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To examine evidence for the role of omega-3 fatty acids in cardiovascular disease.
PubMed was searched for articles on the role of omega-3 fatty acids in cardiovascular disease. Level I and II evidence indicates that omega-3 fatty acids are beneficial in improving cardiovascular outcomes.
Dietary intake of omega-3 fatty acids has declined by 80% during the last 100 years, while intake of omega-6 fatty acids has greatly increased. Omega-3 fatty acids are cardioprotective mainly due to beneficial effects on arrhythmias, atherosclerosis, inflammation, and thrombosis. There is also evidence that they improve endothelial function, lower blood pressure, and significantly lower triglycerides.
There is good evidence in the literature that increasing intake of omega-3 fatty acids improves cardiac outcomes. Physicians need to integrate dietary recommendations for consumption of omega-3 fatty acids into their usual cardiovascular care.
Relever les données sur le rôle des acides gras oméga-3 dans les maladies cardiovasculaires.
On a consulté PubMed, à la recherche d’articles sur le rôle des oméga-3 dans les maladies cardiovasculaires. Il existe des preuves de niveaux I et II indiquant que les oméga-3 ont un effet favorable sur les issues cardiovasculaires.
Au cours des 100 dernières années, la consommation des acides gras oméga-3 a diminué de 80%, pendant que celle des oméga-6 augmentait considérablement. Les oméga-3 sont cardioprotecteurs en raison surtout de leurs effets bénéfiques sur les arythmies, l’athérosclérose, l’inflammation et la thrombose. Selon certaines données, ils améliorent aussi l’activité endothéliale, diminuent la tension artérielle et causent une baisse significative des triglycérides.
Il existe dans la littérature des preuves convaincantes indiquant qu’une consommation accrue d’acides gras oméga-3 améliore les issues cardiaques. Le médecin devrait incorporer aux soins cardiovasculaires habituels des recommandations pour encourager la consommation des oméga-3.
During the last decade, the amount of research on omega-3 fatty acids has increased substantially. As a result, new guidelines recommend that patients at risk of cardiovascular (CV) disease increase their dietary intake of omega-3 fatty acids. This article looks at the role of omega-3 fatty acids of marine (eicosapentenoic acid [EPA], docosahexaenoic acid [DHA]) and plant (alpha-linolenic acid [ALA]) origin in CV health in order to bring family physicians up-to-date on current evidence.
Studies providing level I, II, and III evidence of the benefits of omega-3 fatty acids are reviewed in this article. MEDLINE was searched using the words “omega-3 fatty acids” and “fish oil” combined with “hypertension,” “coronary artery disease,” and “hypertriglyceridemia.” Trials involving humans were chosen.1-16
The lipids essential for health are the omega-3 and omega-6 polyunsaturated fatty acids (PUFA).17 Interest in omega-3 fatty acids began in 1972. Studies by Bang and Dyerberg3 showed that Greenland Inuit who consumed a diet high in protein and fat (mainly from fish) had significantly lower total cholesterol (P<.005), low-density lipoprotein (LDL)(P<.02), and triglyceride (P<.005) levels than most other people had.
Since then, much has been learned about the interaction of omega-6 and omega-3 fatty acids in CV disease and about the ratio between omega-6 and omega-3 fatty acids.18,19 Dietary intake of omega-3 fatty acids has decreased, and dietary intake of omega-6 fatty acids has substantially increased during the last 100 years due to greater use of vegetable oils high in omega-6 fatty acids.18,20 The ratio of omega-6 to omega-3 was about 1.5:1 as recently as 200 years ago and now is estimated at 16:1 in the average North American diet.18 This has resulted in a diet high in omega-6 fatty acids and deficient in omega-3 fatty acids.21
Omega-6 and omega-3 fatty acids compete for the same enzymes. An increase in the diet of one decreases metabolism of the other.22 Omega-6 fatty acid metabolites result in prostaglandins that are inflammatory; omega-3 fatty acids result in prostaglandins that are anti-inflammatory. The actions of omega-3 fatty acids on the CV system are listed in Table 1.1,2,23-33 Omega-3 fatty acids have antiarrhythmic effects, including preventing atrial fibrillation23,24; antithrombotic action25; antiatherogenic effects26; anti-inflammatory effects27,28; and the ability to improve endothelial function,29 lower blood pressure,1,2 lower triglyceride levels,30 increase high-density lipoprotein (HDL) levels,31 and decrease apolipoprotein B-100.32
Trials are listed in Table 2.1-16 Geleijnse et al1 did a meta-analysis of 36 randomized trials (22 of which were double blind) carried out between 1966 and 2001 (level I evidence). The meta-analysis showed that consuming an average of 3.7 g/d of fish oil reduced systolic blood pressure (BP) by 2.1 mm Hg (P<.01) and diastolic BP by 1.6 mm Hg (P<.01). The BP-lowering effects were greater in people older than 45 years and in those whose BP was higher than 140/90 mm Hg.
