Atherosclerosis 193 (2007) 196–203

Inflammatory and anti-inflammatory variable clusters and risk prediction in acute coronary syndrome patients: A factor analysis approach
Dimitrios N. Tziakas a,∗ , Georgios K. Chalikias a , Juan Carlos Kaski b , Angelos Kekes a , Eleni I. Hatzinikolaou a , Dimitrios A. Stakos a , Ioannis K. Tentes c , Alexandros X. Kortsaris c , Dimitrios I. Hatseras a
b

University Cardiology Department, Democritus University of Thrace, Voulgaroktonou 23, 68100 Alexandroupolis, Greece Cardiovascular Biology Research Centre, Division of Cardiac and Vascular Sciences, St. George’s, University of London, London, UK c Department of Biochemistry, Democritus University of Thrace, Alexandroupolis, Greece Received 1 March 2006; received in revised form 4 June 2006; accepted 14 June 2006 Available online 20 July 2006

a

Abstract Background: Numerous inflammatory mediators such as C-reactive protein (CRP), fibrinogen, interleukin-18 (IL-18), and inter-cellular adhesion molecule-1 (ICAM-1) have been proposed for risk stratification in acute coronary syndrome (ACS) patients. However, interactions between these markers have made it difficult to assess their true role in risk prediction. Factor analysis is a multivariable statistical technique that reduces a large number of intercorrelated variables to a smaller set of independent clusters, underlining physiological relationships. The aim of this study was to investigate, using factor analysis, a clustering of pro-inflammatory markers, anti-inflammatory cytokines such as interleukin-10 (IL-10) and HDL cholesterol, and to determine their role in prediction of risk of recurrent coronary events in ACS patients. Methods: We assessed 320 consecutive patients (236 men; 67 years; IQ 58–74 years) admitted with ACS. The composite of cardiac death and re-hospitalization with non-fatal myocardial infarction, or unstable angina, was the pre-specified study end-point. Serum CRP, fibrinogen, HDL cholesterol, IL-10, IL-18 and ICAM-1 levels were measured at study entry. We assessed independent predictors of the combined end-point during a 1-year follow-up using multiple logistic regression analysis. Results: Factor analysis identified three clusters which were arbitrarily interpreted as (1) a “systemic inflammation” cluster with positive loadings of CRP and fibrinogen, (2) a “local inflammation–endothelial dysfunction” cluster with positive loadings of IL-18 and ICAM-1 and (3) an “anti-inflammation” cluster comprising IL-10 and HDL cholesterol. Only the “anti-inflammation” cluster was a significant predictor (OR 0.66, 95% CI: 0.49–0.89) of adverse cardiac events during a 1-year follow-up and remained significant (OR 0.65, 95% CI: 0.48–0.88) in a multivariate model that included all three factors. Conclusions: Although inflammatory markers such as CRP predict future cardiovascular events in ACS patients, when all inflammatory mediators are taken into account in a prospective analysis of risk, markers reflecting anti-inflammatory mechanisms are better prognostic markers. © 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Factor analysis; ACS prognosis; Inflammation

1. Introduction Acute coronary syndromes (ACS) such as unstable angina and myocardial infarction are the clinical manifestations of

Corresponding author. Tel.: +30 25510 35596; fax: +30 25510 35596. E-mail address: dtziakas@med.duth.gr (D.N. Tziakas).

destablization of coronary atherosclerotic plaques. There is increased recognition that inflammation plays a key role in atherosclerosis and its complications [1,2]. Recently, attention has focused on the potential role of circulating markers of inflammation as risk predictors among those who have suffered an acute cardiovascular event [3,4]. Acute phase reactants such as C-reactive protein (CRP)

