Research Article| Volume 29, ISSUE 8, P837-846, August 2019

Download started.


Serum long-chain n-3 polyunsaturated fatty acids and aortic calcification in middle-aged men: The population-based cross-sectional ERA-JUMP study


      • Evidence concerning LCn-3PUFAs and atherosclerosis is limited in the general population.
      • Cross-sectionally examined the relationship of LCn-3 PUFAs to aortic calcification in asymptomatic middle aged men.
      • Overall, LCn-3PUFAs especially DHA was inversely and significantly associated with aortic calcification.
      • No significant interaction between race/ethnicity and total LCn-3 PUFAs, EPA or DHA on aortic calcification.
      • In the general middle-aged male population, DHA may be more anti-atherogenic than EPA.


      Background and aim

      Few studies have examined the association of long-chain n-3 polyunsaturated fatty acids (LCn-3PUFAs) with the measures of atherosclerosis in the general population. This study aimed to examine the relationship of total LCn-3PUFAs, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) with aortic calcification.

      Methods and results

      In a multiethnic population-based cross-sectional study of 998 asymptomatic men aged 40–49 years (300 US-White, 101 US-Black, 287 Japanese American, and 310 Japanese in Japan), we examined the relationship of serum LCn-3PUFAs to aortic calcification (measured by electron-beam computed tomography and quantified using the Agatston method) using Tobit regression and ordinal logistic regression after adjusting for potential confounders. Overall 56.5% participants had an aortic calcification score (AoCaS) > 0. The means (SD) of total LCn-3PUFAs, EPA, and DHA were 5.8% (3.3%), 1.4% (1.3%), and 3.7% (2.1%), respectively. In multivariable-adjusted Tobit regression, a 1-SD increase in total LCn-3PUFAs, EPA, and DHA was associated with 29% (95% CI = 0.51, 1.00), 9% (95% CI = 0.68, 1.23), and 35% (95% CI = 0.46, 0.91) lower AoCaS, respectively. Results were similar in ordinal logistic regression analysis. There was no significant interaction between race/ethnicity and total LCn–3PUFAs, EPA or DHA on aortic calcification.


      This study showed the significant inverse association of LCn-3PUFAs with aortic calcification independent of conventional cardiovascular risk factors among men in the general population. This association appeared to be driven by DHA but not EPA.


      List of abbreviations:

