Higher sST2 Levels Research Articles

Circulating soluble suppression of tumorigenicity-2 and the recurrence of atrial fibrillation after catheter ablation: A meta-analysis.

Soluble suppression of tumorigenicity-2 (sST-2), a marker of myocardial fibrosis and remodeling, has been related to the development of atrial fibrillation (AF). The aim of this meta-analysis was to evaluate the relationship between baseline serum sST-2 levels and the risk of AF recurrence after ablation. Relevant observational studies were retrieved from PubMed, Web of Science, Embase, Wanfang and China National Knowledge Infrastructure (CNKI). A random-effects model was used to combine the data, accounting for between-study heterogeneity. Fourteen prospective cohorts were included. Pooled results showed higher sST-2 levels before ablation in patients with AF recurrence compared to those without AF recurrence (standardized mean difference = 1.15, 95% confidence interval [CI] = 0.67 to 1.63, P < 0.001; I2 = 92%). Meta-regression analysis suggested that the proportion of patients with paroxysmal AF (PaAF) was positively related to the difference in serum sST-2 levels between patients with and without AF recurrence (coefficient = 0.033, P < 0.001). Subgroup analysis showed a more remarkable difference in serum sST-2 levels between patients with and without AF recurrence in studies where PaAF was ≥ 60% compared to those where it was < 60% (P = 0.007). Further analyses showed that high sST-2 levels before ablation were associated with an increased risk of AF recurrence (odds ratio [OR] per 1 ng/mL increment of sST-2 =1.05, OR for high versus low sST-2 = 1.73, both P values < 0.05). In conclusion, high sST-2 baseline levels may be associated with an increased risk of AF recurrence after catheter ablation.

An elevated level of soluble suppression of tumorigenicity 2, but not galectin-3, is associated with the presence of coronary artery disease in hypertensive patients.

We investigated whether there were associations between coronary artery disease (CAD) and soluble suppression of tumorigenicity (sST2) and galectin-3 levels at the time of coronary artery computed tomography angiography (CCTA) for CAD screening. The subjects consisted of 429 patients who underwent CCTA examination. CAD was diagnosed when there was 50% or more stenosis in the coronary artery. Patient backgrounds were collected and plasma levels of sST2 and galectin-3 were measured. The presence or absence of CAD and factors that contributed to CAD were analyzed for all patients and for those with or without hypertension (HTN). The CAD group had significantly higher sST2 levels than the non-CAD group, whereas there was no significant difference in galectin-3 levels. The number of patients in the non-HTN and HTN groups was 174 and 255, respectively. In the HTN group, the CAD group was significantly older than the non-CAD group and had higher sST2 levels. Multivariate analysis showed that the factors that contributed to CAD in the HTN group were age and sST2 levels. On the other hand, in the non-HTN group, the CAD group was significantly older than the non-CAD group, and had a higher proportion of males and higher sST2 levels, while the contributing factors for the CAD group were age and male gender, but not sST2. In conclusion, a higher level of sST2, but not galectin-3, was a contributing factor for CAD in HTN patients. However, in non-HTN patients, a high level of sST2 was not a contributing factor for CAD.

Does the ST2 Level in Pediatric Heart Failure Patients Correlate with Cardiovascular Events and Mortality?

