Abstract
Heart failure is a multifaceted syndrome contributing significantly to mortality and hospitalization rates among the global population1. One of the prevalent causes of heart failure is ischemic heart disease (IHD), often caused by a blockage in a coronary artery, ultimately leading to the loss of myocardial tissue and contractile force2. The impact of this ischemic ambiance on the cardiomyocyte genome and transcriptome has not been thoroughly studied. During normal aging, cardiomyocytes progressively accumulate somatic mutations faster than many dividing cells, suggesting that internal and external factors specific to cardiomyocytes might influence this accumulation3. In this study, we analyzed single-cell whole-genome and transcriptome data from the left ventricle of 5 individuals with IHD and 10 healthy control individuals. We found that somatic DNA alterations significantly increase in IHD cardiomyocytes, with distinct mutational patterns indicating a disrupted DNA repair system and a cytotoxic environment, potentially associated with increased inflammatory response in the myocardium and a compensatory anti-inflammatory response in IHD. An in vitro iPS-derived hypoxic cardiomyocyte mutational profile indicates similar mutational spectra. Transcriptomic analysis revealed increased expression of EGR1, FOS, and collagen genes in ischemic heart cardiomyocytes, leading to a more fibrotic heart. The aberrant accumulation of DNA alterations and changes in transcriptional patterns in the ischemic heart cardiomyocytes provide insight into the development of IHD.