Omega-3 Fatty Acids for Cardioprotection
2008; Elsevier BV; Volume: 83; Issue: 3 Linguagem: Inglês
10.4065/83.3.324
ISSN1942-5546
AutoresJohn H. Lee, James H. O’Keefe, Carl J. Lavie, Roberto Marchioli, William S. Harris,
Tópico(s)Diet and metabolism studies
ResumoThe most compelling evidence for the cardiovascular benefit provided by omega-3 fatty acids comes from 3 large controlled trials of 32,000 participants randomized to receive omega-3 fatty acid supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or to act as controls. These trials showed reductions in cardiovascular events of 19% to 45%. These findings suggest that intake of omega-3 fatty acids, whether from dietary sources or fish oil supplements, should be increased, especially in those with or at risk for coronary artery disease. Patients should consume both DHA and EPA. The target DHA and EPA consumption levels are about 1 g/d for those with known coronary artery disease and at least 500 mg/d for those without disease. Patients with hypertriglyceridemia benefit from treatment with 3 to 4 g/d of DHA and EPA, a dosage that lowers triglyceride levels by 20% to 50%. Although 2 meals of oily fish per week can provide 400 to 500 mg/d of DHA and EPA, secondary prevention patients and those with hypertriglyceridemia must use fish oil supplements if they are to reach 1 g/d and 3 to 4 g/d of DHA and EPA, respectively. Combination therapy with omega-3 fatty acids and a statin is a safe and effective way to improve lipid levels and cardiovascular prognosis beyond the benefits provided by statin therapy alone. Blood DHA and EPA levels could one day be used to identify patients with deficient levels and to individualize therapeutic recommendations. The most compelling evidence for the cardiovascular benefit provided by omega-3 fatty acids comes from 3 large controlled trials of 32,000 participants randomized to receive omega-3 fatty acid supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or to act as controls. These trials showed reductions in cardiovascular events of 19% to 45%. These findings suggest that intake of omega-3 fatty acids, whether from dietary sources or fish oil supplements, should be increased, especially in those with or at risk for coronary artery disease. Patients should consume both DHA and EPA. The target DHA and EPA consumption levels are about 1 g/d for those with known coronary artery disease and at least 500 mg/d for those without disease. Patients with hypertriglyceridemia benefit from treatment with 3 to 4 g/d of DHA and EPA, a dosage that lowers triglyceride levels by 20% to 50%. Although 2 meals of oily fish per week can provide 400 to 500 mg/d of DHA and EPA, secondary prevention patients and those with hypertriglyceridemia must use fish oil supplements if they are to reach 1 g/d and 3 to 4 g/d of DHA and EPA, respectively. Combination therapy with omega-3 fatty acids and a statin is a safe and effective way to improve lipid levels and cardiovascular prognosis beyond the benefits provided by statin therapy alone. Blood DHA and EPA levels could one day be used to identify patients with deficient levels and to individualize therapeutic recommendations. The American Heart Association (AHA) has endorsed the use of omega-3 fatty acids for secondary prevention of cardiovascular (CV) events in people with documented coronary artery disease (CAD). The recommendation calls for approximately 1 g/d of a mixture of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Although the AHA statement identifies oily fish as the ideal source, fish oil (in capsules or liquid form) is also an acceptable option.1Kris-Etherton PM Harris WS Appel LJ American Heart Association Nutrition Committee Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.Circulation. 