Vol. 305, Issue 1, 257-263, April 2003

Amiodarone-Induced Postrepolarization Refractoriness Suppresses Induction of Ventricular Fibrillation

Paulus Kirchhof, Hubertus Degen, Michael R. Franz, Lars Eckardt, Larissa Fabritz, Peter Milberg, Stephanie Läer, Joachim Neumann, Günter Breithardt and Wilhelm Haverkamp

Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, University Hospital Münster, Münster, Germany (P.K., H.D., L.E., L.F., P.M., G.B., W.H.); Cardiology Divisions, Veteran Affairs and Georgetown University Medical Centers, Washington, DC (M.R.F.); Department of Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf, Hamburg-Eppendorf, Germany (S.L.); and Department of Pharmacology and Toxicology, University Hospital Münster, Münster, Germany (J.N.)

It is still incompletely understood why amiodarone is such a potent antiarrhythmic drug. We hypothesized that chronic amiodarone treatment produces postrepolarization refractoriness (PRR) without conduction slowing and that PRR modifies the induction of ventricular arrhythmias. In this study, the hearts of 15 amiodarone-pretreated (50 mg/kg p.o. for 6 weeks) rabbits and 13 controls were isolated and eight monophasic action potentials were simultaneously recorded from the epicardium and endocardium of both ventricles. Steady-state action potential duration (APD), conduction times, refractory periods, and dispersion of action potential durations were determined during programmed stimulation and during 50-Hz burst stimuli, and related to arrhythmia inducibility. Amiodarone prolonged APD by 12 to 15 ms at pacing cycle lengths of 300 to 600 ms (p < 0.05) but did not significantly increase conduction times or dispersion of APD. Amiodarone prolonged refractoriness more than action potential duration, resulting in PRR (refractory period  APD at 90% repolarization, 14 ± 10 ms, p < 0.05 versus controls). PRR curtailed the initial sloped part of the APD restitution curve by 20%. During burst stimulation, pronounced amiodarone-induced PRR (40 ± 15 ms, p < 0.05 versus controls) reduced the inducibility of ventricular arrhythmias (p < 0.05 versus controls). Furthermore, in 35% of bursts only monomorphic ventricular tachycardias and no longer ventricular fibrillation were inducible in amiodarone-treated hearts (p < 0.05 versus controls). Chronic amiodarone treatment prevents ventricular tachycardias by inducing PRR without much conduction slowing, thereby curtailing the initial part of APD restitution. PRR without conduction slowing is a desirable feature of drugs designed to prevent ventricular arrhythmias.