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5 pg/ml. The intra-assay precision and inter-assay precision of the method were 5. Patient management was carried out in accordance with institutional protocols and specific decisions regarding urgent revascularization were left to the discretion of the managing cardiologist. Biochemical data In all patients peripheral blood samples were drawn within 1 h from admission. Furthermore. with a minimum detectable concentration of 3.15]. with a minimum detectable concentration <0. liver or thyroid disease. IL-18 [8]. In this respect. serum samples were frozen and stored at −70 ◦ C until biochemical assessment..g. a variable reduction approach. Japan” [18] commercial kits with monoclonal antibodies.1. R&D Systems Inc. The intra-assay precision and inter-assay precision of the method were 4. and endothelial activation do not occur in isolation. Spain) commercial kits [21]. a potent anti-inflammatory cytokine. telephone contacts and the recording of recurrent cardiac events. 2. the inflammatory cascade has counterbalancing factors that maintain a delicate balance of pro. with a minimum detectable concentration of 12. death from fatal myocardial infarction or death from possible myocardial ischemia. familial hyperlipidaemia. The primary clinical outcome of interest was the composite end-point of major adverse cardiovascular event such as (i) hospital admission with non-fatal MI defined according to European Cardiology Society criteria [14. Serum samples were obtained from every patient at study entry for the assessment of inflammatory markers. undergo elective non-cardiac surgical procedures during follow-up were excluded from the study.D. as well as markers of endothelial activation. patients with infectious or autoimmune diseases. (Marburg. intracellular adhesion molecule-1 (ICAM-1) have also been found to predict future cardiovascular events in prospective studies [6]. and cardiovascular risk is likely to depend on the interaction among these variables.1%. Nagoya. are independent predictors of short. Myocardial infarction (MI) [ST segment elevation (STEMI) and non-ST segment elevation (NSTEMI)] and unstable angina (UA) were diagnosed using European Society of Cardiology criteria [14. We therefore assessed in ACS patients clusters of proinflammatory and anti-inflammatory mediators. Ltd.and long-term mortality in patients with symptomatic coronary artery disease [5].12]. After centrifugation at 3000 rpm for 10 min. pregnancy associated protein-A [9]. raised cardiac troponins and/or cardiac enzymes. Minneapolis. 2.1% and 7. Methods 2. characteristic ECG changes.6%. Sandwich enzyme immunoassay was performed by measuring concentrations of serum ICAM-1 using “human ICAM-1 R&D Systems Inc.e. respectively. USA” [17] commercial kits with monoclonal antibodies. are known to be associated with a more favorable prognosis in patients with ACS in another study [13]. respectively. The intra-assay precision and inter-assay precision of the method were 8.e.15] (e. / Atherosclerosis 193 (2007) 196–203 197 and fibrinogen. Tziakas et al. The study was approved by the Hospital’s Ethics Committee and all patients gave written informed consent prior to study entry. Markers of endothelial activation i. elevated serum levels of IL-10. Germany) [20] commercial kits while fibrinogen was measured using DG-FIB. Using exploratory factor analysis. Although investigators have assessed the individual contribution of each of these molecules to cardiovascular risk. All other biochemistry measurements were carried out by our biochemistry department using standard methods. renal. Grifols (Barcelona. or those scheduled to . neoplastic. Follow-up Patients were followed for up to 1-year after admission using a standardized protocol that included outpatient visits.6%. High sensitivity C-reactive protein (CRP) was measured using Dade Behring. Patients We assessed consecutive patients who were admitted to the Coronary Care Unit of our institution with a diagnosis of ACS. and (iii) cardiac death. we assessed the performance of these clusters individually and their association as markers of future cardiovascular risk.3 ng/ml. 2. anti-inflammatory mechanisms.. USA” [19] commercial kits with monoclonal antibodies.2. defined as sudden unexplained death.5% and 15.. Sandwich enzyme immunoassay was performed for measuring concentrations of serum IL-18 using “MBL Medical and Biological Laboratories Co. Sandwich enzyme immunoassay was performed for measuring concentrations of serum IL-10 using “Quantikine HS human IL-10.61% and 10.and anti-inflammatory molecules that regulate vascular homeostasis [11] and maintain the integrity of the vessel wall [11. (ii) hospital admission with Braunwald’s class IIIb unstable angina requiring medical treatment and/or urgent revascularization i.5 pg/ml. and prolonged typical chest pain). or patients receiving treatment with anti-inflammatory drugs. and neopterin [10] have been associated with poor prognosis in this patient group. Such an assessment is essential because inflammatory pathways. Elevated serum levels of inflammatory mediators such as interleukin (IL)-6 [7]. We did not include patients with a history of hematological. the role of “clustering” of inflammatory and anti-inflammatory markers in risk prediction has not been systematically explored. However. respectively. Minneapolis.3. percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) [16].N.

