Project Summary/Abstract The proposal seeks to establish a pathophysiologic link between premature atrial contractions (PACs) and atrial fibrillation (AF). It has been well established that patients with frequent PACs are more likely to develop incident AF. But whether PACs are causative, or an epiphenomenon, is unclear. We hypothesize that PACs from the pulmonary veins or lateral left atrium (LA) lead to more atrial dyssynchrony compared to PACs from other regions, and that this dyssynchrony leads to atrial structural remodeling (via increased wall stress) and fibrosis that serves to facilitate AF maintenance. Our preliminary data in a swine model of chronic PACs demonstrates that chronic PACs lead to atrial electrophysiologic (slow conduction) and structural (fibrosis) remodeling, which is more pronounced for dyssynchronous PACs from the lateral left atrium compared to synchronous PACs from the septum or controls without PACs. In our first Aim, we will explore in the swine model how differences in PAC coupling- interval and atrial rate affect the degree of atrial remodeling and whether PAC cessation leads to complete regression of remodeling. We will test whether an antifibrotic drug, pirfenidone, prevents adverse atrial structural and electrical remodeling in the presence of PACs. We will also assess which molecular changes precede the development of cardiomyopathy to determine the critical molecular pathways leading to PAC mediated atrial remodeling. In our second Aim, we will establish the importance of these findings in humans by performing a longitudinal case-control study of patients with a high burden of atrial ectopy to identify if chronic PAC-induced atrial dyssynchrony leads to echocardiographic atrial remodeling. We will determine whether patients with frequent PACs have more echocardiographic left atrial remodeling and AF over time compared to those without PACs. We will also determine whether specifically dyssynchronous PACs are more likely to lead to atrial remodeling and AF than synchronous PACs. The significance of the proposed work is that if frequent PACs are found to lead to remodeling that leads to the development of incident AF, early intervention in patients with frequent PACs, with medical therapy or catheter ablation, may prevent the later development of atrial remodeling and AF. Successful prevention of AF could mean that millions of individuals could avoid debilitating loss of quality of life and enormous healthcare costs.