Myxomatous Mitral Valve Disease

Myxomatous mitral valve disease (MMVD), also known as endocardiosis or chronic valvular fibrosis, is the most common acquired cardiac disease in dogs. It is characterized by progressive myxomatous degeneration of the atrioventricular valves, most notably the mitral valve, leading to valve thickening, nodularity, and prolapse. This degeneration results in incomplete leaflet coaptation and mitral regurgitation (MR), which can progress to left atrial enlargement, pulmonary hypertension, congestive heart failure (CHF), and eventually right-sided heart failure. MMVD is a chronic, progressive disease with a variable rate of progression, and its clinical manifestations range from an asymptomatic heart murmur to severe, life-threatening heart failure. The disease is classified into stages (A, B1, B2, C, D) based on clinical signs and echocardiographic findings, guiding therapeutic intervention. MMVD is primarily a disease of small to medium breed dogs, with a strong breed predisposition, and its prevalence increases with age.

The exact etiology of MMVD is not fully understood, but it is considered a degenerative, non-inflammatory process. Genetic factors play a significant role, with a clear breed predisposition in Cavalier King Charles Spaniels, Dachshunds, Miniature Poodles, and other small breeds. A familial basis is suspected, and genome-wide association studies have identified potential candidate genes involved in extracellular matrix remodeling, such as those encoding for collagen and proteoglycans. Environmental factors, including diet and exercise, may influence disease progression but are not primary causes. No infectious, toxic, or autoimmune triggers have been consistently identified. The primary pathological process involves the activation of valvular interstitial cells, leading to the deposition of glycosaminoglycans and proteoglycans, disruption of collagen architecture, and accumulation of myxomatous material within the valve leaflets. This results in leaflet thickening, elongation, and prolapse, with subsequent MR.

MMVD is the most common cardiac disease in dogs, accounting for approximately 75-80% of all canine heart disease cases. It is predominantly seen in small to medium breed dogs, with a higher prevalence in males than females (approximately 1.5:1). The disease is age-related, with a marked increase in prevalence after 8 years of age; nearly all dogs over 13 years of age show some degree of valvular change. Breed predispositions include Cavalier King Charles Spaniels, Dachshunds, Miniature and Toy Poodles, Pomeranians, Chihuahuas, and Cocker Spaniels. In Cavalier King Charles Spaniels, the disease can manifest as early as 2-3 years of age, and by 5 years, over 50% of dogs have echocardiographic evidence of MMVD. The disease is less common in large breed dogs, but when it occurs, it may progress more rapidly. No significant geographic or seasonal variation is reported.

The pathophysiology of MMVD involves a cascade of structural and functional changes. The initial insult is myxomatous degeneration of the mitral valve leaflets, characterized by the accumulation of glycosaminoglycans and proteoglycans within the spongiosa layer, leading to disruption of the collagenous fibrosa. This results in leaflet thickening, nodularity, and prolapse, with subsequent incomplete coaptation and mitral regurgitation (MR). The regurgitant jet causes volume overload of the left atrium and left ventricle, leading to eccentric hypertrophy and progressive chamber enlargement. The left atrium dilates to accommodate the regurgitant volume, and chronic volume overload leads to increased left ventricular end-diastolic pressure and eventually elevated left atrial pressure. As the disease progresses, pulmonary venous congestion ensues, leading to pulmonary edema and clinical signs of left-sided CHF. Chronic MR also contributes to pulmonary hypertension, which can lead to right ventricular hypertrophy and, in advanced stages, right-sided heart failure. Neurohormonal activation, including the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, exacerbates the progression by promoting fluid retention, vasoconstriction, and adverse cardiac remodeling. The disease is progressive, but the rate of progression varies widely among individuals.

Predisposing factors for MMVD include breed, age, sex, and genetic susceptibility. Small breed dogs, particularly Cavalier King Charles Spaniels, Dachshunds, and Miniature Poodles, are at increased risk. Age is a major factor, with the disease being rare in dogs under 4 years and increasingly common with advancing age. Male dogs are more commonly affected than females. Genetic factors are strongly implicated, with a heritable component in certain breeds. Other potential risk factors include obesity, which may exacerbate clinical signs, and concurrent diseases such as systemic hypertension, which can worsen MR. However, these are not primary causes but may influence disease progression. No specific dietary or environmental factors have been definitively linked to the development of MMVD.

