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Sir,—Considerable research energy is being directed towards cell adhesion molecules, and the recent review by Hillis and Flapan1 provides a useful introduction. As they allude to, blockade of the interaction between leucocytes and the endothelium by agents that mimic or inhibit these adhesion molecules may become a new class of therapeutic agent.2 3 However, Hillis and Flapan only briefly draw our attention to the presence of soluble forms of these adhesion molecules in plasma.
The importance of these soluble forms is probably underestimated, as they may interfere with, or frustrate, attempts to reduce leucocyte–endothelial interactions in vivo, as has already been shown in vitro.4 5 In addition, soluble adhesion molecules may be useful in dissecting the various pathophysiological events in cardiovascular disease, as it may be presumed that changes in concentrations may relate to activation or damage to various cells, such as the platelet and endothelium, which are pertinent to cardiovascular pathophysiology.
For example, the selectin family of adhesion molecules has three members, and corresponding soluble concentrations are measurable in the plasma. Soluble P selectin is believed to be the product of activated platelets, despite the endothelium having a membrane bound form.6 7 Increased concentrations have been found in a number of conditions: thrombotic disorders, diabetes, and ischaemic heart disease. Importantly, raised concentrations in the last group of patients is predictive of adverse events.8-10 Although increased concentrations of soluble E selectin are the result of cytokine activation of endothelial cells in vitro,11raised plasma concentrations have been reported in variant angina,12 and in ischaemic heart disease13; in the latter group of patients, raised concentrations do not appear to predict adverse events.14 Finally, it is still unclear whether concentrations of soluble L selectin, derived from leucocytes, are altered in ischaemic heart disease, although we have been unable to demonstrate significant differences between patients with peripheral atherosclerosis and healthy controls.15 However, Siminiak and colleagues16 recently reported raised concentrations within one hour to three days following admission for acute myocardial infarction.
The second major group of adhesion molecules belong to the immunoglobulin supergene family, and three members, with measurable soluble forms, warrant attention. Soluble intercellular adhesion molecule 1 (sICAM-1) is a likely product of many cells, including the endothelium and leucocytes. Also influenced by inflammatory cytokines in vitro,11 raised sICAM-1 concentrations are found in many conditions, including angina12 and both coronary artery disease and peripheral artery disease.17 Raised concentrations in healthy men predict adverse events,18however, the association appears to be weak when there is already a background of existing atherosclerosis.19 Conversely, vascular cell adhesion molecule 1 (sVCAM-1) does not seem to be increased in the plasma of patients with angina or coronary artery disease12 17): nor do concentrations predict adverse outcome.19 However, concentrations do rise slowly (reaching a peak on day 3) after an acute myocardial infarction, and are moderately raised in some forms of peripheral atherosclerosis,19 with some correlation with the extent of disease.20 21 Soluble platelet endothelial cell adhesion molecule 1 (sPECAM-1) may also arise from many cells, including endothelial cells, platelets, and leucocytes. We have however been unable to find differences in the plasma of patients with coronary artery disease or peripheral artery disease compared to controls.22
Despite the above, a firm consensus about the significance and value of concentrations of soluble adhesion molecules in cardiovascular disease has yet to emerge, mainly due to some contradictory results. For example, Frijns et al have reported raised concentrations of soluble E selectin in ischaemic stroke and carotid atherosclerosis, whereas we have been unable to find increased concentrations in patients with peripheral atherosclerosis; conversely, unlike us, they failed to find raised sICAM-1.17 23 De Caterina and colleagues21 reported raised sVCAM-1 in peripheral atherosclerosis, whereas our group and Frijnset al have been unable to do so.17 23
It would be easy to jump to the conclusion that these inconsistencies are due to differences such as those of the type and degree of disease of the subjects, and/or laboratory methods, although most of the latter are commonly used commercial reagents. However, by and large, none of these essentially cross sectional studies have recruited particularly large (> 100) numbers of subjects, so that this may be one source of the inequalities. Until several large, hopefully prospective, studies are published, it seems likely that the simple immunohistochemical demonstration of cell adhesion molecules or the measurement of soluble adhesion molecules has little to offer current practising cardiologists in their quest for improved patient care. Nevertheless, the recognition that cell adhesion molecules do at least play some important role(s) in cardiovascular pathology is a small step forward in the complex field of vascular biology and pathophysiology.
This letter was shown to Drs Hillis and Flapan, who reply as follows:
Drs Blann and Lip provide an excellent appraisal of the current state of research into the role of soluble adhesion molecules in cardiovascular disease. Although this is an area that was only mentioned briefly in our overview we agree that it is of interest and importance.
As they note, soluble adhesion molecules may affect the activity of leucocytes in vivo. Certainly, this has been demonstrated in vitro, where soluble E selectin is capable of increasing neutrophil β2 integrin expression and motility.1-1 This may facilitate their adhesion to damaged arterial endothelium or, potentially, encourage their sequestration in capillary beds that would, in turn, reduce the numbers available at other sites.1-2 An alternative possibility is that soluble adhesion molecules might reduce leucocyte adhesion and/or diapedesis by competing for binding sites or by less direct mechanisms.1-3 Until such issues are resolved, and the precise contribution of each molecule is better understood, therapeutic use of systemic adhesion receptor analogues is some way off—local administration may be a more realistic approach in any case. Similarly, it may become possible within the next few years to combine improved vascular imaging with adhesion receptor labelled vehicles that are capable of binding to, and thus identifying, diseased and activated endothelium.1-4
While soluble adhesion molecules may complicate efforts to manipulate leucocyte–endothelial cell interactions serum concentrations could provide a useful insight as to the health of vascular endothelium. Raised plasma concentrations of sICAM-1 and, to a lesser extent, E selectin appear to be clearly associated with atherosclerosis,1-5 while results regarding sVCAM-1 are less consistent.1-5-1-7 Ridker et alhave recently reported that sICAM-1 concentrations are independent predictors of future acute myocardial infarction1-8 and, although it has been suggested that this association is weakened in patients with existing atherosclerosis,1-6 1-9 the small numbers and diverse end points in the latter cohort make it difficult to draw any firm conclusions.
In addition to the increase of sICAM-1 in stable coronary artery disease, concentrations rise further in unstable disease1-10 1-11—presumably reflecting endothelial damage and activation. These early data exhibit a striking similarity to previous reports linking raised C reactive protein (CRP) to atherosclerosis and cardiovascular risk.1-12 1-13 This suggests that sICAM-1 may serve as a more specific indicator of endothelial dysfunction and inflammation. However, while raised CRP is associated with adverse outcome in acute coronary syndrome, there have been no large trials assessing the predictive value of sICAM in this setting.
Whether soluble cell adhesion molecules prove to be useful diagnostic or prognostic indicators remains to be seen. There is increasing evidence that atherosclerosis shares many of the characteristics of a chronic inflammatory process, that infectious agents may be involved in its cause, and that infiltrating white cells contribute to the instability of atherosclerotic plaques.1-14-1-16 It seems likely, therefore, that molecules that are so fundamental to the interactions between leucocytes and endothelium can give valuable insights into the mechanisms of coronary artery disease and possible outcome.