The suppression of tumorigenicity 2 (ST2) is a receptor member belonging to the interleukin-1 (IL-1) family. The ligand and soluble versions are its two isoforms. The IL-33-ST2L ligand complex's development provides protection against heart fibrosis and hypertrophy. Investigations on heart failure in adults have demonstrated that it does not change by age, body mass index (BMI), creatinine, hemoglobin, and albumin levels, in contrast to NT pro BNP. In adult heart failure patients, it has been demonstrated to be an independent predictor of mortality and cardiovascular events. The most recent guideline recommends using it as class 2b in the diagnosis of adult heart failure. Studies on ST2 in children are rare. The purpose of this study is to assess the prognostic value of ST2 for cardiovascular events in young individuals suffering from heart failure. This study included pediatric patients (0-18 years old) with congenital heart disease or cardiomyopathy who needed medical care, as well as surgical or interventional treatment. Height, weight, gender, saturation, heart failure classification (Ross or NYHA), medications, the electrocardiogram, echocardiography, pro BNP, and sST2 values of the patients, as well as any hospitalization, lower respiratory tract infection, organ dysfunction, or need for angiography or surgery during follow-up data on arrhythmia and death were gathered during a 1-year follow-up. The SPSS software version 25 application was used to carry out the statistical analysis. This study included 59 patients, of whom 27 (46.6%) were male. The average age of the patients was 55.5 months (1-228 months) and the average body weight was 16 kg (2.6-90 kg). Major cardiovascular events occurred in 45 of 59 patients (76.3%). Twenty-four patients experienced one MACE, while twenty-one patients experienced multiple MACEs. Pro BNP and sST2 levels were similar in the groups that developed MACE compared to those that did not. Pro BNP was discovered to be significantly higher in patients with hospitalization, growth retardation, lower respiratory tract infection, and organ failure, however, when assessing each situation (p = 0.001, p = 0.011, p = 0.001, p = 0.007, respectively). Soluble ST2 was found to be higher in patients with growth retardation than in those without (p = 0.037). Although the soluble ST2 level failed to demonstrate a correlation with pro BNP, it did show a positive correlation (r = 0.437) with the Ross score. When compared to other groups, it was discovered to be higher in patients with valvular insufficiency type heart disease. In this study, higher sST2 levels were discovered, particularly in the group with valve insufficiency and children with growth retardation. It was associated with the Ross score, but not with the pro BNP level. Although it increases in correlation with clinical heart failure, its predictive value for MACE is low. Similarly, pro BNP is not proven to be predictive; nonetheless, its high levels in patients with hospitalization, growth retardation, lower respiratory tract infection, and organ failure demonstrate that pro BNP may increase for a variety of causes. Long-term studies with more patients are needed for ST2 to be suitable for clinical use in pediatric patients.

High Soluble Suppression of Tumorigenicity-2 (sST2) is A Risk Factor for Rehospitalization and Mortality in Chronic Heart Failure Patients with Reduced Ejection Fraction

Background: Chronic heart failure (CHF) impairs the heart’s pumping ability due to structural or functional abnormalities. It is a leading cause of death worldwide, with mortality rates of 10-50% based on severity. Risk stratification methods help predict CHF prognosis. ST2, an interleukin-1 receptor, is valuable for forecasting rehospitalization and cardiovascular events. In progressive heart failure, increased sST2 receptor expression inhibits the protective effects of IL-33, worsening the condition. Methods: Chronic heart failure patients with LVEF &lt;40% were studied in a cohort design. After sST2 blood samples were taken, patients were followed for 1 year and 10 months to monitor Major Cardiovascular Events (MACEs) like rehospitalization and mortality. Baseline characteristics included demographic, clinical, comorbidity, laboratory, and echocardiographic data. The best sST2 cut-off was determined using ROC curves. Kaplan-Meier and Cox Regression analyses assessed outcomes using SPSS 26.0. Results: All 80 samples completed the study with no drop-outs. The optimal sST2 cut-off for predicting Major Cardiovascular Events (MACEs) was &gt;19.38 ng/mL (AUC 0.668, CI 95% 0.542-0.794; p=0.023), with 66.7% sensitivity and 66.1% specificity. Survival analysis showed patients with sST2 ≥19.4 ng/mL had lower long-term survival (58.8% vs. 84.8%; p=0.007). Adjusted for age and comorbidities, high sST2 levels significantly predicted MACEs, with a 3.581 times higher risk (95% CI 1.343-9.551; p=0.011) of rehospitalization and mortality. Conclusion: High sST2 levels (≥19.4 ng/mL) were associated as a risk factor of rehospitalization and mortality in chronic heart failure patients with reduced ejection fraction.

High Serum ST2 Level Predicts Progression and Poor Prognosis of Denovomyelodysplastic Syndrome

