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• W2124458610 abstract "HomeCirculationVol. 116, No. 10Omega-3 Fatty Acids and Cardiac Arrhythmias: Prior Studies and Recommendations for Future Research Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBOmega-3 Fatty Acids and Cardiac Arrhythmias: Prior Studies and Recommendations for Future ResearchA Report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop Barry London, Christine Albert, Mark E. Anderson, Wayne R. Giles, David R. Van Wagoner, Ethan Balk, George E. Billman, Mei Chung, William Lands, Alexander Leaf, John McAnulty, Jeffrey R. Martens, Rebecca B. Costello and David A. Lathrop Barry LondonBarry London From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , Christine AlbertChristine Albert From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , Mark E. AndersonMark E. Anderson From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , Wayne R. GilesWayne R. Giles From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , David R. Van WagonerDavid R. Van Wagoner From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , Ethan BalkEthan Balk From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , George E. BillmanGeorge E. Billman From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , Mei ChungMei Chung From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , William LandsWilliam Lands From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , Alexander LeafAlexander Leaf From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , John McAnultyJohn McAnulty From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , Jeffrey R. MartensJeffrey R. Martens From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author , Rebecca B. CostelloRebecca B. Costello From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author and David A. LathropDavid A. Lathrop From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.); Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.A.); Department of Medicine, University of Iowa, Iowa City (M.E.A.); Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada (W.R.G.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.R.V.W.); Department of Medicine, Tufts-New England Medical Center, Boston, Mass (E.B., M.C.); Department of Physiology and Cell Biology, Ohio State University, Columbus (G.E.B.); College Park, Md (W.L.); Department of Medicine, Massachusetts General Hospital, Boston (A.L.); Good Samaritan Hospital, Portland, Ore (J.R.M.); Department of Pharmacology, University of Michigan, Ann Arbor (J.R.M.); Office of Dietary Supplements, National Institutes of Health, Bethesda, Md (R.B.C.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.A.L.). Search for more papers by this author Originally published4 Sep 2007https://doi.org/10.1161/CIRCULATIONAHA.107.712984Circulation. 2007;116:e320–e335Compared with prehistoric times, the ratio of n-6 to n-3 fatty acids in the modern diet has increased ≈10-fold to 20:1.1,2 A substantial body of evidence suggests that n-3 polyunsaturated fatty acids (PUFAs) provide cardiovascular protection and prevent arrhythmias.3–5 This has led to the recommendation by the American Heart Association that all adults eat fatty fish at least 2 times per week and that patients with coronary heart disease (CHD) are advised to consume ≈1 g/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) combined.6,7 The evidence base is not entirely consistent, and a number of randomized trials have failed to show a protective effect of n-3 PUFAs against arrhythmias.8–10 This has led to some uncertainty regarding the appropriate recommendations for their use.11The present review originates from the Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop sponsored by the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements on August 29–30, 2005, and includes the findings from the recently published trials. Data from epidemiological studies, randomized clinical trials, animal studies, and basic science mechanistic studies on the role of n-3 PUFAs in arrhythmia prevention are examined. Areas in which the data are conflicting or our current knowledge is lacking are emphasized.Fatty Acid MetabolismFatty acids are classified by the length of the carbon chain (long chain, n=20 to 22; intermediate chain, n=18) and the number of double bonds (saturated, monounsaturated, polyunsaturated).1,2 For PUFAs, the location of the first double bond relative to the -CH3 or omega (n-) end is given. Long- and intermediate-chain fatty acids must be ingested as part of the diet because they cannot be synthesized by humans and are therefore referred to as essential. The most common dietary fatty acids include (1) the omega-6 linoleic acid 18:2 (n-6) found in corn oil, safflower oil, peanuts, and soybeans; (2) the long-chain omega-3 fatty acids including EPA 20:5 (n-3) and DHA 22:6 (n-3) found predominantly in fish oils; and (3) the intermediate-chain fatty omega-3 fatty acid alpha-linolenic acid (ALA) 18:3 (n-3) found in flaxseed oil, canola oil, and walnuts. ALA can be converted into EPA by the enzyme delta-6 desaturase, although the efficacy appears to vary considerably among different individuals.12 Competition between n-3 and n-6 dietary fatty acids influences the tissue proportions of n-3 and n-6 highly unsaturated fatty acids, which can be monitored and predicted in animals and humans (see http://efaeducation.nih.gov/sig/hufacalc.html).13Fatty acids are an important source of energy in mammals and are the major energy source for the heart. In addition, fatty acids are converted into bioactive eicosanoids (eg, leukotrienes, prostaglandins, and thromboxanes) whose cardiovascular effects differ depending on the parent compounds.Clinical TrialsLong-Chain n-3 