The T-Type Ca 2+ Channel Blocker Mibefradil Prevents the Development of a Substrate for Atrial Fibrillation by Tachycardia-Induced Atrial Remodeling in Dogs

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Abstract
Background —Ca 2+ overload is believed to play a role in tachycardia-induced atrial electrophysiological remodeling. L-type Ca 2+ channel blockers attenuate effective refractory period (ERP) changes caused by 24 hours of atrial tachycardia but may not substantially alter atrial fibrillation (AF) inducibility. This study assessed the effects of the T-type Ca 2+ channel blocker mibefradil on tachycardia-induced atrial remodeling. Methods and Results —Dogs subjected to rapid atrial pacing (400 bpm) for 7 days 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 sites) compared with 10 unpaced control dogs (ERP 114±3 ms, ERP heterogeneity 13.8±0.9%, AF duration 7±3 seconds, AF inducibility 1.9±1.0% of sites). 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. Among mibefradil-treated dogs, ERP, AF duration, and inducibility correlated with plasma drug concentration. Acute mibefradil administration did not alter ERP or AF. Conclusions —Mibefradil, a drug with strong T-type Ca 2+ channel blocking properties, prevents AF-promoting electrophysiological remodeling by atrial tachycardia. These findings have important potential implications for the mechanisms of tachycardia-induced atrial remodeling and demonstrate the feasibility of preventing electrical remodeling caused by several days of atrial tachycardia.