2002; 106: 2747-2757Crossref PubMed Scopus (2877) Google Scholar This is the first time that the AHA has recommended a nutritional supplement for CAD prevention. The omega-3 fatty acid recommendation is based on an extensive and growing body of evidence supporting the CV benefits and triglyceride-lowering effects of omega-3 oils. The Food and Drug Administration (FDA) has approved an omega-3 fatty acid ethyl ester formulation, at a dosage of 4.0 g/d, for the treatment of very high triglyceride levels. Nevertheless, many physicians and patients are confused about the appropriate form, indications, and dosing of omega-3 fatty acids. This review briefly summarizes current scientific data on omega-3 fatty acids and CV health, specifically focusing on indications for use and recommended guidelines for administration and dosing. Throughout, the term omega-3 fatty acids is used to indicate DHA and EPA only; as discussed later, the evidence for a CV benefit from α-linolenic acid (ALA), a plant omega-3 fatty acid, is much weaker than it is for DHA and EPA. During the past 3 decades, thousands of epidemiologic, observational, experimental, and randomized controlled studies have been published on the CV effects of omega-3 fatty acids. In the aggregate, these studies document clear CV protective effects.2Wang C Harris WS Chung M et al.n-3 Fatty acid from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.Am J Clin Nutr. 2006; 84: 5-17Crossref PubMed Scopus (850) Google Scholar The 2 specific omega-3 fatty acids that have been associated with CV benefit and triglyceride lowering are those from fish oils, DHA and EPA. In contrast, ALA, which is found in abundance in flaxseed and to a lesser extent in walnuts and other tree nuts, as well as in trace amounts in green leafy vegetables, is inadequate as the sole dietary source of omega-3 fatty acids because humans convert less than 5% of ALA to EPA (and less to DHA).3Plourde M Cunnane SC Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements.Appl Physiol Nutr Metab. 2007; 32: 619-634Crossref PubMed Scopus (416) Google Scholar In some but not all epidemiologic studies,2Wang C Harris WS Chung M et al.n-3 Fatty acid from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.Am J Clin Nutr. 2006; 84: 5-17Crossref PubMed Scopus (850) Google Scholar ALA intake has been inversely associated with CV events; however, because of the absence of convincing randomized trials with clinically relevant endpoints, its role in cardioprotection is less clear than that of DHA and EPA. Harris et al4Harris WS Poston WC Haddock CK Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events.Atherosclerosis. 2007 Jul; 193 (Epub 2007 May 15.): 1-10Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar reviewed 25 trials that evaluated risk of CAD events as a function of in vivo omega-3 fatty acid levels. The quantity of DHA in plasma and cellular phospholipids, which closely correlates with the quantity of DHA in the myocardium, was inversely related to the risk of events.4Harris WS Poston WC Haddock CK Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events.Atherosclerosis. 2007 Jul; 193 (Epub 2007 May 15.): 1-10Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 5Metcalf RG James MJ Gibson RA et al.Effects of fish-oil supplementation on myocardial fatty acids in humans.Am J Clin Nutr. 2007; 85: 1222-1228PubMed Google Scholar Reduced risk appears to be more clearly linked to increased tissue levels of DHA than EPA (Table 1); however, it is difficult to separate completely the effects of these 2 omega-3 fatty acids that are almost always consumed together.TABLE 1Association Between Tissue Fatty Acids and Risk of CAD Events, Estimated by Effect Sizes in 25 StudiesaALA =α-linolenic acid; CAD = coronary artery disease; CI = confidence interval; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid.Adapted from Atherosclerosis,4Harris WS Poston WC Haddock CK Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events.Atherosclerosis. 