Markers of Plaque Vulnerability Rupture and Thrombosis

C-Reactive Protein

C-reactive protein (CRP) is a hepatically derived pentraxin that serves as the prototypic acute-phase reactant; it has been extensively evaluated for detection of cardiac risk (9). Most studies of CRP have focused on its ability to augment risk assessment for both primary and secondary prevention of cardiovascular events. However, in addition to these uses of CRP, studies have also evaluated CRP in the context of acute presentation with chest discomfort. CRP is elevated in some patients with unstable angina, i.e., in the absence of myocardial necrosis (10), and is associated with a higher risk of fatal complications in that setting (11). However, the concentration of CRP does not increase predictably in the first 96 h after the development of ischemia and does not appear to correlate with the number and duration of ischemic episodes (10). Thus, although CRP and other nonspecific markers of inflammation may serve as early markers of atherothrombosis in some settings, the majority of markers in this class are not likely to confer sufficient specificity for ischemia itself to be useful as a biomarker for its diagnosis. Nevertheless, biomarkers with greater specificity for acute changes within the vulnerable coronary atheroma maintain potential as diagnostic markers for ACS.

Soluble CD40 Ligand

CD40 ligand (CD40L) is a trimeric transmembrane protein that is related to tumor necrosis factor-a (TNF-a) and is present on endothelial cells, monocytes, macrophages, and platelets. It is present already synthesized and is available for release within seconds of the appropriate stimulus. Surface-expressed CD40L is cleaved and persists in the circulation for hours as the active form, sCD40L (12). More than 90% of the sCD40L present in the circulation is derived from platelets, and sCD40L additionally acts as a platelet agonist, thus serving to upregulate platelet activation while weaving platelet activation into further stimulation of the inflammatory cascade (13). A rapid rise in the concentration of sCD40L is thus likely to occur at the time of plaque rupture and thrombosis.

The concentration of sCD40L is elevated in patients with unstable angina and is associated with the risk of death and recurrent ischemic events (14,15). However, as is the case for CRP, this analyte appears to provide primarily prognostic, rather than robust, diagnostic information. In studies of sCD40L in ACS, levels of this biomarker were elevated in <50% of the population (14,15). This finding can be anticipated from its mechanism of release, which is not expected to be present in all patients with ischemia, but may serve to identify those in whom platelet activation and thrombosis is a major contributor.

Myeloperoxidase

Myeloperoxidase (MPO) is a leukocyte enzyme secreted during neutrophil activation that has been implicated in the disruption of atherosclerotic plaques and has been shown to be present in increased concentrations within ruptured compared with stable atheroma. Blood obtained from patients presenting with AMI has levels of MPO that are fourfold higher than that of control patients (16). Among patients with ACS, there is poor correlation between the concentrations of MPO and troponin, soluble CD40L, or CRP (17), suggesting that MPO is not simply a marker of necrosis, platelet activation, or inflammation. A strong association between MPO and the risk of major cardiac events was apparent in at least two studies (17,18). The diagnostic utility of MPO has been proposed based on evidence that it may be a very early marker of plaque destabilization (18). Consistent with this hypothesis, in a study of patients with suspected ACS, MPO was elevated at presentation in a larger proportion of patients than cardiac troponin and preceded elevation of troponin in many who went on to manifest diagnostic criteria for MI (18). Nevertheless, this application requires further study, particularly in populations with low prevalence of disease.

Pregnancy-Associated Plasma Protein A

Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that is expressed in atherosclerotic plaque. Increasing levels of PAPP-A appear to correlate with increasing plaque instability, as well as plaque complexity (19,20). In patients with ACS, the concentration of PAPP-A is elevated in up to two-thirds of patients, rising variably from as early as 2 h or as late as 30 h after the apparent onset of ACS. Moreover, in a study of 200 serial patients with ACS, levels of PAPP-A were independently associated with an increased risk of cardiovascular events (21). When studied as a diagnostic marker for ACS, receiver operator curve analysis supported an optimal cutoff value for PAPP-A of 0.22 mIU/L, with a sensitivity of 66.7% and a specificity of 51.1%. Interestingly, in this population the sensitivity ofcardiac troponin T at presentation was also 51.5%, with a specificity of82.1% (22).

Whole-Blood Choline

Choline is the major enzyme product of phospholipase D, a protein that it is stimulated by the activation of cell-surface receptors on leukocytes and platelets and that appears to be involved in signal transduction during events that lead to plaque destabilization (23, 24). Using nuclear magnetic resonance spectroscopy of whole-blood ultrafiltrates to screen for novel markers associated with ACS, Wevers et al. (25) identified choline as a marker consistently present in the circulation in this setting. In a subsequent clinical study involving 327 patients with ACS, 250 of whom were troponin negative, levels of choline (divided into quartiles) were shown to correlate with the 30-d risk of death, heart failure, and cardiac arrest (Fig. 1) (26). More important, this prognostic relationship was also apparent in the subgroup of patients without elevated levels of cardiac troponin.

However, in the same study, levels of choline were not consistently elevated in patients with MI, and the mean values for patients with noncardiac chest pain (19.4 ± 6.8 pmol/L) were not substantially different from those with low-risk unstable angina (24.5 ± 15 pmol/L). Although the half-life of whole-blood choline in patients with ACS has not yet been defined, it is noteworthy that the highest sensitivity of this analyte was observed with the admission blood sample, implying a short diagnostic half-life and also suggesting that use of

Fig. 1. Risk of cardiac death or arrest stratified by results oftesting for choline and cardiac troponin. (Data from ref. 26.)

whole-blood choline may be limited in patients who present long after their episode of chest discomfort. Further studies will be necessary to evaluate the diagnostic application of this novel marker.

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