Clinical signs of MMVD vary depending on the stage of the disease. In early stages (Stage B1), dogs are typically asymptomatic, with only a heart murmur detected on physical examination. The murmur is typically a systolic, left apical, band-shaped murmur, with intensity graded I to VI. As the disease progresses to Stage B2, dogs may remain asymptomatic but have significant echocardiographic changes, including left atrial and ventricular enlargement. When CHF develops (Stage C), clinical signs include coughing, especially at night or after exercise, tachypnea, dyspnea, exercise intolerance, and in severe cases, syncope. Coughing is often due to left atrial enlargement compressing the left mainstem bronchus or due to pulmonary edema. Other signs may include lethargy, decreased appetite, and weight loss. In advanced stages (Stage D), signs of right-sided heart failure may appear, including ascites, jugular venous distension, and peripheral edema. Physical examination may reveal a rapid, weak femoral pulse, crackles on lung auscultation, and a heart murmur that may be accompanied by a systolic click. In severe MR, a palpable precordial thrill may be present.

Differential diagnoses for MMVD include other causes of heart murmurs and CHF in dogs. These include: 1) Dilated cardiomyopathy (DCM) – typically affects large breed dogs, with a soft murmur or gallop rhythm, and echocardiography shows severe left ventricular dilation and systolic dysfunction. 2) Chronic degenerative mitral valve disease in other breeds – similar but less common. 3) Infective endocarditis – usually presents with fever, lethargy, and a changing murmur; blood cultures and echocardiography may reveal vegetative lesions. 4) Congenital heart diseases, such as patent ductus arteriosus (PDA) – continuous murmur, bounding pulses, and echocardiography can identify the shunt. 5) Tricuspid valve dysplasia – right-sided murmur, ascites, and echocardiographic abnormalities of the tricuspid valve. 6) Pulmonary hypertension – may cause a split S2, right-sided murmur, and echocardiographic evidence of elevated pulmonary artery pressure. 7) Systemic hypertension – may cause a murmur and left ventricular hypertrophy; blood pressure measurement is essential. 8) Anemia – can cause a functional murmur due to decreased blood viscosity. 9) Physiologic murmurs – common in young dogs, but less likely in older dogs. Definitive diagnosis relies on echocardiography, which can differentiate these conditions.

The diagnostic algorithm for MMVD begins with a thorough history and physical examination, with particular attention to the cardiac auscultation. If a systolic murmur is detected at the left apex, the next step is thoracic radiography to assess heart size and pulmonary vasculature. Radiographic findings may include left atrial enlargement (seen as a bulge in the caudal cardiac silhouette), left ventricular enlargement, and pulmonary edema in CHF. If radiographs are inconclusive or if the dog is symptomatic, echocardiography is the gold standard for diagnosis and staging. Echocardiography confirms the presence of myxomatous valve thickening, prolapse, and MR, and quantifies chamber enlargement. The ACVIM staging system (A, B1, B2, C, D) is based on clinical signs and echocardiographic findings. Stage B2 is defined by the presence of left atrial and ventricular enlargement on echocardiography, with a vertebral heart score (VHS) >10.5 on radiographs. Additional tests may include blood pressure measurement to rule out systemic hypertension, and NT-proBNP levels to assess cardiac stress. In cases of suspected CHF, thoracic radiography is essential to confirm pulmonary edema. Advanced imaging such as CT or MRI is rarely needed but may be used for surgical planning in cases of valve repair.