2007 Jul; 193 (Epub 2007 May 15.): 1-10Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar with permission from Elsevier.All studiesFatty acidgbg: Hedges g (effect size), in which the case-control difference is expressed as a fraction of the pooled SD; negative values indicate that fatty acid values were lower in cases relative to controls.P value95% CINo. of studiesEPA-DHA−0.19<.01−0.06 to −0.3319DHA−0.34<.01−0.12 to −0.5919EPA−0.10.080.01 to −0.2115ALA−0.21.03−0.02 to −0.3916a ALA =α-linolenic acid; CAD = coronary artery disease; CI = confidence interval; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid.b g: Hedges g (effect size), in which the case-control difference is expressed as a fraction of the pooled SD; negative values indicate that fatty acid values were lower in cases relative to controls. Open table in a new tab In a randomized trial performed almost 2 decades ago, omega-3 fatty acids, either in the form of oily fish or fish oil capsules, reduced 2-year all-cause mortality by 29% in post-myocardial infarction (MI) patients.6Burr ML Fehily AM Gilbert JF et al.Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).Lancet. 1989; 2: 757-761Abstract PubMed Scopus (2320) Google Scholar More recently, 2 major randomized controlled trials examined the effects of supplemental omega-3 fatty acids on CAD risk. The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione study randomized 11,323 patients who had experienced an MI to omega-3 acid ethyl esters (1 capsule per day, providing 850 mg of DHA and EPA) or usual care. Treatment significantly reduced risk of death from any cause by 28%; after 4 months, risk of sudden cardiac death (SCD) was decreased by 45% (Figure 1).7Marchioli R Barzi F Bomba E GISSI-Prevenzione Investigators et al.Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione.Circulation. 2002; 105: 1897-1903Crossref PubMed Scopus (1178) Google Scholar In another megatrial, the Japan EPA Lipid Intervention Study (JELIS),8Yokoyama M Origasa H Matsuzaki M Japan EPA lipid intervention study (JELIS) Investigators et al.Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis.Lancet. 2007; 369: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (1936) Google Scholar 18,645 patients with hypercholesterolemia (70% women; mean age, 61 years) were randomly assigned to either statin alone or statin and pure EPA (1.8 g/d). During the 5-year study, EPA reduced major adverse CV events by 19% (Figure 2). Omega-3 fatty acid supplementation lowered CV risk in both the GISSI-Prevenzione study and JELIS, despite aggressive therapy with standard pharmacotherapy (eg, statins, aspirin, β-blockers and angiotensin-converting enzyme inhibitors). Additionally, the JELIS trial established the safety and efficacy of combination therapy with EPA and a statin vs statin therapy alone for improving CV prognosis.8Yokoyama M Origasa H Matsuzaki M Japan EPA lipid intervention study (JELIS) Investigators et al.Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis.Lancet. 2007; 369: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (1936) Google ScholarFIGURE 2Eicosapentaenoic acid (EPA) (1.8 g/d) reduced the incidence of major adverse coronary events in the Japan EPA Lipid Intervention Study (JELIS) by 19%. CI = confidence interval. From The Lancet,8Yokoyama M Origasa H Matsuzaki M Japan EPA lipid intervention study (JELIS) Investigators et al.Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis.Lancet. 2007; 369: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (1936) Google Scholar with permission from Elsevier.View Large Image Figure ViewerDownload (PPT) Omega-3 fatty acids appear to confer CV benefits largely through DHA and EPA enrichment of membrane phospholipids.9Harris WS Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor.Pharmacol Res. 2007 Mar; 55 (Epub 2007 Jan 25.): 217-223Crossref PubMed Scopus (204) Google Scholar Via this mechanism, omega-3 fatty acids can ultimately increase arrhythmic thresholds,10Anand RG Alkadri M Lavie CJ Milani RV The role of fish oil in arrhythmia prevention.J Cardiopulm Rehabil Prev. 2008; 28: 2-8PubMed Google Scholar reduce blood pressure,11O'Keefe Jr, JH Abuissa H Sastre A Steinhaus DM Harris WS Effects of omega-3 fatty acids on resting heart rate, heart rate recovery after exercise, and heart rate variability in men with healed myocardial infarctions and depressed ejection fractions.Am J Cardiol. 