Hindawi Publishing Corporation Cardiology Research and Practice Volume 2012, Article ID 303456, 15 pages doi:10.

1155/2012/303456

Review Article The Role of Long-Chained Marine N-3 Polyunsaturated Fatty Acids in Cardiovascular Disease
Hildegunn Aarsetoey,1 Heidi Grundt,1, 2 Ottar Nygaard,2, 3 and Dennis W. T. Nilsen2, 4
1 Department 2 Institute

of Medicine, Stavanger University Hospital, 4011 Stavanger, Norway of Medicine, University of Bergen, 5020 Bergen, Norway 3 Department of Heart Disease, Haukeland University Hospital, 5021 Bergen, Norway 4 Department of Cardiology, Stavanger University Hospital, 4011 Stavanger, Norway Correspondence should be addressed to Heidi Grundt, heidi@madlalia.no Received 10 June 2012; Revised 11 October 2012; Accepted 25 October 2012 Academic Editor: Frederic Kontny Copyright 2012 Hildegunn Aarsetoey et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This paper reviews the current evidence regarding long-chained marine omega-3 polyunsaturated fatty acids (PUFAs) and cardiovascular disease (CVD), their possible mechanisms of action, and results of clinical trials. Also, primary and secondary prevention trials as studies on antiarrhythmic eects and meta-analyses are summarized. However, the individual bioavailability of n-3 PUFAs along with the highly dierent study designs and estimations of FAs intake or supplementation dosages in patient populations with dierent background intake of n-3 PUFAs might be some of the reasons for the inconsistent ndings of the studies evaluating the impact of n-3 PUFAs on CVD. The question of an optimum dose of n-3 PUFAs or whether there exists a dose-response relation for n-3 PUFA supplementation is widely discussed. Moreover, the diculties in interpreting meta-analyses are clearly demonstrated by two recently published meta-analyses (Rizos et al. and Delgado Lista et al.), evaluating the ecacy of n-3 PUFAs on CVD, including 12 common studies, but drawing opposite conclusions. We denitely need more large-scale, randomized clinical trials of long duration, also reporting harmful eects of n-3 PUFAs.

1. Introduction
Unsaturated fatty acids (FAs), especially polyunsaturated fatty acids (PUFAs), have since the 1970s been given a lot of attention due to possible health promoting eects. During the rst decade of research, pilot studies on Greenland Eskimos demonstrated that a diet rich in long-chained marine PUFAs might reduce the incidence of ischemic heart disease [1]. During the following decades, research has to a large extent focused on the prevention and management of cardiovascular disease (CVD). During the same period of time, there has been a large change in our understanding of the atherosclerotic process. From being viewed as inanimate tubes, arteries are now thought of as dynamic tissues, where intimal inammation plays a crucial role in the pathophysiologic process of atherosclerotic development. A thin brous cap is the only structure separating the blood compartment with

its coagulation factors from the prothrombotic material in the lipid core. Enhanced inammation might result in plaque instability. Moreover, the endothelium plays a key role in vascular homeostasis, and endothelial dysfunction seems to be of major importance in the development of a vulnerable plaque. The acute coronary syndrome (ACS) usually results from the erosion or rupture of such a vulnerable atherosclerotic plaque with subsequent coronary artery occlusion as coagulation factors come into contact with tissue factor, the major initiator of the extrinsic coagulation cascade [2]. The complex vascular biology preceding the ACS provides several possible therapeutic targets for PUFAs: reducing atherosclerotic development, stabilizing vulnerable plaques, and limiting the consequences of their disruption. Even though a lot of research has been done trying to elucidate the role of PUFAs in CVD prevention and management, several issues are still under discussion. Clinical studies have provided conicting results, and the optimal intake of PUFAs

2 is not rmly established. Concerns have been raised about environmental contaminants accumulating in sh, especially methylmercury, polychlorinated biphenyls, and dioxins, giving rise to possible deleterious eects [3] and counteracting the benecial cardioprotective eects of marine n-3 PUFAs [4]. Especially mercury has been given a lot of attention due to reports of a probable proatherosclerotic eect [5]. N3 PUFAs might also have a potential to increase oxidative stress, resulting in lipid peroxides [6]. These issues might be related to a dose optimum of n-3 PUFAs, as high doses might exceed an optimum threshold level leading to lack of benecial eects due to lipid peroxidation or accumulation of other toxic substances. This paper reviews the current evidence regarding longchained marine omega-3 PUFAs and CVD, their possible mechanisms of action, and results of clinical trials. 1.1. PUFAsChemistry and Origin. FAs are single-lipid components comprised of a straight hydrocarbon chain terminating with a carboxylic acid group (COOH) at the polar hydrophilic end and a nonpolar hydrophobic methyl group (CH3 ) at the other end. The various FAs are named according to their number of carbon atoms and their number and position of carbon-carbon double bonds. FAs with at least two double bonds are designated as polyunsaturated. For PUFAs, the position of the rst double bond from the methyl- (n/omega-) end of the molecule has given rise to the terminology n-3 (omega-3) FAs, n-6 (omega-6) FAs, and n-9 (omega-9) FAs [7]. According to the accepted terminology, the number of carbon atoms in a PUFA molecule is designated by the rst gure, while the number of double bonds is given by the second gure. N-3 and n-6 PUFAs are not synthesized by the human body, as they are essential FAs that need to be ingested [8]. While n-6 PUFAs and -linolenic acid (18 : 3 n-3) are found in vegetable foods, n-3 PUFAs with more than 20 carbon atoms are made by phytoplankton and mainly ingested from fatty sh and marine animals. The two most important marine FAs with respect to human health are thought to be eicosapentaenoic acid (EPA; 20 : 5 n-3) and docosahexaenoic acid (DHA; 22 : 6 n-3). Even though these two FAs to a small extent also can be derived from -linolenic acid by desaturation and elongation in the liver [8], the main body content of EPA and DHA is dependent on the amount ingested. For the present paper we will focus on these longchained marine n-3 PUFAs.

