Prognostic Value of Myeloperoxidase in Patients with Chest Pain
Marie-Luise Brennan, Ph.D., Marc S. Penn, M.D., Ph.D., Frederick Van Lente, Ph.D., Vijay Nambi, M.D., Mehdi H. Shishehbor, D.O., Ronnier J. Aviles, M.D., Marlene Goormastic, M.P.H., Michael L. Pepoy, B.S., Ellen S. McErlean, M.S.N., Eric J. Topol, M.D., Steven E. Nissen, M.D., and Stanley L. Hazen, M.D., Ph.D.
Background Inflammation is linked to adverse outcomes in acutecoronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme,is elevated in culprit lesions that have fissured or rupturedin patients with sudden death from cardiac causes. Numerouslines of evidence suggest mechanistic links between myeloperoxidaseand both inflammation and cardiovascular disease.
Methods We assessed the value of plasma levels of myeloperoxidaseas a predictor of the risk of cardiovascular events in 604 sequentialpatients presenting to the emergency department with chest pain.
Results Initial plasma myeloperoxidase levels predicted therisk of myocardial infarction, even in patients who are negativefor troponin T (<0.1 ng per milliliter) at base line (P<0.001).Myeloperoxidase levels at presentation also predicted the riskof major adverse cardiac events (myocardial infarction, theneed for revascularization, or death) within 30 days and 6 monthsafter presentation (P<0.001). In patients without evidenceof myocardial necrosis (defined as those who were negative fortroponin T), the base-line myeloperoxidase levels independentlypredicted the risk of major adverse coronary events at 30 days(unadjusted 2nd, 3rd, and 4th quartile odds ratios, 2.2 [95percent confidence interval, 1.1 to 4.6], 4.2 [95 percent confidenceinterval, 2.1 to 8.4], and 4.1 [95 percent confidence interval,2.0 to 8.4], respectively) and at 6 months.
Conclusions A single initial measurement of plasma myeloperoxidaseindependently predicts the early risk of myocardial infarction,as well as the risk of major adverse cardiac events in the ensuing30-day and 6-month periods. Myeloperoxidase levels, in contrastto troponin T, creatine kinase MB isoform, and C-reactive proteinlevels, identified patients at risk for cardiac events in theabsence of myocardial necrosis, highlighting its potential usefulnessfor risk stratification among patients who present with chestpain.
Coronary thrombosis results in serious adverse cardiac events,even in the presence of aggressive intervention and treatment.1,2,3Levels of creatine kinase isoenzymes and cardiac troponins,which are diagnostic biologic markers of myocardial necrosis,are used either alone or in conjunction with levels of C-reactiveprotein as prognostic indicators of myocardial infarction.4,5Many patients with chest pain have normal levels of creatinekinase isoenzymes or troponins at presentation but subsequentlyhave a myocardial infarction, require revascularization, ordie within six months. Additional biochemical measures, ideallybased on the pathophysiology of plaque vulnerability, are needed.
Inflammation has been linked to all stages of the developmentof vulnerable plaque, from initial lipid deposition to plaquerupture and its thrombotic complications. Evidence of leukocyteactivation and degranulation is found in patients with unstableangina,6,7,8 and extensive monocyte and neutrophil infiltrationis seen in fissured, thrombosed plaques in patients with acutecoronary syndromes.9,10 In vitro studies suggest numerous mechanismsthrough which leukocytes may affect the stability of plaquein acute coronary syndromes. One potential participant is theleukocyte enzyme myeloperoxidase.
Myeloperoxidase levels are elevated in persons with angiographicallydocumented cardiovascular disease11 and within culprit lesionsprone to rupture.12 The activation of leukocytes prompts thesecretion of myeloperoxidase and the generation of oxidantsimportant in host defense.13 Myeloperoxidase has been linkedto the development of lipid-laden soft plaque,14,15 the activationof protease cascades affecting the stability and thrombogenicityof plaque,16,17 the production of cytotoxic and prothrombogenicoxidized lipids,15,18 and the consumption of nitric oxide, leadingto vasoconstriction.19,20 In the study reported here, we testedthe hypothesis that plasma levels of myeloperoxidase serve asa novel marker of plaque vulnerability in persons presentingto the emergency department with chest pain.
