Abstract 16944: Cx43 Hemichannel Inhibition Prevents Arrhythmias in Duchenne Muscular Dystrophy Mice
Duchenne muscular dystrophy (DMD) is a fatal disease characterized by skeletal and cardiac muscle pathologies due to the absence of the membrane stabilizing protein dystrophin. Although most research has focused on skeletal muscle, 100% of patients over the age of 18 are diagnosed with cardiomyopathy, associated with the development of arrhythmias and eventual heart failure. The connexin proteins, normally responsible for the formation of gap junctions, are known to play a significant role in cardiac conduction. Remodeling of these proteins has been linked to the development of arrhythmias following myocardial infarction.
Through analysis of Cx43, the most abundant connexin in the heart, we found that both mild mdx and severe mdx:utr(-/-) models of DMD display significant protein upregulation and mislocalization to the lateral sides of cardiomyocytes. Interestingly, this pattern is more extreme in the severe model, consistent with the degree of cardiac phenotype. To assess the role of Cx43 in DMD arrhythmogenesis, anesthetized mice were subjected to isoproterenol challenge (5mg/kg IP) and ECGs were recorded. mdx mice developed non-sustained ventricular tachycardia (VT) while mdx:utr(-/-) mice developed sustained VT and eventually died within 30 minutes of challenge. To specifically inhibit the lateralized hemichannel function of Cx43, the protein mimetics Gap 26 and Gap 19 were administered to mice prior to challenge (1ug/kg IV, 10ug/kg IV). Amazingly, no arrhythmias developed in mdx mice, and mdx:utr(-/-) mice at even late stages of disease showed significantly improved scores with prevention of heart failure and death due to the challenge. In addition, RR and QRS intervals in all mice treated were closer to baseline than following isoproterenol challenge without treatment. These findings represent a novel mechanism to treat DMD cardiomyopathy and may have the potential to treat similar forms of heart disease that display lateralized Cx43.
Author Disclosures: J.P. Gonzalez: Other; Modest; Patent Filing. J. Ramachandran: None. J. Contreras: Other; Modest; Patent Filing. D. Fraidenraich: Other; Modest; Patent Filing.
- © 2014 by American Heart Association, Inc.