Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial

Michael R Flock, Ann C Skulas-Ray, William S Harris, Terry D Etherton, Jennifer A Fleming, Penny M Kris-Etherton, Michael R Flock, Ann C Skulas-Ray, William S Harris, Terry D Etherton, Jennifer A Fleming, Penny M Kris-Etherton

Abstract

Background: The erythrocyte membrane content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which constitutes the omega-3 index (O3I), predicts cardiovascular disease mortality. The amount of EPA+DHA needed to achieve a target O3I is poorly defined, as are the determinants of the O3I response to a change in EPA+DHA intake. The objective of this study was to develop a predictive model of the O3I response to EPA+DHA supplementation in healthy adults, specifically identifying factors that determine the response.

Methods and results: A randomized, placebo-controlled, double-blind, parallel-group study was conducted in 115 healthy men and women. One of 5 doses (0, 300, 600, 900, 1800 mg) of EPA+DHA was given daily as placebo or fish oil supplements for ≈5 months. The O3I was measured at baseline and at the end of the study. There were no significant differences in the clinical characteristics between the groups at baseline. The O3I increased in a dose-dependent manner (P<0.0001), with the dose of EPA+DHA alone accounting for 68% (quadratic, P<0.0001) of the variability in the O3I response. Dose adjusted per unit body weight (g/kg) accounted for 70% (linear, P<0.0001). Additional factors that improved prediction of treatment response were baseline O3I, age, sex, and physical activity. Collectively, these explained 78% of the response variability (P<0.0001).

Conclusions: Our findings validate the O3I as a biomarker of EPA+DHA consumption and identify additional factors, particularly body weight, that can be used to tailor EPA+DHA recommendations to achieve a target O3I.

Trial registration: ClinicalTrials.gov NCT01078909.

Keywords: blood cell; fatty acids; fish oil; metabolism; nutrition.

Figures

Figure 1.
Figure 1.
Schematic of subject flow and reasons for exclusion. BMI indicates body mass index; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid.
Figure 2.
Figure 2.
Distribution of the percentage of red blood cell (RBC) EPA+DHA values (omega‐3 index [O3I]) in the study population at baseline (n=115). Lines at 8% and 4% indicate proposed low‐ and high‐risk horizons, respectively, and the dotted line at 4.3% is the population average. DHA indicates docosahexaenoic acid; EPA, eicosapentaenoic acid.
Figure 3.
Figure 3.
Changes in the omega‐3 index (O3I) before and after healthy adults were supplemented for 5 months with either 0 (A; n=23), 300 (B; n=23), 600 (C; n=21), 900 (D; n=24), or 1800 (E; n=24) mg/day of EPA+DHA. A through E, Each participant is denoted by a solid line with a black triangle (▲). The mean change per group is denoted as a dashed line with a white triangle (△). F, Mean changes for each supplement group of 0 (■), 300 (●), 600 (♦), 900 (○), and 1800 (□) mg/day of EPA+DHA. DHA indicates docosahexaenoic acid; EPA, eicosapentaenoic acid.
Figure 4.
Figure 4.
Treatment dose significantly predicted changes in omega‐3 index (O3I; n=115). DHA indicates docosahexaenoic acid; EPA, eicosapentaenoic acid.
Figure 5.
Figure 5.
The amount of EPA+DHA in grams consumed per kilogram of body weight significantly predicted changes in omega‐3 index (O3I; n = 115). DHA indicates docosahexaenoic acid; EPA, eicosapentaenoic acid.

