High density lipoprotein with apolipoprotein C-III is associated with carotid intima-media thickness among generally healthy individuals


      • Two HDL subspecies had significantly opposite associations with cIMT.
      • HDL that contains apoC-III was directly associated with cIMT.
      • HDL that does not contain apoC-III was inversely associated with cIMT.
      • Neither HDL cholesterol nor apoA-I had a significant association with cIMT.
      • HDL apoC-III is a promising target for atherosclerosis prevention and treatment.


      Background and aims

      About 6–7% of high density lipoprotein (HDL) has a protein called apolipoprotein (apo) C-III that regulates lipoprotein metabolism and can provoke an inflammatory response. HDL without apoC-III is inversely associated with coronary heart disease (CHD), whereas HDL with apoC-III is directly associated with CHD. We investigated how the presence of apoC-III affects the association between HDL and early stages of atherosclerosis measured as carotid intima-media thickness (cIMT).


      We examined the cross-sectional associations between the apoA-I concentrations of HDL subspecies with and without apoC-III and cIMT measured by high resolution B-mode carotid ultrasonography among 847 participants from the European multi-center Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study.


      HDL with and without apoC-III demonstrated significantly opposite associations with both cIMT indexes (p-heterogeneity of associations comparing the two subspecies was 0.002 for cIMT at common carotid artery (cIMT at CCA) and 0.006 for the maximum cIMT in any carotid segment (cIMT max)). Compared to the lowest quintile, the highest quintile of apoA-I in HDL without apoC-III was associated with 3.7% lower cIMT at CCA (p-trend = 0.01) or 7.3% lower cIMT max (p-trend = 0.003), while the highest quintile of apoA-I in HDL with apoC-III was associated with 4.4% higher cIMT at CCA (p-trend = 0.001) or 7.9% higher cIMT max (p-trend = 0.002). Total apoA-I as well as total HDL cholesterol was not associated with cIMT whereas higher levels of total apoC-III and apoC-III contained in HDL were significantly associated with higher cIMT (p-trend<0.01).


      HDL apoC-III is a promising target for atherosclerosis prevention and treatment.


