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Soluble ICAM-1 as a cardiac biomarker for use in the Emergency Department

Three Part Question

In [patients with suspected myocardial ischaemia presenting to the Emergency Department] does [a normal level of soluble ICAM-1 in peripheral blood] enable [accurate exclusion of acute coronary syndrome]?

Clinical Scenario

An eighty year-old man presents to the Emergency Department with central chest pain. He had a myocardial infarction five years ago and can't remember if the pain is similar. His ECG shows left bundle branch block, which is known to be old and has no ischaemic features. You therefore prescribe aspirin, nitrates and clopidogrel and refer for troponin testing at 12 hours.
Having heard about the potential of novel biomarkers to enable early exclusion of acute coronary syndromes (ACS), you wonder if there is any evidence that measuring ICAM-1, a cell adhesion molecule, will enable early exclusion of ACS and accurate risk stratification.

Search Strategy

OVID Medline 1966 - 2005 September Week 1
OVID Embase 1980 - 2005 Week 38
[(exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR exp Chest Pain/ OR ((myocard$ adj (ischem$ OR ischaem$ OR infarct$)).mp. OR (acute coronary syndrome OR heart attack OR ACS OR AMI OR MI).mp.) AND (exp Intercellular Adhesion Molecule-1/ OR (ICAM$ OR I-CAM$).mp.)] limit to human and English language

Search Outcome

Altogether 137 papers were identified using the reported Medline search and 233 in Embase. Three papers addressed the three-part question by evaluating the use of testing ICAM-1 in Emergency Department patients with suspected myocardial ischaemia. Other relevant papers and the pathophysiological rationale for the use of ICAM-1 as a cardiac biomarker are discussed.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Hillis et al
United States
119 consecutive patients presenting to one of two urban Emergency Departments with chest pain suspicious of myocardial ischaemia. Blood was taken at presentation. Follow up for duration of in-patient stay. Primary outcome: Serious adverse cardiovascular events (death, AMI or coronary revascularisation) in the hospital.Prospective observational cohortMean ICAM-1 level (event vs. non-event)Event group: 309+-164ng/ml; Non-event group: 269+/-122ng/ml (p=0.38).No sample size calculation. Small numbers; wide confidence intervals in sensitivity. Gold standard diagnosis of AMI now outdated (utilised CK-MB not troponins). Suboptimal primary outcome. Diagnosis of AMI should not be described as an 'adverse event' as this is the problem the patients were admitted with. Coronary revascularisation depends on physician judgement and may have been guided by factors other than urgent clinical need. Patients were only followed up during their hospital stay, however long that was. Clinical follow up data at 30 days and 6 months would have been more meaningful. Multiple exclusion criteria but number of patients excluded not reported.
ICAM>260ng/ml for prediction of adverse eventEvent group: 19/30 (63.3%) >260ng/ml; Non-event group: 47/89 (52.8%) >260. P=0.40
ICAM>260ng/ml for prediction of adverse eventsSensitivity 63.3% (95% CI 46.1-80.6%); Specificity 47.2% (38.1-56.5%); PPV 28.8%; NPV 79.3%. cf TnI >0.2ng/ml: Sensitivity 43.3%; Specificity 95.5%; PPV 76.5%; NPV 83.3%.
O'Malley et al
241 men aged <65 years presenting to the Emergency Department with chest pain. Blood taken at presentation (mean 7.4 hours from symptom onset). Follow up at 30 days. ICAM-1 levels were compared to those of 82 (of 300 invited) healthy controls randomly selected from a general practice database.Prospective observational cohortICAM-1 levels according to diagnosisRaised in AMI (256+/-85ng/ml), UA (232+/-61ng/ml) and chest pain without evidence of IHD (233+/-70ng/ml) vs. healthy controls (204+/-52ng/ml). P<0.01. No statistical comparison reported between the chest pain groups but there is no apparent difference.Only men included. Results may not be applicable to women, which would effectively preclude clinical implementation. The authors did not justify the exclusion of women. Imperfect gold standards for diagnosis: subjective criteria for diagnosis of UA, modified outdated WHO criteria for diagnosis of AMI. Multiple exclusion criteria but numbers excluded not stated. ICAM-1 levels at follow-up taken after 12-hour fast and 15-20 minutes rest. This is not directly applicable to the setting of clinical out-patient review. ROC curve analysis, sensitivities, specificities, PPV's and NPV's, which would enable evaluation of ICAM-1 as a diagnostic test, were not reported. Despite following patients up at 30 days, value of ICAM-1 levels for prediction of adverse events not reported.
ICAM-1 levels at 3-months follow-upRemained raised in AMI and UA groups vs. controls (P<0.01). No difference between chest pain without evidence of IHD group and controls.
Multivariate analysisICAM-1 correlated with smoking (r=0.47). Following adjustment for confounders, ICAM-1 was significantly greater than controls in the UA group (P<0.01) but not the AMI group.
Hillis et al, 2002
United States
126 consecutive patients presenting to the Emergency Department with chest pain suspicious of myocardial ischaemia. Blood taken at presentation. 113 patients (89.7%) completed follow up at 3 months.Prospective observational cohortICAM-1 for prediction of adverse events at 3 monthsNo significant correlationNo sample size calculation; relatively small numbers. The value of ICAM-1 for diagnosing ACS not evaluated.


