From Inuit to Implementation: Omega-3 Fatty Acids Come of Age
2000; Elsevier BV; Volume: 75; Issue: 6 Linguagem: Inglês
10.4065/75.6.607
ISSN1942-5546
AutoresJames H. O’Keefe, William S. Harris,
Tópico(s)Diet, Metabolism, and Disease
ResumoDuring the past 25 years, the cardiovascular effects of marine omega-3 (ω-3) fatty acids have been the subject of increasing investigation. In the late 1970s, epidemiological studies revealed that Greenland Inuits had substantially reduced rates of acute myocardial infarction compared with Western control subjects. These observations generated more than 4500 studies to explore this and other effects of ω-3 fatty acids on human metabolism and health. From epidemiology to cell culture and animal studies to randomized controlled trials, the cardioprotective effects of ω-3 fatty acids are becoming recognized. These fatty acids, when incorporated into the diet at levels of about 1 g/d, seem to be able to stabilize myocardial membranes electrically, resulting in reduced susceptibility to ventricular dysrhythmias, thereby reducing the risk of sudden death. The recent GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevention study of 11,324 patients showed a 45% decrease in risk of sudden cardiac death and a 20% reduction in all-cause mortality in the group taking 850 mg/d of ω-3 fatty acids. These fatty acids have potent anti-inflammatory effects and may also be antiatherogenic. Higher doses of ω-3 fatty acids can lower elevated serum triglyceride levels; 3 to 5 g/d can reduce triglyceride levels by 30% to 50%, minimizing the risk of both coronary heart disease and acute pancreatitis. This review summarizes the emerging evidence of the use of ω-3 fatty acids in the prevention of coronary heart disease. During the past 25 years, the cardiovascular effects of marine omega-3 (ω-3) fatty acids have been the subject of increasing investigation. In the late 1970s, epidemiological studies revealed that Greenland Inuits had substantially reduced rates of acute myocardial infarction compared with Western control subjects. These observations generated more than 4500 studies to explore this and other effects of ω-3 fatty acids on human metabolism and health. From epidemiology to cell culture and animal studies to randomized controlled trials, the cardioprotective effects of ω-3 fatty acids are becoming recognized. These fatty acids, when incorporated into the diet at levels of about 1 g/d, seem to be able to stabilize myocardial membranes electrically, resulting in reduced susceptibility to ventricular dysrhythmias, thereby reducing the risk of sudden death. The recent GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevention study of 11,324 patients showed a 45% decrease in risk of sudden cardiac death and a 20% reduction in all-cause mortality in the group taking 850 mg/d of ω-3 fatty acids. These fatty acids have potent anti-inflammatory effects and may also be antiatherogenic. Higher doses of ω-3 fatty acids can lower elevated serum triglyceride levels; 3 to 5 g/d can reduce triglyceride levels by 30% to 50%, minimizing the risk of both coronary heart disease and acute pancreatitis. This review summarizes the emerging evidence of the use of ω-3 fatty acids in the prevention of coronary heart disease. The dietary advice of the American Heart Association and the National Cholesterol Education Program (generally accepted by the American public and physicians) focuses on the restriction of total fat, saturated fat, and cholesterol.1Summary of the second report of the National Cholesterol Education Program (NCFP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.JAMA. 1993; 269: 3015-3023Crossref PubMed Scopus (2920) Google Scholar High intakes of omega-6 (ω-6) (or n-6) fatty acids (FAs) (up to 10% of energy) are recommended, and no specific recommendations are made regarding the optimal balance between the ω-6 and the ω-3 (or n-3) classes of polyunsaturated FAs (Figure 1). Several (but not all2Watts GF Lewis B Brunt JN et al.Effects on coronary artery disease of lipid-loweringdiet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study.Lancer. 