Background: Myelodysplastic syndromes (MDS) are heterogeneous hematological stem cell malignancies with a complex pathophysiology involving immune, genetic, and epigenetic changes induced by aging, oxidative stress, and genotoxicity. Dysregulated immune responses and aberrant inflammatory signaling have been identified as critical drivers of MDS development. Recent research has highlighted the significant association of the IL-33/ST2 signaling axis with tumorigenicity and tumor immunity in various cancers. Soluble ST2 (sST2), a transmembrane-free receptor induced by IL-33, negatively regulates the IL-33/ST2 signaling pathway, and elevated levels of sST2 have been reported to correlate with poor prognosis in malignant tumors. However, the specific level of soluble ST2 and the precise role of the IL-33/ST2 signaling axis in the context of MDS remain uncertain and require further investigation. Method: This prospective study enrolled 89 newly diagnosed, untreated outpatient individuals with MDS to assess their clinical prognostic risk using the International Prognostic Scoring System-Revised (IPSS-R) and the International Prognostic Scoring System-Molecular (IPSS-M). A control group of 45 healthy donors (HD) was also included. The levels of various cytokines (sST2, IL-33, IL-2Rα, IL-6, IL-15) were measured using ELISA. Result: Our study revealed that sST2 levels in MDS patients were significantly higher compared to HD (22.18 vs. 12.43 ng/ml, p = 0.0313), with no significant difference between low and high-risk groups. The Receiver Operating Characteristic (ROC) curve analysis showed an Area Under the Curve (AUC) of 0.6140 for sST2 (p = 0.0315, 95%CI 0.5199-0.7081). Using the maximum Youden index, the optimal cut-off value for sST2 (&amp;gt;14.71 ng/ml) was determined with a sensitivity and specificity of 51.69% and 73.33%, respectively. Progressive events include conversion to leukemia(n=8), transfusion-dependent occurrence(n=1) and death (n=29). Patients with higher sST2 levels in both high and low-risk groups demonstrated poorer Event-Free Survival (EFS) (p = 0.0193) and Overall Survival (OS) (p = 0.0130) (Figure 1). Further, multivariate analysis identified cytokine sST2(HR = 0.337, 95%CI 0.163-0.696, P=0.003), blast percentage(HR = 0.472, 95%CI 0.237-0.940, P = 0.033), and transfusion dependence(HR = 0.367, 95%CI 0.179-0.753, P = 0.006) as independent risk factors, indicating sST2's potential in predicting prognosis and adverse event risk in MDS patients. Furthermore, sST2 exhibited a significant correlation with other inflammatory cytokines (IL-2Rα, r = 0.4152, p = 0.0005; IL-6, r = 0.4897, p = 0.0013; IL-15, r = 0.3535, p = 0.0253). This suggests that sST2 plays an active role in immune system activation and chronic inflammation. Multiple attempts to detect IL-33 expression in the serum of MDS patients were unsuccessful, indicating the need for a more sensitive and specific assay. In our study, no statistically significant difference was observed in the level of sST2 between bone marrow and peripheral blood (P=0.2197), as well as before treatment and after chemotherapy (P=0.3965). These findings indicate that sST2 is an easily detectable and relatively stable indicator. Conclusions: sST2 emerges as a significant, independent negative prognostic factor at the time of MDS diagnosis, offering valuable predictive insights into disease progression and a poor prognosis.

Correlation and utility of the changes in sST2 level at clinician determined decompensation and recompensation

Abstract Introduction Soluble Suppressor of Tumorigenicity 2 (sST2) biomarker has been shown to demonstrate prognostic capabilities in patients with heart failure (HF), with serial measurements of sST2 at pre-determined time intervals providing additional predictive value for adverse outcomes. We sought to evaluate what level of sST2 level change, at clinician determined decompensation and recompensation during an acute admission for decompensated HF, could provide prognostic information for adverse outcomes. Methods Between January 2020 and February 2022, consecutive patients hospitalized at a secondary care hospital had sST2 measured within 24 hours of decompensated HF admission and following recompensation assessed by qualified clinicians, as part of the INST2ANT-HF study. sST2 samples were batched analysed at the end of recruitment period with a quantitative turbidimetric immunoassay. The primary outcome was the interval change between admission and discharge sST2 in patients admitted with decompensated heart failure. Related-samples Wilcoxon signed rank test was performed to evaluate for difference in sST2 at decompensation and recompensation. Comparison of median sST2 change was made using independent samples median test comparing alive and deceased patients at one year follow up. Results In 162 consecutive patients with paired samples, median age was 71 (IQR 61-80). 23.5% were female and 34% had an ischaemic aetiology. 94.4% presented with NYHA class III and IV and median ejection fraction was 26% (IQR 17-32). Median length of stay in hospital was 8 (IQR 5-13) days. Median levels of sST2 at decompensation and recompensation were 60.5 and 39.5ng/ml respectively (p&amp;lt;0.001) (Fig.1a). In patients who died within the first year, median levels of sST2, at decompensation and following recompensation, were significantly higher than in patients who were alive. (decompensation sST2 83 vs 56ng/ml; p = 0.007 and recompensation sST2 58 vs 34ng/ml; p = 0.036) (Fig. 1b). There was however no significant difference in the absolute or percentage change in sST2 level between those who died and those who survived (19.5 vs 16ng/ml, p= 0.437; 27 vs 35%, p = 0.363). Conclusion Our initial data demonstrates that in a cohort of patients admitted with acute decompensated HF, there was a significant difference in sST2 levels between clinician determined decompensation and recompensation. Higher levels of sST2 at both decompensation and recompensation were associated with a higher risk of mortality at one year. Utilizing newer biomarkers such as sST2 to predict outcomes may allow better risk stratification and identifying patients needing closer follow up. More research is needed however to determine what values would be useful in clinical practice.Figure 1Figure 2

Specific inflammatory profile of acute ischemic stroke patients with left atrial enlargement.

