Thorough analysis of hiPSC-CM derived from a DSC2 patient, zebrafish and patient cohort, we identified abnormal repolarization dynamicity, prompting the discovery of a short QT interval in some ACM patients. By normalizing the increased repolarization reserve of ACM myocytes, class 3 AADs are likely to be the drugs of first choice for DSC2 patients. These findings may encourage randomized trials to evaluate class 3 antiarrhythmic drugs, alone or in combination with class I medications in ACM patients.

Dear Editor, Arrhythmogenic cardiomyopathy (ACM) is a rare, lifethreatening genetic disease frequently associated with mutations in desmosomal genes. 1 Histopathological hallmark includes fibrofatty replacement of myocardial tissue, potentially consisting of cardiomyocytes transdifferentiation into adipocytes. 2 The ACM involves electromechanical disorders and risks of developing arrhythmias and sudden cardiac death. We recently evidenced early electrical modifications of human-induced pluripotent stem cellsderived cardiomyocytes (hiPSC-CM) obtained from an ACM patient with a missense mutation (c.394C>T) in the DSC2 gene encoding desmocollin 2 (DSC2-hiPSC-CMs). These modifications are risk factors for triggering arrhythmias independently of fibrofatty replacement of myocardial tissue. 3 We now show that PPARγ, a master regulator of the cardiomyocytes transdifferentiation into adipocytes, is critical early in the pro-arrhythmogenic pathogenesis in ACM-DSC2-hiPSC-CMs.Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis of heart samples revealed a higher PPARγ gene expression level in the ACM-heart bearing the DSC2 mutation than in the control heart (Figure S1). We derived hiPSCs from the same ACM-DSC2 patient, differentiated them into hiPSC-CMs, and cultured them for 60 days as described. 3 We found a similar higher expression of PPARγ and of two pro-adipogenic target genes, perilipin and adiponectin, in DSC2-hiPSC-CMs versus control-hiPSC-CMs (Figure 1A-C). Despite lower expression, the pro-cardiac myosin light chain 2 ventricular (MLC2v) validated the cardiomyocyte phenotype of DSC2-hiPSC-CMs (Figure 1D). To confirm the involvement of PPARγ in the genes switch, we challenged DSC2-hiPSC-CMs with T0070907 (T007), which functions as a transcriptionally corepressor-selective PPARγ inverse agonist. 4 Incubation with T007 (1 μM), for 40 days (D20-D60) during the maturation phase, corrected the expres-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.