CLINICAL STUDIES
Serum neopterin and complex stenosis morphology in patients with unstable angina
Xavier Garcia-Moll, MDa,
Fabio Coccolo, MDa,
Della Cole, BSc, RSa and
Juan Carlos Kaski, MD, FESC, FACCa
a Coronary Artery Disease Group, Cardiological Sciences, St. George’s Hospital Medical School, London, United Kingdom
Manuscript received December 7, 1998;
revised manuscript received October 25, 1999,
accepted December 2, 1999.
Reprint requests and correspondence: Professor Juan Carlos Kaski, Coronary Artery Disease Research Group, Cardiological Sciences, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom
jkaski{at}sghms.ac.uk
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Abstract
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OBJECTIVES
We sought to assess the relation between serum neopterin concentration and complex coronary artery stenosis in patients with unstable angina.
BACKGROUND
Monocyte activation is associated with acute atheromatous plaque disruption and acute coronary syndromes. Angiographically demonstrated complex coronary stenosis is often an expression of plaque disruption. Increased serum concentration of neopterin, a pterydine derivative secreted by macrophages after stimulation by interferon-gamma, has been observed in patients with acute coronary syndromes as compared with control subjects and patients with stable angina pectoris.
METHODS
We studied 50 patients with unstable angina (32 men) who underwent coronary angiography after hospital admission. All coronary stenoses with  30% diameter reduction were assessed and classified as "complex" (irregular or scalloped borders, ulceration or filling defects suggesting thrombi) or "smooth" (absence of complex features). Serum neopterin levels were assessed within 24 h of hospital admission using a commercially available immunoassay (enzyme-linked immunosorbent assay kit, IBL, Hamburg, Germany).
RESULTS
Thirty-nine patients were classified in Braunwald class IIIb, four in class IIb and seven in class Ib. The number of complex lesions per patient was 2.6 ± 1.8 (mean ± SD). The mean neopterin concentration was 7.76 ± 3.62 nmol/liter. A significant correlation was observed between neopterin serum concentration and the presence of complex coronary stenoses (r = 0.35, p = 0.015). Multiple regression analysis showed that serum neopterin (p < 0.0001) was independently associated with the number of complex lesions. Other variables associated with complex lesions were the number of vessels with 75% stenosis (p < 0.0001), plasma creatinine (p = 0.003), triglycerides (p = 0.014) and a history of unstable angina (p = 0.032).
CONCLUSIONS
Serum neopterin concentration is associated with the presence of angiographically demonstrated complex lesions in patients with unstable angina and may represent a marker of coronary disease activity.
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Abbreviations and Acronyms
| | CK | = creatine kinase | | ECG | = electrocardiogram, electrocardiographic | | IFN-gamma | = interferon-gamma |
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Disruption of vulnerable atheromatous plaque is the most common pathogenic mechanism in acute coronary syndromes (1). There is increasing evidence that inflammation plays an important role in atherogenesis and may determine plaque vulnerability (2). Recent observations suggest that vulnerable atherosclerotic plaques have an increased number of both macrophages and activated lymphocytes (3). In addition, in previous studies it has been shown that a large lipid core occupying a large proportion of plaque volume and a thin, fibrous plaque cap are of crucial importance for plaque disruption (4,5). Compared with patients with chronic stable angina, patients with acute coronary syndromes have coronary plaques with more extensive macrophage-rich areas (6). Activated macrophages within plaques are capable of producing a range of proteases that lead to proteolytic destruction of the connective tissue matrix (7) and may contribute to the "active" phenomenon of plaque disruption (8). Unstable plaques also contain activated T cells that produce the cytokine interferon-gamma (IFN-gamma), which both activates macrophages present in the atheromatous plaque and interferes with plaque matrix collagen synthesis (9).