1992; 339: 563-569Abstract PubMed Scopus (719) Google Scholar) dietary trials based on the American Heart Association and National Cholesterol Education Program dietary approach have failed to document improved long-term cardiovascular prognosis3Corr LA Oliver MF The low fat/low cholesterol diet is ineffective.Eur Heart J. 1997; 18: 18-22Crossref PubMed Scopus (20) Google Scholar and have produced general skepticism among physicians about the effectiveness of diets. In our experience, many physicians discount the importance of dietary factors if their patients with cardiovascular problems take their statins as prescribed. After more than 4500 studies over 3 decades, it is becoming clear that (ω-3 FAs, especially the marine-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can have beneficial effects on long-term cardiovascular prognosis. In the late 1970s, Danish investigators studied rates of coronary heart disease (CHD) in native populations of Greenland and discovered significantly lower death rates from acute myocardial infarction in Inuits compared with age- and sex-matched Danes.4Bang HO Dyerberg J Lipid metabolism and ischemic heart disease in Greenland Eskimos.in: Draper H Advances in Nutrition Research. Plenum Press, New York, NY1980: 1-22Crossref Google Scholar These investigators concluded that the high level of ω-3 FAs in the sea-based Inuit diet may have accounted for this finding. Similar trends are seen in other fish-eating populations, such as the Japanese5Kagawa Y Nishizawa M Suzuki M et al.Eicosapolyenoic acids of serum lipids of Japanese islanders with low incidence of cardiovascular diseases.J Nutr Sci Vitaminol. 1982; 28: 441-453Crossref PubMed Scopus (235) Google Scholar. Several prospective cohort studies have examined fish intake and CHD. The Zutphen Study found that men who rarely or never ate fish had a higher rate of CHD compared with men who consumed fish 1 or more times per week.6Kromhout D Bosschieter EB dc Lezenne Coulander C The inverse relation between fish consumption and 20-year mortality from coronary heart.disease. N Fngt J Med. 1985; 312: 1205-1209Crossref PubMed Scopus (1831) Google Scholar The 30-year follow-up in the Western Electric Study confirmed these findings,7Daviglus ML Stamler J Orencia AJ et al.Fish consumption and the 30-year risk of fatal myocardial infarction.N EnglJ Med. 1997; 336: 1046-1053Crossref PubMed Scopus (790) Google Scholar as did data from the Multiple Risk Factor Interventional Trial8Dolecek TA Epidemiological evidence of relationships between dielary poilyunsaturated fatty acids and mortality in the Multiple Risk Factor intervention Trial.Proc Soc Exp Biol Med. 1992; 200: 177-182Crossref PubMed Scopus (366) Google Scholar and the Honolulu Heart Program.9Burchfiel CM Reed DM Strong JP Sharp DS Chyou PH Rodriguez BL Predictors of myocardial lesions in men with minimal coronary atherosclerosis at autopsy: the Honolulu Heart Program.Ann Epidemiol. 1996; 6: 137-146Abstract Full Text PDF PubMed Scopus (26) Google Scholar However, not all epidemiological studies have documented benefits from fish consumption.10Guallar E Hennekens CH Sacks FM Willett WC Stampfer MJ A prospective study of plasma fish oil levels and incidence of myocardial infarction in U.S. male physicians.J Am Coll Cardiol. 1995; 25: 387-394Abstract Full Text PDF PubMed Scopus (92) Google Scholar11Ascherio A Rimm EB Stampfer MJ Giovannucci EL Willett WC Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.N EnglJ Med. 1995; 332: 977-982Crossref PubMed Scopus (494) Google Scholar and a recent European study was unable to show that increased levels of adipose tissue DHA were cardioprotective.12Guallar E Aro A Jimenez FJ et al.Omega-3 fatty acids in adipose tissue and risk of myocardial infarction: The EURAM1C study.Arterioscler Thromb Vase Biol. 1999; 19: 1111-1118Crossref PubMed Scopus (152) Google Scholar In contrast, Seidelin et al13Seidelin KN Myrup B Fischcr-Hansen B n-3 Fatty acids in adipose tissue and coronary artery disease are inversely related.Am J ClinNutr. 