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      Evidence that C-Reactive Protein or IL-6 Are Not Surrogates for All Inflammatory Cardiovascular Risk Factors in Hemodialysis Patients

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          Background/Aims: In otherwise healthy adults, high C-reactive protein (CRP) levels are associated with cardiovascular disease and have been linked to an inflammatory state. The presence of vascular disease is also associated with increased expression of adhesion molecules, including soluble intercellular adhesion molecule (sICAM), vascular endothelial growth factor (VEGF) and leukocyte-derived myeloperoxidase (MPO). These associations suggest potential mechanisms whereby inflammation may injure the vascular endothelium, but the recognition of how these mediators act in concert remain poorly characterized. That the prevalence of atherosclerosis and markers of inflammation are increased in renal failure patients suggests that inflammation causes accelerated vascular disease. Methods: In hemodialysis patients, we examined the relationships between plasma CRP and sICAM, VEGF and MPO longitudinally. We determined whether episodes of a high CRP value were paralleled by simultaneous increases in mediators of inflammatory injury or molecules associated with endothelial cell adhesion or growth and whether CRP levels correlated with those of VEGF and MPO. Results: Episodic increases in CRP were accompanied by higher levels of VEGF, sICAM and MPO. However, there was no correlation between serum CRP levels or other acute phase proteins and either MPO or VEGF, nor was there a constant temporal relationship between MPO and CRP. By contrast, MPO and VEGF levels were closely correlated with one another during episodes of inflammation (p = 0.0001), and CRP and interleukin-6 levels were also correlated. Increases in MPO tended to be restricted to patients with grafts or catheters, and not those with AV fistulas. Conclusions: These results suggest that high plasma levels of CRP or other acute phase proteins in cross-sectional studies should be interpreted cautiously when defining mechanisms underlying cardiovascular disease in the hemodialysis patient population. One, or more than one inflammatory repertoire may be activated, one involving hepatic acute phase proteins and the other neutrophil activation and each may contribute separately to outcomes. Better prognostic information may be obtained by measurement of more markers than CRP alone, such as MPO and VEGF.

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          Most cited references 19

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          Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes.

          Polymorphonuclear neutrophils (PMNs) have gained attention as critical mediators of acute coronary syndromes (ACS). Myeloperoxidase (MPO), a hemoprotein abundantly expressed by PMNs and secreted during activation, possesses potent proinflammatory properties and may contribute directly to tissue injury. However, whether MPO also provides prognostic information in patients with ACS remains unknown. MPO serum levels were assessed in 1090 patients with ACS. We recorded death and myocardial infarctions during 6 months of follow-up. MPO levels did not correlate with troponin T, soluble CD40 ligand, or C-reactive protein levels or with ST-segment changes. However, patients with elevated MPO levels (>350 microg/L; 31.3%) experienced a markedly increased cardiac risk (adjusted hazard ratio [HR] 2.25 [1.32 to 3.82]; P=0.003). In particular, MPO serum levels identified patients at risk who had troponin T levels below 0.01 microg/L (adjusted HR 7.48 [95% CI 1.98 to 28.29]; P=0.001). In a multivariate model that included other biochemical markers, troponin T (HR 1.99; P=0.023), C-reactive protein (1.25; P=0.044), vascular endothelial growth factor (HR 1.87; P=0.041), soluble CD40 ligand (HR 2.78; P<0.001), and MPO (HR 2.11; P=0.008) were all independent predictors of the patient's 6-month outcome. In patients with ACS, MPO serum levels powerfully predict an increased risk for subsequent cardiovascular events and extend the prognostic information gained from traditional biochemical markers. Given its proinflammatory properties, MPO may serve as both a marker and mediator of vascular inflammation and further points toward the significance of PMN activation in the pathophysiology of ACS.
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            Association between myeloperoxidase levels and risk of coronary artery disease.

            Myeloperoxidase (MPO), a leukocyte enzyme that promotes oxidation of lipoproteins in atheroma, has been proposed as a possible mediator of atherosclerosis. To determine the association between MPO levels and prevalence of coronary artery disease (CAD). Case-control study conducted from July to September 2000 in a US tertiary care referral center, including 158 patients with established CAD (cases) and 175 patients without angiographically significant CAD (controls). Association of MPO levels per milligram of neutrophil protein (leukocyte-MPO) and MPO levels per milliliter of blood (blood-MPO) with CAD risk. Leukocyte- and blood-MPO levels were both significantly greater in patients with CAD than in controls (P<.001). In multivariable models adjusting for traditional cardiovascular risk factors, Framingham risk score, and white blood cell counts, MPO levels were significantly associated with presence of CAD, with an OR of 11.9 (95% CI, 5.5-25.5) for the highest vs lowest quartiles of leukocyte-MPO and an OR of 20.4 (95% CI, 8.9-47.2) for the highest vs lowest quartiles of blood-MPO. Elevated levels of leukocyte- and blood-MPO are associated with the presence of CAD. These findings support a potential role for MPO as an inflammatory marker in CAD and may have implications for atherosclerosis diagnosis and risk assessment.
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              Myeloperoxidase, a leukocyte-derived vascular NO oxidase.

              Myeloperoxidase (MPO) is an abundant mammalian phagocyte hemoprotein thought to primarily mediate host defense reactions. Although its microbicidal functions are well established in vitro, humans deficient in MPO are not at unusual risk of infection. MPO was observed herein to modulate the vascular signaling and vasodilatory functions of nitric oxide (NO) during acute inflammation. After leukocyte degranulation, MPO localized in and around vascular endothelial cells in a rodent model of acute endotoxemia and impaired endothelium-dependent relaxant responses, to which MPO-deficient mice were resistant. Altered vascular responsiveness was due to catalytic consumption of NO by substrate radicals generated by MPO. Thus MPO can directly modulate vascular inflammatory responses by regulating NO bioavailability.

                Author and article information

                Blood Purif
                Blood Purification
                S. Karger AG
                December 2006
                21 December 2006
                : 24
                : 5-6
                : 508-516
                aDepartment of Internal Medicine, Division of Nephrology, University of California, and Department of Biochemistry and Molecular Medicine, Davis, Calif., bResearch Service, VA Northern California Health Care System, Mather, Calif., cRenal Research Institute, New York, N.Y., dDepartment of Medicine, Division of Nephrology, Baylor College of Medicine, Houston, Tex., and eDepartment of Physiology and Membrane Biology, University of California, Davis, Calif., USA
                96471 Blood Purif 2006;24:508–516
                © 2006 S. Karger AG, Basel

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                Figures: 5, References: 34, Pages: 9
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