Myeloperoxidase is not useful for the early assessment of patients with chest pain

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Clinical Biochemistry 43 (2010) 240 – 245

Myeloperoxidase is not useful for the early assessment of patients with chest pain Kai M. Eggers a,⁎, Mikael Dellborg b , Nina Johnston a , Jonas Oldgren a , Eva Swahn c , Per Venge d , Bertil Lindahl a a

Department of Medical Sciences, Cardiology, Uppsala University Hospital and Uppsala Clinical Research Center, Uppsala, Sweden b Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden c Department of Cardiology, University Hospital Linköping, Linköping, Sweden d Department of Medical Sciences, Clinical Chemistry, Uppsala University Hospital, Uppsala, Sweden Received 31 July 2009; received in revised form 26 September 2009; accepted 29 September 2009 Available online 12 October 2009

Abstract Background: Myeloperoxidase (MPO) has been listed as a potentially useful risk marker in acute coronary syndrome. However, its clinical utility in patients with acute chest pain is not yet defined. Design and methods: MPO (Architect, Abbott Diagnostics) was measured in 120 healthy controls and 303 chest pain patients who had been admitted to the coronary care units of three Swedish hospitals. Results: Chest pain patents had significantly higher median MPO levels compared to healthy controls (120.6 vs. 78. 9 pmol/L; p b 0.001). However, MPO was not useful for the diagnosis of myocardial infarction (c-statistics 0.61 [95% CI 0.54–0.67]), and Cox regression analysis revealed no independent association between MPO and mortality (adjusted hazard ratio 1.3 [95% CI 0.8–2.0]) or the composite endpoint (adjusted hazard ratio 1.1 [95% CI 0.8–1.5]) after a median follow-up of 4.9 years. Conclusions: MPO provided no clinically relevant information in the present population of chest pain patients. © 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: Myeloperoxidase; Acute chest pain; Risk prediction; Prognosis

Introduction There is a growing interest in non-necrosis biomarkers as potentially useful tools for the evaluation of patients with ischemic heart disease. In particular inflammatory biomarkers have been extensively assessed given the fact that vascular inflammation is acknowledged as a key issue in the pathobiology of atherothrombosis. Myeloperoxidase (MPO) is an enzyme that is released from activated polymorphonuclear neutrophils and monocytes and involved in the initiation and propagation of atherosclerotic plaques. As a member of the

⁎ Corresponding author. Department of Medical Sciences, Cardiology, University Hospital Uppsala, S-751 85 Uppsala, Sweden. Fax: +46 18 50 66 38. E-mail address: [email protected] (K.M. Eggers).

heme peroxidase superfamily, MPO generates an array of reactive oxidants and radical species that contribute to the development of atheroma and subsequent plaque rupture [1]. Blood MPO levels are elevated in patients with acute coronary syndromes [2,3] and, moreover, predictive for adverse outcome [2,4–6]. Consequently, MPO has been listed as a potentially useful risk marker in acute coronary syndrome [7], although its role in the clinical work-up of these patients is not yet defined. However, the situation is different in patients with acute chest pain in whom an acute coronary syndrome is suspected but not definitely established. Recent studies have provided conflicting results regarding the prognostic implications of MPO in this setting [8–10] but are limited due to somewhat short periods of follow-up. This probably underestimates the true association between a marker and outcome in chest pain

0009-9120/$ - see front matter © 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2009.09.026

