocrine Serotonin and TGF-beta Signaling in Human Myxomatous Mitral Valve", which is sponsored by the American Heart Association.

4May 2008: Auburn University Researchers Find Possible Link Between Oversized Platelets and MVD in Cavaliers. A team of researchers at Auburn University in Alabama (Drs. B. Davis, M. Toivio-Kinnucan, S. Schuller, M.K. Boudreaux) determined that "a mutation in the gene encoding β1-tubulin correlated with macrothrombocytopenia in CKCS." They concluded that "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." See citation below.

4May 2008: Researchers Need Heart Tissue From Deceased MVD Canines. Dr. Allison M. Heaney, board certified veterinary cardiologist, heads a research program at the College of Veterinary Medicine at Washington State University studying the difference in the balance between these proteins affecting collagen in normal cultured mitral valve cells and mitral valve cells cultured from diseased leaflets. Differences that exist between normal and diseased valve cells will help target future research projects and aid in determining the cause of the breakdown of collagen in diseased valve cells.

Dr. Heaney is requesting mitral valve tissue from dogs of any breed that have died or have been euthanized that have significant degenerative MVD. The valve tissue will be used to culture cells from the tissue in order for the researchers to study the disease from a cell culture perspective. For inclusion in the study, dogs need to have a diagnosis of degenerative mitral valve disease from their veterinarian (if echocardiography findings are available, those should be provided as well) and the owner needs to be willing to let their referring veterinarian remove the mitral valve from the dog after it dies or is euthanized. The tissue should be removed within 2 hours of death or euthanasia.

She requests that the anterior mitral valve leaflet (the larger leaflet most associated with the septum and aorta) -- but if there is any confusion the entire mitral valve can be shipped and they can collect the anterior mitral valve leaflet once it arrives here. The sample should be shipped in phosphate buffered saline. If needed, the researchers can ship tubes of phosphate buffered saline for sample collection. The sample should be shipped on ice overnight to the address below. For more information, contact Dr. Heaney or her research technician, Marsha Robertson, at Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University 100 Dairy Road, Pullman, WA 99164-1120, telephone 509-335-0711, fax 509-335-0880, email aheaney@vetmed.wsu.edu, websites: www.vetmed.wsu.edu.This study is supported by AKC Canine Health Foundation, webpage www.akcchf.org/news/index.cfm?article_id=249

4May 2008: DNA Project Needs UK Cavaliers. Simon Swift, MA VetMB Cert SAC MRCV, at the University of Liverpool, heads a DNA study of Cavalier King Charles spaniels. The study is based upon a novel genetic method intended to discover the genes behind mitral valve disease in the CKCS. The researchers need 100 Cavaliers with early onset MVD (defined as developing mitral insufficiency before age 4 years or developed signs of heart failure before 8 years) and 100 CKCSs with late onset MVD (dogs over 10 years without a murmur or with very mild mitral insufficiency). The group also is currently working to locate qualified dogs in Sweden and Denmark, as well as the UK.

If you live in the UK and have a dog which meets these standards, contact Mr. Swift about obtaining blood samples and pedigrees: (1) Dogs under 4 years with a loud murmur. (2) Dogs under 8 years that have developed heart failure. This does not necessarily mean a cough. They should also have breathlessness, weight loss, and exercise intolerance. They should also need medication. (3) Dogs over 8 years with no murmur or a very quiet one. A cardiologist should examine the dog. There will no charge if the examination is coordinated with Mr. Swift at a participating centre. The researchers are prepared to travel to examine large groups of dogs. The team is rganising a health clinic in Bagworth on September 27, 2008. If you can attend with a suitable dog, please bring your pedigree.

