Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men

Abstract

Background: Consumption of polyunsaturated fatty acids (PUFAs) may reduce coronary heart disease (CHD) risk, but n-6 PUFAs may compete with n-3 PUFA metabolism and attenuate benefits. Additionally, seafood-based, long-chain n-3 PUFAs may modify the effects of plant-based, intermediate-chain n-3 PUFAs. However, the interactions of these PUFAs in relation to CHD risk are not well established.

Methods and results: Among 45,722 men free of known cardiovascular disease in 1986, usual dietary intake was assessed at baseline and every 4 years by using validated food-frequency questionnaires. CHD incidence was prospectively ascertained. Over 14 years of follow-up, participants experienced 218 sudden deaths, 1521 nonfatal myocardial infarctions (MIs), and 2306 total CHD events (combined sudden death, other CHD deaths, and nonfatal MI). In multivariate-adjusted analyses, both long-chain and intermediate-chain n-3 PUFA intakes were associated with lower CHD risk, without modification by n-6 PUFA intake. For example, men with > or = median long-chain n-3 PUFA intake (> or =250 mg/d) had a reduced risk of sudden death whether n-6 PUFA intake was below (<11.2 g/d; hazard ratio [HR]=0.52; 95% confidence interval [CI]=0.34 to 0.79) or above (> or =11.2 g/d; HR=0.60; 95% CI=0.39 to 0.93) the median compared with men with a < median intake of both. In similar analyses, > or = median intake of intermediate-chain n-3 PUFAs (> or =1080 mg/d) was associated with a reduced total CHD risk whether n-6 PUFA intake was lower (HR=0.88; 95% CI=0.78 to 0.99) or higher (HR=0.89; 95% CI=0.79 to 0.99) compared with a < median intake of both. Intermediate-chain n-3 PUFAs were particularly associated with CHD risk when long-chain n-3 PUFA intake was very low (<100 mg/d); among these men, each 1 g/d of intermediate-chain n-3 PUFA intake was associated with an approximately 50% lower risk of nonfatal MI (HR=0.42; 95% CI=0.23 to 0.75) and total CHD (HR=0.53; 95% CI=0.34 to 0.83).

Conclusions: n-3 PUFAs from both seafood and plant sources may reduce CHD risk, with little apparent influence from background n-6 PUFA intake. Plant-based n-3 PUFAs may particularly reduce CHD risk when seafood-based n-3 PUFA intake is low, which has implications for populations with low consumption or availability of fatty fish.

Figure 1

Metabolism of n-6 and n-3 PUFAs. δ-5 and δ-6 desaturase enzymes (ovals) are active in both n-3 and n-6 fatty acid metabolism, converting intermediate-chain n-3 ALA to long-chain n-3 EPA and n-6 linoleic acid (LA) to n-6 arachidonic acid (AA). EPA is converted to prostaglandin E₃ (PGE₃), an eicosanoid with potential antiinflammatory and antithrombotic effects, whereas AA is converted to PGE₂ and leukotriene B₄ (LTB₄), both proinflammatory eicosanoids. Thus, n-3 and n-6 fatty acids compete for common metabolic enzymes, and relative intake of these fatty acids has been hypothesized to determine potential proinflammatory vs antiinflammatory, thrombotic, and aggregatory effects. Metabolites in these pathways also exert feedback inhibition (black arrows); eg, long-chain n-3 EPA inhibits an important step in the elongation of intermediate-chain n-3 ALA. SDA indicates stearidonic acid (octadecatetranoic acid); ETA, eicosatetraenoic acid; GLA, γ-linolenic acid; and DGLA, dihomo-γ-linolenic acid. Other abbreviations are as defined in text.

Figure 2

Relative risks (hazards) of CHD associated with each 1 g/d of ALA intake, among participants with long-chain n-3 PUFA intake ≥ 100 mg/d (n = 38 367, open columns) and among participants with little or no long-chain n-3 PUFA intake (<100 mg/d, n = 7355, filled columns). Long-chain n-3 PUFA intake modified effects of ALA intake for both nonfatal MI (P interaction = 0.003) and total CHD (P interaction = 0.006). Error bars indicate upper limit of 95% CI; probability values for significant relative risks are shown. Adjustments as in multivariate model, Table 2. Abbreviations are as defined in text.