Migration of leucocytes into the intima of coronary vessels is a pivotal step in the development and progression of atherosclerosis. It leads to the expansion of atheroma and an inflammatory process that culminates in destabilisation of the fibrous cap, plaque rupture or erosion and thrombosis. The acute coronary syndromes ensue (Kher et al, 2004; Corti et al, 2004). Leucocyte migration occurs as a result of endothelial dysfunction and activation. Expression of selectins by endothelial cells causes leucocytes to 'roll' on the endothelial surface in the direction of blood flow, 'scanning' the endothelial surface for activating signals from attractant molecules called chemokines. Upon interaction with chemokines, integrins that are expressed on the leucocyte cell surface undergo a conformational change. In order for leucocyte migration to occur, the integrins must then bind to ICAM-1 or VCAM-1 expressed on the endothelial surface. Once this firm adhesion has taken place, the leucocytes migrate across the endothelial surface, following a chemokine concentration gradient to the inflammatory core of the atheromatous plaque (Price et al, 1999). ICAM-1 is a member of the immunoglobulin gene superfamily of cell adhesion molecules. Its soluble form can be detected in peripheral blood following cleavage from endothelial cells (Pigott et al, 1992). As a potential cardiac marker, ICAM-1 is attractive because it may help to identify both ACS and patients who are at high risk of developing ACS in the near future. Unlike troponin, therefore, it could enable early intensive treatment with the goal of preventing rather than responding to myocardial damage. Elevated levels of soluble ICAM-1 have been demonstrated in stable angina and levels have been shown to correlate with the severity of coronary atherosclerosis (Morisaki et al, 1997; Haim et al, 2002; Wallen et al, 1999; Zouridakis et al, 2004; Oishi et al, 2002). ICAM-1 levels may be independent predictors of adverse cardiac events in apparently healthy men (Ridker et al, 1998; Luc et al, 2003) and women (Ridker et al, 2000). Several groups have demonstrated raised levels of ICAM-1 in ACS (Kaikita et al, 1997; Peng et al, 2002; Shyu et al, 1996; Siminiak et al, 1998; Squadrito et al, 1996; Mulvihill et al, 1999; Murphy et al, 2003; Xie et al, 2000; Ghaisas et al, 1997; Mulvihill et al, 2000; Li et al, 1997; Siminiak et al, 1997; Doo et al, 2004; Pudil et al, 1999). Levels in AMI may help to predict mortality (Zeitler et al, 1997), reperfusion arrhythmias (Murohora et al, 2000), early restenosis (Kamijikkoku et al, 1998) and levels in UA have been shown to predict adverse events following PCI (Doo et al, 2005). However, several groups have failed to demonstrate a difference in ICAM-1 levels between patients with ACS and stable angina (Miyao et al, 1999; Mizia-Stec et al, 2002; Balbay et al, 2001; Haught et al, 1996; Soeki et al, 2003; Zeitler et al, 1997; Guray et al, 2004; Parker et al, 2001). Further groups have found no difference between patients with ACS and controls (Maly et al, 2003; Nomoto et al, 2003; Hope et al, 2002; Pellegatta et al, 1997). Further, in addition to secretion by endothelial cells, ICAM-1 is also secreted by leucocytes, hepatocytes and smooth muscle. Elevated levels are known to be found in malignant and inflammatory diseases, in renal failure, septic shock and peripheral atherosclerosis (Gearing et al, 1993; Blann et al, 2002; Blann et al, 1998). As this may lead to a lack of specificity, it may limit the utility of ICAM-1 as a diagnostic test in the Emergency Department. Three groups have reported the use of ICAM-1 levels in Emergency Department patients with undifferentiated chest pain (see Table). All three studies had significant weaknesses. However, Hillis et al (2002) reported that levels showed no correlation with the incdience of adverse events at three months, while O'Malley et al found no significant elevation in ACS compared to patients with probable non-cardiac chest pain. Hillis et al (2001) reported a 63.3% sensitivity, 47.2% specificity and a NPV of 79.3% for the prediction of an in-hospital adverse event. All of these figures are unacceptably low for ICAM-1 to be utilised as a sole diagnostic or prognostic marker in the Emergency Department. While theoretically useful, ICAM-1 may lack the necessary sensitivity and specificity to be utilised in the Emergency Department. While incorporation into a multimarker strategy may improve its performance, other markers may be superior. This does not, however, mark the end of the road for ICAM-1 in IHD. Along with C-reactive protein, it may be useful for guiding primary prevention of cardiac events in general practice. Additionally, ICAM-1 may be a useful therapeutic target for antibodies that aim to limit atheroma progression and reperfusion injury following myocardial infarction. Animal experiments have yielded promising early results (Yamazaki et al, 1993; Simpson et al, 1990).

