Advertisement

Soluble CD40 receptor is a biomarker of the burden of carotid artery atherosclerosis in subjects at high cardiovascular risk

      Highlights

      • The extension of atherosclerosis cannot be accurately predicted using clinical variables.
      • This holds true particularly in populations at high/very-high cardiovascular risk.
      • Several circulating proteins have been evaluated, but none proved powerful enough.
      • 19 plausible biomarkers were ranked in terms of strength and predictive power.
      • CD40R emerged as a the most powerful biomarker of carotid atherosclerosis extension.

      Abstract

      Background and aims

      The severity of the atherosclerotic burden is hardly quantifiable in subjects at high cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules have been proposed as circulating biomarkers of atherosclerosis, but none has emerged as clinically meaningful.

      Methods

      Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell migration, apoptosis and endothelial activity were measured by Proximity Extension Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes (66%) and established CV disease (50%), who underwent ultrasound assessment of carotid atherosclerosis with total plaque area quantification.

      Results

      In patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers were identified as the more closely related to atherosclerosis extension. Compared with a multivariable model including major traditional CV risk factors, the percentage gain of explained variability in total plaque area was the greatest (33%) after inclusion of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1 (15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R, PDGF was hyperbolic. In the whole study cohort, including subjects without carotid plaques, CD40R was the strongest predictor of the presence and extension of carotid atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors.

      Conclusions

      CD40R stands among an extended set of plausible atherosclerosis-related biomarkers as the most powerful predictor of carotid atherosclerosis burden in a high CV risk cohort.

      Graphical abstract

      Keywords

      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:

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

      References

      1. Cardiovascular diseases (CVDs) Fact Sheet, In, World health organization, 2017.

        • Benjamin E.J.
        • Muntner P.
        • Alonso A.
        • et al.
        Heart disease and stroke statistics—2019 update: a report from the American heart association.
        Circulation. 2019; 139: e56-e528
        • Jamthikar A.
        • Gupta D.
        • Saba L.
        • et al.
        Cardiovascular/stroke risk predictive calculators: a comparison between statistical and machine learning models.
        Cardiovasc. Diagn. Ther. 2020; 10: 919-938
        • Collins D.R.J.
        • Tompson A.C.
        • Onakpoya I.J.
        • Roberts N.
        • Ward Am Heneghan C.J.
        Global cardiovascular risk assessment in the primary prevention of cardiovascular disease in adults: systematic review of systematic reviews.
        BMJ Open. 2017; (e013650): 7
        • Song P.
        • Fang Z.
        • Wang H.
        • et al.
        Global and regional prevalence, burden, and risk factors for carotid atherosclerosis: a systematic review, meta-analysis, and modelling study.
        The Lancet Global Health. 2020; 8: e721-e729
        • Chen P.-C.
        • Jeng J.-S.
        • Hsu H.-C.
        • Su T.-C.
        • Chien K.-L.
        • Lee Y.-T.
        Carotid atherosclerosis progression and risk of cardiovascular events in a community in taiwan.
        Sci. Rep. 2016; 6: 25733
        • Yoon H.J.
        • Kim K.H.
        • Park H.
        • et al.
        Carotid plaque rather than intima-media thickness as a predictor of recurrent vascular events in patients with acute ischemic stroke.
        Cardiovasc. Ultrasound. 2017; 15: 19
        • Aono J.
        • Ikeda S.
        • Katsumata Y.
        • et al.
        Correlation between plaque vulnerability of aorta and coronary artery: an evaluation of plaque activity by direct visualization with angioscopy.
        Int. J. Cardiovasc. Imag. 2015; 31: 1107-1114
        • Vasan R.S.
        Biomarkers of cardiovascular disease.
        Circulation. 2006; 113: 2335-2362
        • Roman M.J.
        • Kizer J.R.
        • Best L.G.
        • et al.
        Vascular biomarkers in the prediction of clinical cardiovascular disease: the Strong Heart Study.
        Hypertension (Dallas, Tex. 1979; 2012: 29-35
        • Tardif J.C.
        • Heinonen T.
        • Orloff D.
        • Libby P.
        Vascular biomarkers and surrogates in cardiovascular disease.
        Circulation. 2006; 113: 2936-2942
        • MacNamara J.
        • Eapen D.J.
        • Quyyumi A.
        • Sperling L.
        Novel biomarkers for cardiovascular risk assessment: current status and future directions.
        Future Cardiol. 2015; 11: 597-613
        • Avgerinos E.D.
        • Kadoglou N.P.E.
        • Moulakakis K.G.
        • Giannakopoulos T.G.
        • Liapis C.D.
        Current role of biomarkers in carotid disease: a systematic review.
        Int. J. Stroke. 2011; 6: 337-345
        • Vaidyanathan K.
        • Gopalakrishnan S.
        Nanomedicine in the diagnosis and treatment of atherosclerosis-A systematic review.
        Cardiovasc. Haematol. Disord. - Drug Targets. 2017; 17: 119-131
      2. Libby P, Bornfeldt KE, Tall AR, Atherosclerosis: Successes, Surprises, and Future Challenges. Circ. Res. 2016; 118: 531–534.