Cardiology Research and Practice of membrane uidity, permeability, and electrophysiological characteristics [9]. Changing membrane properties might further aect the ability of membrane receptors to interact with their ligands or intracellular signalling molecules as well as modulate the eect of membrane bound enzymes [10]. There is also evidence for n-3 PUFAs themselves serving as ligands for nuclear receptors aecting gene expression, nuclear factor B (NF-B), and peroxisome proliferatoractivated receptor- (PPAR-) being two of the potential targets [1113]. Furthermore, 20-carbon PUFAs (arachidonic acid (AA) and EPA) released from cell membrane phospholipids by phospholipase A2 are substrates for the synthesis of eicosanoids, a family of biochemical mediators consisting of prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), and hydroxy fatty acids. Eicosanoids possess important vasoactive regulatory properties, such as regulation of platelet aggregability, endothelial cell motility, cell growth, and chemotaxis [8, 14, 15]. With the increasing incorporation of n-3 PUFAs into cell membranes, the production of eicosanoids is shifted from the 4 series of LTs and the 2 series of PGs and TXs generated from AA to the 5 series of LTs and the 3 series of PGs and TXs derived from EPA, the latter being eicosanoid products leading to a more vasodilatory state, reduced inammatory responses in the injured vessel wall, and less potent platelet aggregation [8, 14, 15]. A combination of these mechanisms, summarized in Table 1, seems to be responsible for the majority of the proposed antiatherothrombogenic and antiarrhythmic eects of n-3 PUFAs [8, 14, 16, 17] further outlined below. 2.1. Marine N-3 PUFAs and Anti-Atherothrombogenic Eects. In the early 1990s, the extent of atherosclerotic lesions in the coronary arteries and the aortas from Alaskan natives were demonstrated to be signicantly lower as compared to non-natives in all age-groups [18]. This was one of the rst indications of a possible antiatherosclerotic eect of n-3 PUFAs. In accordance with this nding, a dietary related incorporation of EPA and DHA into advanced human atherosclerotic plaques has been demonstrated [19, 20] along with the development of a more stable plaque morphology, less susceptible to rupture, after n-3 PUFA supplementation [20]. The results from intervention studies on coronary atherosclerosis progression and regression in humans have, however, been highly diverging [2123]. The potential eect on atherosclerosis was initially thought to be related to the modulation of proatherosclerotic risk factors. As compared to Danes, Greenland Inuits had lower serum concentrations of total- and low-density lipoprotein cholesterol, triglycerides, and very low-density lipoprotein cholesterol but higher levels of high density lipoprotein cholesterol [1, 24]. Since then, several studies have conrmed that the increasing amounts of n-3 PUFAs are associated with a more favourable prole of lipoproteins [8]. The clear-cut triglyceride-lowering eect of marine n-3 PUFA especially is undisputed [8]. Several mechanisms may contribute to the triglyceride-lowering eect by marine n3 PUFAs, such as reduced triglyceride synthesis and diminished chylomicron secretion from intestinal cells. Reduced

2. Mechanisms of Action of Long-Chained Marine N-3 PUFAs

The observed health eects of n-3 PUFAs are mainly thought to be mediated by two mechanisms: a change in the properties of the cell membranes and the regulation of gene transcription. As FAs are incorporated into cell membrane phospholipids, the FA composition of this lipid bilayer is reected by the composition of FAs ingested. Increasing the amounts of n-3 PUFAs in the cell membrane alters its biochemical and physical properties with a subsequent change

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Table 1: Mechanisms and biochemical eects of marine PUFA. Anti-inammatory eects (i) Competition with AA for Cox/lipooxygenase sites (ii) Increase of anti-inammatory eicosanoids (iii) Reduction of TNF , IL-1, IL-6 (iv) Reduction of nuclear factor B (NF- B) activation Vascular eects (i) Increased vagal tone (ii) Improved endothelial function (iii) Increase of NO (iv) Reduction of Hcy, VCAM-1, ELAM-1, and ICAM-1 (v) Reduction of ET-1 Antithrombotic eects (i) Reduced platelet aggregation via reduction in TXA2 (ii) Increased bleeding time (high doses) Triglyceride-lowering eect Antiarrhythmic eects (i) Increased membrane stabilization, reduced automaticity, and increased refractory period (ii) Increased EPA : AA ratio in plasma membrane of cardiac myocytes (iii) Reduced production of proarrhythmic eicosanoids (iv) Reduced agonist anity of beta-receptors reduced heart rate (HR), increased HR variability (v) Inhibition of the L-type calcium current (vi) Inhibition of fast voltage-dependent Na+ channels

3 of AA by EPA in inammatory cell membranes, as previously described [8, 14, 15]. During recent years, other antiinammatory eects of n-3 PUFAs, independent of the altered eicosanoid production, have been demonstrated. This comprises a reduced production of the proinammatory cytokines interleukin-1 (IL-1), IL-6, and tumour necrosis factor- (TNF-) from mononuclear cells as well as decreased expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule1 (VCAM-1) on endothelial cells [8], the latter being the molecules essential for the attachment of leucocytes to the endothelium prior to their entrance into the intima. Cellular adhesion molecules are markers of the functional state of the endothelium, and their downregulation by n-3 PUFAs have mainly been demonstrated in studies ex vivo. Moreover, benecial eects on the vasoregulatory secretagogues of the endothelium, such as nitric oxide and prostacycline, have been obtained by n-3 PUFAs [8]. The rst studies from Bang and Dyerberg on Greenland Eskimos also revealed an antithrombotic eect of high doses of n-3 PUFAs associated with increased bleeding time [29, 30]. However, ingestion of less than 4 grams daily has not been associated with increased risk of bleeding [8, 15, 31]. TXA2 is a potent prothrombotic agent, and it is therefore likely that the observed antiplatelet eect of n-3 FAs, at least to some extent, is mediated through a shift in the eicosanoid production. Homocysteine (Hcy) may also exert unfavourable eects on the antithrombotic properties of the endothelium, and in a randomized trial previously presented by our group we observed a reduction of Hcy after treatment with a high dose of n-3 PUFAs as compared to corn oil for 1 year following a myocardial infarction (MI) [32]. The eect of these PUFAs on other haemostatic procoagulant and brinolytic factors is, however, divergent [16, 33, 34], and the nal impact of n-3 PUFA supplementation on the complex processes of vascular injury, thrombosis, and repair still remains an unsettled issue. 2.2. Marine N-3 PUFAs and Antiarrhythmic Eects. The reduction observed in cardiac death with increased intake of n-3 PUFAs has largely been attributed to a potential antiarrhythmic eect. Studies on cell cultures have revealed that this might be related to a membrane stabilizing eect in cardiac myocytes. Supplementation with n-3 PUFAs has been found to enrich myocyte membranes with EPA and DHA [3537]. This induces a conformational change of the cell membrane with eects on ion channels and membranebound proteins resulting in a slight hyperpolarization of the cell membrane, increasing the depolarizing stimuli necessary to induce an action potential with subsequently reduced automaticity. Furthermore, n-3 PUFAs aect the transition of the voltage-gated sodium channel with a shift toward more negative membrane voltages, promoting recovery from the inactive state and thereby increasing the refractory period. Both eects make the myocardium less excitable, especially in ischemic tissue. In these cells, the negative potential required to reactivate the Na channels might not be physiologically obtainable due to the partial depolarization induced by the

