Abstract 16912: Molecular Mechanisms Underlying the Beneficial Effects of Inhibition of Soluble Epoxide Hydrolase in the Prevention of Atrial Fibrillation
Introduction: Atrial fibrillation (AF) represents one of the most common arrhythmias seen clinically and is associated with a significant increase in morbidity and mortality, yet, current treatment paradigms have proven largely inadequate. Inflammation has been shown to play critical roles in the pathophysiology of AF.
Soluble epoxide hydrolase (sEH) catalyzes the hydrolysis of anti-inflammatory epoxyeicosatrienoic acids to corresponding pro-inflammatory diols. We have previously shown beneficial effects of sEH inhibitors (sEHIs) in cardiac failure and in the reduction of atrial arrhythmia inducibility. The objective of this study is to elucidate the molecular mechanisms underlying the prevention of atrial arrhythmia inducibility by sEHIs.
Methods: In vivo pressure-overload model was used to replicate chronic hypertension. Flow cytometry, electrophysiologic studies and optical mapping were used to determine the mechanistic roles of sEHIs on atrial fibrosis and the reversal of electrical remodeling in atrial myocytes.
Results: We demonstrate positive effects of sEHI in AF prevention by reducing 1) inflammation, 2) atrial structural remodeling by suppression of atrial fibrosis and hypertrophy (Fig A-D), and 3) electrical remodeling in atrial myocytes (Fig E-G). Mechanistically, inhibition of sEH enzyme results in a more than three-fold decrease in cytokines and chemokines (n=5, p<0.05), inhibition of NF-κB activation, reduction of oxidative and endoplasmic reticulum stress, and a more than five-fold decline in the phosphorylation of key signaling molecules including ERK1/2 and Smad2/3 in atrial myocytes and atrial fibroblasts (n=4, p<0.05).
Conclusions: This study provides insights into the underlying mechanisms leading to AF by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream molecules to a novel upstream therapeutic target by counteracting the inflammatory processes in AF.
Author Disclosures: P. Sirish: None. N. Li: None. V. Timofeyev: None. X. Zhang: None. L. Wang: None. J. Yang: None. K. Lee: None. A. Bettaieb: None. V. Lau: None. J. Lopez: None. F. Haj: None. C.M. Ripplinger: None. B. Hammock: None. N. Chiamvimonvat: None.
- © 2015 by American Heart Association, Inc.