Abstract
Endothelin-1 (ET-1) and endothelin-3 (ET-3) released in circulation during acute myocardial infarction (AMI) contribute to vasoconstriction, which elevates the severity of the myocardial infarction. This study aims to investigate the role of cumulative ET-1 and ET-3 levels on the major adverse cardiac events (MACE) 1 year after AMI hospitalization. This retrospective cohort study included patients with ST-elevation acute myocardial infarction (STEMI). Baseline data were collected, including sociodemographic characteristics, clinical data, and serum ET-1 and ET-3 levels, measured with ELISA assay. Follow-up was performed 1 year after hospital discharge to identify MACE. A multivariate logistic regression was performed to describe predictors of 1-year MACE. A total of 81 subjects were enrolled and followed up. Subjects were divided into two groups based on their cumulative ET-1 and ET-3 levels, using a rounded cut-off point of 17.0 ng/mL, produced by the ROC curve for MACE. At 1 year MACE occurred in 24 (29.3%) subjects. A multivariate analysis demonstrated that a cumulative ET-1 and ET-3 level >17.0 ng/mL was independently associated with 1-year MACE (aOR = 5.34, 95% CI: 1.36–21.07, p = 0.017). A higher cumulative serum ET-1 and ET-3 level at admission predicts MACE in 1 year of follow-up after STEMI.
Keywords: endothelin-1, endothelin-3, acute myocardial infarction, major adverse cardiac events
Coronary heart disease (CHD) is a leading cause of mortality both in developed and developing countries. Data from the United States reported that the age-standardized prevalence of CHD in 2018 was approximately 6% (4–10.6%), 1 with the mortality rate accounting for 21.8 to 24.3% of total deaths. 2 In Indonesia, data from 2018 estimated that around 15 out of 1,000 inhabitants, or approximately 4.2 million people, suffered from CHD, 3 and it contributed to 14.4% of deaths in Indonesia. 4 Most of the mortality from CHD was due to acute myocardial infarction (AMI) and its sequelae, despite all the advancements in treatment modalities. Data from the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry showed that heart failure was the most common AMI sequelae, which contributed to higher mortality. 5
Early identification of patients with a high risk for adverse sequelae following AMI through measuring specific biomarker concentrations can increase risk stratification accuracy, personalize treatment strategies, and improve prognosis. 6 Various biomarkers have emerged as crucial modalities for the diagnosis, risk stratification, and prognosis of AMI. Among these biomarkers, particularly high-sensitivity cardiac troponin (hs-cTn) has revolutionized the diagnostic pathway for AMI with superior sensitivity and negative predictive value. 7 Currently, the strategy for prognostic stratification in patients with AMI has shifted toward a multi-biomarker approach, which will significantly improve the risk assessment of patients with AMI beyond relying solely on hs-cTn.
Potential alternative biomarkers that have emerged are endothelin-1 (ET-1) and endothelin-3 (ET-3). Over the years, the endothelin system has been identified as critical in the pathogenesis of several cardiovascular diseases, such as hypertension, pulmonary hypertension, heart failure, and coronary artery disease. 8 Previous research has found that ET-1 biomarkers have utility in prognostic stratification in cases of AMI 9 10 and heart failure. 11 Our previous study indicated that ET-1:ET-3 ratio is associated with increased risk for hospital mortality in ST-elevation AMI (STEMI). 12 No study has explored the utility of cumulative ET-1 and ET-3 levels as a prognostic biomarker. Therefore, we aim to investigate the potential of cumulative ET-1 and ET-3 levels as prognostic biomarkers for predicting 1-year major adverse cardiac event (MACE) in patients with STEMI.
