Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs

Background: Tachycardia-induced remodeling likely plays an important role i n atrial fibrillation (AF) maintenance and recurrence after cardioversion, and Ca2+ overload may be an important mediator. This study was designed to evaluate the relative efficacies of selective T-type (mibefradil) and L-typ e (diltiazem) Ca2+-channel blockers in preventing tachycardia-induced atria l remodeling. Methods: Dogs were given daily doses of mibefradil (100 mg), diltiazem (240 mg) or placebo in a blinded fashion, beginning 4 days before and continuing through a 7-day period of atrial pacing at 400 bpm. An elec trophysiological study was then performed to assess changes in refractorine ss, refractoriness heterogeneity and AF duration. Results: Mean duration of burst-pacing induced AF was similar in placebo (567 +/- 203 s) and diltiaz em-treated (963 +/- 280 s, P = NS) animals, but was much less in mibefradil -treated dogs (3.6 +/- 0.9 s, P < 0.002) and non-paced controls (66.6 +/- 2 .7 s). In contrast to mibefradil, diltiazem did not alter tachycardia-induc ed refractoriness abbreviation or heterogeneity. To exclude inadequate dosi ng as an explanation for diltiazem's inefficacy, we studied an additional g roup of dogs treated with 720 mg/day of diltiazem, and again noted no prote ctive effect. Acute intravenous administration of diltiazem to control dogs failed to alter atrial refractoriness or AF duration, excluding a masking of remodeling suppression by offsetting profibrillatory effects of the drug . Conclusions: Whereas the selective T-type Ca2+-channel blocker mibefradil protects against atrial remodeling caused by 7-day atrial tachycardia, the selective L-type blocker diltiazem is without effect. These findings are p otentially important for understanding the mechanisms and prevention of cli nically-relevant atrial-tachycardia-induced remodeling. (C) 2001 Elsevier S cience B.V. All rights reserved.