Arrhythmogenic right ventricular cardiomyopathy (ARVC) is the most arrhythmogenic form of human heart disease, and one of the leading causes of sudden cardiac death in the young. Numerous studies have established the link between endurance exercise and disease penetrance in desmosomal mutation carriers, but the exact mechanism by which exercise alters disease pathogenesis and arrhythmic risk is unclear. There is increasing evidence that mechanical loading can play a defining role in cardiac tissue remodeling, including the regulation of key intercellular proteins such as plakoglobin and connexin-43. For cardiomyopathies affecting anchoring cell-cell junctions, such as ARVC, this lends to the hypothesis that mechanical stimulation may play a role in disease pathogenesis by augmenting electrophysiological or biomechanical defects. Thus far, much of the work characterizing the effects of mechanical loading on ARVC pathogenesis has not been verified in humans - a deficit that limits mechanistic insights, treatment options and patient counseling. In this study, I propose to investigate the influence of mechanical stimulation on cellular and tissue aspects of the disease (apoptosis, fatty deposits, gap junction remodeling, arrhythmia) in 3D tissue models of ARVC. In particular, we will apply strain to engineered heart slices seeded with induced pluripotent stem cells from clinically verified ARVC patients (a hybrid of acellular tissue and organotypic heart slice technology that recapitulates a 3D microenvironment for cell growth and enables mechanical interactions). Following mechanical stimulation, electrophysiological measurements will be used to measure changes in the cardiac action potential, and to determine if mechanical stimulation can cause ectopic rhythms in iPSC-derived model of ARVC. Next, we test the hypothesis that mechanical loading can recapitulate the overt stage phenotype of ARVC. Specifically, we determine if chronic mechanical loading can increase fat deposition, and alter the expression or localization of key proteins (i.e. connexin-43, plakoglobin, troponin-T a-sarcomeric actin, etc.). Finally, we utilize our platform for pharmacological interrogation by determining if treatment with anti-arrhythmic agents or SB216763, a compound shown to have restorative effects in a zebrafish model of ARVC, can be used to prevent the pro-arrhythmic effects of -adrenergic stimulation with isoproterenol, and the development of an overt-stage disease phenotype. Collectively, these studies will provide insight into the role of physio- mimetic mechanical stimulation in the progression of ARVC.