      ALA (α-linolenic acid), AoCaS (Agatston aortic calcification score), ARA (arachidonic acid), BMI (body mass index), CAC (coronary artery calcification), CI (confidence interval), CIMT (carotid intima-media thickness), CHD (coronary heart disease), CRP (C-reactive protein), CVD (cardiovascular disease), DHA (docosahexaenoic acid), DPA (docosapentaenoic acid), EBCT (Electron beam computed tomography), EPA (eicosapentaenoic acid), HDL-C (high-density lipoprotein cholesterol), LA (linoleic acid), LCn-3PUFAs (long-chain n-3 polyunsaturated fatty acids), LDL-C (low-density lipoprotein cholesterol), RCT (randomized controlled trial), SD (standard deviation), SEM (standard error of mean), TR (tobit ratio)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Nutrition, Metabolism and Cardiovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Alexander D.D.
        • Miller P.E.
        • Van Elswyk M.E.
        • Kuratko C.N.
        • Bylsma L.C.
        A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk.
        Mayo Clin Proc: Elsevier. 2017; : 15-29
        • Mozaffarian D.
        • Wu J.H.
        Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events.
        J Am Coll Cardiol. 2011; 58: 2047-2067
        • Mori T.A.
        Dietary n-3 PUFA and CVD: a review of the evidence.
        Proc Nutr Soc. 2014; 73: 57-64
        • Mozaffarian D.
        • Rimm E.
        Fish intake, contaminants, and human health: evaluating the risks and the benefits part 2-health risks and optimal intakes.
        Cardiol Rounds. 2006; 10: 1-6
        • Bhatt D.L.
        • Steg P.G.
        • Miller M.
        • Brinton E.A.
        • Jacobson T.A.
        • Ketchum S.B.
        • et al.
        Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
        N Engl J Med. 2018;
        • Siscovick D.S.
        • Barringer T.A.
        • Fretts A.M.
        • Wu J.H.
        • Lichtenstein A.H.
        • Costello R.B.
        • et al.
        Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American heart association.
        Circulation. 2017; (CIR. 0000000000000482)
        • Watanabe T.
        • Ando K.
        • Daidoji H.
        • Otaki Y.
        • Sugawara S.
        • Matsui M.
        • et al.
        A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins.
        J Cardiol. 2017; 70: 537-544
        • Mita T.
        • Watada H.
        • Ogihara T.
        • Nomiyama T.
        • Ogawa O.
        • Kinoshita J.
        • et al.
        Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes.
        Atherosclerosis. 2007; 191: 162-167
        • Niki T.
        • Wakatsuki T.
        • Yamaguchi K.
        • Taketani Y.
        • Oeduka H.
        • Kusunose K.
        • et al.
        Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound.
        Circ J. 2016; 80: 450-460
        • Alfaddagh A.
        • Elajami T.K.
        • Ashfaque H.
        • Saleh M.
        • Bistrian B.R.
        • FK W.
        Effect of eicosapentaenoic and docosahexaenoic acids added to statin therapy on coronary artery plaque in patients with coronary artery disease: a randomized clinical trial.
        J Am Heart Assoc. 2017; 6
        • Calder P.C.
        The role of marine omega-3 (n-3) fatty acids in inflammatory processes, atherosclerosis and plaque stability.
        Mol Nutr Food Res. 2012; 56: 1073-1080
        • Cawood A.L.
        • Ding R.
        • Napper F.L.
        • Young R.H.
        • Williams J.A.
        • Ward M.J.
        • et al.
        Eicosapentaenoic acid (EPA) from highly concentrated n− 3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability.
        Atherosclerosis. 2010; 212: 252-259
        • Thies F.
        • Garry J.M.
        • Yaqoob P.
        • Rerkasem K.
        • Williams J.
        • Shearman C.P.
        • et al.
        Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial.
        Lancet. 2003; 361: 477-485
        • Burgess N.
        • Reynolds T.
        • Williams N.
        • Pathy A.
        • Smith S.
        Evaluation of four animal models of intrarenal calcium deposition and assessment of the influence of dietary supplementation with essential fatty acids on calcification.
        Urol Res. 1995; 23: 239-242
        • Schlemmer C.
        • Coetzer H.
