HDL cholesterol, leptin and interleukin-6 predict high risk coronary anatomy assessed by CT angiography in patients with stable chest pain


      • CTA describes features of coronary plaques, as location, severity and composition.
      • An integrated CTA score defines individual coronary risk in patients with stable CAD.
      • A biohumoral model outperforms other clinical models in predicting individual risk.
      • HDL, leptin and IL6 are those metabolic/inflammatory markers linked to high risk CAD.



      Coronary computed tomography angiography (CTA) describes several features of coronary plaques, i.e. location, severity, and composition. Integrated CTA scores are able to identify individual patterns of higher risk. We sought to test whether circulating biomarkers related with metabolism and inflammation could predict high risk coronary anatomy at CTA in patients with stable chest pain.


      We evaluated a panel of 17 biomarkers in 429 patients (60.3 ± 0.4 years, 268 males) with stable chest pain who underwent coronary CTA having been enrolled in the Evaluation of Integrated Cardiac Imaging (EVINCI) study. The individual CTA risk score was calculated combining plaque extent, severity, composition, and location. The presence and distribution of non-calcified, mixed and calcified plaques were analyzed in each patient.


      After adjustment for age, sex and medical treatment, high-density lipoprotein (HDL) cholesterol, leptin, and interleukin-6 (IL-6) were independent predictors of CTA risk score at multivariate analysis (P = 0.050, 0.002, and 0.007, respectively). Integrating these biomarkers with common clinical variables, a model was developed which showed a better discriminating ability than the Framingham Risk Score and the Euro-SCORE in identifying the patients with higher CTA risk score (area under the receiver-operating characteristics curve = 0.81, 0.63 and 0.71, respectively, P < 0.001). These three biomarkers were significantly altered in patients with mixed or non-calcified plaques.


      In patients with stable chest pain, low HDL cholesterol, low leptin and high IL-6 are independent predictors of high risk coronary anatomy as defined by an integrated CTA risk score.

