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 in atrial fibrillation (AF) maintenance and recurrence after cardioversion, and Ca(2+) overload may be an important mediator. This study was designed to evaluate the relative efficacies of selective T-type (mibefradil) and L-type (diltiazem) Ca(2+)-channel blockers in preventing tachycardia-induced atrial 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 electrophysiological study was then performed to assess changes in refractoriness, refractoriness heterogeneity and AF duration.


RESULTS
Mean duration of burst-pacing induced AF was similar in placebo (567+/-203 s) and diltiazem-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 (6.6+/-2.7 s). In contrast to mibefradil, diltiazem did not alter tachycardia-induced refractoriness abbreviation or heterogeneity. To exclude inadequate dosing as an explanation for diltiazem's inefficacy, we studied an additional group of dogs treated with 720 mg/day of diltiazem, and again noted no protective 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 Ca(2+)-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 potentially important for understanding the mechanisms and prevention of clinically-relevant atrial-tachycardia-induced remodeling.
Department of Medicine, University of Montreal, Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, H1T 1C8, Quebec, Canada.
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Fareh
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Bénardeau
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Nattel
D000704:Analysis of Variance; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D004110:Diltiazem / Q000494:pharmacology*; D004285:Dogs; D004554:Electric Countershock; D004562:Electrocardiography / Q000187:drug effects; D006325:Heart Atria / Q000378:metabolism; D020748:Mibefradil / Q000494:pharmacology*; D016037:Single-Blind Method; D018709:Statistics, Nonparametric; D013610:Tachycardia / Q000150:complications* / Q000378:metabolism
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D020748:Mibefradil; D004110:Diltiazem