Document Detail

Mechanism of lethal proarrhythmia observed in the Cardiac Arrhythmia Suppression Trial: role of adrenergic modulation of drug binding.
MedLine Citation:
PMID:  9058849     Owner:  NLM     Status:  MEDLINE    
A variety of recent in vivo studies have sought to clarify the mechanism underlying the proarrhythmic response of flecainide in the Cardiac Arrhythmia Suppression Trial (CAST). Increased inducibility of relatively stable ventricular arrhythmias in subacute and chronic postinfarction models has been universally observed. The arrhythmogenesis has been explained in part by drug induced modulation of anisotropic conduction in persistently ischemic tissue, increased durations of vulnerable windows, enhanced generation of unidirectional block with the introduction of extrastimuli, variability of repolarization within the ventricular wall, and the creation of stable reentrant circuits with narrow central zones of propagation. While these data explain arrhythmogenesis in general, malignant ventricular arrhythmia capable of producing the excess sudden or arrhythmic death mortality in the CAST trial have not been universally observed, nor have the proported beneficial effects of beta-blockade seen in the CAST trial and other studies been explained. Additional studies examining the adrenergic modulation of flecainide binding have shown reversal of flecainide effects in normal tissue, but paradoxical amplification of flecainide induced conduction slowing in depolarized tissue. This variable effect in normal versus abnormal tissue produces significant dispersions of conduction with an expected increased propensity for conduction failure in response to ectopy, increased liminal length for impulse propagation, enhanced vulnerability to premature extrastimuli, and completed reentrant circuits in regions of depressed membrane potentials. This, along with the decrease in action potential duration and accompanying refractoriness in the setting of adrenergic modulation may favor more malignant double wavelet or unstable ventricular arrhythmias.
D L Packer; T M Munger; S B Johnson; K T Cragun
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Pacing and clinical electrophysiology : PACE     Volume:  20     ISSN:  0147-8389     ISO Abbreviation:  Pacing Clin Electrophysiol     Publication Date:  1997 Feb 
Date Detail:
Created Date:  1997-06-05     Completed Date:  1997-06-05     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7803944     Medline TA:  Pacing Clin Electrophysiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  455-67     Citation Subset:  IM    
Division of Cardiac Electrophysiology/Cardiology, Mayo Foundation, Rochester, Minnesota, USA.
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MeSH Terms
Arrhythmias, Cardiac / chemically induced*,  etiology*
Flecainide / adverse effects,  antagonists & inhibitors,  pharmacology
Heart Conduction System / drug effects,  physiopathology
Myocardial Infarction / drug therapy,  physiopathology
Reg. No./Substance:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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