Editor Comment

Abbreviations: AMI: acute myocardial infarction; ACS: acute coronary syndrome; UA: unstable angina; PPV: positive predictive value; NPV: negative predictive value; CI: confidence intervals; IHD: ischaemic heart disease; ICAM-1: intercellular adhesion molecule-1; WHO: World Health Organisation

Clinical Bottom Line

ICAM-1 is unsuitable for use as a marker of acute coronary syndromes in the Emergency Department. While incorporation into a multimarker strategy may improve diagnostic performance, other markers may be superior.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.


  1. Hillis GS; Terregino C; Taggart P; Killian A; Zhao N; Kaplan J; Dalsey WC; Mangione A. Soluble intercellular adhesion molecule-1 as a predictor of early adverse events in patients with chest pain compatible with myocardial ischemia Annals of Emergency Medicine 2001; 38(3): 223-228
  2. O'Malley TO; Ludlam CA; Riemermsa RA; Fox KAA. Early increase in levels of soluble inter-cellular adhesion molecule-1 (sICAM-1) European Heart Journal 2001; 22: 1226-1234
  3. Hillis GS; Terregino C; Taggart P; Killian A; Zhao N; Dalsey WC; Mangione A. Elevated soluble P-selectin levels are associated with an increased risk of early adverse events in patients with presumed myocardial ischemia American Heart Journal 2002; 143: 235-241
  4. Shyu KG; Chang H; Lin CC; Kuan P. Circulating intercellular adhesion molecule-1 and E-selectin in patients with acute coronary syndrome Chest 1996; 109: 1627-1630
  5. Kher NK; Marsh JD. Pathobiology of atherosclerosis - a brief review Seminars in Thrombosis and Hemostasis 2004; 30(6): 665-672
  6. Corti R; Hutter R; Badimon JJ; Fuster V. Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis Journal of Thrombosis and Thrombolysis 2004; 17(1): 35-44
  7. Price DT; Loscalzo J. Cellular adhesion molecules and atherogenesis American Journal of Medicine 1999; 107: 85-97
  8. Piggott R; Dillon LP; Hemingway IH; Gearing AJH. Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells. Biochemical and Biophysical Research Communications 1991; 187(2): 584-589
  9. Haim M; Tanne D; Boyko V; Reshef T; Goldbourt U; Leor J; Mekori YA; Behar S. Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with coronary heart disease. Journal of the American College of Cardiology 2002; 39(7): 1133-1138
  10. Zouridakis E; Avanzas P; Arroyo-Espliguero R; Kaski JC. Markers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris Circulation 2004; 110(13): 1747-1753
  11. Oishi Y; Wakatsuki T; Nishikado A; Oki T; Ito S. Circulating adhesion molecules and severity of coronary atherosclerosis [Abstr] Coronary Artery Disease 2000; 11(1): 77-81
  12. Zeitler H; Ko Y; Zimmerman C; Nickenig G; Glanzer K; Walger P; Sachinidis A; Vetter H. Elevated serum concentrations of soluble adhesion molecules in coronary artery disease and acute myocardial infarction [Abstr] European Journal of Medical Research 1997; 2(9): 389-394
  13. Mulvihill NT; Foley JB; Murphy R; Crean P; Walsh M. Evidence of prolonged inflammation in unstable angina and non-Q wave myocardial infarction Journal of the American College of Cardiology 2000; 36(4): 1210-1216
  14. Li YH; Teng JK; Tsai WC; Tsai LM; Lin LJ; Chen JH. Elevation of soluble adhesion molecules is associated with the severity of myocardial damage in acute myocardial infarction American Journal of Cardiology 1997; 80: 1218-1221
  15. Ghaisas NK; Shahi CN; Foley B; Goggins M; Crean P; Kelly A; Kelleher D; Walsh M. Elevated levels of circulating soluble adhesion molecules in peripheral blood of patients with unstable angina. American Journal of Cardiology 1997; 80: 617-619
  16. Guray U; Erbay R; Guray Y; Yilmaz MB; Boyaci AA; Sasmaz H; Korkmaz S; Kutuk E. Levels of soluble adhesion molecules in various clinical presentations of coronary atherosclerosis International Journal of Cardiology 2004; 96: 235-240
