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Clinical Chemistry 55: 93-100, 2009. First published November 21, 2008; 10.1373/clinchem.2008.102905
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(Clinical Chemistry. 2009;55:93-100.)
© 2009 American Association for Clinical Chemistry, Inc.

Proteomics and Protein Markers

Assessment of the Multiple-Biomarker Approach for Diagnosis of Myocardial Infarction in Patients Presenting with Symptoms Suggestive of Acute Coronary Syndrome

Fred S. Apple1,a, Stephen W. Smith2, Lesly A. Pearce3 and MaryAnn M. Murakami1

1 Departments of Laboratory Medicine and Pathology and 2 Department of Emergency Medicine, Hennepin County Medical Center and University of Minnesota School of Medicine, Minneapolis, MN; 3 Biostatistical Consulting, Minot, ND.

aAddress correspondence to this author at: Hennepin County Medical Center, Clinical Labs P4, 701 Park Ave., Minneapolis, MN 55415. Fax 612-904-4229; e-mail apple004{at}umn.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Cardiac troponin is the preferred biomarker for detecting acute myocardial injury and infarction (MI). We studied whether multiple biomarkers of numerous pathophysiological pathways would increase the diagnostic accuracy for detecting MI.

Methods: Seven biomarkers [myeloperoxidase, soluble CD40 ligand, placental growth factor, matrix metalloproteinase 9 (MMP-9), high-sensitivity C-reactive protein (hsCRP), cardiac troponin I (cTnI), N-terminal pro–B-type natriuretic peptide] and estimated glomerular filtration rate were measured in 457 patients presenting on admission with symptoms suggestive of acute coronary syndrome. Twenty-five patients (5.4%) received MI diagnoses. Clinical sensitivities and specificities were evaluated from 99th-percentile reference values. Forward and backward stepwise logistic regression modeling techniques were used to identify biomarkers that were independently predictive of MI.

Results: Biomarker sensitivities ranged from 20% to 96%, and specificities ranged from 19% to 89%. MMP-9 had the highest sensitivity, but its specificity was 19%. cTnI demonstrated a sensitivity of 72% (95% CI, 51%–88%) and a specificity of 89% (95% CI, 85%–92%). In multivariate models, cTnI (P < 0.001) and either hsCRP (P = 0.009) or MMP-9 (P = 0.03) were independently predictive of MI. Addition of hsCRP or MMP-9 increased the specificity to 95% (95% CI, 92%–97%) or 91% (95% CI, 88%–94%), respectively, but reduced the sensitivity to 56% (95% CI, 35%–76%) and 68% (95% CI, 47%–85%) relative to cTnI alone.

Conclusions: Our findings indicate that the most clinically accurate biomarker for the early diagnosis of MI is the use of cTnI alone, rather than a multiple-biomarker approach, when an analytically robust cardiac troponin assay based on the 99th percentile is used.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
An increased circulating cardiac troponin concentration indicates myocardial injury and aids in the diagnosis of acute myocardial infarction (MI)1 (1)(2)(3)(4). Increased cardiac troponin concentrations have been associated with more frequent thrombi, impaired myocardial tissue perfusion, and a higher probability of adverse outcomes following coronary intervention (5)(6)(7). In addition, the risk of both short- and long-term cardiac events and mortality is related strongly and directly to increased cardiac troponin concentrations in patients who present with symptoms of acute coronary syndrome (ACS) (2)(8)(9). The prognostic information obtained from the measurement of cardiac troponin I or T (cTnI or cTnT) has been shown to be independent of clinical risk factors, such as age, electrocardiogram (ECG) results, renal disease, and diabetes mellitus (2)(10). International associations of cardiology, laboratory medicine, epidemiology, and emergency medicine have all issued guidelines that have designated cardiac troponin as the preferred biomarker, both for aiding in MI diagnosis and for risk stratification in patients presenting with suspected ACS, and have recommended that independent studies be conducted to validate all cardiac troponin assays after clearance by the US Food and Drug Administration before they are to be clinically accepted (1)(2)(3)(4)(11).

Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cTnI and cTnT), such as inflammatory cytokines, cellular-adhesion molecules, matrix metalloproteinases (MMPs), acute-phase reactants indicative of general inflammation [e.g., high-sensitivity C-reactive protein (hsCRP)], biomarkers of plaque destabilization and rupture [e.g., CD40 ligand (CD40L)], placental growth factor (PlGF), pregnancy-associated plasma protein A, myeloperoxidase (MPO), biomarkers of ischemia (e.g., choline, unbound free fatty acids, ischemia-modified albumin), and biomarkers of myocardial dysfunction [B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP)], may facilitate an earlier assessment of overall risk and aid in the identification and management of patients with symptoms suggestive of ACS before cell death (12)(13)(14)(15). Few studies, however, have examined upstream biomarkers, either as individual biomarkers or in a multiple-biomarker format, for their potential to aid in the early diagnosis of MI. Several of the nonnecrosis biomarkers studied in the present investigation were previously shown to have potential clinical utility for identifying patients at higher risk for subsequent cardiovascular and mortality events (16)(17)(18)(19)(20)(21)(22)(23). The goal of the present study was to investigate a multimarker strategy for early diagnosis of acute MI. Single samples of blood were drawn from a nonselected, heterogeneous population of patients who had ischemic symptoms suggestive of ACS at the time of their presentation to an inner-city county medical center. We analyzed the samples for markers indicative of myocardial damage, myocardial dysfunction, inflammation, plaque rupture, and ischemia, as well as renal function [estimated glomerular filtration rate (eGFR)]. One potential advantage of a multimarker strategy is the rapid exclusion or confirmation of MI within the emergency department, thereby facilitating early treatment and hospital discharge.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Following institutional review board approval, we prospectively analyzed single plasma samples (heparin-treated; collected as leftover samples) that had been obtained from 457 unselected patients with symptoms suggestive of ACS at the time of their presentation to the Hennepin County Medical Center’s emergency department, a 400-bed, primary- and tertiary-care level 1 trauma center. The study population was enrolled from July 2004 through January 2005 and consisted of a heterogeneous group of patients who had presented within 12 h of the onset of clinical symptoms indicative of ACS and had then been admitted to confirm or exclude the occurrence of acute MI. The median time from symptom onset to presentation was 3.1 h. Although the specific times from presentation to blood draw were not available, other data obtained from this hospital indicate that blood is drawn within 60 min in 95% of suspected MI cases (unpublished data).

The records review included an up-to-date medical history of medical conditions and was carried out blinded to the biomarker results. Criteria for acute MI were defined according to the European Society of Cardiology and American College of Cardiology redefinition of MI guidelines (1) and were based on evidence of myocardial necrosis (increased cardiac troponin) in a clinical setting consistent with myocardial ischemia at presentation. The diagnosis of acute MI was established by the detection of an increase in cTnI (Dade Behring Dimension or Stratus CS instruments, as used in the Hennepin clinical laboratories) above the 99th-percentile reference value (<0.1 µg/L; total imprecision, 12% at 0.2 µg/L) with at least one of the following: symptoms of ischemia, new ST-T changes in the ECG, development of Q waves in the ECG, or imaging evidence of a new loss of viable myocardium. In formulating their final diagnosis, attending physicians based their clinical impressions on patients’ symptoms during their presentation. Cardiac catheterization was not used to exclude a diagnosis of MI. The protocol for hospital orders for serial cTnI monitoring included blood sampling at presentation (baseline) and at 4, 8, and 12 h later. As part of their diagnostic workups, all patients included in the study had cTnI measurements for at least the baseline and 8-h samples.

Plasma was separated from blood cells by centrifugation (2028g for 10 min) within 60 min of collection, stored initially at 4 °C, and then stored frozen at –80 °C within 48–72 h. We recognized that CD40L may be unstable and that a delay of up to 72 h before freezing may lead to degradation of this marker; however, CD40L-stability problems have been documented only in serum, not in plasma (treated with EDTA or citrate) (24)(25). The present study used heparinized plasma.

