Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) allow us to model and investigate human cardiac tissue under healthy and pathological conditions. This in turn produces valuable insight into the structural and functional consequences of genetic cardiac diseases, as well as the underlying mechanisms that produce them. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic cardiomyopathy that affects cardiac desmosomes and cell-to-cell attachment. These discrepancies in tissue electrophysiology create highly pro- arrhythmic tissue that can be used to study arrhythmias. The focus of the parent grant ?ARVD/C Dysfunction in Human Stem Cell-Derived Cardiac Tissue? is to use hiPSC-CMs from ARVC patients seeded onto engineered heart slices (EHS) to create a tissue model that can be used to gain insight into proarrhythmic mechanisms. Currently, ARVC iPSC-lines are relatively immature and therefore do not fully reproduce the pathological phenotype of ARVC. In this project we propose to supplement the parent grant by incorporating adipogenic media to promote disease progression in the slices. Supplementary Aim 1 will determine the degree to which the adipogenic medium augments the transcriptional, protein, structural, and electrophysiological characteristics of ARVC EHS. Supplementary Aim 2 will evaluate how the adipogenic medium affects exercise- enhanced arrhythmia in ARVC EHS. Ultimately, we wish to establish the first working human tissue model of ARVC that faithfully recapitulates its pathophysiological characteristics.
Modified culture media will be used to enhance the disease expression of a genetic cardiac disorder (arrhythmogenic right ventricular dysplasia) in heart cells derived from patient stem cells. Enhancing the manifestation of this disease will help to create the first tissue model of this disease in a dish, that can then be used to test new drug therapies and treatments.
