Medical Treatment of Hypertrophic Cardiomyopathy Mark V. Sherrid, MD, David Gunsburg, MD, Ajay Sharma, DO Hypertrophic Cardiomyopathy Program and Echocardiography Laboratory St. Luke's - Roosevelt Hospital Center Division of Cardiology Columbia University, College of Physicians and Surgeons New York, New York Address for correspondence:   Mark V. Sherrid, MD Division of Cardiology, 3B-30 1000 Tenth Avenue New York, NY 10019 Tel (212) 523-7372 Fax (212) 523-7765 msherrid@slrhc.org Reprinted by permission Current Cardiology Reports 2000;2: 148-153. Current Science Inc.

Abstract: Current medical therapy of hypertrophic cardiomyopathy (HCM) is tailored to relieve symptoms of exercise intolerance, angina or syncope. In recent years new concepts in the pathophysiology of HCM have evolved. These concepts underlie our medical therapy and will be discussed first in this review. Subsequently, the agents available for the medical treatment of HCM are discussed along with a practical strategy for rapid medical reduction of outflow gradients. The mechanism of benefit of negative inotropes for obstruction is described. Newer agents under investigation are discussed. Finally, antiarrhythmic therapy for troubling atrial and ventricular arrhythmias are discussed Introduction New understanding of hypertrophic cardiomyopathy (HCM) pathophysiology form the basis for its medical treatment(1-3). Patients with HCM have diastolic dysfunction due to hypertrophy and myocardial fibrosis. Though increased LV diastolic pressures are often present in HCM, exercise limitation has been shown to correlate with an inability to increase cardiac output with exercise (4). Impaired coronary flow reserve has been shown by various modalities - coronary sinus lactate production, Doppler intracoronary ultrasound and positron emission tomography. The decrease in flow reserve is thought to be the etiology of myocardial ischemia and chest pain (5). Limited flow reserve is likely to have several causes. It may be due to the hypertrophy itself and diastolic dysfunction, or phasic compression "milking" of intramural coronaries in systole and early diastole, or dynamic coronary bridges, or non-atherosclerotic occlusive disease of the intramural coronary arteries. Syncope can occur due to intraventricular obstruction, ventricular arrhythmias, atrial arrhythmias, heart block or inappropriate vasodilatation that can paradoxically occur during or after exertion. All of these symptoms may occur in the absence of intraventricular obstruction. Obstruction occurs in only roughly a quarter of HCM patients. However, in addition to these other abnormalities, obstruction may cause enough symptoms to cause the patient to seek medical attention. Obstruction, increases systolic left ventricular pressure, systolic wall tension and myocardial work. Coronary perfusion pressure is decreased as aortic diastolic pressure falls and left ventricular diastolic pressure rises. Pacing produced ischemia and anaerobic metabolism is documented. These abnormalities in myocardial metabolism and blood flow are reversed by successful myectomy. In addition, SAM causes mitral regurgitation, in which the functional deformation of the mitral valve causes incomplete coaptation. Treatment is often tailored to whether or not a patient has obstruction or not. This dichotomy suffers from a gray zone: patients with a provocable gradient. Provocation with amyl nitrite, exercise or the post-prandial state may transfer a patient previously catalogued as not obstructed to obstructed. Cause of systolic anterior motion Systolic anterior motion (SAM) is the usual mechanism for outflow of obstruction in HCM. Obstructed patients have anatomic features that predispose them to systolic mitral-septal contact. Their mitral valve leaflets are relatively large with increased leaflet area found in 60% of valves removed at surgery or necropsy (5). Residual portions of leaflets extend past the coaptation point and protrude into the outflow tract (6). Most importantly, the mitral valve is situated anteriorly in the left ventricular cavity (7). This is due to anterior displacement of the papillary muscles, a small left ventricle and a bulging septum. The anterior displacement puts the mitral valve into the flow stream of left ventricular ejection, subjecting the mitral valve to the hemodynamic force of ejection flow. There is agreement that that SAM is caused by the action of left ventricular flow on the protruding mitral valve leaflet (2). Initially, investigators hypothesized that anterior motion is caused by a Venturi mechanism, whereby high velocity flow in the outflow tract lifts the mitral valve towards the septum. More recent data has shown that drag, the pushing force of flow, initiates the anterior motion by pushing the protruding mitral leaflet into the septum (7-8). Drag is the component of force on a body that is in the direction of the flow - examples are the familiar force of rushing water or the wind. The mitral valve is swept by the pushing force of flow into the septum (8). After this, the pressure gradient across the protruding mitral leaflet further narrows the orifice, initiating an amplifying feedback loop in which obstruction begets more obstruction. SAM is best described as a flow drag triggered, time dependent, amplifying feedback loop (8). Pharmacologic treatment of obstructive HCM Most symptomatic patients with obstructive HCM can be managed successfully with medication (1-3). Patients are treated first with beta blockade. Unfortunately, this is often not effective in symptomatic patients with high resting gradients. However, beta blockade does prevent the exercise-related rise in gradient. In addition, slowing heart rate improves filling in patients who have significant diastolic abnormalities. Disopyramide is the single most efficacious medication to relieve obstruction (2, 9-14). It is quite effective in lowering outflow gradients and improving symptoms, even in patients with high degrees of resting obstruction. The usual starting dose is 400-600 mg/day, using the controlled release preparation to allow twice a day dosing. Disopyramide increases treadmill exercise time (11). This agent is a potent negative inotrope. In normals it decreases echocardiographic left ventricular fractional shortening by 28%. Despite this decrease in ejection, LV end diastolic pressure falls as well, due to relief of obstruction. A recent study has shown an improvement in coronary vasodilator reserve in patients with obstructive HCM, using intracoronary Doppler ultrasound (12). Another study has examined the effect of disopyramide on the balance of myocardial oxygen supply and demand in obstructive HCM. After disopyramide, resting coronary flow velocity, measured with intracoronary Doppler, was unchanged, while LV external work, from pressure-volume loops, was decreased indicating an improvement in the supply-demand balance (13). Disopyramide levels can be monitored especially in patients with renal failure. Reduction in gradient has been observed with dosages and disopyramide levels lower than those needed for antiarrhythmic therapy (10). Vagolytic side effects, dry mouth and exacerbation of prostatism can limit disopyramide dose. Disopyramide should not be started in patients with prostatism or in patients with impaired global systolic function. We have not observed pro-arrhythmic ventricular tachycardia using disopyramide for obstructive HCM, nor has it been reported in the literature. Disopyramide is most often used in combination with a beta-blocker; beta blockade offers the advantage of slowing the exercise heart rate, and decreasing sympathetic mediated increase in gradient. NEXT PAGE