Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study

Abstract

Background: Long-chain ω-3 polyunsaturated fatty acids (ω3-PUFAs), including eicosapentaenoic acid (EPA) (20:5ω-3), docosapentaenoic acid (DPA) (22:5ω-3), and docosahexaenoic acid (DHA) (22:6ω-3), have been shown to reduce cardiovascular risk, but effects on cause-specific and total mortality and potential dose-responses remain controversial. Most observational studies have assessed self-reported dietary intake and most randomized trials have tested effects of adding supplements to dietary intake and evaluated secondary prevention, thus limiting inference for dietary ω3-PUFAs or primary prevention.

Objective: To investigate associations of plasma phospholipid EPA, DPA, DHA, and total ω3-PUFA levels with total and cause-specific mortality among healthy older adults not receiving supplements.

Design: Prospective cohort study.

Setting: 4 U.S. communities.

Participants: 2692 U.S. adults aged 74 years (±5 years) without prevalent coronary heart disease (CHD), stroke, or heart failure at baseline.

Measurements: Phospholipid fatty acid levels and cardiovascular risk factors were measured in 1992. Relationships with total and cause-specific mortality and incident fatal or nonfatal CHD and stroke through 2008 were assessed.

Results: During 30 829 person-years, 1625 deaths (including 570 cardiovascular deaths), 359 fatal and 371 nonfatal CHD events, and 130 fatal and 276 nonfatal strokes occurred. After adjustment, higher plasma levels of ω3-PUFA biomarkers were associated with lower total mortality, with extreme-quintile hazard ratios of 0.83 for EPA (95% CI, 0.71 to 0.98; P for trend = 0.005), 0.77 for DPA (CI, 0.66 to 0.90; P for trend = 0.008), 0.80 for DHA (CI, 0.67 to 0.94; P for trend = 0.006), and 0.73 for total ω3-PUFAs (CI, 0.61 to 0.86; P for trend < 0.001). Lower risk was largely attributable to fewer cardiovascular than noncardiovascular deaths. Individuals in the highest quintile of phospholipid ω3-PUFA level lived an average of 2.22 more years (CI, 0.75 to 3.13 years) after age 65 years than did those in the lowest quintile.

Limitation: Temporal changes in fatty acid levels and misclassification of causes of death may have resulted in underestimated associations, and unmeasured or imperfectly measured covariates may have caused residual confounding.

Conclusion: Higher circulating individual and total ω3-PUFA levels are associated with lower total mortality, especially CHD death, in older adults.

Primary funding source: National Institutes of Health.

Figure 1

Multivariable-adjusted relationship of plasma phospholipid eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with total mortality among 2,692 older US adults, evaluated using restricted cubic splines. The solid line and shaded area represent the central risk estimate and 95% CIs, respectively. The red vertical lines correspond to the 10^th, 25^th, 50^th, 75^th, and 90^th percentiles for each fatty acid. Adjusted for age (years), sex, race (white, nonwhite), education (<high school, high school, some college, college graduate), enrollment site (4 sites), fatty acid measurement batch (1994–96, 2007–10), smoking (never, former, current), prevalent diabetes (yes, no), prevalent atrial fibrillation (yes, no), prevalent drug-treated hypertension (yes, no), leisure-time physical activity (kcal/wk), body mass index (kg/m²), waist circumference (cm), and alcohol use (6 categories).

Figure 1

Multivariable-adjusted relationship of plasma phospholipid eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with total mortality among 2,692 older US adults, evaluated using restricted cubic splines. The solid line and shaded area represent the central risk estimate and 95% CIs, respectively. The red vertical lines correspond to the 10^th, 25^th, 50^th, 75^th, and 90^th percentiles for each fatty acid. Adjusted for age (years), sex, race (white, nonwhite), education (<high school, high school, some college, college graduate), enrollment site (4 sites), fatty acid measurement batch (1994–96, 2007–10), smoking (never, former, current), prevalent diabetes (yes, no), prevalent atrial fibrillation (yes, no), prevalent drug-treated hypertension (yes, no), leisure-time physical activity (kcal/wk), body mass index (kg/m²), waist circumference (cm), and alcohol use (6 categories).

Figure 2

Relationship between dietary eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) consumption and plasma phospholipid EPA+DHA concentrations among 2,692 older US adults, evaluated using restricted cubic splines, and adjusted for age, sex, race, and education. Because the dietary questionnaire estimated only EPA+DHA (and not DPA), for comparability we evaluated circulating EPA+DHA (rather than EPA+DPA+DHA). Median circulating levels of EPA+DHA in the highest quintile were ~5 percent of total fatty acids. The solid line and shaded area represent the central estimate and 95% CIs, respectively. There was strong evidence for both an overall trend (P<0.001) and nonlinearity of this relationship (P<0.001).