Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease associated with increased risk of sudden cardiac death. The only treatment proven to reduce this risk is an implantable defibrillator. Originally named arrhythmogenic right ventricular dysplasia after autopsy studies revealed fibro-fatty replacement of the right ventricle, nomenclature has been updated to reflect a genetic disease with a structurally normal heart at birth that can perturb myocytes in both ventricles and increase risk for sudden death. In other nonischemic cardiomyopathies, such as hypertrophic or dilated cardiomyopathy, the risk of sudden death is associated with progressive structural remodeling of the heart involving myocyte disarray, fibrosis, and changes in cardiac chamber dimensions. Although progressive myocardial injury and accumulation of fibro-fatty scar tissue contribute to development of arrhythmias in advanced ACM, recent evidence has highlighted the importance of early subclinical electrophysiological changes which contribute to the arrhythmogenic substrate in this disease. 1 Importantly, arrhythmias are typically the first clinical manifestation of ACM and often precede histologic changes in heart muscle or onset of ventricular dysfunction2 supporting a primary mechanism independent of macroscopic or histological changes.

A majority of cases of ACM can be attributed to variants in genes that encode desmosome proteins, such as the desmosomal cadherin, desmoglein 2 (Dsg2). How mutations in cell-cell adhesion components of intercalated discs promote arrhythmias prior to development of structural changes in the myocardium is not well established. However, reduced immunoreactive signal at intercalated discs for the major ventricular gap junction protein, Cx43 (connexin 43), is a prominent