Circulation, Vol 84, 1364-1377, Copyright © 1991 by American Heart Association
CF Starmer, AA Lastra, VV Nesterenko and AO Grant
BACKGROUND. The use of flecainide and encainide was terminated in the
Cardiac Arrhythmia Suppression Trial because of an excess of sudden cardiac
deaths in the active treatment group. Such events might arise from
reentrant rhythms initiated by premature stimulation in the presence of
anisotropic sodium channel availability. Drugs that bind to sodium channels
increase the functional dispersion of refractoriness by slowing (a result
of the drug-unbinding process) the transition from an inexcitable state to
an excitable state. It is interesting that encainide and flecainide unbind
slowly (15-20 seconds), whereas lidocaine and moricizine unbind rapidly
(0.2-1.3 seconds). METHODS AND RESULTS. With a computer representation of a
cable with Beeler-Reuter membrane properties, we found a small (6 msec)
vulnerable window that occurred 338 msec after the last drive stimulus.
Premature stimuli falling within the vulnerable window resulted in
unidirectional block and reentrant activation. In the presence of a slowly
unbinding drug, the window was delayed an additional 341 msec, and its
duration was extended to 38 msec. The delay (antiarrhythmic effect) before
the onset of the vulnerable window and its duration (proarrhythmic effect)
were both dependent on the sodium channel availability and the recovery
process. Both effects were also prolonged when sodium channel availability
was reduced by membrane depolarization. Defining the proarrhythmic
potential as the duration of the vulnerable window, we found that
hypothetical use-dependent class I drugs have a greater proarrhythmic
potential than non-use-dependent drugs. CONCLUSIONS. The antiarrhythmic and
proarrhythmic properties of pure sodium channel antagonists are both
dependent on sodium channel availability. Consequently, the price for
increased antiarrhythmic efficacy (suppressed premature ventricular
contractions) is an increased proarrhythmic vulnerability to unsuppressed
premature ventricular contractions.
ARTICLES
Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments
Department of Medicine, Duke University Medical Center, Durham, N.C. 27710.
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