K.M. Eggers et al. / Clinical Biochemistry 43 (2010) 240–245

patients who carry a lower-risk for future cardiovascular events. The aim of the present study was, therefore, to assess the clinical utility of MPO measured with a new sensitive assay in a sample of fairly unselected chest pain patients who have been followed for several years. Methods Study populations Chest pain patients were participants from the FASTER I (Fast Assessment of Thoracic Pain by Neural Networks) study that was conducted between October 2002 and August 2003 at three investigational centers in Sweden and enrolled 380 subjects [11]. The study inclusion criterion was admittance to the coronary care unit because of chest pain lasting for ≥ 15 min within the previous 8 h. The study exclusion criteria were pathological ST-segment elevation on the admission 12-lead ECG or strong suspicion of acute myocarditis. After admission, patients underwent blood sampling as described below, and a resting 12-lead ECG was obtained. Patients without sinus rhythm, with pathological Q waves, left bundle branch block or significant ST-segment changes were regarded as having an abnormal ECG [11]. All patients received standard therapy according to local routines. Healthy control subjects were randomly chosen from the SWISCH (Swedish Women and Men and Ischemic Heart Disease) study. This study consisted of 429 subjects without cardiovascular or other chronic disease, acute illness, cardiovascular medication or an abnormal resting 12-lead ECG, who had been matched for age and gender with non-ST-segment elevation acute coronary syndrome patients participating in the FRISC II (FRagmin and Fast Revascularization during InStability in Coronary artery disease) study [12]. Verbal and written informed consent was obtained from the participants of both studies and the study protocols had been approved by the institutions independent ethics committees. Biochemical analyses MPO was analyzed in EDTA plasma that had been stored frozen in aliquots at −70 °C. In the FASTER I study, samples had been obtained immediately after enrolment (median delay from hospital admission 47 [25th, 75th percentiles 29–68] min). MPO levels were measured using a chemiluminescent microparticle immunoassay on an Architect i2000SR instrument (Abbott Diagnostics, Abbott Park, IL). According to the manufacturer, this assay has a dynamic range of 0–10,000 pmol/L with a limit of detection of b20.0 pmol/L and a functional sensitivity of b 50.0 pmol/L. The validation of the Architect MPO assay in our laboratory revealed intra- and inter-assay coefficients of variation between 2.7% and 4%. We defined the upper reference level (URL) of MPO on this assay as the 97.5th percentile derived from healthy control subjects. In the FASTER I study, cardiac troponin I (cTnI) was analyzed on Stratus CS instruments (Siemens Healthcare Diagnostics, Deerfield, IL) at the time of enrolment, after 40

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and 80 min and 2, 3, 6 and 12 h, and in case of any cTnI elevation ≥ 0.1 μg/L (lowest concentration measurable with a coefficient of variation b10%) after 24 h. cTnI results were dichotomized at 0.07 μg/L as the 99th percentile among healthy individuals [13]. N-terminal pro-B-type natriuretic peptide (NT-proBNP) was determined with a sandwich immunoassay on an Elecsys 2010 instrument (Roche Diagnostics, Mannheim, Germany). C-reactive protein (CRP) was analyzed with a chemiluminescent enzyme-labelled immunometric assay on an Immulite 1000 analyser (Diagnostic Products Corp., Los Angeles, CA). Growth-differentiation factor-15 (GDF-15) was measured with an immunoradiometric assay [14]. Serum creatinine was determined with the Advia 1650 system (Bayer Diagnostics, Tarrytown, NY), and from that, the creatinineclearance was calculated according to the Cockcroft–Gault formula [15]. Definition of the index diagnosis The index events were classified by independent investigators with access to all clinical and laboratory data but unaware of the patients clinical outcome. Acute myocardial infarction (AMI) was diagnosed in accordance with the ESC/ACC consensus document [16], using cTnI elevation ≥ 0.1 μg/L in at least two measurements within 24 h from admission as biochemical criterion. Patients with typical anginal pain at rest in combination with new ST-segment changes and peak cTnI levels b 0.1 μg/L were considered to suffer from unstable angina. Patients with cardiac disease not fulfilling the criteria for AMI or unstable angina were regarded as having other heart disease. The other diagnostic categories were non-cardiac disease and unspecified chest pain. Follow-up After discharge, patients were followed by research nurses with telephone contacts at 30 days and at 6 (± 1) months. Information regarding mortality was obtained from the Swedish Registry on Mortality, and information regarding (recurrent) AMI from the hospitals diagnosis registries and patient records. To obtain data on long-term follow-up, the Swedish Registry on Mortality and the Swedish Patient Registry, a mandatory registry collecting the ICD-10 codes of all patients hospitalized in Sweden, were queried in December 2008. Statistical analysis Continuous data are described as medians with 25th and 75th percentiles. Between-group comparisons of medians were performed with the Mann–Whitney U test. Categoric variables are expressed as frequencies, and percentages and differences were analyzed with the χ2 test. The study endpoints were total mortality and (recurrent) AMI, alone or as composite. The predictive value of MPO was explored using c-statistics and Cox proportional hazard models without adjustment (model 1) and with adjustment for clinical characteristics significantly related to the long-term composite