The inflammatory process underlying atrial myopathy may affect the inflammatory response activated in acute ischemic stroke (AIS). We aimed to assess whether left atrial enlargement (LAE) as a marker of atrial myopathy is associated with a different profile of circulating inflammatory markers in AIS patients. HIBISCUS-STROKE is a cohort study including anterior circulation AIS patients treated with mechanical thrombectomy following MRI. Ten circulating inflammatory markers were measured at admission and 6, 24, and 48 h after admission. LAE was defined as a left atrial volume index (LAVi) ≥34 ml/m2. A multiple logistic regression model was performed to detect an independent association between the area under the curve (AUC) of these markers and LAE. We included 143 patients. Of them, 85 (59.4%) had LAE. On univariable analysis, we found that patients with LAE had higher soluble form suppression of tumorigenicity 2 (sST2), soluble tumor necrosis factor receptor I (sTNFR1), and vascular cellular adhesion molecule-1 (VCAM-1) AUC, were older, mostly female, had a higher National Institutes of Health Stroke Scale (NIHSS) score and blood glucose level at admission, had more often hypertension, and a cardioembolic source of AIS, such as atrial fibrillation, while they were less frequently current smokers and had a lower rate of tandem occlusion than patients without LAE. On multivariable analysis, we found that among circulating inflammatory markers, only high VCAM-1 (OR: 9.13, 95% CI: 3.21-25.9) and sST2 (OR: 3.40, 95% CI: 1.68-6.86) AUC remained associated with LAE. High VCAM-1 and sST2 levels within the first 48 h are associated with LAE in AIS patients.

Soluble ST2 in Patients with Carotid Artery Stenosis-Association with Plaque Morphology and Long-Term Outcome.

Interleukin (IL-33) and the ST2 receptor are implicated in the pathogenesis of atherosclerosis. Soluble ST2 (sST2), which negatively regulates IL-33 signaling, is an established biomarker in coronary artery disease and heart failure. Here we aimed to investigate the association of sST2 with carotid atherosclerotic plaque morphology, symptom presentation, and the prognostic value of sST2 in patients undergoing carotid endarterectomy. A total of 170 consecutive patients with high-grade asymptomatic or symptomatic carotid artery stenosis undergoing carotid endarterectomy were included in the study. The patients were followed up for 10 years, and the primary endpoint was defined as a composite of adverse cardiovascular events and cardiovascular mortality, with all-cause mortality as the secondary endpoint. The baseline sST2 showed no association with carotid plaque morphology assessed using carotid duplex ultrasound (B 0.051, 95% CI -0.145-0.248, p = 0.609), nor with modified histological AHA classification based on morphological description following surgery (B -0.032, 95% CI -0.194-0.130, p = 0.698). Furthermore, sST2 was not associated with baseline clinical symptoms (B -0.105, 95% CI -0.432-0.214, p = 0.517). On the other hand, sST2 was an independent predictor for long-term adverse cardiovascular events after adjustment for age, sex, and coronary artery disease (HR 1.4, 95% CI 1.0-2.4, p = 0.048), but not for all-cause mortality (HR 1.2, 95% CI 0.8-1.7, p = 0.301). Patients with high baseline sST2 levels had a significantly higher adverse cardiovascular event rate as compared to patients with lower sST2 (log-rank p < 0.001). Although IL-33 and ST2 play a role in the pathogenesis of atherosclerosis, sST2 is not associated with carotid plaque morphology. However, sST2 is an excellent prognostic marker for long-term adverse cardiovascular outcomes in patients with high-grade carotid artery stenosis.

Elevated Soluble Suppressor of Tumorigenicity 2 Predict Hospital Admissions Due to Major Adverse Cardiovascular Events (MACE).

The role of soluble suppression of tumorigenicity (sST2) as a biomarker in predicting clinical outcomes in patients with cardiovascular diseases (CVD) has not been fully elucidated. In this study, we sought to determine the relationship between sST2 levels and any unplanned hospital readmissions due to a major adverse cardiovascular event (MACE) within 1 year of first admission. Patients (n = 250) admitted to the cardiology unit at John Hunter Hospital were recruited. Occurrences of MACE, defined as the composite of total death, myocardial infarction (MI), stroke, readmissions for heart failure (HF), or coronary revascularization, were recorded after 30, 90, 180, and 365 days of first admission. On univariate analysis, patients with atrial fibrillation (AF) and HF had significantly higher sST2 levels vs. those who did not. Increasing levels of sST2 by quartiles were significantly associated with AF, HF, older age, low hemoglobin, low eGFR, and high CRP levels. On multivariate analysis: high sST2 levels and diabetes remained as risk predictors of any MACE occurrence; an sST2 level in the highest quartile (Q4: >28.4 ng/mL) was independently associated with older age, use of beta-blockers, and number of MACE events within a 1 year period. In this patient cohort, elevated sST2 levels are associated with unplanned hospital admission due to MACE within 1 year, independent of the nature of the index cardiovascular admission.

Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition.

Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson's disease (PD). Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

Los niveles de ST2 soluble están relacionados con la fibrosis miocárdica de sustitución en la estenosis aórtica grave

Introduction and objectivesPatients with aortic stenosis (AS) exhibit left ventricular (LV) remodeling and replacement myocardial fibrosis (RMF). Whether sST2 is associated with RMF measured by cardiac magnetic resonance and with sex remains unknown. MethodsWe recruited 79 consecutive patients (73.0 [68.0-78.0] years; 61% men) with severe isolated AS underdoing valve replacement. RMF was identified and quantified by late gadolinium enhancement (LGE). Serum sST2 levels were determined. ResultsRMF was associated with higher circulating sST2 levels, LV hypertrophy and dilation, and lower LV ejection fraction. All patients with LV dysfunction had RMF. Circulating levels of sST2 ≥ 28.8 ng/mL were associated with RMF and greater LV hypertrophy. LGE mass was correlated with LV remodeling and sST2. Of note, sST2 levels were also associated with the RMF pattern, being higher in midwall than in subendocardial fibrosis. Multivariate analyses showed that only LV ejection fraction and sST2 levels were associated with RMF. Moreover, men had higher levels of sST2 and RMF. RMF was associated with higher LV dilation and hypertrophy only in men and was correlated with LGE mass. ConclusionsSST2 was an independent factor for RMF in patients with severe isolated AS. The presence of RMF was predicted by sST2 ≥ 28.2 ng/mL, and was associated with greater LV hypertrophy. sST2 expression and clinical associations may be sex-specific.

A new model for predicting adverse outcomes in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive disease leading to ventricular arrhythmias and heart failure. Determining optimal time for heart transplantation (HTx) is challenging; therefore, it is necessary to identify risk factors for disease progression. The study aimed to identify predictors of end‑stage heart failure and to evaluate the role of biomarkers in predicting adverse outcomes in ARVC. A total of 91 individuals with ARVC (59 men; mean [SD] age, 47 [16] years) were included. In all patients, information on medical history was collected, electrocardiography and echocardiography were performed, and serum levels of selected biomarkers (soluble form of the ST2 protein [sST2], galectin‑3 [Gal‑3], extracellular matrix metalloproteinases [MMP‑2 and MMP‑9], N‑terminal pro-B‑type natriuretic peptide [NT‑proBNP], and high‑sensitivity troponin T [hs‑TnT]) were measured. Thereafter, the participants were followed for the primary end point of death or HTx, as well as the secondary end point of major arrhythmic events (MAEs), defined as sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, or appropriate implantable cardioverter‑defibrillator intervention. During the median (interquartile range) follow‑up of 36.4 (29.8-41.2) months, 13 patients (14%) reached the primary end point of death or HTx, and 27 (30%) experienced MAEs. The patients who achieved the primary end point had higher levels of sST2, MMP‑2, NT‑proBNP, and hs‑TnT, but not of Gal-3 and MMP-9. Three factors turned out to be independent predictors of death or HTx: higher NT‑proBNP concentration (≥890.3 pg/ml), greater right ventricular end‑diastolic area (≥39 cm2), and a history of atrial tachycardia. None of the biomarkers predicted MAEs. An NT‑proBNP concentration greater than or equal to 890.3 pg/ml, right ventricular end-diastolic area of 39 cm2 or greater, and a history of atrial tachycardia were identified as risk factors for death or HTx in ARVC. Higher levels of sST2, MMP‑2, NT‑proBNP, and hs‑TnT were associated with reaching the primary end point of death or HTx. The biomarkers had no value in predicting ventricular arrhythmias.

Biomarker sST2 in Adults with Transposition of the Great Arteries Palliated by Mustard Procedure: A Five-Year Follow-up.