triglyceride formation may partly be due to a reduced pool of fatty acids substrate mediated through suppressed hepatic fatty acid synthesis related to the eect by marine n-3 PUFAs on hepatic gene expression downregulating de novo lipogenesis, increased fatty acid beta-oxidation, and reduced delivery of nonesteried fatty acids to the liver. Besides, marine n-3 PUFAs are poor substrates for enzymes responsible for triglyceride synthesis resulting in reduced and impaired hepatic enzyme activity for triglyceride synthesis and increased hepatic synthesis of phospholipids rather than triglycerides, hereby limiting the secretion from the liver of triglyceride-rich very low-density lipoprotein (VLDL) [8]. Furthermore, ingestion of n-3 PUFAs has been demonstrated to have a blood pressure reducing eect [25], as well as improving glucose metabolism/insulin resistance [26, 27]. The eect of n-3 PUFAs on insulin as a mediator of the metabolic syndrome needs to be claried, but there is some support for a relationship between the content of n-3 PUFAs in cell membranes and the action of insulin [8]. Lately, the role of inammation and endothelial dysfunction in the pathophysiologic process of atherosclerosis generation and disruption of the vulnerable atherosclerotic plaque has been highlighted [28], opening a new area for potential antiatherosclerotic eects of n-3 PUFAs. The rst demonstrated anti-inammatory eects were related to a shift in the production of eicosanoids by partial replacement

4 dysfunctional state of the Na/K-ATPases. Thus, n-3 PUFAs might be important for opposing the eect of functional reentry substrates [9]. They are also capable of inhibiting the voltage-dependent inward calcium current during phase 2 of an action potential. In cooperation with possible eects on the Na/Ca exchanger and receptors in the sarcoplasmatic reticulum, this might contribute to less intracellular Ca uctuations and reduced occurrence of after depolarizations [9]. In addition to these direct eects on the generation and duration of the action potential, other less direct mechanisms of actions have been proposed. There is also evidence for antiarrhythmic eects mediated through a reduced production of proarrhythmic eicosanoids, reduced levels of circulating catecholamines [38], and a reduced agonist anity of beta-receptors [17]. The latter observation might be one of the mechanisms responsible for an improvement in the cardiac sympathetic-vagal balance, revealed clinically as a reduction in the mean heart rate (HR) [39] as well as an increase in HR variability [40]. Both of these parameters have been demonstrated to be related to the risk of malignant arrhythmias and sudden cardiac death (SCD), with increasing HR and decreasing heart rate variability being associated with adverse outcomes [41]. Through these mechanisms, n-3 PUFAs seem to be able to interfere with all the proarrhythmogenic mechanisms responsible for the generation of ventricular arrhythmias. In agreement with these proposed mechanisms, animal experiments have demonstrated a benecial eect of EPA and DHA on the development of ischemia-induced ventricular arrhythmias [42], whereas results from human studies are more divergent. For ventricular arrhythmias generated by other mechanisms, such as myocardial scaring and heart failure, the same protective eect of n-3 PUFAs might not be present, as suggested by the highly discrepant results of n-3 PUFA supplementation in patients with an implantable cardioverter debrillator (ICD) [4347].

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4. N-3 PUFAs and Relation to Cardiovascular Disease

The individual bioavailability of n-3 PUFAs along with highly dierent designs, estimations of FA intake, or supplementation dosages might be some of the reasons for the inconsistent ndings of studies evaluating the impact of n-3 PUFAs on CVD. A summary of the existing knowledge will be given below. 4.1. Primary and Secondary Prevention Trials. The rst evidence of a possible health eect in humans with a diet rich in n-3 PUFAs came from the pioneer studies on Greenland Eskimos in the 1970s [1], reporting lower coronary mortality in this population than in Danish control subjects. Since then, a huge amount of the literature has been published, further investigating the eects of these marinederived PUFAs on CVD. Two of the most cited studies are the Diet and Reinfarction Trial (DART) investigating the eect on recurrent cardiac events of dietary advice after a recent MI [52] and the GISSI-Prevenzione trial in which marine-derived n-3 PUFA supplementation was given for the prevention of death, nonfatal MI, and stroke in patients who had survived an MI during the preceding 3 months [53]. In the DART study, 2 years of followup revealed a 29% reduction in total mortality (P < 0.05) among patients advised to eat fatty sh, mainly due to a reduction in deaths from coronary artery disease (CAD). Comparable to this nding, supplementation with 1 g/day of n-3 PUFAs (850 mg/day of EPA and DHA ethyl esters in a ratio of 1 : 2) for 3.5 years in the open label GISSI-Prevenzione study reduced the composite endpoint of death, nonfatal MI, and stroke by 15% (P = 0.023). In subgroup analyses, the reduction in relative risk was even greater for cardiovascular death and SCD which was reduced by 30% (P = 0.024) and 45% (P = 0.01), respectively. It has been argued that the GISSI-Prevenzione trial was not designed to evaluate SCD, and that it had insucient statistical power. The results of these subgroup analyses should, therefore, be interpreted with caution. Furthermore, there has clearly been an evolvement in the general treatment of CAD from the time of performance of the GISSI trial until today, and it has been argued that supplementation with similar doses of n-3 PUFAs in addition to current guideline-adjusted therapy might not have the same benet. The participants of the GISSI trial were included in the early 1990s, at a time when medical prescriptions and the use of early coronary revascularization were quite dierent from todays management. To investigate this question, Rauch et al. conducted the Omega trial, a randomized, placebocontrolled, and double-blind trial evaluating the eects of 1year treatment with 1 g/day of n-3 PUFAs (380 mg DHA + 460 mg EPA) following an MI [54]. Treatment was initiated 314 days after MI in 3851 patients. As compared to the GISSI trial in which 5% of the patients received coronary revascularization at baseline, 93.8% of the participants of the Omega trial underwent acute percutaneous coronary intervention (PCI). The Omega trial revealed no eect on

3. The Omega-3 Index

The omega-3 index is dened as the content of EPA and DHA in the cell membrane of red blood cells (RBCs), expressed as a weight percentage of total FAs. The omega-3 index correlates highly with the EPA + DHA content in serum, plasma, and whole blood [48, 49], but as opposed to these ndings, RBC EPA + DHA is better correlated to long-term FA intake as evaluated by a food frequency questionnaire (FFQ) and is a more suitable biomarker for the nutritional status of an individual [49]. The half-life of EPA + DHA in RBCs is 46 times longer than in serum [50], with concentrations returning to baseline 16 weeks after supplementation [51]. In addition, the omega-3 index has been found to be highly correlated with cardiac EPA + DHA levels and responds to supplementation in a way very similar to that of myocardial tissue [35, 36]. With RBCs readily available and easy to analyze, this gives us the opportunity to apply the omega-3 index as a surrogate for cardiac omega-3 status in clinical practice.

