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Three Part Question

In [patients with suspected cardiac chest pain presenting to the Emergency Department] does [measurement of plasma E-selectin] enable [exclusion of acute coronary syndromes]?

Clinical Scenario

A fifty year-old lady with a severe needle phobia presents to the Emergency Department with a three-hour history of central tight chest pain. Baseline observations, chest radiograph and initial ECG are normal. You feel that you ought to exclude acute coronary syndrome before discharging her.
Particularly in view of her needle phobia, you would like to be able to exclude the diagnosis using her admission blood samples but you are aware that troponin will be insufficiently sensitive at this time. Serial CK-MBmass would necessitate serial venepuncture. You wonder if there is an early marker you could use. As e-selectin as been proposed as such an early marker, you wonder if its measurement would help in this situation.

Search Strategy

OVID Medline 1966 - Week 3 August 2005
OVID Embase 1980 - 2005 Week 35
[exp Myocardial Infarction/ OR exp Coronary Thrombosis/ OR exp Angina, Unstable/ OR (heart attack OR MI OR AMI O R unstable angina OR (acute adj coronary adj syndrome) OR ACS).mp. OR (myocard$ adj (infarct$ OR ischaem$ OR ischem$).mp.] AND [exp E-Selectin/ OR e selectin.mp. OR endothelial cell leucocyte adhesion molecule$.mp. OR ELAM$.mp.] limit to human and English language

Search Outcome

Altogether 98 papers were identified in Medline and 123 in Embase. One papers that appraised the use of E-selectin in an Emergency Department population with undifferentiated chest pain was identified. Several papers that investigated E-selectin levels in various acute coronary syndromes are discussed, together with other relevant papers.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hope et al 2002 Australia	57 patients presenting to the Emergency Department with chest pain. 13 had AMI, 23 UA and 21 non-cardiac pain. Blood taken at mean 2 hours 17 minutes from symptom onset.	Prospective diagnostic cohort	E-selectin levels according to time of sampling	Levels did not change with time from symptom onset	Small numbers. Suboptimal gold standards: AMI diagnosis not according to WHO guidelines and used CK-MB not troponins as gold standard biochemical markers; UA diagnosis required a minimum of "typical chest pain at rest" with no objective verification; only "some" patients with non-cardiac chest pain underwent exercise testing. No clinical follow up, which is at least as important as comparing diagnosis with accepted gold standards. ROC curve analysis, sensitivity, specificity, PPV and NPV not reported.
			E-selectin levels in AMI, UA and controls	No significant differences between groups

Comment(s)

Leucocyte adhesion and subsequent migration across the endothelium is pivotal to the development of coronary atherosclerosis (Kher et al, 2004). Their initial attachment to endothelial cells is mediated by cell adhesion molecules, including the selectin family. E-selectin is synthesised by endothelial cells in response to stimulation by interleukin-1 and tumour necrosis factor-alpha (Price et al, 1999). It binds to a ligand on the cell surface of leucocytes, causing the leucocytes to 'roll' across the endothelium (Bevilacqua et al, 1987). If the leucocytes then encounter activating signals from other cell adhesion molecules, they adhere firmly to the endothelium and may transmigrate across the endothelium into the intima. From there, macrophages accumulate lipids and secrete proinflammatory and atherogenic cytokines, matrix metalloproteinases that destabilise the fibrous cap of atheroma and the procoagulant tissue factor (Szmitko et al, 2003; Libby et al, 1995; Davies et al, 1996). Inhibition of neutrophil adhesion has been shown to limit myocardial infarct size and reduce myocardial reperfusion injury in animal models (Curtis et al, 1993; Litt et al, 1989). Soluble E-selectin is potentially useful as a biochemical marker as it can be easily measured by ELISA techniques and is stable under laboratory conditions (Hope et al, 2002). Seven authors have reported raised E-selectin levels in AMI (Squadrito et al, 1996; Miyao et al, 1999; Zeitler et al, 1997; Li et al, 1997; Suefuji et al, 2000; Pellegatta et al, 1997; Siminiak et al, 1998). Two authors have demonstrated raised E-selectin in UA (Atalar et al, 2001; Ghaisas et al, 1997). Five authors have reported raised E-selectin in all ACS (Xie et al, 2000; Mulvihill et al, 1999; Mulvihill et al, 2000; Squadrito et al, 1995; Guray et al, 2004). Raised E-selectin levels have been reported following attacks of variant angina (Miwa et al, 1997), although Siminiak et al (1997) found no difference in E-selectin levels during angina attacks. Two authors have reported a reduction in E-selectin following successful reperfusion in AMI (Squadrito et al, 1995; Squadrito et al, 1996). Two authors have also shown a correlation between E-selectin levels and severity of atherosclerosis (Oishi et al, 2000; Parker et al, 2001). Further, Zeitler et al (1997) demonstrated higher E-selectin in those who died of AMI than in survivors. Suefuji et al (2000) found that E-selectin was higher in patients with AMI who had experienced a prodrome of UA. However, three authors have failed to find elevated E-selectin levels in ACS (Gurbel et al, 1998; Galvani et al, 2000; Shyu et al, 1996). There is no clear explanation for the discrepancy in the results. Only one study has investigated E-selectin levels in the Emergency Department population with undifferentiated chest pain. This study failed to demonstrate a difference in E-selectin levels between patients with AMI, UA and controls. However, the study had significant limitations, including small numbers, suboptimal gold standards and no clinical follow-up. The study was not designed to appraise the performance of E-selectin as a diagnostic test for use in the Emergency Department. The available research suggests that E-selectin has promising characteristics for use as a marker of ACS. A large prospective observational cohort study is necessary to evaluate its performance as a diagnostic test. Incorporation into a multimarker strategy with markers that may reflect other aspects of the pathophysiological evolution of ACS may be necessary to obtain sufficient sensitivity.