      Graphical abstract



      CAC (coronary artery calcium), CAD (coronary artery disease), CTA (computed tomography angiography), EVINCI (EValuation of INtegrated Cardiac Imaging), HDL (high density lipoprotein), HOMA (HOmeostatic Model Assessment), hs CRP (high sensitive C reactive protein), IL-6 (interleukin-6), LDL (low density lipoprotein), MMP (matrix metalloproteinases)
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        • Task Force Members
        2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology.
        Eur. Heart J. 2013; 34: 2949-3003
        • American College of Cardiology Foundation Appropriate Use Criteria Task Force
        ACCF/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons.
        J. Am. Coll. Cardiol. 2014; 63: 380-406
        • Skinner J.S.
        • Smeeth L.
        • Kendall J.M.
        • Adams P.C.
        • Timmis A.
        • Chest Pain Guideline Development Group
        NICE guidance. Chest pain of recent onset: assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin.
        Heart. 2010; 96: 974-978
        • Marwan M.
        • Pflederer T.
        • Schepis T.
        • Seltmann M.
        • Klinghammer L.
        • Muschiol G.
        • Ropers D.
        • Daniel W.G.
        • Achenbach S.
        Accuracy of dual-source CT to identify significant coronary artery disease in patients with uncontrolled hypertension presenting with chest pain: comparison with coronary angiography.
        Int. J. Cardiovasc. Imaging. 2012; 28: 1173-1180
        • Pavitt C.W.
        • Harron K.
        • Lindsay A.C.
        • Ray R.
        • Zielke S.
        • Gordon D.
        • Rubens M.B.
        • Padley S.P.
        • Nicol E.
        Deriving coronary artery calcium scores from CT coronary angiography: a proposed algorithm for evaluating stable chest pain.
        Int. J. Cardiovasc. Imaging. 2014 Aug; 30: 1135-1143
        • Miller J.M.
        • Rochitte C.E.
        • Dewey M.
        • Arbab-Zadeh A.
        • Niinuma H.
        • Gottlieb I.
        • Paul N.
        • Clouse M.E.
        • Shapiro E.P.
        • Hoe J.
        • Lardo A.C.
        • Bush D.E.
        • de Roos A.
        • Cox C.
        • Brinker J.
        • Lima J.A.
        Diagnostic performance of coronary angiography by 64-row CT.
        N. Engl. J. Med. 2008; 359: 2324-2336
        • Arbab-Zadeh A.
        • Miller J.M.
        • Rochitte C.E.
        • Dewey M.
        • Niinuma H.
        • Gottlieb I.
        • Paul N.
        • Clouse M.E.
        • Shapiro E.P.
        • Hoe J.
        • Lardo A.C.
        • Bush D.E.
        • de Roos A.
        • Cox C.
        • Brinker J.
        • Lima J.A.
        Diagnostic accuracy of computed tomography coronary angiography according to pre-test probability of coronary artery disease and severity of coronary arterial calcification. The CORE-64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) International Multicenter Study.
        J. Am. Coll. Cardiol. 2012; 59: 379-387
        • Budoff M.J.
        • Dowe D.
        • Jollis J.G.
        • Gitter M.
        • Sutherland J.
        • Halamert E.
        • Scherer M.
        • Bellinger R.
        • Martin A.
        • Benton R.
        • Delago A.
        • Min J.K.
        Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial.
        J. Am. Coll. Cardiol. 2008; 5: 1724-1732
        • Hadamitzky M.
        • Achenbach S.
        • Al-Mallah M.
        • Berman D.
        • et al.
        Optimized prognostic score for coronary computed tomographic angiography: results from the CONFIRM registry (COronary CT Angiography EvaluatioN for Clinical Outcomes: an InteRnational Multicenter Registry).
        J. Am. Coll. Cardiol. 2013; 62: 468-476
        • Min J.K.
        • Shaw L.J.
        • Devereux R.B.
        • Okin P.M.
        • Weinsaft J.W.
        • Russo D.J.
        • Lippolis N.J.
        • Berman D.S.
        • Callister T.Q.
        Prognostic value of multidetector coronary computed tomographic angiography for prediction of all-cause mortality.
        J. Am. Coll. Cardiol. 2007; 50: 1161-1170
        • de Graaf M.A.
        • Broersen A.
        • Ahmed W.
        • Kitslaar P.H.
        • Dijkstra J.
        • Kroft L.J.
        • Delgado V.
        • Bax J.J.
        • Reiber J.H.
        • Scholte A.J.
        Feasibility of an automated quantitative computed tomography angiography-derived risk score for risk stratification of patients with suspected coronary artery disease.
        Am. J. Cardiol. 2014; 113: 1947-1955
        • Gallino A.
        • Stuber M.
        • Crea F.
        • et al.
        “In vivo” imaging of atherosclerosis.
        Atherosclerosis. 2012; 224: 25-36
        • Libby P.
        • Ridker P.M.
        • Hansson G.K.
        Progress and challenges in translating the biology of atherosclerosis.
        Nature. 2011 May 19; 473: 317-325
        • Wilson P.W.
        • D'Agostino R.B.
        • Levy D.
        • Belanger A.M.
        • Silbershatz H.
        • Kannel W.B.
        Prediction of coronary heart disease using risk factor categories.
        Circulation. 1998; 97: 1837-1847
        • Conroy R.M.
        • Pyörälä K.
        • Fitzgerald A.P.
