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Concentrations of neopterin are closely correlated with the extent of carotid atherosclerosis. Future adverse events in patients are predicted by higher neopterin levels. 


The role of neopterin in atherogenesis and cardiovascular risk assessment
Fuchs D, et al. Division of Biological Chemistry, Biocenter, Insnbruck Medical University, Innsbruck, Austria
(Curr Med Chem.2009;16:4644-53)

Neopterin is produced by human and primate monocyte/macrophages upon activation by pro-inflammatory stimuli like Th1-type cytokine interferon-gamma. Neopterin has pro-oxidative properties, which have been demonstrated in vitro in physicochemical and cell culture studies and also in in vivo experiments, e.g. the Langendorff perfusion model of rat hearts. In the past several years, the measurement of neopterin concentrations in body fluids including serum, urine and cerebrospinal fluid has revealed a potential role of this molecule in the prediction of long-term prognosis in both patients with cancer and those with systemic infections such as HIV-1 infection. Moreover, elevated neopterin concentrations have been reported in patients with coronary disease compared to controls and in recent years it has become apparent that increased neopterin concentrations are an independent marker for cardiovascular disease and a predictor of future cardiovascular events in patients with coronary artery disease. Current data suggest that the diagnostic performance of neopterin testing is comparable to that of well established biomarkers such as C-reactive protein and cholesterol plasma levels. The present article reviews the role of neopterin in the pathogenesis of cardiovascular disease and as a marker of coronary artery disease progression.

Neopterin levels and left ventricular dysfunction in patients with chronic stable angina pectoris
Estévez-Loureiro R, et al. Cardiovascular Biology Research Centre, Division of Cardiac and Vascular Sciences, St George's, University of London, London, UK

(Atherosclerosis 2009;207:514-8)

BACKGROUND: Left ventricular ejection fraction (LVEF) is the strongest predictor of survival in patients with chronic stable angina (CSA). Inflammation plays a key role in the pathogenesis of atherosclerosis and an enhanced inflammatory status has a negative impact on patient outcome. It is not known whether a relationship exists between inflammation and LV function in patients with CSA. We therefore sought to investigate whether C reactive protein (CRP) and neopterin correlate with LV dysfunction in patients with CSA. METHODS: We assessed 181 patients with CSA who underwent diagnostic coronary angiography in our institution. High-sensitivity CRP and neopterin serum concentrations were measured immediately before angiography. RESULTS: Baseline neopterin levels - but not CRP - showed a significant inverse correlation with LVEF (r=-0.222; p=0.003 and r=-0.097; p=0.194, respectively). After adjustment for relevant confounders which included, among others, the extent and severity of coronary disease, neopterin was found to be independently associated with LVEF (B -2.36, CI 95% -4.560 to -0.176, p=0.034). Moreover, high neopterin levels were an independent predictor of LV dysfunction (LVEF <45%) (OR, 8.52, CI 95% 1.10-65.64; p=0.040). Receiver operating characteristic analysis for neopterin showed an area under the curve of 0.736 (CI 95% 0.59-0.87, p<0.009) for prediction of LV dysfunction. CONCLUSION: Increased serum neopterin concentrations inversely correlate with LVEF values and high neopterin levels are a predictor of LV dysfunction in patients with CSA, irrespective of the extent and severity of coronary artery disease. Neopterin may thus be clinically useful for patient risk stratification.

