Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality: The Cardiovascular Health Study

Study Questions:

What are the associations between circulating n-6 polyunsaturated fatty acid (PUFA) including linoleic acid (LA) (the major dietary PUFA), γ-linolenic acid (GLA), dihomo-γ–linolenic acid (DGLA), and arachidonic acid (AA), with total and cause-specific mortality in the Cardiovascular Health Study, an elder community-based US cohort?


Among 2,792 participants (ages ≥65 years) free of cardiovascular disease (CVD) at baseline, plasma phospholipid n-6 PUFA was measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident coronary heart disease (CHD) and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression.


At baseline, mean age was 74 years and 64% were women. During 34,291 person-years of follow-up (1992-2010), 1,994 deaths occurred (678 CV deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. Circulating LA showed the greatest dose-response association with intake of LA up to approximately 8% of total daily energy; with relatively smaller increases at intakes >8%. In multivariable models, higher LA was associated with lower total mortality, with extreme-quintile hazard ratio (HR) = 0.87 (p trend = 0.005). Lower death was largely attributable to CVD causes, especially nonarrhythmic CHD mortality (HR, 0.51; 95% confidence interval [CI], 0.32-0.82; p-trend = 0.001). Circulating GLA, DGLA, and AA were not significantly associated with total or cause-specific mortality (e.g., for AA and CHD death). LA showed graded inverse associations with total mortality (p = 0.005). When subjects were stratified based on their joint LA and n-3 PUFA concentrations, those with the highest circulating levels of both LA and n-3 PUFA had 54% lower risk of total mortality and 64% lower risk of CVD mortality relative to those with lowest levels of both.


The authors concluded that high circulating LA, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.


The adjusted 11% reduction in total mortality and 49% lower risk across quintiles among CVD subtypes is impressive. But recommending up to 8% of total calorie intake as LA leaves very little for the other major PUFA, the omega-3 fatty acids. The findings should not be used to justify increasing the PUFAs for CVD risk reduction. The ratio of n-6 to n-3 PUFAs (most common fish products) is important. In this study, subjects in the highest quartile of n-3 PUFA and lowest quartile of n-6 PUFA still had a significant reduction in CVD mortality, while those in the highest quartile of n-6 PUFA had no significant benefit but for those in the highest quartile of n-3 PUFA (see data supplement Figure 2).

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Stroke, Follow-Up Studies, Fatty Acids, Omega-3, Risk Reduction Behavior, Coronary Disease, Risk Factors, Confidence Intervals

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