Do vegetarians have to eat sh for optimal cardiovascular protection?

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Iqwal Mangat
ABSTRACT Interest in the cardiovascular protective effects of n3 (omega-3) fatty acids has continued to evolve during the past 35 y since the original research describing the low cardiovascular event rate in Greenland Inuit was published by Dyerberg et al. Numerous in vitro experiments have shown that n3 fatty acids may confer this benet by several mechanisms: they are antiinammatory, antithrombotic, and antiarrhythmic. The n3 fatty acids that have received the most attention are those that are derived from a sh source: namely, the longer-chain n3 fatty acids eicosapentaenoic acid (EPA; 20:5n3) and docosahexaenoic acid (DHA; 22:6n3). More limited data are available on the cardiovascular effects of n3 fatty acids derived from plants such as a-linolenic acid (ALA; 18:3n3). Observational data suggest that diets rich in EPA, DHA, or ALA do reduce cardiovascular events, including myocardial infarction and sudden cardiac death; however, randomized controlled trial data are somewhat less clear. Several recent meta-analyses have suggested that dietary supplementation with EPA and DHA does not provide additive cardiovascular protection beyond standard care, but the heterogeneity of included studies may reduce the validity of their conclusions. No data exist on the potential therapeutic benet of EPA, DHA, or ALA supplementation on those individuals who already consume a vegetarian diet. Overall, there is insufcient evidence to recommend n3 fatty acid supplementation for the purposes of cardiovascular protection; however, ongoing studies such as the Alpha Omega Trial may provide further information. Am J Clin Nutr 2009;89(suppl):1597S601S.

INTRODUCTION

Much attention has been given to the potential benets of n3 (omega-3) fatty acids for the prevention of various ailments, ranging from cardiovascular disease to cancer. The purpose of this presentation is to critically review the currently available data for the prevention of cardiovascular disease with the use of n3 fatty acids and to discuss their effects on those who consume a vegetarian diet. Polyunsaturated fatty acids are those fatty acids that have .1 double bond between carbon atoms. n3 Fatty acids are polyunsaturated fatty acids that specically have their rst double bond from the methyl (or n) terminal end between the third and fourth carbon atoms. n3 Fatty acids cannot be synthesized by humans and must be consumed in the diet. They exist in many forms and are categorized mostly by their length, ranging from the shortest [a-linolenic acid (ALA; 18:3n3), 18 carbons]

to the longest [docosahexaenoic acid (DHA; 22:6n3), 22 carbons]. ALA is commonly found in plant sources such as leafy vegetables, walnuts, mustard seed oil, canola oil, ax seed oil, and soybean oil. Humans have the ability to convert the shorter n3 fatty acid molecules to the longer ones, but this ability is limited, especially when longer-chain n3 fatty acids are consumed in the diet (1). In vitro, n3 fatty acids have various properties: they are antiinammatory, antithrombotic, and antiarrhythmic. n3 Fatty acids are rapidly incorporated into cell membranes on consumption and, as a result, may displace other phospholipids. Phospholipids within the cell membrane are important for cellcell signaling and for regulating numerous processes within the body. Some cell types have the ability to accumulate high quantities of n3 fatty acid into their cell membranes, and this suggests that these fatty acids play an important role for the proper functioning of those cell types (2). The cardiovascular protective effects of n3 fatty acids were rst hypothesized by Dyerberg et al (3, 4) and Ban et al (5) who were interested in the lack of cardiovascular endpoints in Greenland Inuit, despite a high-fat diet. They implicated the utility of 2 n3 fatty acids commonly found in sh, specically eicosapentaenoic acid (EPA; 20:5n3) and DHA. Importantly, these compounds are found in sh because of their consumption of vast quantities of phytoplankton that synthesize these n3 fatty acids. Since Dyerbergs initial hypothesis, numerous studies (discussed below) have looked at the protective effects of n3 fatty acid on various cardiovascular outcomes. Interestingly, most of these studies have focused on the use of EPA or DHA or both, and only a few studies have assessed the utility of smaller plant-based n3 fatty acids such as ALA. This review focuses on cardiovascular outcomes, including progression of coronary artery disease, myocardial infarction, sudden cardiac death, and total cardiovascular mortality (ie, death from a cardiac cause).

