PO-455617-17 PIRFENIDONE MITIGATES THE DEVELOPMENT OF ARRHYTHMOGENIC ATRIAL FIBROSIS DUE TO PREMATURE ATRIAL COMPLEXES IN A SWINE MODEL

Abstract

Atrial fibrosis is one of the major pathophysiologic mechanisms underlying the progression of atrial arrhythmias. We previously demonstrated in a swine model that frequent premature atrial complexes (PACs) promote atrial fibrillation (AF) via atrial fibrosis and slow conduction. Whether such fibrosis can be reversed or prevented is unknown. To evaluate the effect of (1) PAC eradication and (2) the antifibrotic drug pirfenidone (PFD) on atrial fibrosis in a swine model of frequent, dyssynchronous PACs. Thirty-five swine were exposed to 50% paced PACs from the lateral left atrium (LA) via the coronary sinus for 16 weeks in 4 groups: (1) controls without PACs (CTRL, n=10); (2) PAC group (PAC; n=10); 3) PACs followed by additional 6 weeks of PAC cessation (Rec-PAC, n=10); and (4) PACs treated with oral PFD (801mg 2 times per day) (PFD-PAC; n=5). Detailed EP study and echocardiography were performed at baseline and prior to sacrifice followed by blinded histological quantification of LA fibrosis. In the PAC group, peak atrial strain declined significantly at 16 weeks compared to CTRL. Compared to the PAC group, both the Rec-PAC and PFD-PAC groups had a less significant decline in peak atrial strain (terminal - baseline: PAC -17.7±3.3% vs. Rec-PAC -8.3±3.2% vs. PFD-PAC -11.5±3.0% vs. CTRL -0.7±4.2%; p<0.001). Conduction velocity (CV) was significantly decreased in PAC and Rec-PAC, but this decrease was attenuated in the PFD-PAC group (PAC CV 1.1±0.2m/s vs. Rec-PAC 1.2±0.1 m/s vs. PFD-PAC 1.3±0.1m/s vs. CTRL 1.5±0.2m/s; p<0.001). Posterior wall LA fibrosis was significantly increased in the PAC group, with no significant change after 6 weeks of recovery without PACs. However, the PFD-PAC group showed significantly lower fibrosis than either the PAC or Rec-PAC groups (Figure, Panel A). The PFD-PAC group also had less AF inducibility compared to the PAC and Rec-PAC groups (Panel B). In a swine model, frequent PACs produce atrial fibrosis and arrhythmogenic AF substrate. This fibrotic substrate did not regress after 6 weeks without PACs. However, treatment with PFD significantly attenuated the development of atrial fibrosis and AF inducibility. These findings suggest: (1) early management may be important for preventing ectopy-induced adverse atrial remodeling, and (2) pharmacological therapy targeted at the fibrotic substrate may play an important, novel role in the prevention of atrial remodeling and the substrate for developing AF.