5 or lower assuming cumulative incidence of adverse coronary event rates of 15–20% during 1-year follow-up. 2. Although the normality assumption is not a pre-requisite for factor analysis.D. difference. naming and interpretation of the clusters are arbitrary. Varimax rotation was then performed with identification of variables comprising a factor (cluster) based on loadings greater than 0. Results 3.).198 D.9 or higher and 0. The levels of IL-18. CRP and fibrinogen were not normally distributed. revascularization during follow-up. therefore could have acted as cofounders (data not shown). the sample size of the present study (n = 320) was adequate enough for factor analysis based on the Kaiser–Meyer–Olkin test for sampling adequacy (KMO-test) [23]. ICAM-1.5 [23]. For analysis inflammatory marker levels were modelled in quartiles with odds ratios (ORs) referring to relative risk between the upper and lower quartile.4. Briefly. a cluster score was derived.24]. A p value <0. therefore Spearman’s correlation was used to estimate correlation coefficients between inflammatory markers. 3.6. 2. The threshold value of 0.5. the study had 80% power to detect odds ratios 1. and are often helpful in elucidating pathophysiologic mechanisms [22]. b-blocker. The Kolmogorov–Smirnof test was used to examine the normality of the variables distribution.1. Regression analysis The association of each one of the inflammatory variables independently with risk of adverse cardiovascular events during the 1-year follow-up was assessed using logistic regression analysis. Factor analysis sion. Cluster scores were modelled as continuous independent variables with odds ratios referring to risk of adverse events per 1 S.0 statistical software package (SPSS Inc. as well as for presence of EF < 40%. are useful in subsequent statistical analysis i. predictive regression models. factor analysis was initiated by extraction of an initial solution using principal component analysis.4 or higher and 0. Multivariate models were constructed with adjustment for covariates including diagnosis on admis- Firstly. 51% (164) had a history of dyslipidaemia. Tziakas et al. 30% (96) had a history of diabetes and 38% (122) were current smokers. 49% of the study participants (n = 158) had a history of established coronary artery disease. at the 5% level of significance (two-sided). In the present analysis screen plots were inspected and factors (clusters) with eigen values greater than 1 were retained [23]. In both power analyses an adjustment was made taking into account the multiple regression of the independent variable of interest on the other independent variables in the logistic regression. statin and clopidogrel use. Differences in continuous variables between groups were assessed using Mann–Whitney U test. all of the under investigation variables used in the present study had not an extreme non-normal distribution (skewness <2 and kurtosis <7) [23]. at the 5% levels of significance (two-sided). whereas comparisons between categorical variables were performed by chi-square test or Fischer’s exact test when required.e. 2.05 was considered statistically significant. with a sample size of 320 patients. Similarly. Power analysis Factor analysis simplifies multivariate data consisting of a large number of intercorrelated variables by grouping them into a smaller set of independent factors (clusters) according to basic underlying relationships among variables. statin and clopidogrel use. These scores represent the subjects’ predicted values for each factor (cluster) and are calculated using the factor weights and the original variable values. In addition. For each cluster identified. with a median age of 67 (58–74) years.N. with a sample size of 320 patients. IL-10. All statistical calculations were performed using SPSS 11. HDL cholesterol.5 has been commonly used [23. Statistical analysis Values are expressed as median values with interquartile ranges. Study population-baseline characteristics We recruited 320 consecutive patients (236 (74%) men) with ACS of whom 123 had STEMI. / Atherosclerosis 193 (2007) 196–203 2. as well as for presence of EF < 40%. 30% of them (n = 95) were on lipid lowering treatment (among the 95 patients in the lipid lower- . revascularization during follow-up. 117 NSTEMI and 80 UA. The aforementioned variables were significantly different between patients presenting with and without the study endpoint during the 1-year follow-up. As far as the logistic regression analyses regarding the independent contribution of each one of the under investigation variables to adverse events. b-blocker. This corresponds to retention of factors that contribute to variance greater than any original variable. for the logistic regression analyses regarding the association of clusters with prospective risk of recurrent coronary events. Principal component analysis is a linear transformation of a set of partially correlated variables into an uncorrelated set of factors that are ordered according to progressively decreasing contribution to total variance in the data.7 or lower assuming cumulative incidence of adverse coronary event rates of 15–20% during 1-year follow-up. the study had 80% power to detect odds ratios 1. Factors are fewer in number than the original variables. Sixty five percent (n = 207) of the patients were hypertensives. Of importance. The association of cluster scores with risk of developing adverse cardiac events during the 1-year follow-up was assessed using multivariate regression analysis with covariates including diagnosis on admission.7. account for a significant proportion of data variance.