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Table 1 Baseline characteristics in relation to myeloperoxidase tertiles (in pmol/L). Total (n = 303)

MPO tertiles

p-value

b91.8 pmol/L (n = 98) Median age (years) Males Hypertension Diabetes Hyperlipidemia Current smoking Previous smoking Previous AMI Congestive heart failure Previous PCI/CABG Abnormal admission ECG Biochemical markers Peak cTnI N0.07 μg/L NT-proBNP (ng/L) CRP (mg/dL) GDF-15 (ng/L) Creatinine-clearance (mL/min)

66 (57–76) 200 (66.0%) 113 (37.3%) 49 (16.2%) 129 (42.6%) 52 (17.2%) 138 (45.5%) 103 (34.0%) 50 (16.5%) 48 (15.8%) 146 (48.2%) 122 (40.3%) 172 (60–662) 1.8 (0.9–4.7) 1563 (1145–2199) 57 (45–69)

62 (55–74) 64 (65.3%) 28 (28.6%) 17 (17.3%) 42 (42.9%) 18 (18.4%) 39 (39.8%) 32 (32.7%) 18 (18.4%) 17 (17.3%) 36 (36.7%) 25 (25.5%) 113 (38–423) 1.4 (0.6–3.5) 1328 (970–1922) 59 (46–68)

91.8–151.2 (n = 105) 66 (57–75) 70 (66.7%) 46 (43.8%) 21 (20.0%) 47 (44.8%) 19 (18.1%) 50 (47.6%) 40 (38.1%) 18 (17.1%) 18 (17.1%) 59 (56.2%) 52 (49.5%) 249 (88–740) 2.4 (1.0–4.8) 1575 (1227–2010) 60 (47–72)

N151.2 (n = 100) 70 (59–78) 66 (66.0%) 39 (39.0%) 11 (11.0%) 40 (40.0%) 15 (15.0%) 49 (49.0%) 31 (31.0%) 14 (14.0%) 13 (13.0%) 51 (51.0%) 45 (45.0%) 178 (86–866) 1.9 (1.0–6.4) 1737 (1187–2673) 54 (39–65)

0.03 0.98 0.07 0.20 0.79 0.78 0.37 0.53 0.69 0.64 0.02 0.001 0.01 0.03 0.004 0.03

Values are shown as number of patients and percentages if not stated otherwise. AMI: acute myocardial infarction; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting.

endpoint on univariate analysis (model 2). The proportional hazard assumptions were checked by computing log[−log (event)]plots. Due to skewed levels, MPO was transformed to it's natural logarithm before being entered into these analyses. In all tests, a two-tailed p-value b 0.05 was considered significant. The Statistical Package for Social Sciences (SPSS 14.0) software program (SPSS, Inc., Chicago, IL) was used for the data analysis.

Results Myeloperoxidase levels in healthy control subjects Results for MPO were obtained from 116 healthy control subjects. The median MPO level in this cohort was 78.9 (60.2–99.5 [25th, 75th percentiles]) pmol/L with the 97.5th percentile at 208.1 pmol/L.

