3. For cardiovascular health, a minimum intake of eicosapentaenoic acid and docosahexaenoic acid combined of: 500 mg/day

This recommendation is based on a review of major epidemiologic studies conducted in the US in which the intakes of w3 PUFA among healthy adults were estimated and the subsequent risk for death from CHD was determined. Six such studies were available, and five studies reported statistically significant inverse trends between CHD risk and EPA+DHA intake or a significantly reduced risk at the highest (vs the lowest) quintile of intake. Meta-analysis by intake group of these data showed a significant relationship between risk for CHD death and EPA+DHA intake (p=0.03).  The relative risk reduction in the highest vs. the lowest  intake  groups was 37%, and the intake in that quintile averaged 566 mg EPA+DHA per day. Based on large prospective population studies and well-controlled case-control studies, an intake of about 500 mg of EPA+DHA per day would be expected to significantly reduce risk for death from CHD in healthy adults.  This intake is both safe and achievable by diet alone, even for pregnant and lactating women for whom mercury intake can be an issue.

EPA+DHA Intakes in US Epidemiologic Studies : Eight studies have been reported with the following characteristics : 1) the population was from the US and was CHD-free at baseline, 2) risk for CHD death, primary cardiac arrest, and/or sudden cardiac death were reported, 3) risk was assessed across a range of estimated EPA+DHA intakes, and, 4) multivariate analysis was used to calculate relative risk or odds ratios. Two studies (Morris et al 1995, Hu et al 2003) fitting these criteria were not included because they reported results from either a shorter follow-up (4 yrs  in Morris et al 1995 vs. 11 yrs in Albert et al 1998, both from the Physicians’ Health Study;) or a patient subset (only diabetic nurses from the Nurses Health Study  in Hu et al 2003   vs all participants in Hu et al 2002) from the other studies already included. Of the six remaining studies, five found CHD benefit with increasing intakes of EPA+DHA  or at the highest intake quintile vs the lowest. One study reported no benefit (Ascherio et al 1995). All six studies were included to estimate the EPA+DHA intake associated with the lowest risk for death from CHD (Table 3).

Nurses’ Health Study (NHS) : Beginning in 1976, the NHS enrolled 121,700 registered nurses who completed lifestyle and medical questionnaires (Hu et al 2002). A food frequency questionnaire (FFQ) was used to estimate w3 PUFA intake. The daily EPA+DHA intake was calculated and compared to the risk of CHD death over the ensuing 16 years.

US Physicians’ Health Study (PHS) : This prospective cohort study initiated in 1982 was similar to the NHS, and enrolled a total of 20,551 US male physicians between the ages of 40 and 84 years who were free of major illness (Albert et al 1998).  A FFQ similar to that employed in the NHS was used to assess w3 PUFA intake. The association between the latter and the 11-year risk for sudden cardiac death (and total mortality) was ascertained.

Seattle Primary Cardiac Arrest Study : This was a population-based, case-control study conducted in the Seattle area (Siscovik et al 1995). All cases of primary cardiac arrest in subjects between 25-74 years over a 6-year period were identified. Controls were identified from the same population and matched for age and sex. A total of 295 cases and 398 controls were included in this report. Dietary intake of fish was ascertained using the Seafood Intake Scale, a quantitative FFQ developed for this study. Spouses of both cases and controls were interviewed regarding their partner’s fish intake over the previous month. The odds ratio for being a case (vs. a control) as a function of EPA+DHA intake were calculated.

Multiple Risk Factor Intervention Trial (MRFIT) : MRFIT was a multi-center, open-label study in which 12,866 men at high risk for developing CHD (based on smoking status, serum cholesterol and blood pressure) were randomized to either usual care or to interventions addressing all three risk factors. Dietary data were collected at baseline by standardized 24-hr recall. The present analysis (Dolecek 1992) included health outcomes from those in the usual care group over 10.5 years.

Cardiovascular Health Study (CHS) : The CHS focused on men and women over the age of 65 at entry (Mozaffarian et al 2003). About 5,200 individuals were recruited from four communities from Medicare rolls between 1989 and 1990. A picture version of the National Cancer Institute’s FFQ was administered at baseline and specifically distinguished between tuna/non-fried fish, and fried fish/fish sandwiches. Outcomes were collected for a mean of 9.3 years, and the risk for total ischemic heart disease death was determined in relation to the amount of EPA+DHA consumed.

Health Professionals’ Follow-up Study (HPS) : This study, which was patterned after the NHS and the PHS, began in 1986 and enrolled 51,529 male health professionals (non-physicians such as dentists, pharmacists, etc.) between 40 and 75 years of age (Albert et al 2002). The same FFQ as used in those studies was used here. A total of 44,895 men free of CHD who had satisfactorily completed the FFQ were followed for CHD events for 6 years.

Additional Scandinavian Data : Dietary intake of EPA, DPA and DHA was 1.08 g/d and 0.72 g/d among a national representative sample 1517 men and 1627 women, respectively, (16-79 years of age) in 1993-4 (Johansson et al 1998). Japanese and Icelandic people have an even higher intake of marine w3 PUFA. Life expectancy is among the highest in the world in these countries. Brude et al (1997) challenged the peroxidation fear by giving 5 g/d of w3 PUFA to male smokers with hyperlipidemia for six weeks and measured all parameters of lipid peroxidation in LDL from patients with and without antioxidants. w3 PUFA neither rendered the LDL particles more susceptible to undergo in vitro oxidation nor influenced mononuclear cells’ ability to oxidize autologous LDL, whereas moderate amounts of antioxidants protected LDL against oxidative modification. This represents strong evidence against any harmful effect of w3 PUFA on peroxidation of LDL in plasma.