A meta-analysis (level I evidence) done by Appel et al2 found a significant reduction in BP (5.5 mm Hg systolic BP and 3.5 mm Hg diastolic BP) in untreated hypertensive patients taking supplements of more than 3 g/d of omega-3 PUFA. High doses were required to achieve these results, and patients’ acceptance of the fishy taste and subsequent belching was poor (P<.001). Most trials lasted less than 3 months, so the long-term benefits are unclear.
Bang and Dyerberg3 and Dyerberg et al4 did epidemiologic studies (level II evidence) to establish the cardioprotective effects of omega-3 fatty acids from marine sources in the Inuit people of Greenland in the 1970s. Despite a high-fat diet, the incidence of CV disease was exceptionally low among these people. A Canadian study5 looking at James Bay Cree people reported fewer CV risk factors and higher levels of plasma omega-3 fatty acids in adult Cree living along the coast than in those living inland (level II evidence).
In September 1989, the Diet and Reinfarction Trial (DART)6 (level II evidence) was the first study to show that subjects who followed advice to eat fatty fish (high in omega-3 fatty acids) had a 29% reduction in 2-year all-cause mortality (P<.05). The study allocated 2033 men to 3 groups: group 1 reduced their fat intake and increased their intake of PUFA, group 2 increased their fatty fish intake, and group 3 increased their cereal fibre intake.
The Lyon Diet Heart Study,7 a secondary prevention trial (level I evidence), followed 605 men after myocardial infarction (MI) for 4 years. One group (n=303) received a diet rich in omega-3 and omega-9 fatty acids and low in both omega-6 fatty acids and saturated fats (the Mediterranean diet). The second group (n=302) followed the Prudent Heart Diet, which is similar to the American Heart Association diet. Three end points were used: cardiac death or non-fatal MI; cardiac death or non-fatal MI plus secondary end points including unstable angina, stroke, heart failure, and pulmonary or peripheral embolism; and all of the preceding plus minor events requiring hospital admission. The experimental group following the Mediterranean diet had fewer events at all end points. For the first end point, the first group had 14 events, and the second group 44 events (P<.0002). For the second end point, the first group had 27 events, and the second group had 90 events (P<.0002). For the third end point, the first group had 95 events, and the second group had 180 events (P<.0002)34 (Figure 17). The control group had an omega-6–to–omega-3 ratio of 10:1; the experimental group had a ratio of 4:1. A striking protective effect was reported with a 50% to 70% reduction in risk of recurrence of CV events after 4 years’ follow up.
In the Indo-Mediterranean Diet Heart Study (1000 patients)8 (level I evidence), those in the experimental group (diet high in ALA) had fewer CV events than those in the control group (39 vs 76, P<.001). Also reduced were sudden cardiac death (6 vs 16, P<.015) and non-fatal MI (21 vs 43, P<.001) (Figure 27,34). Omega-6–to–omega-3 ratios were 38:1 before the trial and 33:1 before the intervention; after 2 years in the trial, ratios were 9:1 in the experimental group and 21:1 among controls. The prevalence of coronary artery disease was 2% to 3% in rural areas of India and 9% to 14% in urban populations. The high incidence in urban areas is thought to be due to intake of Indian ghee or clarified butter (rich in cholesterol oxides) and high omega-6–to–omega-3 ratios.35,36
The GISSI-Prevenzione trial (level I evidence)9,10 randomly assigned 11324 patients surviving a recent MI into 4 groups: one took a capsule containing 850 mg/d of omega-3 fatty acids each day, another took 300 IU of vitamin E daily, a third group took both each day, and the control group took nothing. After 3.5 years, overall mortality was reduced by 20% and CV mortality was reduced by 30% in the group taking capsules of omega-3 fatty acids. No benefit was apparent from taking vitamin E alone. A 45% reduction in sudden cardiac death (P=.01) accounted for most of the benefit. Omega-3 fatty acids seem to be able to stabilize contractile heart cells electrically and thus prevent ventricular arrhythmias.23
A meta-analysis by Bucher et al11 (level I evidence) identified 11 trials published between 1966 and 1999 with a total of 7951 patients in intervention groups and 7855 in control groups. They found that intake of fish or fish oil reduced rates of overall mortality (P<.001), fatal MI (P<.001), and sudden cardiac death (P<.01). Mortality from coronary artery disease was reduced by 40% to 60% with consumption of 40 to 60 g of fish daily.