7 (3. During follow-up. With the same magnitude. inter-cellular adhesion molecule. There was a reduction in variable number from the original 6 to 3 composite clusters.194) and IL-10 and HDL (r = 0. 92 patients (29%) were on statins. except for the fact that a higher proportion of patients with recurrent events had STEMI on admission (57% versus 32%. A higher proportion of patients without recurrent events had a revascularization procedure done (CABG or PCI) during follow-up (25% versus 43%.2.022 −0.78 (0.875 Fibrinogen 0. p < 0.D. there were 60 cardiac deaths (18 during hospitalization and 42 after hospital discharge during the 1year follow-up). Tziakas et al. . with positive loadings of IL-10 and HDL cholesterol. Factor analysis Table 3 summarizes factor analysis results for the total group of 320 patients.731 Cluster 3: anti-inflammation IL-10 −0.888 Cluster 2 0.02–1.011 0.001) compared to patients who were event free during follow-up. Table 1 summarizes biochemistry results at study entry.4.500 are in bold.045 0.136 0. The medications taken by both groups during follow-up were similar except for b-blocking agents (29% versus 49%.046 Cluster 3 −0.194* −0.004).028 1 −0.150 −0. interleukin. HDL. No differences in clinical and biochemical variables were found between patients with recurrent cardiac events and those without. interleukin.178).9–5.1–4. p = 0. Fibrinogen HDL cholesterol ICAM-1 1 0.8) 2.045 −0. ICAM.091* 0. 3.05. 3.34% and cluster 3: 18. and also had a higher prevalence of reduced ejection fraction (EF) < 40% (36% versus 15%.2 (153–347. * p < 0.308). IL. ICAM. CRP.091).100* 0.9 (1. five patients (2%) were on fibrates. / Atherosclerosis 193 (2007) 196–203 Table 1 Baseline laboratory values of study population (n = 320) Laboratory variable Interleukin-10 (IL-10) (pg/ml) Interleukin-18 (IL-18) (pg/ml) C-reactive protein (CRP) (mg/l) Fibrinogen (mg/dl) Troponin T (ng/ml) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Inter-cellular adhesion molecule-1 (ICAM-1) (ng/ml) 4. high density lipoprotein.067 0. p < 0. ing arm.308* CRP with positive loadings of CRP and fibrinogen.080 −0. p = 0.3. Correlation analysis Table 2 shows Spearman correlation coefficients between the inflammation.039 0. p < 0.151* −0. cluster 2: 23. These three clusters taken together explained about 70% of the variance in the original data (cluster 1: 27.032 1 IL. albeit inversely.590) and IL-18 and ICAM-1 (r = 0.187 0.3%) was on omega-3 marine triglycerides).820 199 Cluster 2: local inflammation–endothelial dysfunction IL-18 −0.N. CRP.084 IL-18 1 0. More modest but significant correlations were observed between CRP and ICAM-1 (r = 0. p = 0. CRP was correlated with IL-10 (r = −0.148 0.172 HDL cholesterol 0.804 ICAM-1 0.590* −0.625 0. (2) a “local inflammation–endothelial dysfunction” cluster with positive loadings of IL-18 and ICAM-1 and (3) a “protective or antiinflammation” cluster.100). anti-inflammation and endothelial dysfunction markers that were assessed on admission. statins (25% versus 52%. Loadings ≥ 0.001). C-reactive protein. The strongest associations were observed between CRP and fibrinogen (r = 0.001).7) 486 (399–578) 0.212 Values are expressed as medians with interquartile range.408 −0. Logistic regression analysis for adverse cardiovascular events Eighty-four patients had one or more adverse cardiac events and 236 remained event free during the 1-year followup.014) which were significantly more common in the event free group.28%). inter-cellular adhesion molecule.178* 1 0.52%.2) 212 (183–232) 137 (119–151) 43 (38–48) 142 (108–201) 611 (451–886) Table 3 Factor (cluster) analysis results Cluster 1 Cluster 1: systemic inflammation CRP 0. 3. 23% (n = 75) were on b-blockers and 30% (n = 96) were on angiotensin converting enzyme inhibitors before study entry.151) and HDL (r = −0. high density lipoprotein.066 0. These clusters were interpreted as (1) a “systemic inflammation” cluster Table 2 Spearman correlations between assessed markers (n = 320) Marker IL-10 IL-18 CRP Fibrinogen HDL cholesterol ICAM-1 IL-10 1 0. IL-10 and IL-18 (r = 0. three patients (1%) were on ezetimibe and one patient (0. and 14 patients were hospitalized for UA and 10 for a new MI. which was supported by the retention criteria described in Section 2. C-reactive protein.083 0.001) and clopidogrel (21% versus 36%. HDL.8) 236.