The Mustard procedure was an early cardiac surgery for transposition of the great arteries (TGA). Despite being successful, it has been associated with long-term arrhythmias and heart failure. A key factor complicating management in adults with congenital heart disease (CHD) is the deficiency of biomarkers predicting outcome. Soluble suppression of tumorogenicity-2 (sST2) is secreted by cardiomyocytes in response to mechanical strain and fibrosis. We hypothesized that adults with a Mustard procedure would have higher levels of sST2 than healthy individuals, and this would correlate with clinical outcome. We performed a single-center study in patients managed during childhood with a Mustard procedure versus age-matched controls. Clinical and demographic data were collected and biomarkers (sST2, cTnI, BNP, lipid panel, insulin, and glucose) were obtained. There were 18 patients (12 male) in the Mustard cohort and 18 patients (6 male) in the control group (22-49years, mean of 35.8 vs. mean 32.6years, respectively, p = ns). Nine Mustard subjects were NYHA class II, and 9 subjects were class III. The control group was asymptomatic. sST2 in the Mustard group was elevated in 56% vs. 17% in controls (p = 0.035). Of the Mustard subjects with elevated sST2, 60% had elevated cTnI and BNP, and 90% had low HDL. Over five years, the Mustard patients with elevated sST2 values had greater medication use, arrhythmias, hospitalizations, and ablation/pacer implantations than Mustard subjects with normal sST2. Mustard subjects with elevated sST2 had other biomarker abnormalities and clinically worse outcomes. Thus, sST2 may add a predictive value to cardiac-related morbidity and mortality.

Sex and age differences in sST2 in cardiovascular disease.

The goal of this study was to determine whether sex and age differences exist for soluble ST2 (sST2) for several cardiovascular diseases (CVDs). We examined sST2 levels using an ELISA kit for myocarditis (n = 303), cardiomyopathy (n = 293), coronary artery disease (CAD) (n = 239), myocardial infarct (MI) (n = 159), and congestive heart failure (CHF) (n = 286) and compared them to controls that did not have CVDs (n = 234). Myocarditis occurred in this study in relatively young patients around age 40 while the other CVDs occurred more often in older individuals around age 60. We observed a sex difference in sST2 by age only in myocarditis patients (men aged 38, women 46, p = 0.0002), but not for other CVDs. Sera sST2 levels were significantly elevated compared to age-matched controls for all CVDs: myocarditis (p ≤ 0.0001), cardiomyopathy (p = 0.0009), CAD (p = 0.03), MI (p = 0.034), and CHF (p < 0.0001) driven by elevated sST2 levels in females for all CVDs except myocarditis, which was elevated in both females (p = 0.002) and males (p ≤ 0.0001). Sex differences in sST2 levels were found for myocarditis and cardiomyopathy but no other CVDs and were higher in males (myocarditis p = 0.0035; cardiomyopathy p = 0.0047). sST2 levels were higher in women with myocarditis over 50 years of age compared to men (p = 0.0004) or women under 50 years of age (p = 0.015). In cardiomyopathy and MI patients, men over 50 had significantly higher levels of sST2 than women (p = 0.012 and p = 0.043, respectively) but sex and age differences were not detected in other CVDs. However, women with cardiomyopathy that experienced early menopause had higher sST2 levels than those who underwent menopause at a natural age range (p = 0.02). We found that sex and age differences in sera sST2 exist for myocarditis, cardiomyopathy, and MI, but were not observed in other CVDs including CAD and CHF. These initial findings in patients with self-reported CVDs indicate that more research is needed into sex and age differences in sST2 levels in individual CVDs.

Soluble ST2 levels are related to replacement myocardial fibrosis in severe aortic stenosis

Introduction and objectivesPatients with aortic stenosis (AS) exhibit left ventricular (LV) remodeling and replacement myocardial fibrosis (RMF). Whether sST2 is associated with RMF measured by cardiac magnetic resonance and with sex remains unknown. MethodsWe recruited 79 consecutive patients (73.0 [68.0-78.0] years; 61% men) with severe isolated AS underdoing valve replacement. RMF was identified and quantified by late gadolinium enhancement (LGE). Serum sST2 levels were determined. ResultsRMF was associated with higher circulating sST2 levels, LV hypertrophy and dilation, and lower LV ejection fraction. All patients with LV dysfunction had RMF. Circulating levels of sST2 ≥ 28.8 ng/mL were associated with RMF and greater LV hypertrophy. LGE mass was correlated with LV remodeling and sST2. Of note, sST2 levels were also associated with the RMF pattern, being higher in midwall than in subendocardial fibrosis. Multivariate analyses showed that only LV ejection fraction and sST2 levels were associated with RMF. Moreover, men had higher levels of sST2 and RMF. RMF was associated with higher LV dilation and hypertrophy only in men and was correlated with LGE mass. ConclusionsSST2 was an independent factor for RMF in patients with severe isolated AS. The presence of RMF was predicted by sST2 ≥ 28.2 ng/mL, and was associated with greater LV hypertrophy. sST2 expression and clinical associations may be sex-specific.

