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Horm Metab Res 2005; 37: 49-55
DOI: 10.1055/s-2005-861363
Review
© Georg Thieme Verlag KG Stuttgart · New York

Endothelial Dysfunction, Cellular Adhesion Molecules and the Metabolic Syndrome

M.  T.  Schram1 , C.  D.  A.  Stehouwer2
  • 1 Department of Internal Medicine, Erasmus Medical Center, Rotterdam
  • 2 Department of Internal Medicine, University Hospital Maastricht, The Netherlands
Further Information

Publication History

Received 14 October 2004

Accepted after Revision 10 February 2005

Publication Date:
25 May 2005 (online)

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Abstract

Over the last two decades, it has become evident that the endothelium is more than an inert, single-cell lining covering the internal surface of blood vessels. Normally, the endothelium actively decreases vascular tone, maintains vascular permeability within narrow bounds, inhibits platelet adhesion and aggregation, limits activation of the coagulation system, and stimulates fibrinolysis. Endothelium dysfunction can be considered present when its functions, either in the basal state or after stimulation, are altered in a way that is inappropriate to the preservation of organ function. Endothelial dysfunction has been associated to many cardiovascular risk factors including diabetes, hypertension and hypercholesterolemia. In addition, endothelial dysfunction may play a crucial role in the development and progression of atherosclerosis. This review will give a brief overview of the different methods to assess endothelial function, and then will focus on the current knowledge on soluble cellular adhesion molecules in relation to the metabolic syndrome and type 2 diabetes.

Key words

Type 2 diabetes - Cellular adhesion molecules - Endothelium - Metabolic syndrome - Cardiovascular disease

