470 Vol. 24, No. 6 June Mississippi State University Damon B. Rodriguez, DVM

Transcription

1 470 Vol. 24, No. 6 June 2002 CE Article #3 (1.5 contact hours) Refereed Peer Review Comments? Questions? compendium@medimedia.com Web: VetLearn.com Fax: KEY FACTS The decision of whether to initiate treatment with a calcium-channel blocker or β-blocker is often debatable but can be made based on physical examination and diagnostic evaluation findings. Angiotensin-converting enzyme (ACE) inhibitors have recently begun to play a role in managing severe or refractory cases of hypertrophic cardiomyopathy. It is important to prevent dehydration when using diuretics, especially in combination with ACE inhibitors. Treatment of Feline Hypertrophic Cardiomyopathy * Mississippi State University Damon B. Rodriguez, DVM Angell Memorial Animal Hospital Boston, Massachusetts Neil Harpster, VMD, DACVIM (Cardiology) ABSTRACT: The treatment of feline hypertrophic cardiomyopathy (HCM) has traditionally involved the use of calcium-channel blockers or β-blockers. Drugs within these two classes are used to slow the heart rate and potentially improve diastolic filling, myocardial relaxation, and oxygenation. Angiotensin-converting enzyme inhibitors are being used more commonly to treat cats with HCM and may be useful in treating cats with refractory congestive heart failure. Therapeutic decision making should be tailored to each individual patient and must be based on a thorough evaluation of historical, physical, and diagnostic findings. Feline hypertrophic cardiomyopathy (HCM) is an important and common disease in cats. The goals of managing cats with HCM are to improve ventricular filling, prevent recurrent development of pulmonary edema or pleural effusion, and prevent such complications as thromboembolism. This article discusses the various treatment options that are available for cats with HCM. DIURETIC THERAPY Generally, if cats are diagnosed with HCM and are asymptomatic without congestive heart failure (CHF), diuretic therapy is not necessary. When CHF is associated with pulmonary edema or pleural effusion, diuretic therapy is of paramount importance. Active diuresis decreases vascular volume and reduces left ventricular (LV) preload and pulmonary edema. Furosemide Loop diuretics act on the ascending limb of the loop of Henle to inhibit chlo- *A companion article entitled Feline Hypertrophic Cardiomyopathy: Etiology, Pathophysiology, and Clinical Features appeared in the May 2002 (Vol. 24, No. 5) issue of Compendium.

2 Compendium June 2002 Hypertrophic Cardiomyopathy 471 Table 1. Agents Used to Treat Hypertrophic Cardiomyopathy Drug and Classification Uses/Indications Dosage Comments Atenolol (β-blocker) Maintenance therapy mg Effective at treating supraventricular PO sid bid and ventricular tachyarrhythmias; may be more effective than calciumchannel blockers in treating animals with LVOT obstruction Propranolol (β-blocker) Maintenance therapy mg Same as above PO tid Cardizem CD (Biovail Maintenance therapy 10 mg/kg Calcium-channel blockers are a good Corporation, Morrisville, PO sid choice if ventricular arrhythmias and NC; calcium-channel persistent tachycardia are not a major blocker long-acting concern and diastolic relaxation is the preparation) main effect sought Dilacor XR (Watson Maintenance therapy 30 mg PO Same as above Pharmaceuticals, Inc., sid bid Corona, CA; calciumchannel blocker longacting preparation) Diltiazem HCl Maintenance therapy 7.5 mg Same as above (calcium-channel blocker) PO tid Enalapril (angiotensin- Severe left atrial enlargement Monitor serum creatinine; lower converting enzyme and/or CHF mg/kg/day PO the dose of diuretic if possible to inhibitor) avoid azotemia Furosemide (diuretic) Acute pulmonary edema mg/kg For long-term use, find the lowest or recurrent CHF IM, IV, PO, effective dose to prevent CHF; avoid SC (see text for high doses when used in combination dosing frequency) with angiotensin-converting enzyme inhibitors CHF = congestive heart failure; LVOT = left ventricular outflow tract. ride transport and thus promote sodium and water excretion. 1,2 Furosemide is the drug of choice for patients with pulmonary edema and is given at an initial dose of 1 to 2 mg/kg IV or IM (Table 1). 