1992; 55: 1117-1119PubMed Scopus (61) Google Scholar reported an inverse correlation between adipose DHA levels and coronary artery stenosis. In the 20,551 male patients who comprised the US Physicians' Health Study, regular fish consumption (≥1 meal of fish weekly) conferred a 52% risk-adjusted reduction in sudden death compared with consumption of fish less than once monthly.14Albert CM Hennekens CH O'Donnell CJ et al.Fish consumption and risk of sudden cardiac death.JAMA. 1998; 279: 23-28Crossref PubMed Scopus (864) Google Scholar Such observations have raised the possibility of an antidysrhythmic effect of ω-3 FAs. Siscovick et al15Siscovick DS Raghunathan TE King I et al.Dietary intake and cell membrane levels of long-chain n-3 polyunsaturaled fatty acids and the risk of primary cardiac arrest.JAMA. 1995; 274: 1363-1367Crossref PubMed Google Scholar reported that subjects who consumed little or no fish (as evidenced by decreased levels of ω-3 FAs As in their blood) were at an increased risk of sudden cardiac death compared with those who consumed fish regularly (Figure 2). Observational studies suggest that patients who were consuming fatty fish or fish oil supplements at the time of their infarctions had less myocardial necrosis and fewer Q-wave infarcts than did matched controls,16Landmark K Abdelnoor M Urdal P et al.Use of fish oils appears to reduce infarct size as estimated from peak creatine kinase and lactate dehydrogenase activities.Cardiology. 1998; 89: 94-102Crossref PubMed Scopus (34) Google Scholar17Landmark K Abdelnoor M Kilhovd B Dorum HP Eating fish may reduce infarct size and the occurrence of Q wave infarcts.Eur J Clin Nutr. 1998; 52: 40-44Crossref PubMed Scopus (17) Google Scholar suggesting increased resistance of the myocardium to the stress of ischemia. The largest study to examine the cardiovascular benefits of ω-3 FAs is the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevention study.18Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3738) Google Scholar This trial randomized 11,324 Italians (who presumably were eating a Mediterranean diet), who had had a myocardial infarction within the preceding 3 months, to 850 mg of ω-3 FAs, vitamin E (300 mg/d), both, or neither. After 3.5 years, the ω-3 group had a 20% reduction (95% confidence interval [Cl], 6%-33%) in total mortality and a 45% decrease (95% CI, 24%-60%) in sudden cardiac death (Figure 3). The improvements in cardiac prognosis were especially impressive considering that these patients were otherwise well treated medically with antiplatelet drugs, β-blockers, and angiotensin-converting enzyme inhibitors and that 50% were taking statins at the end of the trial. These results imply that 850 mg of ω-3 FAs can be expected to save approximately 20 lives per 1000 patients with CHD treated over a 3.5-year period. This translates into 5.7 lives saved per year and compares well with the 5 lives saved per year with pravastatin in the LIPID (LongTerm Intervention with Pravastatin in Ischaemic Disease) trial.19Long-Term Intervention with Pravastatin in Ischacmic Disease (LIPID) Study Group Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.N Engl J Med. 1998; 339: 1349-1357Crossref PubMed Scopus (5572) Google Scholar Of importance, the benefits of ω-3 FAs on improving survival in the GISSI-Prevention study appeared to be independent of traditional risk factors like lipids and blood pressure and are in addition to the benefits conferred by standard preventive therapies. A previous prospective, randomized, controlled study of fish oil for secondary prevention of CHD was the Diet and Reinfarction Trial (DART).20Burr 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.Lancet. 