Several studies, including the Cardiovascular Health Study,37 the Family Heart Study,38 the Health Professionals Follow-up Study,39 the Multiple Risk Factor Intervention Trial,40 and the Nurses’ Health Study,41 showed benefit of ALA in CV disease. The Zutphen Elderly Study,42 however, found a modest link between ALA and increased risk of CV disease. Excessive consumption of trans fatty acids might have contributed to this.
Although most studies have shown that omega-3 fatty acids are useful for secondary prevention of CV disease, some have shown no statistical benefit. A study done by Nilsen et al12 (level I evidence) showed no benefit for prevention of further cardiac events in 300 patients from Norway. Those patients had significantly lower triglyceride levels (P<.0001) and significantly higher HDL levels (P<.0016) than most people. It is thought that no further benefit was possible among these people who already consumed a great deal of fish in their diet. This study was also shorter than many of the studies listed above.
Supplementation with omega-3 fatty acids has been shown to be of benefit in severe familial hypertriglyceridemia. Richter et al13 (level II evidence) demonstrated that adding 4.32 g/d of omega-3 fatty acids to the diet for 8 weeks reduced serum triglycerides from 18.29 to 10.1 mmol/L. Pschierer et al14 (level II evidence) showed that serum triglycerides had decreased significantly from 16.9 to 11.2 mmol/L after 1 month, and further decreased after 11 months to 10.1 mmol/L on average with supplementation with omega-3 fatty acids.
The effectiveness of statins can be improved by adding omega-3 fatty acids to the diet.43,44 A small study looked at combining statins and fish oil (level II evidence).15 Adding 900 to 1800 mg of EPA to the diet of patients already taking HMG-CoA reductase inhibitors resulted in a further decrease in total cholesterol from 5.63 to 5.02 mmol/L (P<.05) and in triglycerides from 2.07 to 1.08 mmol/L (P<.01). Serum HDL increased significantly from 1.23 to 1.34 mmol/L (P<.01).
In a study done by Eritsland et al16 (level I evidence), 610 patients who underwent coronary artery bypass grafting were assigned to a fish-oil group (4 g/d of fish oil) or to a control group. The end point was patency of the graft at 1 year. A year later, vein graft occlusion was 27% in the experimental group and 33% in the control group (P=.034). Vein graft occlusion was inversely related to the relative change in serum omega-3 fatty acid levels. Initial studies done on coronary angioplasty patients45 showed that fish oil had promise for reducing recurring stenosis, but later studies using higher doses did not show any statistically significant reduction.46
In 1990, Canada was the first country to provide separate dietary recommendations for omega-6 and omega-3 fatty acids for people of all ages.47 For adults between 25 and 49 years old, Health Canada suggests 1500 mg of omega-3 and 9000 mg of omega-6 polyunsaturates daily for men and 1100 mg of omega-3 and 7000 mg of omega-6 fatty acids daily for women. This results in an omega-6–to–omega-3 ratio of 6:1. It is thought that most Canadians do not have this modest daily intake of omega-3 fatty acids. Dietary sources of omega-3 fatty acids and some instructions for making them palatable are shown in Table 3.48 Side effects and interactions associated with consumption of fish oil are listed in Table 4.49-53
The American Heart Association issued new recommendations on consumption of omega-3 fatty acids in 2003.48 These are listed in Table 548,54 along with recommendations from an expert round-table discussion at the 34th Annual Scientific Meeting of the European Society for Clinical Investigation.54
There is now solid evidence that omega-3 fatty acids favourably modulate disease processes, such as hypertension, coronary artery disease, and hypertriglyceridemia. Increasing dietary intake of omega-3 fatty acids and bringing the ratio of omega-3 to omega-6 fatty acids into a healthy balance would improve Canadians’ cardiovascular health.
Level I: At least one properly conducted randomized controlled trial, systematic review, or meta-analysis
Level II: Other comparison trials, non-randomized, cohort, case-control, or epidemiologic studies, and preferably more than one study
Level III: Expert opinion or consensus statements
Dr Schwalfenberg is a family physician in full-time solo practice. He is a member of the Department of Family Practice at the Misericordia Hospital in Edmonton, Alta.
Competing interests: None declared