Methods
Study Design
Recruitment occurred as part of a study comparing troponin Tlevels with the levels of the MB isoform of creatine kinase(CK-MB) for the diagnosis of myocardial infarction.21 Patientspresenting to the emergency department within 24 hours afterthe onset of chest pain of suspected cardiac origin were eligible.
Clinical Diagnosis
Myocardial infarction was defined by troponin T levels of atleast 0.1 ng per milliliter. Unstable angina was ascertainedon the basis of the presence of angina at rest, a sudden increasein episodes of previously stable angina, ST-segment depression,or T-wave inversions, as described previously.21 Electrocardiographicdata were verified independently by personnel at an electrocardiographycore facility who were unaware of the patients' diagnoses. Thediagnosis of an acute coronary syndrome was based on the presenceof myocardial infarction or unstable angina, as defined in theprotocol, and confirmed by a chart review by an investigatorwho was unaware of the patients' diagnoses.21
Definitions of Outcomes
Patients were assessed for major adverse cardiac events (myocardialinfarction, reinfarction, the need for revascularization, ordeath). A review of medical records and follow-up telephoneinterviews were conducted for the 30-day and 6-month outcomes.The need for revascularization was defined as coronary-arterybypass surgery, percutaneous coronary intervention, or catheterizationin which at least two major coronary vessels were found to havestenosis of more than 70 percent.
Determination of Normal Myeloperoxidase Levels
For the determination of normal myeloperoxidase levels, sequentialhealthy subjects who responded to advertisements in a communitynewspaper were recruited between September and November 2002.Subjects who were at least 21 years old and who had no historyor clinical evidence of coronary artery disease were eligibleto participate. The control population had a mean (±SD)age of 49±12.4 years, 54.8 percent were men, 44.3 percenthad a family history of coronary artery disease, 36.5 percentwere current smokers, 2.6 percent had a history of diabetes,2.2 percent had a history of hypertension, and 69.6 percenthad a history of hyperlipidemia flow-density lipoprotein cholesterol(130 mg per deciliter [3.4 mmol per liter]).
All participants gave written informed consent. The institutionalreview board of the Cleveland Clinic Foundation approved thestudy protocol.
Biochemical Analyses
Troponin T levels were measured on an ES300 analyzer (BoehringerMannheim). Base-line myeloperoxidase levels were measured withuse of an enzyme-linked immunosorbent assay (Oxis). Each plateincluded a standard curve with isolated myeloperoxidase (extinctioncoefficient of 178,000 M–1cm–1)22 and controls tocorrect for interplate variability. C-reactive protein levelswere determined by high-sensitivity nephelometry (Dade Behring).CK-MB mass was measured by immunoassay (Abbott Laboratories).
Statistical Analysis
Continuous variables are presented as either means (±SD)or medians (with interquartile ranges), and categorical variablesas numbers and percentages. Differences between groups in theoutcome and associations among categorical variables were assessedwith the use of the Wilcoxon rank-sum test. Trends for unadjustedanalyses were evaluated with the use of the Cochran–Armitagetrend test. Correlations among continuous variables were assessedwith the use of the Spearman rank-correlation coefficient. Multivariatelogistic-regression models (SAS version 8.0, SAS Institute)were developed to calculate odds ratios and 95 percent confidenceintervals.
Results
Characteristics of the Patients
The study population consisted of 604 sequential patients whopresented to the emergency department with chest pain (Table 1).The mean time from the onset of chest pain to presentationwas 4.0 hours. Final diagnoses included myocardial infarctionin 23.5 percent, unstable angina in 17.1 percent, suspectedcoronary syndrome in 37.6 percent, and noncardiac chest painin 21.5 percent. Outcomes at 30 days included myocardial infarctionin 146 patients, death in 9 patients, revascularization in 189patients, and a major adverse cardiac event in 245 patients.
Table 1. Base-Line Characteristics of the 604 Patients.
