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Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n–3 Fatty Acids |
1 From the Institute of Human Nutrition and the Department of Pediatrics, Columbia University Medical Center, New York, NY (RJD, SRA); the Massachusetts General Hospital and Harvard Medical School, Boston, MA (AL); the Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School and Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (DM); the Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University, Atlanta, GA (TAJ); and the Nutrition and Metabolic Diseases Research Center Sanford Research/USD and the Sanford School of Medicine of the University of South Dakota, Sioux City, SD (WSH)
2 Presented at the symposium "Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n–3 Fatty Acids," held in New York, NY, June 9, 2007. 3 Address reprint requests and correspondence to and reprints: SR Akabas, Institute of Human Nutrition, 630 West 168th Street, PH 15-1512, New York, NY 10032. E-mail: sa109{at}columbia.edu.
ABSTRACT
After the symposium "Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n–3 Fatty Acids," faculty who presented at the conference submitted manuscripts relating to their conference topics, and these are presented in this supplement. The content of these manuscripts was reviewed, and 2 conference calls were convened. The objective was to summarize existing evidence, gaps in evidence, and future research needed to strengthen recommendations for specific intakes of n–3 fatty acids for different conditions relating to cardiovascular disease. The following 2 questions were the main items discussed. What are the roles of n–3 fatty acids in primary versus secondary prevention of coronary heart disease? What are the roles of n–3 fatty acids in hypertriglyceridemia, in the metabolic syndrome and type 2 diabetes, and in sudden cardiac death, cardiac arrhythmias, and vulnerable plaque? Each area was summarized by using 2 general categories: 1) current knowledge for which general consensus exists, and 2) recommendations for research and policy. Additional references for these conclusions can be found in the articles included in the supplement.
ROLE OF n–3 FATTY ACIDS IN PRIMARY VERSUS SECONDARY PREVENTION OF CORONARY HEART DISEASE
Current knowledge for which a general consensus exists
Consistent evidence indicates that n–3 fatty acids contribute substantially to lowering coronary heart disease (CHD) mortality risk attributable to reduced arrhythmic death in the primary prevention setting and after an initial cardiac event (secondary prevention). Relative risk reduction appears similar in both of these settings given similar findings of 2 secondary prevention randomized controlled trial (RCTs) and 15 prospective observational studies. Absolute risk reduction will be greater in populations at higher absolute risk. Thus, the benefits associated with secondary prevention are likely to be greater than those for primary prevention. Some evidence suggests that n–3 fatty acids may reduce nonfatal CHD events, particularly at higher doses of consumption, but this body of evidence is smaller than that for prevention of fatal events. Based on data summarized in the article by Mozaffarian in this supplement (1), a daily average intake of 
250 mg of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) appears to be effective in decreasing risk of fatal cardiac events. Most investigations have studied the combination of EPA plus DHA (either dietary or supplements) for prevention and treatment of cardiovascular disease, and insufficient evidence exists to make strong conclusions about optimal relative amounts of each of these individual fatty acids (2). In the JELIS (Japan EPA Lipid Intervention Study), which showed benefits for nonfatal coronary events, highly purified EPA supplements (1.8 g/d) were used in a Japanese population already consuming high amounts of n–3 fatty acids but with very low rates of coronary death (3). Findings from this trial support similar effects on nonfatal events in primary and secondary prevention. Effects of increased 
-linolenic acid, the plant-based n–3 fatty acid, on decreasing cardiovascular disease risk have been studied to a much lesser extent in both primary and secondary prevention settings; some evidence suggests potential benefit, but results have not always been consistent (4). The benefits of increasing EPA and DHA intakes to at least 250 mg/d may never be tested formally in a primary prevention RCT, but based on our experience with exercise and smoking cessation, neither of which has been tested with formal RCTs in primary prevention, reasonable recommendations can be made on the basis of the coherence and breadth of the existing evidence.