Cardiology Research and Practice the rate of SCD (P = 0.84), total death (P = 0.18), nonfatal reinfarction, stroke (P = 0.10), or revascularization procedures in survivors (P = 0.34) after 1 year. The Omega trial might, however, have been underpowered in an era of more aggressive risk factor management. No eect of n-3 PUFA supplementation could be demonstrated on the risk of major cardiovascular events (fatal and nonfatal CVD and cardiac intervention with PCI or coronary artery bypass grafting (CABG)) in the Alpha Omega Trial [55] in which 4837 patients receiving state-of-the-art medical therapy after MI were randomized to one of four margarines for 40 months; a margarine supplemented with a combination of EPA and DHA, a margarine supplemented with alpha-linolenic acid (ALA), a margarine supplemented with EPA/DHA and ALA, or a placebo margarine. The margarine compounds resulted in an uptake of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, respectively. As compared to placebo, neither EPA/DHA nor ALA reduced the occurrence of the primary endpoint (HR with EPA/DHA 1.01 (95% CI 0.871.17; P = 0.93); HR with ALA 0.91 (95% CI 0.781.05, P = 0.20)). However, the dose of marine n-3 PUFA used in this study was less than half of the dose ingested in the GISSI trial [53]. As opposed to these studies, the GISSI-HF trial provided evidence for a small, but benecial, advantage of n-3 PUFA supplementation on risk of total mortality (HR 0.91, 95.5% CI 0.8330.998, P = 0.041) and combined risk of total mortality or admission to hospital for cardiovascular reasons (HR 0.92, 99% CI 0.8490.999, P = 0.009) in patients with heart failure of any cause and irrespective of left ventricular ejection fraction. These patients were given standard care according to guidelines in the early 2000s [56]. In absolute terms, 56 patients needed to be treated for a median duration of 3.9 years to avoid one death or 44 to avoid one combined event of death or admission to hospital for cardiovascular reasons. In this randomized, double-blind, and placebocontrolled trial, patients were given 1 g n-3 PUFAs daily (n = 3494) or placebo (n = 3481) and followed for a median of 3.9 years. Most interestingly, the same study has demonstrated that n-3 PUFAs can provide a small but signicant improvement of left ventricular function in patients with symptomatic heart failure [57]. Left ventricular ejection fraction increased with n-3 PUFAs by 8.1%, 11.1%, and 11.5% after 1, 2, and 3 years, respectively. In the placebo group, the corresponding changes from baseline were 6.3%, 8.2%, and 9.9% (P = 0.005). This nding has recently been veried in two smaller groups of patients with nonischemic dilated cardiomyopathy receiving 14 g/day of n-3 PUFAs versus placebo for 312 months [58, 59]. In one of these studies, administrating supplements for only 3 months, a dose-dependent increase in left ventricular function was observed [58]. As opposed to the DART and GISSI trials, two recent studies from Japan observed the reduction in risk of CAD to be primarily related to nonfatal coronary events. The Japan Public Health Centre-based (JPHC) study included a total of 41 578 Japanese men and women aged 4059 years initially free of CVD [60]. After 10 years of followup, there was a 57% reduction in risk of nonfatal cardiac

5 events for the highest as compared to the lowest quintile of sh intake [HR = 0.43 (0.230.81)], while no favourable eect was observed on fatal events or SCD. In the Japan EPA Lipid Intervention Study (JELIS), supplementation with 1800 mg EPA in combination with a statin was given to 18 645 hypercholesterolemic subjects (total cholesterol 6.5 mmol/L) for a median time of 4.6 years [61]. Twenty percent of these individuals presented with established CAD. As compared to statin treatment alone, there was a 19% relative reduction in the primary outcome measure including SCD, fatal, and nonfatal MI and other nonfatal events such as unstable angina pectoris, angioplasty, stenting, and coronary artery bypass grafting (P = 0.011). Subgroup analyses demonstrated, however, benecial eects mainly in the setting of secondary prevention with a signicant reduction in risk of unstable angina of 28% (P = 0.019). The intake of n-3 PUFAs in these Japanese studies was quite high, with participants of the upper quintile of sh intake in the JPHC study having sh servings at least 8 times per week and the population as a whole having a mean intake of 900 mg n-3 PUFAs/day. In a review of prospective cohort studies and randomized controlled trials, Mozaarian and Rimm [62] demonstrated evidence for a maximal risk reduction of death from CAD with servings amounting to about 250 mg n-3 PUFAs/day. We recently observed a similar though nonsignicant threshold eect of dietary n-3 PUFAs on risk of coronary events among patients undergoing coronary angiography for suspected coronary artery disease [63]. Thus, for populations already consuming 250 mg/day of EPA + DHA, no further risk reduction for cardiac death seems to be achieved. This threshold-related eect may explain the lack of mortality benet observed in the JPHC and JELIS studies. Their background sh intake was associated with very low coronary heart disease death rates (87% lower than in comparable Western populations), and additional n-3 PUFA intake yielded little further reduction in the death rate, as most of the population was already above the threshold for maximum mortality benet. In the JPHC study, only subjects with a mean daily intake of 2.4 g n-3 PUFAs had any reduced risk of nonfatal events, indicating that even greater dosages might be needed to reduce the risk of nonlethal CAD events. The choice of dose (1 g of n-3 fatty acids containing 465 mg EPA and 375 mg DHA per day) and the relatively high background intake of n-3 PUFAs reported in the ORIGIN trial (the Outcome Reduction with an Initial Glargine Intervention) [64] might explain the lack of benecial eects of n-3 PUFAs on cardiovascular mortality and morbidity in this study. This international, multicenter, randomized, and open-label trial with a 2 2 factorial design evaluated the protective eects of n-3 PUFAs in a daily dose of 1 g versus corn oil, and Insulin Glargine (Lantus) versus standard care, on cardiovascular mortality and morbidity during 6 years of followup in 12 536 high-risk subjects with impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes. The estimated median dietary intake of n-3 PUFAs of 210 mg/day might have muted the potential eects of n-3 treatment, assuming that maximal risk reduction is obtained by consuming 250 mg n-3 PUFAs/day, as suggested by Mozaarian and Rimm [62].

