Canine Degenerative Mitral Valve Disease Christian Weder DVM, MS, DACVIM (Cardiology) Great Lakes Veterinary Conference

Introduction Degenerative mitral valve disease (DMVD) is the most common form of acquired in dogs and accounts for approximately 75% of cases of heart disease in the species.1 It is also referred to as chronic valvular heart disease (CVHD), endocardiosis, and myxomatous mitral valve disease (MMVD) in the veterinary literature. While the disease is more commonly diagnosed in small breeds, it can also occur in large dogs. DMVD primarily affects the mitral valve, although approximately 30% of cases have concurrent disease of the tricuspid valve and a smaller proportion have lesions of the aortic valve.2 Males are 1.5 times more likely to develop the disease and often have a younger age of onset.3

DMVD is a form of acquired heart disease that often develops in dogs older than 5 years of age. With that said, Cavalier King Charles Spaniels are predisposed to developing DMVD at a younger age.4 The cause of DMVD is unknown, however, there is undoubtedly a heritable component in many breeds. It is typically recognized by the presence of a systolic over the left cardiac apex. The disease progression is generally slow, although the exact clinical course is often variable and difficult to predict. As dogs age, the prevalence of DMVD increases, with 85% of small breeds showing evidence of valvular lesions by 13 years.5

Classification In 2009, guidelines for the diagnosis and treatment of DMVD were published in the Journal of Veterinary Internal Medicine.2 An update to these guidelines was published in 2019.1 The guidelines provide a useful consensus and structure for the management of DMVD in practice. The staging system outline by the consensus panel describes 4 basic stages of DMVD in dogs and is summarized below.

Stage A Patients with stage A DMVD are at higher than average risk for developing heart failure but do not have any apparent structural abnormality at the time of examination. These patients are identified by the absence of an audible heart murmur. For example, every Cavalier King Charles without a murmur is classified into this stage of DMVD. While the author does not find this stage to be particularly useful, it may justify more frequent screenings and careful , particularly with increasing age. Dog shows and other breed sponsored events with a board-certified cardiologist provide additional screening opportunities for these patients. As these dogs have no evidence of overt disease, no drug therapy or dietary modifications are recommended for stage A DMVD. Repeat screenings should be considered every 6-12 months.

Stage B Stage B refers to dogs with a structural abnormality typical of DMVD but that have never had clinical signs of heart failure. These are patients with a typical left apical systolic murmur but do not have a history of a cardiogenic cough and have a normal respiratory history. Stage B DMVD is typically recognized during routine health exams. Because of the importance of this stage, it is subclassified into B1 and B2, as outlined below. Thoracic radiographs, blood pressure measurement, and echocardiography are recommended in all patients, once a heart murmur is identified. If the client is unable to pursue an echocardiogram, thoracic radiography can be used as the primary diagnostic tool in these patients. Stage B1: Patients with a hemodynamically insignificant amount of valvular regurgitation as assessed through thoracic radiography and/or echocardiography. Stage B1 is characterized by a spectrum of findings that can range from normal left ventricular and left atrial dimensions to evidence of mild chamber enlargement that does not meet the criteria outlined for stage B2. If thoracic radiographs are performed, the vertebral heart score (VHS) should be used to establish a normal cardiac silhouette size.6 If using the VHS, always remember to check for breed specific reference ranges. If no clear cardiac enlargement is established on diagnostics, no drug therapy or dietary modifications are recommended. Recheck imaging is recommended in 6-12 months to primarily assess for progressive cardiomegaly.

Stage B2: Patients with a hemodynamically significant amount of valvular regurgitation. Dogs with stage B2 DMVD are asymptomatic but have severe enough valvular regurgitation to cause significant enough cardiac remodeling that justifies treatment. These patients have murmur intensities of a grade 3 or higher, moderate left ventricular and left atrial enlargement, as well as an increased VHS. There are specific cut- offs for the left ventricular and left atrial dimensions that have been published in the EPIC trial.7 If these specific criteria are met, treatment with pimobendan is recommended at a dosage of 0.25-0.3mg/kg PO q12. There is no clear consensus on the use of angiotensin converting enzyme inhibitors (ACEi) in dogs prior to the onset of congestive heart failure. The author tends to use ACEi in the presence of concurrent systemic hypertension and/or progressive increase in the left atrial dimension on successful monitoring exams. Recheck imaging is recommended every 6-9 months or at the time clinical symptoms develop.

