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Plasma Phospholipid Long-Chain ω-3 Fatty Acids and Total and Cause-Specific Mortality in Older Adults: A Cohort Study

Dariush Mozaffarian, MD, DrPH; Rozenn N. Lemaitre, PhD, MPH; Irena B. King, PhD; Xiaoling Song, PhD; Hongyan Huang, PhD; Frank M. Sacks, MD; Eric B. Rimm, ScD; Molin Wang, PhD; and David S. Siscovick, MD, MPH
[+] Article, Author, and Disclosure Information

From Brigham and Women's Hospital, Harvard Medical School, and Harvard School of Public Health, Boston, Massachusetts; University of New Mexico, Albuquerque, New Mexico; and Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington.

Acknowledgment: The authors thank all CHS participants, CHS investigators, and institutions (see www.chs-nhlbi.org); Donna Spiegelman, ScD, for invaluable guidance on the analyses of life-years lost and measurement error correction; and Fumiaki Imamura, PhD, for assistance with performing regression dilution bias and measurement error correction analyses.

Grant Support: This investigation was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the Office of Dietary Supplements of the National Institutes of Health (R01-HL-085710). The CHS was supported by NHLBI contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and NHLBI grant HL080295, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging. See www.chs-nhlbi.org/pi.htm.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1795.

Reproducible Research Statement: Study protocol: Available from Dr. Mozaffarian (e-mail, dmozaffa@hsph.harvard.edu). Statistical code: Not available. Data set: Not available from the authors. Interested readers can review the CHS procedures for outside investigators to obtain and analyze data (www.chs-nhlbi.org/CHS_DistribPolicy.htm).

Requests for Single Reprints: Dariush Mozaffarian, MD, DrPH, Harvard School of Public Health, 665 Huntington Avenue, Building 2-319, Boston, MA 02115; e-mail, dmozaffa@hsph.harvard.edu.

Current Author Addresses: Dr. Mozaffarian: Harvard School of Public Health, 665 Huntington Avenue, Building 2-319, Boston, MA 02115.

Drs. Lemaitre and Siscovick: Cardiovascular Health Research Unit, 1730 Minor Avenue, Suite 1360, Seattle, WA 98101.

Dr. King: University of New Mexico, 2703 Frontier Avenue NE, Suite 190, Albuquerque, NM 87131.

Dr. Song: Fred Hutchinson Cancer Research Center, M5-A864, 1100 Fairview Avenue N, Seattle, WA 98109.

Drs. Huang, Sacks, Rimm, and Wang: Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115.

Author Contributions: Conception and design: D. Mozaffarian, I.B. King, D.S. Siscovick.

Analysis and interpretation of the data: D. Mozaffarian, X. Song, H. Huang, F.M. Sacks, M. Wang, D.S. Siscovick.

Drafting of the article: D. Mozaffarian.

Critical revision of the article for important intellectual content: D. Mozaffarian, R.N. Lemaitre, H. Huang, F.M. Sacks, E.B. Rimm, D.S. Siscovick.

Final approval of the article: D. Mozaffarian, R.N. Lemaitre, I.B. King, X. Song, H. Huang, F.M. Sacks, M. Wang, D.S. Siscovick.

Statistical expertise: D. Mozaffarian, H. Huang, M. Wang.

Obtaining of funding: D. Mozaffarian, R.N. Lemaitre, I.B. King, D.S. Siscovick.

Administrative, technical, or logistic support: X. Song.

Collection and assembly of data: D. Mozaffarian, X. Song, D.S. Siscovick.

Ann Intern Med. 2013;158(7):515-525. doi:10.7326/0003-4819-158-7-201304020-00003
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Chinese translation

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.


Grahic Jump Location
Figure 1.

Multivariate-adjusted relationship of plasma phospholipid EPA, DPA, and DHA levels with total mortality, evaluated using restricted cubic splines.

The solid lines and shaded areas represent the central risk estimate and 95% CI, respectively, for each fatty acid. The dotted vertical lines correspond to the 10th, 25th, 50th, 75th, and 90th percentiles for each fatty acid. Adjusted for age (years), sex, race (white or nonwhite), education (less than high school, high school, some college, or college graduate), enrollment site (4 sites), fatty acid measurement batch (1994–1996 or 2007–2010), smoking (never, former, or current), prevalent diabetes (yes or no), prevalent atrial fibrillation (yes or no), prevalent drug-treated hypertension (yes or no), leisure-time physical activity (kcal/wk), body mass index (kg/m2), waist circumference (cm), and alcohol use (6 categories). DHA = docosahexaenoic acid; DPA = docosapentaenoic acid; EPA = eicosapentaenoic acid.

