Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
Table of Contents | Next Article »
Stroke. 2002;33:2141-2143
doi: 10.1161/01.STR.0000029008.00497.D3
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Blann, A. D.
Right arrow Articles by Lip, G. Y.H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Blann, A. D.
Right arrow Articles by Lip, G. Y.H.

(Stroke. 2002;33:2141.)
© 2002 American Heart Association, Inc.

Editorials

Inflammation, Cell Adhesion Molecules, and Stroke: Tools in Pathophysiology and Epidemiology?

Andrew D. Blann, PhD, MRCPath; Paul M. Ridker, MD Gregory Y.H. Lip, MD

From the Haemostasis, Thrombosis and Vascular Biology Unit (A.B., G.Y.H.L.), University Department of Medicine, City Hospital, Birmingham, UK, and Center for Cardiovascular Disease Prevention (P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Dr AD Blann, PhD, MRCPath, Haemostasis, Thrombosis, and Vascular Biology Unit, University of Birmingham, University Department of Medicine, City Hospital, Dudley Rd, Birmingham B18 7QH, UK. E-mail a.blann{at}bham.ac.uk


Key Words: cell adhesion molecules • inflammation • risk factors • stroke, ischemic

Since their development approximately a decade ago, cell adhesion molecules have been attracting interest for a number of reasons. For example, the blockade of the interaction between leukocytes and the endothelium by agents that mimic or inhibit these adhesion molecules may provide the basis for a new class of therapeutic agents, although promising studies in animals1–3 have yet to be translated into products proven to be effective in humans. Study of the expression of the molecules on the surface of various cells or of the soluble form in the plasma may provide insights into their role(s) in pathophysiology in cardiovascular, connective tissue and neoplastic diseases,4,5 and differences in levels of soluble cell adhesion molecules in the plasma may be useful tools in stratifying disease severity or prognosis.6,7 However, these aspects may be related, as soluble forms themselves may interfere with leukocyte/endothelial cell interactions, at least in vitro.8,9 Despite this, soluble adhesion molecules may be useful in dissecting the pathophysiological events in cardiovascular disease, as it may be presumed that changes in levels may relate to activation or damage to various cells such as the platelet and endothelium.

The selectin family of adhesion molecules has two principal members. Soluble P-selectin is believed to be the product of activated platelets, although the endothelium displays a membrane-bound form.10,11 Increased levels are found in a number of conditions, including thrombotic disorders, diabetes, and ischemic heart disease,12,13 and raised levels predict adverse events,14 even in apparently healthy individuals.15 Although increased levels of soluble E-selectin are the result of cytokine activation of endothelial cells in vitro,16 and raised levels in the plasma have been reported in variant (but not stable) angina17 and in ischemic heart disease,18 such raised levels seem unable to predict adverse cardiovascular events19 but do predict restenosis following percutaneous angioplasty in the peripheral arteries.20

See article on page 2182

The second major group of adhesion molecules belong to the immunoglobulin supergene family, and 2 members warrant attention. Soluble intercellular adhesion molecule-1 (sICAM-1) is a likely product of many cells, including the endothelium and leukocytes. Also influenced by inflammatory cytokines in vitro,16 raised levels are found in many conditions, including angina17 and both coronary and peripheral artery disease.21 However, although raised levels of sICAM-1 in healthy men and women predict adverse events,6,22 the association is weaker when there is a background of existing atherosclerosis.7 Conversely, despite reports of raised vascular cell adhesion molecule-1 (sVCAM-1) in various cardiovascular conditions,17,18,21,23,24 such levels seem unable to predict adverse outcome.7,25

Increased levels of sICAM-1 and sVCAM-1 are often taken to imply damage and/or stimulation of the endothelium, but the expression of these molecules on smooth muscle cells, leukocytes, and tumor cells suggests some caution may be necessary.26–28 However, despite these caveats, increased levels of these molecules in a variety of cardiovascular, inflammatory, and neoplastic disease are widely reported, and in many individual reports they seem useful in predicting clinical outcome, but the precise mechanisms and consequences of increased levels are often unclear. However, there is also possible conflict: Blankenberg et al29 reported that baseline sVCAM-1, sICAM-1, and sE-selectin were all significantly related to future death from cardiovascular causes among 1246 patients with documented coronary artery disease. Conversely, Malik et al,30 following up 643 men with coronary artery disease and 1278 controls, found that measurement of cell adhesion molecules, while having univariate predictive value, had limited clinical utility in multivariate models, which accounted for established risk factors.

