Abstract 4146109: Genetic Mouse Models of Obesity may provide mechanistic insights into atrial myopathy and atrial fibrillation: Insights from <i>Mc4r</i> -KO Mice

Background: Although a causal relationship between diet-induced obesity (DIO) and atrial fibrillation (AF) has been established, the underlying pathophysiological mechanisms in genetic obesity remain unclear. A high-fat diet (HFD) is used to generate DIO mice, but investigating genetic models of obesity may provide mechanistic insights into atrial myopathy, a precursor state of AF and stroke that is of increasing clinical and research interest. Objective: We used a genetic (melanocortin-4 receptor knockout, Mc4r -KO) mouse model of obesity to test the hypothesis that obesity-mediated atrial myopathy creates an electrophysiologic (EP) substrate for AF. Method: MC4R mutations are the most common monogenic form of obesity in humans. Transesophageal rapid (TE) pacing, invasive electrophysiology studies, immunohistochemistry, western blotting of plasma membrane proteins, mitoSOX staining, and whole-cell patch clamping were performed to evaluate AF burden and analyze the molecular and whole-animal EP phenotype. Results: Mc4r -KO mice were significantly heavier than wild-type lean controls ( Figure A ). AF burden was 257 ± 175 seconds in Mc4r -KO mice vs. 14.4 ± 29 seconds in control mice (P=XX; Figure B-C ). Patch-clamping and optical mapping studies showed that Mc4r -KO mice displayed a shortened atrial action potential (APD) (data&amp;P=) and reduced conduction velocity ( Figure D-F ). Mc4r -KO mice also displayed significantly reduced peak cardiac sodium current (I Na ) and delayed rectifier potassium current (I Kr ), but the L-type Ca 2+ current (I Ca,L ) was unchanged, indicating that the atrial APD changes are mostly due to I Na modulation ( Figure G-H ). Mc4r -KO atrial myocytes showed increased MitoSOX staining, indicating elevated ROS production ( Figure J ). Notably, fibrosis was not increased in Mc4r -KO mice, suggesting AF susceptibility is primarily due to electrical remodeling ( Figure K ). Conclusion: Our study indicates that mice with genetic susceptibility to obesity are more prone to develop AF primarily through electrical remodeling, with minimal structural changes, differing from DIO mice. This risk is in part mediated by modulation of the cardiac Na + channel and increased oxidative stress. These findings may have important implications for the management of obesity-mediated AF in humans.