Biomarker measurements were made without knowledge of the patients’ histories and treatments. All biomarkers were measured according to the assay guidelines provided by the manufacturers of the instruments and assay kits: cTnI, Dade Behring Stratus CS and Dimension RxL; NT-proBNP, Roche Elecsys 2010; hsCRP, Dade Behring Dimension; MPO, Assay Designs ELISA; PlGF, R&D Systems ELISA; CD40L, R&D Systems ELISA; MMP-9, R&D Systems ELISA. Total imprecision (CV) values were evaluated for each assay over at least a 5-day period and were as follows: cTnI, 9.8% at 0.15 µg/L; NT-proBNP, 7.5% at 350 ng/L; hsCRP, 5.1% at 1.8 mg/L; MPO, 8.8% at 251 µg/L; PlGF, 9.1% at 149 ng/L; CD40L, 6.4% at 437 ng/L; MMP-9, 6.9% at 12.2 µg/L. Previously established reference cutoff concentrations were used as diagnostic cutoffs for the following assays cleared by the Food and Drug Administration: cTnI, <0.1 µg/L (26); NT-proBNP, 125 ng/L (age <75 years) and 450 ng/L (age ≥75 years); hsCRP, 1.0 and 3.0 mg/L (19). For the ELISA assays not cleared by the Food and Drug Administration, we used 99th-percentile reference limits established in our laboratory. These 99th-percentile limits, which were based on the same healthy population (108 volunteers between 18 and 55 years with no history of cardiac disease, diabetes, or hypertension), are as follows: MPO, 125 µg/L; PlGF, 17 ng/L; CD40L, 1.08 ng/L; MMP-9, 233 µg/L. eGFR values were calculated with the National Kidney Disease Education Program Modification of Diet in Renal Disease (MDRD) equation, which is based on plasma creatinine concentration, age, sex, and race (27). We considered 2 cutoff values (40 and 60 mL · min–1 · (1.73 m2)–1) in our analysis for separating patients with healthy kidney functions from those with impaired renal functions.

We used the Student t-test or ANOVA for statistical evaluations of differences between groups for continuous data and used the {chi}2 test for categorical data. Clinical sensitivities and specificities for acute MI and areas under the ROC curves were calculated for each biomarker. Forward and backward stepwise logistic regression modeling techniques were used to identify independently predictive biomarkers. Statistical significance was set at the 0.05 level, and all statistical tests were 2-sided. Statistical analyses were performed with MedCalc 9.6.0 (MedCalc Software) and SPSS for Windows 15.0 (SPSS).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Table 1 summarizes the baseline characteristics of the 457 patients studied. The presenting symptoms included the following: chest pain (63%); other typical symptoms, including shortness of breath, nausea and vomiting, sweating, epigastric pain, abdominal pain or heartburn, and neck or shoulder pain (15%); syncope (7%); tachycardia or bradycardia (5%); altered mental status (2%); gastrointestinal bleeding (2%); hypoxia (2%); and unresponsiveness (4%). Of the 25 acute MIs diagnosed (5.4%), 18 patients had an increased cTnI concentration at presentation; 7 patients had a cTnI within the reference interval at presentation and an increased cTnI concentration (measurements with clinical samples) after presentation [at 4 h (n = 6) or at 8 h (n = 1)]. Nine (36%) of the MIs showed an ST-segment elevation on the admitting ECG. The clinical sensitivity for cTnI positivity at presentation was 72%, the clinical specificity was 89%, and the area under the ROC curve was 0.83. Fourteen (56%) of the MI patients were sent to the catheterization laboratory at some time during their admission, and 7 of the patients underwent catheterization within 2 h. Table 1 summarizes the patient characteristics by the categories of true and false positives and true and false negatives with respect to MI diagnosis as determined by the presenting cTnI concentration. Significant relationships were found across these categories for age, increased NT-proBNP, hsCRP >1.0 mg/L, and eGFR decreased to <60 mL · min–1 · (1.73 m2)–1. Table 2 displays the median and interquartile range for biomarker concentrations in the MI and no-MI groups; only cTnI demonstrated a significant difference between the groups (P < 0.01).


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  		Table 1. Patient characteristics by classification based on the presenting cTnI concentration for confirming or excluding acute MI.1


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  		Table 2. Median biomarker concentrations and interquartile ranges by MI status.