        • Claassen N.
        • Kruger M.
        • Rademeyer C.
        • Van Jaarsveld L.
        • et al.
        Ectopic calcification of rat aortas and kidneys is reduced with n-3 fatty acid supplementation.
        Prostagl Leukot Essent Fat Acids. 1998; 59: 221-227
        • Abedin M.
        • Lim J.
        • Tang T.
        • Park D.
        • Demer L.
        • Tintut Y.
        N-3 fatty acids inhibit vascular calcification via the p38-mitogen-activated protein kinase and peroxisome proliferator-activated receptor-γ pathways.
        Circ Res. 2006; 98: 727-729
        • Massaro M.
        • Scoditti E.
        • Carluccio M.
        • Campana M.
        • De Caterina R.
        Omega-3 fatty acids, inflammation and angiogenesis: basic mechanisms behind the cardioprotective effects of fish and fish oils.
        Cell Mol Biol (Noisy-le-Grand, France). 2009; 56: 59-82
        • He K.
        • Liu K.
        • Daviglus M.L.
        • Mayer-Davis E.
        • Jenny N.S.
        • Jiang R.
        • et al.
        Intakes of long-chain n–3 polyunsaturated fatty acids and fish in relation to measurements of subclinical atherosclerosis.
        Am J Clin Nutr. 2008; 88: 1111-1118
        • Heine-Bröring R.C.
        • Brouwer I.A.
        • Proença R.V.
        • van Rooij F.J.
        • Hofman A.
        • Oudkerk M.
        • et al.
        Intake of fish and marine n− 3 fatty acids in relation to coronary calcification: the Rotterdam Study.
        Am J Clin Nutr. 2010; 91: 1317-1323
        • Shang X.
        • Sanders K.M.
        • Scott D.
        • Khan B.
        • Hodge A.
        • Khan N.
        • et al.
        Dietary α-linolenic acid and total ω-3 fatty acids are inversely associated with abdominal aortic calcification in older women, but not in older men.
        J Nutr. 2015; (jn211789)
        • Sekikawa A.
        • Kadowaki T.
        • El-Saed A.
        • Okamura T.
        • Sutton-Tyrrell K.
        • Nakamura Y.
        • et al.
        Differential association of docosahexaenoic and eicosapentaenoic acids with carotid intima-media thickness.
        Stroke. 2011; 42: 2538-2543
        • Lewis J.R.
        • Schousboe J.T.
        • Lim W.H.
        • Wong G.
        • Zhu K.
        • Lim E.M.
        • et al.
        Abdominal aortic calcification identified on lateral spine images from bone densitometers are a marker of generalized atherosclerosis in elderly women.
        Arterioscler Thromb Vasc Biol. 2016; 36: 166-173
        • Gonçalves F.B.
        • Voûte M.T.
        • Hoeks S.E.
        • Chonchol M.B.
        • Boersma E.E.
        • Stolker R.J.
        • et al.
        Calcification of the abdominal aorta as an independent predictor of cardiovascular events: a meta-analysis.
        Heart. 2012; 98: 988-994
        • Iribarren C.
        • Sidney S.
        • Sternfeld B.
        • Browner W.S.
        Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease.
        JAMA. 2000; 283: 2810-2815
        • Criqui M.H.
        • Denenberg J.O.
        • McClelland R.L.
        • Allison M.A.
        • Ix J.H.
        • Guerci A.
        • et al.
        Abdominal aortic calcium, coronary artery calcium, and cardiovascular morbidity and mortality in the Multi-Ethnic Study of Atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2014; 34: 1574-1579
        • Criqui M.H.
        • Kamineni A.
        • Allison M.A.
        • Ix J.H.
        • Carr J.J.
        • Cushman M.
        • et al.
        Risk factor differences for aortic versus coronary calcified atherosclerosis the multiethnic study of atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2010; 30: 2289-2296
        • Kuller L.H.
        • Matthews K.A.
        • Sutton-Tyrrell K.
        • Edmundowicz D.
        • Bunker C.H.
        Coronary and aortic calcification among women 8 Years after menopause and their premenopausal risk factors the healthy women study.
        Arterioscler Thromb Vasc Biol. 1999; 19: 2189-2198
        • Hoffmann U.
        • Massaro J.M.
        • D'Agostino R.B.
        • Kathiresan S.
        • Fox C.S.
        • O'Donnell C.J.
        Cardiovascular event prediction and risk reclassification by coronary, aortic, and valvular calcification in the framingham heart study.
