Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism

Document Type

Journal Article

Publication Date

1-1-2014

Journal

Europace

Volume

16

DOI

10.1093/europace/euu274

Keywords

Action potential duration; Amiodarone; Computer model of human action potential; D-Sotalol; Effective refractory period; Monophasic action potential; Post-repolarization refractoriness

Abstract

© The Author 2014. Aims: We hypothesized that amiodarone (AM), unlike D-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD)but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. Methods and results: We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability.We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16).We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VTwas non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. Conclusion: Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM. Published on behalf of the European Society of Cardiology. All rights reserved.

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