You may contact Mr. Swift at: Small Animal Teaching Hospital, The University of Liverpool. Leahurst, Chester High Road, Neston, Cheshire CH64 7TE; telephone (0151) 795 6100, fax: (0151) 795 6101, email sath@liv.ac.uk, website www.liv.ac.uk/sath/index.htm

4March 2008: Reducing Rejection of Replacement Mitral Valves. Dr. E. Christopher Orton of Colorado State University’s Animal Heart Center in Ft. Collins, Colorado leads a team researching the use of "tissue engineering" to build a better replacement for canine heart valves. “All replacement heart valves in use today are based on non-living tissues and have limitations,” said Dr. Orton in an interview published in CSU's Insight magazine, Spring 2008 issue. “In humans, there are two options, a mechanical valve that requires the patient to be on blood thinners for the rest of their lives, or a bioprosthetic valve, using a pig valve fixed with glutaraldehyde. Humans can tolerate these valves, but dogs not so much. As a species, dogs are more likely to reject foreign tissue.” Dr. Orton’s work focuses on tissue engineering that studies methods for removing antigens from living tissues and repopulating the tissue with the animal’s own cells.

The team is developing new methods for screening a large number of proteins for antigenicity -- the degree to which a substance induces an immune response, across species. To accomplish this, Dr. Orton's team is using proteomics to look at all of the proteins in the tissues used for bioprosthetic heart valves.

Proteomics is a new focus in the field of biotechnology that enables a system-wide analysis of proteins produced by cells. With proteomics, researchers can detect proteins that elicit an immune response, and subsequently identify the protein antigen, categorize the antigens into broad groups according to their origin, and then place them into smaller categories according to structure, type, physical and chemical properties.

By exposing separated proteins to naturally-occurring and acquired antibodies, Dr. Orton seeks to determine which proteins are responsible for the antigenicity of biomaterials, and this knowledge can be used to develop strategies to selectively remove those proteins. This study is expected to provide important insights about the bioprostheses and about tissue transplantation in general.

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!

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

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.

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.

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.

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Breeders' Responsibilities

Early-onset mitral valve disease has been found to be "highly heritable" in the Cavalier King Charles spaniel breed, and "selection against the disease should be successful.", according to an April 2010 research report.

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.

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Mitral Valve Disease Seminars

None scheduled.

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Related Links

MVD Breeding Protocol
Board Certified Veterinary Cardiologists
Questions for Breeders
Syncope
Canine Health Testing Clinics

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

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

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Laura Lang's CKCS Info Center webpage: Mitral Valve Disease

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American College of Veterinary Internal Medicine (ACVIM) Registry of Cardiac Health (ARCH)

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Veterinary Resources

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 and A. M. Roberts. J Physiol 1983 Vol 340 pp 415-433.

Valvular incompetence in cavalier King Charles spaniels. Darke, PG. Vet Rec., Apr 1987; 120: 365 - 366.

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.

Understanding Mitral Valve Problems in Cavaliers. Buchanan J, Beardow A. CNE 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.

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.

Mitral Valve Disease in Cavalier King Charles Spaniels. Darke PG. 1993.

Chronic Mitral Valve Disease in Cavalier King Charles Spaniels: 95 Cases (1987-1991). Beardow A, Buchanan J. JAVMA 1993, Jan; 203(7): 1023-1029.

Plasma concentration of atrial natriuretic peptide in relation to severity of mitral regurgitation in Cavalier King Charles Spaniels. Haggstrom J, Hansson K, Karlberg BE, Kvart C, Olsson K. Am J Vet Res. 1994 May;55(5):698-703.

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

Vertebral Scale System to Measure Canine Heart Size in Radiographs. Buchanan J, Bucheler J. JAVMA 1995, Jan; 206(2): 194-199.

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, phonocardiographic (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."

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. Pedersen HD, Koch J, Poulsen K, Jensen AL, Flagstad A. J Vet Intern Med. 1995 Sep-Oct;9(5):328-31.

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."

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.

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 ration 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."

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

Chronic Valvular Disease in Cavalier King Charles Spaniels: Epidemilogy, inheritance, and pathophysiology. Haggstrom J. 1996.

