Energetic drain driving hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy and is mainly caused by mutations of genes encoding cardiac sarcomeric proteins. HCM is characterized by hypertrophy of the left ventricle, frequently involving the septum, that is not explained solely by loading conditions. HCM has a heterogeneous clinical profile, but diastolic dysfunction and ventricular arrhythmias represent two dominant features of the disease. Preclinical evidence indicates that the enhanced Calcium (Ca2+ ) sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric mutations, but can also result from secondary mutation-driven alterations. Here, we review experimental and clinical evidence indicating that increased myofilament Ca2+ sensitivity lies upstream of numerous cellular derangements which potentially contribute to the progression of HCM toward heart failure and sudden cardiac death.