title: Actions of flecainide on susceptibility to phase-2 ventricular arrhythmias during infarct evolution in rat isolated perfused hearts.
abstract: The mechanism of flecainide-induced unexpected death remains uncertain. Phase-2 ventricular arrhythmias occur during infarct evolution. We examined whether flecainide (0.74 and 1.48 microM, representing the peak unbound plasma and total blood concentrations, respectively, at 'therapeutic' dosage) has proarrhythmic activity on phase-2 arrhythmia susceptibility during infarct evolution. To achieve this, we used the Langendorff-perfused rat heart preparation (n=8 per group) in which baseline phase-2 arrhythmia susceptibility is low. Left main coronary occlusion evoked phase-1 (acute ischaemia-induced) ventricular arrhythmias including fibrillation (VF) in all hearts. By 90 min, hearts were relatively arrhythmia-free. Randomized and blinded switch of perfusion to flecainide at 90 min caused no increase over baseline in the incidence of VF, tachycardia (VT) or premature beats (VPB) during the following 150 min of ischaemia, or during reperfusion (begun 240 min after the onset of ischaemia). In separate hearts, catecholamines (313 nM norepinephrine and 75 nM epinephrine) were co-perfused with flecainide from 90 min of ischaemia. Catecholamine perfusion increased heart rate, coronary flow and QT interval, and shortened PR interval (all P<0.05), actions that were not altered by flecainide. Catecholamine perfusion caused a weak nonsignificant increase in phase-2 VPB, VT and VF incidence, but there was no proarrhythmic interaction with flecainide. In conclusion, the present findings suggest that the increased risk of death associated with clinical use of flecainide is not due to facilitation of phase-2 ventricular arrhythmias.
authors.affiliation: Cardiovascular Division, Kings College London, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Clements-Jewery
authors.forename: Gajen Sunthar
authors.initials: GS
authors.lastname: Kanaganayagam
authors.forename: Ruchi
authors.initials: R
authors.lastname: Kabra
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Curtis
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D004198:Disease Susceptibility; D015195:Drug Design; D005424:Flecainide / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000150:complications*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000889:Anti-Arrhythmia Agents; D005424:Flecainide