Investigating the Role of NOX2 and Fatty Infiltration in Obesity-Induced Atrial Fibrillation

Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase II (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knock-out (KO) mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and human atrial induced pluripotent stem cell-derived cardiomyocytes (hiPSC-aCMs) treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Additionally, serum and heart fractions from DIO mice show increased levels of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and omega-6 polyunsaturated fatty acids (n-6 PUFA) compared to lean controls. We, thus, hypothesize that obesity-induced atrial remodeling is mediated by the differential effects of chronic SFA, MUFA, and n-6 PUFAs using HiPSC-aCMs. HiPSC-aCMs are treated with conjugated PA, oleic acid (OA), or linoleic acid (500 µM) chronically, and changes in atrial ion channel expression and function, lipid peroxidation, and oxidative stress are evaluated using cellular patch clamping, multi-electrode arrays (MEA), qPCR, and western blotting. The direct impact of our studies will enable the development of mechanism-based therapeutic approaches for AF in obese patients, ultimately aiming to improve patient outcomes and reduce the burden of this arrhythmia.