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Three Part Question

In [patients with suspected cardiac chest pain] does [measurement of soluble CD40 ligand] enable [accurate exclusion of acute coronary syndromes]?

Clinical Scenario

A consultant physician informally comments about the high volume of patients with vague central chest pain that pass through the Medical Admissions Unit for exclusion of acute coronary syndromes by troponin testing at 12 hours. Wondering if there is a better way, you perform a quick literature search and find several articles investigating the utility of soluble CD40 ligand as a cardiac marker. You wonder if there is any evidence that it may be useful for exclusion of acute coronary syndromes in the Emergency Department.

Search Strategy

OVID Medline 1966 - 2005 July Week 4
OVID Embase 1966 - 2005 Week 30
[exp Myocardial Infarction/ OR exp Coronary Thrombosis/ OR exp Angina Pectoris/ OR exp Angina, Unstable/ OR (heart attack OR AMI OR MI OR unstable angina OR (acute adj coronary adj syndrome) OR ACS).mp. OR (myocard$ adj (infarct$ OR ischaem$ OR ischem$)).mp.] AND [exp CD40 Ligand/ OR (CD40$ OR sCD40$ OR CD154 OR gp39).mp.] limit to human and English language

Search Outcome

Altogether 127 papers were identified using Embase and 58 using Medline. Seven papers, each identified using both databases, were relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Varo et al 2003 United States	195 cases and 195 controls taken from the placebo arm of the OPUS-TIMI16 trial (which investigated GPIIb/IIIa inhibitors in patients with unstable acute coronary syndromes). Cases were defined as death, myocardial infarction (MI) or new or progressive congestive heart failure (CHF) during 10-month follow up. Blood taken within 72 hours of symptom onset	Case-control study	sCD40L levels	Significantly higher in cases v. controls (p=0.002)	Case-control study is a convenient but suboptimal study design to meet the stated aims. Inclusion criteria were not adequately described.
			Incidence of death/MI/CHF according to sCD40L level (quartiles)	Adjusted hazard ratios 2.0 (p=0.05) and 2.4 (p=0.01) for levels in 3rd and 4th quartiles, respectively
			Multivariate analysis	sCD40L levels remained associated with higher risk of death (p=0.026), MI (p=0.011) and death/MI/CHF (p=0.015).
			Incidence of death/MI/CHF if troponin I and sCD40L both low	4.6% incidence (8/175)
Heeschen et al 2003 Germany	1088 patients with acute coronary syndromes (ACS) who had been included in the CAPTURE trial (placebo v. abciximab). "Baseline" blood samples (sample time not stated). Follow-up at 30 days and 6 months. A separate validation sample of 626 consecutive patients presenting with chest pain <12 hours with no ST elevation on ECG. Follow-up at 30 days. Platelet activation was assessed by flow cytometry in a subgroup of 161 patients with chest pain	Prospective observational cohort	Correlation of CD40L with troponin T or CRP	No correlation (r=0.14 and 0.11, respectively)	Time of samples not stated. Blood samples only available for 86% of patients enrolled in the CAPTURE trial. Although CD40L levels are associated with increased risk of death or MI, the results are not clinically meaningful (cannot rule ACS in or out on the basis of these results)
			CD40L>5ug/l for prediction of adverse events at 72 hours	13.1% v. 4.3% (p<0.001). This gives sensitivity 67%, specificity 62%. Following +ve test, probability of event = 13%. Following -ve test, probability = 4%.
			CD40L>5ug/l for prediction of adverse events at 30 days	14.5% v. 5.3% (p<0.001). This gives sensitivity 65%, specificity 62%. Following +ve test, probability of event = 15%. Following -ve test, probability = 9.5%.
			CD40L>5ug/l for prediction of adverse events at 6 months	18.6% v. 7.1% (p<0.001). This gives sensitivity 64%, specificity 62.5%. Following +ve test, probability of event = 18.5%. Following -ve test, probability = 7%.
