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.