Project Summary Heart failure (HF) continues to have a major clinical and economic burden with stagnation in new therapies over the past two decades. A significant barrier to improved therapies is the incomplete understanding of the role of Na+/Ca2+ dysregulation in HF and its contribution to electrical and mechanical dysfunction. Project 1 of this Program Project Grant (PPG) aims to elucidate the role of Na+/Ca2+ dysregulation in electro-mechanical dysfunction associated with (HF) using human induced pluripotent stem cell-derived cardiomyocytes (iPSC- CMs) based modeling. The Project will first phenotype DCM iPSC-CMs from individuals with heterogeneous causative variants and genome edited controls. Then the role of molecular pathways that regulate Na+/Ca2+ homeostasis will be examined in each of the iPSC-CMs to define major pathways implicated in electro- mechanical dysfunction and delineate genotype-specific mechanisms within DCM. Drug treatment cellular responses and gene expression profiles will then be used to define genotype-specific drug responses and novel drug targets. We are well positioned to achieve the project goals within five years. The ability to define genotype-based mechanisms and drug treatments within HF is well aligned with NIH and NHLBI goals of precision medicine models.