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1 From the Arrhythmia Service, St Michaels Hospital, Toronto, Canada University of Toronto, Toronto, Canada. 2 Presented at the symposium, Fifth International Congress on Vegetarian Nutrition, held in Loma Linda, CA, March 46, 2008. 3 Reprints not available. Address correspondence to I Mangat, St Michaels Hospital Division of Cardiology, 30 Bond Street, Room 6-050 Queen, Toronto, ON M5B 1W8, Canada. E-mail: mangati@smh.toronto.on.ca. First published online March 25, 2009; doi: 10.3945/ajcn.2009.26736I.

Am J Clin Nutr 2009;89(suppl):1597S601S. Printed in USA. 2009 American Society for Nutrition

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OBSERVATIONAL STUDIES

MANGAT

Most observational studies that have evaluated the effects of n3 fatty acid on cardiovascular health outcomes have been positive (69). However, it is important to note, as was the case with vitamin E and hormone replacement therapy, that those studies do not always correlate with the results of rigorous testing used in randomized controlled trials (10, 11). However, it is worth mentioning a few of the large-scale observational studies that specically reported cardiovascular outcomes data. The Physicians Health Study evaluated the dietary intake of 22,000 male US physicians with the use of validated food-frequency questionnaires (6). Importantly, those who consumed higher amounts of sh were more likely to be hypertensive and have elevated cholesterol, but they were also more likely to exercise frequently and eat more fruit and vegetables. Thus, in the presented multivariate analysis, the effects of these factors tended to cancel each other out and did not change the overall outcomes. The study suggested that there was a signicant effect on total mortality and on sudden cardiac death when comparing high sh consumers to low sh consumers. However, there appeared to be no statistically signicant difference in other cardiovascular outcomes, including fatal and nonfatal myocardial infarctions. In addition, there appeared to be a threshold effect such that there was no additional benet beyond the consumption of one sh serving/wk. Interestingly, sh with the highest content of n3 fatty acid (dark meat sh) was associated with the least benet (compared with tuna, shellsh, and other sh types). Another study in the same group of physicians evaluated blood concentrations of n3 fatty acid and correlated these concentrations to risk of sudden cardiac death, in a group of individuals who had no known cardiac disease at baseline (7). That study suggested that there was indeed a dose-response effect between the concentration of n3 fatty acids in blood and the risk of sudden cardiac death, with a relative risk of 0.10 (95% CI: 0.02, 0.48) in the highest quartile (6.87% of all fatty acids were n3 fatty acids, compared with 3.58% in the lowest quartile) of sh consumers. Similar ndings have been noted in the limited number of trials that have investigated plant sources of n3 fatty acid such as ALA. The Nurses Health Study evaluated 76,000 nurses who did not have coronary artery disease at entry into the trial and assessed dietary intake with the use of food-frequency questionnaires (8). During a mean 2-y follow-up period, it was noted in multivariate analysis that those subjects in the highest quintile of ALA intake (1.36 g/d compared with a reference quintile of 0.71 g/d) had a signicant reduction in risk of cardiovascular mortality [hazard ratio (HR): 0.55; 95% CI: 0.32, 0.94; P 0.01).
DATA FROM RANDOMIZED TRIALS AND META-ANALYSES

n3 Fatty acids from sh The Diet and Reinfarction Trial (DART) Study was one of the rst randomized trials that tried to assess the effect of dietary intervention with n3 fatty acids on cardiovascular endpoints (8, 12). In this trial, 2033 men ,70 y who had survived a myocardial infarction were randomly assigned to 1 of 3 treatment strategies for dietary advice: no advice, advice to consume