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

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.

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 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. 1997 Jan;58(1):77-82.

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.

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. 1997 Jul;282(1):23-31.

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.

Hypomagnesemia and mitral valve prolapse in Cavalier King Charles spaniels.  Pedersen HD, Mow T.; Zentralbl Veterinarmed A. 1998 Dec;45(10):607-14. 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 1999Jan-Feb;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. Pedersen HD, Lorentzen KA, Kristensen BO. Vet Rec., Mar 1999; 144: 315 - 320.

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.

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.

 "Acquired valvular heart disease." (Kvart C, Häggström J.) in: Textbook of Veterinary Internal Medicine. 5thed., 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.

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

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.

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.

Efficacy of Enalapril for Prevention of Congestive Heart Failure in Dogs with Myxomatous Valve Disease and Asymptomatic Mitral Regurgitation. 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.

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.

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.

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.

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.

Decreased Plasma Concentration of Nitric Oxide Metabolites in Dogs with Untreated Mitral Regurgitation.  Pedersen H. D., Schütt T., Søndergaard R., Qvortrup K., Olsen L. H., Kristensen A. T. J Vet Intern Med. 2003 Mar;17(2):178-184.

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

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.; Vol. 17, No. 5, pp. 680–686. J Vet Intern Med. 2003 Sep;17(5):680-686.

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.

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."

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).

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 2004;65:198–206.

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.

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.

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.h 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."

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.

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.

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, Dean E, Benalloul T, Pouchelon JL. Can Vet J. 2004 Dec;45(12):1012-5.

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.

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. 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, Kerstin H, Häggström J, Kvart C, Lord P, Veterinary Rad. & Ultrasound, Mar. 2005, 46(2): 122.

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.

Technique and outcome of mitral valve replacement in dogs. Orton EC, Hackett TB, Mama K, Boon JA. J Am Vet Med Assoc. 2005 May 1;226(9):1508-11, 1500.

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).

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).

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.

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.

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.

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.

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. 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.

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.

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.

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. Christophe W. Lombard, Olaf Jöns, and Claudio M. Bussadori. J. Am. Anim. Hosp. Assoc., July/August 2006; 42: 249 - 261.

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.

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.

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;20:1116–1126.

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.

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.

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."

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. 48 (5), 265–270, May 2007. 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".

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. Haggstrom. 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 Reninangiotensin-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."

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: "Results suggested that regurgitant fraction (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. 2007; 21 (4):742-53. Quote: "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."

Modulation of the tissue reninangiotensin-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, Oct 2007;231(7): 1061-1069. Quote: "Chronic enalapril treatment of dogs with naturally occurring, moderate to severe mitral regurgitation (MR) significantly delayed onset of congestive heart failure (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."

A 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(?).

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."

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."

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: "BNZ [benazepril] had beneficial effects in asymptomatic dogs other than CKC [Cavalier King Charles spaniels] and KC [King Charles spaniels] 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, www.medlink-uk.com/_global/downloads/results_2008/MercerJ.pdf  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."

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) 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."

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."

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. 2009 May;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."

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 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."

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 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 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 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 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: ... 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."

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."

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. Haggstrom, R. Hamlin, B. Keene (Chair), V. Luis-Fuentes, and R. Stepien. J Vet Intern Med. Nov/Dec 2009;23(6):1142–1150. Download pdf version here.  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."

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."

Molecular changes in fibrillar collagen in myxomatous mitral valve disease. Mojtaba Hadian, Brendan M. Corcoran, and Jeremy P. Bradshaw. Cardiovascular Pathology, doi:10.1016/j.carpath.2009.05.001. 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."

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."

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;24:27–36. 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."

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."

Heritability of premature mitral valve disease in Cavalier King Charles spaniels. Tom Lewis, Simon Swift, John A. Woolliams, and Sarah Blott. Vet J. May 2010.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.

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. "

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."

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