Stage C Stage C DMVD refers to patients that have current or past clinical signs of congestive heart failure (CHF) but are not refractory to standard therapy. Common clinical signs of include coughing, tachypnea, dyspnea, and restlessness. It is important to note that not every dog that is coughing with a murmur typical of DMVD is in congestive heart failure. Therefore, it is important to differentiate coughing that is due to CHF from that which is due to a primary respiratory etiology (tracheal disease, bronchitis, etc.). Thoracic radiography is the test of choice for definitively determining the presence or absence of pulmonary edema secondary to CHF. While echocardiography is helpful in supporting the diagnosis of CHF and can identify comorbidities, it does not allow for definitive assessment of the pulmonary parenchyma. Basic laboratory testing is indicated in all patients, primarily to evaluated renal function prior to the use of diuretics. Treatment recommendations for stage C can be classified into acute (hospital-based) and chronic (home-based) strategies. Acute Treatment: For the acute treatment of congestive heart failure, the acronym FONS+P can be used. F refers to furosemide, the primary medication used to clear pulmonary edema. The author typically uses a starting bolus of 2mg/kg (range 1-4mg/kg), ideally given via the IV route (or IM). Repeat 2mg/kg boluses can be administered hourly, however, a total dosage of great than 8mg/kg in 4-hour period should be avoided. For life-threatening pulmonary edema, a constant rate infusion of furosemide (0.66-1mg/kg/hr) can also be used following the initial bolus. Supplemental oxygen (O), if needed, should be administered. Although less commonly used, vasodilatory agents can also be considered. Nitroglycerin (N) is a venodilator that can be administered as a paste (1/2” paste per 10kg BW on pinna of ear) to decrease preload. Nitroprusside is a veno- and arteriodilator that is typically reserved for dogs with profound concurrent systemic hypertension. Anxiety associated with dyspnea should be treated with sedation (S). The author typically administers butorphanol at 0.2mg/kg IV, however, other agents such as buprenorphine, morphine, and low dose acepromazine can be used. Finally, if the patient can take oral medications, pimobendan (P) should also be administered in the acute setting (0.25-0.3mg/kg PO). Proper and optimal nursing care is also important to maintain patient comfort and temperature during treatment. Mechanical treatments (abdominocentesis and/or thoracocentesis) should be performed, as needed to relieve effusions

Chronic Treatment: Once a patient has been successfully treated for CHF acutely (if necessary), they should be transitioned to oral medications for home-based care. Furosemide should be administered to effect, but the author typically uses a starting dose of 2mg/kg BID. For recurrent episodes of CHF, dose increases in furosemide are recommended. An ACE inhibitor should be started or continued. The author typically uses enalapril 0.5mg/kg BID, although benazepril is also commonly prescribed. Pimobendan should also be started or continued (0.25-0.3mg/kg BID). Finally, spironolactone (2 mg/kg SID-BID) should also be started after the onset of congestive heart failure. Recheck bloodwork (primarily renal values and electrolytes) is imperative and should be performed 3-14 days after initiating therapy (exact time depends on baseline renal function). If significant alternations in renal values are noted, dose reduction(s) should be considered.

Stage D Stage D DMVD refers to patients with clinical signs that are refractory to standard therapy for stage C. Dogs with this stage of disease typically require a total daily dose of furosemide greater than 8mg/kg/day, in addition to the other standard medications outlined above. Any arrhythmia that is present (i.e. atrial fibrillation, etc.) should be controlled prior to deeming a patient to be refractory. Three times daily dosing of furosemide and pimobendan should be considered in this stage. Torsemide, a potent long-acting loop diuretic, is becoming more common and can replace furosemide in dogs that have become refractory to its effects. Torsemide is approximately 10x as potent as furosemide and, therefore, is typically dosed at approximately 5-10% of the current total daily dose of furosemide.8 Careful monitoring of renal values is recommended as the risk of developing azotemia increased with higher dose diuretic use. Other treatments for patients with stage D DMVD include more vigorous afterload reduction using amlodipine, sildenafil for , and the addition of hydrochlorothiazide for sequential nephron blockade. Cavitary centesis should also be performed, as indicated, to maintain patient comfort. Adjunct therapy for residual coughing can also be considered (see section below).

