STANDARDS of CARE. Canine idiopathic dilated cardiomyopathy (DCM) is a primary EMERGENCY AND CRITICAL CARE MEDICINE CANINE DILATED CARDIOMYOPATHY

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1 Visit us at APRIL 2003 VOL 5.3 STANDARDS of CARE EMERGENCY AND CRITICAL CARE MEDICINE FROM THE PUBLISHER OF COMPENDIUM CANINE DILATED CARDIOMYOPATHY Bruce G. Kornreich, DVM, DACVIM (Cardiology) Department of Molecular Medicine Cornell University Ithaca, New York Canine idiopathic dilated cardiomyopathy (DCM) is a primary myocardial disease characterized by cardiac chamber dilation and systolic and diastolic dysfunction of one or both ventricles. Although these characteristics may be observed in a variety of (secondary) cardiac disease states in dogs, the term DCM is reserved for situations in which etiology cannot be determined. In this respect, DCM is a diagnosis achieved via exclusion of other known causes of cardiac chamber dilation and diminished systolic and diastolic function. The overall prevalence of canine DCM has been established to be between 0.5% and 1.1%, although this value may be increasing due to the popularity of certain predisposed breeds and increased awareness by veterinary clinicians. The prevalence of DCM is highest in large- and giant-breed purebred dogs, and certain breeds are predisposed, including the Doberman pinscher, Great Dane, Irish wolfhound, and the boxer. Geographic variation in prevalence among breeds has been demonstrated by large-scale studies. A significant exception to the increased prevalence of DCM in large- and giant-breed dogs is the relatively high prevalence in the cocker spaniel. Although the etiology of DCM remains unknown, a number of potential causes have been proposed, including inherited and spontaneous abnormalities of myocardial structural, mitochondrial, and ion channel proteins; nutritional deficiencies; infectious diseases; immune-mediated diseases; drugs; toxins; metabolic disorders; and prolonged tachycardias. Gross pathologic findings in DCM include dilation of one or more cardiac chambers, increased heart weight to body weight ratio, and decreased ratio of left ventricular wall thickness to chamber diameter. Histologic findings include foci of myocytolysis, myocyte vacuolization, myocardial degeneration and necrosis, and attenuated, wavy myofibers. Minimal evidence of inflammatory lesions is seen. The primary pathophysiologic effect of DCM on the whole-animal level is diminished ventricular systolic function, evident in decreased indices of ventricular contractility and increased end diastolic and systolic volume. Diastolic function may also manifest as decreased ventricular compliance Questions? Comments? soc.vls@medimedia.com, fax , or post on the Feedback page at and relaxation. Dyspnea, coughing, and tachypnea arise in DCM patients from left-sided congestive failure secondary to elevated end diastolic left ventricular, left atrial, and pulmonary venous pressures. Clinical signs of decreased cardiac output may include weakness, syncope, exercise intolerance, and cardiogenic shock. An important variant of DCM is the occult or subclinical form in which the patient exhibits minimal or no overt clinical signs consistent with myocardial failure or pathologic arrhythmia. This form of the disease has perhaps received the most attention in Doberman pinschers, and recent studies have begun to outline risk factors for those dogs at risk of developing overt heart failure or fatal arrhythmia. Doberman pinschers have been shown to have a diminished fractional shortening and increased incidence of ventricular and supraventricular arrhythmias when compared to other breeds and have also been shown to be at increased risk of developing CHF and to die suddenly. Inside this issue: Peer-Reviewed Articles on 1 Canine Dilated Cardiomyopathy 6 Canine Bradyarrhythmias 10 Back Issue Index 1

