Diagnostic potential of soluble ST2 and D-dimer for Stanford Type B aortic dissection and intramural aortic hematoma.

OBJECTIVE: Type B aortic dissection (TBAD) and intramural aortic hematoma (IMH) are common manifestations of Acute Aortic Syndrome (AAS), exhibiting overlapping clinical features. The timely and accurate diagnosis and differentiation between TBAD and IMH are critical for appropriate management. Tumorigenicity 2 (sST2) and D-dimer have been shown to elevate levels in both TBAD and IMH, making them valuable as "rule-out" markers. Hence, we aimed to assess the diagnostic utility of sST2 and D-dimer in distinguishing TBAD from IMH. METHODS: In this retrospective study, we analyzed serum levels of sST2 and D-dimer in 182 AAS patients, comprising 90 TBAD cases, 92 IMH cases, and 90 non-AAS cases. Serial measurements were taken at 1 h, 6 h, 12 h, 24 h, and 72 h post-admission. Comparative analyses were conducted between TBAD and non-AAS cases, IMH and non-AAS cases, and TBAD and IMH cases. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of sST2 and D-dimer in identifying TBAD or IMH cases. RESULTS: Both TBAD and IMH patients displayed elevated levels of sST2 and D-dimer compared to non-AAS cases. Notably, sST2 levels were significantly higher in TBAD patients than in IMH patients, whereas D-dimer levels exhibited moderate differences. TBAD patients tended to exhibit elevated levels of either sST2 or D-dimer, with a modest correlation between the two (Pearson correlation coefficient = 0.3614). In contrast, IMH patients showed elevations in both markers, with a positive correlation between them (Pearson correlation coefficient = 0.6814). The ROC analysis revealed that both sST2 (AUC, 0.657; 95 % CI, 0.552-0.753; cutoff value, 27.54 ng/ml) and D-dimer (AUC, 0.695; 95 % CI, 0.591-0.787, cutoff value, 1.215 ng/ml) demonstrated favorable diagnostic performance for TBAD. sST2 exhibited a sensitivity of 80.92 % and a specificity of 75.00 %, while D-dimer showed a sensitivity of 80.92 % and a specificity of 75.00 %. For the diagnosis of IMH, the combined assessment of sST2 and D-dimer (AUC, 0.674; 95 % CI, 0.599-0.768; sensitivity, 69.20 %; specificity, 80.00 %) proved effective. CONCLUSIONS: Our results indicate that both sST2 and D-dimer show diagnostic potential for TBAD. Elevated levels of either serve as an indicator of TBAD onset. However, concurrent elevation of both markers seems to be indicative of IMH. The combination of increased sST2 and D-dimer levels demonstrates strong diagnostic performance in identifying IMH cases.

Serum interleukin-33 and soluble suppression of tumorigenicity 2 in pediatric leukemia with febrile neutropenia.

The purpose of this study was to evaluate the association between interleukin-33 (IL-33) and its receptor Soluble Suppression of Tumorigenicity-2 (sST2) levels and bacterial infections during febrile neutropenia (FN) in pediatric patients with acute lymphoblastic leukemia (ALL). In this prospective, case-control study, participants were divided into 3 groups: ALL patients with FN (Group A), ALL patients without neutropenia and fever (Group B), and healthy children without infection and chronic disease (Group C). There were 30 cases in each group. Blood samples for IL-33 and sST2 have been drawn from patients in Group A before the initiation of treatment and on days 1 and 5 of treatment, and from patients in Groups B and C at initiation. At admission, mean IL-33 level (39.02 ± 26.40 ng/L) in Group B and mean sST2 level (185.3 ± 371.49 ng/ml) in Group A were significantly higher than the other groups (p = 0.038, p < 0.001, respectively). No difference was observed in the mean IL-33 and sST2 levels in the 5-day follow-up of patients in Group A (p = 0.82, p = 0.86, respectively). IL-33 and sST2 levels were not associated with fever duration, neutropenia duration or length of hospitalization. While C-reactive protein (CRP) was significantly higher in patients with positive blood culture (p = 0.021), IL-33 (p = 0.49) and sST2 (p = 0.21) levels were not associated with culture positivity.  Conclusion: IL-33 and sST2 levels were not found valuable as diagnostic and prognostic markers to predict bacterial sepsis in patients with FN. What is Known: • Neutropenic patients are at high risk of serious bacterial and viral infections, but the admission symptom is often only fever. • Febrile neutropenia has a high mortality rate if not treated effectively. What is New: • Febrile neutropenia is not only caused by bacterial infections. Therefore, new biomarkers should be identified to prevent overuse of antibiotics. • Specific biomarkers are needed to diagnose bacterial sepsis in the early phase of febrile neutropenia.