73. Discussion Accumulating evidence that inflammation plays a crucial role in pathogenesis of most of the cases of ACS. 95% CI: 0. however.65.32. 95% CI: 3.25].69.343) and the “local inflammation–endothelial dysfunction” cluster (OR 1.381) and the “local inflammation–endothelial dysfunction” cluster (OR 1. as well as presence of EF < 40%). 4.466) and ICAM-1 levels (OR upper versus lower quartile 0.33.85.74.28. (B) Multivariate logistic regression analysis including all three clusters adjusted for diagnosis on admission. as well as for presence of EF < 40%. In contrast.65. 95% CI: 0. 1.007) were “negative” predictors.48–0. statin and clopidogrel use. revascularization during follow-up. and several studies have appeared recently that successfully used this approach [26.62–2. 95% CI: 0. In a multivariate model including all three clusters. IL-18 (OR upper versus lower quartile 3.27].001) were independent predictors of recurrent coronary events. Clustering of independent markers into composite variables represented by factors could potentially be useful in risk assessment by utilization of all information in the data set while at the same time minimizing collinearity problems. p = 0. The association of clusters with prospective risk of recurrent coronary events was assessed using logistic regression analysis. b-blocker.28.8. 95% CI: 0. Our study is among the first to evaluate the clustering of multiple inflammatory markers in the ACS setting. 95% CI: 0. 1B). statin and clopidogrel use. revascularization during follow-up.89. b-blocker.007) while the “systemic inflammation” cluster (OR 1.200 D.33. Three clusters have . However. as in the present study involving several inflammatory markers.003) and CRP levels (OR upper versus lower quartile 9. revascularization during follow-up.60.84–1.55.12–0. Cluster odds ratios (ORs) for adverse cardiovascular events during 1-year follow-up in patients with acute coronary syndrome. multiple logistic regression analysis was performed to assess relative contribution of each one of the under investigation markers to adverse events. / Atherosclerosis 193 (2007) 196–203 After adjustment for all the variables that were associated with presence or absence of recurrent coronary adverse events (diagnosis on admission. Fig. p = 0. and their prognostic ability in these patients. One of the major advantages of this type of analysis is minimization of correlations among variables. 95% CI: 0. p = 0.96–1. and are continuously interacting with each other. p = 0. 95% CI: 0. difference.003) and IL10 levels (OR upper versus lower quartile 0. (A) Separate multivariate logistic regression analysis including one only cluster at a time adjusted for diagnosis on admission.N. p = 0.84. 95% CI: 0. Factor analysis in this study was performed to reduce the complexity of multivariable risk analysis. Tziakas et al. the “protective–anti-inflammation” cluster continued to be a significant “negative” predictor (OR 0.D.109) did not significantly predict adverse cardiac events during 1-year follow-up (Fig.49–0. has rendered their comparison and appraisal problematic. led to the assessment of various circulating inflammatory markers as stable. 95% CI: 1.39–1. Thus.8.26–9. p = 0.68.66.003) while the “systemic inflammation” cluster (OR 1. p = 0. b-blocker. Factor analysis may be a useful approach to increase our understanding of the contributory role of the various molecules involved in the atheromatic process and plaque disruption. In separate multivariate analyses only the “protective–anti-inflammation” cluster was a significant “negative” predictor (OR 0. HDL cholesterol levels (OR upper versus lower quartile 0. 1A).95–1. independent risk predictors in these syndromes [2. p = 0. statin and clopidogrel use. there was a modest change in the magnitude of associations. factor analysis is often useful in settings where collinearity of independent variables is problematic. the fact that all these inflammatory mediators are not expressed in isolation but rather concurrently. Another advantage of factor analysis is the ability to define relationships between variables related to underlying pathophysiologic mechanisms. raised fibrinogen levels (OR upper versus lower quartile 1.83. p < 0. 95% CI: 0. p = 0. p = 0.84.078) continued not to predict future adverse cardiovascular events (Fig. ORs refer to risk of recurrent coronary events for 1 S. statistical assessment of markers is problematic.17.15–0.58–0. 95% CI: 0. p = 0.15. The multivariate statistical technique of factor analysis is a natural approach for investigations when multiple highly correlated variables are concerned. as well as for presence of EF < 40%.88.85–1.659) were not associated with recurrent adverse cardiac events in the multivariable analysis. As atherosclerosis-related inflammation is a complex process given its pathophysiological mechanisms that involve multiple pathways.