Materials and Methods
The study design was a retrospective cohort study. The subjects were patients admitted to the emergency department and treated in the intensive cardiac care unit (ICCU) of Dr Sardjito General Hospital, Yogyakarta, Indonesia, from January 2017 to January 2018 due to STEMI. The enrolment of the subjects was conducted consecutively. The inclusion criteria were: (1) adult patients aged ≥35 years, (2) patients diagnosed with STEMI based on international guidelines as previously described, 13 (3) onset of anginal pain ≤24 hours, and (4) patient provided written consent to participate in the study. Patients with stage IV–V chronic kidney disease, liver cirrhosis, a history of cancer, pregnancy, sepsis, concurrent acute ischemic or hemorrhagic stroke, and acute inflammation (myocarditis, pericarditis, and arthritis) as well as no follow-up data were excluded from this study. Written informed consent was obtained from each eligible subject. This study received ethical approval from the Medical and Health Research Ethics Committee of the Faculty of Medicine, Public Health, and Nursing of Universitas Gadjah Mada and Dr Sardjito General Hospital (Reference number: KE/0645/05/2019).
The subjects' sociodemographic and clinical data were collected by trained research team members upon admission. The subject's age was determined as the age at enrolment. Smoking history refers to an individual's past and current patterns of tobacco use (not including secondhand smoking) and is categorized into a non-smoker, former smoker, and current smoker. History of comorbidity (hypertension, dyslipidemia, diabetes mellitus, and ischemic heart disease) was collected during history taking at admission. Symptom onset was defined as the duration in hours between the symptom related to STEMI and the time of emergency department admission. The Killip classification was used to assess the severity of heart failure due to STEMI.
Upon admission to the emergency department, before revascularization strategies were administered, an antecubital venous blood sample was obtained from each subject for hematological and blood chemistry examinations performed at the hospital's clinical pathology laboratory. For endothelin measurement, the blood samples were graded centrifuged for obtaining sera, aliquoted, and then stored in the −80°C freezer until endothelin analysis. ET-1 and ET-3 were quantified by solid phase sandwich enzyme-linked immunosorbent assay (ELISA) method with endothelin-1 and endothelin-3 assay kits (Immuno-Biological Laboratories Co., Ltd, Japan). Without repeating the freeze/thaw cycle, the aliquoted sera samples were thawed at low temperature, completely mixed and diluted in the diluent buffer. The prepared 100 μL samples were put into suitable wells. The cycle of incubation and washing with wash buffer was performed according to manufacturer protocol, by experienced laboratory technician. The optical densities of the samples and standard were measured against a test sample blank at measurement wavelength of 450 nm. The curve from the standard concentration and its optical density were constructed and the samples' concentration was measured by applying the absorbance of the test samples on a standard curve. To calculate the concentration of the test samples, the measured value was multiplied by the sample's dilution ratio. The ELISA analysis was conducted at the Biomolecular Research Laboratory, Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada. 13
The medications used during treatment in the ICCU and outpatient therapies after hospital discharge were at the discretion of the attending cardiologists. As described previously, the research teams followed up on the subjects on days 30, 90, and 1 year after discharge. 9 The primary endpoint was the occurrence of major adverse cardiac events (MACE) 1 year after hospital discharge. MACE was defined as the composite outcome encompassing death, myocardial infarction, stroke, hospitalization due to heart failure, and revascularization procedures (including percutaneous coronary intervention and coronary artery bypass graft). 14 Deaths were considered attributable to a cardiac cause unless a noncardiac cause of death could be confirmed. A semi-structured questionnaire was developed to ascertain MACE outcomes based on the aforementioned criteria. At 1 year after hospital discharge, subjects were invited to visit our hospital's cardiology research office (CRO) for interviews using the questionnaire by trained research members blinded to endothelin quantification results to determine MACE outcomes. Subjects unable to attend the CRO visit were contacted by telephone and given similar interviews.
For statistical analysis, the patient's baseline characteristics data were presented as mean and standard deviation (SD) or median (Q1-Q3) for continuous data and as frequency for categorical data. ET-1 and ET-3 were categorized based on the cutoff value generated with the Liu Index method to identify an optimal cutoff point that maximizes the difference between the true and false positive rates. 15 From the determined cutoff point, rounded cutoff values were chosen to maximize clinical practice application while maintaining optimal area under the receiver operating characteristic (ROC) curve. A univariable logistic regression analysis was used to examine sociodemographic, clinical, and laboratory variables associated with MACE. All variables with a p -value of <0.250 in the univariable analyses were further analyzed using multivariable logistic regression. A p -value of <0.05 was considered statistically significant. The STATA software version 17 (Stata Corp., TX, USA) was used for the statistical analyses.
