Arrhythmogenic Cardiomyopathy: Exercise Pitfalls, Role of Connexin-43, and Moving beyond Antiarrhythmics

Abstract

Arrhythmogenic Cardiomyopathy (ACM), a Mendelian disorder that can affect both left and right ventricles, is most often associated with pathogenic desmosomal variants that can lead to fibrofatty replacement of the myocardium, a pathological hallmark of this disease. Current therapies are aimed to prevent the worsening of disease phenotypes and sudden cardiac death (SCD). Despite the use of implantable cardioverter defibrillators (ICDs) there is no present therapy that would mitigate the loss in electrical signal and propagation by these fibrofatty barriers. Recent studies have shown the influence of forced vs. voluntary exercise in a variety of healthy and diseased mice; more specifically, that exercised mice show increased Connexin-43 (Cx43) expression levels. Fascinatingly, increased Cx43 expression ameliorated the abnormal electrical signal conduction in the myocardium of diseased mice. These findings point to a major translational pitfall in current therapeutics for ACM patients, who are advised to completely cease exercising and already demonstrate reduced Cx43 levels at the myocyte intercalated disc. Considering cardiac dysfunction in ACM arises from the loss of cardiomyocytes and electrical signal conduction abnormalities, an increase in Cx43 expression-promoted by low to moderate intensity exercise and/or gene therapy-could very well improve cardiac function in ACM patients.

Keywords: arrhythmogenic cardiomyopathy; connexin-43; exercise; fibrofatty infiltration.

Figure 1

Survival analyses in ACM subjects. (A) Event-free survival from VT/VF in ACM patients. (B) Percent survival in ACM mice subjected to forced swim or (C) psychosocial stress. Graphical abstract demonstrating mice under stress whilst performing forced exercises (D), during voluntary exercise (E) demonstrates no psychological and/or psychosocial stress in mice. For (D,E), prior research outcomes *, ^‡, ^†, ^β correspond with the text immediately below the image. [h], human; [m] murine studies. For (A–C), images are reprinted with permission from (A) [94] (2103, Elsevier), (B) [102] (2021, Chelko S.P.) and (C) [97] (2020, Chelko S.P.).