Of the 8 biomarkers, cTnI had the highest diagnostic accuracy (Table 3 ). Although MMP-9, NT-proBNP, MPO, CD40L, and hsCRP all had equal or greater clinical sensitivities compared with cTnI, their clinical specificities and areas under the ROC curves were poor (ranges of 19%–47% and 0.52–0.60, respectively). Stepwise logistic regression multivariate modeling techniques identified 2 models of 2 biomarkers each that were independently predictive of MI: cTnI (odds ratio, 24; 95% CI, 9–61; P < 0.001) and hsCRP >1.0 mg/L (OR, 0.3; 95% CI, 0.1–0.8; P = 0.009); cTnI (OR, 21; 95% CI, 8–52; P < 0.001) and increased MMP-9 (OR, 6.1; 95% CI, 1.0–48; P = 0.03). Patients with an MI were less likely to have an hsCRP concentration >1 mg/L (Table 1Up ). Adding hsCRP <1 mg/L or an increased MMP-9 to classification with cTnI improved the clinical specificity to 95% (95% CI, 92%–97%) and 91% (95% CI, 88%–94%), respectively; however, clinical sensitivities were decreased to 56% (95% CI, 35%–76%) and 68% (95% CI, 47%–85%), respectively.


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  		Table 3. Diagnostic accuracy characteristics for individual biomarkers.1

Patients who were misclassified (49 false positives and 7 false negatives) for acute MI by the cTnI concentration at presentation did not differ significantly in baseline characteristics (Table 3Up ) from those who were correctly classified (18 true positives and 383 true negatives). The most common clinical diagnoses in the 49 patients with a falsely positive cTnI value at presentation (Table 4 ) were congestive heart failure (n = 12; cTnI range, 0.1–2.7 µg/L) and end-stage renal disease (n = 6; cTnI range, 0.1–1.5 µg/L).


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  		Table 4. Diagnoses of patients with increased cTnI concentrations without MI.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study attempted to evaluate the independent diagnostic information contributed by a spectrum of biomarkers representing inflammation, plaque destabilization, plaque rupture, myocardial necrosis, and myocardial dysfunction for a heterogeneous group of low- to high-risk patients who presented with symptoms suggestive of ACS. In our study, cTnI measured with a newer-generation assay was the most effective diagnostic biomarker for detecting MI. No other combination of biomarkers added any diagnostic sensitivity. Only hsCRP and MMP-9 contributed significant, but slight, additional diagnostic specificity. Our data therefore appear to support the current recommendations for use of cardiac troponin in a single-biomarker approach.

Because first-generation cardiac troponin assays were not as analytically robust as current assays, the cutoff concentrations in these early assays were based on higher WHO biomarker criteria in which ROC curve–derived cutoff values were optimized for clinical sensitivity and specificity. Such assays demonstrated clinical specificities of >90%. The clinical specificity of 89% obtained in the present study at baseline with the analytically more sensitive second-generation assay from Siemens (previously Dade Behring) demonstrates that other pathologic mechanisms besides ischemic MI were responsible for myocardial injury. Increases in cardiac troponin concentration are now well known to occur in the absence of overt ischemic heart disease (1)(28). Although 49 of the 67 patients in the current study who had an increased cTnI concentration at initial presentation did not have MI, prognostic value is still conferred with such biomarker information, which the clinician must evaluate in light of the patient’s clinical presentation. Although non-MI increases in cTnI concentration can be obtained analytically on rare occasions (28), the vast majority of such results do not represent "analytical false-positive" findings. Evaluating the etiology of an increased cTnI in a questionable clinical presentation of MI is aided when the clinician also observes a pattern of a temporally increasing cTnI concentration, an observation that also assists in the diagnosis of MI (1)(2). Increased cTnI concentrations that do not change over time are very unlikely to be due to an MI. Such observations are consistent with recent guidelines on the use of cardiac troponin in the initial evaluation of ACS.

