Acute myocardial infarction with ST-segment elevation (STEMI) is a clinical syndrome which reflects the transmural necrosis of myocardia due to occlusive thrombus in the coronary artery segment. The prevalence of STEMI ranges from 25% to 45% among patients with acute myocardial infarction [
Several independent predictors for major adverse cardiac events following STEMI have been identified such as age, Killip class on admission, delay of reperfusion time, cardiac arrest, tachycardia, hypotension, anterior infarct location, previous myocardial infarction, diabetes mellitus, smoking, renal function, and increased biomarkers for myocardial necrosis [
Novel biomarkers have been identified and investigated in their role specifically in acute myocardial infarction. Soluble ST2 (sST2), which is released during myocardial stretching, is one promising biomarker [
Several studies have concluded that increased sST2 in the initial phase of STEMI is associated with adverse cardiac effect, both in the short term and long term. However, currently no guideline recommends the examination of sST2 as a predictor biomarker to guide treatment for STEMI. Therefore, confirmatory research should be performed to provide more solid evidence of sST2 implication in predicting major adverse cardiac events in patients hospitalized with STEMI. Furthermore, the current availability of the sST2 point of care test (POCT), which allows the result to be known more quickly, is suitable in the acute clinical setting such as STEMI. This study aimed to investigate the utility of the sST2 POCT measurement in predicting adverse cardiac events in patients hospitalized with STEMI.
The research used a cohort study design. The subjects were patients with STEMI admitted to the Intensive Cardiac Care Unit (ICCU) of Dr. Sardjito Hospital, Yogyakarta, Indonesia. The subjects were enrolled from the emergency unit of Dr. Sardjito Hospital, Yogyakarta, Indonesia, where they were stabilized and subsequently admitted to ICCU. The subjects’ enrollment (from April 2014 to January 2015) was conducted by consecutive sampling. The diagnosis of STEMI was determined based on international guidelines, that is, angina symptoms, electrocardiogram criteria, and elevated cardiac enzyme markers [
We included the patients diagnosed with STEMI, both male and female patients, with age between 35 and 75 years old, the onset of anginal pain ≤24 hours, and patients without previous fibrinolytic or heparin treatment before reaching our hospital emergency unit. We excluded the patients with previously known chronic heart failure (NYHA class ≥ II), chronic kidney disease stage IV-V, hepatic cirrhosis, chronic inflammatory diseases (such as chronic arthritis, psoriasis, and inflammatory bowel disease), malignancy, and patients with concurrent acute infection, sepsis, and acute stroke during observation. The subjects competed and signed an informed consent form to participate in the research. As controls, we recruited patients with stable coronary artery disease (SCAD) who came to our hospital for coronary angiography and PCI. These patients were assigned as controls in this study. The study was approved by the ethics committee of the Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
For laboratory examination, blood samples were drawn from antecubital veins in a supine position on hospital admission before any procedures were performed. The blood was then centrifuged and inserted into an automated blood cell counter for hematology examination and chemical analyzer for blood chemistry examination. Cardiac biomarkers were measured as routine procedure, that is, CK-MB by the immunological UV assay method with Cobas c501 (Roche) and troponin I by the enzyme-linked fluorescent assay (ELFA) method with VIDAS (Biomerieux) in the central hospital laboratory. In controls, blood samples were drawn from antecubital veins in a supine position on hospital admission before coronary angiography and PCI were performed.
From the blood sample, an aliquot of serum was collected and saved in −80°C freezer until further analysis for sST2 examination. Soluble ST2 level was measured from frozen samples. The aliquot was thawed, left in room temperature, and used for sST2 quantification with ASPECT-PLUS ST2 rapid test (Critical Diagnostics, San Diego, CA, USA). The calculation of sST2 was performed based on the manufacturer’s manual instructions and previous report [
The initial treatments of the subjects with STEMI in the emergency unit were double antiplatelet, revascularization procedure, that is, primary percutaneous coronary intervention (PCI) or fibrinolysis and anticoagulant with heparin. Time for revascularization was determined as time (in minutes) from medical contact (i.e., emergency admission in our hospital) to start of reperfusion therapy by intravenous injection of fibrinolytic agents and time to balloon inflation in subjects treated with fibrinolysis and primary PCI, respectively. The initial management was performed by attending cardiologists according to patients’ clinical condition and severity. After initial treatments, the subjects were transferred to the ICCU and managed according to the discretion of the attending cardiologists.
Transthoracic echocardiography (TTE) was performed on all subjects with STEMI within 48 hours of admission in the ICCU. The GE Vivid S6 (GE Healthcare) echocardiography machine was used for TTE procedure. Left ventricle (LV) ejection fraction was obtained using the modified Simpson’s method on the standard simultaneous apical four-chamber and two-chamber views. The interpretation of TTE results was performed by experienced cardiologists.
The observation of subjects with STEMI was conducted during acute intensive care in the ICCU until discharge from the ICCU or fatal event occurred. The adverse cardiac events were a composite of cardiac death, acute heart failure, cardiogenic shock, reinfarction, and resuscitated ventricular arrhythmia (VT/VF). The adverse cardiac events were assessed and managed by attending cardiologists unaware of the sST2 measurement. A cardiac death was mortality by cardiac causes. Acute heart failure was the clinical symptoms and signs of congestion and the use of intravenous diuretics. Cardiogenic shock was systolic blood pressure <90 mmHg with symptoms and signs of low perfusion and the use of inotropics or/and vasopressor drugs. Reinfarction was newly developed continuous anginal pain, ST-elevation electrocardiogram and increased CK-MB or troponin I in previously stable patients. Resuscitated VT/VF was the return of spontaneous circulation following cardiopulmonary resuscitation and defibrillation after the episode of VT/VF.
The median sST2 level between subjects with STEMI and controls was compared with the Mann–Whitney
The subjects with STEMI for this research were 97 patients. The controls were 10 patients. The sST2 measurement was performed by the ASPECT-PLUS ST2 POCT cassette and ASPECT reader with the detection range of 12.5 ng/mL–250 ng/mL. Two subjects with STEMI were excluded from the analysis because the ASPECT-PLUS ST2 POCT result strip was undetermined. Therefore, 95 subjects with STEMI were analyzed. The median sST2 level was significantly increased in subjects with STEMI as compared to controls (152.1 ng/mL versus 28.5 ng/mL, with
The comparison of characteristics and sST2 level between controls and subjects with STEMI.
Characteristics | Controls, |
Subjects with STEMI, |
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Age (years), mean ± SD | 61.0 ± 2.9 | 58.2 ± 8.5 | 0.30 |
Male sex, |
8 (80.0) | 76 (80.0) | 0.68 |
Body mass index, mean ± SD | 26.3 ± 2.8 | 24.2 ± 2.8 | 0.06 |
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Diabetes mellitus, |
5 (50.0) | 28 (29.5) | 0.18 |
Hypertension, |
10 (100.0) | 55 (57.9) | <0.01 |
Current smoking, |
2 (20.0) | 50 (52.6) | 0.12 |
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Systolic b.p (mmHg), mean ± SD | 132.0 ± 17.5 | 128.9 ± 26.4 | 0.72 |
Diastolic b.p (mmHg), mean ± SD | 73.0 ± 9.7 | 78.9 ± 16.4 | 0.41 |
Heart rate (bpm), mean ± SD | 73.0 ± 9.7 | 76.1 ± 18.5 | 0.60 |
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Hemoglobin (g/dL), mean ± SD | 13.4 ± 1.8 | 13.8 ± 1.8 | 0.48 |
Leucocytes (103/mm3), mean ± SD | 8.3 ± 2.8 | 12.8 ± 3.2 | <0.01 |
Platelets (103/mm3), mean ± SD | 283.5 ± 48.9 | 276.6 ± 97.7 | 0.83 |
Creatinine (mg/dL), mean ± SD | 1.3 ± 0.4 | 1.3 ± 0.5 | 0.58 |
Glucose (mg/dL), mean ± SD | 131.2 ± 41.1 | 181.5 ± 94.8 | <0.01 |
sST2 (ng/mL), median (q1–q3) | 28.5 (22.7–36.9) | 152.1 (72.0–250.0) | <0.01 |
b.p = blood pressure; bpm = beat per minute; q1 = first quartile; q3 = third quartile;
In subjects with STEMI, as many as 32 subjects (33.7%) had sST2 level more than the upper measured limit (i.e., >250 ng/mL) and 1 subject had sST2 level less than the lower measured limit (i.e., <12.5 ng/mL). We determined the level of 250 ng/mL for 32 subjects with value beyond the upper measured limit and 12.5 ng/mL for 1 subject with value below the lower measured limit. The median value of sST2 was 152.1 ng/mL. The supramedian group consisted of 47 subjects and inframedian group consisted of 48 subjects. The distribution of sST2 values is depicted in Figure
The distribution of the sST2 measured level (ng/mL) and median of 152.1 ng/mL as a cutoff point in subjects with STEMI. As many as 32 subjects have the sST2 level more than the upper measured limit (i.e., >250 ng/mL), and 1 subject has sST2 level less than the lower measured limit (i.e., <12.5 ng/mL).
Subjects with supramedian sST2 levels and those with inframedian sST2 had no significant difference in demography, cardiovascular risk factors, admission clinical picture, most of initial laboratory examination, infarct location, and initial treatment strategy. Patients in the supramedian group had significantly higher troponin I and CK-MB levels than the inframedian group, indicating increasing myocardial necrosis. The initial treatments of the subjects did not significantly differ between groups. The comparison of characteristics between the supramedian and inframedian groups is shown in Table
The comparison of characteristics between inframedian and supramedian sST2 in subjects with STEMI.
Characteristics | Inframedian sST2, |
Supramedian sST2, |
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Age (years), mean ± SD | 57.3 ± 8.7 | 59.1 ± 8.2 | 0.31 |
Male sex, |
38 (79.2) | 38 (80.9) | 0.84 |
Body mass index, mean ± SD | 24.3 ± 2.8 | 24.1 ± 3.0 | 0.79 |
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Diabetes mellitus, |
16 (33.3) | 12 (25.5) | 0.41 |
Hypertension, |
30 (62.5) | 25 (53.2) | 0.36 |
Current smoking, |
24 (50.0) | 26 (55.3) | 0.60 |
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Onset (hour), mean ± SD | 8.1 ± 6.9 | 7.4 ± 5.5 | 0.48 |
Systolic b.p (mmHg), mean ± SD | 131.7 ± 27.9 | 126.0 ± 24.7 | 0.29 |
Diastolic b.p (mmHg), mean ± SD | 80.3 ± 17.3 | 77.4 ± 15.4 | 0.39 |
Heart rate (bpm), mean ± SD | 76.8 ± 17.1 | 75.4 ± 19.9 | 0.71 |
Killip II-IV, |
3 (6.2) | 5 (10.6) | 0.44 |
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Hemoglobin (g/dL), mean ± SD | 13.9 ± 1.8 | 13.6 ± 1.9 | 0.25 |
Leucocytes (103/mm3), mean ± SD | 12.9 ± 3.7 | 12.7 ± 2.8 | 0.76 |
Platelets (103/mm3), mean ± SD | 293.6 ± 107.8 | 259.3 ± 83.7 | 0.09 |
Creatinine (mg/dL), mean ± SD | 1.2 ± 0.3 | 1.3 ± 0.7 | 0.09 |
Glucose (mg/dL), mean ± SD | 184.9 ± 92.2 | 177.9 ± 98.4 | 0.72 |
Troponin 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 | <0.01 |
Total cholesterol (mg/dL), mean ± SD | 189.2 ± 58.8 | 181.9 ± 43.7 | 0.50 |
LDL cholesterol (mg/dL), mean ± SD | 123.9 ± 38.1 | 124.7 ± 35.7 | 0.91 |
HDL cholesterol (mg/dL), mean ± SD | 43.8 ± 16.6 | 45.3 ± 8.9 | 0.59 |
Triglyceride (mg/dL), mean ± SD | 134.7 ± 55.2 | 122.2 ± 75.8 | 0.36 |
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Anterior, |
23 (47.9) | 24 (51.1) | 0.83 |
Inferior, |
24 (50.0) | 21 (44.7) | 0.83 |
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Primary PCI, |
17 (35.4) | 17 (36.2) | 0.94 |
Fibrinolysis, |
18 (37.5) | 24 (51.1) | 0.18 |
Heparinization, |
0.96 | ||
LMWH | 4 (8.3) | 5 (10.6) | |
UFH | 37 (77.1) | 36 (76.6) | |
Fondaparinux | 4 (8.3) | 4 (8.5) |
b.p = blood pressure; bpm = beat per minute; LV = left ventricle; LDL = low-density liporotein; HDL = high-density lipoprotein; PCI = percutaneous coronary intervention; LMWH = low molecular weight heparin; UFH = unfractionated heparin;
The proportion of initial revascularization procedure, that is, primary PCI or fibrinolysis, was comparable between groups. In subjects who underwent primary PCI, the time to revascularization was not significantly different between groups. This also applied to the time to revascularization for fibrinolysis. The rate of failed fibrinolysis and subsequent rescue PCI did not significantly differ between groups either. Table
The mode of revascularization and time to revascularization between inframedian and supramedian sST2 in subjects with STEMI.
Mode of revascularization | Inframedian sST2, |
Supramedian sST2, |
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Primary PCI, |
17 (35.4%) | 17 (36.2%) | |
Time to revascularization (minutes), mean ± SD | 179.7 ± 40.3 | 156.4 ± 45.2 | 0.12 |
Fibrinolysis, |
18 (42.9%) | 24 (51.1%) | |
Time to revascularization (minutes), mean ± SD | 68.3 ± 26.3 | 65.6 ± 21.8 | 0.72 |
Failed fibrinolysis and rescue PCI, |
2 (11.1) | 7 (29.2) | 0.15 |
PCI = percutaneous coronary intervention.
The incidence of adverse cardiac events was significantly higher in the supramedian group as compared to those in the inframedian group (38.3% versus 12.5%,
The incidence of adverse cardiac events between inframedian and supramedian sST2 groups. The adverse cardiac events were significantly higher (38.3%) in the supramedian group as compared to the inframedian group (12.5%);
The incidence of individual adverse cardiac events between inframedian and supramedian sST2 groups. The most common adverse cardiac event was acute heart failure. The mortality rate was similar between the supramedian and inframedian sST2 groups.
The boxplot of left ventricle (LV) ejection fraction between inframedian and supramedian sST2 groups. In the supramedian sST2 group, there was significantly reduced LV ejection fraction indicating worse LV systolic dysfunction (Student’s
The median value of sST2 level was significantly highest in subjects with STEMI-experienced adverse cardiac events (246.6 ng/mL), followed by subjects with STEMI with no adverse cardiac events (122.9 ng/mL), and the lowest was in the control (28.5 ng/mL); the
The median sST2 level was significantly the highest in STEMI subjects with adverse cardiac events, followed by STEMI subjects with no adverse cardiac events. The controls had the least median sST2 level.
A univariate analysis showed that supramedian sST2 was significantly associated with increased incidence of adverse cardiac events, with OR 4.35 (95% CI: 1.54–12.27,
Univariate and multivariable analysis of variables as predictors for adverse cardiac events.
Univariate analysis variables | OR (95% confidence interval) |
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Increased age (>60 years) | 1.09 (1.03–1.16) | 0.005 |
Diabetes mellitus | 2.69 (1.02–7.09) | 0.046 |
Heart rate | 1.02 (0.99–1.04) | 0.178 |
Hemoglobin level | 0.63 (0.46–0.86) | 0.004 |
Leukocyte count | 0.85 (0.71–1.02) | 0.078 |
Creatinine level | 1.91 (0.83–4.41) | 0.131 |
Glucose level | 1.01 (1.00–1.01) | 0.071 |
Triglyceride level | 0.99 (0.98–0.99) | 0.015 |
Troponin I level | 1.03 (0.99–1.08) | 0.170 |
Anterior STEMI | 2.58 (0.98–6.81) | 0.055 |
Primary PCI | 2.23 (0.87–5.73) | 0.097 |
Supramedian sST2 | 4.35 (1.54–12.27) | 0.006 |
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Multivariable analysis variables | Adjusted OR (95% confidence interval) |
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Increased age (>60 years) | 1.14 (1.02–1.28) | 0.021 |
Diabetes mellitus | 2.31 (0.29–18.49) | 0.430 |
Heart rate | 1.04 (0.99–1.08) | 0.070 |
Hemoglobin level | 0.77 (0.48–1.23) | 0.273 |
Leukocyte count | 1.06 (0.76–1.48) | 0.740 |
Creatinine level | 2.03 (0.69–5.89) | 0.194 |
Glucose level | 1.00 (0.99–1.01) | 0.965 |
Triglyceride level | 0.96 (0.97–1.01) | 0.078 |
Troponin I level | 1.03 (0.96–1.11) | 0.352 |
Anterior STEMI | 4.73 (0.87–25.72) | 0.072 |
Primary PCI | 2.21 (0.45–10.74) | 0.326 |
Supramedian sST2 | 6.27 (1.33–29.47) | 0.020 |
A stepwise multiple logistic regression analysis showed that supramedian sST2 level was an independent predictor of increased incidence of adverse cardiac events. The adjusted OR was 6.27 (95% CI: 1.33–29.47,
Our study indicates that, on admission, the sST2 POCT measurement in the acute intensive care of STEMI is useful to predict adverse cardiac events during intensive hospitalization. Using median value for cutoff point, the sST2 value above the median is predictive for short-term adverse cardiac events. However, since the range of sST2 value in the POCT system is limited, one third of patients had sST2 level out of the detectable range, mostly beyond it. The simplistic and rapidity nature of the POCT system is beneficial in the acute care setting, where the quick laboratory result is mandatory to guide clinical decisions and treatment strategy. In the context of STEMI, the use of POCT in the biomarker measurement is greatly beneficial to predict adverse cardiac events.
