Preventing Ventricular Fibrillation by Flattening Cardiac Restitution

Ventricular fibrillation is the leading cause of sudden cardiac death. In fibrillation, fragmented electrical waves meander erratically through the heart muscle, creating disordered and ineffective contraction. Theoretical and computer studies, as well as recent experimental evidence, have suggested...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 97; no. 11; pp. 6061 - 6066
Main Authors Garfinkel, Alan, Kim, Young-Hoon, Voroshilovsky, Olga, Qu, Zhilin, Kil, Jong R., Lee, Moon-Hyoung, Karagueuzian, Hrayr S., Weiss, James N., Chen, Peng-Sheng
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences of the United States of America 23.05.2000
National Acad Sciences
National Academy of Sciences
The National Academy of Sciences
SeriesFrom the Cover
Subjects
Action potentials
Action Potentials - drug effects
Animals
Anti-Arrhythmia Agents - pharmacology
Anti-Arrhythmia Agents - therapeutic use
Biological Sciences
Bretylium Compounds - pharmacology
Bretylium Compounds - therapeutic use
Cardiac arrhythmia
Cardiac Pacing, Artificial
Computer Simulation
Cromakalim - pharmacology
Cromakalim - therapeutic use
Diastole - physiology
Drug Design
Drug Evaluation, Preclinical
Electric potential
Fall lines
Fibrillation
Fluorescent Dyes
Heart Conduction System - drug effects
Heart Conduction System - physiopathology
Membrane potential
Models, Biological
Oblateness
Prescription drugs
Pyridinium Compounds
Restitution
Scrolls
Swine
Ventricular fibrillation
Ventricular Fibrillation - drug therapy
Ventricular Fibrillation - physiopathology
Ventricular Fibrillation - prevention & control
Wave fronts
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Summary:Ventricular fibrillation is the leading cause of sudden cardiac death. In fibrillation, fragmented electrical waves meander erratically through the heart muscle, creating disordered and ineffective contraction. Theoretical and computer studies, as well as recent experimental evidence, have suggested that fibrillation is created and sustained by the property of restitution of the cardiac action potential duration (that is, its dependence on the previous diastolic interval). The restitution hypothesis states that steeply sloped restitution curves create unstable wave propagation that results in wave break, the event that is necessary for fibrillation. Here we present experimental evidence supporting this idea. In particular, we identify the action of the drug bretylium as a prototype for the future development of effective restitution-based antifibrillatory agents. We show that bretylium acts in accord with the restitution hypothesis: by flattening restitution curves, it prevents wave break and thus prevents fibrillation. It even converts existing fibrillation, either to a periodic state (ventricular tachycardia, which is much more easily controlled) or to quiescent healthy tissue.
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To whom reprint requests should be addressed at: Division of Cardiology, UCLA School of Medicine, 47–123 CHS, Los Angeles, CA 90095-1679. E-mail: agarfinkel@mednet.ucla.edu.
A.G. and Y.-H.K. contributed equally to this work.
Edited by Robert May, University of Oxford, Oxford, United Kingdom, and approved March 6, 2000
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.090492697