        • et al.
        Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project.
        Eur. Heart J. 2003; 24: 987-1003
        • Neglia D.
        • Rovai D.
        • Caselli C.
        • et al.
        Detection of significant coronary artery disease by non-invasive anatomical and functional imaging.
        Circ. Cardiovasc. Imaging. 2015 Mar; 8
        • Andreini D.
        • Pontone G.
        • Mushtaq S.
        • et al.
        A long-term prognostic value of coronary CT angiography in suspected coronary artery disease.
        J. Am. Coll. Cardiol. Imaging. 2012; 5: 690-701
        • Bamberg F.
        • Sommer W.H.
        • Hoffmann V.
        • Achenbach S.
        • Nikolaou K.
        • Conen D.
        • Reiser M.F.
        • Hoffmann U.
        • Becker C.R.
        Meta-analysis and systematic review of the long-term predictive value of assessment of coronary atherosclerosis by contrast-enhanced coronary computed tomography angiography.
        J. Am. Coll. Cardiol. 2011; 57: 2426-2436
        • Versteylen M.O.
        • Joosen I.A.
        • Kietselaer B.L.
        • Wildberger J.E.
        • Crijns H.J.
        • Hofstra L.
        Gender difference in the prognostic value of CTA?.
        J. Am. Coll. Cardiol. Imaging. 2014; 7: 529-530
        • Pen A.
        • Yam Y.
        • Chen L.
        • Dennie C.
        • McPherson R.
        • Chow B.J.
        Discordance between Framingham Risk Score and atherosclerotic plaque burden.
        Eur. Heart J. 2013; 34: 1075-1082
        • Voros S.
        • Joshi P.
        • Qian Z.
        • Rinehart S.
        • Vazquez-Figueroa J.G.
        • Anderson H.
        • Elashoff M.
        • Murrieta L.
        • Karmpaliotis D.
        • Kalynych A.
        • Brown 3rd, C.
        • Schaefer E.
        • Asztalos B.
        Apoprotein B, small-dense LDL and impaired HDL remodeling is associated with larger plaque burden and more noncalcified plaque as assessed by coronary CT angiography and intravascular ultrasound with radiofrequency backscatter: results from the ATLANTA I study.
        J. Am. Heart Assoc. 2013; 2: e000344
        • Blaha M.J.
        • Rivera J.J.
        • Budoff M.J.
        • Blankstein R.
        • Agatston A.
        • O'Leary D.H.
        • Cushman M.
        • Lakoski S.
        • Criqui M.H.
        • Szklo M.
        • Blumenthal R.S.
        • Nasir K.
        Association between obesity, high-sensitivity C-reactive protein ≥2 mg/L, and subclinical atherosclerosis: implications of JUPITER from the Multi-Ethnic Study of Atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2011; 31: 1430-1438
        • Duivenvoorden R.
        • Mani V.
        • Woodward M.
        • Kallend D.
        • Suchankova G.
        • Fuster V.
        • Rudd J.H.
        • Tawakol A.
        • Farkouh M.E.
        • Fayad Z.A.
        Relationship of serum inflammatory biomarkers with plaque inflammation assessed by FDG PET/CT: the dal-PLAQUE study.
        J. Am. Coll. Cardiol. Imaging. 2013; 6: 1087-1094
        • Tsaknis G.
        • Tsangaris I.
        • Ikonomidis I.
        • Tsantes A.
        Clinical usefulness of novel serum and imaging biomarkers in risk stratification of patients with stable angina.
        Dis. Markers. 2014; 2014: 831364
        • Otsuka K.
        • Fukuda S.
        • Tanaka A.
        • Nakanishi K.
        • Taguchi H.
        • Yoshiyama M.
        • Shimada K.
        • Yoshikawa J.
        Prognosis of vulnerable plaque on computed tomographic coronary angiography with normal myocardial perfusion image.
        Eur. Heart J. Cardiovasc. Imaging. 2014; 15: 332-340
        • 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
        • Di Angelantonio E.
        • Sarwar N.
        • Perry P.
        • Kaptoge S.
        • Ray K.K.
        • Thompson A.
        • Wood A.M.
        • Lewington S.
        • Sattar N.
        • Packard C.J.
        • Collins R.
        • Thompson S.G.
        • Danesh J.
        • Emerging Risk Factors Collaboration
        Major lipids, apolipoproteins, and risk of vascular disease.
        JAMA. 2009; 302: 1993-2000
        • Meikle P.J.
        • Wong G.
        • Tsorotes D.
        • et al.
        Plasma lipidomic analysis of stable and unstable coronary artery disease.
        Arterioscler. Thromb. Vasc. Biol. 2011; 31: 2723-2732
        • Ridker P.M.
        • MacFadyen J.
        • Libby P.
        • Glynn R.J.
        Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).
        Am. J. Cardiol. 2010; 106: 204-209
        • Söderberg S.
        • Ahrén B.
        • Jansson J.H.
        • Johnson O.
        • Hallmans G.
        • Asplund K.
        • Olsson T.
        Leptin is associated with increased risk of myocardial infarction.
        J. Intern. Med. 1999; 246: 409-418
        • Wallace A.M.
        • McMahon A.D.
        • Packard C.J.
        • Kelly A.
        • Shepherd J.
        • Gaw A.
        • Sattar N.
        Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS).
        Circulation. 2001; 104: 3052-3056
        • Piatti P.
        • Di Mario C.
        • Monti L.D.
        • Fragasso G.
        • Sgura F.
        • Caumo A.
        • Setola E.