Editor Comment

Abbreviations: AMI: acute myocardial infarction; UA: unstable angina; ACS: acute coronary syndrome

Clinical Bottom Line

Available research suggests that E-selectin may be a promising marker of ACS but there is currently no available evidence to appraise its use as a diagnostic test in the Emergency Department.

References

1. 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
2. Blann AD; Amiral J; McCollum CN. Prognostic value of increased soluble thrombomodulin and solulbe E-selectin in ischaemic heart disease European Journal of Haematology 1997; 59(2): 115-120
3. 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
4. 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
5. Miwa K; Igawa A; Inoeue H. Soluble E-selectin, ICAM-1 and VCAM-1 levels in systemic and coronary circulation in patients with variant angina Cardiovascular Research 1997; 36: 37-44
6. Shyu KG; Chang H; Lin CC; Cuan P. Circulating inercellular adhesion molecule-1 and E-selectin in patients with acute coronary syndrome. Chest 1996; 109: 1627-1630
7. Galvani M; Ferrini D; Ottani F; Nanni C; Ramberti A; Amboni P; Iamele L; Vernocchi A; Nicolini FA. Soluble E-selectin is not a marker of unstable coronary plaque in serum of patients with ischemic heart disease. Journal of Thrombosis and Thrombolysis 2000; 9: 53-60
8. Gurbel PA; Serebruany VL. Soluble vascular cell adhesion molecule-1 and E-selectin in patients with acute myocardial infarction treated with thrombolytic agents American Journal of Cardiology 1998; 81: 772-775
9. Parker C 3rd; Vita JA; Freedman JE. Soluble adhesion molecules and unstable coronary artery disease Atherosclerosis 2001; 156(2): 417-424
10. Mulvihill NT; Foley JB; Murphy RT; Curtin R; Crean PA; Walsh M. Risk stratification in unstable angina and non-Q wave myocardial infarction using soluble cell adhesion molecules. Heart 2001; 85: 623-627
11. Squadrito F; Altavilla D; Ioculano M; Canale P; Campo GM; Squadrito G; Ditano G; Freni F; Saitta A; Caputi AP. Soluble E-selectin levels in acute human myocardial infarction International Journal of Microcirculation: Clinical and Experimental 1995; 15(2): 80-84
12. 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
13. 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
14. 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
15. Suefuji H; Ogawa H; Yasue H; Sakamoto T; Miyao Y; Kaikita K; Soejima H; Misumi K; Miyamoto S; Kataoka K. Increased plasma level of soluble E-selectin in acute myocardial infarction. American Heart Journal 2000; 140: 243-248
16. 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
17. 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
18. Ghaisas NK; Shahi CN; Foley B; Goggins M; Crean P; Kelly A; Kelleger 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
19. Miyao Y; Miyazaki S; Goto Y; Itoh A; Daikoku S; Morli 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(5): 362-266
20. 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: 1210-1216
21. Guray U; Erbay R; Guray Y; Yilmaz B; 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
22. 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
23. Atalar E; Aytemir K; Haznedaroglu I; Ozer N; Ovunc K; Aksoyek S; Kes S; Kirazli S; Ozmen F. Increased plasma levels of soluble selectins in patients with unstable angina International Journal of Cardiology 2001; 78: 69-73
24. Bevilacqua MP; Pober JS; Mendrick DL; Cotran RS; Gimbrone MA. Identification of an inducible endothelial-leukocyte adhesion molecule Proc Natl Acad Sci USA 1987; 84: 9238-9242
25. Price DT; Loscalzo J. Cellular adhesion molecules and atherogenesis American Journal of Medicine 1999; 107: 85-97
26. Oishi Y; Wakatsuki T; Nishikado A; Ito S. Circulating adhesion molecules and severity of coronary atherosclerosis Coronary Artery Disease 2000; 11(1): 77-81
27. Kher N; Marsh JD. Pathobiology of atherosclerosis - a brief review Seminars in Thrombosis and Hemostasis 2002; 30(6): 665-672
28. Price DT; Loscalzo J. Cellular adhesion molecules and atherogenesis American Journal of Medicine 1999; 107: 85-97
29. Szmitko PE; Wang CH; Weisel RD; de Almeida JR; Anderson TJ; Verma S. New markers of inflammation and endothelial cell activation Part 1 Circulation 2003; 108: 1917-1923
30. Libby P. Molecular bases of the acute coronary syndromes Circulation 1995; 91: 2844-2850
31. Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995 Circulation 1996; 94: 2013-2020
32. Curtis WE; Gillinov AM; Wilson IC; Bator JM; Burch RM; Cameron DE; Gardner TJ. Inhibition of neutrophil adhesion reduces myocardial infarct size. Annals of Thoracic Surgery 1993; 56: 1069-1072
33. Littt Mr; Jeremy RW; Weisman HF; Winkelstein JA; Becker LC. Neutrophil depletion limited to reperfusion reduces myocardial infarct size after 90 minutes of ischemia Circulation 1989; 80: 1816-1827