Do vegetarians have to eat fish for optimal cardiovascular protection? 1 3

Transcription

1 Do vegetarians have to eat fish for optimal cardiovascular protection? 1 3 Iqwal Mangat ABSTRACT Interest in the cardiovascular protective effects of n 3 (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 n 3 fatty acids may confer this benefit by several mechanisms: they are antiinflammatory, antithrombotic, and antiarrhythmic. The n 3 fatty acids that have received the most attention are those that are derived from a fish source: namely, the longer-chain n 3 fatty acids eicosapentaenoic acid (EPA; 20:5n 3) and docosahexaenoic acid (DHA; 22:6n 3). More limited data are available on the cardiovascular effects of n 3 fatty acids derived from plants such as a-linolenic acid (ALA; 18:3n 3). 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 benefit of EPA, DHA, or ALA supplementation on those individuals who already consume a vegetarian diet. Overall, there is insufficient evidence to recommend n 3 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):1597S 601S. INTRODUCTION Much attention has been given to the potential benefits of n 3 (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 n 3 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. n 3 Fatty acids are polyunsaturated fatty acids that specifically have their first double bond from the methyl (or n ) terminal end between the third and fourth carbon atoms. n 3 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; 18:3n 3), 18 carbons] to the longest [docosahexaenoic acid (DHA; 22:6n 3), 22 carbons]. ALA is commonly found in plant sources such as leafy vegetables, walnuts, mustard seed oil, canola oil, flax seed oil, and soybean oil. Humans have the ability to convert the shorter n 3 fatty acid molecules to the longer ones, but this ability is limited, especially when longer-chain n 3 fatty acids are consumed in the diet (1). In vitro, n 3 fatty acids have various properties: they are antiinflammatory, antithrombotic, and antiarrhythmic. n 3 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 n 3 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 n 3 fatty acids were first 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 n 3 fatty acids commonly found in fish, specifically eicosapentaenoic acid (EPA; 20:5n 3) and DHA. Importantly, these compounds are found in fish because of their consumption of vast quantities of phytoplankton that synthesize these n 3 fatty acids. Since Dyerberg s initial hypothesis, numerous studies (discussed below) have looked at the protective effects of n 3 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 n 3 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). 1 From the Arrhythmia Service, St Michael s 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 4 6, Reprints not available. Address correspondence to I Mangat, St Michael s Hospital Division of Cardiology, 30 Bond Street, Room Queen, Toronto, ON M5B 1W8, Canada. mangati@smh.toronto.on.ca. First published online March 25, 2009; doi: /ajcn I. Am J Clin Nutr 2009;89(suppl):1597S 601S. Printed in USA. Ó 2009 American Society for Nutrition 1597S

2 1598S MANGAT OBSERVATIONAL STUDIES Most observational studies that have evaluated the effects of n 3 fatty acid on cardiovascular health outcomes have been positive (6 9). 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 specifically 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 fish 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 significant effect on total mortality and on sudden cardiac death when comparing high fish consumers to low fish consumers. However, there appeared to be no statistically significant 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 benefit beyond the consumption of one fish serving/wk. Interestingly, fish with the highest content of n 3 fatty acid (dark meat fish) was associated with the least benefit (compared with tuna, shellfish, and other fish types). Another study in the same group of physicians evaluated blood concentrations of n 3 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 n 3 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 n 3 fatty acids, compared with 3.58% in the lowest quartile) of fish consumers. Similar findings have been noted in the limited number of trials that have investigated plant sources of n 3 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 significant reduction in risk of cardiovascular mortality [hazard ratio (HR): 0.55; 95% CI: 0.32, 0.94; P ¼ 0.01). DATA FROM RANDOMIZED TRIALS AND META-ANALYSES n 3 Fatty acids from fish The Diet and Reinfarction Trial (DART) Study was one of the first randomized trials that tried to assess the effect of dietary intervention with n 3 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 fish, or advice to consume greater amounts of fiber. The initial outcomes data suggested a benefit within the group that was advised to eat fish, 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 fish (or supplement), consumption of high amounts of fruit and vegetables, a combination of both the above types of advice, or no specific dietary advice. After a mean follow-up time of 4 y, no benefit of fish consumption was noted for overall mortality, cardiovascular mortality, or sudden death. In fact, a trend was observed toward greater mortality within the group given fishspecific advice. On the contrary, the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto miocardico)-prevenzione trial (10) showed a benefit toward n 3 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: n 3 fatty acid, vitamin E, n 3 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 n 3 fatty acid group compared with 10.4% in the control group. Despite this difference being statistically significant, 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 significant proven benefit in a postmyocardial infarction population) put into question the validity of this trial when extrapolating the use of n 3 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 significant 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 fish and plant sources for n 3 fatty acid and used numerous methods to account for the differences between trials. However, no statistically significant benefit of n 3 fatty acid could be found, and the investigators concluded Long chain and shorter chain n 3 fatty acids do not have a clear effect on total mortality, combined cardiovascular events, or cancer. The question of whether n 3 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 n 3 fatty acid consumption to have