Neopterin as a predictor of total and cardiovascular mortality in individuals undergoing angiography in the Ludwigshafen Risk and Cardiovascular Health study

Grammer TB, et al. Synlab Centre of Laboratory Diagnostics Heidelberg, Heidelberg, Germany
(Clin Chem 2009;55:1135-46)

BACKGROUND: Neopterin is produced upon activation of the cell-mediated immune response, and may be a novel risk marker for adverse outcomes resulting from coronary artery disease. METHODS: We measured neopterin in 1801 study participants with and 511 without angiographic coronary artery disease. Rates of death were determined after a median follow-up of 8.0 years. RESULTS: Estimated glomerular filtration rate and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were the strongest predictors of neopterin. Neopterin was positively related to age and inversely related to LDL cholesterol, HDL cholesterol, and triglycerides. Use of lipid-lowering drugs lowered neopterin. Sex, body mass index, diabetes mellitus, hypertension, smoking status, Friesinger coronary score, and clinical instability at presentation were not associated with neopterin. Unlike C-reactive protein, neopterin was not increased in unstable angina pectoris, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction. In the third and fourth quartiles of neopterin, unadjusted hazard ratios for death from any cause were 1.94 (95% CI 1.44-2.61) and 3.32 (95% CI 2.53-4.30) compared to individuals in the first quartile, whereas hazard ratios for death from cardiovascular causes were 2.14 (95% CI 1.44-3.18) and 3.84 (95% CI 2.67-5.52), respectively. Neopterin remained predictive of total and cardiovascular mortality after adjusting for sex, age, body mass index, type 2 diabetes, hypertension, smoking status, LDL cholesterol, HDL cholesterol, triglycerides, estimated glomerular filtration rate, NT-proBNP, and clinical status at presentation, but NT-proBNP substantially weakened this association. CONCLUSIONS: Neopterin is an independent predictor of all-cause and cardiovascular mortality in individuals with or without stable coronary artery disease.

Long-term prognostic value of neopterin: a novel marker of monocyte activation in patients with acute coronary syndrome

Ray KK, et al. Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN, United Kingdom.
(Circulation 2007;115:3071-8)

BACKGROUND: Monocyte activation is believed to play an important role in the pathogenesis of acute coronary syndromes (ACS). Neopterin is a soluble marker of monocyte activation, and elevated levels are of prognostic value in patients with stable coronary artery disease. METHODS AND RESULTS: Neopterin levels were measured on average at 7 days (in 3946 patients) and at 4 months (in 3369 patients) after ACS in the PRavastatin Or atorVastatin Evaluation Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI 22) trial. We assessed the relationship between plasma neopterin levels and the risk of death and death or acute coronary events (nonfatal myocardial infarction or unstable angina) over 2 years. Seven days after an ACS event, neopterin levels > or = 12.11 nmol/L (upper quartile, derived from a post hoc analysis) were associated with an increased risk of death and an increased risk of death or acute coronary events after adjustment for age, gender, history of diabetes mellitus, history of hypertension, history of smoking, type of ACS presentation, use of percutaneous coronary intervention for the index event, statin regimen, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hazard ratio, 1.86 [95% CI, 1.24 to 2.77], P=0.003; and hazard ratio, 1.33 [95% CI, 1.09 to 1.63] P=0.006, respectively). Neopterin levels > or = 12.11 nmol/L at 4 months remained a predictor of death alone and of death or acute coronary events after multivariable adjustment that included adjustment for month 4 low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and statin regimen (hazard ratio, 2.39 [95% CI, 1.43 to 3.99], P=0.001; and hazard ratio, 1.60 [95% CI, 1.21 to 2.11], P=0.001). High-dose atorvastatin significantly attenuated the risk among subjects with neopterin levels > or = 12.11 nmol/L at baseline (interaction P for death or acute coronary event, 0.018). CONCLUSIONS: Increased monocyte activation detected by an elevated plasma neopterin level identifies patients at long-term risk of death or recurrent acute coronary events after ACS. Intensive statin therapy significantly attenuates the risk of recurrent events among patients with an elevated neopterin level.

