Several epidemiologic and clinical studies show that following myocardial infarction, dietary supplements of -3 polyunsaturated fatty acid (3FAs) reduce sudden death. Animal data show that 3FAs have antiarrhythmic properties, but their mechanisms of action require fur-ther elucidation. The effects of 3FAs supplementation were studied in female rabbits to ana-lyze if their antiarrhythmic effects are due to a reduction of triangulation, reverse use-dependence, instability and dispersion of the cardiac action potential (TRIaD as a measure of proarrhythmic effects). In Langendorff-perfused hearts challenged by a selective IKr inhibitor that has been shown to exhibit proarrhythmic effects (dofetilide, 1 to 100 nM), 3FAs pre-treatment (30 days; n=6) (i) prolonged the plateau phase of the monophasic action potential (MAP), (ii) did not slow the terminal fast repolarization; (iii) reduced dofetilide-induced pro-longation of the action potential duration (APD); (iv) reduced dofetilide-induced triangula-tion; (v) reduced dofetilide-induced reverse use-dependence, instability of repolarization and dispersion. Dofetilide reduced excitability in 3FAs pretreated hearts but not in control hearts. Whereas torsades de pointes (TdP) were observed in 5 out of 6 in control hearts, none were observed in 3FAs pretreated hearts. Docosahexaenoic acid (DHA) inhibited INa with ultrafast kinetics. Dietary 3FAs supplementation markedly reduced dofetilide-induced TRIaD and abolished dofetilide-induced TdP. Ultrafast sodium channel block by DHA may account for the antiarrhythmic protection of dietary supplements of 3FAs against dofetilide induced proarrhythmia observed in this animal model.