1 4 This dose may be repeated every 1 to 4 hours as needed to resolve pulmonary edema and ameliorate signs of dyspnea. Once initial control has been achieved, the dose and frequency of furosemide should be reduced to the minimum necessary to control signs and recurrence of pulmonary edema. Patients may require a once- or twice-daily dose or even an every-other-day dose of 0.5 to 1 mg/kg PO. In cats with stable disease, diuretic therapy can eventually be discontinued. 4 Diuretic therapy alone is not appropriate for treating cats with life-threatening dyspnea secondary to pleural effusion. These animals are initially best treated by thoracocentesis. Once the patient is stable, maintenance therapy with furosemide can be administered to prevent reaccumulation of pleural fluid. Cats with pleural effusion may require a higher dose or more frequent administration of furosemide to control fluid reaccumulation compared with cats with pulmonary edema. 5 Many cats with pleural effusion may require repeated thoracocentesis to control the condition. Patients receiving furosemide should be monitored for hypokalemia and hypomagnesemia. When furosemide is combined with angiotensin-converting enzyme (ACE) inhibitors, the dose of furosemide may need to be reduced to avoid azotemia. 2,5 Furthermore, furosemide may lead to dehydration and activation of compensatory mechanisms, including the renin angiotensin aldosterone system and sympathetic nervous

3 472 Small Animal/Exotics Compendium June 2002 system; these may contribute to the progression of heart disease and CHF. Spironolactone Spironolactone is a diuretic that acts by direct receptor inhibition of aldosterone in the distal renal tubule, promoting sodium loss and potassium retention. 2 Spironolactone s diuretic effect is mild. The drug is sometimes used in combination with furosemide if hypokalemia occurs, but it is rarely used alone in patients with CHF. 2 In human medicine, this relatively older drug has received renewed attention because it has been shown to effectively prevent cardiac fibrosis in rats exposed to high levels of aldosterone. 6 This may have relevance to cats since fibrosis is a common pathologic change associated with feline HCM. Studies are still needed to determine whether spironolactone is effective in preventing fibrosis associated with HCM. NITROGLYCERIN Nitroglycerin is a venous dilator that is usually reserved for cases of acute pulmonary edema. It is also a coronary artery vasodilator and may be beneficial in promoting myocardial perfusion. 1,5 Because of its ability to dilate capacitance vessels, blood is diverted away from the heart and lungs, thus reducing preload. Nitroglycerin is absorbed transcutaneously following application to the inner pinnae or clipped body region. A quarter-inch strip is applied every 6 hours 2,3,5 and is usually not used for longer than 2 to 3 days because tolerance often develops. 3,5 Some researchers suggest providing a 12-hour dose-free interval to reduce tolerance. 3,4 Gloves should be worn when administering nitroglycerin to avoid unwanted absorption. β-blockers β-adrenergic receptors are divided into two categories: β 1 and β 2. β 1 -receptors are found mainly in the myocardium; activation results in increased heart rate, contractility, and atrioventricular conduction velocity. β 2 -receptors are found in the smooth muscle of the bronchi and blood vessels, and stimulation promotes bronchodilation and vasodilation, respectively. 2 In the clinical setting, β-blockers are used to mitigate the deleterious effects of sympathetic nervous system hyperactivity. This is achieved by decreasing heart rate, myocardial oxygen consumption, and ventricular and supraventricular arrhythmias. By decreasing heart rate, diastole is prolonged and passive ventricular filling is improved. Prolonged diastolic filling also enhances coronary blood flow and thus improves myocardial perfusion. β-blockers reduce myocardial oxygen requirements by decreasing heart rate, systolic myocardial wall stress, and systemic blood pressure. 1,3,4,7 β-blockers may also decrease LV outflow gradients in cats with left ventricular outflow tract (LVOT) obstructions and may be the drug of choice in these patients. 3,5,8 Numerous human studies have demonstrated the beneficial effects of β-blocker therapy in heart failure patients, including decreased mortality, episodes of CHF, and cardiac events related to fatal arrhythmias Human studies have also demonstrated increased survival and decreased fatal arrhythmias in patients with acute myocardial infarction. 