References

  • 1 Ludmer P L, Selwyn A P, Shook T L, Wayne R R, Mudge G H, Alexander R W, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.  N Engl J Med. 1986;  315 1046-1051
    CrossrefPubMedGoogle Scholar
  • 2 Celermajer D S, Sorensen K E, Gooch V M, Spiegelhalter D J, Miller O I, Sullivan I D, Lloyd J K, Deanfield J E. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.  Lancet.. 1992;  340 1111-1115
    CrossrefPubMedGoogle Scholar
  • 3 Corretti M C, Anderson T J, Benjamin E J, Celermajer D, Charbonneau F, Creager M A, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.  J Am Coll Cardiol.. 2002;  39 257-265
    PubMedGoogle Scholar
  • 4 Ross R. Atherosclerosis - an inflammatory disease.  N Engl J Med.. 1999;  340 115-126
    CrossrefPubMedGoogle Scholar
  • 5 Wagers A J, Lowe J B, Kansas G S. An important role for the alpha 1,3 fucosyltransferase, FucT-VII, in leukocyte adhesion to E-selectin.  Blood.. 1996;  88 2125-2132
    PubMedGoogle Scholar
  • 6 Leeuwenberg J F, Smeets E F, Neefjes J J, Shaffer M A, Cinek T, Jeunhomme T M, Ahern T J, Buurman W A. E-selectin and intercellular adhesion molecule-1 are released by activated human endothelial cells in vitro.  Immunology.. 1992;  77 543-549
    PubMedGoogle Scholar
  • 7 Schmidt A M, Hori O, Chen J X, Li J F, Crandall J, Zhang J, Cao R, Yan S D, Brett J, Stern D. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM- 1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes.  J Clin Invest.. 1995;  96 1395-1403
    CrossrefPubMedGoogle Scholar
  • 8 Blann A D, Tse W, Maxwell S J, Waite M A. Increased levels of the soluble adhesion molecule E-selectin in essential hypertension.  J Hypertens.. 1994;  12 925-928
    PubMedGoogle Scholar
  • 9 De Caterina R, Ghiadoni L, Taddei S, Virdis A, Almerigogna F, Basta G, Lazzerini G, Bernini W, Salvetti A. Soluble E-selectin in essential hypertension: a correlate of vascular structural changes.  Am J Hypertens.. 2001;  14 259-266
    CrossrefPubMedGoogle Scholar
  • 10 Hlubocka Z, Umnerova V, Heller S, Peleska J, Jindra A, Jachymova M, Kvasnicka J, Horky K, Aschermann M. Circulating intercellular cell adhesion molecule-1, endothelin-1 and von Willebrand factor-markers of endothelial dysfunction in uncomplicated essential hypertension: the effect of treatment with ACE inhibitors.  J Hum Hypertens. 2002;  16 557-562
    CrossrefPubMedGoogle Scholar
  • 11 DeSouza C A, Dengel D R, Macko R F, Cox K, Seals D R. Elevated levels of circulating cell adhesion molecules in uncomplicated essential hypertension.  Am J Hypertens. 1997;  10 1335-1341
    PubMedGoogle Scholar
  • 12 Preston R A, Ledford M, Materson B J, Baltodano N M, Memon A, Alonso A. Effects of severe, uncontrolled hypertension on endothelial activation: soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and von Willebrand factor.  J Hypertens. 2002;  20 871-877
    CrossrefPubMedGoogle Scholar
  • 13 Cottone S, Mule G, Amato F, Riccobene R, Vadala A, Lorito M C, Raspanti F, Cerasola G. Amplified biochemical activation of endothelial function in hypertension associated with moderate to severe renal failure.  J Nephrol. 2002;  15 643-648
    PubMedGoogle Scholar
  • 14 Buemi M, Allegra A, Aloisi C, Corica F, Alonci A, Ruello A, Montalto G, Frisina N. Cold pressor test raises serum concentrations of ICAM-1, VCAM-1, and E-selectin in normotensive and hypertensive patients.  Hypertension. 1997;  30 845-847
    PubMedGoogle Scholar
  • 15 Ferri C, Desideri G, Valenti M, Bellini C, Pasin M, Santucci A, De Mattia G. Early upregulation of endothelial adhesion molecules in obese hypertensive men.  Hypertension. 1999;  34 568-573
    PubMedGoogle Scholar
  • 16 Hwang S J, Ballantyne C M, Sharrett A R, Smith L C, Davis C E, Gotto A M Jr, Boerwinkle E. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study.  Circulation. 1997;  96 4219-4225
    PubMedGoogle Scholar
  • 17 Rohde L E, Hennekens C H, Ridker P M. Cross-sectional study of soluble intercellular adhesion molecule-1 and cardiovascular risk factors in apparently healthy men.  Arterioscler Thromb Vasc Biol. 1999;  19 1595-1599
    CrossrefPubMedGoogle Scholar
  • 18 Kuroda Y T, Komamura K, Tatsumi R, Mori K, Yoneda K, Katayama Y, Shigemoto S, Miyatake K, Hanafusa T. Vascular cell adhesion molecule-1 as a biochemical marker of left ventricular mass in the patients with hypertension.  Am J Hypertens. 2001;  14 868-872
    CrossrefPubMedGoogle Scholar
