Number 21, 2003
Hibernation preconditioning

Clinical management of hypertrophic cardiomyopathy

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Rajesh Thaman, Jaymin Shah, William J. McKenna
The Heart Hospital, University College London, London, W1G 8PH, UK
Correspondence: Professor William J. McKenna, The Heart Hospital, 16–18 Westmoreland Street, London W1G 8PH, UK.
Tel: +442075738888 ext 4516, fax: +442075738838, e-mail: william.mckenna@uclh.org

Introduction
Hypertrophic cardiomyopathy (HCM), a familial cardiac disorder with an estimated prevalence of 1 in 500 [1], is defined by the presence of myocardial hypertrophy in the absence of a discernible cause such as systemic hypertension or aortic stenosis. To date, more than 100 mutations in ten genes encoding cardiac sarcomeric proteins that make up the basic contractile apparatus of the cardiac myocyte have been linked to HCM. The clinical manifestations of the condition are diverse, ranging from a benign asymptomatic course to severe heart failure, embolic stroke, and sudden cardiac death. The management of hypertrophic cardiomyopathy is aimed at relieving symptoms, preventing disease-related complications, identifying and treating individuals at increased risk of sudden cardiac death, and screening family members.

Pathophysiology of hypertrophic cardiomyopathy
Hypertrophy usually develops during adolescence, but can occur at any time. Asymmetric septal hypertrophy – ie, hypertrophy affecting the interventricular septum more than the free or posterior walls – is the most common pattern of hypertrophy seen, although concentric and apical hypertrophy, in addition to right ventricular involvement, are recognized. One third of patients have an intraventricular pressure gradient as a result of left ventricular outflow tract (LVOT) obstruction secondary to systolic anterior motion of the mitral valve [2]. Left ventricle systolic function is usually normal or hyperdynamic. Microscopically, hypertrophic cardiomyopathy is characterized by myocyte hypertrophy and disarray; other characteristic features include fibrosis and abnormal intramural coronary arteries with narrowed lumen [3, 4]. Diastolic dysfunction is present in the majority of patients and may be the result of myocardial hypertrophy, disarray, or ischemia, and a minority of patients may have features resembling restrictive cardiomyopathy.

Presentation
The majority of patients do not experience disease-related symptoms; however, some patients complain of exertional and atypical chest pain, dyspnea or exercise limitation, palpitations, syncope, and presyncope. Syncope may be caused by paroxysmal arrhythmia, LVOT obstruction, conduction system disease, or abnormal vascular responses during exercise. Clinical signs are generally limited to patients with LVOT obstruction and include a forceful left ventricular impulse, rapid upstroke to the arterial pulse, a palpable left atrial beat, a fourth heart sound, and a mid-late systolic murmur.

Diagnosis
Hypertrophic cardiomyopathy may be initially suspected because of a heart murmur, family history, new symptoms, or abnormal electrocardiogram (ECG). Diagnosis of hypertrophic cardiomyopathy by identification of a known disease-causing mutation is rarely available, and at present the diagnosis usually rests on echocardiography when there is hypertrophy exceeding two standard deviations from the mean corrected for age, sex, and height [5–7]. The ECG is abnormal in the majority of patients with hypertrophic cardiomyopathy, although no specific changes are diagnostic. Left axis deviation, criteria for left ventricular hypertrophy with or without repolarization changes, left and or right atrial enlargement, and abnormal Q-waves are the most common features [8].

Treatment
In patients with symptoms or significant exercise limitation, decisions regarding symptomatic treatment are generally guided by the presence or absence of LVOT obstruction.

Treatment of patients with LVOT obstruction
β-Blockers are usually tried first. The beneficial effects of β-blockers appear to result from their negative inotropic actions, prolongation of diastole, reduction in myocardial oxygen demand, and reduction in LVOT obstruction. Verapamil is particularly effective in patients with chest pain and may also have beneficial effects on LVOT obstruction; however, in some patients the vasodilative effects may lead to serious hemodynamic compromise and verapamil should therefore be used cautiously in patients with LVOT obstruction.
If β-blockers or verapamil are ineffective, disopyramide can be tried. Disopyramide may reduce LVOT obstruction and relieve symptoms through its negative inotropic properties; however, the initial hemodynamic benefits often decrease with time. Furthermore, patients are often unable to tolerate the high doses often required for symptomatic improvement (up to 600mg/day), because of the anticholinergic side effects. Because disopyramide may shorten the atrioventricular nodal conduction time and thus increase the ventricular rate during paroxysmal atrial tachycardia, which occurs commonly in hypertrophic cardiomyopathy, supplementary treatment with β-blockers in low doses is advisable [9, 10].
For patients with significant LVOT obstruction (≥50mm Hg) in whom medication proves unsuccessful or side effects become intolerable, ventricular septal myotomy-myectomy (Morrow operation) guided by transesophageal echocardiography or alcohol septal ablation should be considered. The aim of myotomy-myectomy is to widen the outflow tract, reducing LVOT obstruction and systolic mitral leaflet septal contact. Success rates of more than 80% are reported, with perioperative mortality rates of 2% or less. Long-term relief of symptoms is maintained in up to 70% of patients [11–13]. Alcohol septal ablation involves the injection of alcohol into the perforators of the left anterior descending coronary artery, to cause a limited septal myocardial infarction. A decrease in outflow tract gradient is reported in 50–70% of patients and complication rates vary considerably, being closely related to the level of expertise at the center at which the procedure is performed [14–16]. The most common complication is high-grade atrioventricular block requiring a permanent pacemaker. For some patients in whom surgery or alcohol septal ablation is contraindicated, A.V. requested pacing using a short-programmed atrioventricular delay leading to delayed activation and less vigorous contraction of the interventricular septum may be an option; this results in gradient reduction in 30% to 50% of patients [17–19].

