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Am J Physiol Heart Circ Physiol 295: H1414-H1421, 2008. First published August 1, 2008; doi:10.1152/ajpheart.01219.2007
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Ultrafast sodium channel block by dietary fish oil prevents dofetilide-induced ventricular arrhythmias in rabbit hearts

K. S. Dujardin,1 B. Dumotier,3 M. David,4,* M. Guizy,4,* C. Valenzuela,4 and L. M. Hondeghem2

1Heilig Hart Kliniek, Division of Cardiovascular Diseases, Roeselare; 2Department of Pharmacology, Katholieke Universiteit Leuven, Leuven, Belgium; 3Novartis Pharma Aktiengesellschaft, Exploratory Development, Basel, Switzerland; 4Instituto de Investigaciones Biomédicas "Alberto Sols" Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid, Spain

Submitted 21 October 2007 ; accepted in final form 28 July 2008

Several epidemiologic and clinical studies show that following myocardial infarction, dietary supplements of {omega}-3 polyunsaturated fatty acids ({omega}3FA) reduce sudden death. Animal data show that {omega}3FA have antiarrhythmic properties, but their mechanisms of action require further elucidation. The effects of {omega}3FA supplementation were studied in female rabbits to analyze whether their antiarrhythmic effects are due to a reduction of triangulation, reverse use-dependence, instability, and dispersion (TRIaD) of the cardiac action potential (TRIaD as a measure of proarrhythmic effects). In Langendorff-perfused hearts challenged by a selective rapidly activating delayed rectifier potassium current inhibitor that has been shown to exhibit proarrhythmic effects (dofetilide; 1 to 100 nM), {omega}3FA pretreatment (30 days; n = 6) prolonged the plateau phase of the monophasic action potential; did not slow the terminal fast repolarization; reduced the dofetilide-induced prolongation of the action potential duration; reduced dofetilide-induced triangulation; and reduced dofetilide-induced reverse use-dependence, instability of repolarization, and dispersion. Dofetilide reduced excitability in {omega}3FA-pretreated hearts but not in control hearts. Whereas torsades de pointes (TdP) were observed in five out of six in control hearts, none were observed in {omega}3FA-pretreated hearts. Docosahexaenoic acid (DHA) inhibited the sodium current with ultrafast kinetics. Dietary {omega}3FA supplementation markedly reduced dofetilide-induced TRIaD and abolished dofetilide-induced TdP. Ultrafast sodium channel block by DHA may account for the antiarrhythmic protection of the dietary supplements of {omega}3FA against dofetilide-induced proarrhythmia observed in this animal model.

antiarrhythmia agents; omega-3 fatty acids; ion channels; torsades de pointes


Address for reprint requests and other correspondence: L. M. Hondeghem, Hondeghem Pharmaceutical Consulting n.v., Westlaan 85, B-8400 Oostende, Belgium (e-mail: luc.hondeghem{at}screenQT.com)






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