  • 19 Ferri C, Bellini C, Desideri G, Giuliani E, De Siati L, Cicogna S, Santucci A. Clustering of endothelial markers of vascular damage in human salt-sensitive hypertension: influence of dietary sodium load and depletion.  Hypertension. 1998;  32 862-868
    PubMedGoogle Scholar
  • 20 Ito H, Ohshima A, Inoue M, Ohto N, Nakasuga K, Kaji Y, Maruyama T, Nishioka K. Weight reduction decreases soluble cellular adhesion molecules in obese women.  Clin Exp Pharmacol Physiol. 2002;  29 399-404
    CrossrefPubMedGoogle Scholar
  • 21 Weyer C, Yudkin J S, Stehouwer C D, Schalkwijk C G, Pratley R E, Tataranni P A. Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians.  Atherosclerosis. 2002;  161 233-242
    CrossrefPubMedGoogle Scholar
  • 22 Matsumoto K, Sera Y, Abe Y, Tominaga T, Horikami K, Hirao K, Ueki Y, Miyake S. High serum concentrations of soluble E-selectin correlate with obesity but not fat distribution in patients with type 2 diabetes mellitus.  Metabolism. 2002;  51 932-934
    CrossrefPubMedGoogle Scholar
  • 23 Krakoff J, Funahashi T, Stehouwer C D, Schalkwijk C G, Tanaka S, Matsuzawa Y, Kobes S, Tataranni P A, Hanson R L, Knowler W C, Lindsay R S. Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian.  Diabetes Care. 2003;  26 1745-1751
    CrossrefPubMedGoogle Scholar
  • 24 Straczkowski M, Lewczuk P, Dzienis-Straczkowska S, Kowalska I, Stepien A, Kinalska I. Elevated soluble intercellular adhesion molecule-1 levels in obesity: relationship to insulin resistance and tumor necrosis factor-alpha system activity.  Metabolism. 2002;  51 75-78
    CrossrefPubMedGoogle Scholar
  • 25 Porreca E, di Febbo C, Fusco L, Moretta V, di Nisio M, Cuccurullo F. Soluble thrombomodulin and vascular adhesion molecule-1 are associated to leptin plasma levels in obese women.  Atherosclerosis. 2004;  172 175-180
    CrossrefPubMedGoogle Scholar
  • 26 Escobar-Morreale H F, Villuendas G, Botella-Carretero J I, Sancho J, San Millan J L. Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women.  Diabetologia. 2003;  46 625-633
    PubMedGoogle Scholar
  • 27 Pontiroli A E, Pizzocri P, Koprivec D, Vedani P, Marchi M, Arcelloni C, Paroni R, Esposito K, Giugliano D. Body weight and glucose metabolism have a different effect on circulating levels of ICAM-1, E-selectin, and endothelin-1 in humans.  Eur J Endocrinol. 2004;  150 195-200
    CrossrefPubMedGoogle Scholar
  • 28 Leinonen E, Hurt-Camejo E, Wiklund O, Hulten L M, Hiukka A, Taskinen M R. Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes.  Atherosclerosis. 2003;  166 387-394
    CrossrefPubMedGoogle Scholar
  • 29 Bagg W, Ferri C, Desideri G, Gamble G, Ockelford P, Braatvedt G D. The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes.  J Clin Endocrinol Metab. 2001;  86 5491-5497
    CrossrefPubMedGoogle Scholar
  • 30 Report of a WHO Consultation .In: Alwan A, King H (eds) Definition, Diagnosis and Classification of Diabetes Mellitus. Geneva; World Health Organization, Department of Noncommunicable Disease Surveillance 1999: 1-59
    Google Scholar
  • 31 Balkau B, Charles M A, Drivsholm T, Borch-Johnsen K, Wareham N, Yudkin J S, Morris R, Zavaroni I, van Dam R, Feskins E, Gabriel R, Diet M, Nilsson P, Hedblad B. Frequency of the WHO metabolic syndrome in European cohorts, and an alternative definition of an insulin resistance syndrome.  Diabetes Metab. 2002;  28 364-376
    PubMedGoogle Scholar
  • 32 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) . Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).  JAMA. 2001;  285 2486-2497
    CrossrefPubMedGoogle Scholar
  • 33 Hackman A, Abe Y, Insull W Jr, Pownall H, Smith L, Dunn K, Gotto A M Jr, Ballantyne C M. Levels of soluble cell adhesion molecules in patients with dyslipidemia.  Circulation. 1996;  93 1334-1338
    PubMedGoogle Scholar
  • 34 Morisaki N, Saito I, Tamura K, Tashiro J, Masuda M, Kanzaki T, Watanabe S, Masuda Y, Saito Y. New indices of ischemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischemic heart disease.  Atherosclerosis. 1997;  131 43-48
    CrossrefPubMedGoogle Scholar
  • 35 Blann A D, Seigneur M, Steiner M, Miller J P, McCollum C N. Circulating ICAM-1 and VCAM-1 in peripheral artery disease and hypercholesterolaemia: relationship to the location of atherosclerotic disease, smoking, and in the prediction of adverse events.  Thromb Haemost. 1998;  79 1080-1085
    PubMedGoogle Scholar
  • 36 Nawawi H, Osman N S, Annuar R, Khalid B A, Yusoff K. Soluble intercellular adhesion molecule-1 and interleukin-6 levels reflect endothelial dysfunction in patients with primary hypercholesterolaemia treated with atorvastatin.  Atherosclerosis. 2003;  169 283-291