D. obesity which is characterized by increased levels of CRP and IL-6 is also associated with a parallel increase of IL-10 [11].or the anti-inflammatory mechanism per se might be the culprit of the increased coronary risk [34.e. suggesting that evaluating the imbalance between pro-inflammatory and antiinflammatory mediators concurrently. Although this was not possible. In addition. and was interpreted as a marker of “systemic inflammation”. reported an inverse association between CRP and IL-10 [13]. However. an endothelial-specific activation marker could minimize the ability of the “local inflammation–endothelial dysfunction” cluster to predict adverse coronary events. our study further supports the concept that in patients with ACS when all inflammatory mediators are . The findings of the present study should be interpreted in light of certain limitations. HDL cholesterol reduces cytokine-mediated up-regulation of cell adhesion molecules. serum concentration of soluble ICAM-1 is a better predictor of future cardiovascular events compared to E-selectin levels [39. In addition. Therefore. In conclusion. Furthermore. is also capable of down-regulating numerous inflammatory pathways that play an important role in the progression and instability of the atherosclerotic plaque. In addition. Different and various direct associations have been reported in the current literature regarding interactions between circulating concentrations of proand anti-inflammatory markers. this cytokine appears to be an excellent candidate liniking local vessel pathology with inflammation.N. CRP and IL-12 correlated negatively with IL10 levels [36]. Clustering of IL-18 with ICAM-1 is in agreement with studies that showed expression of IL-18 in human atherosclerotic plaques [31].e. suppression of cytokine production. Biasucci et al. while others have reported no association at all [37]. the second consisted of IL18 and ICAM-1. among others. The first included CRP and fibrinogen. the present study showed that multivariate risk appraisal is vital because the various risk markers tend to cluster and the risk associated with any particular marker varies widely depending on the amount of clustering. which was interpreted as an indicator of “local inflammation–endothelial dysfunction” and the third comprising both IL-10 and HDL cholesterol.35]. Recent studies supported the notion that a lack of an appropriate antiinflammatory counter-balance to a certain pro-inflammatory reaction rather than the pro. we found that the protective “anti-inflammatory” cluster was significantly associated with a good prognosis in ACS patients during 1-year follow-up. blocks the nuclear-factor kappa B signaling cascade and is associated with reduced matrix metalloproteinases levels [28. suppressed expression of adhesion molecules. Overall. The finding of the present study of a positive association between serum levels of IL-18 and IL-10 is of particular interest. other strong prognostic markers established in risk stratification in ACS patients such as brain natriuretic peptide. Taken account this experimental background. Even with the relatively small sample size the present study shows that markers reflecting anti-inflammatory mechanisms are better