Fig. 1. Myeloperoxidase levels in healthy control subjects and patients with chest pain. Data are presented as box (25th percentile, median, and 75th percentile) and whisker (10th and 90th percentiles) plots. p-values refer to comparisons of myeloperoxidase levels among the respective diagnostic categories to healthy controls.

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Myeloperoxidase levels—relation to clinical data Results for MPO were available in 303 patients from the FASTER I study. The median time from symptom onset to first blood sample was 4.6 (3.2–7.1) h. The index events were classified as AMI in 102 patients (33.7%), unstable angina in 69 patients (22.8%), other heart disease in 8 patients (2.6%), non-cardiac disease in 15 patients (5.0%), and unspecified chest pain in 109 patients (36.0%). Further baseline characteristics are summarized in Table 1. The median MPO level in the total sample population was 120.6 (80.7–186.9) pmol/L (p b 0.001 compared to healthy controls). As shown in Table 1, patients with MPO levels in the highest tertile tended to be older and were more likely to have higher levels of GDF-15 and a poorer renal function. Patients with MPO levels in the second tertile had the highest prevalences of an abnormal admission ECG, peak cTnI levels of N 0.07 μg/L, and the highest levels of NT-proBNP and CRP. This was mainly driven by the differences to the lowest MPO tertile. There were no other significant relationships between clinical data and MPO levels when the URL was considered as threshold (data not shown). Myeloperoxidase levels—relation to index diagnoses The median MPO level in patients with an index diagnosis of AMI was 136.1 (97.7–228.4) pmol/L, 116.7 (80.4–181.9) pmol/ L in patients with unstable angina, 106.7 (64.0–145.9) pmol/L in patients with other cardiac disease, 141.5 (127.8–227.4) pmol/L in patients with non-cardiac disease, and 95.1 (71.1–164.8) pmol/ L in patients with unspecified chest pain (Fig. 1). Compared to healthy controls, median MPO levels were significantly higher in any of these diagnostic groups (p b 0.001) apart from the small subcohort with other heart disease (p = 0.11). Otherwise, median MPO levels did not differ significantly among the diagnostic groups apart from patients with unspecified chest pain having significantly lower MPO levels compared to patients with AMI (p b 0.001) and patients with non-cardiac disease (p = 0.02). The c-statistics of MPO regarding the diagnosis of AMI was 0.61 (95% confidence interval [95% CI] 0.54–0.67) and 0.59

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(95% CI 0.53–0.66) regarding AMI or unstable angina, considered as one diagnostic category. Applying the URL in healthy control subjects as cut-off, the sensitivity of MPO for the diagnosis of AMI was 41.5% with a corresponding specificity of 68.5%. Myeloperoxidase levels—prognostic implications Six-month outcome Complete 6-month follow-up data were available for all patients. After 6 months, 5 patients (1.7%) died, 12 patients (4.0%) had suffered a (recurrent) AMI and 16 patients (5.3%) had reached the composite endpoint. Compared to patients without an event, median MPO levels were non-significantly higher in patients who suffered the composite endpoint (154.8 vs. 114.2; p = 0.06). The c-statistics of MPO regarding the composite endpoint at 6 months was 0.64 (95% CI 0.51–0.77). As demonstrated in Table 2A, neither dichotomization of MPO levels applying tertiles nor using the URL revealed significant associations to outcome. End of follow-up Data on long-term events were available in 296 patients (97.7%) with a median follow-up of 4.9 years. In total, 32 patients (10.8%) died, 34 patients (11.5%) had a (recurrent) AMI and 53 patients (17.9%) had reached the composite endpoint. According to univariate analysis, age, congestive heart failure, a history of AMI and an abnormal admission ECG were significantly related to the composite endpoint, as were levels of NT-proBNP, CRP, GDF-15, creatinine-clearance and a peak cTnI level of N 0.07 μg/L. Median MPO levels obtained at enrolment were nonsignificantly higher in patients who died during long-term follow-up (144.4 vs. 110.4 pmol/L; p = 0.09), who had a (recurrent) AMI (135.4 vs. 111.7 pmol/L; p = 0.53), or who suffered the composite endpoint (138.4 vs. 109.9 pmol/L; p = 0.15). The c-statistics of MPO regarding the composite endpoint was 0.56 (95% CI 0.48–0.65). Only when assessed on the basis of the URL, a significant relation between MPO and