We investigated biomarkers that are considered prenecrosis markers pathophysiologically in an attempt to identify novel and diagnostically useful biomarkers that could be used in combination with cTnI for the early detection of MI and, optimally, for more timely patient triage, therapeutic management, and discharge; however, we were not successful. The potential reasons for the lack of sensitivity and specificity are likely quite diverse, but the more likely reasons include an insufficiently large study population, the heterogeneity of the pathologic presentations, and, most probably, the excellent limit of detection of the cTnI assay we used for comparison. Furthermore, we did not consider the effects of using cutoffs according to the ROC curve analysis. Presently, these novel biomarkers are more suitable as risk-stratification tools, according to the evidence-based literature (12)(14)(15)(23). At the outset of this study, we chose not to study other biomarkers of necrosis, such as heart fatty acid–binding protein, myoglobin, and creatine kinase MB isoenzyme (CK-MB) mass, because previous studies have clearly demonstrated the superiority of cTnI for the accurate detection of MI, thus negating these other biomarkers as effective clinical or cost-effective tools (29)(30).

Over the past several years, numerous groups in clinical and laboratory medicine have published guidelines that have strongly endorsed the use of cardiac troponin (cTnI or cTnT) as the preferred biomarker for detecting myocardial injury (1)(2)(3)(4)(11). The recently published document, "Universal Definition of Myocardial Infarction," supports the use of detection of an increase or decrease in cardiac biomarkers (preferably cardiac troponin) above the 99th-percentile reference value as evidence of myocardial ischemia (1). The timing of blood draws is essential, because a decrease in cardiac troponin concentration after a minimum of 6 h is needed before an MI can be ruled out. Studies have emphasized setting the reference cutoff at the 99th-percentile value with the understanding that not all cardiac troponin assays have equivalent analytical characteristics (31)(32). Although the new definition of MI supports the use of a cardiac troponin assay with a total CV of 10%, the assay used in the current study as a criterion for MI had a CV of 17% at the 99th-percentile reference cutoff (<0.1 µg/L). Studies from the laboratory of the first author and by others have shown that CVs as high as 20% have no significant effect on rates of misclassification as false positives, findings that would be inappropriately classified as MI or indicating a higher risk (33)(34). Furthermore, our criteria required a pattern of a serially increasing cardiac troponin concentrations. Independent reference-value cutoffs need to be determined for each assay. We have learned from studies after the initial redefinition of MI criteria in 2000 by the European Society of Cardiology and American College of Cardiology (4) that lowering the cardiac troponin cutoff to the 99th-percentile value from the older, higher-concentration WHO cutoff substantially increased the number of patients with diagnosed acute MI (11). In a study of patients who presented with symptoms of MI in a community hospital, Lin et al. discovered that implementing cTnI testing with the higher WHO cTnI cutoff detected an additional 73 patients (42%) among the 1719 patients who had CK-MB concentrations within the reference interval (26). Lowering the cTnI cutoff to the 99th percentile identified an additional 136 patients (an 186% increase) among the patients who had typical CK-MB concentrations. Clinical guidelines have influenced manufacturers of cardiac troponin assays to improve their analytical characteristics at lower concentrations (31)(32). Several studies have now demonstrated that the diagnostic accuracy of the newer-generation cardiac troponin assays provide clinical sensitivities of 68%–88% for samples obtained at presentation and clinical specificities of 68%–83% (29)(35)(36)(37).

Surprisingly, very few studies of multiple cardiac biomarkers have been performed in the setting of the diagnosis of acute MI in emergency departments. The studies that have been performed have compared either cTnT or cTnI against CK-MB and myoglobin (38). In the studies that have used the newer-generation cardiac troponin assays, the clinical sensitivities of cardiac troponin outperformed those of both myoglobin and CK-MB, findings that are consistent with the fact that increases in cardiac troponin concentration begin 2 to 4 h after the onset of ischemic symptoms (29)(35)(36)(37)(38). Thus, the use of analytically sensitive cardiac troponin assays at their 99th-percentile cutoff provides all of the diagnostic information required for evaluating patients who present with symptoms of possible acute ischemia.