  17. Mulvihill N; Foley JB; Ghaisas N; Murphy R; Crean P; Walsh M. Early temporal expression of soluble cellular adhesion molecules in patients with unstable angina and subendocardial myocardial infarction American Journal of Cardiology 1999; 83: 1265-1267
  18. Hope SA; Meredith IT; Farouque O; Worthley SG; Plunkett JC; Balazs ND. Time course of plasma adhesion molecules in acute coronary syndromes Coronary Artery Disease 2002; 13: 215-221
  19. Nomoto K; Oguchi S; Watanabe I; Kushiro T; Kanmatsuse K. Involvement of inflammation in acute coronary syndromes assessed by levels of high-sensitivity C-reactive protein, matrix metalloproteinase-9 and soluble vascular adhesion molecule-1 [Abstr] Journal of Cardiology 2003; 42(5): 201-6
  20. Luc G; Arveiler D; Evans A; Amouyel P; Ferrieres J; Bard MJ; Elkhalil L; Fruchart JC; Ducimetiere P. Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and incident coronary heart disease: The PRIME Study Atherosclerosis 2003; 170: 169-176
  21. Mizia-Stec K; Zahorska-Markiewicz B; Mandecki T; Janowska J; Szulc A; Jastrzebska-Maj E. Serum levels of selected adhesion molecules in patients with coronary artery disease. International Journal of Cardiology 2002; 83: 143-150
  22. Peng DQ; Zhao SP; Li YF; Li J; Zhou HN. Elevated soluble CD40 ligand is related to the endothelial adhesion molecules in patients with acute coronary syndrome Clinica Chimica Acta 2002; 319: 19-26
  23. Parker C 3rd; Vita JA; Freedman JE. Soluble adhesion molecules and unstable coronary artery disease Atherosclerosis 2001; 156: 417-424
  24. 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... Atherosclerosis 1997; 131: 43-48
  25. Wallen NH; Held C; Rehnqvist N; Hjemdahl P. Elevated serum intercellular adhesion molecule-1 and vascular adhesion molecule-1 among patients with stable angina pectoris who suffer cardiovascular death or non-fatal myocardial infarction European Heart Journal 1999; 20: 1039-1043
  26. Xie Y; Zhou T; Shen W; Lu G; Yin T; Gong L. Soluble cell adhesion molecules in patients with acute coronary syndrome Chinese Medical Journal 2000; 113(3): 286-288
  27. Miyao Y; Miyazaki S; Goto Y; Itoh A; Daikoku S; Morii I; Matsumoto T; Nonogi H. Role of cytokines and adhesion molecules in ischemia and reperfusion in patients with acute myocardial infarction Japanese Circulation Journal 1999; 63: 362-366
  28. Siminiak T; Dye JF; Egdell RM; More R; Wysocki H; Sheridan DJ. The release of soluble adhesion molecules ICAM-1 and E-selectin after acute myocardial infarction and following coronary angioplasty International Journal of Cardiology 1997; 61: 113-118
  29. Pellegatta F; Pizzetti G; Lu Y; Radaelli A; Pomes D; Carlino M; Meloni C; Belotti G; Galli L; Vidal MJ; Chierchia SL. Soluble E-selectin and intercellular adhesion molecule-1 plasma levels increase during acute myocardial infarction Journal of Cardiovascular Pharmacology 1997; 30: 455-460
  30. Squadrito F; Saitta A; Altavilla D; Ioculano M; Canale P; Campo GM; Squadrito G; Di Tano G; Mazzu A; Caputi AP. Thrombolytic therapy with urokinase reduces increased circulating endothelial adhesion molecules in acute myocardial infarction [Abstr] Inflammation Research 1996; 45(1): 14-19
  31. Siminiak T; Smielecki J; Dye JF; Balinski M; El-Gendi H; Wysocki H; Sheridan DJ. Increased release of the soluble form of the adhesion molecules L-selectin and ICAM-1 but not E-selectin during attacks of angina pectoris [Abstr] Heart & Vessels 1998; 13(4): 189-194
  32. Soeki T; Tamura Y; Shinohara H; Sakabe K; Onose Y; Fukuda N. Increased soluble platelet/endothelial cell adhesion molecule-1 in the early stages of acute coronary syndromes International Journal of Cardiology 2003; 90: 261-268
