Circulation, Vol 87, 562-572, Copyright © 1993 by American Heart Association
SC Krishnan and C Antzelevitch
BACKGROUND. We recently reported that sodium channel block can produce
opposite effects on action potential duration (APD) and refractoriness in
epicardial versus endocardial tissues of the canine ventricle. In addition,
strong sodium channel current inhibition was found to cause loss of the
action potential dome in epicardium but not endocardium, thus inducing a
marked dispersion of repolarization and refractoriness between epicardium
and endocardium as well as among neighboring epicardial sites. The marked
heterogeneity that evolves under these conditions provides a substrate for
the development of arrhythmias. Flecainide was found to induce
extrasystolic activity more readily than other sodium blockers. The present
study contrasts the electrophysiological actions of flecainide in canine
ventricular epicardium and endocardium and examines the characteristics of
flecainide-induced arrhythmias in epicardial sheets of canine ventricle.
METHODS AND RESULTS. Standard microelectrode techniques were used.
Flecainide (10-20 microM) produced either prolongation or marked
abbreviation of APD in epicardium but only minor changes in the APD of
endocardium. Marked abbreviation of APD in epicardium was due to loss of
the action potential dome (plateau phase). Arrhythmias displaying
characteristics of reentry could be readily induced in flecainide- treated
preparations either by increasing the stimulation rate or by introduction
of extrastimuli. Flecainide-induced slowing of conduction, more accentuated
at the faster stimulation rates, appeared to act synergistically with the
drug-induced dispersion of repolarization to generate reentry in these
relatively small sheets of epicardium. 4- Aminopyridine, a transient
outward current (Ito) blocker, reversed the flecainide-induced marked
abbreviation of APD in epicardium and abolished reentrant activity in all
cases. Flecainide failed to induce reentry in preparations pretreated with
4-aminopyridine. CONCLUSIONS. Our data suggest that the presence of a
prominent Ito in epicardium contributes the development of marked
electrical heterogeneity in the ventricle after exposure to flecainide.
Flecainide-induced dispersion of repolarization, especially when
accompanied by prominent conduction delays, results in extrasystolic
activity via a mechanism that we have termed "phase 2 reentry." Our results
also suggest a role for Ito blockers in the treatment of reentrant
arrhythmias.
ARTICLES
Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry?
Masonic Medical Research Laboratory, Utica, N.Y. 13504.
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