1989; 2: 757-761Abstract PubMed Scopus (2328) Google Scholar Men (N=2033) who had a myocardial infarction were randomized to receive different types of dietary advice in an effort to forestall the next myocardial infarction. One half were advised to increase their ω-3 intake by eating oily fish (eg, salmon, herring, mackerel) twice weekly, while the other half received "usual care." Survival over the subsequent 2 years was the primary end point. The group that was told to consume fish had a 29% reduction in overall mortality (P<.05; Figure 4). Because about 25% of the patients did not want to eat fish, they were given fish oil capsules (providing 900 mg/d of EPA and DHA). Even more impressive reductions in CHD events (Figure 5) were noted in this group.21Burr ML Sweetham PM Fehily AM Diet and reinfarction [lett].Eur Heart J. 1994; 15: 1152-1153PubMed Google Scholar In DART, the decrease in total ischemic heart disease events was not statistically significant, but the decrease in fatal myocardial infarctions was statistically significant. These results are consistent with other data and suggest a possible direct protective effect of ω-3 FAs on the myocardium itself, independent of the effect on risk factors or coronary artery atherosclerosis.Figure 5Reductions in ischemic heart disease (IHD) deaths and in total mortality for patients (n=227) in the DART (Diet and Reinfarction Trial) study20Burr 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.Lancet. 1989; 2: 757-761Abstract PubMed Scopus (2328) Google Scholar who, although advised to increase their oily fish intake, did not like fish and were therefore given fish oil capsules (providing 900 mg of eicosapentaenoic acid and docosahexaenoic acid per day). The control group contained matched patients from the group that did not receive advice about fish intake (n=227) whose qualifying heart attacks occurred at similar times as in those who received advice about fish intake.(data from Burr et al21Burr ML Sweetham PM Fehily AM Diet and reinfarction [lett].Eur Heart J. 1994; 15: 1152-1153PubMed Google Scholar)View Large Image Figure ViewerDownload (PPT) Another placebo-controlled trial randomized patients with suspected myocardial infarction to receive fish oil (approximately 2 g/d of ω-3 FAs) or placebo.22Singh RB Niaz MA Sharma JP Kumar R Rastogi V Moshiri M Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival-i.Cardiovasc Drugs Ther. 1997; 11: 485-491Crossref PubMed Scopus (485) Google Scholar After 1 year, serious arrhythmias were reduced by 54% and total cardiac events by 30% (for both, P<.05). Thus, all 3 prospective, randomized trials using fish oil (or EPA and DHA) for secondary prevention of cardiac events showed positive results. The effects of ω-3 FAs on regression of atherosclerotic lesions have been studied in 2 separate trials. In the first trial,23Sacks FM Slonc PH Gibson CM Silverman DI Rosner B Pasternak RC HARP Research Group Controlled trial of fish oil for regression of human coronary atherosclerosis.J Am Coll Cardiol. 1995; 25: 1492-1498Abstract Full Text PDF PubMed Scopus (196) Google Scholar 59 patients were randomized to receive 6 g of EPA and DHA or placebo and followed for 2 years. No differences in the 2 groups were found in the changes in minimal luminal diameter. In the second trial,24von Schacky C Angerer P Kothny W Theisen K Mudra H The effect of dietary w3 fatty acids on coronaty atherosclerosis: a randomized, double-blind, placebo-controlled trial.Ann Intern Med. 1999; 130: 554-562Crossref PubMed Scopus (423) Google Scholar 223 patients with angiographically proven CHD were randomized to receive placebo or 1.5 g/d of ω-3 FAs. After 2 years, the intervention group showed less progression and more regression (P=.04). Total cardiovascular disease events were 7 in the control group and 2 in the ω-3 group; this difference was not statistically significant (P=10). These results suggest that low intakes of these nutrients retard progression, whereas large nonphysiologic doses do not. The relatively small effect on angiographic end points indicates that more studies are needed. Decreased heart rate variability has been strongly associated with increased risk of sudden death.25Fauchier L Babuty D Cosnay P Fauchier JP Prognostic value of heart rale variability for sudden death and major arrhythmic events in patients with idiopathic dilated cardiomyopathy.J Am Coll Cardiol. 