Table 2 Univariate associations between myeloperoxidase levels (in pmol/L) and adverse events at (A) 6-month follow-up and (B) end of follow-up. A MPO tertiles

Death/AMI

MPO URL

b91.8 (n = 98)

91.8–151.2 (n = 105)

N151.2 (n = 100)

p-value

≤208.1 (n = 238)

N208.1 (n = 65)

p-value

3 (3.1%)

5 (4.8%)

8 (8.0%)

0.29

10 (4.2%)

6 (9.2%)

0.12

B MPO tertiles

Death AMI Death/AMI

MPO URL

b91.8 (n = 97)

91.8–151.2 (n = 103)

N151.2 (n = 96)

p-value

≤ 208.1 (n = 235)

N208.1 (n = 61)

p-value

9 (9.3%) 11 (11.3%) 16 (16.5%)

8 (7.8%) 12 (11.7%) 17 (16.5%)

15 (15.6%) 11 (11.5%) 20 (20.8%)

0.17 1.00 0.66

20 (8.5%) 28 (11.9%) 39 (16.6%)

12 (19.7%) 6 (9.8%) 14 (23.0%)

0.02 0.82 0.26

MPO: myeloperoxidase. URL: upper reference level.

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Table 3 Cox regression analysis. Model 1

Death AMI Death/AMI

Model 2

n

HR (95% CI)

p-value

n

HR (95% CI)

p-value

296 277 296

1.6 (1.0–2.4) 1.1 (0.7–1.7) 1.3 (0.9–1.8)

0.04 0.65 0.16

296 277 296

1.3 (0.8–2.0) 1.0 (0.6–1.5) 1.1 (0.8–1.5)

0.28 0.90 0.62

Relation of Myeloperoxidase to adverse events at the end of follow-up. Model 1: unadjusted analysis. Model 2: adjusted for age, congestive heart failure, previous AMI, and abnormal admission ECG. HR denotes hazard ratio for one increment in ln myeloperoxidase, and CI denotes confidence interval.

long-term mortality existed (Table 2B). However, on adjusted multivariable analysis, MPO was not predictive for any endpoint (Table 3). There were no significant associations between MPO tertiles or the MPO URL and long-term risk in subgroups with normal or elevated peak cTnI levels, a normal or abnormal admission ECG, with or without an index diagnosis of AMI, or with or without index diagnoses of AMI and unstable angina considered as one entity (data not shown). Discussion The main finding of the present analysis is that MPO levels did not carry relevant diagnostic or prognostic information in our sample of 303 fairly unselected chest pain patients. This might be unexpected given the fact that, as in other studies, MPO levels were elevated in almost all diagnostic subgroups including patients with unspecified chest pain [2,3,8,17]. MPO has been linked to the initiation and propagation of atherosclerosis by the generation of diffusible oxidants and radical species which result in the oxidation of LDL and generation of other atherogenic lipoproteins, the consumption of nitric oxide and development of endothelial dysfunction [1]. MPO and its oxidation products are enriched in human atheroma [18] and are related to the degree of coronary atherosclerosis [4,19]. An interesting finding in this context is the strong association between MPO and GDF-15, a biomarker that is induced in the myocardium but also in macrophages in atherosclerotic lesions following the generation of oxidative stress in the vessel wall [20,21]. Consequently, the elevation of MPO levels found in the present chest pain population could be regarded as a signal indicating a more severe degree of atherosclerosis and, thereby, a greater propensity towards future cardiovascular events. However, despite a relative high prevalence of NSTE-ACS in our cohort, we found only limited relationships between MPO and conventional cardiovascular risk factors which is consistent with data from other studies assessing populations with ischemic heart disease including acute chest pain [3,5,8,12]. Moreover, MPO was only weakly indicative of the presence of AMI and failed to provide independent prognostic value despite several years of follow-up. These data corroborate with most studies assessing the prognostic implications of MPO in lower-risk populations. Most recently, McCann and colleagues assessed MPO (Biocheck) using the 75th percentile as decision limit in a chest