greater amounts of sh, or advice to consume greater amounts of ber. The initial outcomes data suggested a benet within the group that was advised to eat sh, with an adjusted HR for mortality of 0.73 (95% CI: 0.56, 0.95). Interestingly, when evaluating overall mortality after .10 y of follow-up, the mortality difference was no longer present (adjusted HR: 0.94; 95% CI: 0.85, 1.07) (13). Before the publication of the longterm results, a second version of the DART Study was already under way, and this trial sought to evaluate .3000 men ,70 y of age being treated for angina (14). DART-2 randomly assigned patients to 1 of 4 treatment arms: consumption of high amounts of sh (or supplement), consumption of high amounts of fruit and vegetables, a combination of both the above types of advice, or no specic dietary advice. After a mean follow-up time of 4 y, no benet of sh consumption was noted for overall mortality, cardiovascular mortality, or sudden death. In fact, a trend was observed toward greater mortality within the group given shspecic advice. On the contrary, the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto miocardico)-Prevenzione trial (10) showed a benet toward n3 fatty acid dietary supplementation in the form of capsules (1 g daily). This trial evaluated .11,000 subjects randomly assigned after myocardial infarction (albeit in an open-label fashion with no placebo arm) to 1 of 4 treatment strategies: n3 fatty acid, vitamin E, n3 fatty acid plus vitamin E, or control (ie, standard care, with no supplementation). The absolute mortality after 4-y follow-up was 8.3% in the n3 fatty acid group compared with 10.4% in the control group. Despite this difference being statistically signicant, the lack of blinding or use of placebo and the extremely low rates of b-blocker, angiotensin-converting enzyme inhibitor, and aspirin use (all of signicant proven benet in a postmyocardial infarction population) put into question the validity of this trial when extrapolating the use of n3 fatty acid to current practice. The recently published Japan Eicosapentaenoic Acid Lipid Intervention Study trial evaluated the use of 1.8 g EPA plus statin therapy compared with statin therapy alone in .18,000 hypercholesterolemic patients (15). The combined endpoint of that trial included myocardial infarction, sudden cardiac death, unstable angina, percutaneous coronary intervention, and cardiac bypass surgery. Although there was a statistically signicant advantage to consumption of EPA in that trial, the endpoint was driven almost entirely by the presence of unstable angina, with no difference in myocardial infarction, sudden death, or either cardiovascular or total mortality during a mean follow-up of 4.6 y. A recent systematic review (16) analyzed 48 randomized controlled trials and 41 cohort studies. This included trials that assessed the effect of both sh and plant sources for n3 fatty acid and used numerous methods to account for the differences between trials. However, no statistically signicant benet of n3 fatty acid could be found, and the investigators concluded Long chain and shorter chain n3 fatty acids do not have a clear effect on total mortality, combined cardiovascular events, or cancer. The question of whether n3 fatty acid is truly antiarrhythmic has come up time and again in the cardiovascular literature (17 19). In vitro studies have suggested an effect on numerous cardiac ion channels, including sodium channels and calcium channels (20, 21). For n3 fatty acid consumption to have

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a signicant effect on sudden death, 1 of 2 mechanisms can be postulated: prevention of coronary artery disease progression (thereby reducing the likelihood of plaque rupture, coronary occlusion, and ventricular brillation) or direct prevention of cardiac arrhythmias. Importantly, whether n3 fatty acid has a signicant effect on coronary artery disease progression has been studied extensively (2224). A recent systematic review that evaluated the effect of n3 fatty acid on coronary restenosis concluded the following: The dearth of long-term data on sh consumption or n3 fatty acid supplementation on measures of cardiovascular disease risk severely limits our ability to draw denitive conclusions at this time (25). For the direct antiarrhythmic effect of n3 fatty acids, note that no antiarrhythmic drug to date has been shown to be effective at reducing overall mortality in a cardiovascular population. Indeed, drugs that specically inhibit sodium channels and L-type calcium channels [n3 fatty acids have been shown in vitro to have these effects (20, 21)] have actually been shown to increase mortality in patients with previous myocardial infarction and are thus contraindicated (26, 27). Three signicant trials have evaluated the direct antiarrhythmic properties of n3 fatty acid supplementation. All of these trials evaluated the use of varying doses of n3 fatty acids (sh source) supplied in a capsule form to subjects who were deemed at high risk of ventricular arrhythmias and already had implanted cardioverter debrillators (ICDs). Follow-up time ranged from 1 to 2 y. The study by Leaf et al (28) suggested a 28% reduction in ICD-treated arrhythmic events which was not statistically signicant. In addition, that study showed no difference in mortality between those subjects receiving n3 fatty acid and those receiving olive oil. The investigators, however, noted a signicant noncompliance rate (35%) and suggested that, when probable arrhythmic events were included, there was a signicant benet to n3 fatty acid supplementation. The second study by Brouwer et al (29) was the largest study, enrolling .540 subjects. The Brouwer study (29) used a much lower dose of n3 fatty acid than did the Leaf study (28) (0.9 compared with 2.6 g), but both studies had similar antiarrhythmic drug use rates (25%) and follow-up time (1 y). Again, no signicant advantage was found to n3 fatty acid supplementation when evaluating ICD therapies as an endpoint. Finally, the third study by Raitt et al (30) was the smallest study, but it had the longest follow-up (2 y) and did not allow the use of concomitant antiarrhythmic therapy. That study, interestingly, showed a trend toward detriment (HR: 1.4; 95% CI: 0.96, 2.0) for those subjects receiving n3 fatty acid supplementation compared with placebo. Those 3 studies, taken together, suggest that even in a veryhigh-risk subgroup, sh oil supplementation has minimal if any benecial antiarrhythmic properties and may potentially be detrimental. Indeed, a recent meta-analysis of those 3 trials showed no signicant benet to n3 fatty acid supplementation in .1000 patients with 12 y follow-up (31). n3 Fatty acids from plants Interestingly, despite a number of randomized trials that have evaluated the utility of sh oil at reducing cardiovascular endpoints, there have been few trials that evaluated plant sources of n3 fatty acid. The Lyon Diet Heart Study randomly assigned 605 subjects after their rst myocardial infarction to receive in-