Impact of multiple substance use on circulating ST2, a biomarker of adverse cardiac remodelling, in women

ABSTRACT Context Cardiovascular disease (CVD) and heart failure (HF) are major causes of mortality in low-income populations and differ by sex. Risk assessment that incorporates cardiac biomarkers is common. However, research evaluating the utility of biomarkers rarely includes controlled substances, which may influence biomarker levels and thus influence CVD risk assessment. Materials and Methods We identified the effects of multiple substances on soluble “suppression of tumorigenicity 2” (sST2), a biomarker of adverse cardiac remodelling, in 245 low-income women. Adjusting for CVD risk factors, we examined associations between substance use and sST2 over six monthly visits. Results Median age was 53 years and 74% of participants were ethnic minority women. An sST2 level > 35 ng/mL (suggesting cardiac remodelling) during ≥1 study visit was observed in 44% of participants. In adjusted analysis, higher sST2 levels were significantly and positively associated with the presence of cocaine (Adjusted Linear Effect [ALE]:1.10; 95% CI:1.03-1.19), alcohol (ALE:1.10; 95% CI:1.04-1.17), heroin (ALE:1.25; 95% CI:1.10-1.43), and the interaction between heroin and fentanyl use. Conclusion Results suggest that the use of multiple substances influences the level of sST2, a biomarker often used to evaluate cardiovascular risk. Incorporating substance use alongside cardiac biomarkers may improve CVD risk assessment in vulnerable women.

Association of Blood Biomarkers of Inflammation With Penumbra Consumption After Mechanical Thrombectomy in Patients With Acute Ischemic Stroke.

The objective of this study was to assess the relationship between blood biomarkers of inflammation and lesion growth within the penumbra in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). The HIBISCUS-STROKE cohort enrolled patients admitted in the Lyon Stroke Center for an anterior circulation AIS treated with MT after brain MRI assessment. Lesion growth within the penumbra was assessed on day 6 MRI using a voxel-based nonlinear coregistration method and dichotomized into low and high according to the median value. C-reactive protein, interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1, soluble tumor necrosis factor receptor I, soluble form suppression of tumorigenicity 2 (sST2), soluble P-selectin, vascular cellular adhesion molecule-1, and matrix metalloproteinase-9 were measured in sera at 4 time points within the first 48 hours. Reperfusion was considered as successful if Thrombolysis in Cerebral Infarction score was 2b/2c/3. A multiple logistic regression model was performed to detect any association between area under the curve (AUC) of these biomarkers within the first 48 hours and a high lesion growth within the penumbra. Ninety patients were included. The median lesion growth within the penumbra was 2.3 (0.7-6.2) mL. On multivariable analysis, a high sST2 AUC (OR 3.77, 95% CI 1.36-10.46), a high baseline DWI volume (OR 3.65, 95% CI 1.32-10.12), and a lack of successful reperfusion (OR 0.19, 95% CI 0.04-0.92) were associated with a high lesion growth within the penumbra. When restricting analyses to patients with successful reperfusion (n = 76), a high sST2 AUC (OR 5.03, 95% CI 1.64-15.40), a high baseline DWI volume (OR 3.74, 95% CI 1.22-11.53), and a high penumbra volume (OR 3.25, 95% CI 1.10-9.57) remained associated with a high lesion growth within the penumbra. High sST2 levels within the first 48 hours are associated with a high lesion growth within the penumbra.

Serum Soluble ST2 Is a Valuable Prognostic Biomarker in Patients With Acute Heart Failure.

