Download PDF
Thromb Haemost 2015; 114(03): 632-638
DOI: 10.1160/TH14-12-1014
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

The impact of selectins on mortality in stable carotid atherosclerosis

Matthias Hoke
1   Division of Angiology, Department of Internal Medicine II, Medical University, Vienna, Austria
,
Max-Paul Winter
2   Division of Cardiology, Department of Internal Medicine II, Medical University, Vienna, Austria
,
Oswald Wagner
3   Department of Laboratory Medicine, Medical University, Vienna, Austria
,
Markus Exner
3   Department of Laboratory Medicine, Medical University, Vienna, Austria
,
Martin Schillinger
1   Division of Angiology, Department of Internal Medicine II, Medical University, Vienna, Austria
,
Zsuzsanna Arnold
1   Division of Angiology, Department of Internal Medicine II, Medical University, Vienna, Austria
,
Wolfgang Mlekusch
1   Division of Angiology, Department of Internal Medicine II, Medical University, Vienna, Austria
,
Gerald Maurer
2   Division of Cardiology, Department of Internal Medicine II, Medical University, Vienna, Austria
,
Renate Koppensteiner
1   Division of Angiology, Department of Internal Medicine II, Medical University, Vienna, Austria
,
Erich Minar
1   Division of Angiology, Department of Internal Medicine II, Medical University, Vienna, Austria
,
Georg Goliasch
2   Division of Cardiology, Department of Internal Medicine II, Medical University, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received: 06 December 2014

Accepted after major revision: 10 April 2015

Publication Date:
01 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Cellular adhesion molecules also known as selectins promote recruitment of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to plaque formation. The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the endothelial-leukocyte adhesion molecule 1 (ELAM-1) also known as E-selectin mediate the attachment of leukocytes and have been implicated in the destabilisation of atherosclerotic plaques. Therefore, we hypothesised that plasma selectin levels are associated with adverse clinical outcome. We prospectively studied 855 patients with sonographically confirmed carotid atherosclerosis. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (26 %) died. We detected a significant association between cardiovascular mortality and ICAM-1 (adjusted hazard ratio [HR]: 3.43, 95 % confidence interval [CI] 2.00–5.88, p< 0.001) as well as VCAM-1 (adjusted HR: 2.51, 95 % CI 1.45–4.34, p=0.001) when comparing the fourth with the first quartile. Comparable results were obtained for all-cause mortality. In contrast, we could not detect a significant association between E-selectin and all-cause or cardiovascular mortality. We identified the selectins ICAM-1 and VCAM-1 as strong and independent predictors of all-cause and cardiovascular mortality in patients with stable carotid atherosclerosis. These molecules are elevated in states of endothelial activation and might assist to monitor anti-atherosclerotic therapy and select those patients with carotid atherosclerosis, who are at higher risk for cardiovascular events.