2006 Apr 15; 97 (Epub 2006 Mar 3.): 1127-1130Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 12Ventura HO Milani RV Lavie CJ et al.Cyclosporine-induced hypertension: efficacy of omega-3 fatty acids in patients after cardiac transplantation.Circulation. 1993; 88: II281-II285PubMed Google Scholar improve arterial and endothelial function,13Thies F Garry JM Yaqoob P et al.Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial.Lancet. 2003; 361: 477-485Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar reduce platelet aggregation,14Din JN, Harding SA, Valerio CJ, et al. Dietary intervention with oil rich fish reduces platelet-monocyte aggregation in man [published online ahead of print April 27, 2007]. Atherosclerosis, doi:10.1016/j.atherosclerosis.2007.04 .047.Google Scholar and favorably affect autonomic tone11O'Keefe Jr, JH Abuissa H Sastre A Steinhaus DM Harris WS Effects of omega-3 fatty acids on resting heart rate, heart rate recovery after exercise, and heart rate variability in men with healed myocardial infarctions and depressed ejection fractions.Am J Cardiol. 2006 Apr 15; 97 (Epub 2006 Mar 3.): 1127-1130Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 15Abuissa A O'Keefe Jr, JH Harris WS Lavie CJ Autonomic function, omega-3, and cardiovascular risk [editorial].Chest. 2005; 127: 1088-1091Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar (Table 2). In a meta-regression analysis of 22double-blind studies, Geleijnse et al16Geleijnse JM Giltay EJ Grobbee DE Donders AR Kok FJ Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials.J Hypertens. 2002; 20: 1493-1499Crossref PubMed Scopus (595) Google Scholar reported that consumption of approximately 4.0 g/d of omega-3 fatty acid was associated with a significant 1.7- and 1.5-mm Hg reduction in systolic and diastolic blood pressures, respectively; these reductions were more pronounced in older patients and in those with higher blood pressures. Evidence suggests that lowering systolic blood pressure by as little as 2 mm Hg can yield reductions of 4% in mortality due to CAD.17Ueshima H Stamler J Elliott P INTERMAP Research Group et al.Food omega-3 fatty acid intake of individuals (total, linolenic acid, long-chain) and their blood pressure: INTERMAP study.Hypertension. 2007 Aug; 50 (Epub 2007 Jun 4.): 313-319Crossref PubMed Scopus (182) Google ScholarTABLE 2Possible Omega-3 Fatty Acid BenefitsAntiarrhythmic effectsaConferred at lower doses of docosahexaenoic acid and eicosapentaenoic acid.Decreased blood pressureModulation of autonomic functionaConferred at lower doses of docosahexaenoic acid and eicosapentaenoic acid.Anti-inflammatory effectsDecreased platelet aggregationPlaque stabilizationVasodilationDecreased triglyceridesa Conferred at lower doses of docosahexaenoic acid and eicosapentaenoic acid. Open table in a new tab The antiplatelet, anti-inflammatory, and triglyceride-lowering effects of omega-3 fatty acids require relatively higher doses of DHA and EPA (eg, 3.0-4.0 g/d), whereas the reduction in SCD risk can be achieved at lower intakes (0.5-1.0 g/d).4Harris WS Poston WC Haddock CK Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events.Atherosclerosis. 2007 Jul; 193 (Epub 2007 May 15.): 1-10Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 7Marchioli R Barzi F Bomba E GISSI-Prevenzione Investigators et al.Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione.Circulation. 