2 DIAGNOSTIC CRITERIA Historical Information Gender Predisposition: No gender predisposition has been verified across all species. Some have suggested a male predisposition for Doberman pinschers and Dalmatians with DCM. Age Predisposition: DCM is usually diagnosed in dogs 4 to 10 years of age. Portuguese water dogs may be diagnosed at a much younger age (2 to 32 weeks of age). Breed Predisposition: Doberman pinschers, Irish wolfhounds, Great Danes, boxers, Newfoundlands, Scottish deerhounds, Portuguese water dogs, golden retrievers, and Dalmatians have increased prevalence of DCM. Large- and giant-breed dogs are more likely to be diagnosed, with the significant exception of the cocker spaniel. Significant geographic variation in breed prevalence may exist. Owner Observations: Owners may notice coughing, dyspnea, lethargy, exercise intolerance, and/or syncope. Physical Examination Findings Weak, rapid (± irregular) femoral pulses Systolic atrioventricular (AV) valve murmur(s) (usually 1 to 3/6) Crackles, rales, and/or prominent bronchovesicular sounds S 3 gallop (may be intermittent depending on cardiac rhythm) Jugular pulses and/or hepatomegaly Cardiac cachexia and/or weight loss KEY TO COSTS $ indicates relative costs of any diagnostic and treatment regimens listed. $ costs under $250 $$ costs between $250 $500 $$$ costs between $500 $1000 $$$$ costs over $1000 Laboratory Findings Increased alanine transaminase Increased aspartate transaminase Mild hypoglobulinemia Mildly increased blood urea nitrogen Mildly increased serum creatinine Mild hyponatremia Mild to moderate hyperkalemia with hyponatremia (rare) Moderate lymphopenia Moderate neutrophilia Other Diagnostic Findings Echocardiography (gold standard) $ Increased left ventricular end systolic diameter Increased left ventricular end diastolic diameter Decreased fractional shortening Decreased peak acceleration of aortic flow Decreased time to peak acceleration of aortic flow Mitral regurgitation and left atrial dilation (often) ± right ventricular and right atrial dilation Decreased Systolic Function Decreased velocity of circumferential fiber shortening Decreased ejection fraction Decreased ejection time Increased E point to septal separation Increased preejection period Decreased Diastolic Function Prolonged isovolumic relaxation time Increased E/A wave ratio Electrocardiography $ Note: It is prudent to perform 24-hour ambulatory (Holter) electrocardiography on suspected or documented DCM patients. Increased R wave amplitude Widened QRS complex S T slurring Increased P wave duration and/or amplitude APRIL 2003 VOL 5.3 STANDARDS of CARE EMERGENCY AND CRITICAL CARE MEDICINE Editorial Mission: To provide busy practitioners with concise, peer-reviewed recommendations on current treatment standards drawn from published veterinary medical literature. This publication acknowledges that standards may vary according to individual experience and practices or regional differences. The publisher is not responsible for author errors. Compendium s Standards of Care: Emergency and Critical Care Medicine is published 11 times yearly (January/February is a combined issue) by Veterinary Learning Systems, 780 Township Line Road, Yardley, PA The annual subscription rate is $69. For subscription information, call , fax , soc.vls@medimedia.com, or visit Copyright 2003, Veterinary Learning Systems. Executive Series Editor Richard B. Ford, DVM, MS Editor in Chief Beth Thompson, VMD Editorial Staff Lilliane Anstee, Editorial Director Perri Stark, VMD, Editorial Consultant Cynthia Laufenberg, Managing Editor Chris Reilly, Editorial Assistant Creative Director Sue Wiedorn Art Studio Manager Bethany L. Wakeley Editorial Review Board Nishi Dhupa, DVM, DACVECC Angell Memorial Hospital Cynthia Otto, DVM, DACVECC University of Pennsylvania Mark Rubash, DVM, DACVECC Houston, Texas Gregory Grauer, DVM, MS, DACVIM (Internal Medicine) Kansas State University Thomas Schermerhorn, VMD, DACVIM (Internal Medicine) Kansas State University 2 A P R I L V O L U M E 5. 3

3 TABLE 1 Cardiovascular Therapeutics and Their Physiologic Benefits in Canine DCM Compound Furosemide Spironolactone Chlorothiazide Sodium nitroprusside Dobutamine Enalapril Benazapril Digoxin Atenolol Diltiazem Lidocaine Mexiletine Procainamide Atrial Fibrillation (often) Ventricular premature complexes/ ventricular tachycardia (VT) (especially Doberman pinschers and boxers) Radiography $ Generalized cardiomegaly Left atrial enlargement Perihilar to diffuse bronchointerstitial to alveolar pulmonary parenchymal pattern (pulmonary edema) Dilated caudal vena cava Hepatomegaly Ascites/pleural effusion Summary of Diagnostic Criteria Echocardiographic evidence of Physiologic Benefit Decrease ventricular afterload Increase ventricular contractility Decrease preload/afterload Decrease preload/afterload Increase ventricular contractility Adjunct for refractory ventricular arrhythmias Normalize cardiac beta receptors Improve diastolic