        J Am Heart Assoc. 2016; 5e003144
        • Sekikawa A.
        • Curb J.D.
        • Ueshima H.
        • El-Saed A.
        • Kadowaki T.
        • Abbott R.D.
        • et al.
        Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men: a cross-sectional study.
        J Am Coll Cardiol. 2008; 52: 417-424
        • Fujiyoshi A.
        • Sekikawa A.
        • Shin C.
        • Masaki K.
        • Curb J.D.
        • Ohkubo T.
        • et al.
        A cross-sectional association of obesity with coronary calcium among Japanese, Koreans, Japanese Americans, and US whites.
        Eur Heart J–Cardiovasc Imaging. 2013; (jet080)
        • Choo J.
        • Ueshima H.
        • Curb J.D.
        • Shin C.
        • Evans R.W.
        • El-Saed A.
        • et al.
        Serum n− 6 fatty acids and lipoprotein subclasses in middle-aged men: the population-based cross-sectional ERA-JUMP Study.
        Am J Clin Nutr. 2010; 91: 1195-1203
        • Sekikawa A.
        • Ueshima H.
        • Kadowaki T.
        • El-Saed A.
        • Okamura T.
        • Takamiya T.
        • et al.
        Less subclinical atherosclerosis in Japanese men in Japan than in white men in the United States in the post–World War II birth cohort.
        Am J Epidemiol. 2007; 165: 617-624
        • Sekikawa A.
        • Ueshima H.
        • Zaky W.R.
        • Kadowaki T.
        • Edmundowicz D.
        • Okamura T.
        • et al.
        Much lower prevalence of coronary calcium detected by electron-beam computed tomography among men aged 40–49 in Japan than in the US, despite a less favorable profile of major risk factors.
        Int J Epidemiol. 2005; 34: 173-179
        • Agatston A.S.
        • Janowitz W.R.
        • Hildner F.J.
        • Zusmer N.R.
        • Viamonte M.
        • Detrano R.
        Quantification of coronary artery calcium using ultrafast computed tomography.
        J Am Coll Cardiol. 1990; 15: 827-832
        • Reilly M.P.
        • Wolfe M.L.
        • Localio A.R.
        • Rader D.J.
        Coronary artery calcification and cardiovascular risk factors: impact of the analytic approach.
        Atherosclerosis. 2004; 173: 69-78
        • Tobin J.
        Estimation of relationships for limited dependent variables.
        Econometrica: J Econom Soc. 1958; : 24-36
        • Erkkila A.T.
        • Matthan N.R.
        • Herrington D.M.
        • Lichtenstein A.H.
        Higher plasma docosahexaenoic acid is associated with reduced progression of coronary atherosclerosis in women with CAD.
        J Lipid Res. 2006; 47: 2814-2819
        • Mori T.A.
        • Woodman R.J.
        The independent effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans.
        Curr Opin Clin Nutr Metab Care. 2006; 9: 95-104
        • Morris M.C.
        • Sacks F.
        • Rosner B.
        Does fish oil lower blood pressure? A meta-analysis of controlled trials.
        Circulation. 1993; 88: 523-533
        • Mori T.A.
        • Bao D.Q.
        • Burke V.
        • Puddey I.B.
        • Beilin L.J.
        Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans.
        Hypertension. 1999; 34: 253
        • De Caterina R.
        • Liao J.K.
        • Libby P.
        Fatty acid modulation of endothelial activation.
        Am J Clin Nutr. 2000; 71: 213S-223S
        • Manson J.E.
        • Cook N.R.
        • Lee I.-M.
        • Christen W.
        • Bassuk S.S.
        • Mora S.
        • et al.
        Marine n−3 fatty acids and prevention of cardiovascular disease and cancer.
        N Engl J Med. 2018;
        • Lee J.E.
        • McLerran D.F.
        • Rolland B.
        • Chen Y.
        • Grant E.J.
        • Vedanthan R.
        • et al.
        Meat intake and cause-specific mortality: a pooled analysis of Asian prospective cohort studies.
        Am J Clin Nutr. 2013; 98: 1032-1041
        • Chowdhury R.
        • Warnakula S.
        • Kunutsor S.
        • Crowe F.
        • Ward H.A.
        • Johnson L.
        • et al.
        Association of dietary, circulating, and supplement fatty acids with coronary riska systematic review and meta-analysis.
        Ann Intern Med. 2014; 160: 398-406
        • Serhan C.N.
        Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.
        Am J Pathol. 2010; 177: 1576-1591