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NEJM
Jane E. Freedman, M.D. Platelet activation is central to the formation of thrombus, which precipitates most unstable coronary syndromes. The angiographic severity of coronary stenoses may not predict the occurrence of acute cardiac events, since rupture of atheromatous plaque and subsequent thrombosis in slightly stenosed vessels may underlie many myocardial infarctions. Normally, the intact endothelium prevents platelet activation, but intimal injury associated with endothelial denudation and plaque rupture exposes subendothelial collagen and von Willebrand factor, supporting prompt platelet adhesion and activation. Local platelet activation then promotes the recruitment of platelets and the formation of thrombus. The importance of platelet-dependent thrombosis has made activated platelets a common therapeutic target in acute coronary syndromes. Platelet inhibitors have included aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors. Although these agents have distinct mechanisms of action, all of them inhibit fibrinogen-dependent platelet–platelet associations. However, merely measuring the process of platelet aggregation may not provide relevant information about the myriad complex signaling pathways that lead to the release of substances contributing to inflammation and thrombosis in cardiovascular disease. Acute myocardial infarction is commonly diagnosed by measuring markers of cardiac necrosis. These markers reflect the extent of cardiac damage but fail to provide direct information about plaque disruption or platelet activation. Because the outcome of acute coronary syndromes is highly dependent on inflammation and thrombosis, it is possible that measurement of these two processes will allow better assessment of plaque instability. An established link between inflammation and thrombosis in acute coronary syndromes is the formation of platelet–monocyte (heterotypic) aggregates when platelets bind by way of surface-expressed P-selectin (CD62P) to P-selectin glycoprotein ligand 1, a leukocyte receptor.1,2 Circulating platelet–monocyte aggregates have been shown to be an early marker of acute myocardial infarction3 and to contribute to the formation of atherosclerotic lesions.4 Although platelet–monocyte aggregates can provide useful information about the thrombotic or inflammatory state and can identify patients at high risk for cardiac events, their measurement can be cumbersome. As compared with platelet–monocyte aggregates, measurement of soluble CD40 ligand (also called CD154), an immunomodulator, does not require flow cytometry and can be accomplished with stored samples. CD40 ligand is a trimeric, transmembrane protein of the tumor necrosis factor family and, together with its receptor CD40, is an important contributor to the inflammatory processes that lead to atherosclerosis and thrombosis.5 A large variety of immunologic and vascular cells have been found to express CD40, CD40 ligand, or both. Both CD40 and CD40 ligand have been shown to be present in human atheroma.6 In platelets, CD40 ligand is rapidly translocated to the platelet surface after stimulation and is up-regulated in fresh thrombus.5 The surface-expressed CD40 ligand is then cleaved from the platelets over a period of minutes to hours, subsequently generating a soluble fragment (soluble CD40 ligand).7 Although it may also be shed from stimulated lymphocytes, it is estimated that more than 95 percent of circulating CD40 ligand is derived from platelets.7 Soluble CD40 ligand has been shown to be associated with an increased risk of cardiovascular events in apparently healthy women.8 In this issue of the Journal, Heeschen et al.9 provide important information about the clinical relevance of levels of soluble CD40 ligand in patients presenting with chest pain. In their study, which involved patients who had previously been enrolled in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) study,10 soluble CD40 ligand identified patients at high risk for acute coronary syndromes. In the original CAPTURE report, elevated levels of troponin T identified a subgroup of patients who significantly benefited from treatment with abciximab.10 The current study demonstrates that, in contrast to troponins, the predictive value of the level of soluble CD40 ligand with respect to the effects of abciximab is independent of the presence or absence of recent myocardial infarction. In patients who received placebo, elevated levels of soluble CD40 ligand were associated with a significantly increased risk of death or myocardial infarction. The increased risk associated with elevated levels of soluble CD40 ligand was reduced with abciximab treatment. Taken together, these observations suggest that elevation of soluble CD40 ligand identifies patients with an increased risk of thrombosis. In addition, among patients who were negative for troponin T, soluble CD40 ligand identified those at increased risk for cardiac events, suggesting that measurement of these diagnostic markers of coronary ischemia has additive benefits. Few studies defining the level of soluble CD40 ligand that reflects an increased risk of cardiac events are available. It cannot be assumed that the threshold level chosen for study by Heeschen et al. (5.0 µg per liter) will be relevant to other patient populations; a study in a population of healthy women defined a significantly lower level of soluble CD40 ligand as the threshold for increased cardiovascular risk.8 The demographic limitations of the current study — especially the preponderance of male patients — must be noted as further studies attempt to identify the relevant diagnostic levels. Accordingly, Heeschen et al. also report data from an additional, clinically more diverse, group of patients presenting with chest pain. In that group, patients with an increased risk of acute coronary syndromes had levels of soluble CD40 ligand similar to those reported in the CAPTURE study.9 In the CAPTURE study,9 soluble CD40 ligand did not correlate with markers of inflammation, including C-reactive protein. Although it has clearly been shown that increased levels of C-reactive protein identify persons at risk for cardiovascular events,11 C-reactive protein may be a more general marker of inflammation and atherogenesis than soluble CD40 ligand and may be less reflective of the acute thrombotic process. Clearly, additional studies are needed to define the interaction and relative value of these markers of inflammation. In an additional study, a correlation was found among soluble CD40 ligand, platelet–monocyte aggregates, and surface P-selectin expression, again suggesting the presence of enhanced platelet activation in addition to inflammation. However, from the data provided it is unclear whether the findings can be extended to other glycoprotein IIb/IIIa inhibitors or to thienopyridines. Although the presence of soluble CD40 ligand reflects platelet activation during a cardiac event, does this immunomodulator itself play a part in the acute thrombotic process? On endothelial cells or monocytes, the engagement of CD40 with CD40 ligand leads to the synthesis of adhesion molecules, chemokines, and tissue factor and causes activation of the matrix metalloproteinases that are known to contribute to atherothrombotic pathophysiological changes. Soluble CD40 ligand has a lysine–arginine–glutamic acid motif that allows it to bind to platelet glycoprotein IIb/IIIa. It is possible that such binding is blocked when glycoprotein IIb/IIIa inhibitors are present, potentially altering the clot-stabilizing properties of soluble CD40 ligand.12 The current study does not reveal whether the presence of CD40 ligand is merely an epiphenomenal reflection of the inflammatory and thrombotic processes or whether it directly contributes to acute coronary events, but it does provide encouraging data that may assist in defining unstable coronary syndromes. Although this marker needs further evaluation to establish its reliability in specific patient populations and clinical settings, soluble CD40 ligand may be an indicator of platelet activation and unstable plaque that can provide information in addition to that provided by the commonly used markers of cardiac necrosis. Clearly, there can be no single, perfect marker of the complex pathophysiological events contributing to unstable coronary syndromes, but it is possible that a combination of markers that reflect inflammation and thrombosis, before the onset of damage, would have considerable prognostic and therapeutic value.
From the Evans Department of Medicine, Boston University School of Medicine, Boston. References
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