Research Article| Volume 283, P1-6, April 2019

Download started.


Decrease in oxidized high-density lipoprotein is associated with slowed progression of coronary artery calcification: Subanalysis of a prospective multicenter study


      • This study evaluated the role of oxidized HDL in the development of coronary artery calcification.
      • The decrease in oxidized HDL after statin treatment was associated with attenuation of CAC progression.
      • The findings in this study indicate that oxidized HDL may serve as a target for preventing atherosclerosis.


      Background and aims

      Oxidized high-density lipoprotein (oxHDL) is characterized by reduced anti-inflammatory properties compared with HDL. However, the role of oxHDL in the pathogenesis of coronary artery calcification (CAC), a marker of subclinical atherosclerosis, remains unclear. We prospectively investigated the association between the change in oxHDL and progression of CAC in a substudy of a multicenter study.


      In the principal study, patients with a CAC score of 1–999 were treated with pitavastatin with/without eicosapentaenoic acid. Measurement of CAC with multidetector-row computed tomography and a blood test were performed at baseline and at the 1-year follow-up. In the principal study, the increase in CAC did not differ among treatment groups. In this substudy, patients were divided into two groups: CAC progression (change in Agatston score of >0) and no CAC progression.


      In total, 140 patients were analyzed. The oxHDL level significantly decreased from 167 (132–246) at baseline to 122 (103–149) after treatment (median [25th–75th percentile], U/ml) (p < 0.001). The annual change in CAC was significantly positively associated with changes in oxHDL (r = 0.17, p = 0.04), triglycerides (r = 0.17, p = 0.04), and high-sensitivity C-reactive protein (r = 0.22, p = 0.01) but was not associated with changes in low-density lipoprotein cholesterol or HDL-cholesterol. Multiple logistic analysis demonstrated that the decrease in oxHDL per 10 U/ml was independently associated with CAC progression (odds ratio, 0.95; 95% confidence interval, 0.90–0.99; p = 0.04).


      The decrease in oxHDL is associated with the attenuation of CAC progression, suggesting that oxHDL is a potential target for atherosclerosis prevention.