			CD40L levels in patients with acute chest pain	Significantly higher in patients with ACS (p<0.001). Higher risk of death/MI with CD40L>5ug/l (adjusted hazard ratio 6.65, p<0.001).
			Correlation between CD40L levels and platelet activation	Strong positive correlation (r=0.75, p<0.001)
Yan et al 2004 China	128 patients with ACS with recurrent resting chest pain plus ECG changes and >70% stenosis at coronary angiography. 68 patients with acute chest pain <6 hours and no ST elevation. Follow-up at 1 and 6 months. Timing of blood sample not stated.	Prospective observational cohort	Major adverse cardiovascular events at 30 days and 6 months	Higher incidence with increasing sCD40L (p<0.0001 at both times; patients split into three groups according to sCD40L level for analysis)	Blood sample time not stated Primary outcomes not clearly defined No statistical analysis reported in acute chest pain group
			Correlation of sCD40L with troponin T levels	Weak positive correlation (r=0.21, p=0.0369)
			sCD40L levels in patients with acute chest pain	Significantly higher levels in those subsequently diagnosed with ACS (no statistical analysis reported)
Yan et al 2004 China	12 with acute MI (AMI), 20 with unstable angina (UA), 24 with stable angina (SA) undergoing diagnostic coronary angiography and 16 healthy controls Time of sampling not stated	Prospective observational study	Plasma sCD40L levels	Higher in patients with UA (10.0+/-3.4ug/l) or AMI (10.6+/-3.8) compared with SA patients or controls (p<0.01 for both). No significant difference between UA and AMI	Time of sampling not stated (presumably before angiography) Small numbers Diagnosis had already been made at time of enrolment
			Correlation between sCD40 levels and complex stenosis morphology on angiography	Positive correlation (r=0.60, p=0.003).
Garlichs et al 2001 Germany	15 patients with AMI, 25 patients with UA, 15 matched patients with SA and 12 matched controls with atypical chest pain. All patients had undergone coronary angiography; all but the controls had at least one coronary stenosis >75%.	Prospective observational cohort	sCD40L levels	Higher in UA v. AMI (p<0.001); lower again in SA (p<0.001 v MI and UA) and in controls (p<0.001 v MI and UA; not significant v SA)	Patients identified for enrolment according to angiographic features - not clinically relevant sample. Small numbers. Timing of samples not stated (possibly after angiography, which may significantly bias the results).
			sCD40L levels at 6-month follow-up	Significantly lower in UA (p<0.001) and AMI (p<0.01). Patients who had a recurrent event had a significantly higher CD40L than those without (p<0.05)
Yan et al 2002 China	12 patients with AMI, 20 with UA, 24 with SA and 16 controls. Method of identification and time of blood sampling not stated.	Prospective observational study	sCD40L levels	Higher in SA, UA and AMI compared with controls (no P value or confidence intervals)	Inclusion criteria not stated. No objective criteria for diagnosis of AMI Baseline characteristics not stated. Notably suboptimal statistical analysis.
Aukrust et al 1999 Norway	26 with UA and 29 matched patients with SA who underwent diagnostic angiography, plus 19 matched controls.	Prospective observational study	sCD40L levels	Significantly higher in UA v. controls (p<0.001) and UA v. SA (p<0.05). Higher in SA v. controls (no P value given).	Timing of blood samples not stated No follow-up or outcome data Small numbers
Peng et al 2002 China	80 cardiology in-patients, 15 with AMI, 12 with UA, 23 with SA and 30 controls (chest pain but normal angiography or supraventricular tachycardia for radio-ablation)	Prospective observational study	Plasma sCD40L levels	Higher in ACS than controls (p<0.01) and SA (p<0.05). No significant difference between UA and AMI	Blood sampling time not standardised. AMI patients had blood drawn "before thrombolysis" but were cardiology in-patients. No follow up

Comment(s)

