Electrophysiologic Effects of the New Class III Antiarrhythmic Drug Dofetilide in an Experimental Canine Model of Pacing-induced Atrial Fibrillation

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Abstract
Background: Dofetilide is a new class III antiarrhythmic drug currently under investigation for the treatment of supraventricular arrhythmias in humans. Dofetilide have been previously shown to be highly effective in terminating and suppressing reentrant atrial flutter in the experimental canine crush-injury model, in which its antiarrhythmic efficacy was correlated with prolongation of wavelength and reduction in dispersion of refractoriness, effects not produced by the class IA antiarrhythmic drug quinidine. The purpose of this study was to evaluate the antiarrhythmic efficacy and mechanisms of action of dofetilide in an experimen tal model of atrial fibrillation. Methods and Results: Dofetilide was administered intravenously to seven open-chest dogs with acute sustained atrial fibrillation induced by rapid atrial pacing for up to 4 hours. Mean atrial effective refractory period (ERP), dispersion of ERP, conduction velocity and wave length were determined by multipoint right atrial programmed stimulation and activation mapping using a 56-electrode mapping plaque on the right atrial free wall. Dofetilide pro longed average ERP by 22% from 104 ± 13 to 127 ± 15 ms (P < .001), prolonged maximum ERP by 11% from 129 ± 7 to 143 ± 10 (P < .003), had no effect on conduction velocity at 200 ms pacing cycle length, slowed conduction velocity by 16% from 0.89 ± 12 to 0.75 ± .17 ms at 150 ms pacing cycle length ( P < .001), increased wavelength by 20% from 93 ± 7 to 112 ± 9 mm ( P < .01), reduced dispersion of ERP by 24% from 11.4 ± 2.9 to 8.7 ± 2.3 (P = .016), and reduced the number of adjacent electrodes with ERP difference ≥20 ms by 67% from 18.4 ± 7.1 to 6.1 ± 4.2 (P < .001). Dofetilide reduced the number of excitation wavelets (total over three beats) entering the region of the mapping plaque by 38% from 5.0 ± .8 to 3.1 ± .4 (P < .002). Dofetilide terminated atrial fibrillation in all seven dogs at a mean of 3.4 ± 2.2 minutes into the loading infusion and prevented reinduction of atrial fibrillation in all seven dogs after completion of the loading infusion, while on maintenance infusion. Time to termination of atrial fibrillation correlated closely with change in ERP (r = 0.78, P = .036). Conclusions: Dofetilide was highly effective in terminating and suppressing sustained pac ing induced atrial fibrillation in this canine model. Time to termination of atrial fibrillation correlated with the degree of change in ERP produced by dofetilide. The mechanism of ter mination of atrial fibrillation by dofetilide appeared to be a progressive reduction and even tual extinction of re-entrant wavelets. The predominant electrophysiologic effects of dofetilide were prolongation of ERP and wavelength and a reduction in dispersion of refrac toriness. Dofetilide had little effect on conduction velocity in this model, except at very short pacing cycle lengths.

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