Neopterin, a pterydine derivative, is secreted by macrophages after stimulation by IFN-gamma (10) and has been shown to be elevated in the serum of patients with unstable angina and acute myocardial infarction as compared with control subjects and patients with stable angina pectoris (11,12). It has also been established that patients with unstable angina have a higher incidence of angiographically demonstrated complex coronary stenoses as compared with patients with stable angina (13). Complex lesions are associated with rapid disease progression (14,15) and a higher restenosis rate after percutaneous transluminal coronary angioplasty as compared with smooth lesions, probably reflecting a tendency toward thrombogenesis or further plaque disruption, or both (16). The aim of this study was to assess whether serum neopterin concentration is related to the presence of angiographically demonstrated complex lesions in patients with unstable angina.
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Methods
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Patients.
We studied 50 patients (32 men) who were admitted to the Coronary Care Unit of St. George’s Hospital in London between September 1996 and June 1997 with the diagnosis of unstable angina and who underwent coronary arteriography after hospital admission. Unstable angina was defined and classified according to Braunwald (17). Class I indicates new onset or severe, accelerated angina; class II indicates angina at rest during the previous month before admission but not within the last 48 h before admission; and class III indicates angina at rest during the last 48 h before admission. All patients had primary unstable angina, corresponding to subclass "b" of Braunwald’s classification (17). These patients were part of a larger cohort of 101 consecutive patients with unstable angina, 13 of whom developed a Q wave myocardial infarction, according to electrocardiographic (ECG) criteria, and had raised creatine kinase (CK) and CK, MB fraction levels during the first 48 h of admission, and seven of whom were excluded owing to ongoing systemic or cardiac inflammatory processes. Also excluded were 31 patients who did not undergo coronary angiography. The patients’ clinical management and the decision to proceed with cardiac catheterization was left to the discretion of the managing cardiologist. Thirty-nine patients were in Braunwald class IIIb, seven were in class Ib and four were in class IIb. All had a transient ECG diagnostic of myocardial ischemia. The patients’ baseline clinical characteristics at initial presentation are summarized in Table 1. All patients gave written, informed consent before study entry, and the study was approved by the local Ethics Committee.
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Table 1 Baseline Variables, Risk Factors, Past Medical History and Treatment at Hospital Admission in 50 Patients With Unstable Angina
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Neopterin measurements.
Neopterin serum concentration was measured using a commercially available immunoassay (enzyme-linked immunosorbent assay kit, IBL, Hamburg, Germany). The limit of detection was 1.5 nmol/liter. The analytic precision of the assay was <3% at the level of 7.7 nmol/liter, and <4% at the level of 20 nmol/liter. All other biochemistry measurements were carried out by the Analytical Unit of the Biochemistry Department of our institution, using standard methods.
Angiographic analyses.
Coronary angiography was carried out according to the Judkins technique, and images of the coronary tree were obtained in routine, standardized projections with the digital Philips Integris 3000 system (Philips, Holland) in all patients. Two experienced cardiologists who had no knowledge of the patients’ clinical characteristics and biochemical results visually reviewed all angiographic images to assess the extent of coronary artery disease and morphology of all coronary artery stenoses with 30% reduction in diameter.
Angiographic scoring system (the Sullivan score)
Sullivan’s scoring system (18) was used to assess the extension of atherosclerotic disease in the coronary artery tree, as described in previous studies from our group (19). An example is shown in Figure 1. Coronary angiograms were assessed and scored according to the system of Sullivan et al. (18), which includes vessel score, stenosis score and extension score. Vessel score is based on the number of coronary arteries showing 75% stenosis reduction in lumen diameter. Stenosis score is aimed at reflecting the most severe stenosis observed in each of the main coronary vessels assessed. Grading is as follows: grade 1 = 1% to 49% reduction in coronary lumen diameter; grade 2 = stenosis with 50% to 74% reduction in lumen diameter; grade 3 = stenosis with 75% to 99% reduction in lumen diameter; and grade 4 = total coronary occlusions. Finally, extension score refers to the proportion of the coronary artery tree showing angiographically detectable atheroma. The observed proportion in each vessel is multiplied by a factor that varies according to the artery involved: left main stem, 5; left anterior descending coronary artery, 20; main diagonal branch, 10; first septal perforator, 5; left circumflex artery, 20; obtuse marginal and posterolateral vessels, 10; right coronary artery, 20; and main posterior descending branch, 10. When the major lateral wall branch was a large obtuse marginal or intermediate vessel, this was given a factor of 20, and the left circumflex artery, a factor of 10. When a vessel was occluded and the distal bed was not fully visualized by collateral flow, the proportion of vessel not visualized was given the mean extent score of the remaining vessels. The scores for each vessel or branch were added to give a total score out of 100; this total score represents the percentage of the coronary luminal surface area involved by atheroma (18). Interobserver variability (the standard deviation of the mean unsigned difference between paired estimates) for the extent score in this study was 4.9%.