9,10 These findings may be of clinical relevance in cats since myocardial ischemia and infarction may occur in feline HCM. 3,4,11,12 Propranolol is a nonspecific β-blocker that antagonizes both β 1 - and β 2 -receptors. It is usually given at a dose of 2.5 mg q8h and can be titrated to as high as 10 mg q8h as needed to control heart rate and arrhythmia. 1 4 Because propranolol may cause bronchoconstriction, it is not advisable to use this drug in cats with pulmonary edema, especially those with a history of asthmatic disease. Atenolol is a β 1 -specific blocker that has a longer half-life than propranolol and can be given once or twice daily. An initial dose of 6.25 mg/day may be titrated to as high as 12.5 mg bid as needed to control heart rate and arrhythmia. 1 4 In our opinion, β-blockers are the treatment of choice in cats with HCM that have ventricular arrhythmias, persistent sinus tachycardia (heart rate greater than 220 beats/min), or LVOT obstruction. CALCIUM-CHANNEL BLOCKERS Calcium-channel blockers reduce transmembrane calcium ion movement from the extracellular to the intracellular compartments of both cardiac and vascular smooth muscle. 2 This class of drugs potentially improves diastolic function (by decreasing heart rate), myocardial perfusion (by dilating coronary arteries), and myocardial relaxation (by decreasing cellular calcium levels necessary for contraction). 13,14 A degree of systemic arterial vasodilation is also caused by calciumchannel blockers. 13,14 Cellular calcium overload has been implicated as a final event in the mechanism of ischemia-induced myocardial necrosis. 15 In addition, the failing heart generally has a decreased ability to restore low cytosolic calcium levels during diastole. 16 This results in impaired myocardial relaxation, myocardial stiffness, and, consequently, reduced diastolic ventricular filling. 2 Thus if cellular calcium levels could be decreased, toxic effects on the cell may be reduced and myocyte function preserved. 15 Diltiazem HCl is the calcium-channel blocker used to treat feline HCM. In a study of cats with HCM,

4 474 Small Animal/Exotics Compendium June 2002 treatment using diltiazem HCl decreased mortality and increased survival. 13 Beneficial effects observed in symptomatic cats included decreased heart and respiratory rates and alleviation of pulmonary edema. 13 Echocardiographic improvement was noted, characterized by a reduction in left atrial size and an increase in the size of the LV during diastole. 13 Diltiazem HCl should be administered at a dose of 1.75 to 2.5 mg/kg q8h or one quarter of a 30-mg tablet tid. 2,3,4,13 Extended-release formulations of diltiazem HCl (Dilacor XR [Watson Pharmaceuticals, Inc., Corona, CA] and Cardizem CD [Biovail Corporation, Morrisville, NC]) allow a once- or twice-daily dose. 3 5,17 The pharmacokinetics of Cardizem CD have been evaluated in cats, and the drug has been found to be effective at a dose of 10 mg/kg sid. 17 Because formulations are available only in capsule form, compounding is necessary to appropriately dose a cat. Dilacor XR is available in 240-mg capsules, which contain four small 60-mg tablets. The starting dose is 30 mg once or twice daily. 3 5 The drug may be given at 60 mg sid, but some cats exhibit signs of hypotension, weakness, and anorexia when given this dose. 5 We use diltiazem HCl when ventricular tachyarrhythmias, persistent tachycardia, and LVOT obstruction are not present and the primary desired effects are diastolic relaxation and mild to moderate heart rate reduction. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS Angiotensin-converting enzyme inhibitors have been observed to be beneficial in treating both cats 18,19 and humans with CHF. 20 The beneficial properties of ACE inhibitors are their ability to alter adverse hemodynamic and neurohormonal changes that occur with CHF. 21 The conversion of angiotensin I to angiotensin II is prevented by ACE inhibitors. Angiotensin II has multiple adverse effects on the circulation and possibly the myocardium itself. 22 Enalapril, an ACE inhibitor, appears to be well tolerated in cats and has been found to be beneficial when given to cats with HCM regardless of whether they have CHF. 19 Beneficial effects of enalapril observed in cats with HCM included significant decreases in mean left atrial size as well as decreases in the thickness of the interventricular septum during systole and diastole and in the LV free wall during diastole. 