pain population with a 53% prevalence of AMI [10]. They found no relationship between MPO and death or AMI at 1 year, similar to results from Apple and colleagues who studied a lower-risk chest pain population throughout 6 months using the MPO 99th percentile (Assay Design) as prognostic cut-off [9]. In another population with stable coronary artery disease, MPO tertiles (Mercodia) were not independently predictive despite 3.5 years of follow-up [22]. Contrasting to these data, Brennan and colleagues demonstrated an independent relationship between increasing MPO quartiles (Oxis) and major cardiac events including coronary revascularization during 6-month follow-up in a sample of chest pain patients with a 24% prevalence of AMI [8]. However, disparate endpoint definitions were used in that study which limits the interpretation of results. Moreover, MPO was elevated only at borderline significance levels in nonsurvivors in that study which is consistent with our results. What could be the reasons for the inconsistency of these study results although several lines of evidence support the role of MPO in the development and destabilization of atherosclerotic coronary plaques [1,18]? First, assessing a heterogeneous chest pain population always carries a risk that the true association between a prognostic marker and outcome will be underestimated. For instance, MPO levels might have been influenced by acute infections or inflammatory states, conditions that were not used as exclusion criteria in our study. Consequently, MPO might be more valuable in high-risk populations with acute coronary syndrome [2,4–6] even though a subanalysis in the present study did not confirm an increased risk assigned to patients with index diagnoses of AMI or unstable angina. Moreover, MPO levels could also reflect neutrophil activation by unstable atherosclerotic plaques elsewhere in the vasculature, thereby explaining the neutral relationship to the prespecified endpoints in our study. Finally, assay-related issues such as the use of different detection antibodies limit the transferability of results obtained on one MPO assay to another. In fact, the Architect MPO ELISA demonstrated a surprisingly low correlation to MPO results obtained on an in-house ELISA developed at our institution (r = 0.68; p b 0.001; unpublished data). This emphasizes that for a comparison of results obtained from different MPO assays, a systematic review of their analytical characteristics is needed, as pointed out in a recent editorial by Wu [23]. In conclusion, MPO provided no relevant clinical information in patients admitted because of acute chest pain which contrasts to the prognostic value of MPO found in patients with

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established acute coronary syndrome [2–6]. Given the summarized evidence from our and previous studies, it thus is doubtful whether MPO is useful for the clinical work-up of patients admitted because of acute chest pain.

[7]

Limitations

[8]

We recognize that our study is not without limitations. As we were unable to discern the cause of death in our study population, we cannot compare the rates for cardiovascular death. The study included only 303 patients which decrease its generalizability. However, this is to some extent counterbalanced by the long period of follow-up as compared to other studies in chest pain patients. Conflicts of interest P.V. has received research honoraria from Abbott Diagnostics, Roche Diagnostics and Siemens Healthcare Diagnostics. B.L. has served as a consultant for Siemens Healthcare Diagnostics and has received honoraria for educational lectures from that company and Roche Diagnostics.