There is growing interest in the search for new cardiac markers that may allow earlier exclusion of ACS and superior risk stratification than is currently possible with troponins. Whereas troponins and CK-MB are markers of myocardial necrosis, which is the endpoint of the disease process, research is currently focusing on markers of earlier stages in the pathophysiological evolution of ACS. Soluble CD40 ligand is a transmembrane protein that is expressed by T cells, activated platelets, smooth muscle cells and endothelial cells within coronary atheroma (Schonbeck et al, 2001). It binds with CD40, leading to the release of procoagulant and atherogenic substances and enzymes which degrade the fibrous cap of atheroma rendering it unstable, and it impairs the regeneration of endothelial cells (Mach et al, 1997; Schonbeck et al, 1997; Zhou et al, 1998; Urbich et al, 2002). Raised levels in healthy women have been shown to predict adverse cardiovascular events. There is ample evidence that raised levels of sCD40L occur in ACS and are associated with an increased risk for recurrent events. However, there is insufficient information to recommend its implementation as a diagnostic test. Data from patients enrolled in the CAPTURE trial (Heeschens et al, 2003; tabulated) suggest that sCD40L levels can neither rule in nor rule out acute coronary syndromes. Future investigation should include large, well-designed prospective observational cohort studies of patients with undifferentiated chest pain, in order to evaluate the performance of sCD40L as a diagnostic test for ACS. Incorporation into a multimarker strategy may be more likely to yield positive results.

Clinical Bottom Line

Soluble CD40 ligand shows promise as an early marker for acute coronary syndromes but large, well-designed prospective observational cohort studies are necessary before it can be implemented as a diagnostic test.

References

1. Varo N; de Lemos JA; Libby P; Morrow DA; Murphy SA; Nuzzo R; Gibson CM; Cannon CP; Braunwald E; Schonbeck U Coluble CD40L: Risk prediction after acute coronary syndromes Circulation 108; 1049-1052
2. Heeschens C; Dimmeler S; Hamm CW; Van den Brand MJ; Boersma E; Zeiher AM; Simoons ML; for the CAPTURE Study Investigators Soluble CD40 ligand in acute coronary syndromes New England Journal of Medicine 2003; 348: 1104-1111
3. Yan JC; Zhu J; Gao L; Wu ZG; Kong XT; Zong RQ; Zhan LZ The effect of elevated serum soluble CD40 ligand on the prognostic value in patients with acute coronary syndromes Clinica Chimica Acta 2004; 343: 155-159
4. Yan JC; Wu ZG; Kong XT; Zong RQ; Zhan LZ Relation between upregulation of CD40 system and complex stenosis morphology in patients with acute coronary syndrome Acta Pharmacologica Sinica 2004; 25(2): 251-256
5. Garlichs CD; Eskafi S; Raaz D; Schmidt A; Ludwig J; Herrmann M; Klinghammer L; Daniel WG; Schmeisser A Patients with acute coronoary syndromes express enhanced CD40 ligand/CD154 on platelets Heart 2001; 86: 649-655
6. Yan J; Wu Z; Huang Z; Li L; Zhong R; Kong X Clinical implications of increased expression of CD40L in patients with acute coronary syndromes Chinese Medical Journal 2002; 115(4): 491-493
7. Aukrust P; Muller F; Ueland T; Berget T; Aaser E; Brunsvig A; Solum NO; Forfang K; Froland SS; Gullestad L Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndrome Circulation 1999; 100: 614-620
8. 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
9. Schonbeck U; Libby P The CD40/CD154 receptor/ligand dyad Cellular and Mollecular Life Sciences 2001; 58: 4-43
10. Mach F; Schonbeck U; Bonnefoy JY; Pober JS; Libby P Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40 Circulation 1997; 96: 396-399
11. Schonbeck U; Mach F; Sukhova GK; Murphy C; Bonnefoy JY; Fabunmi RP; Libby P Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? Circulation Research 1997; 81: 448-454
12. Zhou L; Stordeur P; de Lavareille A; Thielemans K; Capel P; Goldman M; Pradier O CD40 engagement on endothelial cells promotes tissue factor-dependent procoagulant activity Thrombosis and Haemostasis 1998; 79: 1025-1028
13. Urbich C; Dernbach E; Aicher A; Zeiher AM; Dimmeler S CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species Circulation 2002; 106: 981-986