6 Several other trials have conrmed an inverse association between intake of n-3 PUFAs and risk of CAD [3, 6570], especially fatal cardiac events [65, 6770]. This nding has been evident both in the setting of primary [3, 65, 66, 68 70] and secondary prevention [52, 53, 67]. Only a few epidemiological studies and randomized controlled trials have presented results indicative of a lack of eect [54, 55, 71 74] or a direct harmful eect of a high intake of n-3 PUFAs [75, 76]. The lack of eect on CAD from a relatively high intake of n-3 PUFAs in Western coastal populations has been suggested to be due to a concomitant high intake of saturated FAs and monounsaturated FAs [77]. The Western coastal populations dier not only from the Japanese with respect to n-3 PUFA levels; they also ingest more of the apparently unhealthy FAs with a possible attenuation of the health eects of n-3 PUFAs. In this setting we cannot rule out the harmful eects of environmental contaminants of sh and increases of oxidative stress, as previously discussed. The major clinical trial data for primary and secondary prevention of CVD are summarized in Table 2(a). 4.2. Studies on Antiarrhythmic Eects. Time-course analyses of the GISSI-Prevenzione study with a reduction in SCD already after 4 months of supplementation [83] have given rise to the hypothesis of a predominant antiarrhythmic eect of n-3 PUFAs. This hypothesis is supported by a case control study including 334 patients with primary cardiac arrest performed by Siscovick et al. [84] who demonstrated that an intake of 5.5 g of n-3 PUFAs per month (equivalent to one fatty sh meal per week) as compared to no intake was associated with a 50% reduction in the risk of cardiac arrest (95% CI 0.40.8). All cases and controls were free of prior clinical heart disease. In the same study, there was an inverse relationship between blood measurements of EPA + DHA and risk of cardiac arrest. The same has been evident for SCD in the Physicians Health Study [85] and for fatal ischemic heart disease in the Cardiovascular Health Study [86]. In the latter study, patients over the age of 65 had a 77% lower risk of assumed arrhythmic death for each standard deviation increase in plasma phospholipid DHA + EPA. None of these studies can, however, document an antiarrhythmic mechanism of protection against SCD, as the electrical activity of the myocardium at the moment of cardiac arrest was not systematically registered. The rst evidence of an antiarrhythmic potential of n3 PUFAs came from experimental work in animal models [8790], and in a systematic review and meta-analysis of the impact of n-3 PUFAs on selected arrhythmia outcomes in these animal models, Matthan et al. [90] conclude that there is a benecial eect of EPA and DHA on ischemiainduced ventricular brillation (VF) and ventricular brillation (VT) across all species. For ventricular arrhythmias induced by reperfusion, the results were inconsistent, and none of the animal models evaluated other arrhythmogenic mechanisms, such as scar-related malignant arrhythmias. In attempts to determine whether n-3 PUFAs could have the same antiarrhythmic eects in humans, several studies have been performed in ICD patients with a high

Cardiology Research and Practice risk of recurrent ventricular arrhythmias. Schrepf et al. [45] were able to abort the inducibility of VT in 5 out of 7 ICD patients undergoing electrophysiological testing by intravenously infusing 3.8 g of n-3 PUFAs. The same nding was recently published by Madsen et al. [81] testing eight ICD patients undergoing a randomized, placebo-controlled, crossover study with electrophysiological testing performed both after infusion of 3.9 g of n-3 PUFAs and placebo. Of the 5 patients who were inducible after placebo, 2 were no longer inducible after n-3 PUFAs infusion, and another 2 required stronger stimulation to induce VT. Comparable to these ndings, Christensen et al. [46] have also demonstrated that ICD patients with a low content of n-3 PUFAs in serum have a higher incidence of ventricular arrhythmias as compared to patients with high serum levels (P < 0.05). Results have been less consistent in studies of orally administered supplementation of n-3 PUFAs. Leaf et al. [47] could only demonstrate a trend toward prolonged time to the rst ICD event (VF or VT) for patients receiving 4 g/day of sh oil supplements (total dose of EPA and DHA of 2.6 g/day) as compared to olive oil supplements for 12 months, while Metcalf et al. [44] found that a daily dose of 3 g encapsulated sh oil for approximately 6 weeks resulted in noninducible or less inducible VT in a group of patients with ischemic cardiomyopathy. Brouwer and colleagues [78] found no strong evidence for a protective eect of a daily dose of 0.9 g n-3 PUFAs for 1 year as compared to that of sunower oil in 546 ICD patients. A similar dose (1 g/day of n-3 PUFAs) did, however, result in a trend toward protection in a substudy of the GISSI-HF trial when given to 566 patients for a median followup duration of 928 days [79]. There was a nonsignicant 20% reduction in appropriate ICD managed VT/VF events in the n-3 PUFA group as compared to placebo. Interestingly, this did not result in any mortality benet. There was actually a minimal excess in total mortality observed in the group treated with n-3 PUFAs (26.6% versus 24.3%). This is in some contrast to the results of the main study where the greatest proportion of the absolute risk reduction of total mortality by n-3 PUFA supplementation was attributable to a reduction in presumed arrhythmic deaths [56]. Moreover, in the study by Raitt et al. [80], recurrent episodes of VT or VF during 2 years of followup occurred more frequently and with reduced time to event in patients receiving 1.3 g/day of EPA/DHA as compared to olive oil. As previously mentioned, the protective eect of n-3 PUFAs might be strongest for ischemia-induced ventricular arrhythmias. The implantation of an ICD is more often performed in the setting of VF or VT without a concomitant MI or any reversible cause or in the case of high risk of SCD, such as excessive heart failure or demonstration of inducible VF/VT at electrophysiological examination. Even though ischemia might contribute to recurrent arrhythmic events, these patients may also have other arrhythmic substrates which to a lesser degree may be aected by n-3 PUFAs. The mixture of both VF and VT as a primary endpoint in most of the ICD studies also complicates the comparisons. The study by Christensen et al. [46] demonstrating a signicantly lower frequency of ICD events for patients with

Table 2: (a) Major clinical trial data for primary and secondary prevention of cardiovascular disease. (b) Major clinical trial data on antiarrhythmic end points.
(a)

Study All-cause 0.95 (0.561.60) 0.95 (0.681.32) SCD

Dose of FAs

Control

N Followup

Prior MI/CAD RCTs, blinded Mortality Cardiac 100% 100% 41.8% 59% 100% 100% RCTs, unblended

Nonfatal MI

All CVDevents

Stroke

Cardiology Research and Practice

Omega [54] 1.9 g ALA or placebo 4837 6975 12536 300 360 1 Year 18 Months 6 Years 3.9 Years 40 Months Placebo 1 g Olive oil 4 g Corn oil 2.9 ALA or placebo 2033 male 2 Years 3.5 Years 4.6 Years 39 Years Observational 84688 21185 4 Years 16 Years 0% 0.55 (0.330.90) 100% 20% 100% 100% 11324 18645 3114

1 g/d n-3 FAs

1 g Olive oil

3851

1 Year

Alpha Omega Trial [55]

226 mg EPA + 150 mg DHA

1.21 (0.961.52) 1.1 (0.871.17)

GISSI-HF [56]

1 g/d n-3 FAs

ORIGIN [64]

1 g n-3 FAs

OFAMI [74]

4 g n-3 FAs

1.25 (0.901.72) 1.01 (0.821.24) 0.91 (0.830.99) 0.98 (0.891.07) 1.0 (0.452.2) 0.93 (0.791.08) 1.10 (0.931.30) 1.0 (0.392.6) 0.52 0.24 (0.290.95) (0.051.1) 1.4 (0.72.6) 0.52 (0.30.9)

IEIS-4 [67]

1.08 g EPA

1.01 0.92 (0.931.10) (0.791.08) 1.1 (0.841.3) 0.71 (0.481.1)

DART [52]

Fish 200400 g/week

GISSI [53] Statin Intake of fruits, vegetables, and oats

1 g/d n-3 FAs

Fruits and vegetables Vitamin E or placebo

JELIS [61]

1800 mg EPA

0.71 (0.540.93) 0.79 (0.660.93) 1.09 (0.921.28) 1.15 (0.961.36)

DART 2 [75]

2 meals of sh/week or 3 g n-3 FA suppl.