Additional Treatment Considerations Diet Diet is an important, but often overlooked, aspect in the management of DMVD. Cardiac cachexia or loss of lean muscle or body mass associated with heart failure has been shown to be a substantial negative prognostic indicator for dogs with DMVD.9 Dietary modifications are often made as early as stage B2. Dietary recommendations in this stage should include a mild restriction in sodium intake and a diet with adequate protein and caloric content should be fed.10 The primary goal is to maintain optimal body condition. If a patient experiences congestive heart failure (stage C DMVD), dietary modifications are strongly recommended. Weight loss often occurs after the onset of CHF so attention should be paid to caloric intake as well as recording accurate body weights at every office visit. Diets should contain adequate protein to maintain muscle mass and low protein diets such as those for chronic kidney disease should be avoided. There should be a modest restriction in sodium content and treats that are high in sodium should be avoided. A very useful resource for both veterinarians and owners is the HeartSmart website through the Cummings Veterinary Medical Center at Tufts University. It provides information on maintain optimal body weight, important nutrients, restricted nutrients, as well as an extensive reduced sodium diet and treat list. For a cardiac specific diet, the author usually recommends the Early Cardiac diet made by Royal Canin or h/d offered by Hills. Although uncommon in dogs, serum potassium should be monitored for the occurrence of hypokalemia. If identified, potassium supplementation (dietary or commercial) should be recommended.

Supplements While there is no available literature investigating the efficacy of supplements in DMVD, the author encourages interested owners to pursue this treatment option. As with any supplement, canine specific dosing and formulations are ideal. As such, the author typically recommends Cardio Strength by VetriSCIENCE. This product is specifically formulated for dogs and includes dosing instructions based on weight. If a patient is experiencing significant weight loss and/or cardiac cachexia, supplementation with omega 3 fatty acids can be helpful.11

Monitoring The author generally advocates for owner participation in at-home monitoring early in the disease process and particularly after the onset of congestive heart failure. This monitoring can include recording body weight, appetite, respiratory rate and heart rate. In fact, an increased respiratory rate is one of the most independent and early predictors of CHF in dogs with both DCM and DMVD.12 The author typically targets a resting respiratory rate <30 breaths/min, although <40/min can also be normal. It is important to have owners establish a normal for each individual patient. Identification of increases above normal has the best predictive value of any variable for clinical decompensation.13 It is important to remind owners that this measurement should be taken when the patient is completely at rest (ideally sleeping) and not in the presence of any stimulation. If atrial fibrillation is diagnosed, at home heart rate monitoring can be quite useful as it is performed without the stress of being in the veterinary office. Palpation of the apical beat with manual counting of the heart rate is often a difficult and unreliable measurement tool, especially for owners. Therefore, devices such as Holter monitors and the AliveCor Kardia device ($99 on Amazon) are often used to provide a more accurate and objective assessment.

Prognosis The prognosis for dogs with DMVD is highly variable. In general, the condition is slowly progressive and most dogs that are affected are clinically asymptomatic for long periods of time. However, approximately 30% of dogs with DMVD will progress to congestive heart failure and die as a consequence of their heart disease. The prognosis for dogs with stage B disease is variable as many of these patients will not progress to congestive heart failure. Dogs with significant left atrial enlargement and/or progressive dilation on subsequent exams are deemed to be at some risk for the development of heart failure in the future. Whereas dogs with stable left sided dimensions can often remain as such for the duration of their lives. If a dog progresses to congestive heart failure, the average prognosis is 1-1.5 years with appropriate medical management. These patients often have a good quality of life for this time period and owners typically report a high level of satisfaction. The prognosis for stage D is often considered poor to grave with many dogs only living months after they become refractory to standard care. With that said, recent surgical advancements have provided a viable definitive treatment option that can drastically improve the prognosis associated with DMVD (see below).

