| Summary: | Summary: Thick-filament sarcomere mutations are a common cause of hypertrophic cardiomyopathy (HCM), a disorder of heart muscle thickening associated with sudden cardiac death and heart failure, with unclear mechanisms. We engineered four isogenic induced pluripotent stem cell (iPSC) models of β-myosin heavy chain and myosin-binding protein C3 mutations, and studied iPSC-derived cardiomyocytes in cardiac microtissue assays that resemble cardiac architecture and biomechanics. All HCM mutations resulted in hypercontractility with prolonged relaxation kinetics in proportion to mutation pathogenicity, but not changes in calcium handling. RNA sequencing and expression studies of HCM models identified p53 activation, oxidative stress, and cytotoxicity induced by metabolic stress that can be reversed by p53 genetic ablation. Our findings implicate hypercontractility as a direct consequence of thick-filament mutations, irrespective of mutation localization, and the p53 pathway as a molecular marker of contraction stress and candidate therapeutic target for HCM patients. : Cohn et al. show that thick-filament sarcomere mutations that cause hypertrophic cardiomyopathy result in hypercontractility in human cardiac microtissues engineered from isogenic iPSCs. These findings illustrate that hypercontractility is independent from changes in calcium handling and mutation location, but results in oxidative stress, p53 activation, and increased p53-dependent cell death with metabolic stress. Keywords: induced pluripotent stem cells, cardiomyopathy, heart failure, tissue engineering, sarcomere function, hypertrophyp53 signaling
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