      Graphical abstract


      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


        • Osawa K.
        • Nakanishi R.
        • Budoff M.
        Coronary artery calcification.
        Glob Heart. 2016; 11: 287-293
        • Greenland P.
        • LaBree L.
        • Azen S.P.
        • Doherty T.M.
        • Detrano R.C.
        Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals.
        J. Am. Med. Assoc. 2004; 291: 210-215
        • Radford N.B.
        • DeFina L.F.
        • Barlow C.E.
        • Lakoski S.G.
        • Leonard D.
        • et al.
        Progression of CAC score and risk of incident CVD.
        JACC. Cardiovascular imaging. 2016; 9: 1420-1429
        • Miyoshi T.
        • Kohno K.
        • Asonuma H.
        • Sakuragi S.
        • Nakahama M.
        • et al.
        Effect of intensive and standard pitavastatin treatment with or without eicosapentaenoic acid on progression of coronary artery calcification over 12 Months- prospective multicenter study.
        Circ. J. : OffC.J. Jpn.Circ. Soc. 2018; 82: 532-540
        • Stone N.J.
        • Robinson J.G.
        • Lichtenstein A.H.
        • Bairey Merz C.N.
        • Blum C.B.
        • et al.
        ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults.
        J. Am. Coll. Cardiol. 2013; 2014: 2889-2934
        • Boden W.E.
        • Probstfield J.L.
        • Anderson T.
        • Chaitman B.R.
        • Desvignes-Nickens P.
        • et al.
        Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
        N. Engl. J. Med. 2011; 365: 2255-2267
        • Schwartz G.G.
        • Olsson A.G.
        • Abt M.
        • Ballantyne C.M.
        • Barter P.J.
        • et al.
        Effects of dalcetrapib in patients with a recent acute coronary syndrome.
        N. Engl. J. Med. 2012; 367: 2089-2099
        • Barter P.J.
        • Caulfield M.
        • Eriksson M.
        • Grundy S.M.
        • Kastelein J.J.
        • et al.
        Effects of torcetrapib in patients at high risk for coronary events.
        N. Engl. J. Med. 2007; 357: 2109-2122
        • Navab M.
        • Reddy S.T.
        • Van Lenten B.J.
        • Fogelman A.M.
        HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms.
        Nat. Rev. Cardiol. 2011; 8: 222-232
        • Khera A.V.
        • Cuchel M.
        • de la Llera-Moya M.
        • Rodrigues A.
        • Burke M.F.
        • et al.
        Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.
        N. Engl. J. Med. 2011; 364: 127-135
        • Rohatgi A.
        • Khera A.
        • Berry J.D.
        • Givens E.G.
        • Ayers C.R.
        • et al.
        HDL cholesterol efflux capacity and incident cardiovascular events.
        N. Engl. J. Med. 2014; 371: 2383-2393
        • Ueda M.
        • Hayase Y.
        • Mashiba S.
        Establishment and evaluation of 2 monoclonal antibodies against oxidized apolipoprotein A-I (apoA-I) and its application to determine blood oxidized apoA-I levels.
        Clin. Chim. Acta. 2007; 378: 105-111
        • Honda H.
        • Ueda M.
        • Kojima S.
        • Mashiba S.
        • Suzuki H.
        • et al.
        Oxidized high-density lipoprotein is associated with protein-energy wasting in maintenance hemodialysis patients.
        Clin. J. Am. Soc. Nephrol. 2010; 5: 1021-1028
        • Honda H.
        • Ueda M.
        • Kojima S.
        • Mashiba S.
        • Michihata T.
        • et al.
        Oxidized high-density lipoprotein as a risk factor for cardiovascular events in prevalent hemodialysis patients.
        Atherosclerosis. 2012; 220: 493-501
        • Agatston A.S.
        • Janowitz W.R.
        • Hildner F.J.
        • Zusmer N.R.
        • Viamonte Jr., M.
        • et al.
        Quantification of coronary artery calcium using ultrafast computed tomography.
        J. Am. Coll. Cardiol. 1990; 15: 827-832
        • Aslan M.
        • Nazligul Y.
        • Horoz M.
        • Bolukbas C.
        • Bolukbas F.F.
        • et al.
        Serum paraoxonase-1 activity in Helicobacter pylori infected subjects.
        Atherosclerosis. 2008; 196: 270-274
        • Budoff M.J.
        • Hokanson J.E.
        • Nasir K.
        • Shaw L.J.
        • Kinney G.L.
        • et al.
        Progression of coronary artery calcium predicts all-cause mortality.
        JACC Cardiovasc Imaging. 2010; 3: 1229-1236
        • Raggi P.
        • Cooil B.
        • Ratti C.
        • Callister T.Q.
        • Budoff M.
        Progression of coronary artery calcium and occurrence of myocardial infarction in patients with and without diabetes mellitus.
        Hypertension. 2005; 46: 238-243
        • Nakanishi R.
        • Ceponiene I.
        • Osawa K.
        • Luo Y.
        • Kanisawa M.
        • et al.
        Plaque progression assessed by a novel semi-automated quantitative plaque software on coronary computed tomography angiography between diabetes and non-diabetes patients: a propensity-score matching study.
        Atherosclerosis. 2016; 255: 73-79
        • Getz G.S.
        • Reardon C.A.
        Paraoxonase, a cardioprotective enzyme: continuing issues.
        Curr. Opin. Lipidol. 2004; 15: 261-267
        • Wheeler J.G.
        • Keavney B.D.
        • Watkins H.
        • Collins R.
        • Danesh J.
        Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies.
        Lancet. 2004; 363: 689-695
        • Kresanov P.
        • Vasankari T.
        • Ahotupa M.
        • Kaikkonen J.
        • Hutri-Kahonen N.
        • et al.
        Paraoxonase-1 and oxidized lipoprotein lipids. The Cardiovascular Risk in Young Finns study.
        Atherosclerosis. 2015; 241: 502-506
        • Berrougui H.
        • Loued S.
        • Khalil A.
        Purified human paraoxonase-1 interacts with plasma membrane lipid rafts and mediates cholesterol efflux from macrophages.
        Free Radic. Biol. Med. 2012; 52: 1372-1381
        • Ahotupa M.
        Oxidized lipoprotein lipids and atherosclerosis.
        Free Radic. Res. 2017; 51: 439-447
        • Nofer J.R.
        • Walter M.
        • Kehrel B.
        • Wierwille S.
        • Tepel M.
        • et al.
        HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinositide-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate.
        Arterioscler. Thromb. Vasc. Biol. 1998; 18: 861-869
        • Uittenbogaard A.
        • Shaul P.W.
        • Yuhanna I.S.
        • Blair A.
        • Smart E.J.
        High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae.
        J. Biol. Chem. 2000; 275: 11278-11283
        • Sharma N.
        • Desigan B.
        • Ghosh S.
        • Sanyal S.N.
        • Ganguly N.K.
        • et al.
        The role of oxidized HDL in monocyte/macrophage functions in the pathogenesis of atherosclerosis in Rhesus monkeys.
        Scand. J. Clin. Lab. Invest. 1999; 59: 215-225
        • Nakagomi A.
        • Shibui T.
        • Kohashi K.
        • Kosugi M.
        • Kusama Y.
        • et al.
        Differential effects of atorvastatin and pitavastatin on inflammation, insulin resistance, and the carotid intima-media thickness in patients with dyslipidemia.
        J. Atherosclerosis Thromb. 2015; 22: 1158-1171
        • Kei A.
        • Tellis C.
        • Liberopoulos E.
        • Tselepis A.
        • Elisaf M.
        Effect of switch to the highest dose of rosuvastatin versus add-on-statin fenofibrate versus add-on-statin nicotinic acid/laropiprant on oxidative stress markers in patients with mixed dyslipidemia.
        Cardiovasc Ther. 2014; 32: 139-146
        • Takaki A.
        • Umemoto S.
        • Ono K.
        • Seki K.
        • Ryoke T.
        • et al.
        Add-on therapy of EPA reduces oxidative stress and inhibits the progression of aortic stiffness in patients with coronary artery disease and statin therapy: a randomized controlled study.
        J. Atherosclerosis Thromb. 2011; 18: 857-866