19 The LV diameter in diastole also increased significantly. 18,19 When enalapril therapy is initiated, serum creatinine concentration should be reassessed 7 to 10 days later. 5 Enalapril should be administered at a dose of 0.25 to 0.5 mg/kg/day PO. 2 5,23 It was traditionally thought that the use of vasodilators was contraindicated in patients with LVOT obstruction because greater LV shortening could potentially place the interventricular septum and mitral valve in closer apposition. 3,4,19 This could potentially worsen LVOT obstruction, leading to increased mitral regurgitation and decreased cardiac output and blood pressure. 19 This complication has not been identified in cats with a narrowed LVOT treated with enalapril. 19 Azotemia is a possible side effect of ACE inhibitors but usually occurs only in dehydrated cats, cats on high doses of furosemide, or those with preexisting renal disease. 2,5 Lowering the diuretic dose usually improves azotemia. 2,5 Benazepril, another ACE inhibitor with properties similar to enalapril, has been shown to be well tolerated in cats. 2 4,24 It is eliminated primarily by hepatic mechanisms as compared with enalapril, which is primarily excreted renally and thus may be useful in patients with mild to moderate renal dysfunction. 1,2 The dose of benazepril in cats is the same as for enalapril. 3,4 PROGNOSIS With appropriate diagnosis and treatment, prognosis for cats with HCM is variable but perhaps better than previously thought. 25 In one study, when comparing survivors with nonsurvivors at follow-up, some mor-

5 Compendium June 2002 Hypertrophic Cardiomyopathy 475 phologic differences could be documented that predicted clinical outcome. 12 Greater wall thickness and large left atrial dimensions were negatively correlated with survival. Interestingly, systolic anterior motion of the mitral valve was more common in survivors than in nonsurvivors. In a study of 61 cats with HCM, median survival time was 732 days. 26 The most important predictor of outcome in this study was the presence or absence of clinical signs (i.e., cats without clinical signs lived longer than those with clinical signs). Cats without clinical signs had a median survival time of 1830 days compared with 92 and 61 days for cats with heart failure and embolism, respectively. 26 REFERENCES 1. Plumb DC: Veterinary Drug Handbook. Ames, Iowa State University Press, Ware WA: Management of congestive heart failure, in Nelson RW, Couto CG (eds): Essentials of Small Animal Internal Medicine. St. Louis, Mosby, 1998, pp Fox PR: Feline cardiomyopathies, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders Co, 2000, pp Fox PR: Feline cardiomyopathies, in Fox PR, Sisson D, Moise NS (eds): Textbook of Canine and Feline Cardiology. Philadelphia, WB Saunders Co, 1999, pp Rush JE: Therapy of feline hypertrophic cardiomyopathy. Vet Clin North Am Small Anim Pract 28(6): , Lijnen P, Petrov V: Induction of cardiac fibrosis by aldosterone. J Mol Cell Cardiol 32: , Newton GE, Parker JD: Acute effects of beta 1-selective and nonselective beta-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation 94(3): , Heidenreich PA, Lee TT, Massie BM: Effect of beta-blockade on mortality in patients with heart failure: A meta-analysis of randomized clinical trials. J Am Coll Cardiol 30:27 34, Kennedy HL, Brooks MM, Barker AH, et al: Beta-blocker therapy in the Cardiac Arrhythmia Suppression Trial. Am J Cardiol 74: , Teo KK, Yusuf S, Furberg CD: Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. JAMA 270: , Liu SK, Roberts WC, Maron BJ: Comparison of morphologic findings in spontaneously occurring hypertrophic cardiomyopathy in humans, cats, and dogs. Am J Cardiol 72: , Fox PR, Liu SK, Maron BJ: Echocardiographic assessment of spontaneously occurring feline hypertrophic cardiomyopathy: An animal model of human disease. Circulation 92: , Bright JM, Golden AL, Gompf RE, et al: Evaluation of the calcium channel blocking agents diltiazem and verapamil for treatment of feline hypertrophic cardiomyopathy. J Vet Intern Med 5: , Walsh RA: The effects of calcium-entry blockade on left ventricular systolic and diastolic function. Circulation 75(6 Pt 2): V43 V55, Skolnick