There is a rapidly growing appreciation of the importance of biomarkers for identifying and therapeutically managing patients who present with acute symptoms suggestive of ACS. Reports of biomarkers that address myocardial injury and dysfunction and that differentiate the pathophysiologies of inflammation, plaque vulnerability, and ischemic myocardium are appearing in increasing numbers (29)(35)(36)(37)(38). We previously published findings for this same biomarker set for detecting adverse outcomes over a 4-month follow-up period (23). We learned that it was important to define outcomes by cardiac events and separate these outcomes from all-cause mortality. We found that increased cTnI in this heterogeneous population was predictive of both higher all-cause mortality and rates of cardiac events; however, only an increased NT-proBNP concentration was also independently predictive of cardiac events, whereas NT-proBNP, as well as PlGF, hsCRP, and eGFR, predicted death.

Our findings are unique in that instead of accepting the non–peer-reviewed cutoff concentrations provided in assay package inserts, we independently determined or confirmed biomarker reference limits in our laboratory with the same healthy population that we used to establish the cutoffs for the novel biomarkers studied. We recognize that our study is not without potential limitations. First, the data set includes only 457 patients and 25 MIs, which reduce the statistical power. In addition, the size of the MI patient group may have been too small for adequate multivariate analysis (39); however, this was the MI prevalence we had during our study period. Second, except for cTnI, the biomarkers were measured only in a single sample obtained at the time of enrollment. Serial measurements of the multiple biomarkers over time would potentially be of great interest for better understanding the differences in biomarker kinetics, as well as for future elucidation of effective therapeutic strategies. Third, we would have liked to have included one of the biomarkers of ischemia, such as choline or ischemia-modified albumin, but the small volumes of our samples and the lack of commercially available assays precluded performing such assays. Fourth, sample processing before CD40L measurement may have affected the stability of this analyte. We do acknowledge that platelet-poor plasma is the only way to absolutely minimize the potential variable contribution of platelets to the actual CD40L concentration (24)(25). Fifth, we recognize that cTnI, the biomarker observed to be the most clinically sensitive, is an integral component of the definition of MI.

In conclusion, our findings confirm that a single biomarker, cardiac troponin, was optimal for the early diagnosis of acute MI in the heterogeneous patient population we studied. Crossing the boundary from research to the clinical application of novel biomarkers for the sensitive and specific diagnosis of MI will be challenging. As novel biomarkers emerge for diagnostics or risk assessment (either as independent markers or as part of multimarker strategies for individual proteomic profiling) in patients presenting with symptoms suggestive of ACS, quality specifications regarding each assay used to measure such biomarkers need to be developed. As we have learned from the cardiac troponin (32) and natriuretic peptide (40) assays, not all assays are created equal. The "complexity" of assay-validation studies will be extremely important for the acceptance and implementation of biomarkers into clinical practice as single tests or as part of a multimarker panel. Our findings challenge investigators to perform additional prospective studies in larger and more diverse sets of patients presenting with ischemia to better understand the nuances of the disease spectrum and its effect on multiple-biomarker findings and their interpretation.


   Acknowledgments
 
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors’ Disclosures of Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: F.S. Apple, Abbott Laboratories, Ortho Clinical Diagnostics, InterMune, Biosite, Beckman Coulter, and Sensera.

Stock Ownership: None declared.

Honoraria: F.S. Apple, Abbott Laboratories, Biosite, Siemens, Beckman Coulter, and Ortho Clinical Diagnostics.

Research Funding: F.S. Apple, Abbott Laboratories, Biosite, Siemens, Beckman Coulter, Ortho Clinical Diagnostics, Roche Diagnostics, Mitsubishi, Response Biomedical, and Radiometer. This study was funded in part by Ortho Clinical Diagnostics.

Expert Testimony: None declared.

Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.


   Footnotes
 
1 Nonstandard abbreviations: MI, myocardial infarction; ACS, acute coronary syndrome; cTnI, cardiac troponin I; cTnT, cardiac troponin T; ECG, electrocardiogram; MMP, matrix metalloproteinase; hsCRP, high-sensitivity C-reactive protein; CD40L, CD40 ligand; PlGF, placental growth factor; MPO, myeloperoxidase; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal proBNP; eGFR, estimated glomerular filtration rate; CK-MB, creatine kinase MB isoenzyme.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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