Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Association of endothelial and oxidative stress with metabolic syndrome and subclinical atherosclerosis: multi-ethnic study of atherosclerosis

European Journal of Clinical Nutrition volume 65, pages 818–825 (2011)Cite this article

Subjects

Abstract

Background/Objectives:

A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress.

Subjects/Methods:

Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of 45- to 84-year-old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand factor, soluble intercellular adhesion molecule-1 (sICAM-1), CD40 ligand (CD40L), soluble thrombomodulin, E-selectin and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal–medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods.

Results:

MetS was associated with higher levels of each of the biomarkers (P<0.001, CD40L-suggestive association P=0.004), with greater IMT (P<0.001), and with greater extent of CAC in those in whom CAC was detectable (P=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (P=0.005) and thicker internal carotid IMT (P=0.002), whereas sICAM-1was significantly associated with greater prevalence of detectable CAC (P=0.001).

Conclusions:

The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  • Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte Jr M, Detrano R (1990). Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15, 827–832.

    Article  CAS  Google Scholar 

  • Aukrust P, Muller F, Ueland T, Berget T, Aaser E, Brunsvig A et al. (1999). Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 100, 614–620.

    Article  CAS  Google Scholar 

  • Bertoni AG, Wong ND, Shea S, Ma S, Liu K, Preethi S et al. (2007). Insulin resistance, metabolic syndrome, and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 30, 2951–2956.

    Article  CAS  Google Scholar 

  • Blann AD, Lip GY, McCollum CN (2002). Changes in von Willebrand factor and soluble ICAM, but not soluble VCAM, soluble E selectin or soluble thrombomodulin, reflect the natural history of the progression of atherosclerosis. Atherosclerosis 165, 389–391.

    Article  CAS  Google Scholar 

  • Carr JJ, Nelson JC, Wong ND, McNitt-Gray M, Arad Y, Jacobs Jr DR et al. (2005). Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study. Radiology 234, 35–43.

    Article  Google Scholar 

  • Constans J, Conri C (2006). Circulating markers of endothelial function in cardiovascular disease. Clin Chim Acta 368, 33–47.

    Article  CAS  Google Scholar 

  • Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA et al. (2005). Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112, 2735–2752.

    Article  Google Scholar 

  • Halcox JP, Donald AE, Ellins E, Witte DR, Shipley MJ, Brunner EJ et al. (2009). Endothelial function predicts progression of carotid intima-media thickness. Circulation 119, 1005–1012.

    Article  Google Scholar 

  • Hamburg NM, Larson MG, Vita JA, Vasan RS, Keyes MJ, Widlansky ME et al. (2008). Metabolic syndrome, insulin resistance, and brachial artery vasodilator function in Framingham Offspring participants without clinical evidence of cardiovascular disease. Am J Cardiol 101, 82–88.

    Article  CAS  Google Scholar 

  • Holvoet P (2008). Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease. Verh K Acad Geneeskd Belg 70, 193–219.

    CAS  PubMed  Google Scholar 

  • Holvoet P, Collen D (1994). Oxidized lipoproteins in atherosclerosis and thrombosis. FASEB J 8, 1279–1284.

    Article  CAS  Google Scholar 

  • Holvoet P, Harris TB, Tracy RP, Verhamme P, Newman AB, Rubin SM et al. (2003). Association of high coronary heart disease risk status with circulating oxidized LDL in the well-functioning elderly: findings from the Health, Aging, and Body Composition study. Arterioscler Thromb Vasc Biol 23, 1444–1448.

    Article  CAS  Google Scholar 

  • Holvoet P, Jenny NS, Schreiner PJ, Tracy RP, Jacobs DR (2007). The relationship between oxidized LDL and other cardiovascular risk factors and subclinical CVD in different ethnic groups: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 194, 245–252.

    Article  CAS  Google Scholar 

  • Holvoet P, Kritchevsky SB, Tracy RP, Mertens A, Rubin SM, Butler J et al. (2004). The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort. Diabetes 53, 1068–1073.

    Article  CAS  Google Scholar 

  • Holvoet P, Lee DH, Steffes M, Gross M, Jacobs Jr DR (2008). Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome. JAMA 299, 2287–2293.