struction on modifying their diet to consume less saturated fats and greater amounts of products high in ALA, including an ALAfortied margarine compared with no specic dietary instruction (32). During a mean 27-mo follow-up, both total mortality and cardiovascular death were signicantly reduced in the group of patients receiving dietary intervention (HR: 0.30; 95% CI: 0.11, 0.82; P 0.02; and HR: 0.24; 95% CI: 0.07, 0.85; P 0.02, respectively). In a subset of subjects, blood samples were drawn to show that the dietary intervention indeed led to greater plasma concentrations of n3 fatty acid. The Indo-Mediterranean Diet Heart Study randomly assigned 1000 patients to either a diet rich in ALA (using whole grains, fruit, vegetables, walnuts, and almonds) or a local diet similar to the National Cholesterol Education Program Step-I diet (33). On the basis of diet diaries, the ALA group consumed 1.8 g ALA daily compared with the control group at 0.8 g. The primary combined endpoint of fatal and nonfatal myocardial infarctions and sudden cardiac death was signicantly reduced in the group consuming a diet rich in ALA (7.8% compared with 15.2%; P , 0.001) during a 2-y follow-up period. Secondary endpoints of sudden death and nonfatal myocardial infarction were similarly reduced. There was no difference between the groups in terms of other risk factors for cardiac events; however, the study subjects were not blinded to the intervention.
LIMITATIONS OF STUDIES ON n3 FATTY ACID SUPPLEMENTATION

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The primary limitation to using currently available data and making recommendations about the use of n3 fatty acid is that the data are at best inconclusive. In addition, randomized trials that have been performed with the use of n3 fatty acid supplementation have had variable results, and meta-analyses have suggested no specic benet to cardiovascular protection. The results of the GISSI-Prevenzione trial prompted the establishment of European recommendations for n3 fatty acid supplementation in cardiac patients; however, the patients enrolled in that trial are different from contemporary cardiac patients mainly because of the extremely low use of statins, b-blockers, and angiotensin-converting enzyme inhibitors. Even in high risk individuals, n3 fatty acid supplementation has not consistently been shown to reduce the risk of ventricular arrhythmias, a surrogate of sudden cardiac death. Randomized, controlled data with ALA as a source of n3 fatty acid are extremely limited.
EFFECT OF n3 FATTY ACID SUPPLEMENTATION WHEN CONSUMING A VEGETARIAN DIET

None of the studies to date that have looked at n3 fatty acid supplementation have specically assessed the effects on those who consume a vegetarian diet. Indeed, the consumption of a vegetarian diet by itself has been shown to have signicant health benets. Numerous observational studies have suggested that vegetarians live longer than their nonvegetarian counterparts and have 25% lower cardiovascular mortality (3436). Vegetarians already have a diet that is high in n3 fatty acid, although this comes from ALA, a plant source. It is unknown whether a sh source of n3 fatty acid can have benecial effects on those that already consume high quantities of plant-source n3 fatty acid. Certainly, if this question is to be addressed, a trial of