Results
Baseline Characteristics
A total of 122 consecutive patients with AMI were screened for inclusion in this study. Inclusion criteria for this study were met by 92 patients. Of these, 11 patients were excluded. Therefore, 81 STEMI patients were eligible and analyzed for the study ( Fig. 1 ).
Fig. 1.
The subjects' enrolment and follow-up flowchart.
Most subjects were males (95.1%), with a median age of 55 (ranging from 45 to 64). Even though the majority of subjects did not have any previous history of ischemic heart disease (79%), smoking habits (63%), hypertension (40.7%), dyslipidemia (24.7%), and diabetes mellitus (24.7%) were the risk factors found among them. While 68 subjects (85.2%) came to the emergency department without any sign of heart failure (Killip I classification), 15 subjects (14.8%) presented with minimal rales in the lung, which matched with Killip II classification. Most subjects had anginal pain onset of less than 6 hours (65.4%). Most subjects underwent revascularization procedures (85.2%), either primary percutaneous coronary intervention or fibrinolysis. There were 54 patients undergoing coronary angiography, and 61.1% of the patients had >1 vessel disease. Within 1 year after hospital discharge, 24 (29.3%) subjects experienced MACE. The baseline characteristics of subjects are shown in Table 1 .
Table 1. Subject's baseline characteristics ( n = 81) .
| Characteristics | Frequency |
|---|---|
| Age (years), mean ± SD | 54.6 ± 9.2 |
| Male sex, n (%) | 77 (95.1) |
| Smoking history, n (%) | |
| Non-smoker | 20 (24.7) |
| Ex-smoker | 10 (12.3) |
| Current smoker | 51 (63.0) |
| Hypertension, n (%) | 33 (40.7) |
| Dyslipidemia, n (%) | 20 (24.7) |
| Diabetes mellitus, n (%) | 20 (24.7) |
| History of ischemic heart disease, n (%) | 17 (21.0) |
| Symptom onset, n (%) | |
| ≤6 hours | 58 (71.6) |
| >6 hours | 23 (28.4) |
| Killip classification, n (%) | |
| Killip I | 69 (85.2) |
| Killip II–IV | 12 (14.8) |
| Revascularization, n (%) | 69 (85.2) |
| Blood glucose >200 mg/dL | 19 (23.5) |
| Creatinine >1.17 mg/dL | 34 (42.0) |
| Troponin-I, median (Q1–Q3) (ng/mL) | 0.7 (0.1–2.4) |
| ET-1, median (Q1–Q3) (ng/mL) | 10.8 (8.5–13.2) |
| ET-3, median (Q1–Q3) (ng/mL) | 7.0 (6.3–7.9) |
| Cumulative ET-1 and ET-3, median (Q1–Q3) (ng/mL) | 17.9 (14.9–21.0) |
Abbreviations: ET-1, endothelin-1; ET-3, endothelin-3; SD, standard deviation.
Cumulative ET-1 and ET-3 Cutoff Value
For the individual ET-1 and ET-3 values, the cutoff determination analysis using the Liu Index for optimal discrimination for 1-year MACE showed values of 10.27 ng/mL (sensitivity = 0.71, specificity = 0.54, area under the curve [AUC] = 0.630) and 6.77 ng/mL (sensitivity = 0.79, specificity = 0.54, AUC = 0.670), respectively. With rounded cutoff points for feasible clinical application, an ET-1 value of 10.0 ng/mL corresponds to a sensitivity of 75.0%, specificity of 50.9%, and AUC of 0.629, and an ET-3 value of 7.0 ng/mL corresponds to a sensitivity of 62.5%, specificity of 57.9%, and AUC of 0.602, for the discrimination for 1-year MACE. From the cutoff determination analysis using the Liu Index, we found that the cutoff point for the cumulative ET-1 and ET-3 level value for optimal discrimination for 1-year MACE was 16.78 ng/mL (sensitivity = 0.79, specificity = 0.53, AUC = 0.660). For feasible clinical application, we used a rounded cutoff value of 17.0 ng/mL, corresponding to a sensitivity of 75.0%, specificity of 52.6%, and AUC of 0.638 for the 1-year MACE discrimination ( Fig. 2 ). Therefore, subjects were divided into two groups based on their cumulative ET-1 and ET-3 level cutoff points, namely, the high-value group (cumulative ET-1 and ET-3 >17.0 ng/mL) and the low-value group (cumulative ET-1 and ET-3 ≤17.0 ng/mL). The subjects' characteristics based on this cumulative value groups are shown in Table 2 .