        • Palombo C.
        • Kozakova M.
        Arterial stiffness, atherosclerosis and cardiovascular risk: pathophysiologic mechanisms and emerging clinical indications.
        Vasc. Pharmacol. 2016; 77: 1-7
        • Abbas A.
        • Aukrust P.
        • Russell D.
        • et al.
        Matrix metalloproteinase 7 is associated with symptomatic lesions and adverse events in patients with carotid atherosclerosis.
        PLoS One. 2014; 9: e84935
        • Lien L.M.
        • Hsieh Y.C.
        • Bai C.H.
        • et al.
        Association of blood active matrix metalloproteinase-3 with carotid plaque score from a community population in Taiwan.
        Atherosclerosis. 2010; 212: 595-600
        • Goncalves I.
        • Bengtsson E.
        • Colhoun H.M.
        • et al.
        Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes.
        Arterioscler. Thromb. Vasc. Biol. 2015; 35: 1723-1731
        • Shore A.C.
        • Colhoun H.M.
        • Natali A.
        • et al.
        Use of vascular assessments and novel biomarkers to predict cardiovascular events in type 2 diabetes: the SUMMIT VIP study.
        Diabetes Care. 2018; 41: 2212-2219
        • Nilsson J.
        • Volk-Jovinge S.
        • Svensson J.
        • Landou C.
        • De Faire U.
        • Hamsten A.
        Association between high levels of growth factors in plasma and progression of coronary atherosclerosis.
        J. Intern. Med. 1992; 232: 397-404
        • Kim S.
        • Graham M.J.
        • Lee R.G.
        • et al.
        Heparin-binding EGF-like growth factor (HB-EGF) antisense oligonucleotide protected against hyperlipidemia-associated atherosclerosis.
        Nutr. Metabol. Cardiovasc. Dis. 2019; 29: 306-315
        • Zeboudj L.
        • Giraud A.
        • Guyonnet L.
        • et al.
        Selective EGFR (epidermal growth factor receptor) deletion in myeloid cells limits atherosclerosis-brief report.
        Arterioscler. Thromb. Vasc. Biol. 2018; 38: 114-119
        • Garg P.K.
        • Buzkova P.
        • Wassell C.L.
        • et al.
        Association of circulating hepatocyte growth factor and risk of incident peripheral artery disease: the multi-ethnic study of atherosclerosis.
        Angiology. 2020; 71: 544-551
        • Khurana R.
        • Moons L.
        • Shafi S.
        • et al.
        Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation.
        Circulation. 2005; 111: 2828-2836
        • Matsui M.
        • Uemura S.
        • Takeda Y.
        • et al.
        Placental growth factor as a predictor of cardiovascular events in patients with CKD from the NARA-CKD study.
        J. Am. Soc. Nephrol. 2015; 26: 2871-2881
        • Sandhofer A.
        • Tatarczyk T.
        • Kirchmair R.
        • et al.
        Are plasma VEGF and its soluble receptor sFlt-1 atherogenic risk factors? Cross-sectional data from the SAPHIR study.
        Atherosclerosis. 2009; 206: 265-269
        • Paone S.
        • Baxter A.A.
        • Hulett Md Poon I.K.H.
        Endothelial cell apoptosis and the role of endothelial cell-derived extracellular vesicles in the progression of atherosclerosis.
        Cell. Mol. Life Sci. 2019; 76: 1093-1106
        • Gonçalves I.
        • Singh P.
        • Tengryd C.
        • et al.
        sTRAIL-R2 (soluble TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2) a marker of plaque cell apoptosis and cardiovascular events.
        Stroke. 2019; 50: 1989-1996
        • Elkind M.S.
        • Cheng J.
        • Boden-Albala B.
        • et al.
        Tumor necrosis factor receptor levels are associated with carotid atherosclerosis.