predictors of adverse events when compared to markers of endothelial dysfunction. was considered to represent a protective “anti-inflammatory” marker. / Atherosclerosis 193 (2007) 196–203 201 emerged in the present analysis from concurrent admission measurement of inflammation mediators levels. matrix metalloproteinases and soluble CD40 ligand have not been measured. a potent antiinflammatory cytokine is in accordance with studies in the literature [28. Similarly.29]. The major contribution of this study is the inclusion of a representative marker of the anti-inflammatory pathway and HDL cholesterol levels. Inclusion of the above markers into the factor analysis derived clusters would be of importance. statin or b-blocker users. these studies were conducted in highly selective populations and neither included a “true” anti-inflammatory mediator. Secondly.29]. Clustering of HDL cholesterol with IL-10. IL-10. In accordance to our study. Firstly. ICAM-1 is also expressed by a great variety of non-endothelial cells therefore does not reflect specifically endothelial dysfunction-activation as E-selectin [38].40]. The above mechanisms may possibly account for the protective role of the “antiinflammation” cluster in ACS patients. and inhibition of the release of potent chemoattractants [30]. may be of significance in risk prediction in ACS patients.27]. the present study design did not allow us to assess the predictive value of the under investigation clusters in sub-group of patients i. reduced tissue factor expression. Heeschen et al. as well as IL-18 induced expression of adhesion molecules in vitro [32]. reduced matrix metalloproteinase production. reflects the presence of systemic low grade inflammation in the coronary arteries or elsewhere [33]. clustering of CRP and fibrinogen. showed that levels of the pro-inflammatory markers IL-6. Finally. the use of Eselectin. These findings are in keeping with prior data published by our group [34] and others [35]. the inhibition of the pro-inflammatory transcription factor nuclear factor kappa B. two acute phase proteins. It is possible that expression of anti-inflammatory molecules to reflect a counter-regulatory mechanism in response to inflammatory stimuli. Although previous studies have examined prospective associations between inflammatory clusters and risk of cardiovascular events [26. Yamashita et al. In terms of anti-inflammatory effects. which has been shown to be low in ACS patients compared to stable angina [17]. showed that in unstable angina patients circulating levels of the antiinflammatory marker IL-1 receptor antagonist was directly associated with IL-1 and IL-6 probably reflecting disease activity [7]. our investigation due to the relative small sample size was subject to type II error regarding the prognosis assessment of the “local inflammation–endothelial dysfunction” cluster. the “anti-inflammatory” cluster had better prognostic ability when compared to the “systemic inflammation” and the “local inflammation–endothelial dysfunction” clusters. Tziakas et al. or circulating indices reflecting plaque activation i. These include. in addition to several markers of inflammation. Furthermore.

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