Abstract P476: Determinants Of Atrial Fibrillation Mechanisms Using Metabolomic Profiling

Abstract

Introduction: Atrial fibrillation (AF) represents one of the most common arrhythmias seen clinically, yet, current treatment paradigms have proven largely inadequate. One of the main contributors to the pathophysiology of AF is inflammation. Hence, reduction of inflammation associated atrial remodeling represents a novel therapeutic strategy for the treatment of AF. Oxylipins are derived from arachidonic acid, which is metabolized through three pathways including the cytochrome P450 (CYP450) pathway. The CYP450 products, epoxyeicosatrienoic acids (EETs), are major anti-inflammatory metabolites with several cardioprotective effects. The central hypothesis to be tested is that patients with AF will demonstrate an increase in oxylipin profiles towards inflammatory features compared to patients with normal sinus rhythm (NSR). We further hypothesize that lipid mediators may represent a new therapeutic target for AF. Methods: In the cross sectional study, human atrial appendage specimens and blood from informed and consented patients undergoing coronary artery bypass graft surgery were obtained in accordance with the approved UC Davis IRB protocol. Metabolomic profiling and inflammatory cytokines were assessed from the plasma of patients using LC-MS/MS. The underlying mechanisms of AF were determined using an integrated approach with molecular biology, flow cytometry, and electrophysiology. Results: Metabolomic profiling shows a significant decrease in the EETs/DHETs ratios and EpOMEs/DiHOMEs ratios in the cohort with AF compared to patients in NSR. There was a significant increase in inflammatory cytokine, chemokine levels and oxidative stress in patients with AF compared to patients in NSR. There was a significant increase in nuclear translocation of NF-κB (nNF-κB) from patients with AF compared to NSR using western blot analysis. Assessment of total IκB and phosphorylated-IκB (pIκB) levels showed a decrease in IκB level and an increase in the pIκB levels associated with the activation of NF-κB in AF compared to the NSR cohort. Conclusions: The study provides important insights into metabolomic profiles in patients with AF and reveals the prospect of oxylipins being a novel therapeutic target in the treatment of AF.