      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 Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Assmann G.
        • Schulte H.
        • von Eckardstein A.
        • Huang Y.
        High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport.
        Atherosclerosis. 1996; 124: S11-S20
        • Emerging Risk Factors C.
        • Di Angelantonio E.
        • Sarwar N.
        • Perry P.
        • Kaptoge S.
        • Ray K.K.
        • et al.
        Major lipids, apolipoproteins, and risk of vascular disease.
        Jama. 2009; 302: 1993-2000
        • Gordon T.
        • Castelli W.P.
        • Hjortland M.C.
        • Kannel W.B.
        • Dawber T.R.
        High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study.
        Am J Med. 1977; 62: 707-714
        • Sharrett A.R.
        • Ballantyne C.M.
        • Coady S.A.
        • Heiss G.
        • Sorlie P.D.
        • Catellier D.
        • et al.
        Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the atherosclerosis risk in communities (ARIC) study.
        Circulation. 2001; 104: 1108-1113
        • McQueen M.J.
        • Hawken S.
        • Wang X.
        • Ounpuu S.
        • Sniderman A.
        • Probstfield J.
        • et al.
        Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study.
        Lancet. 2008; 372: 224-233
        • Zanoni P.
        • Khetarpal S.A.
        • Larach D.B.
        • Hancock-Cerutti W.F.
        • Millar J.S.
        • Cuchel M.
        • et al.
        Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
        Science. 2016; 351: 1166-1171
        • Haase C.L.
        • Tybjaerg-Hansen A.
        • Qayyum A.A.
        • Schou J.
        • Nordestgaard B.G.
        • Frikke-Schmidt R.L.C.A.T.
        HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals.
        J. Clin. Endocrinol. Metabol. 2012; 97: E248-E256
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • Stene M.C.
        • Sethi A.A.
        • Remaley A.T.
        • Schnohr P.
        • et al.
        Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.
        Jama. 2008; 299: 2524-2532
        • Voight B.F.
        • Peloso G.M.
        • Orho-Melander M.
        • Frikke-Schmidt R.
        • Barbalic M.
        • Jensen M.K.
        • et al.
        Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.
        Lancet. 2012; 380: 572-580
        • Helgadottir A.
        • Gretarsdottir S.
        • Thorleifsson G.
        • Hjartarson E.
        • Sigurdsson A.
        • Magnusdottir A.
        • et al.
        Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease.
        Nat. Genet. 2016; 48: 634-639
        • Holmes M.V.
        • Asselbergs F.W.
        • Palmer T.M.
        • Drenos F.
        • Lanktree M.B.
        • Nelson C.P.
        • et al.
        Mendelian randomization of blood lipids for coronary heart disease.
        Eur. Heart J. 2015; 36: 539-550
        • Do R.
        • Willer C.J.
        • Schmidt E.M.
        • Sengupta S.
        • Gao C.
        • Peloso G.M.
        • et al.
        Common variants associated with plasma triglycerides and risk for coronary artery disease.
        Nat. Genet. 2013; 45: 1345-1352
        • Barter P.J.
        • Caulfield M.
        • Eriksson M.
        • Grundy S.M.
        • Kastelein J.J.
        • Komajda M.
        • et al.
        Effects of torcetrapib in patients at high risk for coronary events.
        N. Engl. J. Med. 2007; 357: 2109-2122
        • Schwartz G.G.
        • Olsson A.G.
        • Abt M.
        • Ballantyne C.M.
        • Barter P.J.
        • Brumm J.
        • et al.
        Effects of dalcetrapib in patients with a recent acute coronary syndrome.
        N. Engl. J. Med. 2012; 367: 2089-2099
        • Group H.T.C.
        • Landray M.J.
        • Haynes R.
        • Hopewell J.C.
        • Parish S.
        • Aung T.
        • et al.
        Effects of extended-release niacin with laropiprant in high-risk patients.
        N. Engl. J. Med. 2014; 371: 203-212
        • Di Bartolo B.A.
        • Duong M.
        • Nicholls S.J.
        Clinical trials with cholesteryl ester transfer protein inhibitors.
        Curr. Opin. Lipidol. 2016 Dec; 27: 545-549
        • Zheng C.
        • Azcutia V.
        • Aikawa E.
        • Figueiredo J.L.
        • Croce K.
        • Sonoki H.
        • et al.
        Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion.
        Eur. Heart J. 2013; 34: 615-624
        • Mendivil C.O.
        • Zheng C.
        • Furtado J.
        • Lel J.
        • Sacks F.M.
        Metabolism of very-low-density lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins.
        Arterioscler. Thromb. Vasc. Biol. 2010; 30: 239-245
        • Zheng C.
        • Khoo C.
        • Furtado J.
        • Sacks F.M.
        Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype.
        Circulation. 2010; 121: 1722-1734
        • Qamar A.
        • Khetarpal S.A.
        • Khera A.V.
        • Qasim A.
        • Rader D.J.
        • Reilly M.P.
        Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics.
        Arterioscler. Thromb. Vasc. Biol. 2015; 35: 1880-1888
        • Talayero B.
        • Wang L.
        • Furtado J.
        • Carey V.J.
        • Bray G.A.
        • Sacks F.M.
        Obesity favors apolipoprotein E- and C-III-containing high density lipoprotein subfractions associated with risk of heart disease.
        J. Lipid Res. 2014; 55: 2167-2177
        • Jensen M.K.
        • Rimm E.B.
        • Furtado J.D.
        • Sacks F.M.
