Actions of flecainide on susceptibility to phase‐2 ventricular arrhythmias during infarct evolution in rat isolated perfused hearts

Abstract

1 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 mM, representing the peak unbound plasma and total blood concentrations, respectively, at 'therapeutic' dosage) has proarrhythmic activity on phase-2 arrhythmia susceptibility during infarct evolution. 2 To achieve this, we used the Langendorff-perfused rat heart preparation (n ¼ 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. 3 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). 4 In separate hearts, catecholamines (313 nM norepinephrine and 75 nM epinephrine) were coperfused with flecainide from 90 min of ischaemia. Catecholamine perfusion increased heart rate, coronary flow and QT interval, and shortened PR interval (all Po0.05), 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. 5 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.

Facilitation of ischaemia‐induced ventricular fibrillation by catecholamines is mediated by β1 and β2 agonism in the rat heart in vitro

“…CAT perfusion increased QT interval in the catecholamines + antagonist study (Figure D), as found previously (Clements‐Jewery et al, ; Clements‐Jewery et al, ). In previous studies, CATs were introduced 90 min after the onset of regional ischaemia to hearts that had, by this time, recovered sinus rhythm following the paroxysms of early (phase 1) arrhythmias (Clements‐Jewery et al, ).…”

“…As in previous studies (Clements‐Jewery et al, ; Clements‐Jewery et al, ), our method of mimicking sympathetic influence in a preparation that ordinarily has none is a practicable and tractable approach, and one that is validated in terms of achievement of what is intended – restoration of cardiac variables to levels typical of the conscious rat (Clements‐Jewery et al, ). However, perfusion with any mix of NA and adrenaline cannot mimic precisely the influence of the sympathetic nervous system on the heart in vivo , which comprises a mix of circulating CATs and noradrenergic neurotransmission, neither of which are ever in true steady state, meaning the possibility of additional VF‐facilitating actions secondary to autonomic turbulence.…”

“…At this time, rat hearts are susceptible to developing phase 2 arrhythmias, which manifest primarily by non‐re‐entrant mechanisms (Clements‐Jewery et al, ), different from the flow of injury current and re‐entry that operate during the first 30 min of ischaemia (phase 1) (Sidorov et al, ). CAT perfusion failed to facilitate phase 2 arrhythmias (Clements‐Jewery et al, ; Clements‐Jewery et al, ), despite the fact that the (predominantly non‐re‐entrant) mechanisms of phase 2 are supposedly highly susceptible to facilitation by CATs (Antzelevitch and Burashnikov, ). If the QT prolongation observed in the present study was to have had any effect on the re‐entrant mechanisms occurring during phase 1, suppression of VF rather than facilitation would be the expected outcome (Nattel, ).…”

Predicting drug‐induced slowing of conduction and pro‐arrhythmia: identifying the ‘bad’ sodium current blockers

“…Several studies show that Ic anti‐arrhythmic drugs like flecainide indeed enhance ischaemia‐induced VT and VF in isolated rat, feline and rabbit perfused hearts (Amitzur et al. , 2003; Clements‐Jewery et al. , 2006), in dogs in vivo (Patterson et al.…”

Contractile function assessment by intraventricular balloon alters the ability of regional ischaemia to evoke ventricular fibrillation

“…An intraventricular balloon (IVB) is commonly used in the rat isolated Langendorff perfused heart in order to measure left ventricular (LV) contractile function (Ridley and Curtis, ; Farkas et al ., ; Crook and Curtis, ). In addition, the rat isolated heart is also used to evaluate ischaemia‐induced and reperfusion‐induced cardiac arrhythmias such as ventricular fibrillation (VF) (Ridley et al ., ; Clements‐Jewery et al ., ; Crook and Curtis, ). Assessment of rhythm and LV contractility simultaneously in a single experiment is a strategy that would give a more comprehensive assessment of drug effects with reduced animal usage.…”