Contemporary treatment of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a fascinating disease that for the past 50 years has captured the interest of clinicians and surgeons alike. It is a primary disease of cardiac myocytes that is characterized by concentric, yet asymmetric, cardiac hypertrophy and by an increased or preserved left ventricular ejection fraction (LVEF). Despite the descriptions of the pathologic phenotype by Liouville in 18691 as cardiac contraction below the aortic valve and by Schmincke in 19072 as diffuse muscular “hyperplasia” at the left ventricular outflow tract (LVOT), the clinical recognition of HCM had to await the development of advanced diagnostic tools in the 2nd half of the 20th century. Accordingly, Braunwald and colleagues, in the 1960s, emphasized the hemodynamic features of HCM and coined the term “idiopathic hypertrophic subaortic stenosis” or “IHSS” to describe the LVOT obstruction.3,4 The recognition of LVOT obstruction as a major characteristic of HCM led to the 1st performance of a surgical transaortic septal myectomy, described by Morrow and colleagues in 1964.5 The asymmetric type of cardiac hypertrophy in HCM was recognized very early, and the finding of asymmetric septal hypertrophy on an echocardiogram became the sine qua non for a diagnosis of HCM.6 The application of Doppler echocardiography to the evaluation of patients with HCM shed further light on the physiology of the LVOT obstruction and helped in the evaluation of diastolic function.7–10 More recently, tissue Doppler imaging (TDI) has been applied to obtain an early diagnosis of HCM (before, and independent of, the development of cardiac hypertrophy) and to further evaluate myocardial function in HCM.11,12 Consequently, echocardiography, including Doppler evaluation, is the most commonly used diagnostic technique in HCM—supplanting cardiac catheterization, which is now reserved for specific indications. The seminal work of Seidman and associates13 led to the discovery, in 1990, of the 1st causal gene and mutation for HCM, ushering in a new era of molecular genetics in application to the disorder. The discovery had a watershed effect, as it led to partial elucidation of the molecular genetic basis of HCM and to the identification of more than a dozen causal genes that encode sarcomeric proteins.14 Accordingly, HCM is now recognized as a disease of sarcomeric proteins. Advances in the molecular genetics of HCM have raised considerable interest in early diagnosis and in genotype-dependent risk stratification and treatment. These studies, on the other hand, have illustrated the presence of considerable phenotypic variability among subjects with identical causal mutations; hence, they have emphasized the importance of considering the plurality of determinants of clinical phenotypes. Similarly, molecular genetic studies have illustrated the shortcomings of clinical diagnosis in distinguishing between HCM and HCM-phenocopy conditions (conditions that mimic HCM, such as storage diseases). Despite considerable advances in the clinical recognition and molecular genetics of HCM, the pharmacologic treatment of patients with HCM has remained largely unchanged during the past several decades. However, 2 major non-pharmacologic interventions—percutaneous transcatheter septal ablation (or alcohol septal ablation) and the implantation of internal cardioverter-defibrillators (ICDs)—have changed the landscape significantly. Sigwart15 introduced the catheter-based reduction of septal hypertrophy for the treatment of LVOT obstruction in 1995. The procedure has proved a highly effective method for the reduction of LVOT obstruction and alleviation of symptoms.16–18 The potential for arrhythmogenesis, which can originate from the local site of induced myocardial injury, has somewhat subdued enthusiasm for the routine use of alcohol septal ablation, particularly in consideration of the fact that HCM is an arrhythmogenic phenotype. Indeed, HCM remains the most common discernible cause of sudden cardiac death (SCD) in the young—particularly in competitive athletes.19,20 The advent of implantable defibrillators has provided physicians with an effective option for primary and secondary prevention of SCD in high-risk patients.21,22 However, implantable defibrillators have no substantial effects on the underlying phenotype of cardiac hypertrophy and its accompanying fibrosis, so additional therapies are needed. Experimental data obtained from the study of animal models of HCM have suggested the potential usefulness of various pharmacologic agents—including statins, inhibitors of the renin-angiotensin-aldosterone system (RAAS), and N-acetylcysteine—in the prevention and reversal of the cardiac phenotype in HCM.23–27 The field awaits large-scale randomized clinical studies in human beings who have HCM, in order to determine the potential beneficial effects of these novel therapeutic and preventive interventions.