Combined effects of up- and downstream therapies on atrial fibrillation in a canine rapid stimulation model

Background: Recent reports suggest angiotensin receptor blockers (ARBs) and some antiarrhythmic agents affect atrial remodeling in atrial fibrillation (AF). We evaluated the effect of combination therapy with olmesartan (Olm) and bepridil (Bep) in a canine model of AF. Methods and results: An atrial stimulation device was implanted in 10 dogs undergoing 6-week pacing at 400 bpm. They were divided into Olm (2 mg/kg/day) (n=5) and Olm+Bep (Olm, 2 mg/kg/day; Bep, 10 mg/kg/day) groups (n=5). Atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated weekly, and hemodynamics, atrial histology, and mRNA expression and protein expression of ion-channel and gap junction-related molecules at 6 weeks. Data were compared between groups and with non-pacing control and pacing-control groups from our previous report. The pacing-control group exhibited shortened AERP, decreased CV, increased AF inducibility and tissue fibrosis, and down-regulated L-type Ca2+ channel (LCC), SCN5A, Kv4.3 and connexin43 (Cx43). By comparison, the Olm group exhibited suppression of the decrease in CV and of the increase in AF inducibility, but no change in AERP shortening. The Olm+Bep group exhibited suppression of AERP shortening as well as the greatest decrease in AF inducibility. Histologically, tissue fibrosis was suppressed in Olm and Olm+Bep groups. Down-regulation of Cx43 was partly suppressed in the Olm group while that of LCC, SCN5A, and Cx43 was suppressed in the Olm+Bep group. Conclusion: Olm and Bep in combination suppressed AF inducibility more strongly than Olm alone, and may be more useful in the suppression of AF. (C) 2010 Elsevier Ireland Ltd. All rights reserved.