The T-Type Ca2+ channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs

Background-Ca2+ overload is believed to play a role in tachycardia-induced atrial electrophysiological remodeling. L-type Ca2+ channel blockers attenu ate effective refractory period (ERP) changes caused by 24 hours of atrial tachycardia but may not substantially alter atrial fibrillation (AF) induci bility, This study assessed the effects of the T-type Ca2+ channel blocker mibefradil on tachycardia-induced atrial remodeling. Methods and Results-Dogs subjected to rapid atrial pacing (400 bpm) for 7 d ays were treated with mibefradil (100 mg/d, n=8) or matching placebo (n=10) in blinded fashion. Radiofrequency ablation of atrioventricular conduction and ventricular pacing were used to control ventricular rate. Placebo dogs showed significant decreases in atrial ERP (76+/-5 ms at a cycle length of 300 ms) and increases in ERP heterogeneity (27.7+/-2.4%), AF duration (414 +/-232 seconds), and AF inducibility by single extrastimuli (41+/-10% of si tes) compared with 10 unpaced control dogs (ERP 114+/-3 ms, ERP heterogenei ty 13.8+/-0.9%, AF duration 7+/-3 seconds, AF inducibility 1.9+/-1.0% of si tes). The changes caused by atrial tachycardia were strongly attenuated in mibefradil dogs, with ERPs averaging 102+/-7 ms, ERP heterogeneity 18.8+/-1 .4%, AF duration 3+/-1 seconds, and AF inducibility 9.6+/-4.0% of sites. Am ong mibefradil-treated dogs, ERP, AF duration, and inducibility correlated with plasma drug concentration. Acute mibefradil administration did not alt er ERP or AF. Conclusions-Mibefradil, a drug with strong T-type Ca2+ channel blocking pro perties, prevents AF-promoting electrophysiological remodeling by atrial ta chycardia. These findings have important potential implications for the mec hanisms of tachycardia-induced atrial remodeling and demonstrate the feasib ility of preventing electrical remodeling caused by several days of atrial tachycardia.