Effects of verapamil on atrial fibrillation and its electrophysiological determinants in dogs.
BACKGROUND
Atrial tachycardia-induced remodeling promotes the occurrence and maintenance of atrial fibrillation (AF) and decreases L-type Ca(2+) current. There is also a clinical suggestion that acute L-type Ca(2) channel blockade can promote AF, consistent with an AF promoting effect of Ca(2+) channel inhibition.


METHODS
To evaluate the potential mechanisms of AF promotion by Ca(2+) channel blockers, we administered verapamil to morphine-chloralose anesthetized dogs. Diltiazem was used as a comparison drug and autonomic blockade with atropine and nadolol was applied in some experiments. Epicardial mapping with 240 epicardial electrodes was used to evaluate activation during AF.


RESULTS
Verapamil caused AF promotion in six dogs, increasing mean duration of AF induced by burst pacing, from 8+/-4 s (mean+/-S.E.) to 95+/-39 s (P<0.01 vs. control) at a loading dose of 0.1 mg/kg and 228+/-101 s (P<0.0005 vs. control) at a dose of 0.2 mg/kg. Underlying electrophysiological mechanisms were studied in detail in five additional dogs under control conditions and in the presence of the higher dose of verapamil. In these experiments, verapamil shortened mean effective refractory period (ERP) from 122+/-5 to 114+/-4 ms (P<0.02) at a cycle length of 300 ms, decreased ERP heterogeneity (from 15+/-1 to 10+/-1%, P<0.05), heterogeneously accelerated atrial conduction and decreased the cycle length of AF (94+/-4 to 84+/-3 ms, P<0.005). Diltiazem did not affect ERP, AF cycle length or AF duration, but produced conduction acceleration similar to that caused by verapamil (n=5). In the presence of autonomic blockade, verapamil failed to promote AF and increased, rather than decreasing, refractoriness. Neither verapamil nor diltiazem affected atrial conduction in the presence of autonomic blockade. Epicardial mapping suggested that verapamil promoted AF by increasing the number of simultaneous wavefronts reflected by separate zones of reactivation in each cycle.


CONCLUSIONS
Verapamil promotes AF in normal dogs by promoting multiple circuit reentry, an effect dependent on intact autonomic tone and not shared by diltiazem.
Department of Medicine and Research Center, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
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Bénardeau
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Fareh
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Nattel
D000818:Animals; D001281:Atrial Fibrillation / Q000139:chemically induced* / Q000503:physiopathology; D001341:Autonomic Nervous System / Q000503:physiopathology; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000633:toxicity*; D004110:Diltiazem / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006329:Heart Conduction System / Q000187:drug effects; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D014665:Vasodilator Agents / Q000633:toxicity*; D014700:Verapamil / Q000633:toxicity*
D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; D014700:Verapamil; D004110:Diltiazem; D002118:Calcium