Elevated serum neopterin predicts future adverse cardiac events in patients with chronic stable angina pectoris

Avanzas P, et al. Coronary Artery Disease Research Unit, Department of Cardiological Sciences, St George's Hospital Medical School, London, UK  
(Eur Heart J 2005;26:457-63)  

AIMS: Serum levels of neopterin, an immune modulator secreted by activated macrophages, are elevated in patients with acute coronary syndromes compared with stable angina patients and control subjects. In unstable angina, serum neopterin levels correlate with the presence of vulnerable coronary stenosis, multiple complex coronary lesions, and patient outcome. The present study assessed the prognostic significance of raised serum neopterin concentrations in patients with stable angina pectoris. METHODS AND RESULTS: We carried out a 1-year follow-up prospective study in 297 patients with chronic stable chest pain undergoing diagnostic coronary angiography. The primary study endpoint was the composite of non-fatal myocardial infarction, unstable angina, and cardiac death. Fifty-one patients (17.2%) had adverse coronary events during follow-up. Mean serum neopterin levels were significantly higher in patients with events compared with those without (P=0.02). On multiple regression analysis, neopterin levels (P=0.021), severity of coronary artery disease (P=0.009), and a history of previous myocardial infarction (P=0.001) were independent predictors of adverse events. CONCLUSIONS: Serum neopterin is an independent predictor of major adverse coronary events in patients with chronic stable angina pectoris. This marker of macrophage activation may be useful for risk stratification in patients with chronic stable angina.

Markers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris

Zouridakis E, zt al. Coronary Artery Disease Research Unit, Department of Cardiological Sciences, St George's Hospital Medical School, London, UK
(Circulation 2004; 110: 1747-53)

Both endothelial cell activation and macrophage activation play a significant role in atherogenesis and atheromatous plaque vulnerability and may determine rapid coronary artery disease (CAD) progression. We sought to assess the association between serum inflammatory markers and rapid CAD progression in patients with chronic stable angina pectoris. We studied 124 chronic stable angina pectoris patients (84 men; mean age, 61+/-10 years) who were on a waiting list for coronary angioplasty for a mean time of 4.8+/-2.4 months. CAD progression was defined as > or =10% diameter reduction of a pre-existing stenosis > or =50%, > or =30% diameter reduction of a stenosis <50%, development of a new stenosis > or =30% in a previously normal segment, or progression of any stenosis to total occlusion. CAD progression occurred in 35 patients (28%). After adjustment with binary logistic regression, neopterin (P<0.001), high-sensitivity C-reactive protein (P=0.017), matrix metalloproteinase-9 (P=0.002), soluble intercellular adhesion molecule 1 (P<0.001), and previous history of unstable angina (P=0.01) were independent predictors of rapid CAD progression. The association between rapid disease progression and inflammatory markers remained significant even when presence of complex lesions was introduced into the multivariate model. Rapid CAD progression in patients with stable angina pectoris is associated with increased C-reactive protein levels and raised concentrations of biochemical markers of endothelial and macrophage activation.

 HMG-CoA reductase inhibitors are associated with decreased serum neopterin levels in stable coronary artery disease.

Walter RB, et al. Department of Internal Medicine, Kantonsspital, Chur, Switzerland
(Clin Chem Lab Med 2003; 41: 1314-1319)
Neopterin, a marker of stimulated cellular immune response, is increased in unstable angina, acute myocardial infarction and possibly stable coronary artery disease. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have anti-inflammatory properties, but their effect on neopterin is largely unknown. Neopterin was measured in 232 patients undergoing elective coronary angiography and compared to the degree of atherosclerosis, use of concomitant medications and demographics. Neopterin was lower in subjects using statins (n = 66) compared to those not taking statins (median (range): 6.65 (4.1-18.3) vs. 7.70 (3.6-29.1) nmol/l, p < 0.0001). This association was also found in the subgroup of patients with coronary artery disease (1-3-vessel disease, n = 164; 6.60 (4.1-18.3) vs. 7.80 (3.6-29.1) nmol/l, p = 0.0012), whereas only a slight tendency toward lower neopterin levels was found in the group without atherosclerosis (6.90 (5.1-16.0) vs. 7.60 (4.0-18.5) nmol/l, p = 0.17). In patients with coronary atherosclerosis, neopterin concentrations were lower in smokers (n = 105) compared to non-smokers (7.20 (3.6-29.1) vs. 7.90 (4.4-18.6) nmol/l, p < 0.02), confirming previous observations. However, use of statins was associated with lower neopterin levels in both non-smokers and smokers (6.70 (4.1-18.3) vs. 7.60 (3.6-29.1) nmol/l, p < 0.05, and 6.20 (5.2-16.0) vs. 7.80 (4.4-18.6) nmol/l, p < 0.05, respectively). Overall, similar serum neopterin concentrations were found in patients with coronary atherosclerosis and those without. In accordance with their anti-inflammatory effects, the use of statins is associated with lower neopterin levels in patients undergoing elective coronary angiography.

