American College of Cardiology

MARON AND MCKENNA et al., ACC/ESC Expert Consensus Document on Hypertrophic Cardiomyopathy
JACC 2003; 42: 000-000

American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy

A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines

Symptoms and Pharmacological Management Strategies
A fundamental goal of treatment in HCM is the alleviation of symptoms related to heart failure (Fig. 1). Pharmacological therapy has traditionally been the initial therapeutic approach for relieving disabling symptoms of exertional dyspnea (with or without associated chest pain) and improving exercise capacity for more than 35 years, since the introduction of beta-blockers in the mid-1960s (3,10,14, 168 –179). Also, drugs are often the sole therapeutic option available to the many patients without obstruction to LV outflow, under resting or provocable conditions, who constitute a substantial proportion of the HCM population. Indeed, it is the convention to empirically initiate pharmacologic therapy when symptoms of exercise intolerance intervene, although there have been few randomized trials to compare the effect of drugs in HCM (5,7,11,179) (Fig. 1).

Exertional dyspnea and disability (often associated chest pain), dizziness, presyncope and syncope usually occur in the presence of preserved systolic function and a nondilated LV (5,7,11,14,180). Symptoms appear to be caused in large measure by diastolic dysfunction with impaired filling due to abnormal relaxation and increased chamber stiffness, leading in turn to elevated left atrial and LV end-diastolic pressures (with reduced stroke volume and cardiac output) (181–188), pulmonary congestion, and impaired exercise performance with reduced oxygen consumption at peak exercise (189).

The pathophysiology of such symptoms, due to this form of diastolic heart failure, may also be intertwined with other important pathophysiologic mechanisms such as myocardial ischemia (190 –201), outflow obstruction associated with mitral regurgitation (13,127), and AF (163). Indeed, many patients may experience symptoms largely from diastolic dysfunction or myocardial ischemia in the absence of out-flow obstruction (or severe hypertrophy). Other patients (i.e., those with LV outflow obstruction) are more disabled by elevated LV pressures and concomitant mitral regurgitation than by diastolic dysfunction, as is evidenced by the often dramatic symptomatic benefit derived from major therapeutic interventions that reduce or obliterate outflow gradient (most frequently myectomy or alcohol ablation) (7,13–15,49,81,83–88,90 –95,102–106,202).

Chest pain in the absence of atherosclerotic CAD may be typical of angina pectoris or atypical in character. Most chest discomfort is probably due by bursts of myocardial ischemia, evidenced by the findings of scars at autopsy (51,195,199,203), fixed or reversible myocardial perfusion defects and the suggestion of scarring by magnetic resonance imaging (129), net lactate release during atrial pacing, and impaired coronary vasodilator capacity (190,192,193, 198,201,204). Myocardial ischemia is probably a consequence of abnormal microvasculature, consisting of intramural coronary arterioles with thickened walls (from medial hypertrophy) and narrowed lumen (195–201), and/or a mismatch between the greatly increased LV mass and coronary flow. Because typical anginal chest pain may be part of the HCM symptom-complex, associated atherosclerotic CAD (which may complicate clinical course) is often overlooked in these patients. Therefore, coronary arteriography is indicated in patients with HCM and persistent angina who are over 40 years of age or who have risk factors for CAD, or when CAD is judged possible prior to any invasive treatment for HCM such as septal myectomy (or alcohol septal ablation).

Beta-adrenergic blocking agents. Beta-blockers are negative inotropic drugs that have traditionally been administered to HCM patients with or without obstruction, usually relying on the patient’s own subjective and historical perception of benefit (11,14,168,169,172,179). However, judgments regarding treatment strategies in HCM with beta-blockers are often difficult, taking into account the frequent day-to-day variability in magnitude of symptoms. Treadmill or bicycle exercise—with or without measurement of peak oxygen consumption (189)— have proved helpful in targeting patients for therapy or determining when changes in dosage or drugs are appropriate. If limiting symptoms progress, drug dosage may be increased within the accepted therapeutic range. Patient responses to drugs are highly variable in terms of magnitude and duration of benefit, and the selection of medications has not achieved widespread standardization and has been dependent, in part, on the experiences of individual practitioners, investigators, and centers.

Propranolol was the first drug used in the medical management of HCM, and long-acting preparations of propranolol or agents such as atenolol, metoprolol, or nadolol have been employed more recently. There are many reports of subjective symptomatic improvement and enhanced exercise capacity in a dose range of up to 480 mg per day for propranolol (2 mg/kg in children), both in patients with and without outflow obstruction. Although some investigators have administered massive doses of propranolol (up to 1,000 mg per day), claiming symptomatic benefit and long-term survival without major side effects (172), this is not generally accepted practice. However, even moderate doses of beta-blockers may affect growth in young children or impair school performance, or trigger depression in children and adolescents, and should be closely monitored in such patients. Substantial experience suggests that standard dosages of these drugs can mitigate disabling symptoms and limit the latent outflow gradient provoked during exercise when sympathetic tone is high and heart failure symptoms occur. However, there is little evidence that beta-blocking agents consistently reduce outflow obstruction under resting conditions. Consequently, beta-blockers are a preferred drug treatment strategy for symptomatic patients with outflow gradients present only with exertion. The beneficial effects of beta-blockers on symptoms of exertional dyspnea and exercise intolerance appear to be attributable largely to a decrease in the heart rate with a consequent prolongation of diastole and relaxation and an increase in passive ventricular filling. These agents lessen LV contractility and myocardial oxygen demand and possibly reduce microvascular myocardial ischemia. Potential side effects include fatigue, impotence, sleep disturbances, and chronotropic incompetence.

