Abstract 14729: Weight Loss Reduces Atrial Fibrillation Inducibility and Burden in Severe Obesity Induced by Either High-Fat Diet or Genetic Hyperphagia in Mice

Abstract

Introduction: Atrial fibrillation (AF), the most common sustained arrhythmia worldwide, is associated with increased morbidity and mortality. Obesity is increasingly recognized as an important risk factor to develop AF and heart disease with a diet rich in fats leading to morbid obesity. Melanocortin-4 receptor (MC4R) gene is a critical regulator of energy homeostasis, and homozygous loss-of-function mutations cause hyperphagia and morbid obesity. Hypothesis: We hypothesized that obesity and its comorbidities can create a profibrillatory substrate for AF in high fat diet-induced obese (DIO) and MC4R knock-out (MC4R-KO) mice, and that this substrate can be reversed by weight loss. Methods: Transesophageal rapid pacing was performed using atrial burst pacing (cycle length: 50-15 ms, for 15 s) to determine AF inducibility (% of mice that develop AF) and AF burden (number of AF episodes and total AF duration/mouse) in lightly anesthesized normotensive mice (C57bl6 mice [LEAN], DIO, and MC4R-KO), with continuous ECG monitoring. Transthoracic echocardiography was performed to assess right (R) and left (L) atrial appendage (AA) sizes. Results: Atrial burst pacing induced AF in 91% of DIO and 100% of MC4R-KO vs. 50% of LEAN (P<0.01, N=8 mice/group). Compared to LEAN, both DIO and MC4R-KO exhibited greater number of inducible AF episodes (0.7±0.2 vs. 1.8±0.2 vs. 1.8±0.1, P<0.01, N=15 mice/group) with longer duration (17.9±3 vs. 196±22 vs. 244±34 s, P<0.0001, N=15 mice/group; Figure). Both DIO and MC4R-KO had greater LAA volumes as compared with LEAN (5.2±0.2 vs. 6.7±0.4 vs. 4.1±0.1 μl, P<0.01, N=8 mice/group). RAA volume was similar across groups. After 20% weight loss, both AF burden and LAA volumes were significantly reduced to those seen in LEAN (22±5 s, 4.5±0.1 μl, P<0.001, N=8 mice/group). Conclusions: High-fat diet or genetic hyperphagia-induced obesity increases LAA volume and creates a profibrillatory substrate for AF that can be reversed with weight loss.