CRP as a Marker of Widespread Inflammation

One of the limitations of CRP as a marker of cardiovascular disease activity is that CRP represents a sensitive but nonspecific marker. It is not specific to vascular or plaque inflammation and, therefore, correlating this protein with CVD is difficult. The more recent and continuously evolving knowledge regarding the pathobiology of ACS suggests a complex and possibly systemic involvement of the endothelium, blood cells, and proteins. The reasons for adverse prognosis in patients with elevated CRP levels are still poorly understood (Fig. 3). Liuzzo et al. (38,39) have described a monoclonal T-cell proliferation in patients with ACS and the expansion of a specific clone displaying CD4+CD28-null receptors. The expansion of these inflammatory cells paralleled the risk profile of patients with ACS, providing evidence not only of their importance with respect to risk but also with respect to the pathophysiological mechanism of plaque infiltration and rupture. Furthermore, activated T-cells were also found diffusely in epicardial coronary arteries and in ischemic and nonischemic myocardium in patients with ACS (40,41). These findings led to the concept of widespread inflammation in ACS not confined to culprit plaque or vessel, but involving the entire coronary circulation, the myocardium, and possibly also other vascular districts (40-44). Abbate et al. (42) have reported the presence of widespread inflammation in the myocardium in two-thirds of patients with recent AMI. Others confirmed that the concentration of CRP in patients with ACS correlates with the presence of multiple coronary plaques (43), and complexity of atherosclerotic plaques involving the carotid artery (44).

Given the apparent important role of T-lymphocytes and the fact that these cells have antigen-restricted T-cell receptors, several groups have attempted to search for the culprit

Fig. 3. Complex interplay between inflammatory response and progression ofatherosclerosis. Inflammatory response is indeed observed in patients with ACSs. The stimuli for inflammation, however, are poorly understood. Several stimuli may be involved, including oxidized low-density lipoprotein (ox-LDL) and other sources of endothelial injury. Localized or systemic infections, in particular from Helicobacter pylori (HP), Chlamydia pneumoniae (CP), and cytomegalovirus (CMV), have been suggested as promoters of enhanced inflammatory response, but their role is controversial. The inflammatory reaction is responsible for the secondary effects of cytokine production—liver synthesis of acute-phase reactants. CRP, SAA, and fibrinogen are the most widely studied acute-phase proteins. CRP itself is responsible for amplification ofthe inflammatory response by a direct effect on endothelium, platelets, coagulation, and eventually thrombosis, and the development of acute atherothrombosis further enhances the inflammatory response. vWF, von Willebrand factor.

Fig. 3. Complex interplay between inflammatory response and progression ofatherosclerosis. Inflammatory response is indeed observed in patients with ACSs. The stimuli for inflammation, however, are poorly understood. Several stimuli may be involved, including oxidized low-density lipoprotein (ox-LDL) and other sources of endothelial injury. Localized or systemic infections, in particular from Helicobacter pylori (HP), Chlamydia pneumoniae (CP), and cytomegalovirus (CMV), have been suggested as promoters of enhanced inflammatory response, but their role is controversial. The inflammatory reaction is responsible for the secondary effects of cytokine production—liver synthesis of acute-phase reactants. CRP, SAA, and fibrinogen are the most widely studied acute-phase proteins. CRP itself is responsible for amplification ofthe inflammatory response by a direct effect on endothelium, platelets, coagulation, and eventually thrombosis, and the development of acute atherothrombosis further enhances the inflammatory response. vWF, von Willebrand factor.

antigen. Biasucci et al. (45) showed that seropositivity for C. pneumoniae heat-shock pro-tein-60 appears to be a very sensitive and specific marker of ACS, unrelated to C. pneumoniae IgG antibody titers or high-sensitivity CRP (hsCRP) or troponin T levels, suggesting the possibility ofantigen mimicry as a potential mechanism ofacute plaque destabilization.

The evidence that patients with ACS and persistently elevated levels of CRP (Fig. 4) have a higher recurrence of events (18) and that these patients respond exaggeratedly to challenges such as coronary angiogram or in vitro stimulation of monocyte with lipopolysac-charide also suggests that subjects with persistently elevated CRP production are prone to overreact to otherwise "mild" stimuli (46) with release ofproinflammatory and prothrombo-tic mediators that may contribute to endothelial erosion and plaque rupture. Alternatively, CRP may also act as a direct participant in promoting atherothrombosis (Fig. 5). Regarding the latter possibility, it is of particular interest that the pattern ofthe relationship between CRP concentration and cardiovascular risk suggests that CRP behaves as a typical risk factor.

Was this article helpful?

0 0

Post a comment