Hypertrophic cardiomyopathy HCM is a genetic disorder in the heart caused by variants in sarcomeric proteins that disrupt myocardial function, leading to hypercontractility, hypertrophy, and fibrosis. Optimal cardiac function relies on the precise coordination of thin and thick filament proteins that control the timing, magnitude of cellular force generation and relaxation, and in vivo systolic and diastolic function.
Sarcomeric proteins, such as cardiac myosin binding protein C cMyBP-C play a crucial role in myocardial contractile function by modulating actomyosin interactions. This review explores the molecular mechanisms underpinning HCM and the rapidly advancing field of HCM translational research, including gene therapy and small-molecule interventions targeting sarcomere function. We will highlight novel approaches, including gene therapy using recombinant AAV vectors and small-molecule drugs targeting sarcomere function.
Heart disease is a major health challenge in the United States, contributing to millions of hospitalizations and accounts for 1 in every 5 deaths annually 1. Among the various forms of heart disease, hypertrophic cardiomyopathy HCM is the most common genetic cardiomyopathy, affecting approximately 1 in people in the U.
GWAS studies have shown that HCM is an autosomal dominant disease caused by one or more genetic variants in sarcomeric proteins 3 β 7. Alterations to sarcomere proteins result in either a gain or loss of function at the cellular level. This leads to dysregulation in the precise coordination of cardiac contraction and relaxation at the whole organ level.
Clinically, HCM presents as a heterogeneous phenotype that leads to variable degrees of cardiac remodeling 8 β Common features of HCM include asymmetrical thickening of the left ventricular LV wall, hyperdynamic systolic performance, and a preserved or elevated left ventricular ejection fraction LVEF 10 , Historically, therapeutic interventions such as beta-blockers b-blockers , and non-dihydropyridine calcium channel blockers CCBs have been used to treat HCM symptoms by modulating adrenergic and calcium signaling pathways to improve patient quality of life 10 , 13 , but these therapies do not directly address the underlying problem of pathogenic variants in sarcomeric proteins 10 , Recent advances in therapeutic interventions are shifting toward directly targeting the primary defects found in altered sarcomere proteins to restore normal cardiac function at the molecular level 13 , This emerging paradigm highlights the growing interest in linking genotype to phenotype and connecting basic research to clinical practice.