Keywords

Cell adhesion molecules - carotid atherosclerosis - risk prediction
 

  • References

  • 1 Mozaffarian D, Benjamin EJ, Go AS. et al. Heart disease and stroke statistics-2015 update: a report from the american heart association. Circulation 2015; 131: e29-e322.
    CrossrefPubMedGoogle Scholar
  • 2 Santos-Gallego CG, Picatoste B, Badimon JJ. Pathophysiology of acute coronary syndrome. Curr Atheroscl Rep 2014; 16: 401.
    CrossrefPubMedGoogle Scholar
  • 3 Silvestre-Roig C, de Winther MP, Weber C. et al. Atherosclerotic plaque destabilisation: mechanisms, models, and therapeutic strategies. Circulation Res 2014; 114: 214-226.
    CrossrefPubMedGoogle Scholar
  • 4 Jaipersad AS, Lip GY, Silverman S. et al. The role of monocytes in angiogenesis and atherosclerosis. J Am Coll Cardiol 2014; 63: 1-11.
    CrossrefPubMedGoogle Scholar
  • 5 Hwang SJ, Ballantyne CM, Sharrett AR. et al. 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.
    CrossrefPubMedGoogle Scholar
  • 6 Ridker PM, Hennekens CH, Roitman-Johnson B. et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998; 351: 88-92.
    CrossrefPubMedGoogle Scholar
  • 7 Schillinger M, Exner M, Mlekusch W. et al. Inflammation and Carotid Artery--Risk for Atherosclerosis Study (ICARAS). Circulation 2005; 111: 2203-2209.
    CrossrefPubMedGoogle Scholar
  • 8 Kapiotis S, Holzer G, Schaller G. et al. A proinflammatory state is detectable in obese children and is accompanied by functional and morphological vascular changes. Arterioscl Thromb Vasc Biol 2006; 26: 2541-2546.
    CrossrefPubMedGoogle Scholar
  • 9 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nature Med 2011; 17: 1410-1422.
    CrossrefPubMedGoogle Scholar
  • 10 Bourdillon MC, Poston RN, Covacho C. et al. ICAM-1 deficiency reduces atherosclerotic lesions in double-knockout mice (ApoE(-/-)/ICAM-1(-/-)) fed a fat or a chow diet. Arterioscl Thromb Vasc Biol 2000; 20: 2630-2635.
    CrossrefPubMedGoogle Scholar
  • 11 Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury. FASEB J 1994; 08: 504-512.
    CrossrefPubMedGoogle Scholar
  • 12 Eriksson EE, Xie X, Werr J. et al. Direct viewing of atherosclerosis in vivo: plaque invasion by leukocytes is initiated by the endothelial selectins. FASEB J 2001; 15: 1149-1157.
    CrossrefPubMedGoogle Scholar
  • 13 Nakashima Y, Raines EW, Plump AS. et al. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscl Thromb Vasc Biol 1998; 18: 842-851.
    CrossrefPubMedGoogle Scholar
  • 14 de Boer OJ, van der Wal AC, Teeling P. et al. Leucocyte recruitment in rupture prone regions of lipid-rich plaques: a prominent role for neovascularisation?. Cardiovasc Res 1999; 41: 443-449.
    CrossrefPubMedGoogle Scholar
  • 15 DeGraba TJ. Expression of inflammatory mediators and adhesion molecules in human atherosclerotic plaque. Neurology 1997; 49: S15-19.
    PubMedGoogle Scholar
  • 16 Davies MJ, Gordon JL, Gearing AJ. et al. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol 1993; 171: 223-229.
    CrossrefPubMedGoogle Scholar
  • 17 Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993; 14: 506-512.
    CrossrefPubMedGoogle Scholar
  • 18 Blankenberg S, Rupprecht HJ, Bickel C. et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 2001; 104: 1336-1342.
    CrossrefPubMedGoogle Scholar
  • 19 Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis 2003; 170: 191-203.
    CrossrefPubMedGoogle Scholar
  • 20 Hackman A, Abe Y, Insull W Jr.. et al. Levels of soluble cell adhesion molecules in patients with dyslipidemia. Circulation 1996; 93: 1334-1338.
    CrossrefPubMedGoogle Scholar
  • 21 Mazzone A, Cusa C, Mazzucchelli I. et al. Cigarette smoking and hypertension influence nitric oxide release and plasma levels of adhesion molecules. Clin Chem Lab Med 2001; 39: 822-826.
    CrossrefPubMedGoogle Scholar
  • 22 Li YH, Teng JK, Tsai WC. et al. Elevation of soluble adhesion molecules is associated with the severity of myocardial damage in acute myocardial infarction. Am J Cardiol 1997; 80: 1218-1221.
    CrossrefPubMedGoogle Scholar
