Most heart conditions leading to sudden death or impaired heart pumping functions in the young people (< 35 years old) are the results of genetic mutations inherited from parents. It is very difficult to find curative therapy for these inherited heart diseases due to late diagnosis and lack of understanding in how genetic mutations cause heart dysfunction. One of these inherited heart diseases is named arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C). The signature features of sick ARVD/C hearts are progressive heart muscle loss and their replacement by fat and scar tissues, which can lead to lethal irregular heart rhythms or heart failure. We made significant breakthrough and successfully modeled sick ARVD/C heart muscles in cell cultures using versatile stem cells derived from ARVD/C patients’ skin cells with genetic mutations in desmosomal proteins (a specific type of cell-cell junctions in hearts), e.g. plakophilin-2 (Pkp2). These disease-specific stem cells can give rise to heart cells, which allow us to discover specific abnormalities in energy consumption of ARVD/C heart muscles that lead to their dysfunction and death. In Year 3, we have created and characterized additional stem cells lines from ARVD/C patients with different desmosomal mutations from Pkp2 mutations. We confirmed that the same metabolic deregulation occurred in heart muscles derived from new ARVD/C patient-specific stem cells with different mutations from Pkp2. Most importantly and in the Year 3, we cracked the disease codes and elucidated the entire key pathogenic networks underlying how mutations in Pkp2 lead to metabolic derangement in ARVD/C heart cells. Based on these novel findings, we have identified two potential and clinically safe prototype drugs that may slow down ARVD/C disease progression. We have requested a 7-month extension so that we could test these two new prototype drugs in their efficacy of treating an established ARVD/C mouse model so that we could obtain animal therapeutic and toxicity data in preparation for future clinical therapeutic testing in human patients with ARVD/C.