Laboratory findings in MMVD are often unremarkable in early stages. In advanced stages, especially with CHF, there may be evidence of prerenal azotemia due to decreased cardiac output and reduced renal perfusion. Serum biochemistry may show elevated liver enzymes (ALT, ALP) due to hepatic congestion. NT-proBNP is a useful biomarker; elevated levels (>800 pmol/L) are associated with CHF and can help differentiate cardiac from respiratory causes of dyspnea. Cardiac troponin I may be elevated in cases of myocardial injury, but is not specific. In dogs with CHF, arterial blood gas analysis may reveal hypoxemia and respiratory alkalosis. Urinalysis is typically normal, but proteinuria may be present in dogs with concurrent chronic kidney disease. Complete blood count is usually normal, but may show stress leukogram. In dogs with right-sided heart failure, liver enzymes may be markedly elevated, and ascites fluid analysis may reveal a modified transudate.

Thoracic radiography is the primary imaging modality for assessing MMVD. Findings include left atrial enlargement, which is best seen on the dorsoventral view as a bulge in the caudal cardiac silhouette, and on the lateral view as an increased angle between the trachea and the mainstem bronchus. Left ventricular enlargement is seen as an increased cardiac silhouette, with a vertebral heart score (VHS) >10.5. In CHF, interstitial or alveolar pulmonary edema is present, typically in the perihilar region. Echocardiography is the gold standard for diagnosis and staging. Two-dimensional echocardiography reveals thickened, nodular mitral valve leaflets, with prolapse into the left atrium. Color flow Doppler demonstrates MR, and pulse wave Doppler can assess the severity of regurgitation. Left atrial and ventricular dimensions are measured, and the left atrial to aortic root ratio (LA/Ao) is calculated; an LA/Ao >1.6 indicates significant enlargement. Advanced imaging such as CT or MRI is rarely needed but may be used for surgical planning in cases of valve repair.

Cytology and histopathology are not typically performed for the diagnosis of MMVD, as the disease is diagnosed based on clinical and echocardiographic findings. However, if a valve is examined histopathologically, it shows myxomatous degeneration with accumulation of glycosaminoglycans and proteoglycans in the spongiosa layer, disruption of collagen fibers, and fibrosis. The valve leaflets are thickened and nodular. In advanced cases, there may be areas of calcification. These findings are characteristic of endocardiosis. Cytology is not applicable, as the disease is not characterized by an inflammatory or neoplastic process.

Treatment of MMVD depends on the stage of the disease. In Stage B1 (asymptomatic with no cardiomegaly), no treatment is indicated, but regular monitoring is recommended. In Stage B2 (asymptomatic with cardiomegaly), the ACVIM consensus recommends the use of pimobendan (0.25-0.3 mg/kg PO q12h) to delay the onset of CHF. In Stage C (CHF), treatment includes diuretics (furosemide 2-4 mg/kg PO/IV q8-12h, titrated to effect), pimobendan, and an ACE inhibitor (enalapril 0.5 mg/kg PO q12h or benazepril 0.25-0.5 mg/kg PO q24h). Spironolactone (2 mg/kg PO q24h) may be added for its aldosterone antagonist effects. In refractory cases (Stage D), additional diuretics such as torsemide (0.1-0.3 mg/kg PO q24h) may be used, and other vasodilators like hydralazine (0.5-2 mg/kg PO q12h) or amlodipine (0.05-0.1 mg/kg PO q24h) may be considered. In acute CHF, oxygen therapy, furosemide IV, and nitroglycerin paste (0.25-0.5 inch q6-8h) are used. Surgical intervention, such as mitral valve repair or replacement, is an option in select cases but is not widely available. Dietary management includes a low-sodium diet in CHF. Exercise restriction is recommended in symptomatic dogs.

The prognosis for MMVD varies widely. Dogs in Stage B1 have a good prognosis, with many living for years without developing CHF. The median survival time for dogs in Stage B2 treated with pimobendan is approximately 15 months, compared to 9 months for placebo. Once CHF develops (Stage C), the median survival time is approximately 9-12 months with appropriate therapy. Dogs in Stage D have a poorer prognosis, with a median survival of 6 months or less. Negative prognostic indicators include severe left atrial enlargement (LA/Ao >2.0), high NT-proBNP levels, presence of pulmonary hypertension, and lack of response to initial therapy. The disease is progressive, but with appropriate management, many dogs can maintain a good quality of life for an extended period.

