Beyond the Mediterranean Diet: The Role of Omega-3 Fatty Acids in the Prevention of Coronary Heart Disease

Charles R. Harper, MD, Terry A. Jacobson, MD


Prev Cardiol. 2003;6(3) 

In This Article

Epidemiologic Studies

In the 1970s Bang and Dyerberg[1] studied the dietary habits of Greenland Inuits, as this population was known to have a low mortality rate from CHD ( Table I[7]). This was one of the earliest epidemiologic studies looking at the relationship of dietary n-3 fatty acid intake to the rate of CHD. Dietary surveys indicated that the Inuit diet was not a low-fat diet and that approximately 39% of caloric intake was from fat. Additional analysis revealed their consumption of saturated fat to be low (9% of total calories) while their dietary consumption of n-3 PUFA was high (4.2% of total calories). These findings contrasted sharply with the dietary habits of an ethnically similar population in Denmark with much higher rates of CHD.[8] The Danish diet had a comparable amount of total fat (42% of total calories) but a much lower intake of n-3 PUFA (<1% of total calories) and a much higher intake of saturated fat (22%).

In addition to cross-cultural epidemiologic studies, various prospective observational cohort studies have suggested a cardioprotective effect from dietary n-3 fatty acids. Early important cohort studies include the Zutphen and Western Electric studies,[9,10] which demonstrated an inverse relation between fish consumption and mortality from CHD.

A more recent prospective cohort study, the US Physicians Health Study,[11] evaluated 20,551 US male physicians. The cohort consisted of physicians aged 40-84 without cardiovascular disease. Participants were asked to complete food frequency questionnaires on fish consumption and were then followed for 11 years. Consumption of at least one fish meal per week reduced the risk of sudden cardiac death by 52% (p=0.03), when compared with those consuming fish once a month. All levels of fish consumption up to one meal per week were associated with a decreased risk of sudden death. At levels of consumption greater than one fish meal per week the risk reduction did not change indicating a threshold effect.

Participants in the Physicians Health Study were also involved in a prospective, nested, case-control analysis of whole blood fatty acid composition.[12] The fatty acid composition of previously collected blood was analyzed from 94 men in whom sudden death was the first manifestation of CHD and matched with 184 controls based on age and smoking status. Blood levels of long-chain n-3 fatty acids were inversely related to risk of sudden death both before and after adjustment for potential confounders (p=0.007, for trend). As compared with men whose blood levels of long-chain n-3 fatty acids were in the lowest quartile, the relative risk of sudden death was significantly lower among men with levels in the highest quartile (adjusted relative risk, 0.19; 95% confidence interval [CI], 0.05-0.71).

A large prospective cohort study with women has also been completed. Participants in the Nurses Health Study[13] included more than 84,000 female nurses aged 34-59 years without known CHD. Investigators examined the association between fish and long-chain n-3 fatty acid intake and incidence of CHD among women in the cohort during 16 years of follow-up. Compared with women who rarely ate fish (<1 time per month), those with a higher intake of fish had a lower risk of CHD. After adjustment for age, smoking status, and other cardiac risk factors, the multivariate relative risks of CHD were 0.79 (95% CI, 0.64-0.97) for fish consumption one to three times per month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88) for two to four times per week, and 0.66 (95% CI, 0.50-0.89) for five or more times per week (p=0.001, for the trend).

In addition to analyzing the intake of n-3 fatty acids from marine sources (EPA and DHA), The Nurses Health Study[14] examined plant-based sources of n-3 fatty acids (ALA). The intake of ALA was determined from a 116-item food frequency questionnaire. After adjustment for several possible confounding variables, a higher intake of ALA was associated with a lower relative risk of fatal CHD. The relative risks from lowest to highest quintiles ranged from 1.0-0.55 (p=0.01 for trend). The finding that consumption of foods known to be rich dietary sources of ALA was associated with reduced CHD risk further substantiated this inverse association between ALA and fatal CHD. Specifically, women who consumed salad dressings made from oil and vinegar frequently were found to be at lower risk for fatal CHD. Salad dressings are typically made from nonhydrogenated soybean oil which contains about 7% ALA.

In the usual care cohort (n=6250 men) of the Multiple Risk Factor Intervention Trial (MRFIT),[15] multivariate regression analysis was used to determine the effect dietary PUFA intakes had on 10.5-year mortality rates. PUFA intake was calculated from four dietary recall interviews at baseline and follow-up visits at 1, 2, and 3 years. Significant inverse associations were demonstrated for the intake of the n-3 PUFA, ALA, on mortality from CHD (p<0.04), total cardiovascular disease (p<0.03), and all-cause mortality (p<0.02).

Not all prospective cohort studies of the relationship between n-3 fatty acids consumption and cardiovascular mortality have reported inverse associations. Rodriguez et al.[16] evaluated participants of the Honolulu Heart program. This program was started in 1965 and involved 8006 Japanese American men aged 45-65 who lived in Hawaii. Fish intake was measured at baseline by a questionnaire. Fish intake was defined as low if less than two times per week and high if fish was eaten two or more times per week. No significant differences in CHD incidence or CHD mortality were observed between these two fish intake categories (p<0.05).

In another large prospective cohort study, The Health Professionals Follow-up Study,[17] 44,895 male health professionals 40-75 years of age who were free of known cardiovascular disease completed detailed and validated dietary questionnaires. After controlling for age and other coronary risk factors, no significant associations were observed between dietary intake of n-3 fatty acids or fish intake and the risk of coronary disease. For men in the top fifth quintile of intake of n-3 fatty acids, the multivariate risk of CHD was 1.12 (95% CI, 0.96-1.31) compared with men in the bottom fifth.

These studies with negative results involved cohorts with higher baseline intakes of n-3 PUFAs than the earlier cohort studies.[16,17] In addition, these studies had very few participants who consumed less than one fish meal per week and most participants were already at very low risk of CHD. A threshold effect, where fish intake is cardioprotective in very small amounts, could possibly explain these discordant results.

Finally, a recent systematic review of 11 prospective cohort studies by Marckmann and Gronbaek[18] examined the relationship between fish intake and CHD mortality. Four of these studies were assessed to be high quality in terms of study design. Two of the high-quality studies were performed on low-risk populations and demonstrated no cardioprotective effect from fish consumption. The other two high-quality studies were performed on populations at higher risk for CHD. In these higher-risk cohorts they found an inverse association between fish consumption and CHD death. It was suggested that in these higher-risk cohorts, 40-60 g of fish per day could reduce the risk of CHD death by 40%-60%.


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