Mechanisms and Therapies of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common myocardial genetic disease characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction with preserved or elevated ejection fraction. Thirty-five years after the identification of the first genetic variant in myosin heavy chain 7, other variants have been discovered in numerous components of the sarcomere, pointing to a primary defect in cardiomyocyte contractility. Still, a large portion of HCM patients does not have a pathogenic variant and others present with LVH of another genetic origin. Research has uncovered a primary driver of hypercontractility at the sarcomere level and diverse molecular and cellular mechanisms contributing to HCM, including alterations of calcium handling and proteolysis, microtubule modifications, energy deficiency, and the impact of noncardiomyocyte cell types. These discoveries have fueled preclinical and translational research, leading to the development of myosin inhibitors, which are now on the market, and gene-based therapeutic products. This review summarizes current knowledge on the genetics, mechanisms, and targeted treatments of HCM.