Stroke is also a case in point. Not surprisingly, numerous groups have reported raised levels of various markers in the short period following stroke,31–34 some proposing that changes may be related to the profound alterations in the metabolic homeostasis in the patients. Therefore, the pursuit of the mechanisms leading to the changes in these makers may provide additional clues to the pathophysiology of this disease. In this respect, Rohde et al35 reported a strong correlation between carotid artery intima-media thickness and plasma sICAM-1. However, despite these interesting short-term and cross-sectional reports, what would be most valuable to the clinician would be to know whether these raised levels predict adverse outcome in a long-term study. To date, few prospective data have been available for cerebrovascular disease, although in the Women’s Health Study, sICAM-1 levels were predictive of future thromboembolic stroke events.22

The article by Tanne et al36 in this current issue ofStroke goes some way to answer this question. Their nested case-control study of subjects with existing coronary artery disease found raised diabetes, smoking, plasma fibrinogen, and serum sICAM-1 (see Table 1 in the article) in the 134 cases who, after 8.2 years, suffered a stroke, compared with 134 controls who did not have an end point. It has long been established that fibrinogen is a risk factor for cardiovascular disease,37 and those patients whose fibrinogen and sICAM-1 were both in the highest tertile were at the highest risk of stroke, suggesting an additive effect (see Figure 2). However, smoking and diabetes can influence sICAM-1,38,39 and smoking can increase fibrinogen.40 After multivariable adjustment for either smoking or lipids, the relative risk of stroke became more significant. However, after adjustment for the combination of diabetes, smoking, hypertension, and previous myocardial infarction, with or without fibrinogen or white blood cell count, these previously significant trends became not significant (see Table 2).

A further mechanism to linking sICAM-1, thrombosis, and fibrinogen (and, indeed, many other possible plasma molecules and markers) is inflammation, possibly related to smoking.16,41,42 Like fibrinogen and smoking, the most widely accepted marker of inflammation (C-reactive protein [CRP]) is also associated with an increased risk of the development of cardiovascular disease,43 including stroke.22,44,45 Two questions, one pathophysiologic and one clinical, are therefore immediately relevant. First, what are the interrelationships between different plasma markers of inflammation and what do these tell us about the pathophysiology of cardiovascular and cerebrovascular disease? Second, which of the inflammatory markers has the most to offer clinically in terms of predicting which apparently healthy patients are at highest risk of suffering a future vascular event? The answer to the former will be of interest to those seeking to understand the mechanisms leading to thrombosis, and thus how to minimize the risk of its occurrence. The answer to the latter will be eagerly awaited by epidemiologists and clinicians. To date, few studies have directly compared fibrinogen, IL-6, ICAM, VCAM, P-selectin, and CRP, but those that have consistently found CRP to have the greatest prognostic utility.22,46 It is important to recognize, however, that the apparent superior clinical performance of CRP is due largely to the fact that this biomarker has a long half-life, is stable from a clinical chemistry perspective, has no circadian variation, and can be measured with a simple reproducible bioassay in a wide variety of clinical outpatient settings.47 Thus, while CRP is likely to be the inflammatory biomarker of choice for clinical purposes, these data do not imply that CRP is necessarily more important from a biologic perspective when compared with upstream cytokines, fibrinogen, or soluble cell adhesion molecules. We must therefore keep an open mind as to what the appropriate pharmacologic targets for vascular inflammation might be in the future.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.

Dr Ridker is listed as a co-inventor in patents filed by Brigham and Women’s Hospital that relate to inflammatory biomarkers in cardiovascular disease.

Received June 18, 2002; accepted June 19, 2002.