        Stroke. 2002; 33: 31-37
        • Mattisson I.Y.
        • Björkbacka H.
        • Wigren M.
        • et al.
        Elevated markers of death receptor-activated apoptosis are associated with increased risk for development of diabetes and cardiovascular disease.
        EBioMedicine. 2017; 26: 187-197
        • Luomala M.
        • Laaksonen R.
        • Janatuinen T.
        • et al.
        High plasma levels of CD40 are associated with low coenzyme Q and vitamin E content of low-density lipoprotein in healthy men.
        Scand. J. Clin. Lab. Invest. 2007; 67: 115-122
        • Bosmans L.A.
        • Bosch L.
        • Kusters P.J.H.
        • Lutgens E.
        • seijkens T.T.P.
        The CD40-CD40L dyad as immunotherapeutic target in cardiovascular disease.
        J Cardiovasc Transl Res. 2020; 14: 13-22
        • Venturi E.
        • Pinnola S.
        • Morizzo C.
        • et al.
        Clinical phenotype and microvascular dynamics of subjects with endothelial dysfunction as assessed by peripheral tonometry.
        Microcirculation. 2016; 23: 230-239
        • Daghem M.
        • Bing R.
        • Fayad Z.A.
        • Dweck M.R.
        Noninvasive Imaging to Assess Atherosclerotic Plaque Composition and Disease Activity: Coronary and Carotid Applications.
        JACC: Cardiovascular Imaging. 2020; 13: 1055-1068
        • Johri A.M.
        • Nambi V.
        • Naqvi T.Z.
        • et al.
        Recommendations for the assessment of carotid arterial plaque by ultrasound for the characterization of atherosclerosis and evaluation of cardiovascular risk: from the American society of echocardiography.
        J. Am. Soc. Echocardiogr. 2020; 33: 917-933
        • Thapar A.
        • Jenkins I.H.
        • Mehta A Davies A.H.
        Diagnosis and management of carotid atherosclerosis. BMJ.
        Br. Med. J. 2013; 346: f1485
        • Wendelhag I.
        • Liang Q.
        • Gustavsson T.
        • Wikstrand J.
        A new automated computerized analyzing system simplifies readings and reduces the variability in ultrasound measurement of intima-media thickness.
        Stroke. 1997; 28: 2195-2200
        • Spence J.D.
        Ultrasound measurement of carotid plaque as a surrogate outcome for coronary artery disease.
        Am. J. Cardiol. 2002; 89: 10-15
        • Tomiyama H.
        • Yamashina A.
        Ankle-brachial pressure Index and pulse wave velocity in cardiovascular risk assessment.
        in: Vasan R.S. Sawyer D.B. Encyclopedia of Cardiovascular Research and Medicine. Elsevier, Oxford2018: 111-122
        • Libby P.
        • Buring J.E.
        • Badimon L.
        • et al.
        Atherosclerosis. Nature Reviews Disease Primers. 2019; 5: 56
        • West N.E.J.
        • Corrigan J.P.
        • Owen R.H.G.
        • et al.
        Percutaneous sampling of local biomolecule gradients across coronary artery atherosclerotic plaques.
        JACC Basic Transl Sci. 2017; 2: 646-654
        • Inaba Y.
        • Chen J.A.
        • Bergmann S.R.
        Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis.
        Atherosclerosis. 2012; 220: 128-133
        • Wickham H.
        ggplot2: Elegant Graphics for Data Analysis.
        2016
        • Wood S.N.
        Generalized Additive Models: an Introduction with R.
        second ed. CRC Press., 2017
        • Wilke C.O.
        Cowplot: Streamlined Plot Theme and Plot Annotations for 'ggplot2'.
        2020
      3. Nesti L, Mengozzi A, Natali A. Statins, LDL Cholesterol Control, Cardiovascular Disease Prevention, and Atherosclerosis Progression: A clinical perspective. Am. J. Cardiovasc. Drugs 2020; 20: 405–412.