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Figure 1 A, Representative angiogram of a patient with one-vessel disease (obtuse marginal vessel with >75% stenosis). The right coronary artery was completely normal. B, Angiographic scores as suggested by Sullivan et al. (18), with the final (total) score along the bottom (see text for details).
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Angiographic coronary stenosis morphology
All coronary stenoses with 30% diameter reduction were assessed by two experienced cardiologists who had no knowledge of the neopterin results or the identity and clinical characteristics of the patients. Stenosis morphology was assessed as reported previously in several studies from our group (14,19–21). Briefly, stenoses were considered to be complex or smooth. Complex lesions were defined by the following features: 1) irregular morphology or scalloped borders, or both; 2) overhanging or abrupt edges perpendicular to the vessel wall; 3) ulceration (i.e., outpouchings within the stenosis); and/or 4) the presence of filling defects consistent with intracoronary thrombus (22). Coronary stenoses with no complex features were classified as smooth lesions. When discrepancies arose regarding the morphologic appearance of a lesion, a third experienced observer was involved, and the lesion was classified by consensus. The reproducibility of the morphologic classification was determined by repeat analysis at >3-month intervals independently by two observers who had no knowledge of the stenosis classification obtained at the first reading. Interobserver agreement regarding qualitative morphologic analyses of all significant stenoses was 97%.
Statistical analysis.
Results for normally distributed continuous variables are expressed as the mean value ± SD, and continuous variables with non-normal distribution are presented as the median value (interquartile interval). Continuous variables were analyzed using the unpaired t test and the Mann-Whitney U test, as appropriate. The Spearman two-way test was used to assess the relation between two quantitative variables with non-normal distribution. The Pearson two-way test was used to assess the relation between two quantitative variables with normal distributions. We assessed independent predictors of complex stenoses using multiple regression analysis. As it has been established that renal function is a major determinant of neopterin levels in blood (23), neopterin levels were adjusted for creatinine levels when correlated with other variables. Creatinine was included in the multiple regression analysis where the dependent variable was the number of complex lesions, and the independent variables were those which showed, on univariate analysis, a significant correlation with the number of complex lesions. Differences were considered to be statistically significant if the null hypothesis could be rejected with >95% confidence. The SPSS 7.0 statistical software package was used for all calculations.
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Results
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The baseline clinical characteristics and angiographic results in the 50 patients (32 men) included in the study are shown in Tables 1 and 2, respectively.
Eighty percent of patients had complex lesions >30%; three patients had complex lesions only; seven patients had smooth lesions only; and three patients had no stenoses 30%. In 30 patients, both complex and smooth stenoses were observed.
Univariate analysis revealed that age, neopterin serum concentration and angiographic stenosis severity were significantly correlated with the number of complex lesions (Table 3), as were the use of digoxin (p = 0.029) and nitrates (p = 0.048). Complex stenosis morphology was associated, albeit nonsignificantly, with a history of unstable angina (p = 0.08) and unstable angina (Braunwald class IIIb) on hospital admission (p = 0.096).