2002; 105: 1897-1903Crossref PubMed Scopus (1178) Google Scholar Omega-3 fatty acids have been shown to suppress production of proinflammatory cytokines such as interleukin 6, interleukin 1β, and tissue necrosis factor α.18Zhao G Etherton TD Martin KR Gilles PJ West SG Kris-Etherton PM Dietary α-linolenic acid inhibits proinflammatory cytokine production by peripheral blood mononuclear cells in hypercholesterolemic subjects.Am J Clin Nutr. 2007; 85: 385-391PubMed Google Scholar Additionally, when administered to people who were obese, 1.8 g/d of EPA increased the level of adiponectin, which can reduce inflammation and improve insulin sensitivity.19Itoh M Suganami T Satoh N et al.Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects.Arterioscler Thromb Vasc Biol. 2007 Sep; 27 (Epub 2007 Jan 14.): 1918-1925Crossref PubMed Scopus (254) Google Scholar Very high doses of omega-3 fatty acids (ie, 8.0 g/d) have been shown to have anti-inflammatory effects and to improve body composition in patients with heart failure.20Mehra MR Lavie CJ Ventura HO Milani RV Fish oils produce anti-inflammatory effects and improve body weight in severe heart failure.J Heart Lung Transplant. 2006 Jul; 25 (Epub 2006 May 24.): 834-838Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar However, omega-3 fatty acids have not been shown consistently to lower C-reactive protein levels.21Madsen T Schmidt EB Christensen JH The effect of n-3 fatty acids on C-reactive protein levels in patients with chronic renal failure.J Ren Nutr. 2007; 17: 258-263Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar A "GISSI" dose of DHA and EPA (810 mg/d) given to stable CAD patients decreased resting heart rate, increased postexercise heart rate recovery, and increased beat-to-beat heart rate variability (in the high-frequency band).11O'Keefe Jr, JH Abuissa H Sastre A Steinhaus DM Harris WS Effects of omega-3 fatty acids on resting heart rate, heart rate recovery after exercise, and heart rate variability in men with healed myocardial infarctions and depressed ejection fractions.Am J Cardiol. 2006 Apr 15; 97 (Epub 2006 Mar 3.): 1127-1130Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar These changes are consistent with augmented vagal tone, suggesting that omega-3 fatty acids could confer cardioprotection in part by improving autonomic sympathovagal balance.11O'Keefe Jr, JH Abuissa H Sastre A Steinhaus DM Harris WS Effects of omega-3 fatty acids on resting heart rate, heart rate recovery after exercise, and heart rate variability in men with healed myocardial infarctions and depressed ejection fractions.Am J Cardiol. 2006 Apr 15; 97 (Epub 2006 Mar 3.): 1127-1130Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 15Abuissa A O'Keefe Jr, JH Harris WS Lavie CJ Autonomic function, omega-3, and cardiovascular risk [editorial].Chest. 2005; 127: 1088-1091Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar However, other studies in patients undergoing heart transplant suggest that omega-3 fatty acids can reduce heart rate independently of vagal activation.22Harris WS Gonzales M Laney N Sastre A Borkon AM Effects of omega-3 fatty acids on heart rate in cardiac transplant recipients.Am J Cardiol. 2006 Nov 15; 98 (Epub 2006 Oct 2.): 1393-1395Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar To the extent that the omega-3 fatty acid cardioprotection is mediated by changes in cell membrane composition, the much higher levels of DHA than EPA in membrane phospholipids5Metcalf RG James MJ Gibson RA et al.Effects of fish-oil supplementation on myocardial fatty acids in humans.Am J Clin Nutr. 2007; 85: 1222-1228PubMed Google Scholar, 14Din JN, Harding SA, Valerio CJ, et al. Dietary intervention with oil rich fish reduces platelet-monocyte aggregation in man [published online ahead of print April 27, 2007]. Atherosclerosis, doi:10.1016/j.atherosclerosis.2007.04 .047.Google Scholar suggest that DHA is the more important of the 2 omega-3 fatty acids. However, data from JELIS demonstrated the efficacy of EPA, which is integrally involved in the antiplatelet and anti-inflammatory activities of omega-3 fatty acids. Although EPA can compete with arachidonic acid (AA) as a substrate for the production of cyclooxygenase- and lipoxygenase-derived eicosanoids, it is a much poorer substrate than AA.23Wada M Delong CJ Hong YH et al.Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products.J Biol Chem. 2007 Aug 3; 282 (Epub 2007 May 22.): 22254-22266Crossref PubMed Scopus (323) Google Scholar Given that membranes typically contain 10 times as much AA as EPA, the beneficial effects of omega-3 fatty acids are not likely due to EPA-derived eicosanoids. As discussed earlier, the presence of both DHA and EPA in cellular membranes can alter the activity of membrane-bound proteins (receptors, ion channels, etc), and both omega-3 fatty acids can work synergistically to alter metabolism via this mechanism. Some of the cardioprotective effects of omega-3 fatty acids, particularly at higher doses, could result from their favorable effects on the lipid profile. Davidson et al24Davidson MH Stein EA Bayes HE COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators et al.Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study.Clin Ther. 2007; 29: 1354-1367Abstract Full Text PDF PubMed Scopus (370) Google Scholar recently reported that 3.4 g/d of omega-3 acid ethyl esters, when added to baseline simvastatin therapy, produced additional reductions of 29.5% in triglyceride levels and 9.0% in non-high-density lipoprotein (HDL) cholesterol levels, with a small but significant increase in HDL levels (Figure 3). Omega-3 fatty acids induce variable effects on low-density lipoprotein (LDL), depending on the baseline lipid profile. In JELIS, EPA reduced LDL by approximately 10%; however, omega-3 fatty acids can increase LDL by up to 10% when used in high doses to treat moderately elevated triglyceride levels,25Harris WS n-3 fatty acids and serum lipoproteins: human studies.Am J Clin Nutr. 1997; 65: 1645s-1654sCrossref PubMed Scopus (972) Google Scholar and by 32% (from 79 to 104 mg/dL [to convert to millimoles per liter, multiply by 0.0113]) in patients with very high baseline triglyceride levels.26Harris WS Ginsberg HN Arunakul N et al.Safety and efficacy of Omacor in severe hypertriglyceridemia.J Cardiovas Risk. 1997; 4: 385-391Crossref PubMed Scopus (304) Google Scholar Both DHA and EPA are present in all oily fish, although at variable ratios (Table 3).27USDA Agricultural Research Service Nutrient Data Laboratory.http://www.ars.usda.gov/nutrientdataGoogle Scholar Most commonly consumed fish, such as salmon, contain DHA and EPA in a ratio of approximately 2:1, whereas standard fish oil (usually derived from menhaden, an oily fish of the herring family) contains DHA and EPA in a 2:3 ratio. To a small extent, DHA can be retroconverted to EPA28Conquer JA Holub BJ Dietary docosahexaenoic acid as a source of eicosapentaenoic acid in vegetarians and omnivores.Lipids. 1997; 32: 341-345Crossref PubMed Scopus (118) Google Scholar; however, EPA supplementation does not increase tissue or blood levels of DHA.29Park Y Harris WS Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance.J Lipid Res. 2003 Mar; 44 (Epub 2002 Dec 1.): 455-463Crossref PubMed Scopus (282) Google Scholar In vitro studies have shown both fatty acids to alter ion channel function.30Harris WS Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor.Pharmacol Res. 2007 Mar; 55 (Epub 2007 Jan 25.): 217-223Crossref PubMed Scopus (93) Google ScholarTABLE 3Fish Content of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA)aData from reference 27.TypeDHA (g/100 g)EPA (g/100 g)DHA and EPA (g/100 g)Ratio DHA:EPATuna Bluefin1.1410.3631.5043.1:1.0 Light, canned in water0.2230.0470.2704.8:1.0 Albacore, canned in water0.6290.2330.8622.7:1.0Salmon Atlantic, farmed1.4570.6902.1472.1:1.0 Atlantic, wild1.4290.4111.8403.5:1.0 Chinook0.7271.0101.7371.0:1.4 Sockeye0.7000.5301.2301.3:1.0Mackerel, Atlantic0.6990.5041.2031.4:1.0Herring, Atlantic1.1050.9092.0141.2:1.0Trout