Increased concentrations of neopterin in carotid atherosclerosis.

Weiss G, et al. Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Innsbruck, Austria

Activation of T-cells and macrophages may play a role in the pathogenesis of atherosclerosis. Therefore, serum concentrations of the immune activation markers neopterin and soluble interleukin-2 receptor were compared with routine laboratory parameters, candidate risk variables and degree of carotid atherosclerosis. Study subjects were 561 individuals (293 men and 268 women) aged between 50 and 79 years who were enrolled in a cross-sectional community based study (Ischemic Heart Disease and Stroke Prevention Study, Bruneck, Italy). Extent of carotid atherosclerosis was quantitated by an ultrasound B-mode procedure based scoring system. Detailed physical examination and quantification of laboratory and candidate risk variables were performed. By univariate as well as multivariate statistical analyses, serum concentrations of neopterin but not soluble interleukin-2 receptor were significantly higher in subjects with carotid atherosclerosis (men, 8.5 +/- 2.7 nmol/l neopterin; women, 9.6 +/- 3.3) than in those without (men, 6.7 +/- 2.3, P < 0.0001; women, 7.5 +/- 2.3, P < 0.0001). The data show that the macrophage-derived immune activation marker neopterin is closely correlated with the extent of carotid atherosclerosis. Chronic activation of immune cells, preferentially of macrophages, may play a key role in atherogenesis and/or progression of atherosclerosis.

 Elevated serum neopterin levels in atherosclerosis.

Tatzber F, et al. Institute of Biochemistry, University of Graz, Graz, Austria
(Atherosclerosis 1991; 89: 203-208)

Plasma levels of neopterin were determined in patients with different clinical stages of atherosclerosis. Non-hospitalized patients with atherosclerosis had serum and plasma neopterin levels within the normal range of the assay (6 +/- 2 nM). These values were not significantly different from those reported for healthy blood donors (5 +/- 2 nM). In contrast, about 50% (29 out of 61) of hospitalized patients undergoing conservative or surgical therapy had neopterin plasma levels, which exceeded the normal range (greater than 10 nM) up to 10-fold. The two groups differ on a significance level of P less than 0.01. For further evaluation hospitalized patients were subgrouped according to neopterin levels. In the subgroup with elevated neopterin levels patients with higher Frederickson types of atherosclerosis were overrepresented compared to patients with normal neopterin levels. Type 4 differed significantly from patients without pathological changes of lipoprotein (P less than 0.05). Only 3 patients suffered from minimal skin necrosis, two of them had elevated neopterin levels. Significantly more patients with peripheral artery occlusions had elevated neopterin levels than patients with occlusions of central arteries (P less than 0.05). All other criteria used for comparison (sex, age, smoking, antioxidant status, diabetes, hypertension, adipositas, hyperuricemia) did not vary significantly in both subgroups. These data indicate that neopterin plasma levels might be a valuable parameter in activity staging and therapeutic follow up of atherosclerotic patients. Additionally, an involvement of the nonspecific immune system in atherogenesis is suggested by the increased plasma neopterin concentrations.