Performance Evaluation of AFIAS ST2 and Ichroma ST2 Assays in Comparison with Presage ST2 Assay.

Background: Elevated soluble suppression of tumorigenicity 2 (sST2) levels may predict mortality in heart failure (HF) patients. The AFIAS ST2 assay (AFIAS ST2, Boditech Med Inc., Chuncheon, Korea) and ichroma ST2 assay (ichroma ST2, Boditech Med Inc.) are newly developed point-of-care (POC) assays for measuring sST2 level. We evaluated the performance of these assays, in terms of cut-off validation and prognosis, and compared them with that of the Presage ST2 assay (Presage ST2, Critical Diagnostics, San Diego, CA, USA). Methods: We validated the US FDA-claimed sST2 clinical cut-off of 35 ng/mL using 420 serum samples (298 samples from the universal sample bank of the American Association for Clinical Chemistry and 122 samples from reference individuals from Konkuk University Medical Center). We compared AFIAS ST2 and ichroma ST2 with Presage ST2, using 206 samples from patients with HF. We assessed prognosis using the three assays in 252 samples from the Barcelona ambulatory HF cohort subsets. Results: The upper reference limits of AFIAS ST2 and ichroma ST2 were within the clinical cut-off of Presage ST2. The results of AFIAS ST2 and ichroma ST2 were highly correlated with those of Presage ST2 (r = 0.82 and 0.81, respectively). Based on this cut-off, all three assays predicted cardiovascular death. Conclusions: The new POC assays, AFIAS ST2 and ichroma ST2, would be useful in clinical practice for managing HF patients, with performances equivalent to that of Presage ST2.

Circulating Gal-3 and sST2 are associated with acute exercise-induced sustained endothelial activation: Possible relevance for fibrosis development?

Long-term, intense endurance exercise training can occasionally induce endothelial micro-damage and cardiac fibrosis. The underlying mechanisms are incompletely understood. Twenty healthy, well-trained male participants (10 runners and 10 cyclists) performed a strenuous high-intensity interval training (HIIT) session matched by age, height, weight and maximal oxygen consumption. We assessed the acute exercise response of novel cardiac biomarkers of fibrosis [e.g., galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2)] per exercise modality and their relationship with haemodynamic contributors, such as preload, afterload and cardiac contractility index (CTi), in addition to endothelial damage by sustained activation and shedding of endothelial cells (ECs). Serum Gal-3 and sST2 concentrations were investigated by enzyme-linked immunosorbent assays; haemodynamics were analysed via impedance plethysmography and circulating ECs by flow cytometry. The Gal-3 and sST2 concentrations and ECs were elevated after exercise (P < 0.001), without interaction between exercise modalities. Circulating Gal-3 and sST2 concentrations both showed a positive relationship with ECs (rrm  = 0.68, P = 0.001 and rrm  = 0.57, P = 0.010, respectively, both n = 18). The EC association with Gal-3 was significant only in cyclists, but equally strong for both modalities. Gal-3 was also related to exercise-induced CTi (rrm  = 0.57, P = 0.011, n = 18). Cardiac wall stress is increased after an acute HIIT session but does not differ between exercise modalities. Exercise-released Gal-3 from cardiac macrophages could very probably drive systemic endothelial damage, based on an enhanced CTi. The importance of acute exercise-induced vascular resistances and cardiac contractility for the release of fibrotic biomarkers and any long-term pathological endothelial adaptation should be investigated further, also relative to the exercise modality. NEW FINDINGS: What is the central question of this study? Circulating biomarkers of cardiac wall stress and fibrosis are influenced by physical exercise. The underlying mechanisms per exercise modality are still unclear. What is the main finding and its importance? We show that galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2) are increased after acute exercise but do not differ between running and cycling. One haemodynamic contributor to the secretion of Gal-3 is an enhanced cardiac contractility. Acute exercise-released Gal-3 and sST2 are linked to sustained endothelial activation and cell shedding. This could be relevant in the context of fibrosis development and could identify athletes at risk for pathological endothelial adaptations.

The Interleukin-33/ST2 Axis Enhances Lung-Resident CD14+ Monocyte Function in Patients with Non-Small Cell Lung Cancer.

Interleukin-33 (IL-33) binds to its cognate receptor suppression of tumorigenicity 2 (ST2), leading to critical modulatory roles in immune responses during inflammation and cancers. The aim of this study was to investigate the role of IL-33/ST2 signaling in monocyte function in non-small cell lung cancer (NSCLC). Sixty-two NSCLC patients and nineteen controls were enrolled. IL-33 levels and ST2 expression were measured in peripheral blood and bronchoalveolar lavage fluid (BALF) by ELISA and flow cytometry. HLA-DR expression by CD14+ monocytes, granzyme B and proinflammatory cytokine secretion were also investigated in lipopolysaccharide-stimulated cells. CD14+ monocytes purified from BALF in the tumor site were stimulated with IL-33 in vitro, and co-cultured with a lung cancer cell line A549 cells. The cytotoxicity of monocytes with IL-33 stimulation was then assessed. IL-33 levels were lower in the peripheral blood and tumor microenvironment of NSCLC patients. There was no significant difference in peripheral ST2 expression between NSCLC patients and controls. Soluble ST2 levels were increased but membrane-bound ST2 expression in CD14+ monocytes was decreased in tumor microenvironment of NSCLC patients. There were no remarkable differences in either HLA-DR expression or proinflammatory cytokine secretion by circulating CD14+ monocytes between NSCLC patients and controls. CD14+ monocytes in the tumor microenvironment revealed a dysfunctional phenotype, which presented as lower HLA-DR expression and reduced granzyme B and proinflammatory cytokines. A higher concentration of IL-33 stimulation promoted tumor-resident CD14+ monocyte-induced target cell death. The present study indicates that IL-33/ST2 signaling pathway might enhance the activity of tumor-resident CD14+ monocytes in NSCLC.

sST2 Levels Show No Association with Helicobacter pylori Infection in Asymptomatic Patients: Implications for Biomarker Research.

INTRODUCTION: Helicobacter pylori (H. pylori) is a prevalent stomach bacterium that can cause a range of clinical outcomes, including gastric cancer. In recent years, soluble suppression of tumorigenicity-2 (sST2) has gained attention as a biomarker associated with various diseases, such as gastric cancer. The purpose of this study was to explore the possible connection between H. pylori infection and sST2 levels in patients who do not exhibit symptoms. METHODS: A total of 694 patients from the Salzburg Colon Cancer Prevention Initiative (Sakkopi) were included in the study. The prevalence of H. pylori infection was determined by histology, and sST2 levels were measured in serum samples. Clinical and laboratory parameters, such as age, sex, BMI, smoking status, hypertension, and metabolic syndrome, were also collected. RESULTS: The median sST2 concentration was similar between patients with (9.62; 7.18-13.44 ng/mL; p = 0.66) and without (9.67; 7.08-13.06 ng/mL) H. pylori. Logistic regression analysis did not show any association (OR 1.00; 95%CI 0.97-1.04; p = 0.93) between sST2 levels and H. pylori infection, which remained so (aOR 0.99; 95%CI 0.95-1.03; p = 0.60) after adjustment for age, sex, educational status, and metabolic syndrome. In addition, sensitivity analyses stratified by age, sex, BMI, smoking status, educational status, and the concomitant diagnosis of metabolic syndrome could not show any association between sST2 levels and H. pylori infection. CONCLUSION: The results indicate that sST2 may not serve as a valuable biomarker in the diagnosis and treatment of H. pylori infection. Our findings are of relevance for further research investigating sST2, as we could not find an influence of asymptomatic H. pylori infection on sST2 concentration. WHAT IS ALREADY KNOWN?: Soluble suppression of tumorigenicity-2 (sST2) has gained attention as a biomarker associated with various diseases, such as gastric cancer. WHAT IS NEW IN THIS STUDY?: The median sST2 concentration was similar between patients with (9.62; 7.18-13.44 ng/mL; p = 0.66) and without (9.67; 7.08-13.06 ng/mL) H. pylori. WHAT ARE THE FUTURE CLINICAL AND RESEARCH IMPLICATIONS OF THE STUDY FINDINGS?: The results indicate that sST2 may not serve as a valuable biomarker in the diagnosis and treatment of H. pylori infection.

Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor.

BACKGROUND: The cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy. METHODS: We administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice. RESULTS: BAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19+ B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33-treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33-stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)-depleted splenocytes. Wild-type mice infused with IL-33-treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution. CONCLUSIONS: IL-33-expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.

Serum-soluble suppression of tumourigenicity-2 as a biomarker in children with congestive heart failure.

BACKGROUND: We aimed to evaluate serum soluble suppression of tumorigenicity-2 in children with congestive heart failure, to assess the diagnostic and prognostic values of soluble suppression of tumorigenicity-2 in these patients, and to correlate its levels with various clinical and echocardiographic data. METHODS: We included 60 children with congestive heart failure as the patient group. Sixty healthy children of matched age and sex served as the control group. Patients were evaluated clinically and by echocardiography. Serum level of suppression of tumorigenicity-2 was measured for patients at admission. All patients were followed up for death or readmission for a period of one year. RESULTS: Soluble suppression of tumorigenicity-2 was significantly higher in children with congestive heart failure as compared to the control group. Soluble suppression of tumorigenicity-2 was significantly increased in patients with higher severity of congestive heart failure. There was a significant increase in soluble suppression of tumorigenicity-2 in patients with bad prognosis compared to those with good prognosis. There was a significant positive correlation between soluble suppression of tumorigenicity-2 and respiratory rate, heart rate, and clinical stage of congenital heart failure, while there was a significant negative correlation between soluble suppression of tumorigenicity-2 and left ventricular systolic and diastolic function. The best cut-off of soluble suppression of tumorigenicity-2 to diagnose congestive heart failure was > 3.6 with 87% sensitivity and 79% specificity. The cut-off point of soluble suppression of tumorigenicity-2 to diagnose congestive heart failure in children was ≥ 31.56 ng/ml, with 95% sensitivity and 91.37% specificity. Moreover, the cut-off point of soluble suppression of tumorigenicity-2 to predict bad prognosis in children with congestive heart failure was ≥ 255.5 ng/ml, with 92% sensitivity and 89.0% specificity. CONCLUSION: Soluble suppression of tumorigenicity-2 is a good diagnostic and predictive biomarker in children with congestive heart failure.

Role of Soluble ST2 Biomarker in Predicting Recurrence of Atrial Fibrillation after Electrical Cardioversion or Pulmonary Vein Isolation.

This study aims to determine the predictive value of the soluble suppression of tumorigenicity 2 (sST2) biomarker in atrial fibrillation (AF) recurrence. This prospective, observational study included patients with AF referred for electrical cardioversion (ECV) or pulmonary vein isolation (PVI) procedures. Baseline characteristics were collected, and sST2 was determined at baseline and at 3 and 6 months of follow-up. sST2 was determined at baseline in a matched control group. Left atrial voltage mapping was performed in patients undergoing PVI. The sST2 maximal predictive capacity of AF recurrence was at the 3-month FU in the cohort of patients undergoing ECV with respect to 6-month AF recurrence with an AUC of 0.669, a cut-off point of 15,511 pg/mL, a sensitivity of 60.97%, and a specificity of 69.81%. The ROC curve of the sST2 biomarker at baseline and 3 months in the cohort of patients undergoing PVI showed AUCs of 0.539 and 0.490, respectively. The logistic regression model identified the rhythm (AF) and the sST2 biomarker at 3 months as independent factors for recurrence at 6 months in the ECV cohort. In the logistic regression model, sST2 was not an independent factor for recurrence at 6 months of follow-up in the PVI cohort. In patients who underwent ECV, sST2 values at 3 months may provide utility to predict AF recurrence at 6 months of follow-up. In patients who underwent PVI, sST2 had no value in predicting AF recurrence at 6 months of follow-up.

Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation.