Arrhythmias Clinically significant arrhythmias are relatively uncommon in small breed dogs with DMVD, however, they do occur. Isolated atrial premature contractions (APCs) can occur but often do not require any specific treatment as they do not pose a hemodynamic risk to the patient. Ventricular premature contractions (VPCs) can also occur but are less common than in larger breed dogs. If VPCs are present, a Holter monitor should be considered to help guide therapeutic recommendations. Sotalol (1-2mg/kg BID) is the most common ventricular anti-arrhythmic, however, it is not often prescribed in small breed dogs. If prescribed, care should be taken to fully evaluate the extend and severity of the underlying heart disease as sotalol has the potential to be a negative inotrope and, therefore, could result in patient decompensation. Atrial fibrillation (AF) is the most common clinically significant arrhythmia in dogs with DMVD. In the presence of underlying structural abnormalities (i.e. DMVD), dogs with AF often have a rapid ventricular response rate (heart rate often >200/min). Diltiazem is often used as an initial therapy to attempt to obtain heart rate control. Care should be taken to specify the exact formulation of diltiazem as both standard and long acting preparations are commonly prescribed. Digoxin (0.0025-0.005mg/kg PO BID) is often used as an adjunct therapy for AF, if appropriate rate control cannot be obtained with diltiazem alone. Plasma concentrations should be measured if digoxin is used chronically and this drug should be avoided, or dose reduced, in the presence of concurrent renal dysfunction. The author usually targets a resting heart rate of less than 140/min in the hospital for dogs with AF secondary to DMVD.

Systemic Hypertension Similar to DMVD, a consensus statement has been published on guidelines for identification and management of systemic hypertension in dogs and cats.14 Systemic hypertension is an important consideration in dogs with DMVD as it represents an increase in afterload on the left ventricle and can potentially hasten progression of the underlying valve disease. It is important to realize that systemic hypertension in dogs with DMVD is often due to comorbidities and not the underlying heart disease itself. Common secondary causes of systemic hypertension in dogs include kidney disease (acute and chronic), hyperadrenocorticism, diabetes mellitus, obesity, primary hyperaldosteronism, and pheochromocytoma.14 While secondary systemic hypertension is most common, white coat and idiopathic hypertension can also occur. Care should be taken to obtain the most accurate blood pressure measurement in all patients. This includes creating a standard protocol in your practice and taking measures to limit patient stress and anxiety. As blood pressure in dogs and cats can be highly variable and dependent on breed, temperament, patient position, measurement method, and operator experience, it is difficult to determine a “normal” single value and range that is applicable to all dogs. The variables listed above should be taken into account when interpreting any measurement. With that said, when the systolic blood pressure is greater than 160mmHg, there is likely risk of target organ damage (TOD). If there is evidence of TOD on bloodwork, urinalysis (with urine protein:creatinine ratio), ophthalmic or neurologic exams, and/or thoracic radiographs/echocardiography, treatment should be considered. Goals of treatment should be to decrease the systolic blood pressure to less than <140mmHg (optimal or <160mmHg minimal) in an attempt to reduce the likelihood and severity of TOD. If an underlying cause for the hypertension can be identified (secondary hypertension), it should be treated appropriately. For cases of mild hypertension (160- 190mmHg systolic) and especially in the presence of proteinuria, the author usually recommends treatment with an ACE inhibitor. Enalapril (0.5mg/kg BID) is most commonly used. If the blood pressure cannot be controlled with an ACE inhibitor alone or in cases of profound hypertension (>190mmHg systolic), calcium channel blockers are typically added. The author prefers amlodipine (0.1-0.5mg/kg SID). Doses can be increased based on subsequent recheck blood pressure measurements.

Pulmonary Hypertension Pulmonary hypertension (PH) in dogs is usually defined as a pulmonary arterial systolic pressure greater than approximately 30mmHg.15 An estimate of the pulmonary arterial systolic pressure is often obtained during echocardiography (using tricuspid regurgitant velocity). There are many causes of PH in dogs including both pre- and post-capillary etiologies. DMVD is a common post-capillary cause of PH in dogs and the prevalence of PH in DMVD has been estimated to be as high as 53%.16 Furthermore, PH has been shown to be associated with a greater likelihood of CHF and death in Cavalier King Charles spaniels with DMVD.17 Given these facts, the identification and treatment of PH in dogs with DMVD can be an important factor in improving their overall quality of life and survival. Clinical signs that can be associated with PH include syncope, tachypnea, dyspnea, exercise intolerance, and ascites (right sided heart failure). If PH is left untreated, these signs can persist in dogs with DMVD, despite appropriate medical therapy for their valve disease and CHF. If clinically significant PH is diagnosed on echocardiography, sildenafil (1-3mg/kg TID) is added to the treatment protocol. It is important to realize that while PH can be solely secondary to DMVD, many patients have comorbidities that are contributing to their PH. The most common comorbidity is chronic airway disease and, therefore, attempts should be made to optimize treatment of residual coughing (see below), etc., if present.