Follow-up for MMVD depends on the stage. Dogs in Stage B1 should be re-examined every 6-12 months, including physical examination and possibly echocardiography to monitor progression. Dogs in Stage B2 should be re-evaluated every 3-6 months, with echocardiography to assess for progression to CHF. Dogs in Stage C or D require more frequent monitoring, initially every 1-2 weeks until stabilized, then every 1-3 months. Monitoring includes physical examination, body weight, thoracic radiographs to assess pulmonary edema, and echocardiography to assess cardiac remodeling. Serum biochemistry and NT-proBNP may be measured periodically. Drug dosages, particularly furosemide, should be adjusted based on clinical signs and renal function. Owners should be educated to monitor respiratory rate at home; an increase in resting respiratory rate >30 breaths per minute may indicate impending CHF.

Pearls: 1) A left apical systolic murmur in a small breed dog over 8 years old is highly suggestive of MMVD. 2) In asymptomatic dogs with a murmur, thoracic radiographs and echocardiography are essential to stage the disease and determine if treatment is needed. 3) Pimobendan is the only drug proven to delay the onset of CHF in Stage B2 dogs. 4) In acute CHF, furosemide IV is the first-line treatment; administer 2-4 mg/kg IV, and repeat as needed. 5) Home monitoring of resting respiratory rate is a valuable tool for early detection of CHF. Pitfalls: 1) Do not start treatment in Stage B1 dogs, as it is not beneficial and may cause side effects. 2) Avoid overuse of furosemide, which can lead to azotemia and electrolyte imbalances. 3) Do not use ACE inhibitors alone in Stage B2; pimobendan is the preferred first-line therapy. 4) Be cautious with the use of NSAIDs in dogs with CHF, as they can cause fluid retention and worsen heart failure. 5) Do not forget to rule out other causes of cough, such as respiratory disease, in dogs with MMVD.

Based on Plumb's Veterinary Drug Handbook, the following drug protocols are recommended for MMVD: 1) Pimobendan: 0.25-0.3 mg/kg PO q12h, given 1 hour before food. It is used in Stage B2, C, and D. It is contraindicated in hypertrophic cardiomyopathy. 2) Furosemide: 2-4 mg/kg PO/IV/SC q8-12h, titrated to the lowest effective dose. In acute CHF, 2-4 mg/kg IV, may repeat q1-2h until respiratory rate improves. 3) Enalapril: 0.5 mg/kg PO q12h, or Benazepril: 0.25-0.5 mg/kg PO q24h. ACE inhibitors are used in Stage C and D. 4) Spironolactone: 2 mg/kg PO q24h, used in Stage C and D. 5) Torsemide: 0.1-0.3 mg/kg PO q24h, used in refractory CHF. 6) Hydralazine: 0.5-2 mg/kg PO q12h, used as an arteriodilator in refractory CHF. 7) Amlodipine: 0.05-0.1 mg/kg PO q24h, used for systemic hypertension or as a vasodilator. 8) Nitroglycerin paste: 0.25-0.5 inch topically q6-8h, used in acute CHF. 9) Oxygen therapy: 40-60% inspired oxygen in acute CHF. 10) In cases of atrial fibrillation, digoxin (0.005-0.01 mg/kg PO q12h) or diltiazem (0.5-1.5 mg/kg PO q8h) may be used. Dosages should be adjusted for renal or hepatic impairment, and drug interactions should be considered, particularly with diuretics and ACE inhibitors.

The evidence base for MMVD management is robust. The EPIC study (2016) demonstrated that pimobendan significantly delays the onset of CHF in Stage B2 dogs, with a median time to CHF of 1228 days vs. 766 days for placebo. The QUEST study (2008) showed that pimobendan is superior to benazepril in dogs with CHF due to MMVD, with a median survival of 267 days vs. 140 days. The ACVIM consensus statement on MMVD (2019) provides evidence-based guidelines for staging and treatment. Other studies have evaluated the use of ACE inhibitors, spironolactone, and torsemide. The use of NT-proBNP as a biomarker has been validated in multiple studies. Overall, the literature supports the use of pimobendan as the cornerstone of therapy, with diuretics and ACE inhibitors as adjuncts in CHF.