(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.
(OVERVIEW) Heart failure (HF) is a complex disease that can lead to arrhythmias, and in many cases to sudden cardiac death. However, it remains elusive why some patients with the disease die suddenly while others have a more benign course. We aim to explain some of this variability by studying the effects of specific genes that cause the disease. This will ultimately lead to Precision Medicine treatments for HF with improved ability to inform each patient about their risk of sudden cardiac death and identify treatments that best benefit them based on their exact genetic, cellular, and molecular profiles.
