Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by ventricular arrhythmias and a fibrous or fibro-fatty infiltration of the heart muscle, which can be detected on cardiac magnetic resonance imaging and from the endomyocardial biopsy. However, these findings may not be apparent in the early stages of the disease, leading to diagnostic difficulties and an increased propensity for sudden death in the young. We aimed to establish a model of human heart disease in a dish using ARVC patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and determine whether the model could recapitulate key features of the disease phenotype.

Methods and results: Peripheral blood mononuclear cells (PBMCs) samples were obtained, after informed consent was obtained from all subjects, from a 61-year-old with a clinical diagnosis of ARVC, harboring a plakophilin 2 (PKP2) heterozygous stop codon mutation and healthy donor. Stable iPSC lines from healthy and patient donors were generated using non-integrating viral vectors for reprogramming after approval of the local ethical committee. After reprogramming, the karyotype showed genomic integrity in all iPSC lines and PKP2 mutation was confirmed in PKP2-iPSC with Sanger sequencing method. CMs derived from PKP2-iPSCs exhibited significantly reduced protein level of PKP2 when compared with control CMs (1.0 ± 0.24 versus 0.31 ± 0.04 respectively; p < 0.01). In addition, significant desmosomes abnormalities in the PKP2-iPSC-CMs in both the transmission electron microscopy (TEM) as well as PKP2 and plakoglobin immunofluorescence staining. Further, TEM showed that PKP2-iPSC-derived CMs were contained lipid droplets accumulation and sarcomeric proteins disorders compared with control CMs. CMs derived from ARVC-iPSCs exhibited markedly abnormal in frequency of intracellular calcium ([Ca²⁺]_i) oscillation rate compared with control CMs (1.0 ± 0.10 versus 0.5 ± 0.2 respectively; p < 0.001).

Conclusion: Patient-specific iPSC-derived CMs display key features of ARVC, which will help for understanding the disease. Consequently, detect the changes in heart muscle disorder at an early stage and thereby potentially advance treatment strategies for patients.