References

    1. Kris‐Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega‐3 fatty acids, and cardiovascular disease. Circulation. 2002; 106:2747-2757
    1. Simopoulos AP, Leaf A, Salem N., Jr Workshop statement on the essentiality of and recommended dietary intakes for omega‐6 and omega‐3 fatty acids. Prostaglandins Leukot Essent Fatty Acids. 2000; 63:119-121
    1. EFSA Scientific opinion of the panel on dietetic products, nutrition and allergies on a request from European Commission related to related to dietary reference values for fat. EFSA J. 2009; 8:1461
    1. USDA Dietary Guidelines for Americans 2010. 20107th edWashington, D.C.U.S. Government Printing Office
    1. Flock MR, Harris WS, Kris‐Etherton PM. Long‐chain omega‐3 fatty acids: time to establish a dietary reference intake. Nutr Rev. 2013; 71:692-707
    1. Harris WS. The omega‐3 index as a risk factor for coronary heart disease. Am J Clin Nutr. 2008; 87:1997S-2002S
    1. Harris WS, Von Schacky C. The omega‐3 index: a new risk factor for death from coronary heart disease? Prev Med. 2004; 39:212-220
    1. Metcalf RG, James MJ, Gibson RA, Edwards JR, Stubberfield J, Stuklis R, Roberts‐Thomson K, Young GD, Cleland LG. Effects of fish‐oil supplementation on myocardial fatty acids in humans. Am J Clin Nutr. 2007; 85:1222-1228
    1. Owen AJ, Peter‐Przyborowska BA, Hoy AJ, McLennan PL. Dietary fish oil dose‐ and time‐response effects on cardiac phospholipid fatty acid composition. Lipids. 2004; 39:955-961
    1. Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG, Albright J, Bovbjerg V, Arbogast P, Smith H, Kushi LH, Cobb LA, Copass MK, Psaty BM, Lemaitre R, Retzlaff B, Childs M, Knopp RH. Dietary intake and cell membrane levels of long‐chain n‐3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995; 274:1363-1367
    1. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J. Blood levels of long‐chain n‐3 fatty acids and the risk of sudden death. N Engl J Med. 2002; 346:1113-1118
    1. von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H. The effect of dietary ω‐3 fatty acids on coronary atherosclerosis: a randomized, double‐blind, placebo‐controlled trial. Ann Intern Med. 1999; 130:554-562
    1. Block RC, Harris WS, Reid KJ, Sands SA, Spertus JA. EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls. Atherosclerosis. 2008; 197:821-828
    1. Park Y, Lim J, Lee J, Kim SG. Erythrocyte fatty acid profiles can predict acute non‐fatal myocardial infarction. Br J Nutr. 2009; 102:1355-1361
    1. Sands SA, Reid KJ, Windsor SL, Harris WS. The impact of age, body mass index, and fish intake on the EPA and DHA content of human erythrocytes. Lipids. 2005; 40:343-347
    1. Cao J, Schwichtenberg KA, Hanson NQ, Tsai MY. Incorporation and clearance of omega‐3 fatty acids in erythrocyte membranes and plasma phospholipids. Clin Chem. 2006; 52:2265-2272
    1. Sun Q, Ma J, Campos H, Hankinson SE, Hu FB. Comparison between plasma and erythrocyte fatty acid content as biomarkers of fatty acid intake in US women. Am J Clin Nutr. 2007; 86:74-81
    1. Donadio JV, Bergstralh EJ, Bibus DM, Grande JP. Is body size a biomarker for optimizing dosing of omega‐3 polyunsaturated fatty acids in the treatment of patients with IgA nephropathy? Clin J Am Soc Nephrol. 2006; 1:933-939
    1. Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, McConnell JP. Eryhtrocyte omega‐3 fatty acids increase and linoleic acid decreases with age: observations in 160,000 patients. Prostaglandins Leukot Essent Fatty Acids. 2013; 88:257-263
    1. Harris WS, Pottala JV, Lacey SM, Vasan RS, Larson MG, Robins SJ. Clinical correlates and heritability of erythrocyte eicosapentaenoic and docosahexaenoic acid content in the Framingham Heart Study. Atherosclerosis. 2012; 225:425-431
    1. Sala‐Vila A, Harris WS, Cofan M, Perez‐Heras AM, Pinto X, Lamuela‐Raventos RM, Covas MI, Estruch R, Ros E. Determinants of the omega‐3 index in a Mediterranean population at increased risk for CHD. Br J Nutr. 2011; 106:425-431
    1. Itomura M, Fujioka S, Hamazaki K, Kobayashi K, Nagasawa T, Sawazaki S, Kirihara Y, Hamazaki T. Factors influencing EPA+DHA levels in red blood cells in Japan. In Vivo. 2008; 22:131-135
    1. Salisbury AC, Amin AP, Harris WS, Chan PS, Gosch KL, Rich MW, O'Keefe JH, Jr, Spertus JA. Predictors of omega‐3 index in patients with acute myocardial infarction. Mayo Clin Proc. 2011; 86:626-632
    1. Byers T. Food frequency dietary assessment: how bad is good enough? Am J Epidemiol. 2001; 154:1087-1088
    1. Skulas‐Ray AC, Kris‐Etherton PM, Harris WS, Vanden Heuvel JP, Wagner PR, West SG. Dose‐response effects of omega‐3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr. 2011; 93:243-252
    1. Metherel AH, Armstrong JM, Patterson AC, Stark KD. Assessment of blood measures of n‐3 polyunsaturated fatty acids with acute fish oil supplementation and washout in men and women. Prostaglandins Leukot Essent Fatty Acids. 2009; 81:23-29
    1. Keenan AH, Pedersen TL, Fillaus K, Larson MK, Shearer GC, Newman JW. Basal omega‐3 fatty acid status affects fatty acid and oxylipin responses to high‐dose n3‐HUFA in healthy volunteers. J Lipid Res. 2012; 53:1662-1669