Fatty Acids and Ventricular ArrhythmiasObservational DataCoronary Heart DiseaseA large body of observational data from epidemiological studies has accumulated over many years in support of the hypothesis that increased consumption of the long-chain n-3 PUFAs found in fish, most notably EPA and DHA, lowers the risk of dying from CHD.5,6 In the 1970s, Danish investigators first proposed that the low rate of CHD death observed among the Greenland Inuits was due to the abundance of n-3 fatty acids from seafood in their diet, which was estimated to be 400 g/d.14 Similarly low CHD death rates were also found in the Japanese, particularly in Okinawa, where fish consumption is twice as high as in mainland Japan.15 These cross-sectional ecological studies were followed by a large number of prospective epidemiological investigations regarding the association between fish intake and CHD. Most16,17 but not all18–21 prospective cohort studies reported inverse associations between fish consumption and CHD mortality. In general, high levels of fish intake have been associated with lower risks of CHD death in populations in which a substantial proportion of the population rarely or never consumed fish. In a recent meta-analysis combining these cohort studies, a 7% lower risk of CHD mortality was observed for each 20-g/d increase in fish intake (P for trend=0.03).22 In contrast, the few studies that have examined nonfatal CHD end points have found either no18,23,24 or weaker25 associations with nonfatal myocardial infarction (MI), and when combined in meta-analysis,22 the results for nonfatal MI are null. A recent study published after this meta-analysis, which was performed in a Japanese population, found a significant association between very high levels of dietary fish intake (≈8 fish meals per week) and nonfatal coronary events compared with those with lower levels (≈1 fish meal per week), suggesting that there may be antithrombotic or atherogenic actions at higher doses of fish intake.26A potential antiarrhythmic action of low doses of n-3 fatty acids could explain, at least in part, this differential effect on fatal versus nonfatal CHD events at dosages of fish intake traditionally observed in Western populations. If n-3 fatty acids specifically reduce the risk of fatal ventricular arrhythmias associated with CHD, rather than the development of CHD, a preferential effect on CHD mortality would be expected.Sudden Cardiac DeathIf the n-3 fatty acids have antiarrhythmic properties, one would hypothesize that these fatty acids should have their greatest impact on risk of sudden cardiac death (SCD) because ventricular arrhythmias underlie ≈80% to ≈90% of these deaths.27,28 Indeed, the 4 observational studies that have specifically examined the association between dietary intake of long-chain n-3 fatty acids and SCD have all reported protective associations. Siscovick et al29 first reported an inverse association between dietary intake and blood levels of n-3 fatty acids and the risk of primary cardiac arrest utilizing a retrospective population-based case-control design. These data have subsequently been confirmed in 2 prospective cohort studies of male health professionals23,30 and another study conducted among older individuals (aged >65 years).24 In all of these studies, consuming fish ≈1 to 2 times per week was associated with significant 42% to 50% reductions in SCD risk.23,24,29,30 In 2 of these studies, the benefits were even more striking when n-3 fatty acids were measured directly in blood.29,31 Those in the highest quartile of n-3 fatty acid blood level were found to have 81% to 90% reductions in SCD risk compared with those in the lowest quartile, even after adjustment for other fatty acids. Of note, all of these studies were performed in populations who were apparently healthy and free of known CHD at inception.Significant limitations are present in these observational studies. In most of them, SCD was assumed to be the result of MI and was included in the CHD end point. This is usually but not always the case. In addition, death certificates were often used to determine the cause of death. These limitations may account for some of the variability in study results.Randomized TrialsPatients With Prior CHDIn addition to these observational studies, several randomized treatment trials utilizing long-chain n-3 fatty acids have been conducted among patients with known preexisting cardiac disease. Two of the largest randomized trials have involved dietary interventions. The first such trial, the Diet and Reinfarction Trial (DART) published in 1989, randomly assigned 2033 men after MI to receive or to not receive advice to eat at least 2 portions of fatty fish per week.32 The men assigned to the fish advice arm experienced a 29% reduction in total mortality (primarily composed of CHD deaths) without any benefit on nonfatal MI. These results, in combination with the observational data described above, provided further support to the hypothesis that these agents might possess antiarrhythmic properties. In contrast, the follow-up DART-2 trial, which was conducted among 3114 men with self-reported “chronic angina,” found a 26% higher risk of cardiac death and a 54% increased risk of SCD among men randomly assigned to the fish advice group.33 However, this second trial had an interruption of the study for 1 year because of inadequate funds and a rerandomization. The effect that the study interruption had on dietary patterns and lost to follow-up rates is unknown, but it likely had some impact on the validity of these results.Several trials have also tested the efficacy of n-3 fatty acid supplements, and the data on all these trials have been reviewed elsewhere recently.34 By far, the largest published trial to date is the Gruppo Italiano per la Sperimentazione della Streptochinasi nell’Infarto miocardico (GISSI)-Prevenzione trial, which tested a combination of 850 mg EPA and DHA daily in an open-label fashion among 11 324 patients with recent MI.35 The patients assigned to n-3 PUFA had a significant reduction in the primary end point (death, nonfatal MI, and nonfatal stroke), primarily because of a statistically significant reduction in SCD (45%) without any benefit on nonfatal MI or stroke. The survival curves for n-3 PUFA treatment diverged early after randomization. Total mortality was significantly lower after 3 months of treatment, and the reduction in risk of sudden death was already statistically significant at 4 months (relative risk, 0.47; P=0.048).36 The authors concluded that this early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death lends further support to the postulated antiarrhythmic mechanism of the n-3 fatty acids. Subsequent subgroup analyses from this trial suggested that the benefit on SCD risk may be greater among patients with systolic dysfunction (left ventricular ejection fraction ≤40%) compared with those with preserved left ventricular ejection fraction (left ventricular ejection fraction >50%).37 Although the GISSI-Prevenzione trial is the largest trial published to date, its open label design and lack of an appropriate placebo control group are important limitations.On the basis of the data from observational epidemiological studies and the aforementioned randomized clinical trials, as well as plausible mechanisms for benefit, the American Heart Association in 2002 and 2003 recommended that all adults eat fish, particularly fatty fish, at least 2 times per week.6,7 On the basis primarily on the results of the GISSI-Prevenzione trial, patients with CHD are advised to consume ≈1 g/d of EPA and DHA combined.7Unpublished, Ongoing, or Planned Randomized Trials With Cardiovascular End PointsPreliminary results have recently become available from another large-scale randomized trial, the Japan EPA Lipid Intervention Study (JELIS), presented at the 2005 American Heart Association meetings in Dallas.38 This trial enrolled 18 645 participants with hypercholesterolemia, of which 14 981 had no history of CHD, to high-dose EPA (1.8 g/d) in combination with statins versus a statin alone. At the time of presentation, the authors reported a 19% reduction in a composite CHD end point including SCD, MI, unstable angina, and coronary revascularization. Data on cause-specific event rates are not yet available. Of note, this trial will be one of the first large-scale primary prevention trials of the long-chain n-3 fatty acids.In addition to this recently completed trial, several planned or ongoing large-scale randomized trials in Europe involve various cardiovascular end points as outcomes. Only 1 trial, the Omega trial, plans to examine SCD as the primary end point. This trial seeks to randomize 3800 patients with a recent MI to 1 g of long-chain n-3 fatty acids or placebo. Several other planned trials will examine composite end points, with SCD as a secondary end point. As a follow-up to the GISSI-Prevenzione trial, the GISSI-Heart Failure trial has already randomized, in a double-blind 2×2 factorial design, a heterogeneous group of ≈7000 patients with class II to IV heart failure (≈50% have a CHD etiology for congestive heart failure) to receive either 1 g of EPA/DHA, rosuvastatin, both active drugs, or both placebos.39 The primary end point in this trial will be all-cause mortality or hospitalizations for cardiovascular reasons. Two other large-scale randomized trials are also planned in diabetic patients. The A Study of Cardiovascular Events in Diabetes (ASCEND) trial plans to randomize 10 000 diabetic patients in a 2×2 factorial design to low-dose aspirin versus 1 g long-chain omega-3 fatty acid supplementation versus placebo, and the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial plans to enroll 10 000 diabetic patients with a history of cardiovascular disease to insulin glargine versus 1 g long-chain omega-3 fatty acid supplementation versus placebo. Both trials will examine composite end points involving all serious cardiovascular events.Trials in Patients With ICDs and a History of Ventricular Tachycardia/Ventricular Fibrillation: Primary Ventricular Arrhythmia End PointsThe reduction in SCD risk reported in observational studies and clinical trials, along with the basic science data, has led many to hypothesize that these long-chain n-3 fatty acids are antiarrhythmic in humans and thus may prevent ventricular arrhythmias in high-risk patients. Although SCD is often the result of a ventricular arrhythmia, other processes are involved, and the trials outlined in the prior section have been unable to definitively decipher the mechanism(s) of action of these long-chain n-3 fatty acids. The growing use and capabilities of implantable cardioverter-defibrillators (ICDs) have created a unique research opportunity to begin to determine whether these long-chain n-3 fatty acids specifically reduce ventricular arrhythmias. On this basis, 3 separate groups of investigators undertook double-blind, randomized trials among ICD patients who had already experienced a life-threatening ventricular tachycardia/ventricular fibrillation (VT/VF) event.The first trial, published by Raitt et al,10 reported that fish oil did not reduce the risk of VT/VF in 200 ICD patients with an episode" @default.
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• W2124458610 title "Omega-3 Fatty Acids and Cardiac Arrhythmias: Prior Studies and Recommendations for Future Research" @default.
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