PROJECT SUMMARY (OVERVIEW) The overarching goal of this Program Project Grant (PPG) is to better understand the mechanisms by which altered sodium (Na+) and calcium (Ca2+) signaling contribute to electromechanical dysfunction in heart failure (HF). Project 1 (Wu) will define the mechanism of Na+-Ca2+ dysregulation leading to arrhythmia in HF and explore the impact of genetic heterogeneity on this phenomenon in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from patients with mutations associated with dilated cardiomyopathy (DCM), which is a major cause of heart failure. Project 2 (Bers) will do parallel mechanistic studies in adult HF rabbit myocytes and intact hearts to understand how to break the vicious cycle Na+/Ca2+ dysregulation. Importantly, quantitative mechanistic results will inform and be validated by rabbit and human computational models. Project 3 (Mercola) will advance these investigations by taking a high-throughput approach to the electrophysiological phenotypes to elucidate the role of non-ion channel proteins in the cellular dysfunction and drug-induced arrhythmia, identifying novel therapeutic targets in this pathway, and generate an in silico model to predict arrhythmia susceptibility. An Administrative Core A (Wu) will support the three projects. Computational Modeling Core B (Grandi) will support all three projects by creating multi-scale computational models of iPSC- CMs and adult myocytes and tissues that incorporate patient-specific channel and drug effects. Together, these cross-disciplinary and synergistic studies will help lead to our goal of “Precision Medicine” for preventing HF and sudden cardiac death.