  • 23 Shyu KG, Chang H, Lin CC. et al. Circulating intercellular adhesion molecule-1 and E-selectin in patients with acute coronary syndrome. Chest 1996; 109: 1627-1630.
    CrossrefPubMedGoogle Scholar
  • 24 Mulvihill NT, Foley JB, Murphy R. et al. Evidence of prolonged inflammation in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol 2000; 36: 1210-1216.
    CrossrefPubMedGoogle Scholar
  • 25 Mulvihill NT, Foley JB, Murphy RT. et al. Risk stratification in unstable angina and non-Q wave myocardial infarction using soluble cell adhesion molecules. Heart 2001; 85: 623-627.
    CrossrefPubMedGoogle Scholar
  • 26 Haim M, Tanne D, Boyko V. et al. Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with chronic coronary heart disease. Data from the Bezafibrate Infarction Prevention (BIP) Study. J Am Coll Cardiol 2002; 39: 1133-1138.
    CrossrefPubMedGoogle Scholar
  • 27 Jager A, van Hinsbergh VW, Kostense PJ. et al. 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.
    CrossrefPubMedGoogle Scholar
  • 28 de Lemos JA, Hennekens CH, Ridker PM. Plasma concentration of soluble vascular cell adhesion molecule-1 and subsequent cardiovascular risk. J Am Coll Cardiol 2000; 36: 423-426.
    CrossrefPubMedGoogle Scholar
  • 29 O’Brien KD, Allen MD, McDonald TO. et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest 1993; 92: 945-951.
    CrossrefPubMedGoogle Scholar
  • 30 Cybulsky MI, Iiyama K, Li H. et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 2001; 107: 1255-1262.
    CrossrefPubMedGoogle Scholar
  • 31 Pradhan AD, Rifai N, Ridker PM. Soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and the development of symptomatic peripheral arterial disease in men. Circulation 2002; 106: 820-825.
    CrossrefPubMedGoogle Scholar
  • 32 De Caterina R, Basta G, Lazzerini G. et al. Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis. Arterioscl Thromb Vasc Biol 1997; 17: 2646-2654.
    CrossrefPubMedGoogle Scholar
  • 33 Peter K, Nawroth P, Conradt C. et al. Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin. Arterioscl Thromb Vasc Biol 1997; 17: 505-512.
    CrossrefPubMedGoogle Scholar
  • 34 Tzoulaki I, Murray GD, Lee AJ. et al. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation 2005; 112: 976-983.
    CrossrefPubMedGoogle Scholar
  • 35 Holmlund A, Hulthe J, Millgard J. et al. Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory function in healthy individuals. Atherosclerosis 2002; 165: 271-276.
    CrossrefPubMedGoogle Scholar
  • 36 Rauchhaus M, Gross M, Schulz S. et al. The E-selectin SER128ARG gene polymorphism and restenosis after successful coronary angioplasty. Intern J Cardiol 2002; 83: 249-257.
    CrossrefPubMedGoogle Scholar
  • 37 Dong ZM, Chapman SM, Brown AA. et al. The combined role of P- and E-selec-tins in atherosclerosis. J Clin Invest 1998; 102: 145-152.
    CrossrefPubMedGoogle Scholar
  • 38 Bonaterra GA, Zugel S, Kinscherf R. Novel systemic cardiovascular disease biomarkers. Curr Mol Med 2010; 10: 180-205.
    CrossrefPubMedGoogle Scholar
  • 39 Simundic AM, Basic V, Topic E. et al. Soluble adhesion molecules in acute ischemic stroke. Clin Invest Med 2004; 27: 86-92.
    PubMedGoogle Scholar
  • 40 Frijns CJ, Kappelle LJ. Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke 2002; 33: 2115-2122.
    CrossrefPubMedGoogle Scholar
  • 41 Supanc V, Biloglav Z, Kes VB. et al. Role of cell adhesion molecules in acute ischemic stroke. Ann Saudi Med 2011; 31: 365-370.
    CrossrefPubMedGoogle Scholar
  • 42 Castillo J, Alvarez-Sabin J, Martinez-Vila E. et al. Inflammation markers and prediction of post-stroke vascular disease recurrence: the MITICO study. J Neurol 2009; 256: 217-224.
    CrossrefPubMedGoogle Scholar
  • 43 Enlimomab Acute Stroke Trial I.. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 2001; 57: 1428-1434.
    CrossrefPubMedGoogle Scholar
  • 44 Furuya K, Takeda H, Azhar S. et al. Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine anti-human intercellular adhesion molecule-1 antibody: a bedside-to-bench study. Stroke 2001; 32: 2665-2674.
    CrossrefPubMedGoogle Scholar