Abstract 20445: Highly-Reactive Isolevuglandins Promote Atrial Arrhythmia Susceptibility in Obesity
Introduction: Obesity is a powerful independent risk factor for atrial fibrillation (AF) with a 5% risk of AF for every unit of BMI increase. Recent evidence reveals structural abnormalities in established, obesity-related AF, but the factors that initiate these processes are poorly understood. Both obesity and AF are linked to oxidative stress, but upstream therapy with conventional antioxidants has been disappointing. Highly-reactive dicarbonyl products of lipid peroxidation known as isolevuglandins (IsoLGs), that rapidly adduct and modify proteins, were recently identified as causative mediators for hypertension. We hypothesize that oxidative stress-mediated IsoLG formation promotes atrial cell injury and AF susceptibility in obesity.
Methods: C57BL/6J mice were fed either a low-fat (10%kcal from fat) diet (LFD) or high-fat (60%kcal from fat) diet (HFD) plus a potent IsoLG scavenger, 2-hydroxybenzylamine (2-HOBA), or an inactive structural analog, 4-hydroxybenzylamine (4-HOBA), that cannot scavenge IsoLG, for a total of 12 weeks with weight and tail-cuff blood pressures. AF inducibility was determined using a well-described transesophageal burst pacing model measuring parameters of inducible AF (n=10 in each group).
Results: Mice fed a high-fat diet experienced progressive weight gain compared to low-fat fed mice (Figure). HFD mice co-treated with 2-HOBA demonstrated a mild decrease in systolic BP and substantial protection from HFD-induced AF, not observed in animals co-treated with 4-HOBA, with no fibrosis, amyloid, or other gross pathologic defect.
Conclusion: These results demonstrate that IsoLGs have a critical role in the obesity-related AF substrate and support the concept of preemptively scavenging reactive dicarbonyl compounds as a novel therapeutic approach to prevent AF susceptibility.
Author Disclosures: J.K. Prinsen: None. P.J. Kannankeril: None. L.V. Yermalitskaya: None. S.R. Jafarian-Kerman: None. T.N. Sidorova: None. J.V. Barnett: None. O. Boutaud: None. A.H. Hasty: None. K.T. Murray: None.
- © 2016 by American Heart Association, Inc.