Project Summary: Previous research has shown that abnormal electrical conduction in the infarct border zone is important in the pathogenesis of ventricular arrhythmias in the setting of coronary artery disease. These abnormalities are due to remodeling in tissue architecture (fibrosis) and of connexins in gap junctions. Similarly, structural remodeling from congestive heart failure (CHF) leads to diffuse fibrosis and altered connexin expression that thus predispose to arrhythmias. This proposal seeks to investigate therapeutics that target these distinct features of remodeling (abnormal connexin function/distribution and fibrosis) in order to suppress ventricular arrhythmias that can lead to sudden cardiac death. Pirfenidone (PIRF) is an anti-fibrosis agent that has been shown to significantly diminish and possibly reverse collagen formation in various animal models, likely through inhibition of transforming growth factor-61. Using canine models of CHF and healed myocardial infarction (Ml), we will assess the effects of pirfenidone on ventricular fibrosis and test the hypothesis that attenuation of such ventricular fibrosis will decrease adverse electrophysiologic remodeling and thus ameliorate the arrhythmogenic potential of ventricular remodeling. We will correlate various measures of fibrosis to electrophysiologic parameters, such as conduction heterogeneity, dispersion of repolarization, and ventricular arrhythmia susceptibility. Rotigaptide (ZP123) is a novel hexapeptide that promotes cell-cell coupling through improved gap junction conductance without affecting membrane currents. We will use the same canine models of healed Ml and CHF to study the effects of rotigaptide on ventricular arrhythmia susceptibility and connexin remodeling using optical mapping, molecular, immunohistochemistry, electrophysiologic and histological studies. The results of these studies may add supporting evidence for pirfenidone and rotigaptide as potential therapeutic agents for the treatment of arrhythmias, particularly those that can lead to sudden cardiac death. Relevance: Nearly half a million people die from sudden cardiac death annually in the United States, with the vast majority of cases due to fatal cardiac arrhythmias. Current drug therapy is marginally effective, and we propose to study two drugs with potential anti-arrhythmic effects: rotigaptide, which improves connections between heart cells, and pirfenidone, which reverses adverse structural changes in the heart. We plan to show that the actions of these drugs will decrease fatal cardiac arrhythmias in animal models of congestive heart failure and myocardial infarction.