Novel biochemical markers of vascular inflammation

Biochemical markers not only have contributed to a better understanding of the underlying pathophysiological mechanisms of ACSs but have also improved the evaluation of patients with acute chest pain who are suspected of having an ACS. For many years, unstable angina has been considered an intermediate "syndrome" between chronic stable angina and AMI. However, the pathophysiology of the ACS has now been clarified, with concurrent major advances in its management. The current pathophysiological concept describes ACSs as being related to an acute or a subacute primary reduction in myocardial oxygen supply that is provoked by disruption of an atherosclerotic plaque associated with thrombosis, vasoconstriction, and microembolization. Convincing evidence suggests that both inflammatory and thrombotic mechanisms are involved in the pathogenesis of ACSs (3,4). Inflammatory reactions promote plaque Assuring or erosion, which exposes throm-bogenic contents such as collagen to the circulation, followed by platelet activation and platelet adhesion. It is now apparent that ACSs, namely unstable angina and evolving MI, share a common anatomic substrate: pathological, angioscopic, and biological observations have demonstrated that unstable angina and MI are only different clinical presentations that result from a common underlying pathophysiological mechanism—atherosclerotic plaque rupture or erosion—with differing degrees of superimposed thrombosis and distal embolization (Fig. 1) (2,5).

Elevated levels of circulating cardiac troponin, a marker of myocardial necrosis, are found in about one-third of patients with ACS and are associated with an increased short-term risk of death and nonfatal MI (6-9). Although the absolute short-term risk of tropo-nin-negative patients is significantly lower compared with troponin-positive patients, the large number of patients without troponin elevation remains clinically challenging with respect to risk assessment and therapeutic management. Specifically, the 6-mo risk of death or nonfatal MI in troponin-negative patients was 8.4% in the CAPTURE (c7E3 Anti Platelet Therapy in Unstable Refractory angina) trial (10). Therefore, the availability of a sensitive and specific early marker of plaque instability, wherein levels become elevated before or even in the absence of myocardial necrosis, should improve diagnostic and therapeutic decision making.

Of the numerous inflammatory markers that have been investigated over the past decade, C-reactive protein (CRP) is clearly the most widely studied. There is compelling epide-miological evidence that CRP is a sensitive marker of inflammation and/or metabolic processes associated with atherogenesis and the occurrence of cardiovascular events. Although

Thrombo-inflammatory activation • Vascular inflammation

■ Plaque destahfi"tinn o

glycoprotein llb/llla inhibitors

Thrombo-inflammatory activation • Vascular inflammation

■ Plaque destahfi"tinn o

Unstable thrombus formation

• Embolization from thrombus formation

• Myocardial cell injury (troponins)

• Stratification for invasive therapy I

glycoprotein llb/llla inhibitors

Unstable thrombus formation

• Embolization from thrombus formation

• Myocardial cell injury (troponins)

• Stratification for invasive therapy I

Fig. 1. Earlier markers ofvascular inflammatory and thromboinflammatory activation, respectively, may precede the development of myocardial injury (troponin release) or neurohumoral activation (B-type natriuretic peptide [BNP] or NT-proBNP release) in patients with ACS.

CRP has been shown to be useful for risk assessment in different cohorts (11-13), the debate as to whether or not CRP is indeed a clinically useful biomarker continues. The data that Danesh et al. (13) reported derived from the Reykjavik prospective cohort study, which included 2459 patients with stable coronary heart disease and 3969 selected control subjects, suggested that the predictive value of a single baseline measurement of CRP for the 20-yr incidence of cardiovascular events was much less impressive than in previously published data (14,15). They found that CRP adds little to the predictive value provided by the assessment oftraditional risk factors, including low-density lipoprotein (LDL) cholesterol. By contrast, Ridker et al. (16) previously reported that CRP could be even more predictive than LDL. Since the Reykjavik study included by far the largest number of events (albeit during a rather long follow-up period of 20 yr) that have been studied in such analyses, the new findings emphasize the need for more research to clarify the use of CRP as a marker of cardiovascular risk in clinical practice. Specifically, future studies will have to reliably characterize the shape of the relationship between CRP values and coronary risk as well as to investigate the use of CRP for risk prediction in particular subgroups (e.g., in those with different serum lipid concentrations and for different periods of follow-up).

In patients with ACSs, elevated levels of CRP are associated with higher future risk of cardiovascular events (17-19). The CAPTURE trial investigators found that, although only troponin T was predictive in the initial 72-h period, CRP was an independent predictor ofcardiovascular risk at 6 mo (19). Investigators ofthe FRISC study, the TIMI 11A sub-study, and the GUSTO IV substudy also reported that the risk associated with elevated CRP levels at the time of the index event continues to increase during follow-up (18,20,21). More important, however, the exact source of elevated CRP levels among patients with unstable coronary syndromes remains unclear. Given that myocardial damage is also a major inflammatory stimulus, it is important to note that in a recent combined analysis of FRISC-II and GUSTO-IV, CRP elevation over a period of up to 120 h after the onset of symptoms was found only in patients with elevated troponin levels (21). Consistently, in CAPTURE patients, CRP levels were significantly higher in troponin-positive patients (19), suggesting that an acute inflammatory process induced by myocardial damage is superimposed on a chronic inflammatory condition, both of which might influence long-term outcome in unstable CAD.

Type 2 secretory phospholipase A2 (sPLA2) is also an acute-phase reactant, which accumulates in atherosclerotic arterial walls, elicits several effects on monocytes, and provides a link between inflammation and lipid accumulation in atherosclerotic plaques. sPLA2 is present in the media of normal as well as diseased arteries, hydrolyzes phospholipids, and contributes to the production of oxidized LDL, which is taken up by macrophages, resulting in enhanced transformation into foam cells. sPLA2 exhibits features similar to those of CRP as a marker of plaque inflammation as well as endothelial dysfunction (22,23) and may predict coronary events independently of other risk factors in patients with unstable angina (24). Similarly, elevated levels ofthe lipoprotein-associated PLA2 (Lp-PLA2), a different approach to determine PLA2 activation, have been shown to predict future coronary events in apparently healthy middle-aged men with moderately elevated total cholesterol, independent of CRP (25). No data on the predictive value of Lp-PLA2 in patients with ACS have been published to date.

Therefore, as a result of lack of specificity of acute-phase proteins for detecting the underlying vascular inflammation in patients with ACS, research activities have shifted to the identification of more upstream markers of the inflammatory cascade, which may be more representative of vascular inflammation (Fig. 2). These novel inflammatory markers include pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), soluble CD40 ligand (sCD40L), and myeloperoxidase (MPO).

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