PlGF as a Primary Vascular Inflammatory Instigator

PlGF, a member of the vascular endothelial growth factor (VEGF) family of growth factors, was recently shown to be profoundly upregulated in early and advanced atherosclerotic lesions (32). Originally identified in the placenta (33), PlGF stimulates vascular smooth muscle growth, recruits macrophages into atherosclerotic lesions, upregulates

Fig. 4. PlGF levels in patients with acute chest pain presenting to emergency rooms. Patients were categorized according to their final diagnosis at the time of discharge. *,p < 0.01 vs non-cardiac chest pain; **,p < 0.01 vs stable angina.

tumor necrosis factor-a (TNF-a) and monocyte chemoattractant protein-1 production by macrophages, enhances production oftissue factor, and stimulates pathological angiogen-esis (32,34). All these processes are known contributors to plaque progression and desta-bilization. Most important, however, inhibition of the effects of PlGF by blocking its receptor Flt-1 was experimentally shown to suppress both atherosclerotic plaque growth and vulnerability via inhibition of inflammatory cell infiltration (32). These data suggest that PlGF may act as a primary inflammatory instigator of atherosclerotic plaque instability. Indeed, PlGF serum levels are markedly upregulated in patients with ACS independent of the presence of myocardial injury (Fig. 4) (35). Moreover, data from the CAPTURE trial established PlGF blood levels as a novel, powerful, independent prognostic determinant of clinical outcome in patients with ACS (Fig. 5) (35). The predictive value of PlGF levels is independent of myocardial necrosis, as evidenced by elevated troponin levels (36), as well as platelet activation, as evidenced by elevation of sCD40L (37). Intrigu-ingly, elevated PlGF levels identified not only those patients with acute chest pain with ACS, but also those patients who had an increased risk of recurrent instability from an initial ACS after discharge. Thus, measuring PlGF levels may represent not only a reliable and powerful clinical tool for identifying patients with high-risk lesion formation, but also those with ongoing vascular inflammation of the coronary circulation.

The role ofPlGF as a primary inflammatory instigator of atherosclerotic lesion instability can be substantiated by its well-documented proinflammatory effects in animal models of atherosclerosis or arthritis (32). Although PlGF belongs to the family of VEGF, its etiopathogenetic role appears to be related more to vascular inflammation than to angio-genesis (32). Indeed, whereas VEGF is activated by hypoxia and elevation in VEGF levels is regarded as an early adaptation of the myocardium to deprivation of blood flow (38), PlGF is not affected or even downregulated by hypoxia (39,40). In line with these data, analysis of the CAPTURE data did not reveal any correlation between PlGF levels and VEGF

Before PCI f After PCI 6 months of follow-up

Fig. 5. Predictive value ofPlGF in patients with ACS. The cumulative incidence of death or nonfatal MI at 72 h and 6 mo of follow-up by baseline PlGF levels in CAPTURE patients receiving placebo treatment (n = 547) is shown. PCI, percutaneous coronary intervention.

Before PCI f After PCI 6 months of follow-up

Fig. 5. Predictive value ofPlGF in patients with ACS. The cumulative incidence of death or nonfatal MI at 72 h and 6 mo of follow-up by baseline PlGF levels in CAPTURE patients receiving placebo treatment (n = 547) is shown. PCI, percutaneous coronary intervention.

levels as a marker of myocardial ischemia or between PlGF levels and troponin levels as a marker of myocardial necrosis. Thus, PlGF levels do not appear to be confounded by myocardial necrosis, whereas VEGF levels are linked to troponin elevation, impaired TIMI flow, and clinical evidence of myocardial ischemia (41). Lack of PlGF-level sensitivity to minor myocardial injury might be particularly important in patients with ACS, of whom approximately one-third are positive for troponin at the time of arrival in the hospital (42).

In summary, PlGF plasma levels represent a powerful and reliable clinical biomarker of vascular inflammation and adverse outcome in patients with ACS. Measuring PlGF levels significantly extends the predictive and prognostic information gained from traditional inflammatory markers in ACS. Most notably, because the proinflammatory effects of PlGF can be specifically inhibited by blocking its receptor Flt-1, these findings may also provide a rationale for a novel anti-inflammatory therapeutic target in patients with CAD (43).

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