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.
Project 1 Narrative Heart failure remains a major cause of significant morbidity and mortality due to pump failure and arrhythmia. A major barrier to progress in treating these mechanical and electrical problems is the incomplete understanding of cellular mechanisms leading to this condition. Project 1 will create heart cells from patients with heart failure, called induced pluripotent stem cell-derived cardiomyocytes, to study the cellular mechanisms causing impaired contraction and arrhythmia in these patients, impact of genetic variation on these mechanisms, and identify new drug treatments. This stands to provide tremendous improvement to patients with heart failure.