| Mechanism of lethal proarrhythmia observed in the Cardiac Arrhythmia Suppression Trial: role of adrenergic modulation of drug binding. | |
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MedLine Citation:
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PMID: 9058849 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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D L Packer; T M Munger; S B Johnson; K T Cragun |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Review |
Journal Detail:
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Title: Pacing and clinical electrophysiology : PACE Volume: 20 ISSN: 0147-8389 ISO Abbreviation: Pacing Clin Electrophysiol Publication Date: 1997 Feb |
Date Detail:
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Created Date: 1997-06-05 Completed Date: 1997-06-05 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7803944 Medline TA: Pacing Clin Electrophysiol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 455-67 Citation Subset: IM |
Affiliation:
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Division of Cardiac Electrophysiology/Cardiology, Mayo Foundation, Rochester, Minnesota, USA. packer@mayo.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arrhythmias, Cardiac / chemically induced*, etiology* Flecainide / adverse effects, antagonists & inhibitors, pharmacology Heart Conduction System / drug effects, physiopathology Humans Myocardial Infarction / drug therapy, physiopathology |
| Chemical | |
Reg. No./Substance:
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54143-55-4/Flecainide |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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