Abstract 813: Downregulation of the Cardiac Sodium Channel Nav1.5 Mediates Obesity-Induced Atrial Fibrillation

Abstract

Background: Obesity increases atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. Emerging evidence supports reduced cardiac Na + channel (Nav1.5) expression and current ( I Na ) as one potential mechanism. Objective: We used an acquired (diet-induced obese, DIO) obese mouse model to test the hypothesis that obesity increases AF risk by downregulating Nav1.5. Methods: Weight, BP, plasma glucose, and F 2 -isoprostanes were measured in DIO mice and compared to controls. Echocardiography, EP studies, immunohistochemistry, Western blotting, cellular patch clamping and optical mapping studies were performed. Results: DIO (37.5±3.8) mice were heavier than controls ( 24.3 ±4.1;P <0.001). AF burden was 355±383 sec in DIO mice vs. 8.3± 21.4 sec in controls ( P <0.0001). Nav1.5 expression, I Na , atrial action potential duration (APD) and conduction velocity (CV) were reduced, and F 2 -IsoPs were increased. AF burden was reduced in the DIO model after chronic treatment with MitoTEMPO antioxidant, with partial restoration of the APD90, I Na and AP upstroke and reduction in F 2 -IsoPs. Conclusions: Mice with either acquired or genetic susceptibility to obesity are more prone to develop AF. And this is partially mediated by increased oxidative stress leading to downregulation of Nav1.5, shortened atrial APD and reduced atrial conduction velocity suggesting a possible reentrant mechanism of AF.