Familial Hypertrophic Cardiomyopathy: Diagnosis and Management

Abstract

Hypertrophic cardiomyopathy (HCM) is widely recognized as one of the most common inheritable cardiac disorders. Since its initial description over 60 years ago, advances in multimodality imaging and translational genetics have revolutionized our understanding of the disorder. The diagnosis and management of patients with HCM are optimized with a multidisciplinary approach. This, along with increased safety and efficacy of medical, percutaneous, and surgical therapies for HCM, has afforded more personalized care and improved outcomes for this patient population. In this review, we will discuss our modern understanding of the molecular pathophysiology that underlies HCM. We will describe the range of clinical presentations and discuss the role of genetic testing in diagnosis. Finally, we will summarize management strategies for the hemodynamic subtypes of HCM with specific emphasis on the rationale and evidence for the use of implantable cardioverter defibrillators, septal reduction therapy, and cardiac myosin inhibitors.

Keywords: genetics; heart failure; hypertrophic cardiomyopathy; mavacamten; myosin.

Figure 1

Phenotypic subtypes of hypertrophic cardiomyopathy, differentiated by region of hypertrophy. (A) Representation of a normal human heart. (B) Type A/type I hypertrophy results in a sigmoid septum with discrete hypertrophy of the basilar septum with less severe hypertrophy of the basolateral wall. (C) Type B/Type II hypertrophy involves the majority of the basilar septum and in three dimensions spirals anteriorly as it tracts down to the apex. (D) Type C hypertrophy (a subclass of Type III hypertrophy) denotes primarily uniform hypertrophy of both the septum and the posterior wall. (E) Type D (a subclass of Type IV hypertrophy) primarily involves the apex with minimal hypertrophy in the septum or posterior wall. (F) Type E (a subclass of Type III hypertrophy) involves both the septum and the posterior wall with minimal apical involvement and can lead to mid-cavitary gradients.

Figure 2

Left ventricle to aortic root angulation and its impact on left ventricular outflow tract gradient. (A) In structurally normal hearts, the left ventricular to aortic root angle (LVARA) is greater than 140°. (B) With septal hypertrophy, the LVARA decreases, and more blood is directed toward the anterior leaflet of the mitral valve. This is thought to promote a Venturi effect and drag forces that increase the left ventricular outflow tract gradient and promote systolic anterior motion of the mitral valve.