Connexin43 as a Therapeutic To Restore Cardiac Structure in Arrhythmogenic Heart Disease

Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is termed a fatal “disease of the desmosome” as 40–50% of patients harbor mutations in genes associated with the desmosome, a mechanical based cell‐cell junction structure found between cardiac muscle cells. Connexin43, the most dominant gap junction protein in ventricles, has been classically associated with electrical functions between adjacent cardiac cells, is consistently downregulated and considered an early disease hallmark of ARVD/C. However, limited efforts have focused on dissecting the role of connexin43 in ARVD/C, especially during end‐stage cardiac disease, where structural alterations are integral in facilitating ventricular failure, arrhythmias and premature death. Here we show that genetic restoration of connexin43 in human and mouse models of ARVD/C is sufficient to bypass desmosomal structural deficits as well as circumvent disease and premature death. In vitro studies demonstrated the ability of human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes to recapitulate classic variations in desmosomal structural defects and reveal connexin43 loss as a molecular predictor of physiological severity within ARVD/C hearts in a donor‐specific manner. Adenoviral restoration of connexin43 could rescue baseline and catecholamine induced electrical and contractile physiological deficits in ARVC hiPSC derived cardiomyocytes in absence or presence of desmosomal structural alterations. Furthermore, in vivo cardiac‐specific connexin43 gene therapy could prolong lifespan and restore cardiac structure (desmosomal protein expression) in a mouse model with end‐stage ARVC, in a dose‐dependent manner. Our results provide evidence for non‐canonical and independent functions for connexin43 in mechanical modulation of junctions. We anticipate that our findings will have broad implications in exploiting connexin43 as a viable therapeutic target in advanced diseases associated with underlying structural defects.Support or Funding InformationDepartment of Defense (PR170125); National Institutes of Health (NIH R01 HL142251‐A1); American Heart Association Postdoctoral Fellowship (18POST34060228)