Treatment of patients without LVOT obstruction
Patients without LVOT obstruction constitute the majority of patients with hypertrophic cardiomyopathy. In these patients, β-blockers or calcium antagonists (verapamil or diltiazem) can be used to optimize heart rate, leading to inherent improvements in myocyte relaxation and cardiac filling, and possibly a reduction in myocardial ischemia.

Heart failure
In a minority of patients, symptoms of heart failure may accompany hypertrophic cardiomyopathy, associated with ventricular enlargement and wall thinning or restrictive physiology. Conventional heart failure management strategies should be used in these patients: eg, diuretics and angiotensin-converting enzyme inhibitors. However, because many of these patients have diastolic dysfunction and require relatively high filling pressures to achieve adequate ventricular filling, diuretics should be used cautiously. Some patients may eventually require heart transplantation.

Supraventricular arrhythmias
Supraventricular arrhythmias – in particular atrial fibrillation and flutter – occur in 20% to 30% of patients with hypertrophic cardiomyopathy and often develop in association with progressive atrial enlargement, secondary to LVOT obstruction, diastolic dysfunction, mitral valve dysfunction, or combinations thereof. These arrhythmias can lead to profound hemodynamic compromise, although they are usually well tolerated if the ventricular rate can be controlled. New onset atrial fibrillation should be cardioverted. If that is unsuccessful, β-blockers and verapamil are usually efficacious in controlling the heart rate. Ablation of the atrioventricular node and implantation of a pacemaker is rarely required. Amiodarone is the most effective antiarrhythmic agent for the prevention of recurrent episodes of supraventricular tachyarrhythmia. Recurrent or even brief episodes of atrial fibrillation/flutter in hypertrophic cardiomyopathy are associated with a significant risk of systemic embolization, therefore the threshold for the initiation of anticoagulation treatment should be low.

Sudden death and risk stratification
Sudden death is the most devastating consequence of hypertrophic cardiomyopathy and often occurs in otherwise healthy individuals. Reported annual mortality rates from sudden death are 1% to 2% and are greatest in adolescents and young adults. Sudden death occurs most commonly at rest or during mild exertion, but is not infrequently related to physical exertion. Ventricular tachyarrhythmia appears to be the final common pathway for sudden death in most patients [20]. The exact trigger for this arrhythmia is unknown, although myocardial ischemia, diastolic dysfunction, outflow tract obstruction, inappropriate systemic arterial vasodilatation, or supraventricular tachyarrhythmias may contribute. Bradyarrhythmias as a result of sinus node dysfunction or atrioventricular block may also be responsible in some patients.
Patients who have survived a cardiac arrest are at greatest risk [21]. Most other patients at risk can be identified by noninvasive assessment, which should include history, 48-hour Holter monitoring, and cardiopulmonary exercise testing. Established risk markers for sudden death include nonsustained ventricular tachycardia, left ventricular wall thickness ≥30mm, abnormal blood pressure response in those younger than 45 years, family history of sudden cardiac death, and recurrent unexplained syncope [22–26].

Prevention of sudden cardiac death
Prophylactic treatment to prevent sudden cardiac death is most strongly warranted for patients with previous cardiac arrest or sustained spontaneous ventricular tachycardia. Patients with two or more risk factors have annual sudden death rates of 2% to 4% and should also be offered prophylactic treatment [27]. Although amiodarone has been used for prophylaxis, the implantable cardioverter defibrillator is increasingly seen as the preferred treatment in most high-risk patients [28–30]. Criteria for use of prophylactic treatment in patients with a single risk factor have not been established, and decisions should be made on an individual basis, taking into account the age of the patient, strength of the risk factor, and the level of risk acceptable to the patient and family.

Screening
All first-degree relatives of affected patients should be offered screening; any identified affected family members should then undergo risk stratification. Currently, evaluation of family members relies on history, examination, and echocardiographic and electrocardiographic evidence of left ventricular hypertrophy. In the future, however, gene testing will enable a more reliable and conclusive diagnosis to be made and prevent the need for continued clinical screening. ▪

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REFERENCES

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