021P Institute of Education, London
Winter Meeting December 2005


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

Hugh Clements-Jewery, Gajen S Kanaganayagam, Ruchi Kabra & Michael J Curtis, Cardiovascular Division, King’s College London, Rayne Institute, St. Thomas’ Hospital, London, SE17EH, UK.

Flecainide (FL) increased mortality following myocardial infarction (MI) in the Cardiac Arrhythmias Suppression (CAST) trial (Echt et al., 1991) by a mechanism that was not determined, but that has been speculated to involve an exacerbated risk of ventricular arrhythmias (VA) during the early phase of ischemia or, later, during infarct evolution (Greenberg et al., 1995; Hallstrom et al., 1995). Previously we found a weak proarrhythmic effect of FL on the “phase-1” arrhythmias occurring during early ischaemia in a perfused rat heart model (Farkas et al., 2002). Here we examined whether FL can exacerbate the “phase-2” VA that occur during infarct evolution, using a model with low baseline phase-2 VA susceptibility (Clements-Jewery et al., 2005).

Male Wistar rats (180-250g) were anaesthetized with 60 mg kg -1 pentobarbitone (i.p.) plus 250 iu heparin. Excised hearts were perfused (Langendorff mode) with Krebs’ modified to contain 3 meql -1 K + . The left main coronary artery was ligated for 240 min. Phase-2 VA occur >90 min after the onset of ischaemia (Clements-Jewery et al., 2005), so test solutions were introduced at 90 min. Hearts (n=8/group) received 0.74 or 1.48 m M FL, representing the peak unbound plasma and total blood concentrations, respectively, at therapeutic dosage (Farkas et al., 2002; Woosley et al., 1984), or vehicle (0.018% ethanol in Krebs’). Because it has been speculated that an interaction between catecholamines (CA) and FL contributes to FL’s proarrhythmic propensity (Packer et al., 1997), the protocol was repeated in separate hearts with 313 nM norepinep hri ne plus 75 nM epinephrine co-perfused with FL from 90 min. This CA protocol restores heart rate to levels seen in vivo , and increases coronary flow and QT interval, and shortens PR interval, by activation of cardiac β 1 and α 1 receptors (Clements-Jewery et al., 2002). Standard statistical methods were used ( Clements-Jewery et al., 2002 ).

Phase-1 ventricular fibrillation (VF) occurred in 88-100% of hearts in each group (p>0.05). FL caused no increase in the incidence of phase-2 VF (0% in all 3 groups), tachycardia (VT; range of incidences 13-25%) or premature beats (VPBs; 50-75%). The high FL concentration slowed heart rate by <10% (P<0.05) but had no other vascular or ECG effects. CA had the expected vascular and ECG effects (all p<0.05) noted above , and these were not altered by FL co-perfusion. CA caused a weak non-significant increase in phase-2 VF, VT and VPB incidence, but there was no proarrhythmic interaction with FL (incidence ranges, 0-25%, 0-38% and 75-100%, respectively).

In conclusion, FL-induced proarrhythmic activity does not appear to encompass independent facilitation of phase-2 VA, or a phase-2 interaction with CA.


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