References

  1. Hayward R, Campbell B, Shin YK, Scalia R, Lefer AM. Recombinant soluble P-selectin ligand-1 protects against myocardial ischemic reperfusion in cats. Cardiovasc Res. 1999; 41: 65–76.[Abstract/Free Full Text]
  2. Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM, Anderson DC. Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke. 1995; 26: 1438–1443.[Abstract/Free Full Text]
  3. Tsukamoto K, Yokono K, Amano K, Nagata M, Yagi N, Tominaga Y, Moriyama H, Miki M, Okamoto N, Yoneda R, et al. Administration of monoclonal antibodies against vascular cell adhesion molecule-1/very late antigen-4 abrogates predisposing autoimmune diabetes in NOD mice. Cell Immunol. 1995; 165: 193–201.[CrossRef][Medline] [Order article via Infotrieve]
  4. Tanio JW, Chandrasekar BB, Albelda SM, Eisen HJ. Differential expression of the cell adhesion molecules ICAM-1, VCAM-1 and E-selectin in normal and post-transplantation myocardium. Circulation. 1994; 89: 1760–1768.[Abstract/Free Full Text]
  5. Kuzu I, Bicknell R, Fletcher CDM, Gatter KC. Expression of adhesion molecules on the endothelium of normal tissue vessels and vascular tumours. Lab Invest. 1993; 69: 322–328.[Medline] [Order article via Infotrieve]
  6. Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J. Plasma concentrations of soluble intercellular adhesion molecule-1 and risks of future myocardial infarction in apparently healthy men. Lancet. 1998; 351: 88–92.[CrossRef][Medline] [Order article via Infotrieve]
  7. Blann AD, Seigneur M, Steiner M, Miller JP, McCollum CN. 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.[Medline] [Order article via Infotrieve]
  8. Schleiffenbaum B, Spertinin O, Tedder TF. Soluble L-selectin is present in human plasma at high levels and retains functional activity. J Cell Biol. 1992; 11: 229–238.
  9. Gamble JR, Skinner MP, Berndt MC, Vadas MA. Prevention of activated neutrophil adhesion to endothelium by soluble adhesion protein GMP 140. Science. 1990; 249: 414–417.[Abstract/Free Full Text]
  10. Fijnheer R, Frijns CJM, Korteweg J, Rommes H, Peters JH, Sixma JJ, Nieuwenhuis HK. The origin of P-selectin as a circulating plasma protein. Thromb Haemost. 1997; 77: 1081.[Medline] [Order article via Infotrieve]
  11. Blann AD, Lip GYH. Hypothesis: is soluble P-selectin a new marker of platelet activation? Atherosclerosis. 1997; 128: 135–138.[CrossRef][Medline] [Order article via Infotrieve]
  12. Chong BH, Murray B, Berndt MC, Dunlop LC, Brighton T, Chesterman CN. Plasma P-selectin is increased in thrombotic consumptive disorders. Blood. 1994; 83: 1535–1541.[Abstract/Free Full Text]
  13. Jilma B, Fasching P, Ruthner C, Rumplmayr A, Ruzicka S, Kapiotis S, Wagner OF, Eichler HG. Elevated circulating P-selectin in insulin dependent diabetes mellitus. Thromb Haemost. 1996; 76: 328–332.[Medline] [Order article via Infotrieve]
  14. Blann AD, Faragher EB, McCollum CN. Increased soluble P-selectin following myocardial infarction: a new marker for the progression of atherosclerosis. Blood Coagul Fibrinolysis. 1997; 8: 383–390.[Medline] [Order article via Infotrieve]
  15. Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation. 2001; 103: 491–495.[Abstract/Free Full Text]
  16. Pigott R, Dillon LP, Hemingway IH, Gearing AJ. Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells. Biochem Biophys Res Commun. 1992; 187: 584–589.[CrossRef][Medline] [Order article via Infotrieve]
  17. Miwa K, Igawa A, Inoue H. Soluble E-selectin, ICAM-1, and VCAM-1 in systemic and coronary circulation in patients with variant angina. Cardiovasc Res. 1997; 36: 37–44.[Abstract/Free Full Text]
  18. Blann AD, Amiral J, McCollum CN. Circulating endothelial cell/leucocyte adhesion molecules in ischaemic heart disease. Br J Haematol. 1996; 95: 263–265.[CrossRef][Medline] [Order article via Infotrieve]