Rainbow, farmed0.8200.3341.1542.5:1.0 Rainbow, wild0.5200.4680.9881.1:1.0Halibut0.3740.0910.4654.1:1.0Cod0.1540.0040.15838.5:1.0Haddock0.1620.0760.2382.1:1.0Catfish Channel, farmed0.1280.0490.1772.6:1.0 Channel, wild0.1370.1000.2371.4:1.0Swordfish0.6810.0870.7687.8:1.0Grouper0.2130.0350.2486.1:1.0Shrimp0.1440.1710.3151.0:1.2a Data from reference 27USDA Agricultural Research Service Nutrient Data Laboratory.http://www.ars.usda.gov/nutrientdataGoogle Scholar. Open table in a new tab A recent meta-analysis pooling the results of prospective clinical trials and epidemiologic studies suggests that most of the reduction in risk of CAD death is conferred with modest omega-3 fatty acid consumption (approximately 250-500 mg/d of DHA and EPA, corresponding to approximately 1-2 servings per week of oily fish) (Figure 4).31Mozaffarian D Rimm EB Fish intake, contaminants, and human health: evaluating the risks and the benefits.JAMA. 2006; 296: 1885-1899Crossref PubMed Scopus (1541) Google Scholar Thus, the antiarrhythmic effects32Reiffel JA McDonald A Antiarrhythmic effects of omega-3 fatty acids.Am J Cardiol. 2006 Aug 21; 98 (Epub 2006 May 26.): 50i-60iAbstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar are apparent in studies in which the background intake of omega-3 fatty acids is already low and the risk of SCD is high. The reductions in SCD and fatal CAD in the GISSI-Prevenzione study appeared quickly, within weeks of initiating omega-3 fatty acid therapy. On the basis of the JELIS trial, the reduction in nonfatal CAD events could require higher doses (eg, 2000 mg/d of DHA and EPA) and a longer duration of treatment (3-5 years). In a recent review of the cumulative data, Anand et al10Anand RG Alkadri M Lavie CJ Milani RV The role of fish oil in arrhythmia prevention.J Cardiopulm Rehabil Prev. 2008; 28: 2-8PubMed Google Scholar showed significant benefits of DHA and EPA against atrial fibrillation,33Calo L Bianconi L Colivicchi F et al.N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial.J Am Coll Cardiol. 2005; 45: 1723-1728Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar as well as trends toward benefits in malignant ventricular arrhythmias.10Anand RG Alkadri M Lavie CJ Milani RV The role of fish oil in arrhythmia prevention.J Cardiopulm Rehabil Prev. 2008; 28: 2-8PubMed Google Scholar, 34Raitt MH Connor WE Morris C et al.Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implant able defibrillators: a randomized controlled trial.JAMA. 2005; 293: 2884-2891Crossref PubMed Scopus (347) Google Scholar, 35Brouwer IA Zock PL Camm AJ SOFA Study Group et al.Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators.JAMA. 2006; 295: 2613-2619Crossref PubMed Scopus (257) Google Scholar, 36Leaf A Albert CM Josephson M et al.Fatty Acid Antiarrhythmia Trial Investigators. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake.Circulation. 2005; 112: 2762-2768Crossref PubMed Scopus (343) Google Scholar In a randomized trial of 160 patients with CAD, omega-3 fatty acid supplementation (1700 mg/d of DHA and EPA) reduced the occurrence of atrial fibrillation after coronary artery bypass surgery by 54% vs placebo.33Calo L Bianconi L Colivicchi F et al.N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial.J Am Coll Cardiol. 2005; 45: 1723-1728Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar Although omega-3 fatty acids are effective at reducing SCD in patients with CAD and reducedleft-ventricular systolic function,37Macchia A Levantesi G Franzosi MG GISSI-Prevenzione Investigators et al.Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids.Eur J Heart Fail. 2005; 7: 904-909Crossref PubMed Scopus (109) Google Scholar mixed results were reported for 3 trials using omega-3 fatty acids in patients with implantable cardioverter-defibrillators.34Raitt MH Connor WE Morris C et al.Fish oil supplementation and risk of ventricular tachycardia and ventricul
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