Abstract 14413: Febuxostat Prevents Atrial Remodeling via Decreasing Production of Reactive Oxygen Species in Canine Model of Atrial Fibrillation
Background: In a canine model of atrial fibrillation (AF), we have demonstrated that the increased fibrosis and production of reactive oxygen species (ROS) in the atrial tissue along with increase in atrial vulnerability. These changes were shown to be suppressed by carvedilol, a beta-blocker with anti-oxidative action. In this study, we examined the effect of ebuxostat, a xanthine oxidase (XO) inhibitor, on the atrial remodeling in the canine AF model to clarify the anti-remodeling effect of pure antioxidant.
Methods: AF model was produced by performing 3-week rapid atrial pacing in 13 dogs. They were divided into 3 groups; febuxostat group (n=6): pacing with febuxostat (50mg/day), control group (n=4): pacing without febuxostat, and non-pacing group (n=3). Electrophysiological study was carried out every week and the left atrial dimension was measured by echocardiography. At the end of protocol, atrial tissues were extracted for histological examination. To evaluate the production and in situ localization of ROS, frozen sections of left atrial tissues were stained with fluorophores sensitive to O2–, dihydroethydium(DHE), or hydrogen peroxide (H2O2), 5-(and 6)-chloromethyl-2,7-dichlorodihydrofluorescein diacetate, acetyl ester (DCF-DA).
Results: The electrophysiological changes, i.e., shortening of refractory period, decrease in conduction velocity and increase in AF inducibility appeared gradually in the control group, which were significantly suppressed in febuxostat group (p<0.05). The left atrial dimension was larger in the control group with more prominent histological changes, including dys-alignment of myocytes and extracellular fibrosis. In contrast in the febuxostat group, left atrial expansion was not observed, and the degree of tissue fibrosis was suppressed. In DHE and DCF-DA staining, the control group exhibited obvious increase in quantity of fluorescence in the nucleus (DHE) and cytoplasm (DFC-DA), however, such exhibition of oxidative stress was suppressed in the febuxostat group.
Conclusion: Febuxostat consistently suppressed the progression of atrial tissue fibrosis and electrophysiological changes. The anti-oxidant effect of febuxostat may achieve an anti-remodeling effect in this AF model.
- © 2013 by American Heart Association, Inc.