Suppression of tumorigenicity 2 or ST2 is a receptor protein which is initially recognized as an orphan protein involved in the regulation of inflammation [
The expression of ST2 protein is significant in myocardia [
The circulating sST2 acts as a decoy receptor for IL-33, which is attached to the transmembrane form of ST2 and conditions myocardial adaptation from mechanical strain [
Our study shows that sST2 POCT measurement on admission is useful to identify patients with higher risk to develop adverse cardiac events during intensive care. The risk is about sixfold higher in those with sST2 supramedian levels on admission. The risk has been predicted early in the admission phase before the patients finally develop overt clinical events during acute intensive care, mostly due to left ventricular dysfunction. Currently, circulating sST2 has not been approved in the clinical guideline as a prognostic biomarker of adverse outcomes in acute myocardial infarction. In the guideline of heart failure, sST2 determination is useful as a biomarker for additive risk stratification, especially in the acute phase [
Our study findings corroborated other clinical trials that have concluded the role of sST2 in predicting major adverse cardiovascular events following the episode of STEMI. Shimpo et al. investigated the impact of circulating sST2 in STEMI patients and found that sST2 highest quintiles associated with increased major adverse cardiovascular events during intensive hospitalization and 30 days after hospitalization [
In STEMI, primary PCI and fibrinolysis are recommended as modalities of revascularization. Our hospital is a PCI-capable hospital which has routinely performed primary PCI for STEMI patients. However, due to time delays in performing primary PCI, fibrinolytic treatment is still more often performed in our hospital. In this study, the proportion of primary PCI or fibrinolysis was not significantly different between groups, although in the supramedian group, the proportion of fibrinolysis tended to be higher. Additionally, the time to revascularization was not significantly different between groups, both in primary PCI and fibrinolysis.
In-hospital course of STEMI patients worsened in those with sST2 value >35 ng/mL, that is, the cutoff value of increased sST2 level in heart failure [
The practicality and simplicity of the POCT test in acute coronary syndrome is of paramount importance, because the fast result can rapidly guide the clinical decision. The enzyme-linked immunosorbent assay is a more sensitive method of measurement than POCT, however it is robust, time-consuming, and impractical causing its limited use in clinical daily practice. The ASPECT-PLUS ST2 test is a rapid quantitative lateral flow immunoassay for measurement of sST2 in human plasma. The fluorescent signal indicates interaction between antibodies against human sST2 which are tagged with a fluorescent dye [
Several limitations were identified in our study. Firstly, the number of subjects was not large enough to support strong conclusions with sufficient statistical power for generalizability. Secondly, the blood samples used in this study were thawed-frozen samples which are not compatible in the real setting of acute disease, which preferably uses fresh samples. Last but not least was the uncertain determination of the cutoff value using the current POCT system because a significant amount of patients had the sST2 level beyond the detection range using the POCT.
In conclusion, the sST2 POCT measurement on admission was useful to identify patients at high risk to develop adverse cardiac events during acute intensive care of STEMI. Supramedian sST2 levels independently predicted adverse cardiac events during acute intensive care of STEMI.
All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
The authors declare that they have no conflicts of interest.
The authors acknowledge the following persons who were helpful during the study: Farid Abdullah from the Department of Clinical Pathology, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada, Yogyakarta, for his technical assistance on blood sample handling and analysis, Annisa Dian (MD) and Adysti Dhian Rizky Paramytha (MD) for their assistance on blood sample handling and kit measurement, and Kurniasari Endah MD from UBC Medical Indonesia for kindly providing ASPECT PLUS ST2 READER and ASPECT PLUS ST2 rapid test cassette. The authors are indebted to Dr. Teguh Triyono (MD) and Umi Solekhah Intansari (MD) from the Department of Clinical Pathology, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada, Yogyakarta, for the permission to use the lab facility. The authors also express appreciation to the fellow cardiologists and ICCU staff for their assistance and cooperation during this study. The authors express gratitude to Klinik Bahasa (Office of Research and Publication, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada) for English language and grammar editing of the manuscript. This study was supported by Dana Masyarakat, Faculty of Medicine, Universitas Gadjah Mada, fiscal year 2016 (A.B.H as Principal Investigator).