1999; 33: 1203-1207Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar A small randomized trial evaluated the effects of fish oil vs placebo on heart rate variability in 52 patients who had a myocardial infarction.26Christensen JH Gustenhoff P Korup E et al.Effect offish oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial.BMJ. 1996; 312: 677-678Crossref PubMed Scopus (220) Google Scholar Significant increases in R-R variability were observed in the ω-3 FA-treated patients. In addition, a significant positive relationship was noted between platelet DHA levels (reflective of increased ω-3 FA intake) and increased heart rate variability, suggesting increased cardiac parasympathetic tone. These changes in cardiac autonomic tone likely contribute to the antidysrhythmic effects and reduced sudden death rates noted in the large ω-3 FA trials. Another prospective trial using 1 tablespoon of cod liver oil (2.4 g of ω-3) daily vs placebo was conducted in 79 patients with frequent ventricular ectopy.27Sellmayer A Witzgall H Lorenz R Weber PC Effects of dietary fish oil on ventricular premature complexes.Am J Cardiol. 1995; 76: 974-977Abstract Full Text PDF PubMed Scopus (125) Google Scholar After 16 weeks, the ω-3 group had a 48% decrease in total premature ventricular complexes (P=.052), with 3 times as many ω-3 patients as controls experiencing a 70% or greater reduction in premature complexes (P<.0l). Many studies have tested the ability of fish oil to reduce restenosis rates after percutaneous coronary intervention, and results have been mixed. A meta-analysis of older studies28O'Connor GT Malcnka DJ Olmstead EM Johnson PS Hennekens CH A meta-analysis of randomized trials of fish oil in prevention of restenosis following coronary angioplasty.Am J Prev Med. 1992; 8: 186-192PubMed Google Scholar suggested a significant benefit, as did a more recent trial29Bairati I Roy L Meyer F Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary angioplasty.Circulation. 1992; 85: 950-956Crossref PubMed Scopus (129) Google Scholar of 205 patients who were treated with fish oil 3 weeks before undergoing angioplasty. However, in 2 of the largest studies,30Leaf A Jorgenscn MB Jacobs AK et al.Do fish oils prevent restenosis after coronary angioplasty?.Circulation. 1994; 90: 2248-2257Crossref PubMed Scopus (201) Google Scholar31Cairns JA Gill J Morton B et al.Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty: the EMPAR study.Circulation. 1996; 94: 1553-1560Crossref PubMed Scopus (140) Google Scholar ω-3 FAs As provided no benefit. The effects of ω-3 FAs on vein graft occlusion rates were reported by Eritsland et al.32Eritsland J Arnesen H Gronseth K Fjeld NB Abdelnoor M Effect of dielary supplementation with n-3 fatty acids on coronary artery bypass graft patency.Am J Cardiol. 1996; 77: 31-36Abstract Full Text PDF PubMed Scopus (208) Google Scholar These investigators randomized 610 patients to receive either placebo or ω-3 FAs (3.4 g/d) with or without warfarin. At the end of the first postoperative year, a lower graft occlusion rate was noted in the fish oil group (P=.03). The combination of warfarin or aspirin with fish oil did not result in significant additional benefit or bleeding complications. Although the vast majority of the data on the potential benefits of ω-3 FAs As on CHD have been obtained with use of the long-chain, marine-derived FAs, EPA and DHA, there is growing evidence for a benefit of the metabolic parent of these 2 FAs, a-linolenic acid (Figure 1). This is a plant-derived ω-3 FA found in soybean, canoIa, and, especially, flaxseed oil, in nuts (primarily walnuts), and in green leafy vegetables. After ingestion, a small (as yet illdefined) portion of α-linolenic acid (<10%; possibly <1%) is converted into EPA and DHA.33Salem Jr, N Wegher B Mena P Uauy RD Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants.Proc Natl Acad Sci U SA. 1996; 93: 49-54Crossref PubMed Scopus (421) Google Scholar34Marangoni F Angeli MT Colli S et al.Changes of n-i and n-6 fatty acids in plasma and circulating cells of normal