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Grahic Jump Location
Figure 2.

Relationship between dietary EPA plus DHA consumption and plasma phospholipid EPA plus DHA concentrations, evaluated using restricted cubic splines and adjusted for age, sex, race, and education.

Because the dietary questionnaire assessed only EPA plus DHA (and not DPA), for comparability we evaluated circulating EPA plus DHA (rather than EPA plus DPA plus DHA) level. Median circulating levels of EPA plus DHA in the highest quintile were approximately 5% of total fatty acids. The solid line and shaded area represent the central estimate and 95% CI, respectively. There was strong evidence for both an overall trend (P < 0.001) and nonlinearity of this relationship (P < 0.001). DHA = docosahexaenoic acid; DPA = docosapentaenoic acid; EPA = eicosapentaenoic acid.

Grahic Jump Location




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Submit a Comment/Letter
Letter to Editor
Posted on April 9, 2013
Ankit Rathod*, Apurva Badheka
*Department of Cardiology,Cedars Sinai Medical Center
Conflict of Interest: None Declared

We read with great interest the recent article in the Journal by Mozaffarian et al.(1) The researchers conducted a nice cohort study to establish the association of plasma phospholipid omega-3 polyunsaturated fatty acids (PUFA) with beneficial effects on cardiovascular and all cause mortality in older adults. Recently there have been a few randomized controlled trials investigating the relationship of diet and cardiovascular mortality in both primary and secondary prevention.(2) These trials and the observational data from previous studies however did not specifically look into the geriatric population. Benefits of healthy lifestyle including a cardioproctective diet even in a geriatric population need to be underlined.

We had the opportunity to carry out a similar analysis addressing the benefit of higher healthy eating index (HEI) in a nationally representative population from National health and nutritional examination survey III (NHANES) cohort.(3) The HEI, developed by the US Department of Agriculture's Center for Nutrition Policy and Promotion, comprises 10 dietary components that measure diet quality. Our study population was stratified into 3 categories according to HEI scores (>80 indicates a “good” diet; 51-80, “fair”; and <51, a “poor” diet).We found the “good” HEI group, compared with the “fair” and “poor” groups, had fewer total deaths (62% vs 71% vs 78%, respectively [P = .001]) and cardiovascular deaths (33% vs 34% vs 36%, respectively [P = .001]). We believe study by Mozaffarian et al. provides the mechanistic explanation for the observed benefits. This is further proven by the fact that several studies have shown correlation of higher PUFA levels with higher HEI although in different age groups.(4, 5)

We acknowledge that our study was limited because of the lack of correlation data for HEI and PUFA levels. Our study, however, adds to the existing published reports on the benefits of healthy diet on cardiovascular health of geriatric adults. It provides a strong basis to further study these relationships in a prospective randomized trial.


1. Mozaffarian D, Lemaitre RN, King IB, et al. Plasma Phospholipid Long-Chain omega-3 Fatty Acids and Total and Cause-Specific Mortality in Older Adults: A Cohort Study. Ann Intern Med. 2013;158(7):515-25.

2. Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279-90.

3. Rathod AD, Bharadwaj AS, Badheka AO, Kizilbash M, Afonso L. Healthy Eating Index and mortality in a nationally representative elderly cohort. Arch Intern Med. 2012;172(3):275-7.

4. Gesteiro E, Rodriguez Bernal B, Bastida S, Sanchez-Muniz FJ. Maternal diets with low healthy eating index or Mediterranean diet adherence scores are associated with high cord-blood insulin levels and insulin resistance markers at birth. Eur J Clin Nutr. 2012;66(9):1008-15.

5. O'Neil CE, Nicklas TA, Zanovec M, Cho SS, Kleinman R. Consumption of whole grains is associated with improved diet quality and nutrient intake in children and adolescents: the National Health and Nutrition Examination Survey 1999-2004. Public Health Nutr. 2011;14(2):347-55.

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