Fig. 2.
The receiver operating characteristic (ROC) curve of cumulative endothelin-1 (ET-1) and endothelin-3 (ET-3) level value of 17 ng/mL for 1-year major adverse cardiac events (MACE) after ST-elevation acute myocardial infarction (STEMI).
Table 2. Subject's baseline characteristics based on value of cumulative ET-1 and ET-3 level.
| Characteristics | ET-1 + ET-3 ≤17.0 ng/mL (low value) |
ET-1 + ET-3 >17.0 ng/mL (high value) |
|---|---|---|
| Age (years), mean ± SD | 55.8 ± 9.4 | 53.2 ± 9.0 |
| Male sex, n (%) | 34 (94.4) | 43 (95.6) |
| Smoking history, n (%) | ||
| Non-smoker | 7 (19.4) | 13 (28.9) |
| Ex-smoker | 4 (11.1) | 6 (13.3) |
| Current smoker | 25 (69.5) | 26 (57.8) |
| Hypertension, n (%) | 14 (38.9) | 19 (42.2) |
| Dyslipidemia, n (%) | 9 (25.0) | 11 (24.4) |
| Diabetes mellitus, n (%) | 9 (25.0) | 11 (24.4) |
| History of ischemic heart disease, n (%) | 7 (19.4) | 10 (22.2) |
| Symptom onset, n (%) | ||
| ≤6 hours | 29 (80.6) | 29 (64.4) |
| >6 hours | 7 (19.4) | 16 (35.6) |
| Killip classification, n (%) | ||
| Killip I | 32 (88.9) | 37 (82.2) |
| Killip II–IV | 4 (11.1) | 8 (17.8) |
| Revascularization, n (%) | 34 (94.4) | 35 (77.8) |
| Blood glucose (mg/dL), median (min–max) | 135.5 (87–360) | 129 (95–407) |
| Creatinine (mg/dL), median (Q1–Q3) | 1.13 (0.90–1.30) | 1.13 (1.00–1.30) |
| Troponin-I (ng/mL), median (Q1–Q3) | 0.6 (0.1–2.3) | 0.8 (0.3–3.0) |
| ET-1 (ng/mL), median (Q1–Q3) | 8.4 (7.4–8.9) | 13.2 (11.3–14.4) |
| ET-3 (ng/mL), median (Q1–Q3) | 6.3 (5.9–6.8) | 7.5 (6.9–8.5) |
| Cumulative ET-1 and ET-3 (ng/mL), median (Q1–Q3) | 14.9 (13.7–15.7) | 20.2 (19.1–22.4) |
Abbreviations: ET-1, endothelin-1; ET-3, endothelin-3; SD, standard deviation.
Predictors of MACE
The data in Table 3 depict the characteristics of patients who experienced MACE during 1-year follow-up. From univariate and multivariate analysis, the high value of cumulative ET-1 and ET-3 level (>17.0 ng/mL) independently predicts 1-year MACE (adjusted odds ratio [aOR] 4.97, 95% confidence interval [CI]: 1.29–19.10, p = 0.020) ( Table 3 ). Other independent predictors were hypertension and dyslipidemia.
