br Arrhythmogenic right ventricular cardiomyopathy ARVC an i
Arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart muscle disease, is associated with a high risk of arrhythmias and sudden cardiac death . It is characterized primarily by fibrofatty replacement of the right ventricular myocardium, which is often accompanied by subsequent progression to the left ventricle . ARVC is genetically determined by autosomal dominant inheritance, although recessive subtypes have been observed . Mutations in genes coding for desmosomal proteins, including desmoplakin, plakoglobin, plakophilin 2 (PKP 2), desmoglein 2, and desmocollin 2, have been identified in a significant number of patients . The clinical presentation of ARVC varies widely; diagnosis is often complex and involves structural, histological, electrocardiographic, arrhythmic, and genetic tests for the disease . Diagnosis is particularly difficult during the early phases of the disease when structural changes are not well-developed, leading to under-diagnosis. However, in this usually asymptomatic phase, some individuals may be at risk of sudden cardiac death. As such, it is important to increase the understanding of this complex condition through more patient-centered approaches, which may help with both diagnosis and management. Animal models have provided insight into the underlying mechanisms and pathophysiology of ARVC . However, differences in functional and conduction properties between animal and human cardiomyocytes limit the general applicability of these results. The advent of induced pluripotent stem cell (iPSC) technology has greatly changed the landscape . iPSCs are pluripotent stem diazoxide derived from somatic cells through the induction of gene expression; these cells can then be reprogrammed to differentiate into other mature cell lines. In 2006, Yamanaka et al. pioneered this technology in mice followed by in human cells . Since then, human iPSCs have been shown to be capable of differentiating into cardiomyocytes with cardiac-specific molecular, structural, and functional properties, indicating their great potential for the development of models of genetic cardiomyopathies . Models patient-specific iPSCs have been used to study various inherited cardiac disorders. iPSC models were developed for the examination of long QT syndrome and have shed light on the mechanism of arrhythmogenicity in these cells (such as early-after depolarizations and triggered arrhythmias) and were used to evaluate the effectiveness of current and new agents to treat the disease phenotype . For hypertrophic cardiomyopathy, iPSC models have increased the understanding of the molecular pathways of hypertrophy and arrhythmogenesis involved in abnormal calcium regulation and homeostasis within the cardiac sacromere . Similar models have shed light on the pathogenesis and treatment of other cardiac disorders such as familial dilated cardiomyopathy and catecholaminergic polymorphic ventricular tachycardia . Thus, using patient-specific iPSCs models for studying ARVC has immense potential benefits, allowing for an increased understanding of the pathogenesis, risk stratification, and diagnosis of ARVC patients, as well as exploration of potential therapeutic options. However, stem cell models must accurately reflect the mutations and characteristics of the disease. In a histopathological study involving myocardial biopsy samples acquired from patients with ARVC, Asimaki et al. found a marked reduction in immunoreactive signals for plakoglobin, but normal levels of the non-desmosomal adhesion molecule N-cadherin in ARVC patients . The authors suggested that this is a potentially useful new diagnostic test with a sensitivity and specificity of 91% and 82%, respectively. The test is limited because it requires myocardial biopsy, an invasive procedure with associated risks. Therefore, a less invasive but accurate and specific test may be more acceptable to patients and have a greater clinical impact. The first cellular model of ARVC by using patient-specific iPSC-derived cardiomyocytes was described by Ma et al. in 2012. They produced functional iPSC-derived cardiomyocytes by retroviral reprogramming of dermal fibroblasts taken from a male with clinical features of ARVC harboring a PKP2 gene mutation . The results provided novel insights into the disease. First, reduced gene expression of desmosomal proteins (PKP2 and plakoglobin) was observed compared to controls, with lower immunofluorescence signals for these proteins at the cell periphery. Second, after exposure of cardiomyocytes to adipogenic differentiation medium for 2 weeks, the investigators found greater amounts of lipids in ARVC cells compared to in control cells. This was confirmed by both Oil Red O staining for intracellular lipid droplets and qualitatively based on transmission electron microscopy. These findings indicate the abnormal trafficking or expression of desmosomal proteins in mutant cells and indicate an increased adipogenic potential in mutant cells, which may predispose patients to fibro-fatty changes observed in ARVC.