0.84 (0.661.07) 0.65 0.55 0.91 0.80 1.2 (0.510.82) (0.510.82) (0.680.94) (0.680.94) (0.811.9) 0.94 1.06 0.75 0.81 1.02 (0.571.56) (0.552.07) (0.541.04) (0.690.95) (0.911.13) 1.54 1.26 (1.062.23) (1.01.56) 0.73 0.66 (0.511.04) (0.500.89) 1.2 (0.62.2)

Nurses Health Study [66] The Physicians health study [71] 1373 40 Years 0%

The Zutphen study [70] 41578 2412 10 Years

0.73 0.89 (0.471.13) (0.342.30) 0%

JPHC study [60]

WENBIT [63]

Intake of sh (meals/week) Intake of sh (meals/week) Intake of sh (meals/week) or estimated EPA + DHA/d Quintiles of sh intake Quartiles of n-3 FA intake 57 Months 90%

1.08 1.14 0.43 (0.422.76) (0.363.63) (0.230.81) 1.35 1.11 (0.731.67) (0.752.42)

(b)

Study RCTs, blinded 78% 4 g/day n-3 FAs 4 g corn oil 402 12 months Time to rst ICD-event for VT/VF

Inclusion criteria

Prior MI/CAD Dose of FAs Control N Followup Endpoint Event rate (%)

Leaf et al. [47]

Rate of ICD-event: 28% (n-3 FAs) versus 39%, RR 0.67 (0.470.95) 30% versus 33% with sustained ICD intervention or death HR 0.86 (0.641.16)

Brouwer et al. [78] (SOFA) 70% 546 0.9 g/day n-3 FAs

ICD due to SCA, spontaneous or inducible sustained VT. One episode of spontaneous VT or VF in the preceding year, ICD implanted 2 g high-oleic acid sun-lower oil Appropriate ICD intervention for VT 12 months or VF, or all-cause death 928 days Incidence of ICD-interventions 41.7% 1 g/day n-3 FAs Placebo 566

Finzi et al. [79] (GISSI-HF)

ICD due to SCA, sustained VT or for primary prevention of syncope.

ICD events 27.3% versus 34.0%, HR 0.80 (0.591.09). Mortality 26.6% versus 24.3%, HR 1.25 (0.891.75)

Raitt et al. [80] 200 2 years

ICD and a recurrent episode of VT or VF. 73% Olive oil (73% oleic acid) RCTs, non-blinded 83% Intervention studies, non-randomized 3.9 g n-3 FAs 0.9% saline 6

1.8 g/day n-3 FAs (1.3 g EPA/ DHA)

Time to rst ICD-event for VT/VF and frequency of recurrent VT/VF events

65% versus 59% with ICD therapy. Recurrent VT/VF more common in n-3 FA group (P < 0.001)

Madsen et al. [81]

Inducible sustained monomorphic VT

Level of stimulation required to induce monomorphic VT

2 of 6 noninducible 2 of 6 increased stimulation required

Schrepf et al. [45]

Repeated episodes of sustained VT 90%

3.8 g n-3 FAs as IV infusion

10

2 of 7 patients (29%)

Metcalf et al. [44]

ICD and inducible sustained monomorphic VT 100% 3 g/day n-3 FAs

No dietary manipulation Observational

26

6 weeks

Inducibilty of sustained VT in patients with a positive test at baseline Level of stimulation required to induce monomorphic VT

42% versus 7% without inducible VT.

Aarsetoey et al. [82]

SCA with documented VF during the ischemic phase of an MI 100%

Blood omega-3 index

Omega-3 index in MI patients without SCA

195

The omega-3 index in 1% increase of the omega-3 SCA patients versus index associated with 48% MI patients free of reduction in risk of VF SCA

Cardiology Research and Practice

RCT: randomized controlled trial, EPA: eicosapentaenoic acid, DHA: docosahexaenoic acid, ALA: alpha-linolenic acid, VT: ventricular tachycardia, VF: ventricular brillation, and SCA: sudden cardiac arrest.

Cardiology Research and Practice the highest serum content of n-3 PUFAs reported only a reduction in the presence of VF. Even though a reduction in inducible VT has been achieved in both animals and humans after infusion of n-3 PUFAs as well as after highdose supplementation [44], it is not known whether these marine PUFAs in normal dietary or supplementary ingested doses have the same potential to reduce the occurrence of spontaneous VT as compared to VF. It is, however, interesting to note that those studies reporting no benecial eect of oral supplementation seem to have the highest proportion of patients with only VT prior to inclusion [78, 80]. Furthermore, there is a high diversity between the ICD studies in supplementation doses and the length of the intervention, making an overall conclusion even harder to achieve. In agreement with a possible antiarrhythmic eect in the setting of ischemia-induced ventricular arrhythmias, we have recently presented evidence for a reduced risk of VF during the acute ischemic phase of an MI with high levels of cellular EPA and DHA [91]. After adjustment for other potential predictors of risk of VF, our case-control study including 10 patients with VF during the initial 6 hours of symptom onset suggested a 48% reduction in risk of this life-threatening arrhythmia with a 1% increase of the omega-3 index. We have later been able to reproduce the same nding in another SCD population comprising 12 case patients with a rst-time MI [82]. The main strength of both of these studies is the documentation of VF at the time of cardiac arrest, lending support to the hypothesis of an antiarrhythmic eect of n-3 PUFAs. Interestingly, results of the electrophysiological studies performed both in animals [88] and humans [45, 81], demonstrating reduced inducibility or termination of ventricular arrhythmias immediately after IV infusion of n-3 PUFAs, also suggest that incorporation of marine PUFAs into cell membranes might not be necessary for their antiarrhythmic eect. The major clinical trial data on antiarrhythmic eects are given in Table 2(b). 4.3. Meta-Analyses. A meta-analysis by Hooper et al. published in Britical Medical Journal (BMJ) in 2006 was given a lot of attention in media due to the conclusion that n-3 PUFAs given for at least 6 months had no clear eect on total mortality or combined CVD events [92]. This analysis was based on 41 cohort studies and 48 randomized intervention trials including both patients with and without established CVD but has later been criticized for several methodological problems. A recently published meta-analysis by Filion et al. [93] comprising 29 randomized controlled trials (RCTs) including 35 144 high-risk CVD patients could neither demonstrate a statistically signicant decrease in total mortality (RR 0.88, 95% CI 0.641.03) nor an eect on restenosis prevention (RR 0.89, 95% CI 0.721.06) by n-3 PUFAs. The results of these reviews dier, however, from several other meta-analyses evaluating observational studies and RCTs [9499]. They all demonstrate a reduced risk of cardiac death with increasing intake of marine PUFAs. The review by He et al. [95] could actually demonstrate a 7% lower risk of coronary heart disease mortality for each 20 g/day

