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      Plasma Phospholipid Fatty Acid Biomarkers of Dietary Fat Quality and Endogenous Metabolism Predict Coronary Heart Disease Risk: A Nested Case‐Control Study Within the Women's Health Initiative Observational Study

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          Although the relationship between dietary fat quality and coronary heart disease (CHD) risk has been evaluated, typically using diet questionnaires, results are inconsistent and data in postmenopausal women are limited. Plasma phospholipid fatty acid (PL‐FA) profiles, reflecting dietary intake and endogenous FA metabolism, may better predict diet–CHD risk.

          Methods and Results

          Using a nested case‐control design, we assessed the association between plasma PL‐FA profiles and CHD risk in 2448 postmenopausal women (1224 cases with confirmed CHD and 1224 controls matched for age, enrollment date, race/ethnicity, and absence of CHD at baseline and after 4.5 years of follow‐up) participating in the Women's Health Initiative observational study. PL‐FA profile was measured using gas chromatography. Product/precursor ratios were used to estimate stearoyl‐CoA‐desaturase (16:1n‐7/16:0, 18:1n‐9/18:0), Δ6‐desaturase (20:3n‐6/18:2n‐6), and Δ5‐desaturase (20:4n‐6/20:3n‐6) activities, indicators of endogenous FA metabolism. Multivariate conditional logistic regression was used to obtain odds ratios (95% CIs) for CHD risk. While no associations were observed for the predominant PL fatty acid (16:0, 18:0, 18:1n‐9, and 18:2n‐6), plasma PL–saturated fatty acid (1.20 [1.08 to 1.32]) and endogenously synthesized PL ω6 fatty acids (20:3n‐6; 3.22 [1.95 to 5.32]), 22:5n‐6; 1.63 [1.20 to 2.23]) and Δ6‐desaturase (1.25 [1.11 to 1.41]) were positively associated with CHD risk. PL‐ω3 fatty acids (20:5n‐3; 0.73 [0.58 to 0.93], 22:5n‐3; 0.56 [0.33 to 0.94], 22:6n‐3; 0.56 [0.39 to 0.80]), 18:1n‐7 (0.54 [0.29 to 0.99]), and Δ5‐desaturase (0.78 [0.70 to 0.88]) were inversely associated with CHD risk. Results support current guidelines regarding regular fish consumption. Additional findings include associations between endogenously synthesized fatty acids and CHD risk, which were partly explained by changes in Δ6‐desaturase and Δ5‐desaturase indexes, suggesting that in vivo metabolism may also play an important role in predicting CHD risk in this cohort of postmenopausal women.

          Clinical Trial Registration

          URL:, Unique identifier: NCT01864122.

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          Most cited references 59

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          Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group.

          The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the components--dietary modification (DM) or hormone replacement therapy (HRT)--of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.
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            Blood levels of long-chain n-3 fatty acids and the risk of sudden death.

            Experimental data suggest that long-chain n-3 polyunsaturated fatty acids found in fish have antiarrhythmic properties, and a randomized trial suggested that dietary supplements of n-3 fatty acids may reduce the risk of sudden death among survivors of myocardial infarction. Whether long-chain n-3 fatty acids are also associated with the risk of sudden death in those without a history of cardiovascular disease is unknown. We conducted a prospective, nested case-control analysis among apparently healthy men who were followed for up to 17 years in the Physicians' Health Study. The fatty-acid composition of previously collected blood was analyzed by gas-liquid chromatography for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched with them for age and smoking status. Base-line blood levels of long-chain n-3 fatty acids were inversely related to the risk of sudden death both before adjustment for potential confounders (P for trend = 0.004) and after such adjustment (P for trend = 0.007). As compared with men whose blood levels of long-chain n-3 fatty acids were in the lowest quartile, the relative risk of sudden death was significantly lower among men with levels in the third quartile (adjusted relative risk, 0.28; 95 percent confidence interval, 0.09 to 0.87) and the fourth quartile (adjusted relative risk, 0.19; 95 percent confidence interval, 0.05 to 0.71). The n-3 fatty acids found in fish are strongly associated with a reduced risk of sudden death among men without evidence of prior cardiovascular disease.
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              Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis

              Objective To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death. Design Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data. Setting Ambulatory, coronary care clinic in Sydney, Australia. Participants 458 men aged 30-59 years with a recent coronary event. Interventions Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups. Outcome measures All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group. Results The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07). Conclusions Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats. Trial registration Clinical trials NCT01621087.

                Author and article information

                J Am Heart Assoc
                J Am Heart Assoc
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                Blackwell Publishing Ltd
                August 2014
                13 August 2014
                : 3
                : 4
                [1 ]Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (N.R.M., A.H.L.)
                [2 ]School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia (E.M.O.)
                [3 ]Northwestern University, Chicago, IL (L.V.H.)
                [4 ]Fred Hutchinson Cancer Research Center, Seattle, WA (M.L.N.)
                [5 ]School of Medicine, Flinders University, Bedford Park, SA, Australia (R.W.)
                Author notes
                Correspondence to: Nirupa Matthan, PhD, Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington St, Boston, MA 02111. E‐mail: nirupa.matthan@
                © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Original Research

                Cardiovascular Medicine

                diet, fatty acids, risk factors, women


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