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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 2001 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 cohort	Mean 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 Gold standard diagnosis of AMI now outdated (utilised CK-MB not troponins).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 event	Event 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 events	Sensitivity 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 2001 Scotland	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 cohort	ICAM-1 levels according to diagnosis	Raised 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-up	Remained raised in AMI and UA groups vs. controls (P<0.01). No difference between chest pain without evidence of IHD group and controls.
			Multivariate analysis	ICAM-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 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 cohort	ICAM-1 for prediction of adverse events at 3 months	No significant correlation	No sample size calculation; relatively small numbers. The value of ICAM-1 for diagnosing ACS not evaluated.

Comment(s)

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.

References

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