  33. Murohara T; Kamijikkoku S; Honda T. Increased circulating soluble intercellular adhesion molecule-1 in acute myocardial infarction: A possible predictor of reperfusion ventricular arrhythmias Critical Care Medicine 2000; 28(6): 1861-1864
  34. Ridker PM; Hennekens CH; Buring JE; Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women New England Journal of Medicine 2000; 342: 836-843
  35. Pudil R; Pidrman V; Krejsek J; Gregor J; Tichy M; Andrys C; Drahosova M. Cytokines and adhesion molecules in the course of acute myocardial infarction Clinica Chimica Acta 1999; 280: 127-134
  36. Kamijikkoku S; Murohara T; Tayama S; Matsuyama K; Honda T; Ando M; Hayasaki K. Acute myocardial infarction and increased soluble intercellular adhesion molecule-1: A marker of vascular inflammation and a risk of early restenosis? American Heart Journal 1998; 136(2): 231-236
  37. Ridker PM; Hennekens CH; Roitman-Johnson B; Stampfer MJ; Allen J. Plasma concentration of soluble intercellular adhesion molecule-1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998; 351: 88-92
  38. Kaikita K; Ogawa H; Yasue H; Sakamoto T; Miyao Y; Suefuji H; Soejima H; Tayama S; Hayasaki K; Honda T; Kamijikkoku S. Increased plasma soluble intercellular adhesion molecule-1 levels in patients with acute myocardial infarction Japanese Circulation Journal 1997; 61: 741-748
  39. Haught WH; Mansour M; Rothlein R; Kishimoto TK; Mainolfi EA; Hendricks JB; Hendricks C; Mehta JL. Alterations in circulating intercellular adhesion molecule-1 and L-selectin: Further evidence for chronic inflammation in ischemic heart disease American Heart Journal 1996; 132(1): 1-8
  40. Balbay Y; Tikiz H; Baptiste RJ; Ayaz S; Sasmaz H; Korkmaz S. Circulating interleukin-1 beta, interleukin-6, tumour necrosis factor-alpha, and soluble ICAM-1 in patients with chronic stable angina and myocardial infarction [Abstr] Angiology 2001; 52(2): 109-114
  41. Doo YC; Han SJ; Park WJ; Kim SM; Choi SH; Cho GY; Hong KS; Han KR; Lee NH; Oh DJ; Ryu KH; Rhim CY; Lee KH; Lee Y. Associations between C-reactive protein and circulating cell adhesion molecules in patients with unstable angina undergoing coronary intervention and their clinical implication Clinical Cardiology 2005; 28(1): 47-51
  42. Doo YC; Han SJ; Lee JH; Cho GY; Hong KS; Han KR; Lee NH; Oh DJ; Ryu KH; Rhim CY; Lee KH; Lee Y. Associations among oxidized low-density lipoprotein antibody, C-reactive protein, interleukin-6, and circulating cell adhesion molecules in patients with unstable angina pectoris American Journal of Cardiology 2004; 93: 554-558
  43. Gearing AJH; Newman W. Circulating adhesion molecules in disease Immunology Today 1993; 14(10): 506-512
  44. Blann AD; McCollum CN. Circulating ICAM-1 in peripheral arterial disease as a predictor of adverse events Lancet 1998; 351: 1135
  45. Blann AD; Lip GYH; McCollum CN. Changes in von Willebrand factor and soluble ICAM, but not soluble VCAM, soluble E selectin or soluble thrombomodulin, reflect the natural progression of atherosclerosis Atherosclerosis 2002; 165: 389-391
  46. Maly M; Vojacek J; Hrabos V; Kvasnicka J; Salaj P; Durdil V. Tissue factor, tissue factor pathway inhibitor and cytoadhesive molecules in patients with an acute coronary syndrome. Physiology Research 2003; 52: 719-728
  47. Yamazaki T; Seko Y; Tamatani T; Miyasaka M; Yagita H; Okumura K; Nagai R; Yazaki Y. Expression of intercellular adhesion molecule-1 in rat heart with ischemia/reperfusion and limitation of infarct size by treatment with antibodies against cell adhesion molecules [Abstr] American Journal of Pathology 1993; 143(2): 410-418
  48. Simpson PJ; Todd RF; Mickelson JK; Fantone JC; Gallagher KP; Lee KA; Tamura Y; Croninn M; Lucchesi BT. Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function Circulation 1990; 81: 226-237