Effect of irbesartan on development of atrial fibrosis and atrial fibrillation in a canine atrial tachycardia model with left ventricular dysfunction, association with p53.

Abstract

Effects of an angiotensin II receptor blocker, irbesartan (IRB), on the development of atrial fibrosis and atrial fibrillation (AF) were assessed in a canine model of atrial tachycardia remodeling (ATR) with left ventricular dysfunction, together with its possible association with involvement of p53. Atrial tachypacing (400&#xa0;bpm for 4&#xa0;weeks) was used to induce ATR in beagles treated with placebo (ATR-dogs, n&#xa0;=&#xa0;6) or irbesartan (IRB-dogs, n&#xa0;=&#xa0;5). Non-paced sham dogs served as control (Control-dogs, n&#xa0;=&#xa0;4). ATR- and IRB-dogs developed tachycardia-induced left ventricular dysfunction. Atrial effective refractory period (AERP) shortened (83&#xa0;&#xb1;&#xa0;5&#xa0;ms, p&#xa0;<&#xa0;0.05), inter-atrial conduction time prolonged (72&#xa0;&#xb1;&#xa0;2&#xa0;ms, p&#xa0;<&#xa0;0.05), and AF duration increased (29&#xa0;&#xb1;&#xa0;5&#xa0;s, p&#xa0;<&#xa0;0.05 vs. baseline) after 4&#xa0;weeks in ATR-dogs. ATR-dogs also had a larger area of atrial fibrous tissue (5.2&#xa0;&#xb1;&#xa0;0.5&#xa0;%, p&#xa0;<&#xa0;0.05 vs. Control). All these changes, except for AERP, were attenuated in IRB-dogs (92&#xa0;&#xb1;&#xa0;3&#xa0;ms, 56&#xa0;&#xb1;&#xa0;3&#xa0;ms, 9&#xa0;&#xb1;&#xa0;5&#xa0;s, and 2.5&#xa0;&#xb1;&#xa0;0.7&#xa0;%, respectively; p&#xa0;<&#xa0;0.05 vs. ATR for each). In ATR-dogs, p53 expression in the left atrium decreased by 42&#xa0;% compared with Control-dogs (p&#xa0;<&#xa0;0.05); however, it was highly expressed in IRB-dogs (+89&#xa0;% vs. ATR). Transforming growth factor (TGF)-&#x3b2;1 expression was enhanced in ATR-dogs (p&#xa0;<&#xa0;0.05 vs. Control) but reduced in IRB-dogs (p&#xa0;<&#xa0;0.05 vs. ATR). Irbesartan suppresses atrial fibrosis and AF development in a canine ATR model with left ventricular dysfunction in association with p53.