    CrossrefPubMedGoogle Scholar
  • 37 Kvasnicka T, Kvasnicka J, Ceska R, Vrablik M. Increase of inflammatory state in overweight adults with combined hyperlipidemia.  Nutr Metab Cardiovasc Dis. 2003;  13 227-231
    PubMedGoogle Scholar
  • 38 Kvasnicka T, Kvasnicka J, Ceska R, Grauova B, Vrablik M. Increasing plasma levels of soluble cell adhesion molecules (sE-Selectin, sP-Selectin and sICAM-1) in overweight adults with combined hyperlipidemia.  Sb Lek. 2001;  102 473-477
    PubMedGoogle Scholar
  • 39 Blann A D, Davis A, Miller J P, McCollum C N. Von Willebrand factor and soluble E-selectin in hyperlipidaemia: relationship to lipids and vascular disease.  Am J Hematol. 1997;  55 15-23
    CrossrefPubMedGoogle Scholar
  • 40 Abe Y, El Masri B, Kimball K T, Pownall H, Reilly C F, Osmundsen K, Smith C W, Ballantyne C M. Soluble cell adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion.  Arterioscler Thromb Vasc Biol. 1998;  18 723-731
    PubMedGoogle Scholar
  • 41 Sampietro T, Tuoni M, Ferdeghini M, Ciardi A, Marraccini P, Prontera C, Sassi G, Taddei M, Bionda A. Plasma cholesterol regulates soluble cell adhesion molecule expression in familial hypercholesterolemia.  Circulation. 1997;  96 1381-1385
    PubMedGoogle Scholar
  • 42 Paiker J E, Raal F J, Veller M, von Arb M, Chetty N, Naran N H. Cell adhesion molecules - can they be used to predict coronary artery disease in patients with familial hypercholesterolaemia?.  Clin Chim Acta. 2000;  293 105-113
    CrossrefPubMedGoogle Scholar
  • 43 Calabresi L, Gomaraschi M, Villa B, Omoboni L, Dmitrieff C, Franceschini G. Elevated soluble cellular adhesion molecules in subjects with low HDL-cholesterol.  Arterioscler Thromb Vasc Biol. 2002;  22 656-661
    PubMedGoogle Scholar
  • 44 Chen N G, Holmes M, Reaven G M. Relationship between insulin resistance, soluble adhesion molecules, and mononuclear cell binding in healthy volunteers.  J Clin Endocrinol Metab. 1999;  84 3485-3489
    CrossrefPubMedGoogle Scholar
  • 45 Chen N G, Azhar S, Abbasi F, Carantoni M, Reaven G M. The relationship between plasma glucose and insulin responses to oral glucose, LDL oxidation, and soluble intercellular adhesion molecule-1 in healthy volunteers.  Atherosclerosis. 2000;  152 203-208
    CrossrefPubMedGoogle Scholar
  • 46 Hak A E, Pols H A, Stehouwer C D, Meijer J, Kiliaan A J, Hofman A, Breteler M M, Witteman J C. Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study.  J Clin Endocrinol Metab. 2001;  86 4398-4405
    CrossrefPubMedGoogle Scholar
  • 47 Matsumoto K, Miyake S, Yano M, Ueki Y, Tominaga Y. High serum concentrations of soluble E-selectin in patients with impaired glucose tolerance with hyperinsulinemia.  Atherosclerosis. 2000;  152 415-420
    CrossrefPubMedGoogle Scholar
  • 48 Jager A, Van Hinsbergh V W, Kostense P J, Emeis J J, Nijpels G, Dekker J M, Heine R J, Bouter L M, Stehouwer C D. Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study.  Diabetes. 2000;  49 485-491
    PubMedGoogle Scholar
  • 49 Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna R C, Muggeo M. Metabolic syndrome: epidemiology and more extensive phenotypic description. Cross-sectional data from the Bruneck Study.  Int J Obes Relat Metab Disord. 2003;  27 1283-1289
    CrossrefPubMedGoogle Scholar
  • 50 Bluher M, Unger R, Rassoul F, Richter V, Paschke R. Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes.  Diabetologia. 2002;  45 210-216
    CrossrefPubMedGoogle Scholar
  • 51 Caballero A E, Arora S, Saouaf R, Lim S C, Smakowski P, Park J Y, King G L, LoGerfo F W, Horton E S, Veves A. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.  Diabetes. 1999;  48 1856-1862
    CrossrefPubMedGoogle Scholar
  • 52 Targher G, Bonadonna R C, Alberiche M, Zenere M B, Muggeo M, Bonora E. Relation between soluble adhesion molecules and insulin sensitivity in type 2 diabetic individuals: role of adipose tissue.  Diabetes Care. 2001;  24 1961-1966
    CrossrefPubMedGoogle Scholar
  • 53 Matsumoto K, Sera Y, Abe Y, Ueki Y, Miyake S. Serum concentrations of soluble vascular cell adhesion molecule-1 and E-selectin are elevated in insulin-resistant patients with type 2 diabetes.  Diabetes Care. 2001;  24 1697-1698
    PubMedGoogle Scholar
  • 54 Steiner M, Reinhardt K M, Krammer B, Ernst B, Blann A D. Increased levels of soluble adhesion molecules in type 2 (non-insulin dependent) diabetes mellitus are independent of glycaemic control.  Thromb Haemost. 1994;  72 979-984