Myeloperoxidase Levels in Patients and Controls
Plasma levels of myeloperoxidase in patients presenting withchest pain ranged from 0 to 4666 pM, with a median of 198 pMand an interquartile range of 119 to 394 pM. These levels weresignificantly higher than those observed in the 115 controlsubjects (median, 120 pM; interquartile range, 97 to 146 pM;P<0.001). Myeloperoxidase levels in the patients were correlatedweakly with peak troponin T levels (r=0.21, P<0.001), C-reactiveprotein levels (r=0.10, P=0.01), and age (r=0.11, P=0.01) butnot the white-cell count (P=0.11). Median myeloperoxidase levelswere higher in men than in women (213 vs. 184 pM, P=0.05). Medianmyeloperoxidase levels did not differ significantly accordingto smoking status or the presence or absence of a history ofdiabetes, hypertension, myocardial infarction, or coronary arterydisease, but they were significantly higher in patients witha history of either hyperlipidemia (232 vs. 181 pM, P<0.01)or revascularization (234 vs. 189 pM, P<0.01).
Base-Line Myeloperoxidase Levels and Risk at Presentation
Myeloperoxidase levels were higher in patients who had a myocardialinfarction within 16 hours after presentation than in thosewho did not (median, 320 vs. 178 pM; P<0.001). Among patientswho had no biochemical evidence of clinically significant myocardialnecrosis at presentation, base-line myeloperoxidase levels weresignificantly elevated in those who had elevated cardiac troponinT levels (0.1 ng per milliliter) within the ensuing4 to 16 hours, but not in those who were consistently negativefor troponin T (median, 353 vs. 309 pM; P<0.001).
The incidence of myocardial infarction increased with increasingquartiles of myeloperoxidase levels: it was 13.9 percent inquartile 1 (less than 119.4 pM), 16.6 percent in quartile 2(119.4 to 197.9 pM), 25.2 percent in quartile 3 (198.0 to 393.9pM), and 38.4 percent in quartile 4 (394.0 pM or more) (P<0.001for trend). Patients who were initially negative for troponinT who subsequently had measurable levels at 4 to 16 hours weremore likely to be in the third or fourth myeloperoxidase quartilethan in the first or second quartile (proportion with 0.1ng per milliliter troponin T levels, 5.3 percent of those inboth quartile 1 and quartile 2, 8.0 percent of those in quartile3, and 17.2 percent of those in quartile 4; P<0.001 for trend).Myeloperoxidase levels also correlated with the frequency ofan adjudicated diagnosis of an acute coronary syndrome, increasingfrom 22.5 percent in quartile 1 to 58.0 percent in quartile4 (P<0.001 for trend).
Base-Line Levels and 30-Day and 6-Month Outcomes
Base-line myeloperoxidase levels were higher among patientswho subsequently required revascularization or had a major adversecardiac event (myocardial infarction, reinfarction, need forrevascularization, or death) in the ensuing 30-day and 6-monthperiods than in those who did not have such complications (P<0.001for all comparisons). Myeloperoxidase levels were also higheramong the 34 patients who died within six months after presentationthan among the 570 patients who did not die (median, 270 vs.194 pM; P=0.05).
Myeloperoxidase levels were highest among patients who presentedwithin 4.0 to 9.6 hours after the onset of symptoms (mean ±SE,351±47 pM; P=0.041 for the comparison with patients whopresented less than 2.0 hours after the onset of symptoms; P=0.002for the comparison with those who presented more than 9.6 hoursafter the onset of symptoms). Myeloperoxidase levels remaineda robust predictor of outcomes across the distribution of timesbetween the onset of symptoms and the time of blood collection.Moreover, plasma myeloperoxidase levels in patients who presentedless than two hours after the onset of symptoms (mean ±SE,291±32 pM) were significantly higher than those in thecontrol subjects (P<0.001).