  19. Blann AD, Amiral J, McCollum CN. Prognostic value of increased soluble thrombomodulin and increased soluble E-selectin in ischaemic heart disease. Eur J Haematol. 1997; 59: 115–120.[Medline] [Order article via Infotrieve]
  20. Belch JJF, Shaw JW, Kirk G, McLaren M, Robb R, Maple C, Morse P. The white blood cell adhesion molecule E-selectin predicts restenosis in patients with intermittent claudication undergoing percutaneous transluminal angioplasty. Circulation. 1997; 95: 2027–2031.[Abstract/Free Full Text]
  21. Blann AD, McCollum CN. Increased levels of soluble adhesion molecules in atherosclerosis. Thromb Haemost. 1994; 72: 151–154.[Medline] [Order article via Infotrieve]
  22. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.[Abstract/Free Full Text]
  23. Peter K, Nawroth P, Conradt C, Norbt T, Weiss T, Boehme M, Wunsch A, Allenberg J, Kubler W, Bode C. Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating ICAM-1, E-selectin, P-selectin and thrombomodulin. Arterioscler Thromb Vasc Biol. 1997; 17: 505–512.[Abstract/Free Full Text]
  24. De Caterina R, Basta G, Lazzerini G, Dell’Omo G, Petrucci R, Morale M, Carmassi F, Pedrinelli R. Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 2646–2654.[Abstract/Free Full Text]
  25. 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.[Abstract/Free Full Text]
  26. Braun M, Pietsch P, Schror K, Baumann G, Felix SB. Cellular adhesion molecules on vascular smooth muscle cells. Cardiovasc Res. 1999; 41: 395–341.[Abstract/Free Full Text]
  27. Wittig BM, Treichel U, Blaheta R, Schreiter T, Schwarting A, Buschenfelde KHM, Mayet W. Soluble E-selectin enhances intercellular adhesion molecule-1 (ICAM-1) expression in human tumour cell lines. Exp Cell Res. 1997; 237: 364–370.[CrossRef][Medline] [Order article via Infotrieve]
  28. Couffinhal T, Duplaa C, Labat L, Lamaziere JMD, Moreau C, Printseva O, Bonnet J. Tumour necrosis factor-alpha stimulates ICAM-1 expression in human vascular smooth muscle cells. Arterioscler Thromb. 1993; 13: 407–414.[Abstract/Free Full Text]
  29. Blankenberg S, Rupprecht HJ, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001; 104: 1336–1342.[Abstract/Free Full Text]
  30. Malik I, Danesh J, Whincup P, Bhatia V, Papacosta O, Walker M, Lennon L, Thomson A, Haskard D. Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis. Lancet. 2001; 358: 971–975.[CrossRef][Medline] [Order article via Infotrieve]
  31. Bitsch A, Klene W, Murtada L, Prange H, Rieckmann P. A longitudinal prospective study of soluble adhesion molecules in acute stroke. Stroke. 1998; 29: 2129–2135.[Abstract/Free Full Text]
  32. Frijns CJM, Kappelle LJ, van Gijn J, Nieuwenhuis HK, Sixma JJ, Fijnheer R. Soluble adhesion molecules reflect endothelial cell activation in ischaemic stroke and in carotid atherosclerosis. Stroke. 1997; 28: 2214–2218.[Abstract/Free Full Text]
  33. Fassbender K, Mossner R, Motsch L, Kischka U, Grau A, Hennerici M. Circulating selectin and immunoglobulin type adhesion molecules in acute ischaemic stroke. Stroke. 1995; 26: 1361–1364.[Abstract/Free Full Text]
  34. Blann AD, Kumar P, Krupinski J, McCollum CN, Beevers DG, Lip GYH. E selectin, intercellular adhesion molecules-1, vascular adhesion molecule-1 and von Willebrand factor following stroke. Blood Coagul Fibrinolysis. 1999; 10: 277–284.[Medline] [Order article via Infotrieve]
  35. Rohde LE, Lee RT, Rivero J, Jamacochian M, Arroyo LH, Briggs W, Rifai, Libby P, Creager MA, Ridker PM, Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis. Arterioscler Thromb Vasc Biol. . 1998; 18: 1765–1770.[Abstract/Free Full Text]
