Abstract 14079: Inhibition of NOX2 Prevents Obesity-Mediated Atrial Fibrillation

Abstract

Introduction: Obesity is an independent risk factor for atrial fibrillation (AF). While oxidative stress plays an important role in obesity-mediated AF, the specific pathways that cause atrial remodeling remain unclear. NADPH oxidase 2 (NOX2), a major source of cytosolic reactive oxygen species (ROS) production in the heart, is increased in diet-induced obese (DIO) mice and can independently predispose to post-operative AF via atrial remodeling. Hypothesis: We used a Nox2 -knock-out (KO) mouse model and mature human iPSC-derived atrial cardiomyocytes (hiPSC-aCMs) to test the hypothesis that NOX2 increase modulates ion channel remodeling in obesity-mediated AF. Methods: DIO mice and palmitic acid (PA)-treated hiPSC-aCMs were given a NOX blocker (apocynin), and GSK2793059, a NOX2-specific small molecule inhibitor respectively. Trans-esophageal rapid (TE) pacing was used to examine changes to the AF phenotype. Whole-cell patch clamping, qPCR, Western blotting, and electrical mapping were performed to study ion channel remodeling in both models. Results: DIO, DIO-Apocynin, and DIO Nox2 -KO mice displayed increased weight compared to control and Nox2 -KO mice (Figure A). After TE pacing, DIO-Apocynin mice displayed 28.2 ± 25.4 s and DIO Nox2 -KO mice displayed 17.4 ± 31.8 s compared to 167.3 ± 168.9 s in DIO mice (Figure B). Electrophysiological studies show that Nox2 inhibition reverses ion channel remodeling in I Na , I Ks , and I Ca,L (Figure D-F), and atrial fibrosis (Figure H) and prolongs the atrial action potential (AP; Figure C) and increases conduction velocity (CV; Figure G-I) in both DIO mice (Figure C-I) and PA-hiPSC-aCMs (Figure J-L). Conclusions: Collectively, genetic and pharmacological inhibition of NOX2 in DIO mice and PA-treated hiPSC-aCMs abrogate ion channel and structural remodeling and prevents the development of obesity-mediated AF. These findings have important implications for targeted antioxidant therapy for obese patients with AF.