        • Mulhaupt F.
        • Matter C.M.
        • Kwak B.R.
        • et al.
        Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells.
        Cardiovasc. Res. 2003; 59: 755-766
        • Belhassena I.
        • Nouari W.
        • Messaoud A.
        • et al.
        Aspirin enhances regulatory functional activities of monocytes and downregulates CD16 and CD40 expression in myocardial infarction autoinflammatory disease.
        Int. Immunopharm. 2020; 83: 106349
        • Lutgens E.
        • Lievens D.
        • Beckers L.
        • et al.
        Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile.
        J. Exp. Med. 2010; 207: 391-404
        • Shami A.
        • Edsfeldt A.
        • Shore A.C.
        • et al.
        CD40 levels in plasma are associated with cardiovascular disease and in carotid plaques with a vulnerable plaque phenotype and remodelling.
        Eur. Heart J. 2020; : 41
        • Jiao M.
        • Li J.
        • Zhang Q.
        • et al.
        Identification of four potential biomarkers associated with coronary artery disease in non-diabetic patients by gene Co-expression network analysis.
        Front. Genet. 2020; : 11
        • Bruemmer D.
        • Riggers U.
        • Holzmeister J.
        • et al.
        Expression of CD40 in vascular smooth muscle cells and macrophages is associated with early development of human atherosclerotic lesions.
        Am. J. Cardiol. 2001; 87: 21-27
        • Sultan C.S.
        • Weitnauer M.
        • Turinsky M.
        • et al.
        Functional association of a CD40 gene single-nucleotide polymorphism with the pathogenesis of coronary heart disease.
        Cardiovasc. Res. 2019; 116: 1214-1225
        • Tone M.
        • Tone Y.
        • Fairchild P.J.
        • Wykes M.
        • Waldmann H.
        Regulation of CD40 function by its isoforms generated through alternative splicing.
        Proc. Natl. Acad. Sci. Unit. States Am. 2001; 98: 1751-1756
        • Pereira-da-Silva T.
        • Ferreira V.
        • Castelo A.
        • et al.
        Soluble CD40 ligand expression in stable atherosclerosis: a systematic review and meta-analysis.
        Atherosclerosis. 2021; 319: 86-100
        • Schönbeck U.
        • Libby P.
        CD40 signaling and plaque instability.
        Circ. Res. 2001; 89: 1092-1103
        • Blake G.J.
        • Ostfeld R.J.
        • Yucel E.K.
        • et al.
        Soluble CD40 ligand levels indicate lipid accumulation in carotid atheroma: an in vivo study with high-resolution MRI.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: e11-14
        • Wang J.H.
        • Zhang Y.W.
        • Zhang P.
        • et al.
        CD40 ligand as a potential biomarker for atherosclerotic instability.
        Neurol. Res. 2013; 35: 693-700
        • Vaidya D.
        • Szklo M.
        • Cushman M.
        • et al.
        Association of endothelial and oxidative stress with metabolic syndrome and subclinical atherosclerosis: multi-ethnic study of atherosclerosis.
        Eur. J. Clin. Nutr. 2011; 65: 818-825
        • Visseren F.L.J.
        • Mach F.
        • Smulders Y.M.
        • et al.
        ESC Guidelines on cardiovascular disease prevention in clinical practice.
        Eur. Heart J. 2021; 2021: 3227-3337