subjects, after prolonged administration of 20:5 (EPA) and 22:6 (DHA) ethyl esters and prolonged washout.Biochim Biophys Acia. 1993; 1210: 55-62Crossref PubMed Scopus (118) Google Scholar The evidence includes 2 large epidemiological studies that have shown positive associations with a-linolenic acid intake35Ascherio A Rimm EB Giovannucci EL Spiegelman D Siampfer M Willett WC Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States.BMJ. 1996; 313: 84-90Crossref PubMed Scopus (598) Google Scholar, 36Hu FB Stampfer MJ Manson JE et al.Dietary intake of α-linolcnic acid and risk of fatal ischetmic heart disease among women.Am J Clin Nutr. 1999; 69: 890-897Crossref PubMed Scopus (458) Google Scholar and 1 arm of the Indian study previously noted22Singh RB Niaz MA Sharma JP Kumar R Rastogi V Moshiri M Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival-i.Cardiovasc Drugs Ther. 1997; 11: 485-491Crossref PubMed Scopus (485) Google Scholar in which patients who were randomized to receive 20 mL of mustard seed oil (providing 2.9 g of a-linolenic acid) for 1 year had signifi- cant reductions in cardiac events. The Lyon Diet Heart Study also supports the a-linolenic hypothesis.37de Lorgeril M Salen P Martin JL Monjaud I Delaye J Mamelle N Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.Circulation. 1999; 99: 779-785Crossref PubMed Scopus (2330) Google Scholar This randomized trial compared a Mediterranean-type diet containing olive and canola oils (sources of a-linolenic acid) with a standard American Heart Association diet in 605 patients who had a myocardial infarction. After about 4 years, the patients consuming the Mediterranean diet experienced a 55% reduction in all-cause mortality (P=.03). Since blood levels of both α-linolenic acid and EPA were significantly increased in the experimental group,38de Lorgeril M Renaud S Mamelle N et al.Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease.Lancet. 1994; 343: 1454-1459Abstract PubMed Scopus (1797) Google Scholar this study strengthens the case for a-linolenic acid. However, the large number of other dietary variables (less cream, butter, and meat and more fruit, vegetables, and legumes) weakens the conclusion that the effect was solely ω-3 FA-mediated. Accordingly, further studies to examine the possible protective value of α-linolenic acid are warranted. Several potential mechanisms explain the aforementioned observations (Table 1). Cell culture, animal, and human studies have reported potent antidysrhythmic effects of ω-3 FAs, especially for preventing fatal ischemia-induced malignant ventricular rhythms.39Billman GE Hallaq H Leaf A Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids.Proc Natl Acad Sci U S A. 1994; 91: 4427-4430Crossref PubMed Scopus (253) Google Scholar, 40Leaf A Kang JX Prevention of cardiac sudden death by N-3 fatty acids: a review of the evidence.J Intern Med. 1996; 240: 5-12Crossref PubMed Scopus (66) Google Scholar The first evidence that 0)-3 FAs may suppress malignant ventricular rhythms41Culp BR Lands WE Lucches BR Pitt B Romson J The effect of dietary supplementation of fish oil on experimental myocardial infarction.Prostaglandins. 1980; 20: 1021-1031Crossref PubMed Scopus (161) Google Scholar, 42Hock CE Holahan MA Rcibel DK Effect of dietary fish oil on myocardial phospholipids and myocardial ischemic damage.Am J Physiol. 1987; 252: H554-H560PubMed Google Scholar, 43McLennan PL Abcywardena MY Charnock JS Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and rcperfusion.Am Heart J. 1988; 116: 709-717Abstract Full Text PDF PubMed Scopus (299) Google Scholar was from studies of experimental myocardial infarction. In 1 study, rats were fed fish oil for 1 month, after which myocardial ischemia was induced by tying off the left main coronary artery for 15 minutes, followed by reperfusion for 6 hours. Among the control animals, 90% had ventricular tachycardia, fibrillation, or both, and 59% died. In contrast, only 14% of rats receiving fish oil had ventricular tachycardia, fibrillation, or both, and 24% died.44Hock CE Beck LD Bodine RC Reibel DK influence of dietary w-3 fatty acids on myocardial ischemia and reperfusion.Am J Physiol. 