    1. Vidgren HM, Agren JJ, Schwab U, Rissanen T, Hanninen O, Uusitupa MI. Incorporation of n‐3 fatty acids into plasma lipid fractions, and erythrocyte membranes and platelets during dietary supplementation with fish, fish oil, and docosahexaenoic acid‐rich oil among healthy young men. Lipids. 1997; 32:697-705
    1. Katan MB, Deslypere JP, van Birgelen AP, Penders M, Zegwaard M. Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18‐month controlled study. J Lipid Res. 1997; 38:2012-2022
    1. Browning LM, Walker CG, Mander AP, West AL, Madden J, Gambell JM, Young S, Wang L, Jebb SA, Calder PC. Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish. Am J Clin Nutr. 2012; 96:748-758
    1. U.S. Department of Agriculture ARS USDA National Nutrient Database for Standard Reference, Release 25. 2012Washington, D.C.U.S. Department of Agriculture ARS
    1. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low‐density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499-502
    1. USDA Nutrient Intakes From Food: mean Amounts Consumed per Individual, by Gender and Age, What We Eat in America, NHANES 2009–2010. 2012Washington, D.C.USDA
    1. Dietary supplementation with n‐3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI‐Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto miocardico. Lancet. 1999; 354:447-455
    1. Iso H, Kobayashi M, Ishihara J, Sasaki S, Okada K, Kita Y, Kokubo Y, Tsugane SJPHC Study Group Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center‐based (JPHC) study cohort I. Circulation. 2006; 113:195-202
    1. Brown AJ, Pang E, Roberts DC. Persistent changes in the fatty acid composition of erythrocyte membranes after moderate intake of n‐3 polyunsaturated fatty acids: study design implications. Am J Clin Nutr. 1991; 54:668-673
    1. Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n‐3 fatty acids in humans. Am J Clin Nutr. 2006; 83:S1467-S1476
    1. Food and Drug Administration Gras Notice No. Grn 000138: Fish Oil. 2002Washington, D.C.Center for Food Safety and Applied Nutrition, Food and Drug Administration
    1. Mozaffarian D, Wu JH. (n‐3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr. 2012; 142:614S-625S
    1. IOM Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). 2005Washington, D.C.IOM
    1. Hibbeln JR, Makino KK, Martin CE, Dickerson F, Boronow J, Fenton WS. Smoking, gender, and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder. Biol Psychiatry. 2003; 53:431-441
    1. Vandal M, Freemantle E, Tremblay‐Mercier J, Plourde M, Fortier M, Bruneau J, Gagnon J, Begin M, Cunnane SC. Plasma omega‐3 fatty acid response to a fish oil supplement in the healthy elderly. Lipids. 2008; 43:1085-1089
    1. Plourde M, Fortier M, Vandal M, Tremblay‐Mercier J, Freemantle E, Bégin M, Pifferi F, Cunnane SC. Unresolved issues in the link between docosahexaenoic acid and Alzheimer's disease. Prostaglandins Leukot Essent Fatty Acids. 2007; 77:301-308
    1. Cohen BE, Garg SK, Ali S, Harris WS, Whooley MA. Red blood cell docosahexaenoic acid and eicosapentaenoic acid concentrations are positively associated with socioeconomic status in patients with established coronary artery disease: data from the Heart and Soul Study. J Nutr. 2008; 138:1135-1140
    1. Farzaneh‐Far R, Harris WS, Garg S, Na B, Whooley MA. Inverse association of erythrocyte n‐3 fatty acid levels with inflammatory biomarkers in patients with stable coronary artery disease: the Heart and Soul Study. Atherosclerosis. 2009; 205:538-543
    1. Ogura T, Takada H, Okuno M, Kitade H, Matsuura T, Kwon M, Arita S, Hamazaki K, Itomura M, Hamazaki T. Fatty acid composition of plasma, erythrocytes and adipose: their correlations and effects of age and sex. Lipids. 2010; 45:137-144
    1. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega‐3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006; 189:19-30
    1. Kris‐Etherton PM, Harris WS, Appel LJ. Omega‐3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol. 2003; 23:151-152
    1. Lemaitre RN, Tanaka T, Tang W, Manichaikul A, Foy M, Kabagambe EK, Nettleton JA, King IB, Weng LC, Bhattacharya S, Bandinelli S, Bis JC, Rich SS, Jacobs DR, Jr, Cherubini A, McKnight B, Liang S, Gu X, Rice K, Laurie CC, Lumley T, Browning BL, Psaty BM, Chen YD, Friedlander Y, Djousse L, Wu JH, Siscovick DS, Uitterlinden AG, Arnett DK, Ferrucci L, Fornage M, Tsai MY, Mozaffarian D, Steffen LM. Genetic loci associated with plasma phospholipid n‐3 fatty acids: a meta‐analysis of genome‐wide association studies from the CHARGE Consortium. PLoS Genet. 2011; 7:e1002193.
    1. Cabre E, Periago JL, Mingorance MD, Fernandez‐Banares F, Abad A, Esteve M, Gil A, Lachica M, Gonzalez‐Huix F, Gassull MA. Factors related to the plasma fatty acid profile in healthy subjects, with special reference to antioxidant micronutrient status: a multivariate analysis. Am J Clin Nutr. 1992; 55:831-837
    1. Kraus A, Roth HP, Kirchgessner M. Supplementation with vitamin C, vitamin E or beta‐carotene influences osmotic fragility and oxidative damage of erythrocytes of zinc‐deficient rats. J Nutr. 1997; 127:1290-1296
    1. West AA, Yan J, Jiang X, Perry CA, Innis SM, Caudill MA. Choline intake influences phosphatidylcholine DHA enrichment in nonpregnant women but not in pregnant women in the third trimester. Am J Clin Nutr. 2013; 97:718-727

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться