TheUtilityofPointofCareTestforSolubleST2inPredicting ... · 2019. 7. 30. ·...

Research ArticleThe Utility of Point of Care Test for Soluble ST2 in PredictingAdverse Cardiac Events during Acute Care of ST-SegmentElevation Myocardial Infarction

Anggoro Budi Hartopo ,1 Indah Sukmasari,2 and Ira Puspitawati2

1Department of Cardiology and Vascular Medicine, Faculty of Medicine, Public Health and Nursing,Universitas Gadjah Mada and Dr. Sardjito Hospital, Yogyakarta, Indonesia2Department of Clinical Pathology, Faculty of Medicine, Public Health and Nursing,Universitas Gadjah Mada and Dr. Sardjito Hospital, Yogyakarta, Indonesia

Correspondence should be addressed to Anggoro Budi Hartopo; [email protected]

Received 22 January 2018; Revised 15 May 2018; Accepted 4 June 2018; Published 26 June 2018

Academic Editor: Syed Wamique Yusuf

Copyright © 2018 Anggoro Budi Hartopo et al.-is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Introduction. Soluble ST2 (sST2) is increased during acute myocardial infarction. -e point of care test (POCT) for sST2 iscurrently available. -e aim of this study was to investigate the utility of the sST2 POCT measurement for predicting adversecardiac events during acute care of ST-elevation myocardial infarction (STEMI). Patients and Methods. -is research useda cohort study design. Consecutive patients with STEMI were enrolled. Soluble ST2 level was measured from peripheral bloodtaken on admission with POCT. Observation during acute intensive care was conducted to record adverse cardiac events. Twogroups were assigned based on median sST2 level, that is, supramedian and inframedian group. -e incidence of adverse cardiacevents between groups was analyzed. A p value< 0.05 was statistically significant. Results. We analyzed 95 subjects with STEMIand 10 patients with stable coronary artery disease as controls. -e median sST2 level was significantly higher in subjects withSTEMI as compared to controls (152.1 ng/mL versus 28.5 ng/mL, p< 0.01). Among subjects with STEMI, the supramedian grouphad higher incidence of adverse cardiac events than the inframedian group (38.3% versus 12.5%, p � 0.004). Multivariable analysisshowed that supramedian sST2 level was independently associated with increased incidence of adverse cardiac events (adjustedOR 6.27; 95% CI: 1.33–29.47, p � 0.020). Conclusions. -e sST2 POCTmeasurement was useful to independently predict adversecardiac events during acute intensive care of STEMI.

1. Introduction

Acute myocardial infarction with ST-segment elevation(STEMI) is a clinical syndrome which reflects the transmuralnecrosis of myocardia due to occlusive thrombus in thecoronary artery segment. -e prevalence of STEMI rangesfrom 25% to 45% among patients with acute myocardialinfarction [1]. -e management of STEMI with reperfusionstrategies, both fibrinolysis and primary coronary in-tervention, and pharmacology therapy have successfullyreduced the major adverse cardiac events and mortality [1].However, in many high-risk patients, the mortality andmajor adverse cardiac events rate are persistently high [2].

Several independent predictors for major adverse cardiacevents following STEMI have been identified such as age,Killip class on admission, delay of reperfusion time, cardiacarrest, tachycardia, hypotension, anterior infarct location,previous myocardial infarction, diabetes mellitus, smoking,renal function, and increased biomarkers for myocardialnecrosis [3]. Until recently, the role of biomarkers asa predictor for major adverse cardiac events and mortality inacute hospital care has not been well established. -e bio-markers of myocardial necrosis, such as creatine kinase-MB(CK-MB) and troponin, have been included in the Gracescoring system which estimates the risk for mortality andnonfatal major adverse cardiac events during hospitalization

HindawiCardiology Research and PracticeVolume 2018, Article ID 3048941, 9 pageshttps://doi.org/10.1155/2018/3048941

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among acute coronary syndrome patients. However, it is notconsidered specifically useful for STEMI [3].

Novel biomarkers have been identified and investigatedin their role specifically in acute myocardial infarction.Soluble ST2 (sST2), which is released during myocardialstretching, is one promising biomarker [4]. In patients withSTEMI, in which transmural myocardial injury occurred,myocardia in the left ventricle undergoes additionalstretching. -is process involves the release of biomarkerssuch as NT-proBNP and sST2 by myocardia and cardiacfibroblasts [4]. In the initial phase, during which clinicalsigns and symptoms of left ventricle dysfunction have notyet appeared, the release of sST2 may give an indication ofongoing left ventricle stretching and predict the develop-ment of left ventricle dysfunction.

Several studies have concluded that increased sST2 in theinitial phase of STEMI is associated with adverse cardiaceffect, both in the short term and long term. However,currently no guideline recommends the examination of sST2as a predictor biomarker to guide treatment for STEMI.-erefore, confirmatory research should be performed toprovide more solid evidence of sST2 implication in pre-dicting major adverse cardiac events in patients hospitalizedwith STEMI. Furthermore, the current availability of thesST2 point of care test (POCT), which allows the result to beknown more quickly, is suitable in the acute clinical settingsuch as STEMI. -is study aimed to investigate the utility ofthe sST2 POCTmeasurement in predicting adverse cardiacevents in patients hospitalized with STEMI.

2. Methods

2.1. Research Design. -e research used a cohort study de-sign. -e subjects were patients with STEMI admitted to theIntensive Cardiac Care Unit (ICCU) of Dr. Sardjito Hospital,Yogyakarta, Indonesia. -e subjects were enrolled from theemergency unit of Dr. Sardjito Hospital, Yogyakarta,Indonesia, where they were stabilized and subsequentlyadmitted to ICCU. -e subjects’ enrollment (from April2014 to January 2015) was conducted by consecutive sam-pling. -e diagnosis of STEMI was determined based oninternational guidelines, that is, angina symptoms, elec-trocardiogram criteria, and elevated cardiac enzymemarkers[5]. -e observations of subjects were conducted duringintensive cardiac care in the ICCU.

2.2. Research Subjects. We included the patients diagnosedwith STEMI, both male and female patients, with age be-tween 35 and 75 years old, the onset of anginal pain ≤24hours, and patients without previous fibrinolytic or heparintreatment before reaching our hospital emergency unit. Weexcluded the patients with previously known chronic heartfailure (NYHA class≥ II), chronic kidney disease stage IV-V,hepatic cirrhosis, chronic inflammatory diseases (such aschronic arthritis, psoriasis, and inflammatory bowel dis-ease), malignancy, and patients with concurrent acute in-fection, sepsis, and acute stroke during observation. -esubjects competed and signed an informed consent form to

participate in the research. As controls, we recruited patientswith stable coronary artery disease (SCAD) who came to ourhospital for coronary angiography and PCI. -ese patientswere assigned as controls in this study. -e study was ap-proved by the ethics committee of the Faculty of Medicine,Public Health and Nursing, Universitas Gadjah Mada,Yogyakarta, Indonesia.

2.3. Laboratory Examination. For laboratory examination,blood samples were drawn from antecubital veins in a supineposition on hospital admission before any procedures wereperformed.-e blood was then centrifuged and inserted intoan automated blood cell counter for hematology examina-tion and chemical analyzer for blood chemistry examination.Cardiac biomarkers were measured as routine procedure,that is, CK-MB by the immunological UV assaymethod withCobas c501 (Roche) and troponin I by the enzyme-linkedfluorescent assay (ELFA) method with VIDAS (Biomerieux)in the central hospital laboratory. In controls, blood sampleswere drawn from antecubital veins in a supine position onhospital admission before coronary angiography and PCIwere performed.

From the blood sample, an aliquot of serum was col-lected and saved in −80°C freezer until further analysis forsST2 examination. Soluble ST2 level was measured fromfrozen samples. -e aliquot was thawed, left in roomtemperature, and used for sST2 quantification withASPECT-PLUS ST2 rapid test (Critical Diagnostics, SanDiego, CA, USA). -e calculation of sST2 was performedbased on the manufacturer’s manual instructions and pre-vious report [6]. Briefly, the ASPECT-PLUS ST2 test cassettewas warmed under room temperature for 15 minutes, thefoil pouch was opened, and 30–40 microliter serum samplewas dropped into the sample well. An amount of 2 drops oftest buffer was placed into the test buffer well. -e ASPECT-PLUS ST2 test cassette was inserted into the ASPECTreader(Critical Diagnostics, San Diego, CA, USA). -e readerprocessed the measurement (±20 minutes), and the quan-titative sST2 levels (ng/mL) were exhibited on the display.We recorded the result of sST2 measurement in print. Basedon a measurement limit, serum sST2 levels 250 ng/mL were reported by the ASPECT Reader as250 ng/mL value [6].

2.4. Observation and Outcome. -e initial treatments of thesubjects with STEMI in the emergency unit were doubleantiplatelet, revascularization procedure, that is, primarypercutaneous coronary intervention (PCI) or fibrinolysisand anticoagulant with heparin. Time for revascularizationwas determined as time (in minutes) from medical contact(i.e., emergency admission in our hospital) to start ofreperfusion therapy by intravenous injection of fibrinolyticagents and time to balloon inflation in subjects treated withfibrinolysis and primary PCI, respectively. -e initialmanagement was performed by attending cardiologistsaccording to patients’ clinical condition and severity. Afterinitial treatments, the subjects were transferred to the ICCU

2 Cardiology Research and Practice

and managed according to the discretion of the attendingcardiologists.

Transthoracic echocardiography (TTE) was performedon all subjects with STEMI within 48 hours of admission inthe ICCU. -e GE Vivid S6 (GE Healthcare) echocardi-ography machine was used for TTE procedure. Left ventricle(LV) ejection fraction was obtained using the modifiedSimpson’s method on the standard simultaneous apicalfour-chamber and two-chamber views. -e interpretation ofTTE results was performed by experienced cardiologists.

-e observation of subjects with STEMI was conductedduring acute intensive care in the ICCU until discharge fromthe ICCU or fatal event occurred.-e adverse cardiac eventswere a composite of cardiac death, acute heart failure,cardiogenic shock, reinfarction, and resuscitated ventriculararrhythmia (VT/VF). -e adverse cardiac events wereassessed and managed by attending cardiologists unaware ofthe sST2 measurement. A cardiac death was mortality bycardiac causes. Acute heart failure was the clinical symptomsand signs of congestion and the use of intravenous diuretics.Cardiogenic shock was systolic blood pressure 250 ng/mL) and 1 subject had sST2 level less than thelower measured limit (i.e.,

sST2 was 152.1 ng/mL. �e supramedian group consisted of47 subjects and inframedian group consisted of 48 subjects.�e distribution of sST2 values is depicted in Figure 1.

Subjects with supramedian sST2 levels and those withinframedian sST2 had no signicant dierence in de-mography, cardiovascular risk factors, admission clinicalpicture, most of initial laboratory examination, infarct lo-cation, and initial treatment strategy. Patients in thesupramedian group had signicantly higher troponin I andCK-MB levels than the inframedian group, indicating in-creasing myocardial necrosis. �e initial treatments of thesubjects did not signicantly dier between groups. �ecomparison of characteristics between the supramedian andinframedian groups is shown in Table 2.

�e proportion of initial revascularization procedure,that is, primary PCI or brinolysis, was comparable betweengroups. In subjects who underwent primary PCI, the time torevascularization was not signicantly dierent betweengroups. �is also applied to the time to revascularization forbrinolysis. �e rate of failed brinolysis and subsequentrescue PCI did not signicantly dier between groups either.Table 3 shows the mode of revascularization and time torevascularization between supramedian and inframediangroups.

�e incidence of adverse cardiac events was signi-cantly higher in the supramedian group as compared tothose in the inframedian group (38.3% versus 12.5%, pvalue � 0.04, resp., as shown in Figure 2). Among adversecardiac events, acute heart failure was the most frequentlyoccurring event in the supramedian group (19.1% versus2.1%, resp.), whereas mortality was similar betweengroups. Figure 3 shows the incidence of individual adversecardiac events between the supramedian and inframediangroups. Furthermore, the supramedian group had sig-nicantly reduced LV ejection fraction measured duringintensive hospitalization as compared to the inframediangroup (46.4 ± 4.7% versus 56.9 ± 6.0%, p value < 0.01),indicating reduced LV systolic function in subjects withhigher sST2 level during hospitalization (as shown inFigure 4).

�e median value of sST2 level was signicantly highestin subjects with STEMI-experienced adverse cardiac events(246.6 ng/mL), followed by subjects with STEMI with noadverse cardiac events (122.9 ng/mL), and the lowest was inthe control (28.5 ng/mL); the p value of dierence was 250 ng/mL), and 1 subject has sST2 level lessthan the lower measured limit (i.e.,

activated and form a stunted shape of ST2, dubbed sST2,which can be detected in the blood circulation [11]. In themyocardia and cardiac fibroblasts, activation of the pro-moter region results in the majority of sST2 production andthe minority of transmembrane ST2 transcripts [10, 11]. Inacute myocardial infarction, necrotic and penumbra partsof left ventricular myocardia diminish their mobile andstretch capability. -erefore, the intraventricular pressureis delivered among healthy myocardia which endure ad-ditional wall tension. As a reaction to increased left

ventricular wall tension and augmented intraventricularpressure, cardiomyocytes expand and release several fac-tors which function to increase the myocardial perfor-mance [12]. Under this mechanical stretching, in thecontext of STEMI, the ST2 gene is activated and sST2protein is released in the circulation [10].

-e circulating sST2 acts as a decoy receptor for IL-33,which is attached to the transmembrane form of ST2and conditions myocardial adaptation from mechanicalstrain [4, 10]. -e ligation of IL-33 with sST2 in the

Table 2: -e comparison of characteristics between inframedian and supramedian sST2 in subjects with STEMI.

Characteristics Inframedian sST2, n � 48 Supramedian sST2, n � 47 p valueDemographyAge (years), mean± SD 57.3± 8.7 59.1± 8.2 0.31Male sex, n (%) 38 (79.2) 38 (80.9) 0.84Body mass index, mean± SD 24.3± 2.8 24.1± 3.0 0.79Risk factorsDiabetes mellitus, n (%) 16 (33.3) 12 (25.5) 0.41Hypertension, n (%) 30 (62.5) 25 (53.2) 0.36Current smoking, n (%) 24 (50.0) 26 (55.3) 0.60Clinical parametersOnset (hour), mean± SD 8.1± 6.9 7.4± 5.5 0.48Systolic b.p (mmHg), mean± SD 131.7± 27.9 126.0± 24.7 0.29Diastolic b.p (mmHg), mean± SD 80.3± 17.3 77.4± 15.4 0.39Heart rate (bpm), mean± SD 76.8± 17.1 75.4± 19.9 0.71Killip II-IV, n (%) 3 (6.2) 5 (10.6) 0.44Laboratory examinationHemoglobin (g/dL), mean± SD 13.9± 1.8 13.6± 1.9 0.25Leucocytes (103/mm3), mean± SD 12.9± 3.7 12.7± 2.8 0.76Platelets (103/mm3), mean± SD 293.6± 107.8 259.3± 83.7 0.09Creatinine (mg/dL), mean± SD 1.2± 0.3 1.3± 0.7 0.09Glucose (mg/dL), mean± SD 184.9± 92.2 177.9± 98.4 0.72Troponin I (ng/dL), mean± SD 6.5± 10.5 9.4± 10.5 0.03∗Creatine kinase-MB (IU), mean± SD 93.2± 79.2 200.9± 204.3

circulation reduces attachment capacity of IL-33 to myo-cardial transmembrane ST2, hence lessening the protection ofcardiomyocytes mediated by IL-33-ST2 ligation [10]. �eligation of IL-33 with transmembrane ST2 is cardioprotectiveto salvage cardiomyocytes from apoptosis due to strained leftventricular dimensions [13, 14]. �e loss of protective eects,due to increased circulating sST2 and consequently higherdecoy IL-33 ligation, puts left ventricular (LV) function at

risk. Our study shows that the supramedian level of sST2 isassociated with cardiac adverse events during intensive carewhich is mostly due to LV dysfunction. �e admission Killipclass, an indication of LV disturbance due to myocardialinfarction, tended to be higher in patients with supramediansST2. Furthermore, our results showed that subjects withsupramedian sST2 also had reduced LV ejection fraction,indicating LV systolic dysfunction.

Our study shows that sST2 POCT measurement onadmission is useful to identify patients with higher risk to

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Figure 2: �e incidence of adverse cardiac events betweeninframedian and supramedian sST2 groups. �e adverse cardiacevents were signicantly higher (38.3%) in the supramedian groupas compared to the inframedian group (12.5%); p value for thedierence was 0.04 (chi-squared test).

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Figure 3: �e incidence of individual adverse cardiac events be-tween inframedian and supramedian sST2 groups. �e mostcommon adverse cardiac event was acute heart failure. �e mor-tality rate was similar between the supramedian and inframediansST2 groups.

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Figure 4: �e boxplot of left ventricle (LV) ejection fraction be-tween inframedian and supramedian sST2 groups. In the supra-median sST2 group, there was signicantly reduced LV ejectionfraction indicating worse LV systolic dysfunction (Student’s t-test,p value< 0.01).

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Figure 5: �e median sST2 level was signicantly the highest inSTEMI subjects with adverse cardiac events, followed by STEMIsubjects with no adverse cardiac events. �e controls had the leastmedian sST2 level.


develop adverse cardiac events during intensive care. -erisk is about sixfold higher in those with sST2 supramedianlevels on admission. -e risk has been predicted early in theadmission phase before the patients finally develop overtclinical events during acute intensive care, mostly due to leftventricular dysfunction. Currently, circulating sST2 has notbeen approved in the clinical guideline as a prognosticbiomarker of adverse outcomes in acute myocardial in-farction. In the guideline of heart failure, sST2 de-termination is useful as a biomarker for additive riskstratification, especially in the acute phase [15]. However, atpresent, there is still a lack of definite evidence for the utilityof sST2 measurement in heart failure management practice[16].

Our study findings corroborated other clinical trials thathave concluded the role of sST2 in predicting major adversecardiovascular events following the episode of STEMI.Shimpo et al. investigated the impact of circulating sST2 inSTEMI patients and found that sST2 highest quintiles as-sociated with increased major adverse cardiovascular eventsduring intensive hospitalization and 30 days after hospi-talization [17]. Sabatine et al. found that supramedian valuesof circulating sST2 predicted in-hospital death and sub-sequent adverse cardiovascular events in STEMI patientsundergoing fibrinolytic therapy [18].

In STEMI, primary PCI and fibrinolysis are recom-mended as modalities of revascularization. Our hospital isa PCI-capable hospital which has routinely performedprimary PCI for STEMI patients. However, due to timedelays in performing primary PCI, fibrinolytic treatment isstill more often performed in our hospital. In this study, the

proportion of primary PCI or fibrinolysis was not signifi-cantly different between groups, although in the supra-median group, the proportion of fibrinolysis tended to behigher. Additionally, the time to revascularization was notsignificantly different between groups, both in primary PCIand fibrinolysis.

In-hospital course of STEMI patients worsened in thosewith sST2 value >35 ng/mL, that is, the cutoff value of in-creased sST2 level in heart failure [19]. Other investigatorshave concluded similar findings with longer observationperiods [20, 21]. Among myocardial stress biomarkers, sST2has the strongest odds ratio to detect 30-day cardiovasculardeath and heart failure, even if compared with NT-proBNPand MR-proANP [22]. -ese studies used enzyme-linkedimmunoassay for sST2 measurement, which are completelydifferent from our method of sST2 quantification. Similar toprevious studies, our study also utilized thawed-frozen se-rum sample for sST2 measurement.

-e practicality and simplicity of the POCT test in acutecoronary syndrome is of paramount importance, becausethe fast result can rapidly guide the clinical decision. -eenzyme-linked immunosorbent assay is a more sensitivemethod of measurement than POCT, however it is robust,time-consuming, and impractical causing its limited use inclinical daily practice. -e ASPECT-PLUS ST2 test is a rapidquantitative lateral flow immunoassay for measurement ofsST2 in human plasma. -e fluorescent signal indicatesinteraction between antibodies against human sST2 whichare tagged with a fluorescent dye [6]. -e signal is measuredwith the ASPECT reader. -e quantitative sST2 values aredetermined based on the linear calibration curve unique to

Table 4: Univariate and multivariable analysis of variables as predictors for adverse cardiac events.

Univariate analysis variables OR (95% confidence interval) p valueIncreased age (>60 years) 1.09 (1.03–1.16) 0.005Diabetes mellitus 2.69 (1.02–7.09) 0.046Heart rate 1.02 (0.99–1.04) 0.178Hemoglobin level 0.63 (0.46–0.86) 0.004Leukocyte count 0.85 (0.71–1.02) 0.078Creatinine level 1.91 (0.83–4.41) 0.131Glucose level 1.01 (1.00–1.01) 0.071Triglyceride level 0.99 (0.98–0.99) 0.015Troponin I level 1.03 (0.99–1.08) 0.170Anterior STEMI 2.58 (0.98–6.81) 0.055Primary PCI 2.23 (0.87–5.73) 0.097Supramedian sST2 4.35 (1.54–12.27) 0.006Multivariable analysis variables Adjusted OR (95% confidence interval) p valueIncreased age (>60 years) 1.14 (1.02–1.28) 0.021Diabetes mellitus 2.31 (0.29–18.49) 0.430Heart rate 1.04 (0.99–1.08) 0.070Hemoglobin level 0.77 (0.48–1.23) 0.273Leukocyte count 1.06 (0.76–1.48) 0.740Creatinine level 2.03 (0.69–5.89) 0.194Glucose level 1.00 (0.99–1.01) 0.965Triglyceride level 0.96 (0.97–1.01) 0.078Troponin I level 1.03 (0.96–1.11) 0.352Anterior STEMI 4.73 (0.87–25.72) 0.072Primary PCI 2.21 (0.45–10.74) 0.326Supramedian sST2 6.27 (1.33–29.47) 0.020

Cardiology Research and Practice 7

each lot and are given as ng/mL [6]. -e total duration fromsample preparation to result interpretation is no more than35 minutes which is sufficiently rapid. -e promptness ofPOCT is its superiority over other test methods which arecrucial factors in the setting of STEMI.

Several limitations were identified in our study.Firstly, the number of subjects was not large enough tosupport strong conclusions with sufficient statisticalpower for generalizability. Secondly, the blood samplesused in this study were thawed-frozen samples which arenot compatible in the real setting of acute disease, whichpreferably uses fresh samples. Last but not least was theuncertain determination of the cutoff value using thecurrent POCT system because a significant amount ofpatients had the sST2 level beyond the detection rangeusing the POCT.

In conclusion, the sST2 POCT measurement on ad-mission was useful to identify patients at high risk to developadverse cardiac events during acute intensive care of STEMI.Supramedian sST2 levels independently predicted adversecardiac events during acute intensive care of STEMI.

Data Availability

All authors take responsibility for all aspects of the reliabilityand freedom from bias of the data presented and theirdiscussed interpretation.

Conflicts of Interest

-e authors declare that they have no conflicts of interest.

Acknowledgments

-e authors acknowledge the following persons who werehelpful during the study: Farid Abdullah from the De-partment of Clinical Pathology, Faculty of Medicine, PublicHealth and Nursing Universitas Gadjah Mada, Yogyakarta,for his technical assistance on blood sample handling andanalysis, Annisa Dian (MD) and Adysti Dhian Rizky Par-amytha (MD) for their assistance on blood sample handlingand kit measurement, and Kurniasari Endah MD from UBCMedical Indonesia for kindly providing ASPECT PLUS ST2READER and ASPECT PLUS ST2 rapid test cassette. -eauthors are indebted to Dr. Teguh Triyono (MD) and UmiSolekhah Intansari (MD) from the Department of ClinicalPathology, Faculty of Medicine, Public Health and NursingUniversitas Gadjah Mada, Yogyakarta, for the permission touse the lab facility. -e authors also express appreciation tothe fellow cardiologists and ICCU staff for their assistanceand cooperation during this study. -e authors expressgratitude to Klinik Bahasa (Office of Research and Publi-cation, Faculty of Medicine, Public Health and Nursing,Universitas Gadjah Mada) for English language andgrammar editing of the manuscript. -is study was sup-ported by Dana Masyarakat, Faculty of Medicine, Uni-versitas Gadjah Mada, fiscal year 2016 (A.B.H as PrincipalInvestigator).

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[20] O. S. Dhillon, H. K. Narayan, S. Q. Khan et al., “Pre-dischargerisk stratification in unselected STEMI: Is there a role for ST2or its natural ligand IL-33 when compared with contemporaryrisk markers?,” International Journal of Cardiology, vol. 167,no. 5, pp. 2182–2188, 2013.

[21] S. Demyanets,W. S. Speidl, I. Tentzeris et al., “Soluble ST2 andinterleukin-33 levels in coronary artery disease: relation todisease activity and adverse outcome,” PLoS One, vol. 9, no. 4,Article ID e95055, 2014.

[22] M. L. O’Donoghue, D. A. Morrow, C. P. Cannon et al.,“Multimarker risk stratification in patients with acute myo-cardial infarction,” Journal of the American Heart Association,vol. 5, no. 5, article e002586, 2016.

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