Variant-specific alterations of myocardial metabolism in patient-derived iPSC-cardiomyocyte models of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and linked to different variants in genes encoding sarcomeric proteins. Energy deficiency plays an important role in HCM, which may favourably respond to substrate manipulation and metabolic therapies. However, investigations on metabolic alterations in HCM are scarce and the impact of different sarcomeric variants on cardiac energetics remains unknown. We recently demonstrated disturbances of cellular metabolism, oxygen consumption rate, and contractility in genetically modified human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with sarcomeric mutations. To better understand altered energetic states and links to pathogenic sarcomeric variants, we plan to perform phenotyping via proteomics-based computational modeling of myocardial metabolism in iPSC-CMs obtained from HCM patients. This data will be correlated with advanced cardiac magnetic resonance imaging of myocardial function, energetics, and oxygenation. We do this to identify therapeutic targets in HCM and nucleate an immortalized cell biobank of patient iPSCs.