Antiremodeling Effect of Xanthine Oxidase Inhibition in a Canine Model of Atrial Fibrillation

Abstract

In a canine rapid atrial stimulation model of atrial fibrillation (AF), we have demonstrated an increased production of reactive oxygen species (ROS) along with electrical and structural remodeling. In the present study, we hypothesized that antioxidants can suppress atrial remodeling canines with AF. We therefore evaluated the effect of febuxostat, a xanthine oxidase (XO) inhibitor and a pure antioxidant, on atrial remodeling.AF was produced by performing a 3-week rapid atrial pacing (400 bpm) in 13 dogs divided into three groups: pacing + febuxostat group (n = 5; atrial pacing with 50 mg/day of febuxostat (administration); pacing control group (n = 5; atrial pacing without any drug administration); and non-pacing group (n = 3). Electrophysiological studies were conducted in the first 2 groups every week. Atrial tissue fibrosis was evaluated by Azan and immunofluorescent staining of fibronectin. Oxidative stress was evaluated by DHE and FCF-DA staining.Shortening of the refractory period and increase in AF inducibility appeared gradually in the pacing control group, but such changes were suppressed in the pacing + febuxostat group (P = 0.05). The pacing control group showed increase in fibrosis, which was suppressed in the febuxostat group. In DHE and DCF-DA staining, the pacing control group showed an increase in oxidative stress, which was suppressed in the pacing + febuxostat group. The pacing control group exhibited fibronectin expression, which was suppressed in the pacing + febuxostat group.The antioxidant effect of febuxostat may achieve an inhibition of new-onset AF in canines.

Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

“…In this context, CB13 abrogated AMPK downregulation and increased phosphorylation at its activation site, presumably improving metabolic and cellular function. Although we did not demonstrate a direct link between the electrophysiological effects and metabolic findings, we speculate that improved metabolic conditions of atrial cells in the presence of CB13 lead to less oxidative stress-dependent AERP shortening (Korantzopoulos et al, 2007;Yoshizawa et al, 2018). However, this hypothesis will have to be addressed more directly in future studies.…”

Serum uric acid and incident atrial fibrillation: A systematic review and dose–response meta‐analysis

“…Subsequently, several animal studies have examined the effect of uric acid reduction on atrial fibrillation. In a canine rapid atrial stimulation model of atrial fibrillation, Yoshizawa found an anti‐remodelling effect of allopurinol or febuxostat 51 . Furthermore, another study showed that this potential effect of allopurinol was mediated by the oxidative stress 52,53 .…”

“…In a canine rapid atrial stimulation model of atrial fibrillation, Yoshizawa found an anti-remodelling effect of allopurinol or febuxostat. 51 Furthermore, another study showed that this potential effect of allopurinol was mediated by the oxidative stress. 52,53 However, due to the limited sample size, the association of SUA lowering therapy and the incidence of atrial fibrillation should be further confirmed, especially in the young population.…”

Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction

“…7,11) Inhibition of myocardial fibrosis and oxidative stress can reduce AF occurrence. 12) These causes suggests that suppressing the process of atrial inflammation and fibrosis is a potential therapeutic target of AF.…”