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

Fareh, Samir ; Bénardeau, Agnès ; Nattel, Stanley

In: Cardiovascular Research, 2001, vol. 49, no. 4, p. 762-770

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    Titre
    • Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs
    Auteur
    • Fareh, Samir. Department of Medicine, University of Montreal, Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
    • Bénardeau, Agnès. Department of Medicine, University of Montreal, Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
    • Nattel, Stanley. Department of Medicine, University of Montreal, Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
    Type de document
    • Postprint
    Identifiant OAI-PMH
    • oai:doc.rero.ch:292049
    Summary
    Background: Tachycardia-induced remodeling likely plays an important role in 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-type (diltiazem) Ca2+-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 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 potentially important for understanding the mechanisms and prevention of clinically-relevant atrial-tachycardia-induced remodeling