BackgroundThis study aimed to investigate the clinical utility of different soluble suppression of tumorigenicity 2 (sST2) levels in assessing the severity and prognosis of patients with acute heart failure (AHF).MethodsThis was a prospective cohort study. Three hundred and thirty-one consecutively enrolled AHF patients from March 2018 to November 2019 were divided into 3 subgroups according to sST2 levels: T1 (1.15–7.70 ng/ml; N = 110), T2 (7.71–17.24 ng/ml; N = 111), and T3 (17.26–47.42 ng/ml; N = 110). The patients were followed up for a median period of 21.0 months for the development of the primary endpoint. Cox proportional hazards model was performed to evaluate the prognostic value of sST2 for the clinical outcomes.ResultsThe mean age of patients was 69 years (range, 34–93 years), and 70.4% were male. During the follow-up period, 63 participants died. Patients with higher sST2 levels had lower left ventricular ejection fraction (correlation = −0.119, P = 0.031), and higher New York Heart Association classification (correlation = 0.443, P < 0.001) and N-terminal pro-B type natriuretic peptide (NT-proBNP) levels (correlation = 0.392, P < 0.001). Higher sST2 was also associated with creatinine, urea nitrogen, hemoglobin, and left ventricular mass index. Multivariate analysis revealed that sST2 (per log unit, hazard ratio: 2.174, 95% confidence interval [CI] 1.012–4.67, P = 0.047) and NT-proBNP (per log unit, HR 2.171, 95%CI 1.169–4.032, P < 0.001) were independent risk factors for the primary outcome in all patients with AHF.ConclusionsST2 can provide prognostic information in AHF. The higher the sST2 level in patients with AHF, the higher the incidence of cardiovascular death.

The prognostic value of sST2 in connective tissue disease patients with pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a severe complication of CTD, being one of the leading causes of mortality for patients with this condition. Soluble suppression of tumorigenicity 2 (sST2) is a novel biomarker associated with adverse clinical outcomes in cardiovascular patients. In this study, we investigated the role of sST2 as a predictor of poor clinical outcome in patients with CTD associated with pulmonary hypertension (CTD-PH). This retrospective cohort study enrolled 71 CTD-PH patients diagnosed by echocardiography. Twenty-one CTD patients without PH were selected for a control group. A receiver operating characteristic (ROC) curve assessed the predictive value of sST2 in assessing 3-year clinical worsening. Hazard ratios associated with potential predictors of clinical worsening were estimated using Cox proportional hazard models. The primary end point was clinical worsening. The level of sST2 was significantly elevated in CTD-PH patients compared with the control group. After a mean follow-up of 25.29 (1.88) months, end point events occurred in 26 patients. sST2 was an independent predictor of clinical worsening and all-cause death in patients with CTD-PH. sST2 ≥ 39.99 ng/ml discriminated 3-year clinical worsening with a sensitivity and specificity of 100% and 84.9%, respectively. The patients with both higher levels of sST2 (≥39.99 ng/ml) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (≥300 ng/l) had the worst prognosis. sST2 ≥ 39.99 ng/ml predicts higher incidence of clinical worsening events in CTD-PH patients. Furthermore, patients with elevated sST2 had significantly worse prognosis among those with high NT-proBNP.

Role of the IL-33/ST2 axis in cardiovascular disease: A systematic review and meta-analysis.

Interleukin (IL)-33 and its unique receptor, ST2, play a pivotal role in the immune response to infection and stress. However, there have been conflicting reports of the role of IL-33 in cardiovascular disease (CVD) and the potential of this axis in differentiating CVD patients and controls and with CVD disease severity, remains unclear.Aims1) To quantify differences in circulating IL-33 and/or sST2 levels between CVD patients versus controls. 2) Determine association of these biomarkers with mortality in CVD and community cohorts.Methods and resultsUsing Pubmed/MEDLINE, Web of Science, Prospero and Cochrane databases, systematic review of studies published on IL-33 and/or sST2 levels in patients with CVD (heart failure, acute coronary syndrome, atrial fibrillation, stroke, coronary artery disease and hypertension) vs controls, and in cohorts of each CVD subtype was performed. Pooled standardised mean difference (SMD) of biomarker levels between CVD-cases versus controls and hazard ratios (HRs) for risk of mortality during follow-up in CVD patients, were assessed by random effects meta-analyses. Heterogeneity was evaluated with random-effects meta-regressions. From 1071 studies screened, 77 were meta-analysed. IL-33 levels were lower in HF and CAD patients vs controls, however levels were higher in stroke patients compared controls [Meta-SMD 1.455, 95% CI 0.372–2.537; p = 0.008, I2 = 97.645]. Soluble ST2 had a stronger association with risk of all-cause mortality in ACS (Meta-multivariate HR 2.207, 95% CI 1.160–4.198; p = 0.016, I2 = 95.661) than risk of all-cause mortality in HF (Meta-multivariate HR 1.425, 95% CI 1.268–1.601; p<0.0001, I2 = 92.276). There were insufficient data to examine the association of IL-33 with clinical outcomes in CVD.ConclusionsIL-33 and sST2 levels differ between CVD patients and controls. Higher levels of sST2 are associated with increased mortality in individuals with CVD. Further study of IL-33/ST2 in cardiovascular studies is essential to progress diagnostic and therapeutic advances related to IL-33/ST2 signalling.