Inefficacy of a Highly Selective T‐Type Calcium Channel Blocker in Preventing Atrial Fibrillation Related Remodeling

Effects of T-Type Calcium Channel Blockade on AFBackground The T-type Ca2+ channel (ICaT) blocker mibefradil prevents AF-promoting remodeling occurring with atrial tachycardia, an action that has been attributed to ICaT inhibition. However, mibefradil has other effects, including ability to inhibit L-type Ca2+ channels, Na+ channels and cytochromes. Thus, the relationship between ICaT inhibition and remodeling protection in AF is still unknown. Objective To assess the effects of a novel highly selective Cav3 (ICaT) blocker, AZ9112, on atrial remodeling induced by 1-week atrial tachypacing (AT-P) in dogs. Methods Mongrel dogs were subjected to AT-P at 400 bpm for 7 days, with atrioventricular-node ablation and right-ventricular demand pacing (80 bpm) to control ventricular rate. Four groups of dogs were studied in investigator-blinded fashion: (1) a sham group, instrumented but without tachypacing or drug therapy (n = 5); (2) a placebo group, tachypaced but receiving placebo (n = 6); (3) a positive control tachypacing group receiving mibefradil (n = 6); and (4) a test drug group, subjected to tachypacing during oral treatment with AZ9112 (n = 8). Results One-week AT-P decreased atrial effective refractory period (ERP) at 6 of 8 sites and diminished rate-dependent atrial ERP abbreviation. Mibefradil eliminated AT-P-induced ERP-abbreviation at 4 of these 6 sites, while AZ9112 failed to affect ERP at any. Neither drug significantly affected AF vulnerability or AF duration. Conclusions ICaT blockade with the highly selective compound AZ9112 failed to prevent rate-related atrial remodeling. Thus, prevention of atrial electrophysiological remodeling by mibefradil cannot be attributed exclusively to ICaT blockade. These results indicate that ICaT inhibition is not likely to be a useful approach for AF therapy.