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Table 3 Univariate Correlation (r Value) Among Baseline Variables and Complex Coronary Artery Stenoses in 50 Patients With Unstable Angina
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As expected, serum neopterin concentration showed a significant correlation with creatinine levels (r = 0.34, p = 0.014). Neopterin also showed a highly significant correlation with the number of complex lesions (r = 0.35, p = 0.015) (Table 3). Neopterin, however, was not significantly associated with disease extent and severity, as assessed by vessel score, stenosis score and extension score. Similarly, neopterin levels were not associated with the number of smooth coronary stenoses or left ventricular ejection fraction (Table 4).
Interestingly, women had significantly higher adjusted neopterin levels than did men (mean difference, 3.25 nmol/liter [95% confidence interval 1.24 to 5.27], p = 0.002) and a trend toward less severe coronary artery disease. Figure 2 shows scatter plots for neopterin levels and the number of complex lesions in men and women.
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Figure 2 Relation between neopterin levels and complex coronary artery stenoses in men and women (see text for details).
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White blood cell (r = –0.012, p = 0.94) and monocyte (r = –0.072, p = 0.64) counts were not significantly associated with neopterin levels in our study. Similarly, we did not observe an association between the time elapsed from the last episode of angina and the drawing of blood samples for the assessment of neopterin (r = 0.031, p = 0.83). We performed backward stepwise multiple regression analysis where we included both the variables shown to have a relation with complex lesions in the univariate analysis and the variables showing a trend (p < 0.20). Creatinine was also included in the model, as this variable is known to have a direct effect on neopterin levels. We found that the following variables remained independent predictors of the number of complex lesions in this model: neopterin (p < 0.001), vessel score (p = 0.001), plasma creatinine (p = 0.003), plasma triglycerides (p = 0.01) and a history of unstable angina (p = 0.03) (Table 5). Multiple regression analysis showed that neopterin level and the number of diseased vessels were the most important predictors of the number of angiographically demonstrated complex stenoses. Findings in this multiple regression analysis model explain 69% of the variation in the number of complex lesions (adjusted r2 = 0.69).
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Table 5 Multiple Regression Analysis With Significant Univariate Predictive Variables for Number of Complex Lesions
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Discussion
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In this study, we have assessed for the first time, to our knowledge, the relation between serum neopterin concentration and angiographically demonstrated complex stenoses in patients with unstable angina pectoris.
Neopterin and coronary artery disease activity.
We observed that neopterin levels had a significant relation with the number of complex lesions. However, neopterin levels did not correlate with vessel score, number of smooth lesions or stenosis severity. This finding is in contrast to a recent study where neopterin was found to correlate with the extent of coronary artery disease (24). The study by Gurfinkel et al. (24), however, included a small number of patients; multiple regression analysis was not performed to assess whether neopterin was independently associated with the extent of coronary artery disease; and neopterin levels were not adjusted for creatinine levels.
Our findings suggest that neopterin may be a marker of coronary disease activity rather than a measure of the anatomic extent of coronary artery disease. The results of the present study are more expansive than those of previous studies from our group (11), which showed that neopterin is elevated in patients with unstable angina and in patients with acute myocardial infarction as compared with patients with chronic myocardial infarction and normal control subjects. Further, support to the notion that neopterin is a marker of plaque activity is provided by a recent study of Schumacher et al. (12), who showed that neopterin was elevated in patients with acute myocardial infarction (mean ± SD, 13.7 ± 2.4 nmol/liter) as compared with patients with chronic stable angina (8.6 ± 3.4 nmol/liter) or healthy control subjects (6.8 ± 1.8 nmol/liter). Neopterin levels in patients with chronic stable angina in Schumacher et al.’s report (12) were not related to the number of diseased coronary vessels.
Neopterin, inflammation and complex lesions.