    Article  CAS  Google Scholar 

  • Holvoet P, Vanhaecke J, Janssens S, Van de Werf F, Collen D (1998). Oxidized LDL and malondialdehyde-modified LDL in patients with acute coronary syndromes and stable coronary artery disease. Circulation 98, 1487–1494.

    Article  CAS  Google Scholar 

  • Jacobs M, van Greevenbroek MM, van der Kallen CJ, Ferreira I, Blaak EE, Feskens EJ et al. (2009). Low-grade inflammation can partly explain the association between the metabolic syndrome and either coronary artery disease or severity of peripheral arterial disease: the CODAM study. Eur J Clin Invest 39, 437–444.

    Article  CAS  Google Scholar 

  • Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G et al. (2000). (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85, 2402–2410.

    Article  CAS  Google Scholar 

  • Lawson C, Wolf S (2009). ICAM-1 signaling in endothelial cells. Pharmacol Rep 61, 22–32.

    Article  CAS  Google Scholar 

  • Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 28, 412–419.

    Article  CAS  Google Scholar 

  • NCBI (2011) SNP Database. Vol. 2009. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=5491 (Accessed 4 April 2011).

  • O’Leary DH, Polak JF, Wolfson Jr SK, Bond MG, Bommer W, Sheth S et al. (1991). Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. Stroke 22, 1155–1163.

    Article  Google Scholar 

  • Register TC, Burdon KP, Lenchik L, Bowden DW, Hawkins GA, Nicklas BJ et al. (2004). Variability of serum soluble intercellular adhesion molecule-1 measurements attributable to a common polymorphism. Clin Chem 50, 2185–2187.

    Article  CAS  Google Scholar 

  • Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP (2000). Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 152, 897–907.

    Article  CAS  Google Scholar 

  • Schonbeck U, Libby P (2001). CD40 signaling and plaque instability. Circ Res 89, 1092–1103.

    Article  CAS  Google Scholar 

  • Spiel AO, Gilbert JC, Jilma B (2008). von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 117, 1449–1459.

    Article  CAS  Google Scholar 

  • Tang W, Pankow JS, Carr JJ, Tracy RP, Bielinski SJ, North KE et al. (2007). Association of sICAM-1 and MCP-1 with coronary artery calcification in families enriched for coronary heart disease or hypertension: the NHLBI Family Heart Study. BMC Cardiovasc Disord 7, 30.

    Article  Google Scholar 

  • Vaidya D, Szklo M, Ding J, Tracy R, Liu K, Saad M et al. (2007). Agreement of two metabolic syndrome definitions and their association with subclinical atherosclerosis: multi-ethnic study of atherosclerosis cross sectional study. Metab Syndr Relat Disord 5, 343–352.

    Article  CAS  Google Scholar 

  • Wu KK (2003). Soluble thrombomodulin and coronary heart disease. Curr Opin Lipidol 14, 373–375.

    Article  CAS  Google Scholar 

  • Wu KK, Aleksic N, Ballantyne CM, Ahn C, Juneja H, Boerwinkle E (2003). Interaction between soluble thrombomodulin and intercellular adhesion molecule-1 in predicting risk of coronary heart disease. Circulation 107, 1729–1732.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung and Blood Institute. We thank the other investigators, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. In addition, DV was supported by UL1 RR 025005 from the National Center for Research Resources, and funding for PH was provided by the Interuniversitaire Attractiepolen Programma of the Belgian Federal Government (P06/30) and the Bijzonder Onderzoeksfonds of the Katholieke Universiteit Leuven (OT/06/56).

Author information

Authors and Affiliations

  1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D Vaidya & P Ouyang

  2. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    M Szklo

  3. Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA

    M Cushman & N S Jenny

  4. Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Leuven, Belgium

    P Holvoet

  5. Department of Radiology, Tufts University School of Medicine, Boston, MA, USA

    J Polak

  6. Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

    H Bahrami

Authors
  1. D Vaidya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Szklo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Cushman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Holvoet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Polak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Bahrami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N S Jenny
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Vaidya.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on European Journal of Clinical Nutrition website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 65, 818–825 (2011). https://doi.org/10.1038/ejcn.2011.47

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ejcn.2011.47

Keywords

This article is cited by

Search

Advanced search

Quick links