9 increase in sh intake. The results are less consistent when evaluating the eect of n-3 PUFAs on nonfatal CVD events. Yzebe and Lievre [96], including 10 RCTs comprising 14 727 patients in their analysis, found no signicant eects on nonfatal MI, nonfatal stroke, or the presence of angina pectoris. The same lack of inuence by n-3 PUFAs on the incidence of nonfatal MI was observed by Bucher et al. [99]. This is opposed to the outcome from the review of 11 RCTs including 39 044 patients performed by Marik and Varon [97] where dietary supplementation with n-3 PUFAs signicantly reduced the risk of nonfatal CVD events (OR 0.92, P = 0.02). The latter nding might, however, be due to the fact that 48% of the patients included in that metaanalysis belonged to the JELIS study [61]. Furthermore, the heterogeneity of the eect of n-3 PUFA intake on CVD outcome might be related to the impact of varying doses and time of followup. In a meta-analysis by Kwak et al. [100] involving 20 485 patients with a history of cardiovascular disease from 14 randomized, double-blind, and placebo-controlled studies, intervention with EPA and DHA showed insucient evidence of a secondary preventive eect of n-3 PUFA supplements against overall cardiovascular events. JELIS [61] and GISSI 4 [53] were excluded from this analyses, as these were open studies. The reduced risk of cardiac death associated with the intake of n-3 PUFAs has largely been attributed to the prevention of SCD. Two meta-analyses have specically evaluated this outcome. Both Marik and Varon [97] and Chen et al. [98] found a reduced risk of SCD to be associated with the intake of n-3 PUFAs. In the study by Chen et al., this eect was, however, limited to CVD patients without guideline-adjusted therapy (RR 0.64, 95% CI 0.510.80). There are only a couple of meta-analyses available regarding the eect of n-3 PUFAs in ICD patients [43, 101], both of which include the previously described studies by Leaf et al. [47], Brouwer et al. [78], and Raitt et al. [80]. None of these studies support a protective eect of n-3 PUFAs from sh oil on cardiac arrhythmia in patients with an ICD. However, the diculties in interpreting meta-analyses are clearly demonstrated by the recently published two meta-analyses by Rizos et al. [102] and Delgado-Lista et al. [103] evaluating the ecacy of omega-3 PUFAs on CVD, including 12 of the same studies, but drawing opposite conclusions. Both include randomized controlled trials in primary and secondary prevention, but the endpoints dier. Rizos et al. [102], including 20 studies, conclude that omega3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke, based on relative and absolute measures of association. On the contrary, DelgadoLista et al. [103], including 21 studies, conclude in favour of omega-3 fatty acids, stating that marine omega-3 fatty acids are eective in preventing cardiovascular events of any kind (composite endpoint of stroke, coronary events, myocardial infarction or angina pectoris, peripheral limb disease events, or death from cardiovascular causes), cardiac death, and coronary events, especially in persons with high cardiovascular risk.

10 4.4. Studies on Triglycerides. The triglyceride-lowering eect of marine n-3 PUFAs is well recognized and has been demonstrated to be linearly dose-dependent across a wide range of consumption. As early as in 1990, Schmidt et al. performed their dose-response studies on the eect of marine n-3 PUFAs on triglyceride levels, showing that 6 weeks of supplementation with 1.3, 4, and 9 grams of n3 PUFAs daily to healthy normolipidemic men resulted in a reduction in plasma triglycerides by 9%, 25%, and 33%, respectively, in response to increasing doses of n-3 PUFAs [33] The minimal eective dose of marine n-3 PUFAs has been demonstrated to be about 1 gram daily, also in accordance with observations in the GISSI study, where 1 g marine n-3 PUFAs for 6 months resulted in a small, but signicant, triglyceride reduction [53]. Even greater dose-dependent reductions in plasma levels of triglycerides of 40%50% have been observed among individuals with hypertriglyceridemia. The American Heart Association (AHA) [104] recommendations state that EPADHA supplements may be useful in patients with severe hypertriglyceridemia (>500 mg of triglycerides per deciliter (5.6 mmol per liter)) in doses of 2 to 4 g of EPA-DHA per day to lower triglyceride levels by 20% to 40% in people in whom diet and lifestyle measures have not led to appropriate concentrations of triglycerides. This is also in agreement with the US National Cholesterol Education Program (NCEP) [105]. However, a meta-analysis studying the triglyceride-lowering eect of marine n-3 PUFAs in a daily dose of 4 grams administered to subjects with moderate hypertriglyceridemia (triglycerides 150500 mg/dL) concludes that marine n-3 PUFAs are eective in reducing triglycerides by approximately 30% [106]. Additional lipid disturbances and CVD risk factors should be considered before therapeutic decisions are made. Although clinical studies have reported considerable triglyceride-lowering eects by marine n-3 PUFA supplementation, no data for clinical endpoints are available to lend support to this recommendation. Further investigation is needed to explore this area.

Cardiology Research and Practice have, however, in two dierent populations of rst-time MIpatients demonstrated low levels of the omega-3 index to be independently associated with increased risk of cardiac arrest/VF during the acute ischemic phase of an MI [82, 91]. The omega-3 index appears to fulll many of the criteria required for a risk marker/risk factor, especially for SCD [48, 107, 108]. It has been estimated that the highest risk of cardiac death is associated with an omega-3 index below 4%, with a level of 8% oering the greatest degree of cardioprotection [48, 108]. These estimates correspond well with the actual measurements in our cardiac arrest patients but could not be conrmed as cut-points to classify patients at low, intermediate, or high risk in our prognostic study. Further studies are needed to elucidate the nal role of the omega-3 index in a clinical setting.