    PubMedGoogle Scholar
  • 55 Devaraj S, Jialal I. Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation.  Circulation. 2000;  102 191-196
    PubMedGoogle Scholar
  • 56 Kado S, Nagata N. Circulating intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in patients with type 2 diabetes mellitus.  Diabetes Res Clin Pract. 1999;  46 143-148
    CrossrefPubMedGoogle Scholar
  • 57 Guler S, Cakir B, Demirbas B, Yonem A, Odabasi E, Onde U, Aykut O, Gursoy G. Plasma soluble intercellular adhesion molecule 1 levels are increased in type 2 diabetic patients with nephropathy.  Horm Res. 2002;  58 67-70
    CrossrefPubMedGoogle Scholar
  • 58 Kawamura T, Umemura T, Kanai A, Uno T, Matsumae H, Sano T, Sakamoto N, Sakakibara T, Nakamura J, Hotta N. The incidence and characteristics of silent cerebral infarction in elderly diabetic patients: association with serum-soluble adhesion molecules.  Diabetologia. 1998;  41 911-917
    CrossrefPubMedGoogle Scholar
  • 59 Takeuchi N, Kawamura T, Kanai A, Nakamura N, Uno T, Hara T, Sano T, Sakamoto N, Hamada Y, Nakamura J, Hotta N. The effect of cigarette smoking on soluble adhesion molecules in middle-aged patients with Type 2 diabetes mellitus.  Diabet Med. 2002;  19 57-64
    CrossrefPubMedGoogle Scholar
  • 60 Leinonen E S, Hiukka A, Hurt-Camejo E, Wiklund O, Sarna S S, Mattson H L, Westerbacka J, Salonen R M, Salonen J T, Taskinen M R. Low-grade inflammation, endothelial activation and carotid intima-media thickness in type 2 diabetes.  J Intern Med. 2004;  256 119-127
    CrossrefPubMedGoogle Scholar
  • 61 Becker A, Van Hinsbergh V W, Jager A, Kostense P J, Dekker J M, Nijpels G, Heine R J, Bouter L M, Stehouwer C D. Why is soluble intercellular adhesion molecule-1 related to cardiovascular mortality?.  Eur J Clin Invest. 2002;  32 1-8
    PubMedGoogle Scholar
  • 62 Schmidt A M, Crandall J, Hori O, Cao R, Lakatta E. Elevated plasma levels of vascular cell adhesion molecule-1 (VCAM-1) in diabetic patients with microalbuminuria: a marker of vascular dysfunction and progressive vascular disease.  Br J Haematol. 1996;  92 747-750
    CrossrefPubMedGoogle Scholar
  • 63 Koga M, Otsuki M, Kubo M, Hashimoto J, Kasayama S. Relationship between circulating vascular cell adhesion molecule-1 and microvascular complications in type 2 diabetes mellitus.  Diabet Med. 1998;  15 661-667
    CrossrefPubMedGoogle Scholar
  • 64 Lim S C, Caballero A E, Smakowski P, LoGerfo F W, Horton E S, Veves A. Soluble intercellular adhesion molecule, vascular cell adhesion molecule, and impaired microvascular reactivity are early markers of vasculopathy in type 2 diabetic individuals without microalbuminuria.  Diabetes Care. 1999;  22 1865-1870
    PubMedGoogle Scholar
  • 65 Jager A, Van Hinsbergh V W, Kostense P J, Emeis J J, Nijpels G, Dekker J M, Heine R J, Bouter L M, Stehouwer C D. C-reactive protein and soluble vascular cell adhesion molecule-1 are associated with elevated urinary albumin excretion but do not explain its link with cardiovascular risk.  Arterioscler Thromb Vasc Biol. 2002;  22 593-598
    PubMedGoogle Scholar
  • 66 Stehouwer C D, Gall M A, Twisk J W, Knudsen E, Emeis J J, Parving H H. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death.  Diabetes. 2002;  51 1157-1165
    CrossrefPubMedGoogle Scholar
  • 67 Yoshizawa M, Nagai Y, Ohsawa K, Ohta M, Yamashita H, Hisada A, Miyamoto I, Miura K, Takamura T, Kobayashi K. Elevated serum levels of soluble vascular cell adhesion molecule-1 in NIDDM patients with proliferative diabetic retinopathy.  Diabetes Res Clin Pract. 1998;  42 65-70
    CrossrefPubMedGoogle Scholar
  • 68 Meigs J B, Hu F B, Rifai N, Manson J E. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus.  JAMA. 2004;  291 1978-1986
    CrossrefPubMedGoogle Scholar
  • 69 Stehouwer C D. Endothelial dysfunction in diabetic nephropathy: state of the art and potential significance for non-diabetic renal disease.  Nephrol Dial Transplant. 2004;  19 778-781
    PubMedGoogle Scholar
  • 70 Wong T Y, Klein R, Sharrett A R, Duncan B B, Couper D J, Tielsch J M, Klein B E, Hubbard L D. Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study.  JAMA. 2002;  287 1153-1159
    CrossrefPubMedGoogle Scholar

Prof. C. D. A. Stehouwer

Department of Internal Medicine, University Hospital Maastricht

PO Box 5800 · 6202 AZ Maastricht · The Netherlands

Phone: +31 (0)43 387 7041

Email: csteh@sint.azm.nl

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