dysfunction (?) Sotalol (?) Carvedilol Normalize cardiac beta receptors (?) Decrease ventricular afterload (?) SVT = Supraventricular tachycardia? = Effect/benefit controversial univentricular or biventricular dilation with systolic and diastolic dysfunction of unknown cause (left ventricle more common); this is the gold standard of diagnosis. Echocardiographic evidence of uniatrial or biatrial dilation (left atrium more common) Thoracic radiographic evidence of pericardiomegaly with or without evidence of left atrial enlargement and congestive heart failure Electrocardiographic documentation of increased R-wave amplitude, increased P-wave amplitude and/or duration, S T slurring, and sinus tachycardia ± atrial fibrillation, ventricular premature complexes, and/or ventricular tachycardia Weak, rapid (± irregular) femoral pulses, S 3 gallop, and systolic AV regurgitant murmur Occult form may present with only ventricular ectopy and minimal to no evidence of systolic and diastolic dysfunction (especially Doberman pinschers and boxers). Differential Diagnoses Chronic AV valve regurgitation with volume overload; rule out via history (valvular regurgitation often chronic, secondary to endocardiosis) and echocardiographic evidence of valvular regurgitation and determination of systolic/diastolic function. Pericardial effusion; rule out via echocardiography. Iatrogenic (i.e., doxorubicin, beta/calcium channel blockers); rule out via medical history. Infectious myocarditis; rule out via appropriate diagnostics for organism (i.e., Lyme disease). TREATMENT RECOMMENDATIONS Initial Treatment Acute, Severe Congestive Heart Failure (CHF) Furosemide: 6 to 8 mg/kg IV q4h for 12 hours; then decrease to lowest dose that maintains respiratory rate below 30 breaths/minute. Alternatively, 2 to 4 mg/kg IV at 1- to 2-hour intervals until a response is demonstrated. $ Sodium nitroprusside: 2.5 to 10 µg/kg/min IV constant rate infusion (CRI) in combination with furosemide (severe cases). Titrate to effect; maintain mean blood pressure above 70 mmhg. $ Oxygen supplementation $ Dobutamine: 2.5 to 5 µg/kg/min IV CRI in combination with diuretic/vasodilator with extreme systolic dysfunction; increase in 2.5 µg/kg/min increments until maximum dose of 15 µg/kg/min or excessive tachycardia/ventricular STANDARDS of CARE: EMERGENCY AND CRITICAL CARE MEDICINE 3

4 ectopy; do not use simultaneously with sodium nitroprusside. $ Begin oral diuretics/vasodilators once IV medication is discontinued (see below). Chronic CHF Furosemide: Lowest dose that maintains eupnea (usually 1 to 4 mg/kg PO bid to tid) Angiotensin converting enzyme inhibitor (ACEI): In combination with diuretic Enalapril: 0.25 to 0.5 mg/kg PO sid to bid $ Benazepril: 0.25 to 0.5 mg/kg PO sid to bid; ± preferred with renal disease $ Digoxin: In combination with diuretics/acei in most cases to 0.01 mg/kg PO bid; titrate to therapeutic range (1 to 2.4 ng/ml) Taurine and carnitine supplementation: In cocker spaniels and possibly golden retrievers, see Alternative/Optional Treatments/Therapy. Arrhythmias Treat atrial fibrillation/flutter/ tachycardia with ventricular response rates above 160 bpm with digoxin, to 0.01 mg/kg PO bid; target ventricular rate is 120 to 140 bpm; rapid IV digitalization may be attempted but may be associated with increased proarrhythmia; maximum dose in Doberman pinschers is 0.25 mg PO bid. $ Diltiazem: 1 to 1.5 mg/kg PO bid or atenolol 12.5 mg PO sid to start with large dogs; used in combination with digoxin if inadequate rate control with digoxin monotherapy; use caution with beta blockers (acute bradycardia and decreased cardiac output); titrate beta blockers to effect in 25% dosage increments. $ Ventricular arrhythmias treated if frequent/rapid enough to cause debilitation (i.e., sustained ventricular tachyardia [VT], VT rate >200 bpm); start with lidocaine 2 mg/kg boluses to maximum dose of 8 mg/kg over a 5-minute period, then 25 to 80 µg/kg/min IV CRI at lowest dose that controls ectopy. Mexiletine 4 to 8 mg/kg PO bid to tid may be efficacious if ectopy is lidocaine responsive. $ Procainamide: 5 to 15 mg/kg IV bolus (slow); titrate to effect; 25 to 50 µg/kg/min IV CRI if effective; attempt if no response to lidocaine; 10 to 20 mg/kg PO qid (tid with sustained-release formulation) may be instituted once IV discontinued; beta blocker may be added to control ectopy in refractory cases. $ Sotalol: 1 to 2 mg/kg PO bid may