Table 3. Univariate and multivariable analysis of sociodemographic and clinical factors associated with 1-year MACE.
| Variable | 1-year MACE n (%) |
Unadjusted OR (95% CI) | p -Value | Adjusted OR (95% CI) |
p -Value |
|---|---|---|---|---|---|
| Age (years) | – | 1.04 (0.98–1.10) | 0.191 | 1.05 (0.98–1.12) | 0.177 |
| Sex | |||||
| Female | 2 (8.3) | Ref | |||
| Male | 22 (91.7) | 0.40 (0.05–3.02) | 0.374 | ||
| Smoking history | |||||
| Non-smoker | 7 (29.2) | Ref | Ref | ||
| Ex-smoker | 1 (4.2) | 0.21 (0.02–1.98) | 0.171 | 0.21 (0.01–2.98) | 0.247 |
| Current smoker | 16 (66.7) | 0.85 (0.28–2.53) | 0.769 | 1.66 (0.41–6.67) | 0.472 |
| Hypertension | |||||
| No | 11 (45.8) | Ref | Ref | ||
| Yes | 13 (54.2) | 2.19 (0.83–5.77) | 0.114 | 5.48 (1.35–22.33) | 0.018 |
| Dyslipidemia | |||||
| No | 22 (91.7) | Ref | Ref | ||
| Yes | 2 (8.3) | 0.20 (0.04–0.93) | 0.040 | 0.06 (0.01–0.47) | 0.007 |
| Diabetes mellitus | |||||
| No | 17 (70.8) | Ref | |||
| Yes | 7 (29.2) | 1.39 (0.48–4.09) | 0.545 | ||
| Ischemic heart disease | |||||
| No | 20 (83.3) | Ref | |||
| Yes | 4 (16.7) | 0.68 (0.20–2.34) | 0.537 | ||
| Random blood sugar | |||||
| ≤200 mg/dL | 17 (70.8) | Ref | |||
| >200 mg/dL | 7 (29.2) | 1.54 (0.52–4.58) | 0.433 | ||
| Creatinine | |||||
| ≤1.17 mg/dL | 11 (45.8) | Ref | Ref | ||
| >1.17 mg/dL | 13 (54.2) | 2.02 (0.77–5.33) | 0.152 | 2.06 (0.59–7.20) | 0.256 |
| Troponin-I | |||||
| ≤0.355 ng/mL | 5 (20.8) | Ref | Ref | ||
| >0.355 ng/mL | 19 (79.2) | 2.76 (0.90–8.44) | 0.074 | 1.28 (0.31–5.22) | 0.731 |
| Symptom onset | |||||
| ≤6 hours | 16 (66.7) | Ref | |||
| >6 hours | 8 (33.3) | 1.40 (0.50–3.93) | 0.523 | ||
| Killip classification | |||||
| Killip I | 17 (73.9) | Ref | Ref | ||
| Killip II | 6 (26.1) | 2.83 (0.81–9.91) | 0.103 | 1.46 (0.30–7.02) | 0.639 |
| Cumulative ET1 + ET3 | |||||
| ≤17.0 | 6 (25.0) | Ref | Ref | ||
| >17.0 | 18 (75.0) | 3.33 (1.15–9.62) | 0.026 | 4.97 (1.29–19.10) | 0.020 |
Abbreviations: CI, confidence interval; DM, diabetes mellitus; ET-1, endothelin-1; ET-3, endothelin-3; IHD, ischemic heart disease; MACE, major adverse cardiovascular events; OR, odds ratio; Ref, reference.
Discussion
In this retrospective study, 81 patients admitted to the emergency department with STEMI were analyzed. Blood samples were collected prior to revascularization to minimize the influence of reperfusion injury, which is known to elevate endothelin levels. The incidence of 1-year MACE in our study was 29.6%, notably higher than findings from other studies. 16 17 This finding highlights a significant disparity in cardiovascular care and outcomes that need to be addressed and underscores the opportunity for the development and integration of additional prognostic markers in identifying patients who are at higher risk for experiencing MACE.
