Human hearts have an intrinsic regenerative potential following myocardial infarction

Abstract Myocardial infarction (MI) is a leading cause of death worldwide and can eliminate up to a third of the cardiomyocytes (CMs) within the heart. Several non-human mammalian models and a limited number of human heart studies suggest that CMs can proliferate during early development, but most CMs stop regenerating soon after birth. In contrast, rodent MI models show that CMs increase their regenerative capacity in response to ischemia, however this has not been shown in humans. Using immunostaining, multi-omics and a unique pre-mortem human heart collected 5 days post-MI, we show that adult human CMs exhibit an increased intrinsic regenerative potential in response to ischemia. Furthermore, single nucleus ribonucleic acid sequencing (snRNAseq) reveals the unique gene expression of post-MI proliferative human CMs. Finally, we demonstrate a novel clinical method to safely biopsy peri-ischemic post-MI human heart tissue and provide further evidence of ischemic CM regeneration. Developing a means to enhance this intrinsic CM regenerative potential could lead to novel therapeutics for cardiac injury and heart failure.