AE, Frishman WH: Calcium channel blockers in myocardial infarction. Arch Intern Med 149: , Behrend EN, Grauer GF, Greco DS: Feline hypertrophic cardiomyopathy, Part 2. Feline Pract 25(1):9 12, Johnson LM, Atkins CE, Keene BW, Bai SA: Pharmacokinetic and pharmacodynamic properties of conventional and CDformulated diltiazem in cats. J Vet Intern Med 10(5): , Freeman LM, Brown DJ, Smith FW, Rush JE: Magnesium status and the effect of magnesium supplementation in feline hypertrophic cardiomyopathy. Can J Vet Res 61: , Rush JE, Freeman LM, Brown DJ, Smith Jr FW: The use of enalapril in the treatment of feline hypertrophic cardiomyopathy. JAAHA 34:38 41, Results of the cooperative north Scandinavian enalapril survival study (CONSENSUS): Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 316: , Packer M: The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 20: , Tan L, Jalil JE, Pick R, et al: Cardiac myocyte necrosis induced by angiotensin II. Circ Res 69: , Sanders N, Hamlin R, Buffington T, et al: Effects of enalapril on healthy cats (abstract). J Vet Intern Med 6(2):139, King JN, Humbert-Droz E, Maurer M: Pharmacokinetics of benazepril and inhibition of plasma ACE activity in cats. J Vet Intern Med 10:163, Laste NJ, Harpster NK: A retrospective study of 100 cases of feline distal aortic thromboembolism: JAAHA 31: , Atkins CE, Gallo AM, Kurzman ID, Cowen P: Risk factors, clinical signs, and survival in cats with a clinical diagnosis of idiopathic hypertrophic cardiomyopathy: 74 cases ( ). JAVMA 201(4): , ARTICLE #3 CE TEST The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from the Auburn University College of Veterinary Medicine. Choose the best answer to each of the following questions; then mark your answers on the postage-paid envelope inserted in Compendium. 1. When combining furosemide with an ACE inhibitor, a dose reduction may be necessary to avoid a. excitement. d. dyspnea. b. hyperthermia. e. azotemia. c. bradycardia. 2. Propranolol and atenolol exert their effects on the heart by a. agonizing β 1 -receptors. b. antagonizing β 1 -receptors. c. agonizing β 2 -receptors. d. antagonizing β 2 -receptors. e. agonizing α 1 -receptors. 3. A beneficial effect of using diltiazem HCl in the treatment of HCM is a. improved myocardial relaxation as a result of reduced cellular calcium levels.

6 476 Small Animal/Exotics Compendium June 2002 b. improved myocardial contractility as a result of elevated cellular calcium levels. c. a profound diuretic effect. d. positive chronotropy. e. none of the above 4. The two major classes of drugs used to treat feline HCM are a. digitalis glycosides and diuretics. b. class I antiarrhythmia drugs and diuretics. c. ACE inhibitors and calcium-channel blockers. d. calcium-channel blockers and β-blockers. e. none of the above 5. An ACE inhibitor can be beneficial in managing HCM because it a. prevents conversion of angiotensin I to angiotensin II, thus mitigating adverse effects on circulation. b. is beneficial in the acute treatment of pulmonary edema. c. can actively dissolve a thrombus. d. can increase intraventricular pressure gradients. e. can reverse the changes of myofibrillar disarray. 6. When using diuretics to treat CHF, a. the maximal dose possible should be given in all cases. b. concurrent intravenous fluids must always be administered. c. oxygen should not be given concurrently. d. treatment may be required indefinitely. e. only the minimum dose and frequency necessary to achieve a therapeutic effect should be given. 7. β-blockers may be useful in a. reducing LV outflow gradients associated with LVOT obstruction. b. treating patients with third-degree heart block. c. treating patients with seizure disorders. d. treating hypotensive patients. e. none of the above 8. Calcium-channel blockers may reduce afterload by a. increasing contractility. b. increasing heart rate. c. causing a degree of systemic arterial vasodilation. d. decreasing stroke volume. e. promoting arrhythmias. 9. ACE inhibitors should be used with caution in patients with a. renal failure. d. diarrhea. b. hypertension. e. anxiety disorders. c. congestive heart failure. 10. Nitroglycerin is useful in the treatment of pulmonary edema because it a. increases contractility. b. reduces preload by dilating capacitance vessels. c. induces rapid diuresis. d. is a negative chronotrope. e. reduces anxiety.