EP News: Basic and Translational

Abstract

Toepfer et al (Circulation 2020;141:828–824; PMID 31983222) investigated molecular mechanisms underlying the pathogenesis of hypertrophic cardiomyopathy (HCM), which is caused by pathogenic variants in sarcomere protein genes. Pathogenic missense variants in myosin, linked to HCM, have been shown to cluster in residues that participate in dynamic conformational states of sarcomere proteins. Myosin ATP binding was assayed to define the proportions of myosin in super relaxed state (SRX) or disordered relaxed state (DRX) conformations in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. Myosins undergo physiological shifts between SRX conformations that maximize energy conservation and active states (DRX) that enable cross-bridge formation with greater ATP consumption. Pathogenic variants destabilized SRX conformations and increased the proportion of DRX myosins, which enhanced cardiomyocyte contractility but impaired relaxation, and evoked hypertrophic remodeling with increased energetic stress. The authors conclude that myosin conformations establish work–energy balance that is essential for lifelong cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in HCM patients.