How Hypertrophic Cardiomyopathy Became a Contemporary Treatable Genetic Disease With Low Mortality

Abstract

A lmost since its inception, hypertrophic cardiomyopathy (HCM) has been regarded as a clinically and morphologi-cally heterogeneous genetic heart disease 1,2 often asso-ciated with a generally unfavorable prognosis, unrelenting progres-sion, premature death, and encumbered by ineffective treatment strategies. 3,4 Although this perspective is becoming less entrenched, 5 contrary myths persist, 6-11 and new management approaches, as yet, may not have penetrated systematically into the consciousness of the practicing community. In this review, the treatment advances that are now available to patients with HCM, and that have reduced dis-ease-related mortality and improved quality of life, are presented and discussed. Hypertrophic cardiomyopathy was first described at autopsy in 1958 12 and subsequently came to be regarded as the most com-mon nontraumatic cause of sudden death among young adults. This disease emerged as a clinical entity largely through the work of Braunwald et al 13 at the National Institutes of Health in the 10 years from 1958 to 1968, which began the formative investiga-tional era for HCM. Initially, HCM was regarded as a disease of left ventricular (LV) outflow obstruction, largely without management strategies that could favorably influence its course. 13 However, the ventricu-lar septal myectomy operation to relieve obstruction and reverse heart failure symptoms was soon introduced first at the National Institutes of Health (and selectively elsewhere, including Mayo Clinic). 14,15 The myectomy operation was gradually recognized as an important treatment for heart failure symptoms, 15-20 despite periodic misguided efforts that casted doubt on the pathophysi-ologic significance of the subaortic gradient. 21 In 1964, pharmaco-logic therapy to mitigate symptoms with β-blockers was intro-duced to patients with HCM by Braunwald, 5-13 and it persists as a first-line therapy, even now, and was later followed by the calcium antagonist verapamil 22 and the negative inotrope/antiarrhythmic disopyramide. 23 Beginning in the early 1990s, a few patients with nonobstruc-tive HCM and unrelenting heart failure were referred for heart transplantation. 24 However, the devastating and highly visible complication of unexpected arrhythmic sudden death remained, without any preventive strategies, as the greatest source of anxiety Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease encumbered throughout much of its almost 60-year history by a large measure of misunderstanding and the perception of a grim outcome without effective treatment options. However, it is now apparent that the majority of patients affected with HCM can achieve normal or near-normal life expectancy without disability, and usually do not require major treatment interventions. Nevertheless, for those patients with HCM who are at risk for (or experience) disease-related complications, a constellation of comprehensive nonpharmacologic management strategies have evolved over the last 15 years, altering the natural history and disease course for many, including implantable defibrillators, heart transplant, external defibrillation/therapeutic hypothermia, advances in surgical myectomy, and alcohol ablation. In particular, expanded contemporary risk stratification strategies have led to a more reliable selection of patients likely to achieve primary prevention of sudden death with implantable defibrillators. Most recently, large cohort studies using current management strategies and therapeutic measures have shown that it is now possible to achieve significantly improved survival with a low HCM-related mortality of 0.5% per year across all ages, and including children and young adults characteristically with the most aggressive disease course. These clinical management initiatives, instituted by the practicing cardiology community, have succeeded in preserving life and restoring an active lifestyle for thousands of patients with HCM, while providing many with a measure of reassurance and a reasonable expectation for an extended (if not normal) life span.