Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol

Objective: The present study was designed to examine the effects of chronic amiodarone on the different ventricular cell subtypes in situ and to evalu ate its interactions with sotalol. Methods: Three groups of dogs were studi ed. Group I (n=8) received no treatment. Group II (n=7) and group III (n=8) received, respectively, 100 and 200 mg amiodarone orally twice a day for 6 weeks to 8 months. In vivo studies were performed under halothane anesthes ia 14 h after the last administration of amiodarone. Three leads EGG, femor al blood pressure and left ventricular intramural monophasic action potenti als (MAP) were continuously recorded. Bradycardia was obtained by clamping the sinus node and beta-blockade and the heart was driven by atrial pacing. Three weeks before the in vivo experiments, the cellular electrophysiologi c properties of right ventricular tissues obtained by cardiac biopsy in six treated and six control dogs were studied with standard microelectrodes. R esults: Amiodarone produced a dose-dependent decrease in plasma levels of t riiodothyronine (T-3; 5.9+/-0.4 pM in control dogs, 3.1+/-0.2 pM in group I II, P<0.001) without affecting thyroxine (T-4). Under anesthesia, the QT in terval was 14% larger in group III compared to group I at a paced cycle len gth (PCL) of 1500 ms (P<0.05). This is consistent with the 10% increase in endocardial MAP duration in group III at the same PCL (P<0.05). There was n o significant increase in transmural dispersion of MAP duration. In group I , sotalol induced a significant reverse use-dependent increase in MAP durat ion. This effect was reduced in group II and completely suppressed in group III. Amiodarone prevented the sotalol-induced increase in transmural dispe rsion of ventricular repolarization which was 69+/-12 ms in untreated dogs, 41+/-8 ms in group II (P<0.05) and 34+/-8 ms (P<0.05) in group III at PCL= 1500 ms. Amiodarone also prevented the sotalol-induced ventricular tachyarr hythmias. In vitro, the action potential duration was longer in amiodarone- treated dogs that in control ones (208+/-5 ms versus 188+/-9 ms at PCL=1000 ms, P<0.05),The sotalol-induced prolongation of repolarization was reduced in amiodarone-treated dogs. Conclusion: Chronic treatment of dogs with ami odarone induced a moderate prolongation of the QT interval and MAP duration without affecting transmural dispersion of repolarization and inhibited th e effects of acute sotalol, including the prolongation of repolarization, t he increase in transmural dispersion of repolarization and the induction of arrhythmias. (C) 1999 Elsevier Science B.V. All rights reserved.