Myeloperoxidase Level as an Independent Predictor of Risk
The risk of myocardial infarction at presentation increasedwith increasing quartiles of base-line myeloperoxidase levels,both for the entire cohort and for patients with initially undetectabletroponin T levels (P<0.001) (Table 2). Base-line myeloperoxidaselevels also predicted the risk of major adverse cardiac eventsover the following 30-day and 6-month periods (P<0.001) (Table 2).The unadjusted odds ratios for major adverse cardiac outcomeswithin 30 days and 6 months for the highest quartile of plasmamyeloperoxidase levels were 4.7 (95 percent confidence interval,2.8 to 7.7; P<0.001) at 30 days and 4.7 (95 percent confidenceinterval, 2.9 to 7.7; P<0.001) at 6 months. Similar oddsratios and 95 percent confidence intervals were observed forplasma myeloperoxidase levels as a predictor of revascularizationat both 30 days and 6 months (data not shown). Stratificationbased on sex revealed that although myeloperoxidase levels werelower in female patients than in male patients (P=0.05), theselevels were similarly predictive of the risk of major adversecardiac events at 30 days in both sexes (odds ratio for a majoradverse cardiac event associated with a myeloperoxidase levelin the fourth quartile, 8.3 [95 percent confidence interval,3.4 to 20.2] for women and 3.5 [95 percent confidence interval,1.9 to 6.5] for men).
Table 2. Odds Ratio for Major Adverse Cardiac Events According to the Quartile of Myeloperoxidase and C-Reactive Protein Level.
To ascertain whether plasma myeloperoxidase levels independentlypredict the risk of revascularization, myocardial infarction,and major adverse coronary events, we used multivariate logistic-regressionmodels. Adjustments were made for variables associated withmyeloperoxidase levels or outcomes in univariate models (age;sex; C-reactive protein level; presence or absence of a historyof hyperlipidemia, a history of revascularization, and a historyof myocardial infarction; and electrocardiographic changes consistentwith a diagnosis of an acute coronary syndrome). Adjusted oddsratios and 95 percent confidence intervals for the entire cohortwere virtually identical to the unadjusted odds ratios, confirmingthat an elevated level of myeloperoxidase served as an independentpredictor of increased risk of myocardial infarction, the needfor revascularization, and major adverse coronary outcomes within30 days and 6 months after presentation (P<0.001 for eachcomparison).
Clinical Outcomes in Patients Who Were Consistently Negative for Troponin T
To test whether myeloperoxidase levels serve not only as a markerof inflammation in response to myocardial necrosis, but alsoas a sensitive predictor of the presence of vulnerable plaques,we examined whether plasma myeloperoxidase levels predictedrisk among patients presenting to the emergency department withchest pain but who have no evidence of myocardial necrosis (i.e.,who are negative for troponin T throughout the monitoring period,from 0 to 16 hours after entry). Within this cohort of 462 patients,myeloperoxidase levels were significantly higher at base linein patients who had major adverse cardiac events in the subsequent30 days and 6 months than in those who did not have such anevent (median, 268 pM [interquartile range, 152 to 444] vs.158 pM [interquartile range, 100 to 307]; P<0.001). Amongpatients who were negative for troponin T throughout the indexpresentation, the frequency of major adverse cardiac eventsat 30 days and 6 months increased with increasing base-linemyeloperoxidase quartiles (P<0.001 for trend).
For patients who were consistently negative for troponin T,the risk of revascularization and other major adverse cardiacevents at 30 days and 6 months increased with increasing quartilesof myeloperoxidase (Table 2). Figure 1 shows the unadjustedand adjusted odds ratios and 95 percent confidence intervalsfor myeloperoxidase quartiles as predictors of revascularizationand major adverse cardiac events among these patients. Multivariateadjustment for factors associated with plasma myeloperoxidaselevels and outcomes in the cohort had no significant effecton the risks, confirming that plasma levels of myeloperoxidasewere strong and independent predictors of the 30-day and 6-monthrisks of revascularization and major adverse coronary events(Figure 1).
Figure 1. Risks of Revascularization and Major Adverse Cardiac Events among Patients Who Were Consistently Negative for Troponin T, According to Base-Line Myeloperoxidase Levels.
Odds ratios and 95 percent confidence intervals are shown. Adjusted odds ratios were adjusted for age; sex; C-reactive protein level; presence or absence of a history of hyperlipidemia, revascularization, or myocardial infarction; and electrocardiographic changes consistent with a diagnosis of acute coronary syndromes. For each comparison, the first quartile served as the reference group.