The present study specifically assessed whether a relation exists between serum neopterin concentration, a marker of macrophage activity, and angiographically demonstrated complex stenoses in patients with unstable angina pectoris. Compared with patients with stable angina pectoris, those with unstable angina have a higher number of complex coronary lesions (22,25). It has been shown that the progression of these stenoses is faster than that of smooth stenoses. A larger proportion of complex stenoses, as compared with smooth stenoses, progress rapidly in both patients with stabilized unstable angina (21) and those with chronic stable angina (14). It has been suggested that angiographically demonstrated complex lesions represent vulnerable plaques prone to disruption or truly disrupted plaques (5,6,22). Plaque vulnerability is a function of the increased number of macrophages and activated lymphocytes (4). Coronary plaques of patients with unstable angina have more extensive macrophage-rich areas than those of patients with stable angina (3,6). These macrophages appear to play a key role in weakening the fibrous cap of atherosclerotic plaques by secreting proteases that contribute to the "active" phenomenon of plaque disruption (8). Vulnerable plaques also have activated T cells that produce the cytokine IFN-gamma and activate the macrophages (9,26). Importantly, IFN-gamma–stimulated macrophages produce neopterin (10). The results of our study lend further support to the notion that inflammatory processes (as shown with C-reactive protein and serum amyloid A protein) (27,28) and immune activation may play a pathogenic role in acute coronary syndromes (28,29). White blood cell and monocyte counts were not associated with neopterin in our study. This finding is not surprising, as neopterin production is more likely to be the expression of monocyte activation than of increased monocyte number (10). We observed no relation between the time elapsed between the last episode of pain and neopterin levels. Again, neopterin levels are most probably the result of immune activation related to the atherogenic process, as well as the inflammatory mechanism that leads to acute coronary events. It is unlikely that this molecule represents a marker of transient ischemia.
Complex lesions and independent predictors by multiple regression analysis.
Our findings in the present study—mainly that in patients with rapidly stabilized unstable angina, the number of complex lesions correlates with serum neopterin concentration and triglyceride levels—are consistent with previous observations that contributed to our current pathophysiologic knowledge regarding acute coronary syndromes (30–35). Interestingly, in the present study, we confirmed the previous findings of our group—that is, a past history of unstable angina is an independent predictor of the number of complex coronary stenoses and is associated with rapid coronary stenosis progression (36). In this study, multiple regression analysis showed that serum creatinine levels remained significantly associated with the number of complex lesions, probably reflecting the previously described close relation between neopterin and creatinine concentrations (23).
Conclusions.
Our study has shown that neopterin serum concentration is independently related to the number of complex stenoses in patients with unstable angina, even after adjustment for confounding variables. This study gives support to the hypothesis that activation of immune cells in angiographically complex plaques may play a pathogenic role in unstable coronary syndromes. Neopterin serum concentration may be a useful clinical marker of disease activity (37), and further studies are necessary to substantiate this.
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Footnotes
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Dr. Garcia-Moll is supported by fellowships from both the Spanish Society of Cardiology and the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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A. Mauriello, G. Sangiorgi, S. Fratoni, G. Palmieri, E. Bonanno, L. Anemona, R. S. Schwartz, and L. G. Spagnoli
Diffuse and Active Inflammation Occurs in Both Vulnerable and Stable Plaques of the Entire Coronary Tree: A Histopathologic Study of Patients Dying of Acute Myocardial Infarction
J. Am. Coll. Cardiol.,
May 17, 2005;
45(10):
1585 - 1593.
[Abstract]
[Full Text]
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J. A. Ambrose and D. J. D'Agate
Plaque rupture and intracoronary thrombus in nonculprit vessels: An eyewitness account
J. Am. Coll. Cardiol.,
March 1, 2005;
45(5):
659 - 660.
[Full Text]
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P. Avanzas, R. Arroyo-Espliguero, J. Quiles, D. Roy, and J. C. Kaski
Elevated serum neopterin predicts future adverse cardiac events in patients with chronic stable angina pectoris
Eur. Heart J.,
March 1, 2005;
26(5):
457 - 463.