Recommendations for research and policy
-linolenic acid on coronary artery disease prevention require further study. HYPERTRIGYCERIDEMIA
Current knowledge for which a general consensus exists
All faculty agreed that marine n–3 fatty acids (ie, DHA and EPA) are effective in lowering elevated plasma triacylglycerol concentrations. However, the dose of n–3 fatty acid required to achieve these effects (3–4 g/d) is much higher than the doses (0.25–1 g/d) needed for reduction in coronary mortality in secondary and primary prevention (5). Also, there is little evidence that reducing elevated plasma triacylglycerol concentrations by any means will have a significant effect on cardiovascular disease mortality and morbidity. Of note, in both the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto)-Prevenzione and JELIS trials, there were only relatively minor changes in plasma triacylglycerol concentrations and no changes in other lipoprotein fractions in the control compared with treatment group, but there were significant reductions in cardiac events (3, 6). Thus, the major mechanisms underlying the beneficial effects of n–3 fatty acids in the prevention and treatment of coronary artery disease appears to be distinct from effects on lowering plasma triacylglycerol concentrations.
Recommendations for research and policy
METABOLIC SYNDROME AND TYPE 2 DIABETES
Current knowledge for which a general consensus exists
n–3 Fatty acids are effective in diminishing several risk factors associated with insulin resistance and the metabolic syndrome (7). Examples include lowering of blood triacylglycerol concentrations, modest decreases in systolic and diastolic blood pressures, and possible antiinflammatory effects (7). Lowering of blood triacylglycerol concentrations can be associated with increasing HDL cholesterol levels and increased LDL particle size (but the latter does not typically manifest until triacylglycerol concentrations of <150 mg/dL are achieved) (7). There is little evidence that n–3 fatty acids (at doses of 3 g/d or below) affect insulin sensitivity, and there remain concerns that at higher doses it may somewhat worsen (7).
Recommendations for research and policy
SUDDEN CARDIAC DEATH, CARDIAC ARRHYTHMIAS, AND VULNERABLE PLAQUE
Current knowledge for which a general consensus exists
There is a strong body of evidence showing that n–3 fatty acids are effective in reducing the risk for sudden cardiac death, of which cardiac arrhythmias are a major contributor both for primary and secondary events (8). Small clinical trials suggest that n–3 fatty acids may be less effective for recurrent ventricular arrhythmias in patients with implantable cardioverter-defibrillator devices, but these studies may have been underpowered, and the appropriateness of the population with implantable cardioverter-defibrillator devices for testing the antiarrhythmic hypothesis has been questioned (9, 10). Most cardiac arrhythmias are associated with underlying coronary pathological conditions, which predispose to arrhythmias. These include ischemic events, obstruction of coronary arteries, and other pathways associated with vulnerable atherosclerotic plaque. Many of the individual mechanisms that contribute to vulnerable plaque have been shown to respond in a beneficial direction to n–3 fatty acids in in vitro studies and studies in animals (11). Nevertheless, in terms of a role in acute and chronic myocardial insult, most of these individual pathways have not been studied in the context of an overall role of n–3 fatty acids in the prevention, stabilization, and reversal of vulnerable plaque. Nonfatal acute coronary syndromes including nonfatal myocardial infarction may be good proxies for vulnerable plaque. Although the results from clinical trials, such as the JELIS trial, suggest that n–3 fatty acids supplementation could be associated with plaque stabilization, the GISSI trial did not show a clinically significant reduction in nonfatal myocardial infarction (3, 6).
Recommendations for research and policy
GENERAL CONCLUSIONS
-linolenic acid is smaller and less consistent. More research on -linolenic acid is still required as its evidence base does not include enough well-designed randomized trials. ACKNOWLEDGMENTS
The authors' responsibilities were as follows—RJD, SRA, AL, DM, TAJ, and WSH: contributed to the conception, drafting, and revision of this manuscript. TAJ has served as a consultant to Reliant Pharmaceuticals and other manufacturers of lipid-lowering therapies. None of the other authors had a personal or financial conflict of interest.
REFERENCES
-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 2006;84:5–17.
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