Comparison with Established Diagnostic and Prognostic Biologic Markers
To assess whether the predictive value of plasma myeloperoxidaselevels is additive to that of C-reactive protein levels, parallelanalyses were performed for C-reactive protein levels (Table 2).C-reactive protein levels predicted the risk of myocardialinfarction at presentation for the entire cohort but were notpredictive of major adverse cardiac events in the group thatwas negative for troponin T.
Receiver-operating-characteristic curves for the predictionof acute coronary syndromes and major adverse cardiac eventswere plotted for the entire cohort and for the cohort of patientswho were consistently negative for troponin T (Figure 2). Inthe cohort that was consistently negative for troponin T, theareas under the curve were highest for myeloperoxidase —significantly higher than those for troponin T (with the useof values of less than 0.1 ng per milliliter), CK-MB (P<0.001for all comparisons for both outcomes), and C-reactive protein(P<0.001 for both outcomes). Using a cutoff point for myeloperoxidase(198 pM) that was derived from the receiver-operating-characteristiccurve for the entire cohort (Figure 2C), and established cutoffpoints for the other biologic markers,23 we calculated the sensitivity,specificity, and positive and negative predictive values fortroponin T (58.0 percent, 100.0 percent, 100.0 percent, and77.7 percent, respectively), CK-MB (42.4 percent, 94.7 percent,84.6 percent, and 70.7 percent, respectively), C-reactive protein(31.7 percent, 68.9 percent, 40.6 percent, and 60.0 percent,respectively) and myeloperoxidase (65.7 percent, 60.7 percent,53.3 percent, and 72.2 percent, respectively).
Figure 2. Receiver-Operating-Characteristic Curve Analyses of Biologic Markers for All 604 Patients (Panels A and C) and for the 462 Patients Who Were Consistently Negative for Troponin T (Panels B and D) for the Diagnosis of Acute Coronary Syndromes (Panels A and B) and Major Adverse Cardiac Events within 30 Days (Panels C and D).
Shown are receiver-operating-characteristic curves for the maximal values of troponin T and creatine kinase MB isoform (CK-MB) and base-line values of C-reactive protein (CRP) and myeloperoxidase. A negative result on the assay for troponin T was defined as a level of less than 0.1 ng per milliliter. The true positive fraction (sensitivity) is plotted against the false positive fraction (1 – sensitivity) to quantitate the diagnostic accuracy of each biologic marker.
To evaluate the potential clinical value of base-line myeloperoxidaselevels, we compared the positive test results with the negativetest results for myeloperoxidase and other established biologicmarkers as a means of predicting unstable angina, myocardialinfarction, acute coronary syndromes at presentation and majoradverse cardiac events at 30 days (Table 3). Base-line measurementof myeloperoxidase levels significantly enhanced the identificationof patients at risk despite being negative for troponin T, ascompared with other markers (Table 3). The addition of myeloperoxidaseto troponin T in the screening test significantly improved theability to identify patients at risk for major adverse cardiacevents at 30 days. With the use of troponin T alone, 58.0 percentof major adverse cardiac events were predicted, as comparedwith 84.5 percent with the addition of myeloperoxidase (P<0.001).Among patients who were consistently negative for troponin T,22.3 percent still had a major adverse cardiac event in theensuing 30-day period; however, with the addition of myeloperoxidasemeasurement to the screening test, this value was significantlyreduced to 14.8 percent (P<0.01).
Table 3. Comparison of Positive with Negative Test Results for the Measurement of Troponin T, Creatine Kinase MB, C-Reactive Protein, and Myeloperoxidase as a Means of Predicting Unstable Angina, Myocardial Infarction, and Acute Coronary Syndromes at Base Line and Major Adverse Cardiac Events (MACE) at 30 Days.
