Prostaglandins, Leukotrienes and Essential Fatty Acids

It has been known since the 1970s that an increased co fatty acids such as eicosapentaenoic acid and docosa Epidemiological studies have reported that this effect responsible for sudden cardiac death. Mechanistically, d give an explanation. Among them, there are a direct ef channels and/or a modification of the regulation of ion 78/$ see front matter & 2010 Elsevier Ltd. A 016/j.plefa.2010.02.024 espondence to: Physiopathologie Cardiovas de Villeneuve, 371 Avenue du Doyen Gaston , France. Tel.: +33 4 6741 5244; fax : +33 4 6 ail address: Jean-Yves.Le-Guennec@Univ-Mon nsumption of n-3 long chain polyunsaturated hexaenoic acid has cardioprotective effects. is due to the prevention of the arrhythmias ifferent hypotheses have been put forward to fect of the polyunsaturated fatty acids on ion channels by protein kinase C’s. & 2010 Elsevier Ltd. All rights reserved. 1. Cardioprotective effects of n-3 PUFAs Epidemiological studies conducted since the 1970s indicate that increased consumption of n-3 long chain polyunsaturated fatty acids (n-3 PUFAs) is associated with cardioprotective effects [1,2]. The first clinical trial of n-3 PUFAs reporting hard cardiovascular endpoints was reported in 1989 [3]. The authors showed that mortality was reduced by 29% after 2 years in a group of men who had already suffered a myocardial infarction and who were advised to eat fatty fish at least twice weekly as compared to others who did not receive any recommendation. The reduced mortality was not associated with reduced ischemic heart disease events or levels of total cholesterol, but suggested an anti-arrhythmic effect since arrhythmias are likely to be the main cause of sudden death following myocardial infarct. More recently, a large prospective, randomized clinical trial with 11,324 patients who had survived a recent myocardial infarction was reported [4]. In this trial, patients were randomly assigned to one of four groups to test the effects of a daily dose of (a) 850 mg EPA plus DHA (less than the American Heart Association recommendation of 1000 mg per day [5]), (b) 300 mg of a-tocopherol (vitamin E, an anti-oxidant), (c) n-3 PUFAs plus vitamin E and (d) a control group that received neither fatty acids nor vitamin E. This supplementation was in addition to routine pharmacological treatment. After 3.5 years, vitamin E did not bring significant benefits while n-3 PUFAs lowered the risk of cardiovascular death by 17% (2-way analysis) or 30% (4-way analysis). A 45% reduction in sudden death at 3.5 years, which started to be significant 4 months after the beginning of the supplementation ll rights reserved. culaire, Inserm U637, CHU Giraud, 340295 Montpellier 741 5242. tp2.Fr (J.-Y. Le Guennec). [6], was also observed. This latter observation strongly suggests that the benefit of n-3 PUFAs may not be mediated via anti-atherosclerotic and anti-thrombotic actions but very likely involves antiarrhythmic effects. The first study investigating the possible anti-arrhythmic effects of fish oil fatty acids on animals was performed in 1988 [7]. In these experiments, rats were fed diets in which the major fat component was controlled. At the end of the 3 months dietary period, the left anterior descending coronary artery was ligated and the number of animals that died from sustained ventricular fibrillation counted. It was found that, while some rats died of arrhythmias in the group receiving sunflower seed oil, no rat died in the group receiving tuna fish oil (rich in n-3 PUFAs). A similar anti-arrhythmic action of the n-3 PUFAs in marmosets was reported [8] as shown in Fig. 1. Fatal ventricular arrhythmias induced by coronary ligation could be prevented by a fish oil emulsion containing primarily a mixture of eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) infused intravenously just prior to the ischemic stress in conscious exercising dogs [9,10]. To understand the anti-arrhythmic mechanism(s) of n-3 PUFAs, experiments have been undertaken at the cellular level. Studies using isolated neonatal rat cardiac myocytes have confirmed a putative anti-arrhythmic effect of acutely applied PUFAs [11–13]. The mechanisms of the anti-arrhythmic actions of n-3 PUFAs are not well understood. Among several hypotheses, two major ones have been put forward: direct effects on ion channels and modulation of the protein kinase C (PKC) pathways. 1.1. n-3 PUFAs and ion channels It has been described that 10 mM EPA stabilised the resting membrane potential, increased the threshold to trigger an action