[Abstract]
[Full Text]
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M. Madjid, A. Zarrabi, S. Litovsky, J. T. Willerson, and W. Casscells
Finding Vulnerable Atherosclerotic Plaques: Is It Worth the Effort?
Arterioscler Thromb Vasc Biol,
October 1, 2004;
24(10):
1775 - 1782.
[Abstract]
[Full Text]
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E. Zouridakis, P. Avanzas, R. Arroyo-Espliguero, S. Fredericks, and J. C. Kaski
Markers of Inflammation and Rapid Coronary Artery Disease Progression in Patients With Stable Angina Pectoris
Circulation,
September 28, 2004;
110(13):
1747 - 1753.
[Abstract]
[Full Text]
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P Avanzas, R Arroyo-Espliguero, J Cosin-Sales, G Aldama, C Pizzi, J Quiles, and J C Kaski
Markers of inflammation and multiple complex stenoses (pancoronary plaque vulnerability) in patients with non-ST segment elevation acute coronary syndromes
Heart,
August 1, 2004;
90(8):
847 - 852.
[Abstract]
[Full Text]
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J. Cosin-Sales, M. Christiansen, P. Kaminski, C. Oxvig, M. T. Overgaard, D. Cole, D. W. Holt, and J. C. Kaski
Pregnancy-Associated Plasma Protein A and Its Endogenous Inhibitor, the Proform of Eosinophil Major Basic Protein (proMBP), Are Related to Complex Stenosis Morphology in Patients With Stable Angina Pectoris
Circulation,
April 13, 2004;
109(14):
1724 - 1728.
[Abstract]
[Full Text]
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R. Arroyo-Espliguero, P. Avanzas, J. Cosin-Sales, G. Aldama, C. Pizzi, and J. C. Kaski
C-reactive protein elevation and disease activity in patients with coronary artery disease
Eur. Heart J.,
March 1, 2004;
25(5):
401 - 408.
[Abstract]
[Full Text]
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H. R. Chandra, J. A. Goldstein, N. Choudhary, C. S. O'Neill, P. B. George, S. R. Gangasani, L. Cronin, P. A. Marcovitz, A. M. Hauser, and W. W. O'Neill
Adverse outcome in aortic sclerosis is associated with coronary artery disease and inflammation
J. Am. Coll. Cardiol.,
January 21, 2004;
43(2):
169 - 175.
[Abstract]
[Full Text]
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J. C. Kaski, P. Avanzas, and R. Arroyo-Espliguero
Neopterin--a forgotten biomarker
J. Am. Coll. Cardiol.,
September 17, 2003;
42(6):
1142 - 1143.
[Full Text]
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J. A. Goldstein
Angiographic plaque complexity: the tip of the unstable plaque iceberg
J. Am. Coll. Cardiol.,
May 1, 2002;
39(9):
1464 - 1467.
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D. A. Smith, S. D. Irving, J. Sheldon, D. Cole, and J. C. Kaski
Serum Levels of the Antiinflammatory Cytokine Interleukin-10 Are Decreased in Patients With Unstable Angina
Circulation,
August 14, 2001;
104(7):
746 - 749.
[Abstract]
[Full Text]
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C. J. Wiedermann, S. Kiechl, P. Schratzberger, S. Dunzendorfer, G. Weiss, and J. Willeit
The role of immune activation in endotoxin-induced atherogenesis
Innate Immunity,
August 1, 2001;
7(4):
322 - 326.
[Abstract]
[PDF]
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J.C. Kaski and E.G. Zouridakis
Inflammation, infection and acute coronary plaque events
Eur. Heart J. Suppl.,
August 1, 2001;
3(suppl_I):
I10 - I15.
[Abstract]
[PDF]
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J. A. Goldstein, D. Demetriou, C. L. Grines, M. Pica, M. Shoukfeh, and W. W. O'Neill
Multiple Complex Coronary Plaques in Patients with Acute Myocardial Infarction
N. Engl. J. Med.,
September 28, 2000;
343(13):
915 - 922.
[Abstract]
[Full Text]
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