        Apolipoprotein C-III as a potential modulator of the association between HDL-cholesterol and incident coronary heart disease.
        J. Am. Heart Assoc. 2012; 1
        • Hodis H.N.
        • Mack W.J.
        • LaBree L.
        • Selzer R.H.
        • Liu C.
        • Liu C.
        • et al.
        Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial.
        Ann. Intern. Med. 1996; 124: 548-556
        • O'Leary D.H.
        • Polak J.F.
        • Kronmal R.A.
        • Savage P.J.
        • Borhani N.O.
        • Kittner S.J.
        • et al.
        Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health study collaborative research group.
        Stroke a J. Cerebr. Circ. 1996; 27: 224-231
        • O'Leary D.H.
        • Polak J.F.
        • Kronmal R.A.
        • Manolio T.A.
        • Burke G.L.
        • Wolfson Jr., S.K.
        Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular health study collaborative research group.
        N. Engl. J. Med. 1999; 340: 14-22
        • Mendivil C.O.
        • Rimm E.B.
        • Furtado J.
        • Chiuve S.E.
        • Sacks F.M.
        Low-density lipoproteins containing apolipoprotein C-III and the risk of coronary heart disease.
        Circulation. 2011; 124: 2065-2072
        • Hills S.A.
        • Balkau B.
        • Coppack S.W.
        • Dekker J.M.
        • Mari A.
        • Natali A.
        • et al.
        The EGIR-RISC STUDY (The European group for the study of insulin resistance: relationship between insulin sensitivity and cardiovascular disease risk): I. Methodology and objectives.
        Diabetologia. 2004; 47: 566-570
        • Craig C.L.
        • Marshall A.L.
        • Sjostrom M.
        • Bauman A.E.
        • Booth M.L.
        • Ainsworth B.E.
        • et al.
        International physical activity questionnaire: 12-country reliability and validity.
        Med. Sci. Sports Exerc. 2003; 35: 1381-1395
        • Rosner B.
        • Cook N.
        • Portman R.
        • Daniels S.
        • Falkner B.
        Determination of blood pressure percentiles in normal-weight children: some methodological issues.
        Am. J. Epidemiol. 2008; 167: 653-666
        • Rosner B.
        Fundamentals of Biostatistics.
        seventh ed. Brooks/Cole, Cengage Learning, Boston2011 (xvii, 859 pp)
        • Rosner B.
        Percentage points for a generalized ESD many outlier procedure.
        Technometrics. 1983; 25: 165-172
        • Calabresi L.
        • Gomaraschi M.
        • Simonelli S.
        • Bernini F.
        • Franceschini G.
        HDL and atherosclerosis: insights from inherited HDL disorders.
        Biochim. Biophys. Acta. 2015; 1851: 13-18
        • Amarenco P.
        • Labreuche J.
        • Touboul P.J.
        High-density lipoprotein-cholesterol and risk of stroke and carotid atherosclerosis: a systematic review.
        Atherosclerosis. 2008; 196: 489-496
        • Mackinnon A.D.
        • Jerrard-Dunne P.
        • Sitzer M.
        • Buehler A.
        • von Kegler S.
        • Markus H.S.
        Rates and determinants of site-specific progression of carotid artery intima-media thickness: the carotid atherosclerosis progression study.
        Stroke a J. Cerebr. Circ. 2004; 35: 2150-2154
        • Paramsothy P.
        • Knopp R.H.
        • Bertoni A.G.
        • Blumenthal R.S.
        • Wasserman B.A.
        • Tsai M.Y.
        • et al.
        Association of combinations of lipid parameters with carotid intima-media thickness and coronary artery calcium in the MESA (Multi-ethnic study of atherosclerosis).
        J. Am. Coll. Cardiol. 2010; 56: 1034-1041
        • Zhu Y.M.
        • Verma S.
        • Fung M.
        • McQueen M.J.
        • Anderson T.J.
        • Lonn E.M.
        Association of apolipoproteins B and A-1 with markers of vascular Health or cardiovascular events.
        Can. J. Cardiol. 2017; 33: 1305-1311
        • Huang F.
        • Yang Z.
        • Xu B.
        • Bi Y.
        • Xu M.
        • Xu Y.
        • et al.
        Both serum apolipoprotein B and the apolipoprotein B/apolipoprotein A-I ratio are associated with carotid intima-media thickness.
        PLoS One. 2013; 8e54628
        • Sehayek E.
        • Eisenberg S.
        Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway.
        J. Biol. Chem. 1991; 266: 18259-18267
        • Windler E.
        • Havel R.J.
        Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceride-rich lipoproteins and their remnants by the perfused rat liver.
        J. Lipid Res. 1985; 26: 556-565
        • Lee S.J.
        • Campos H.
        • Moye L.A.
        • Sacks F.M.
        LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 853-858
        • Rundek T.
        • Blanton S.H.
        • Bartels S.
        • Dong C.
        • Raval A.
        • Demmer R.T.
        • et al.
        Traditional risk factors are not major contributors to the variance in carotid intima-media thickness.
        Stroke a J. Cerebr. Circ. 2013; 44: 2101-2108
        • Santos I.S.
        • Alencar A.P.
        • Rundek T.
        • Goulart A.C.
        • Barreto S.M.
        • Pereira A.C.
        • et al.
        Low impact of traditional risk factors on carotid intima-media thickness: the ELSA-Brasil cohort.
        Arterioscler. Thromb. Vasc. Biol. 2015; 35: 2054-2059
        • Touboul P.J.
        • Vicaut E.
        • Labreuche J.
        • Belliard J.P.
        • Cohen S.
        • Kownator S.
        • et al.
        Correlation between the Framingham risk score and intima media thickness: the Paroi Arterielle et Risque Cardio-vasculaire (PARC) study.
        Atherosclerosis. 2007; 192: 363-369