Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive heart condition which causes fibro-fatty myocardial scarring, ventricular arrhythmias, and sudden cardiac death. Most cases of ARVC can be linked to pathogenic mutations in the cardiac desmosome, but the pathophysiology is not well understood, particularly in early phases when arrhythmias can develop prior to structural changes. Here, we created a novel human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of ARVC from a patient with a c.2358delA variant in desmoglein-2 (DSG2). These DSG2-mutant (DSG2Mut) hiPSC-CMs were compared against two wildtype hiPSC-CM lines via immunostaining, RT-qPCR, Western blot, RNA-Seq, cytokine expression and optical mapping. Mutant cells expressed reduced DSG2 mRNA and had altered localization of desmoglein-2 protein alongside thinner, more disorganized myofibrils. No major changes in other desmosomal proteins were noted. There was increased pro-inflammatory cytokine expression that may be linked to canonical and non-canonical NFκB signaling. Action potentials in DSG2Mut CMs were shorter with increased upstroke heterogeneity, while time-to-peak calcium and calcium decay rate were reduced. These were accompanied by changes in ion channel and calcium handling gene expression. Lastly, suppressing DSG2 in control lines via siRNA allowed partial recapitulation of electrical anomalies noted in DSG2Mut cells. In conclusion, the aberrant cytoskeletal organization, cytokine expression, and electrophysiology found DSG2Mut hiPSC-CMs could underlie early mechanisms of disease manifestation in ARVC patients.

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Non-CDC High Risk 4316 (88.5%) 16 (0.3%) 171 (3.5%) 17 (0.4%) 243 (5.6%) TOTAL 4877 21 (0.4%) 248 (5.0%) 22 (0.5%) 309 (6.3%) *CDC High Risk was determined by screening questions only, other CDC recommended screening including physical assessment fi ndings, hemodilution etc. were not included in this analysis. ** p< .000121/4877 (0.4%) potential donors tested HIV-1/2 antibody positive. The incidence in the CDC-HR group was 5/561 (0.9%) vs.16/4316 (0.3%) in the Non-CDC HR group (p= 0.15). The incidence of HCV+ tests in the CDC-HR group was 77/561 (13.7%) as compared to 171/4316 (3.5%) in the Non-CDC-HR group (p<.0001). The incidence of HBsAg + tests in the CDC-HR was 0.9% vs. 0.4% in the Non-CDC HR group (p=.18). The incidence of HB Ab+ tests in the CDC HR group was 66/561 (12%) vs. 243/4316 (5.6%) in the Non-CDC HR group (P<.0001). Summary and Conclusions: There was a trend for higher incidence of positive serology for all tests in the CDC HR group but this was signifi cant only for HCV and HB c Ab. The majority of positive cases for each of the tests were in the non High Risk group. These data need further confi rmation and should be considered when contemplating routine prospective NAT testing for potential organ donors. Considerations of logistics, cost and potential inadvertent loss of donors and organs associated with prospective NAT testing need to be weighed against the current low incidence of disease transmission.