Myocyte necrosis initiates progressive myocardial damage, inflammation, calcification, and fibrosis in a transgenic mouse model and human proband with DSG2-related ARVC.
This study identifies myocyte necrosis as the primary initiator of progressive myocardial damage in DSG2-related ARVC, providing a mechanistic target for future therapies.
Mutations in the cardiac desmosomal protein desmoglein-2 (DSG2) are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). We studied the explanted heart of a proband carrying the DSG2-N266S mutation as well as transgenic mice (Tg-NS) with cardiac overexpression of the mouse equivalent of this mutation, N271S-dsg2, with the aim of investigating the pathophysiological mechanisms involved. Transgenic mice recapitulated the clinical features of ARVC, including sudden death at young age, spontaneous ventricular arrhythmias, cardiac dysfunction, and biventricular dilatation and aneurysms. Investigation of transgenic lines with different levels of transgene expression attested to a dose-dependent dominant-negative effect of the mutation. We demonstrate for the first time that myocyte necrosis is the key initiator of myocardial injury, triggering progressive myocardial damage, including an inflammatory response and massive calcification within the myocardium, followed by injury repair with fibrous tissue replacement, and myocardial atrophy. These observations were supported by findings in the explanted heart from the patient. Insight into mechanisms initiating myocardial damage in ARVC is a prerequisite to the future development of new therapies aimed at delaying onset or progression of the disease.
Pilichou et al. (Mon,) conducted a other in Arrhythmogenic right ventricular cardiomyopathy (ARVC). DSG2-N266S / N271S-dsg2 mutation was evaluated on Pathophysiological mechanisms of myocardial injury. Myocyte necrosis initiates progressive myocardial damage, inflammation, calcification, and fibrosis in a transgenic mouse model and human proband with DSG2-related ARVC.