Grades of Mitral Valve Disease Murmurs

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

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

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

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

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

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

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

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.

-- auscultation (stethoscope)

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

-- 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.    Return to Top

-- ultrasound (echocardiography)

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

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

-- 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.   Return to Top

Progression

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

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

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

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.    Return to Top

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-

Preventative Vitamins and Supplements?

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

Vitamin C (300 to 400 mg. daily)

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

CoQ10 (30 mg. daily)

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

prohibitive and would require that the dog's renal system and other vital organs be in ideal condition. Therefore, MVD typically is treated by managing heart failure. The goals of the veterinary cardiologist are to improve the dog's quality of life and to increase the length of its life.

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

-- mild murmur

A Cavalier with early mitral valve disease has a mild murmur but otherwise is symptom-free (asymptomatic). 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]) 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.    Return to Top

-- moderate MVD

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

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

ACE Inhibitors -- More Pluses Or Minuses?

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

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

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

the worst of its negative side effects. Researchers have found that extensive use of diuretics alone may contribute to renal dysfunction by activating the renin-angiotensin aldosterone system (RAAS) , as well as dehydration, azotemia, and hypokalemia.

However, another increasingly popular diuretic in treating MVD patients, spironolactone (Aldactone, Prilactone) -- 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.    Return to Top

-- severe MVD

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

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

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

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).   Return to Top

A Few Words About Pimobendan (Vetmedin®)

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

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

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

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

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

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

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

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

Most recently -- July 2008, Drs. Häggström, Boswood, O'Grady and several others reported that in a comparison study of pimobendan and benazepril hydrochloride, "Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD [myxomatous mitral valve disease] compared with benazepril plus conventional therapy." Of the 190 dogs, the median time to death (called the "endpoint") was 267 days for pimobendan and 140 days for benazepril. They concluded that "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."

Pimobendan also may begin to be considered for Cavaliers in the early stages of MVD. However, great caution should be taken when considering treating any dog suffering only from mild, asymptomatic MVD. There is evidence from recent studies that treatment with pimobendan of dogs not in CHF may accelerate the symptoms of MVD, including increased regurgitation of blood through the mitral valve, deterioration of the chordae tendinea, and enlargement of the left side of the heart. Most recently, in the 2007 French study, "Comparative Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A Prospective, Controlled, Blinded, and Randomized Study", the researchers found (a) "increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening"; (b) "the maximum area and peak velocity of the regurgitant jet signal increased, whereas these variables remained stable in the BNZ group"; (c) "histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group"; and (d) "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." They concluded: "PIMO has adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD." Bottom line: pimobendan is hazardous to the health of Cavaliers with MVD murmurs but no symptoms.

See also the 2005 study "Increased Mitral Valve Regurgitation and Myocardial Hypertrophy in Two Dogs With Long-Term Pimobendan Therapy". To the contrary, however, in a 2007 study, "Evaluation of Pimobendan in the Treatment of Early Mitral Valve Disease", the researchers concluded from their study of 26 dogs that their "data suggest a possible non-sustained positive inotropic effect and a reduction of the (mitral regurgitation fraction) at 90 days with the administration of pimobendan in early chronic MVD." They concluded, however, that more data are needed to further assess their findings. A positive inotropic effect means that the drug increases the strength with which the heart muscle contracts.

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

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

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

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-- end stage of MVD

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.

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.       Return to Top

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

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

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 ... ."

4May 2009: Researchers need dogs with Grade 3 heart murmurs. Free screening tests -- a consultation,an echocardiogram, chest radiographs, blood sample analysis and ECG -- are included. The University of Pennsylvania's Veterinary Hospital (VHUP), in Philadelphia, PA, is 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 to VHUP 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 study is being led by Dr. Mark A. Oyama. For more information, please contact Dana Durso at email Durso@vet.upenn.edu or telephone 215-573-6553.

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.

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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Mitral Valve Disease Seminars

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Related Links

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

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

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

Veterinary Resources

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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.

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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.

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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.

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.

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."

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 DMVDin 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."

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."

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."

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