        • Lucotti P.
        • Galluccio E.
        • Ronchi C.
        • Origgi A.
        • Zavaroni I.
        • Margonato A.
        • Colombo A.
        Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting.
        Circulation. 2003; 108: 2074-2081
        • Söderberg S.
        • Stegmayr B.
        • Stenlund H.
        • Sjöström L.G.
        • Agren A.
        • Johansson L.
        • Weinehall L.
        • Olsson T.
        Leptin, but not adiponectin, predicts stroke in males.
        J. Intern. Med. 2004; 256: 128-136
        • Sattar N.
        • Wannamethee G.
        • Sarwar N.
        • Chernova J.
        • Lawlor D.A.
        • Kelly A.
        • Wallace A.M.
        • Danesh J.
        • Whincup P.H.
        Leptin and coronary heart disease: prospective study and systematic review.
        J. Am. Coll. Cardiol. 2009; 53: 167-175
        • Banks W.A.
        • Kastin A.J.
        • Huang W.
        • Jaspan J.B.
        • Maness L.M.
        Leptin enters the brain by a saturable system independent of insulin.
        Peptides. 1996; 17: 305-311
        • Van Heek M.
        • Compton D.S.
        • France C.F.
        • Tedesco R.P.
        • Fawzi A.B.
        • Graziano M.P.
        • Sybertz E.J.
        • Strader C.D.
        • Davis Jr., H.R.
        Diet-induced obese mice develop peripheral, but not central, resistance to leptin.
        J. Clin. Invest. 1997; 99: 385-390
        • Vecchione C.
        • Maffei A.
        • Colella S.
        • Aretini A.
        • Poulet R.
        • Frati G.
        • Gentile M.T.
        • Fratta L.
        • Trimarco V.
        • Trimarco B.
        • Lembo G.
        Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway.
        Diabetes. 2002; 51: 168-173
        • Sundell J.
        Obesity and diabetes as risk factors for coronary artery disease: from the epidemiological aspect to the initial vascular mechanisms.
        Diabetes Obes. Metab. 2005; 7: 9-20
        • Yudkin J.S.
        • Eringa E.
        • Stehouwer C.D.
        “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease.
        Lancet. 2005; 365: 1817-1820
        • Harada K.
        • Amano T.
        • Uetani T.
        • Yoshida T.
        • Kato B.
        • Kato M.
        • Marui N.
        • Kumagai S.
        • Ando H.
        • Ishii H.
        • Matsubara T.
        • Murohara T.
        Association of inflammatory markers with the morphology and extent of coronary plaque as evaluated by 64-slice multidetector computed tomography in patients with stable coronary artery disease.
        Int. J. Cardiovasc. Imaging. 2013; 29: 1149-1158
        • Ikonomidis I.
        • Stamatelopoulos K.
        • Lekakis J.
        • Vamvakou G.D.
        • Kremastinos D.T.
        Inflammatory and non-invasive vascular markers: the multimarker approach for risk stratification in coronary artery disease.
        Atherosclerosis. 2008; 199: 3-11
        • Ikonomidis I.
        • Andreotti F.
        • Economou E.
        • Stefanadis C.
        • Toutouzas P.
        • Nihoyannopoulos P.
        Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin.
        Circulation. 1999; 100: 793-798
        • Jenny N.S.
        • Tracy R.P.
        • Ogg M.S.
        • Luong le A.
        • Kuller L.H.
        • Arnold A.M.
        • Sharrett A.R.
        • Humphries S.E.
        In the elderly, interleukin-6 plasma levels and the -174G>C polymorphism are associated with the development of cardiovascular disease.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 2066-2071
        • Ridker P.M.
        • Rifai N.
        • Stampfer M.J.
        • Hennekens C.H.
        Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.
        Circulation. 2000; 101: 1767-1772
        • Cesari M.
        • Penninx B.W.
        • Newman A.B.
        • Kritchevsky S.B.
        • Nicklas B.J.
        • Sutton-Tyrrell K.
        • Rubin S.M.
        • Ding J.
        • Simonsick E.M.
        • Harris T.B.
        • Pahor M.
        Inflammatory markers and onset of cardiovascular events: results from the Health ABC study.
        Circulation. 2003; 108: 2317-2322
        • Koenig W.
        • Khuseyinova N.
        • Baumert J.
        • Thorand B.
        • Loewel H.
        • Chambless L.
        • Meisinger C.
        • Schneider A.
        • Martin S.
        • Kolb H.
        • Herder C.
        Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women: results from the MONICA/KORA Augsburg case-cohort study, 1984–2002.
        Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2745-2751
        • Sukhija R.
        • Fahdi I.
        • Garza L.
        • Fink L.
        • Scott M.
        • Aude W.
        • Pacheco R.
        • Bursac Z.
        • Grant A.
        • Mehta J.L.
        Inflammatory markers, angiographic severity of coronary artery disease, and patient outcome.
        Am. J. Cardiol. 2007; 99: 879-884
        • Drakopoulou M.
        • Toutouzas K.
        • Stefanadi E.
        • Tsiamis E.
        • Tousoulis D.
        • Stefanadis C.
        Association of inflammatory markers with angiographic severity and extent of coronary artery disease.
        Atherosclerosis. 2009; 206: 335-339