6. Conclusions and Further Perspectives

Despite a signicant amount of research since the pioneering work of Bang and Dyerberg in the 1970s attempting to elucidate the possible health eects of n-3 PUFAs, there are still several areas of uncertainty. The existing literature is, however, mainly supportive of a cardioprotective eect of marine sh oils, even though there is some disagreement as to whether this eect is mediated through a reduced risk of fatal or nonfatal cardiac disease. This might, however, be a question of an optimum dose or whether there exists a doseresponse relation for n-3 PUFA supplementation. A nal conclusion is dicult to reach, as studies dier in design and are performed in highly dierent patient populations with dierent background intake of sh and reect the administration of a wide range of supplement doses of n3 PUFAs for varying periods of time. We denitely need more high quality, large-scale, randomized, and controlled clinical trials of long-term duration also reporting possible harmful eects. Furthermore, studies on out-of-hospital cardiac arrest will hopefully answer some more questions related to the association between n-3 PUFAs and risk of SCD. Moreover, to diminish diculties in interpreting meta-analyses, future meta-analyses should strive to include trials with more homogenous designs and populations with respect to cardiovascular risk prole, using similar doses of marine n-3 PUFAs, with precisely dened endpoints. We are still awaiting results of three large-scaled trials which might contribute to a further understanding of the appropriate role of n-3 PUFAs in the primary prevention of cardiovascular events in both high- and low-risk participants. In the large ASCEND (A Study of Cardiovascular Events in Diabetes) trial, 15 480 diabetic patients (type I and II) without CVD at the time of inclusion were randomized with a 2 2 factorial design to receive low-dose aspirin (100 mg), n-3 PUFA 1 g/day, both regimens or placebo in a 2 2. Followup is scheduled to continue until 2017. No publication is yet available. The Rischio and Prevenzione study has between 2004 and 2007 randomized 12 513 participants without a previous MI to a daily dose of 1 g of n-3 PUFAs or placebo (olive oil) for 5 years to evaluate the inuence of n-3 PUFAs on death or hospitalization

5. The Omega-3 IndexA New Risk Factor for CAD?

The omega-3 index has during the recent decade been proposed as a new risk factor for CVD, especially for fatal cardiac events [48, 107, 108]. This index is an independent measurement of the amount of EPA and DHA available in the body, highly reecting the FA composition of the myocardium [3537]. In case-control studies the omega3 index has been demonstrated to be an independent risk marker for SCD [84] and for the development of an ACS [109, 110]. We could, however, not demonstrate any prognostic utility of the omega-3 index in the setting of secondary prevention in 460 ACS patients from the Risk Markers in the Acute Coronary Syndrome study (RACS) [111] with respect to future cardiac events or risk of death after adjustment for traditional risk factors and established risk markers. We

Cardiology Research and Practice

Table 3: Ocial recommendations for the use of marine n-3 fatty acids in CVD prevention. Primary prevention Eat a variety of sh, preferably oily sh (salmon, tuna, mackerel, herring, and trout), at least twice a week. Consuming sh oil supplements should only be considered by people with high levels of triglycerides who consult with their physicians. Eat sh twice a week, of which once oily sh2 . The recommended doses of total EPA and DHA to lower triglycerides have varied between 2 and 4 g/day. Use of n-3 fatty acids (prescription products) as an adjunct to the diet if triglycerides exceed 5.6 mmol/L (496 mg/dL)3 . Secondary prevention

11

The American Heart Association (AHA)1

European Society of Cardiology (ESC)

American College of Cardiology (ACC) International Society for the Study of Fatty Acids and Lipids (ISSFAL)5 Scientic Advisory Committee on Nutrition, United Kingdom (UK SACN)6 World Health Organization (WHO)7
1 http://www.heart.org/.

No recommendation.

Consume about 1 gram per day of the sh oils EPA and DHA (eicosapentaenoic and docosahexaenoic acids), preferably from oily sh, although EPA + DHA supplements could be considered in consultation with their physicians. People who have elevated triglycerides may need two to four grams of EPA and DHA per day provided as capsules under a physicians care. Eat sh twice a week, of which once oily sh2 . The recommended doses of total EPA and DHA to lower triglycerides have varied between 2 and 4 g/day. Use of n-3 fatty acids (prescription products) as an adjunct to the diet if triglycerides exceed 5.6 mmol/L (496 mg/dL)3 . Encourages increased consumption of omega-3 fatty acids in the form of sh or in capsule form (1 g/d) for risk reduction. For treatment of elevated triglycerides, higher doses are usually necessary for risk reduction4 . No recommendation. Recommends the equivalent of 450 mg marine omega-3 daily and an increase in population oily sh consumption to one portion a week. Regular sh consumption (1-2 servings per week) is protective against coronary heart disease and ischaemic stroke and is recommended. The serving should provide an equivalent of 200500 mg of eicosapentaenoic and docosahexaenoic acid.

A minimum intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) combined, of 500 mg/d. Recommends the equivalent of 450 mg marine omega-3 daily and an increase in population oily sh consumption to one portion a week. Regular sh consumption (1-2 servings per week) is protective against coronary heart disease and ischaemic stroke and is recommended. The serving should provide an equivalent of 200500 mg of eicosapentaenoic and docosahexaenoic acid.

Guidelines on cardiovascular disease prevention in clincal practice (version 2012). The fth joint task. Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. EHJ 2012; 33: 1635-1701. 3 ESC/EAS Guidelines for the management of dyslipidaemia. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). EHJ 2011; 32(14): 1769-1818. 4 AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease: 2006 update endorsed by the National Heart, Lung, and Blood Institute. JACC 2006; 47(10): 2130-9. 5 http://www.issfal.org/. 6 Advice on Fish Consumption: Benets and Risks was published in 2004 by the joint SACN/COT Subgroup (SACN 2004). 7 World Health Organization (WHO) 2003: Diet, Nutrition and the Prevention of Chronic Diseases.

2 European

for cardiovascular events. Finally, the third large study, the Vitamin D and Omega-3 Trial (VITAL), is currently recruiting 20 000 participants in the US without a history of CVD and cancer, for supplementation with Vitamin D and/or 1 g n-3 PUFAs, to assess the preventive eects of n3 PUFAs on these conditions. The ocial recommendations for the use of marine n3 fatty acids in CVD prevention by major ocial organizations such as The American Heart Association (AHA), the European Society of Cardiology (ESC), the International Society for the Study of Fatty Acids and Lipids (ISSFAL), and the World Health Organization (WHO) are given in Table 3. However, based on the existing knowledge, the general recommendation of sh or sh oil supplements in patients at risk of, or with established CVD, has not

been substantiated, but high doses of n-3 PUFAs appear to be safe in combination with current recommendations regarding medical treatment of CAD patients, especially when combined with aspirin and clopidogrel [112].

References
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12
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