Chronic Cough While congestive heart failure can cause coughing in dogs with DMVD, it is certainly not the only etiology. In fact, a recent study indicated that CHF is not significantly associated with coughing in dogs with DMVD.18 Instead, tachypnea and dyspnea are the most common presenting complaints for dogs with CHF secondary to DMVD. Unfortunately, small breed dogs that are diagnosed with DMVD are also predisposed to developing concurrent airway disease. This includes tracheal collapse, chronic bronchitis, and bronchomalacia. Significant left atrial enlargement in the absence of pulmonary edema may also contribute to chronic coughing via compression of the trachea and mainstem bronchi. Because of this, it is important to always remember that a chronic cough in a dog with a heart murmur does not necessarily indicate the presence of congestive heart failure and, in fact, is probably unlikely due to active CHF. As such, thoracic radiography is imperative to differentiate coughing due to pulmonary edema and that which can be attributed to a respiratory etiology. If active CHF has been ruled out via thoracic radiographs, treatment of concurrent airway disease is often recommended. With that said, it is important to have owners realize that these dogs often do not have complete resolution of their coughing. Instead, goals of therapy should be aimed at decreasing the frequency and the severity of the cough to a degree that it no longer impacts the dog’s quality of life. Cough suppressants are one of the most commonly used strategies for controlling a chronic, intractable cough in dogs with heart disease. Hydrocodone (0.22mg/kgBID-TID) is the authors preferred cough suppressant. Some dogs can also respond to a course of doxycycline (5mg/kg BID), particularly if there is an infectious component to the signs. While not ideal in the presence of chronic heart disease, short courses of prednisone at an anti-inflammatory dose (0.5-1mg/kg/day tapering course) may be considered. The author has found that steroid treatment at these doses is often well tolerated by patients with DMVD. Finally, bronchodilators (i.e. theophylline) can also be considered, although the author has had limited success with the use of this medication class.

Syncope Syncope is defined as a transient loss of consciousness due to a decreased delivery of essential nutrients (primarily oxygen and/or glucose) to the brain. Syncopal episodes are usually sudden onset, brief in duration, and often have a very quick and complete recovery.19 While somewhat uncommon, dogs with DMVD can present with syncope and it has been associated with an increased risk of death in these patients.20 While syncope in larger breed dogs is often arrhythmic in origin, this does not appear to be the case in smaller dogs with DMVD.19 Syncope in small breed dogs with DMVD is more commonly neurocardiogenic in origin and occurs during times of sympathetic stimulation. In the authors opinion, this form of syncope can often respond well to treatment with pimobendan by augmenting cardiac output and potentially improving cerebral perfusion. Syncope can also occur in the presence of pulmonary edema, so thoracic radiographs should always be considered, especially if respiratory signs are present. Pulmonary hypertension is another common cause of syncope in dogs with DMVD and, if present, can often be palliated via treatment with sildenafil. It is important to also realize that the patient may experiencing and alternative form of syncope unrelated to its DMVD and, therefore, all potential etiologies should be considered. Syncope should also be differentiated from seizures. If an arrhythmia is suspected as the cause of the syncope, a Holter monitor (24-48 hour ambulatory ECG can be performed).

Surgical Repair Definitive treatment of DMVD through surgical intervention is currently available.21 Surgical intervention is ideally performed in dogs with advanced stage B2 or early stage C disease. This procedure has been described in the veterinary literature and typically entails repair of the native mitral valve along with a suture annuloplasty and placement of artificial chordae tendineae under cardiopulmonary bypass.22 It is performed at few centers around the world but does offer effective and long-term durability with acceptably low complication rates. Mitral valve repair is expensive ($20-30k) and is, therefore, quite limited in its availability. However, interested owners can contact the Mighty Hearts Project. Mitral valve replacement via less invasive techniques and without the use of cardiopulmonary bypass is being explored, however, no viable and safe option is currently available.

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