  36. Tanne D, Haim M, Boyko V, Goldbourt U, Reshef T, Matetzky S, Adler Y, Mekori YA, Behar S. Soluble intercellular adhesion molecule-1 and risk of future ischaemic stroke: a nested case-control study from the Bezafibrate Infarction Prevention (BIP) study cohort. Stroke. 2002; 33: 2182–2186.[Abstract/Free Full Text]
  37. Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW, for the ECAT group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. . 1995; 332: 635–641.[Abstract/Free Full Text]
  38. Blann AD, Steele C, McCollum CN. Influence of smoking on soluble adhesion molecules and endothelial cell markers. Thromb Res. 1997; 85: 433–438.[CrossRef][Medline] [Order article via Infotrieve]
  39. Steiner M, Reinhardt KM, Krammer B, Ernst B, Blann AD. Increased levels of soluble adhesion molecules in type (non-insulin) diabetes mellitus are independent of glycaemic control. Thromb Haemost. 1994; 72: 979–984.[Medline] [Order article via Infotrieve]
  40. Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other characteristics on clotting and the risk of ischaemic heart disease. Lancet. 1987; ii: 986–988.
  41. Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation. 2001; 103: 1718–1720.[Free Full Text]
  42. Das I. Raised C-reactive protein levels in serum from smokers. Clin Chem Acta. 1985; 153: 9–13.[CrossRef][Medline] [Order article via Infotrieve]
  43. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998; 97: 425–428.[Abstract/Free Full Text]
  44. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.[Abstract/Free Full Text]
  45. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW. Plasma concentration of C-reactive protein and risk of ischaemic stroke and transient ischaemic attack: the Framingham study. Stroke. 2001; 32: 2575–2579.[Abstract/Free Full Text]
  46. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein (a) and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001; 285: 2481–2485.[Abstract/Free Full Text]
  47. Roberts WL, Moulton L, Law TC, Farrow G, Cooper-Anderson M, Savory J, Rifai N. Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications, part 2. Clin Chem. 2001; 47: 418–425.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Occup. Environ. Med.Home page
M S O'Neill, A Veves, J A Sarnat, A Zanobetti, D R Gold, P A Economides, E S Horton, and J Schwartz
Air pollution and inflammation in type 2 diabetes: a mechanism for susceptibility
Occup. Environ. Med., June 1, 2007; 64(6): 373 - 379.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
R. Vemuganti, R. J. Dempsey, and K. K. Bowen
Inhibition of Intercellular Adhesion Molecule-1 Protein Expression by Antisense Oligonucleotides Is Neuroprotective After Transient Middle Cerebral Artery Occlusion in Rat
Stroke, January 1, 2004; 35(1): 179 - 184.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
P. Cherian, G. J. Hankey, J. W. Eikelboom, J. Thom, R. I. Baker, A. McQuillan, J. Staton, and Q. Yi
Endothelial and Platelet Activation in Acute Ischemic Stroke and Its Etiological Subtypes
Stroke, September 1, 2003; 34(9): 2132 - 2137.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
K. Tsong Tan and A. D. Blann
To stroke or not to stroke: Is ICAM-1 or CRP the answer?
Neurology, June 24, 2003; 60(12): 1884 - 1885.
[Full Text] [PDF]

Home page
 CirculationHome page
J. D. Curb, R. D. Abbott, B. L. Rodriguez, P. Sakkinen, J. S. Popper, K. Yano, and R. P. Tracy
C-Reactive Protein and the Future Risk of Thromboembolic Stroke in Healthy Men
Circulation, April 22, 2003; 107(15): 2016 - 2020.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Blann, A. D.
Right arrow Articles by Lip, G. Y.H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Blann, A. D.
Right arrow Articles by Lip, G. Y.H.

Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2002 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.