[9]

[10]

[11]

[12]

[13]

Acknowledgments The authors are indebted to the clinicians and staff of all participating study centers for their skillful and invaluable assistance, especially the research nurses Catrin Henriksson, Elisabeth Logander and Helena Svensson. We also wish to thank Drs. Kempf and Wollert, Hannover Medical School, Germany, for conducting the analyses of GDF-15 in this study and providing intellectual input. The reagents for the analysis of MPO were provided by Abbott Diagnostics. The FAST II and FASTER I studies had been supported by grants from Dade Behring AB, Skärholmen, Sweden (now Siemens Healthcare Diagnostics) and Cardiological Decision Support Uppsala AB, Uppsala, Sweden.

[14]

[15] [16]

[17]

[18]

References [1] Nicholl SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005;25:1102–11. [2] Mocatta TJ, Pilbrow AP, Cameron VA, et al. Plasma concentrations of myeloperoxidase predict mortality after myocardial infarction. J Am Coll Cardiol 2007;49:1993–2000. [3] Ndrepepa G, Braun S, Mehilli J, von Beckerath N, Schömig A, Kastrati A. Myeloperoxidase level in patients with stable coronary artery disease and acute coronary syndromes. Eur J Clin Invest 2008;38:90–6. [4] Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 2003;108:1440–5. [5] Cavusoglu E, Ruwende C, Eng C, et al. Usefulness of baseline plasma myeloperoxidase levels as an independent predictor of myocardial infarction at two years in patients presenting with acute coronary syndrome. Am J Cardiol 2007;99:1364–8. [6] Morrow DA, Sabatine MS, Brennan ML, et al. Concurrent evaluation of novel cardiac biomarkers in acute coronary syndrome: myeloperoxidase

[19]

[20]

[21]

[22]

[23]

245

and soluble CD40 ligand and the risk of recurrent ischaemic events in TACTICS-TIMI 18. Eur Heart J 2008;29:1096–102. Morrow DA, Cannon CP, Jesse RL, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Clin Chem 2007;53:552–74. Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349: 1595–604. Apple FS, Pearce LA, Chung A, Ler R, Murakami MM. Multiple biomarker use for the detection of adverse events in patients presenting with symptoms suggestive of acute coronary syndrome. Clin Chem 2007;53:874–81. McCann CJ, Glover BM, Menown IB, et al. Prognostic value of a multimarker approach for patients presenting to the hospital with acute chest pain. Am J Cardiol 2009;103:22–8. Eggers KM, Ellenius J, Dellborg M, et al. Artificial neural network algorithms for early diagnosis of acute myocardial infarction and prediction of infarct size in chest pain patients. Int J Cardiol 2007;114: 366–74. Johnston N, Jernberg T, Lindahl B, et al. Biochemical indicators of cardiac and renal function in a healthy elderly population. Clin Biochem 2004;37: 210–6. Panteghini M, Pagani F, Yeo KT, et al. Evaluation of imprecision for cardiac troponin assays at low-range concentrations. Clin Chem 2004;50: 327–32. Kempf T, Horn-Wichmann R, Brabant G, et al. Circulating concentrations of growth- differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay. Clin Chem 2007;53:284–91. Cockgroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 2007;28:1598–660. Zhang R, Brennan ML, Fu X, et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001;286: 2136–42. Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol 2001;158:879–91. Cavusoglu E, Chopra V, Gupta A, et al. Usefulness of the white blood cell count as a predictor of angiographic findings in an unselected population referred for coronary angiography. Am J Cardiol 2006;98: 1189–93. Schlittenhardt D, Schober A, Strelau J, et al. Involvement of growthdifferentiation factor 15/macrophage inhibitory cytokine-1 (GDF 15/ MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in atherosclerotic lesions. Cell Tissue Res 2004;318:325–33. Kempf T, Eden M, Strelau J, et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006;98:351–60. Stefanescu A, Braun S, Ndrepepa G, et al. Prognostic value of plasma myeloperoxidase concentration in patients with stable coronary artery disease. Am Heart J 2008;155:356–60. Wu AH. Novel biomarkers of cardiovascular disease: myeloperoxidase for acute and/or chronic heart failure? Clin Chem 2009;55:12–4.