1990; 259: 1518-1526Google Scholar Dog studies have shown that acute infusion of EPA can prevent ventricular tachycardia and fibrillation in experimental myocardial infarction.45Billman GE Kang JX Leaf A Prevention of sudden cardiac death by dietary pure w-3 polyunsaturated fatty acids in dogs.Circulation. 1999; 99: 2452-2457Crossref PubMed Scopus (393) Google Scholar Kang and Leaf46Kang JX Leaf A Antiarrhythmic effects of polyunsaturated fatty acids: recent studies.Circulation. 1996; 94: 1774-1780Crossref PubMed Scopus (216) Google Scholar showed that the presence of ω-3 FAs in the myocardial cell membranes electrically stabilizes the cells and prolongs the relative refractory period. Because prospective studies have demonstrated ω-3 FAs to be especially effective in decreasing cardiac death, these electrophysiologic changes may be their most important effects. Indeed, ω-3 FAs As may be the first agents (other than β-blockers) that can beneficially modulate rhythm disorders and improve overall survival rates.TABLE 1Card iop rot ective Mechanisms of ω-3 Fatty Acids Reduces susceptibility to ventricular dysrhythmiaSlows heart rate and increases left ventricular diaslolic fillingIncreases heart rate variabilityPromotes nitric onide-induced endothelial relaxationLowers postprandial triglyceride levelsReduces expression of cell adhesion moleculesDecreases secretion of platelet-derived growth factorReduces transcription of inflammatory cytokines Open table in a new tab Another possible mechanism relates to the effect of ω-3 FAs on eicosanoid metabolism.47Lands WE n-3 Fatty acids as precursors for active metabolic substances: dissonance between expected and observed events.J Intern MedSuppl. 1989; 225: 11-20Google Scholar Both platelet function and inflammatory responses are mediated by these compounds, and both have critical roles in atherosclerosis and its complications.48Ridker PM Inflammation, infection, and cardiovascular risk: how good is the clinical evidence?.Circulation. 1998; 97: 1671-1674Crossref PubMed Scopus (135) Google Scholar, 49DcCatcrina R Giannessi D Mazzone A et al.Vascular prosta-cyclin is increased in patientsingesting ü)-3 polyunsaturated fatty acids before coronary artery bypass graft surgery.Circulation. 1990; 82: 428-438Crossref PubMed Scopus (120) Google Scholar Excessive intake of linoleic acid (00–6 FA) may (via its conversion to arachidonic acid and subsequently prostaglandins) contribute to increased platelet aggregation, vasoconstriction, and dysrhythmias,50Lands WEM Fish and Human Health. Academic Press, Orlando, Fla1986Google Scholar and by promoting chronic inflammation may predispose to plaque instability.51l-ee RT Libhy P The unstable alheroma.Arterioscler Thromb VascBiol. 1997; 17: 1859-1867Crossref PubMed Scopus (505) Google Scholar Arachidonic acid is also the precursor of leukotriene B 4—a chemotactic substance that recruits leukocytes to the site of inflammation.52Lee TIL Hoover RL Williams JD et al.Effect of dietary enrichment with eicosapentaenoic acid and docosahexacnoic acids on in vitro neuirophil and monocytc leukotriene generation and nculro-phil function.N EnglJ Med. 1985; 312: 1217-1224Crossref PubMed Scopus (1121) Google Scholar Evidence suggests that primitive humans consumed a diet with an ω-6/ω-3 ratio of about 1:1; our current ratio is about 20:1.53Simopoulos AP Robinson J The Omega Diet: The Lifesaving Nutritional Program Based on the Diet of the Island of Crete. HarperCollins Publishers, Inc, New York, NY1999Google Scholar Adequate levels of ω-3 FAs balance or block many of these potentially adverse consequences of excessive ω-6 FAs. For example, ω-3 FAs As facilitate the production of leukotriene B5, which has only about 3% of the chemotactic potency of leukotriene B4,54Broughton KS Johnson CS Pace BK Licbman M Kleppinger KM Reduced asthma symptoms with n-3 fatty acidingestion are related to 5-series leukotri
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