Abstract 11604: Does T-type Calcium Channel Blockade Protect against Atrial Fibrillation Related Remodeling?
Background and objectives: The T-type Ca2+-channel (ICaT) blocker mibefradil (Mib) prevents AF-promoting remodeling occurring with atrial tachycardia. However, Mib has a variety of other actions, 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. AstraZeneca has developed a highly-selective Cav3 (ICaT) blocker (>50-fold selectivity for Cav3 over L-type Cav1.2, hERG, Nav1.5, Kv1.5, IKs, Ito, HCN4), AZ13399112 (AZ). We evaluated the effects AZ on atrial remodeling induced by 1-week atrial tachypacing (ATP) in dogs.
Methods and results: Mongrel dogs were subjected to ATP at 400 bpm for 7 days. Radiofrequency ablation of atrioventricular conduction and right-ventricular demand pacing (80 bpm) were used to control ventricular rate. Four groups of dogs were studied: 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 Mib (100 mg po daily; N=6); and 4) a test drug group, subjected to tachypacing during oral treatment with AZ (N=8). ATP decreased atrial effective refractory period (ERP) at 6 of 8 sites and diminished rate-dependent atrial ERP abbreviation. Mibefradil eliminated ATP-induced ERP-abbreviation at 4 of these 6 sites, while AZ failed to affect ERP at any (Table). Neither of the drugs significantly affected ventricular ERP or AF vulnerability. AZ plasma concentrations were measured and well within the pharmacologically active range.
Conclusions: Contrary to previous suggestions based on the poorly-selective compound Mib, ICaT blockade with the highly-selective AZ compound failed to prevent rate-related atrial remodeling. Thus, atrial remodeling prevention with Mib cannot be attributed exclusively to ICaT blockade, but requires other actions instead of, or in addition to, ICaT inhibition.
- © 2012 by American Heart Association, Inc.