Discussion
Clinical criteria, electrocardiographic criteria, and conventionallaboratory tests do not adequately predict the risk of cardiovascularevents in patients presenting with acute coronary syndromes.The use of C-reactive protein and other biologic markers hasbeen advocated as a more accurate means of gauging risk, butadditional tools that can predict the vulnerability of coronaryarteries to major events in the near term are needed for patientswho present with suspected acute coronary syndromes. Myeloperoxidaseis an excellent candidate for the prediction of acute coronarysyndromes because it is released by activated leukocytes, iselevated and catalytically active in vulnerable plaques, andhas been mechanistically linked to factors affecting the developmentand stability of plaque.
Our results show that plasma myeloperoxidase levels predictcardiovascular risks independently of the levels of C-reactiveprotein and other markers of inflammation. An initial plasmamyeloperoxidase level in patients who presented to the emergencydepartment with chest pain provided information useful in determiningthe risk of myocardial infarction, revascularization, and majoradverse cardiac events during the subsequent six months. Perhapsmore important, even in patients in whom a myocardial infarctionwas ruled out on the basis of serial measurements of troponinT, an elevated myeloperoxidase level at presentation was predictiveof subsequent major adverse cardiovascular outcomes.
Plasma myeloperoxidase levels correlated with troponin T levelsand were predictive of acute myocardial infarction. However,whereas troponin T takes three to six hours to rise to measurablecirculating levels after myocardial injury, myeloperoxidaselevels were significantly elevated at base line (even withintwo hours after the onset of symptoms) in patients who wereinitially negative for troponin T. These findings suggest thatmeasurement of myeloperoxidase levels may be useful in triagein the emergency department and that elevated plasma myeloperoxidaselevels may be a marker of unstable angina preceding myocardialnecrosis and therefore a predictor of vulnerable plaque.
Patients who present with chest pain but without evidence ofmyocardial necrosis are a diagnostically challenging group forrisk stratification and one in which a means of identifyingvulnerable plaque is needed. Perhaps the most interesting findingin the present study is that plasma levels of myeloperoxidaseserved as an excellent predictor of risk even in patients whowere consistently negative for troponin T. In contrast, levelsof C-reactive protein were not significantly predictive of riskin this group. C-reactive protein has been reported to serveas a predictor of the short-term risk of major adverse cardiacevents in a subgroup of patients with acute coronary syndromesand undetectable levels of troponin T — those with persistentchest pain at rest.24 However, a substantial proportion of patientswho are negative for troponin T at presentation have more diagnosticallychallenging histories, and elevated levels of C-reactive proteinare seen in less than 50 percent of patients in whom myocardialinfarction is not preceded by unstable angina.25
Our findings suggest that myeloperoxidase serves as a markerof the vulnerable plaque and one that can be used to identifypatients at imminent risk for major adverse cardiac events,independently of evidence of myocardial necrosis. Our resultssuggest that the addition of the measurement of myeloperoxidaseto initial risk-stratification screening of patients presentingwith chest pain may identify those at increased risk who mightnot otherwise be identified without invasive diagnostic testing.Further studies assessing free and leukocyte-associated myeloperoxidaselevels as predictors of the short- and long-term risk of cardiovascularevents, as well as the potential benefits of myeloperoxidaseinhibition in patients with cardiovascular disease, are warranted.
Supported by grants from the National Institutes of Health (HL70621,HL62526, HL61878, and CA96348) and the Cleveland Clinic FoundationGeneral Clinical Research Center (M01 RR018390).
Dr. Hazen is named as a co-inventor on pending patents filedby the Cleveland Clinic Foundation that relate to the use ofbiologic markers of inflammation and cardiovascular disease.
Source Information
From the Departments of Cell Biology (M.-L.B., M.S.P., S.L.H.), Clinical Pathology (F.V.L.), Cardiovascular Medicine (M.S.P., V.N., R.J.A., M.G., M.L.P., E.S.M., E.J.T., S.E.N., S.L.H.), and Internal Medicine (M.H.S.) and the Center for Cardiovascular Diagnostics and Prevention (M.-L.B., M.S.P., M.H.S., R.J.A., M.L.P., S.L.H.), Cleveland Clinic Foundation, Cleveland.
Address reprint requests to Dr. Hazen at the Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, 9500 Euclid Ave., NC10, Cleveland, OH 44195, or at hazens{at}ccf.org.
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130 mg per deciliter [3.4 mmol per liter]). 
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