**3.3 Arrhythmogenic right ventricular cardiomyopathy (ARVC)**

ARVC is rare genetic cardiac disease with the prevalence ranging from 1:000 to 1:5000 worldwide. The histopathological hallmark of ARVC is the substitution of the cardiac myocytes with fibro-fatty deposits, particularly within the free wall of the right ventricle. The consequent results from the disruption of normal myocardial architecture can lead to right ventricular dysfunction, life-threatening arrhythmias, and SCD [100]. ARVC is caused by mutations in genes encoding desmosomal proteins such as plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2 (DSC2) [100]. Similar to immunohistological results from the biopsy sample from ARVC patients [101], ARVC hiPSC-CMs harboring a plakophilin 2 (PKP2) gene mutation mimicked the reduced *PKP2* immunosignal [102, 103]. In addition, clusters of lipid droplets accumulating within the cytoplasm were identified in ARVC-hiPSC-CMs associated with structural distortion of desmosomes [103]**.** Another study showed that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor gamma (PPARγ) activation underlie the pathogenesis of ARVC [104]. It has been observed that male ARVC patients develop earlier and more severe phenotype than female ARVC patients [105]. To understand whether sex hormones in serum may contribute to the major arrhythmic cardiovascular events in ARVC, Akdis and co-workers combined a clinical study and in vitro

hiPSC-CM model and showed that increased levels of testosterone accelerate ARVC pathologies, while premenopausal female estradiol levels slow down exaggerated apoptosis and lipid accumulation in ARVC hiPSC-CMs [106].