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chain fatty acids and partitioning towards beta-oxidation in older men. Br J Nutr 2003;90:31121. Surette ME. The science behind dietary omega-3 fatty acids. CMAJ 2008;178:17780. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet 1978;2:1179. Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr 1975;28:95866. Bang HO, Dyerberg J, Nielsen AB. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet 1971;1:11435. Albert CM, Hennekens CH, ODonnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA 1998;279:238. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n3 fatty acids and the risk of sudden death. N Engl J Med 2002;346: 11138. Hu FB, Stampfer MJ, Manson JE, et al. Dietary intake of a-linolenic acid and risk of fatal ischemic heart disease among women. Am J Clin Nutr 1999;69:8907. Mozaffarian D, Ascherio A, Hu FB, et al. Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation 2005;111:15764. Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto miocardico. Dietary supplementation with n3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:44755. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:15460. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, sh, and bre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 1989;2:75761. Ness AR, Hughes J, Elwood PC, Whitley E, Smith GD, Burr ML. The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction Trial (DART). Eur J Clin Nutr 2002;56:5128. Burr ML, Asheld-Watt PA, Dunstan FD, et al. Lack of benet of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003;57:193200. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:10908. Hooper L, Thompson RL, Harrison RA, et al. Risks and benets of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ 2006;332:75260. Billman GE, Kang JX, Leaf A. Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation 1999;99:24527. Billman GE, Hallaq H, Leaf A. Prevention of ischemia-induced ventricular brillation by omega 3 fatty acids. Proc Natl Acad Sci USA 1994;91:442730. McLennan PL. Relative effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on cardiac arrhythmias in rats. Am J Clin Nutr 1993;57:20712. Xiao YF, Kang JX, Morgan JP, Leaf A. Blocking effects of polyunsaturated fatty acids on Na1 channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci USA 1995;92:110004. Xiao YF, Gomez AM, Morgan JP, Lederer WJ, Leaf A. Suppression of voltage-gated L-type Ca21 currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc Natl Acad Sci USA 1997;94:41827. Maresta A, Balduccelli M, Varani E, et al. Prevention of postcoronary angioplasty restenosis by omega-3 fatty acids: main results of the Esapent for Prevention of Restenosis ITalian Study (ESPRIT). Am Heart J 2002;143:E5. Johansen O, Brekke M, Seljeot I, Abdelnoor M, Arnesen H. n3 Fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial. J Am Coll Cardiol 1999;33:161926. Cairns 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;94:155360.

participants who consume a vegetarian diet randomized in a blinded fashion to a plant source of n3 fatty acid (either ALA or DHA and EPA) may be feasible.
FUTURE DIRECTIONS

2. 3.

Clearly, the information presented herein suggests that the role for dietary supplementation with n3 fatty acids is uncertain, and the data are not sufcient to make a blanket recommendation for their use, either for high-risk cardiovascular patients or for the general population. The Alpha Omega Trial, organized by the Division of Human Nutrition at Wageningen University, the National Institute for Public Health and the Environment, and the Netherlands Heart Foundation, is a large randomized trial that may help to further dene the role of various types of n3 fatty acid supplementation (37). It is a trial that has enrolled 4837 patients with a history of myocardial infarction to 1 of 4 arms: supplementation with 2 g ALA, supplementation with 400 mg EPA plus DHA, supplementation of 2 g ALA combined with 400 mg EPA plus DHA, or placebo. The interventions are being administered by means of 4 different types of margarine, which are being used as a spread by the study participants. The study is now in follow-up phase, and we can likely expect completion of the study toward the end of 2009. Newer plant sources of long-chain n3 fatty acid are also being investigated. The plant Echium plantagineum is used to extract stearidonic acid that is more readily converted to longer-chain fatty acids in humans. In addition, one study has shown that echium oil has similar effects on plasma cholesterol concentrations as do sh sources of n3 fatty acid (38). In addition, microalgae oil derived from phytoplankton is now available as a supplement, with signicant concentrations of DHA (and lesser amounts of EPA) that rival traditionally available sh oil supplements.
CONCLUSIONS

4. 5. 6. 7.

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Combined with the lack of convincing clinical data in favor of n3 fatty acid supplementation for cardiovascular endpoints and the lack of data in those that consume a vegetarian diet, it is difcult to make the recommendation that vegetarians should consume sh to optimize their cardiovascular mortality. In addition, it is unlikely that vegetarians would welcome the opportunity to participate in a randomized trial of sh-source n3 fatty acid supplementation. Nevertheless, some of the trials mentioned earlier may shed further light on the role for routine use of n3 fatty acid supplementation, either for primary prophylaxis in at-risk individuals or for those who have established cardiac disease. Interestingly, if it is deemed that long-chain n3 fatty acid supplementation is benecial, newer plant-based sources of these compounds may be more palatable for vegetarian use. (Other articles in this supplement to the Journal include references 3965.)
IM is the sole author and had no acknowledgments to make or disclosures to report.

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