title: Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism.
abstract: OBJECTIVE
  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.
  
  
  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 VT was 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiology Division, Veteran Affairs Medical Center, 50 Irving St, NW, Washington 20422, DC, USA Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA michael.r.franz@verizon.net.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Franz
authors.affiliation: Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gray
authors.affiliation: Cardiology Division, Veteran Affairs Medical Center, 50 Irving St, NW, Washington 20422, DC, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Karasik
authors.affiliation: Cardiology Division, Veteran Affairs Medical Center, 50 Irving St, NW, Washington 20422, DC, USA.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Moore
authors.affiliation: Cardiology Division, Veteran Affairs Medical Center, 50 Irving St, NW, Washington 20422, DC, USA Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Singh
mesh_terms: D000200:Action Potentials; D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone / Q000627:therapeutic use*; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D002304:Cardiac Pacing, Artificial; D003198:Computer Simulation; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D009716:Numerical Analysis, Computer-Assisted; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013015:Sotalol / Q000627:therapeutic use*; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012964:Sodium; D013015:Sotalol; D000638:Amiodarone
keywords: Action potential duration; Amiodarone; Computer model of human action potential; Effective refractory period; Monophasic action potential; Post-repolarization refractoriness; d-Sotalol