Studying ET-1 and ET-3 might give insight into the incidence of MACE due to their significant role in vasoconstriction and the regulation of vascular tone and complex interaction. A previous study using a rat model found that intravitreal injection of ET-3 into the retina initially increased retinal blood flow, followed by a subsequent decrease. This response was likely mediated by the activation of ET A receptors by ET-1. 18 To further investigate ETA receptor activation, another study using a rat model administered ET A antagonists, such as BQ123 and FR-139317, in an isolated perfused rat kidney. The study found that only 25 to 50% of the vasoconstrictive effect was inhibited, highlighting the significant role of the ETB receptor activation by ET-3 in mediating vascular vasoconstriction. 19
Elevated ET-3 levels indicate an attempt to counteract these effects, potentially signaling scar healing and stabilization during post-infarct remodeling. However, in pathological conditions such as acute coronary syndrome, damage to the endothelium can lead to altered ETB receptor behavior, contributing to vasoconstriction. In a study, the administration of S6c (an ETB receptor agonist) was compared with ET-1 injection in the brachial artery of both healthy and atherosclerotic animal models. 20 The results revealed that, in the atherosclerotic group, S6c induced a more robust vasoconstrictive response than ET-1, leading to restricted blood flow in the caudal region, which was not observed in the healthy group. 20 Additionally, another study highlighted the role of ETB receptors in contributing to mild-to-moderate vasoconstriction in human arteries. 21 Interestingly, transient vasodilation was observed initially in the presence of elevated ET-3 levels, followed by a shift toward vasoconstriction, suggesting complex regulatory dynamics of endothelin in vascular tone. 21
Therefore, ET-1 and ET-3 could act as potent vasoconstrictors, contributing to increasing vascular resistance and impaired blood flow, exacerbating conditions such as atherosclerosis and hypertension, key risk factors for MACE. 20 22 Additionally, endothelin is involved in endothelial dysfunction, a critical feature in the progression of cardiovascular diseases, including myocardial infarction and heart failure. Beyond vasoconstriction, ET-1 and ET-3 influence inflammation and thrombosis, further promoting atherosclerotic plaque development and rupture, which may lead to acute events with worse clinical outcomes, 23 making them potential biomarkers for assessing cardiovascular risk and potential therapeutic targets to mitigate the incidence and severity of MACE.
Exploring ET-1 and ET-3 cumulative levels may provide a broader understanding of the impact of the endothelin system on MACE. Our study revealed that MACE, including death, heart failure, cardiogenic shock, reinfarction, and resuscitated ventricular arrhythmias, were three times more common in patients with cumulative ET-1 and ET-3 levels above a defined cut-off value. Furthermore, we found that subjects with a delayed onset of symptoms demonstrated higher cumulative endothelin levels upon admission, suggesting the need for early reperfusion therapy. However, even after reperfusion therapy, previous studies have shown that elevated endothelin levels are linked to microvascular injury and ventricular dysfunction. 24 Additionally, many patients in our cohort have multivessel disease, underscoring the importance of complete revascularization, as current guidelines recommend, to improve long-term outcomes.
This study has several limitations that should be acknowledged. This study is a single-center study, which may limit the generalizability of the findings. Additionally, several factors that could influence endothelin levels, such as peripheral vascular atherosclerosis and infections, were not excluded, as the data were not captured in this study. Furthermore, the assessment of MACE outcomes was limited by the availability of data at only four time points, and there was a potential recall bias in patients' interpretations of long-term MACE outcomes. Capturing several MACE outcomes, such as ventricular arrhythmia, were challenging due to undocumented events and patients' difficulties in recognizing these events.
Conclusion
High cumulative serum ET-1 and ET-3 level of >17.0 ng/mL at admission is significantly associated with 1-year MACE after admission for STEMI. This indicates that the rise of serum ET-1 and ET-3 at admission contributes to the poor prognosis of the patient after STEMI.
Clinical Relevance
Endothelin-1 (ET-1) and endothelin-3 (ET-3) have prediction value for occurrence of MACE within 1 year after STEMI.
Cumulative circulating ET-1 and ET-3 levels are associated with increased MACE occurrence within 1 year after STEMI.
The role of endothelin antagonists in STEMI warrants further research.
Funding Statement
Funding This study and publication was supported by: (1) Dana Masyarakat FK-KMK Universitas Gadjah Mada, Yogyakarta, Indonesia (Number: 761/UN1/FKKMK/PPKE/PT/2023), and (2) Academic Excellence Improvement Program Universitas Gadjah Mada, under Grant (Number: 7725/UN1.P.II/Dit-Lit/PT.01.03/2023).
Footnotes
Conflict of Interest None declared.
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