3 DO VEGETARIANS HAVE TO EAT FISH? 1599S a significant 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 fibrillation) or direct prevention of cardiac arrhythmias. Importantly, whether n 3 fatty acid has a significant effect on coronary artery disease progression has been studied extensively (22 24). A recent systematic review that evaluated the effect of n 3 fatty acid on coronary restenosis concluded the following: The dearth of long-term data on fish consumption or n 3 fatty acid supplementation on measures of cardiovascular disease risk severely limits our ability to draw definitive conclusions at this time (25). For the direct antiarrhythmic effect of n 3 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 specifically inhibit sodium channels and L-type calcium channels [n 3 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 significant trials have evaluated the direct antiarrhythmic properties of n 3 fatty acid supplementation. All of these trials evaluated the use of varying doses of n 3 fatty acids (fish source) supplied in a capsule form to subjects who were deemed at high risk of ventricular arrhythmias and already had implanted cardioverter defibrillators (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 significant. In addition, that study showed no difference in mortality between those subjects receiving n 3 fatty acid and those receiving olive oil. The investigators, however, noted a significant noncompliance rate (35%) and suggested that, when probable arrhythmic events were included, there was a significant benefit to n 3 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 n 3 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 significant advantage was found to n 3 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 n 3 fatty acid supplementation compared with placebo. Those 3 studies, taken together, suggest that even in a veryhigh-risk subgroup, fish oil supplementation has minimal if any beneficial antiarrhythmic properties and may potentially be detrimental. Indeed, a recent meta-analysis of those 3 trials showed no significant benefit to n 3 fatty acid supplementation in.1000 patients with 1 2 y follow-up (31). n 3 Fatty acids from plants Interestingly, despite a number of randomized trials that have evaluated the utility of fish oil at reducing cardiovascular endpoints, there have been few trials that evaluated plant sources of n 3 fatty acid. The Lyon Diet Heart Study randomly assigned 605 subjects after their first myocardial infarction to receive instruction on modifying their diet to consume less saturated fats and greater amounts of products high in ALA, including an ALAfortified margarine compared with no specific dietary instruction (32). During a mean 27-mo follow-up, both total mortality and cardiovascular death were significantly reduced in the group of patients receiving dietary intervention (HR: 0.30; 95% CI: 0.11, 0.82; P ¼ 0.02; and HR: 0.24; 95% CI: 0.07, 0.85; P ¼ 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 n 3 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 significantly 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 n 3 FATTY ACID SUPPLEMENTATION The primary limitation to using currently available data and making recommendations about the use of n 3 fatty acid is that the data are at best inconclusive. In addition, randomized trials that have been performed with the use of n 3 fatty acid supplementation have had variable results, and meta-analyses have suggested no specific benefit to cardiovascular protection. The results of the GISSI-Prevenzione trial prompted the establishment of European recommendations for n 3 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, n 3 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 n 3 fatty acid are extremely limited. EFFECT OF n 3 FATTY ACID SUPPLEMENTATION WHEN CONSUMING A VEGETARIAN DIET None of the studies to date that have looked at n 3 fatty acid supplementation have specifically assessed the effects on those who consume a vegetarian diet. Indeed, the consumption of a vegetarian diet by itself has been shown to have significant health benefits. Numerous observational studies have suggested that vegetarians live longer than their nonvegetarian counterparts and have 25% lower cardiovascular mortality (34 36). Vegetarians already have a diet that is high in n 3 fatty acid, although this comes from ALA, a plant source. It is unknown whether a fish source of n 3 fatty acid can have beneficial effects on those that already consume high quantities of plant-source n 3 fatty acid. Certainly, if this question is to be addressed, a trial of

4 1600S MANGAT participants who consume a vegetarian diet randomized in a blinded fashion to a plant source of n 3 fatty acid (either ALA or DHA and EPA) may be feasible. FUTURE DIRECTIONS Clearly, the information presented herein suggests that the role for dietary supplementation with n 3 fatty acids is uncertain, and the data are not sufficient 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 define the role of various types of n 3 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 Newer plant sources of long-chain n 3 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 fish sources of n 3 fatty acid (38). In addition, microalgae oil derived from phytoplankton is now available as a supplement, with significant concentrations of DHA (and lesser amounts of EPA) that rival traditionally available fish oil supplements. CONCLUSIONS Combined with the lack of convincing clinical data in favor of n 3 fatty acid supplementation for cardiovascular endpoints and the lack of data in those that consume a vegetarian diet, it is difficult to make the recommendation that vegetarians should consume fish to optimize their cardiovascular mortality. In addition, it is unlikely that vegetarians would welcome the opportunity to participate in a randomized trial of fish-source n 3 fatty acid supplementation. Nevertheless, some of the trials mentioned earlier may shed further light on the role for routine use of n 3 fatty acid supplementation, either for primary prophylaxis in at-risk individuals or for those who have established cardiac disease. 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