Most clinicians favor using beta-blockers over verapamil for the initial medical treatment of exertional dyspnea, although it does not appear to be of crucial importance which drug is administered first. It has been common practice, however, to administer verapamil to those patients who do not experience a benefit from beta-blockers or who have a history of asthma. Improvement with verapamil may be due to the primary actions of the drug, and in some instances, partially attributable to withdrawal of beta-blockers and the abolition of side effects that evolved insidiously over time. At present, there is no evidence that combined medical therapy with administration of beta-blockers and verapamil is more advantageous than the use of either drug alone.

Disopyramide. The negative inotropic and type I-A antiarrhythmic agent disopyramide was introduced into the treatment regimen for patients with obstructive HCM in 1982. There are reports of disopyramide producing symptomatic benefit (at 300 to 600 mg per day with a dose-response effect) in severely limited patients with resting obstruction, because of a decrease in SAM, outflow obstruction, and mitral regurgitant volume (168,171,173,174,177). Anti-cholinergic side effects such as dry mouth and eyes, constipation, indigestion, and difficulty in micturition may be reduced by long-acting preparations through which cardioactive benefits are more sustained. Because disopyramide may cause accelerated atrioventricular (A-V) nodal conduction and thus increase ventricular rate during AF, supplemental therapy with beta-blockers in low doses to achieve normal resting heart rate has been advised.

Although disopyramide incorporates antiarrhythmic properties, there is little evidence that proarrhythmic effects have intervened in HCM patients. Nevertheless, this issue remains of some concern in a disease associated with an arrhythmogenic LV substrate; prolongation of the QT interval should be monitored while administering the drug. Furthermore, disopyramide administration may be deleterious in nonobstructive HCM by decreasing cardiac output, causing most investigators to limit its use to patients with outflow obstruction who have not responded to beta-blockers or verapamil.

At present, the information regarding drugs such as sotalol and other calcium antagonists (such as diltiazem) is insufficient to recommend their use in HCM. Diuretic agents may be added to the cardioactive drug regimen prudently—preferably in the absence of marked outflow obstruction. Because many patients have diastolic dysfunction and require relatively high filling pressures to achieve adequate ventricular filling, it may be advisable to administer diuretics cautiously. Nifedipine, because of its particularly potent vasodilating properties, may be deleterious, particularly for patients with outflow obstruction. Combined therapy with disopyramide and amiodarone (or diso-pyramide and sotalol), or quinidine and verapamil (or quinidine and procainamide), should also be avoided due to concern over proarrhythmia; also, administration of nitroglycerine, ACE inhibitors or digitalis are generally contraindicated or discouraged in the presence of resting or provocable outflow obstruction. In patients with severe heart failure refractory to other medications, caution is advised in administrating amiodarone in a high dosage (greater than or equal to 400 mg per day). In patients with erectile dysfunction, phosphodiesterase inhibitors should be used with the awareness that a mild afterload reducing effect may be deleterious in patients with resting or provocable obstruction.

Drugs in end-stage phase. A small but important sub-group of patients with nonobstructive HCM develops systolic ventricular dysfunction and severe heart failure, usually associated with LV remodeling demonstrable as wall thinning and chamber enlargement. This particular evolution of HCM occurs in only about 5% of patients and has been variously known as the “end-stage,”“burnt-out,” or “dilated” phase (7,37,160). Drug treatment strategies in such patients with systolic failure differ substantially from those approaches in HCM patients with typical LVH, nondilated chambers, and preserved systolic function (i.e., involving conversion to after load-reducing agents such as ACE inhibitors or angiotensin-II receptor blockers or diuretics, digitalis, beta-blockers or spironolactone) (Fig. 1). There is no evidence, however, that beta-blockers prevent or convey a benefit to congestive heart failure and ventricular systolic dysfunction of the “end-of-stage” (by contrast with the experience in dilated cardiomyopathy and CAD). Ultimately, patients with end-stage heart failure may become candidates for heart transplantation, and they represent the primary subgroup within the broad disease spectrum of HCM for when this treatment option is considered (207) (Fig. 1).

Asymptomatic patients. Data from largely unselected cohorts and genotyping studies in families suggest that most HCM patients, including many who are not even aware of their disease, probably have no symptoms or only mild symptoms (5–7,17–19,30,50,55,59,64,65,164). While most of the asymptomatic patients do not require treatment, some represent therapeutic dilemmas because of their youthful age and the consideration for prophylactic therapy to prevent SCD or disease progression (21,27,127,208,209).

Prophylactic drug therapy in asymptomatic (or mildly symptomatic) patients to prevent or delay development of symptoms and improve prognosis has been the subject of debate for many years, but it remains on an entirely empiric basis without controlled data to either support or contradict its potential efficacy (11). This issue is unresolved due to the relatively small patient populations previously available for study, as well as the infrequency with which adverse end points occur prematurely in this disease. Additionally, there is a growing awareness that an important proportion of HCM patients achieve normal life expectancy (30–32,34,55). In general, treatments to delay or prevent progression of the disease due to heart failure-related symptoms are most appropriately directed toward relieving LV outflow tract obstruction and controlling or abolishing AF through pharmacologic or intervention-based strategies. Indeed, treatments targeted at aborting the disease progression are now confined to those patients judged to be at high-risk for SCD (as discussed under Risk Stratification and Sudden Cardiac Death). The efficacy of empiric, prophylactic drug treatment with beta-blockers, verapamil or disopyramide for delaying the onset of symptoms and favorably altering the clinical course or outcome in asymptomatic young patients with particularly marked LV outflow tract gradients (about 75 to 100 mm Hg or more) is unresolved.