be effective in some cases; titrate dose upward to effect. $ Alternative/Optional Treatments/Therapy Carnitine: 50 to 100 mg/kg PO tid; use L-carnitine (controversial); controversial benefit, however risk/benefit favorable; use in combination with standard therapy. $ Taurine: 500 mg PO bid (cocker spaniels), up to 1,500 mg PO bid to tid for large and giant breeds; controversial benefit but shows promise, risk/benefit favorable, especially in cocker spaniels and Portuguese water dogs; use in combination with standard therapy ± carnitine. $ Pimobendan: 0.3 to 0.6 mg/kg PO/day; controversial benefit; use in combination with standard therapy; not FDA approved in the United States. $ ON THE NEWS FRONT Beta blockers (i.e., carvedilol): Controversial benefit; risk/benefit may be significant; some promise in human studies; not for use in decompensated patients. Sequential nephron blockade Spironolactone: 1 to 2 mg/kg PO bid; use in combination with standard therapy; potassium sparing. $ Chlorothiazide: 10 to 20 mg/kg PO bid; use in combination with standard therapy. $ Supportive Treatment Moderately sodium-restricted diet Ensure adequate caloric intake (increased metabolic demand with CHF). Exercise restriction Patient Monitoring Monitor respiratory rate. Monitor heart rate. Monitor weight. Perform periodic rechecks for physical examination, serum biochemistry (if receiving diuretics and/or ACEI), serum digoxin level (8 to 12 hours after the last dose if receiving digoxin therapy), thoracic radiography, and six lead electrocardiogram ± Holter monitor (especially with arrhythmias). Milestones/Recovery Time Frames Eupnea Respiratory rate < 30 breaths/min Improved strength/endurance Improved appetite Although not yet approved for use in veterinary patients in the United States, a recent, double-blind, randomized, placebo-controlled study showed that the phosphodiesterase III inhibitor/calcium sensitizer pimobendan improved New York Heart Association functional heart failure class in both Doberman pinschers and English cocker spaniels and increased survival time in Doberman pinschers when added to standard therapy with furosemide, enalapril, and digoxin. 4 A P R I L V O L U M E 5. 3

5 CHECKPOINT The detection of and therapy for asymptomatic or occult DCM is a topic of debate among veterinary cardiologists and researchers. Proposed diagnostic tests include Holter monitoring, measurement of adrenoreceptor density on circulating lymphocytes, and measurement of circulating atrial natriuretic peptide and/or brain natriuretic peptide. It is unclear whether therapy with ACE inhibitors and/or beta-blockers provides a therapeutic benefit in canine patients, but studies to address these important issues are ongoing. Treatment Contraindications Avoid negative inotropic agents (± except low-dose beta blockers in stabilized patients). Avoid overzealous IV fluid administration. Avoid anesthesia if possible. Avoid potentially proarrhythmic drugs. PROGNOSIS DCM is always fatal, although survival times may vary considerably among canine patients. Due to inconsistencies in studies addressing this issue, it is difficult to provide definitive guidelines for prognosis. The following, however, are extracted from recent studies: Favorable Criteria Age greater than 5 years Improved systolic function on echocardiogram in response to taurine/carnitine Unfavorable Criteria Dyspnea at presentation Ascites at presentation Doberman pinscher (compared with other breeds) Atrial fibrillation at presentation Pulmonary edema at presentation History of syncopal episodes at presentation Ventricular arrhythmias at presentation RECOMMENDED READING Borgarelli M, Tarducci A, Tidholm A, Haggstrom J: Canine idiopathic dilated cardiomyopathy. Part II: Pathophysiology and therapy. Vet J 162(3): , Elliot J, Marr CM: Understanding the pathophysiology is the key to novel therapies for canine dilated cardiomyopathy. Vet J 162(3): , Fuentes VL, Corcoran V, French A, et al: A double-blind, randomized, placebocontrolled study of pimobendan in dogs with dilated cardiomyopathy. J Vet Intern Med 16(3): , Plumb DC: Veterinary Drug Handbook. Ames, Iowa, Iowa State Press, Sisson D, O Grady MR, Calvert CA: Myocardial diseases of dogs, in Fox P, Sisson D, Moise NS (eds): Textbook of Canine and Feline Cardiology: Principles and Clinical Practice. Philadelphia, WB Saunders, 1999, pp STANDARDS of CARE: EMERGENCY AND CRITICAL CARE MEDICINE 5