With the advent of an aging society, the incidence of dementia is increasing, resulting in a vast burden on society. It is increasingly acknowledged that neuroinflammation is implicated in various neurological diseases with cognitive dysfunction such as Alzheimer's disease, multiple sclerosis, ischemic stroke, traumatic brain injury, and central nervous system infections. As an important neuroinflammatory factor, interleukin-33 (IL-33) is highly expressed in various tissues and cells in the mammalian brain, where it plays a role in the pathogenesis of a number of central nervous system conditions. Reams of previous studies have shown that IL-33 has both pro- and anti-inflammatory effects, playing dual roles in the progression of diseases linked to cognitive impairment by regulating the activation and polarization of immune cells, apoptosis, and synaptic plasticity. This article will summarize the current findings on the effects IL-33 exerts on cognitive function by regulating neuroinflammation, and attempt to explore possible therapeutic strategies for cognitive disorders based on the adverse and protective mechanisms of IL-33.

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

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Association of Soluble Suppression of Tumorigenicity 2 with New-Onset Atrial Fibrillation in Acute Myocardial Infarction.

BACKGROUND: The combination of acute myocardial infarction (AMI) and atrial fibrillation (AF) is still a thorny problem in the clinic. At present, there are few reports on the role of soluble suppression of tumorigenicity 2 (sST2) in AF after AMI. This study was to explore the predictive value of sST2 in patients with AMI for new-onset AF. METHODS: This is a single-center retrospective clinical observation study. We continuously included AMI patients from September 2019 to November 2021. The concentration of sST2 in blood samples was determined. During admission, a suspicious heart rhythm was recorded by electrocardiogram (ECG) monitoring, and new-onset AF was confirmed by immediate body surface ECG. RESULTS: After multiple factors were included, age, right coronary artery, high-sensitivity C-reactive protein, left ventricular ejection fraction, and sST2 were still risk factors for new-onset AF. The area under curve value of age and sST2 was more than 0.7, which showed good diagnostic value. For reevaluation, the sST2 was added to the clinical new-onset AF prediction model. It was found that the integrated discrimination improvement and net reclassification index in the model were improved significantly. CONCLUSION: sST2 is an independent predictor of new-onset AF in patients with AMI and can improve the accuracy of the AF risk model.

Role of the IL-33/ST2 pathway in renal allograft rejection.

The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway modulates immune response and inflammation, associated with allograft dysfunction and rejection. We hypothesized that IL-33/ST2 is a marker of renal allograft rejection and IL-33/ST2 expression may differ according to rejection type. IL-33/ST2 expression was measured in sera and kidney tissues from recipients with acute antibody-mediated rejection (AAMR), acute cell-mediated rejection (ACMR), chronic antibody-mediated rejection (CAMR), and healthy controls. The soluble ST2 and IL-33/ST2 expression levels were higher in participants with all three rejection types than in controls. Although the expression levels in recipients with AAMR and ACMR were significantly higher than those with CAMR, there was no significant difference between the expression levels in AAMR and ACMR. Although IL-33, IL-8, and fibronectin expression were significantly increased after the addition of the recipients' serum in primary cultured human renal proximal tubular epithelial cells, the levels decreased after treatment with an anti-ST2 antibody. Furthermore, the anti-ST2 antibody specifically suppressed the upregulation of the mixed lymphocyte reaction. Boyden chamber assays demonstrated that anti-ST2 antibody abrogated chemotaxis induced by recombinant IL-33. Thus, IL-33 and ST2 are potent mediators of rejection. Treatment with an anti-ST2 antibody ameliorates rejection and could be a potential therapeutic strategy for renal allograft rejection.

Serum Cardiac Biomarkers in Asymptomatic Hemodialysis Patients: Role of Soluble Suppression of Tumorigenicity-2.

INTRODUCTION: Cardiovascular events (CVE) remain the leading cause of mortality in hemodialysis (HD) patients. The ability to assess the risk of short-term CVE is of great importance. Soluble suppression of tumorogenicity-2 (sST2) is a novel biomarker that better stratifies risk of CVE than troponins in patients with heart failure. Few studies have investigated the role of sST2 in the HD population. The aim of this single-center study was to assess the predictive ability of sST2 on CVE in comparison to high-sensitive cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP) in HD patients. METHODS: This study used a prospective, observational cohort design. We enrolled 40 chronic HD patients asymptomatic for chest pain and without recent history of acute coronary syndrome. We tested sST2 pre-/post-HD, hs-cTnI, and BNP. Demographic/dialytic/echocardiographic data were evaluated. We recorded the number of CVE for 12 months. The patients were classified into 2 groups: those who developed CVE and those who did not. RESULTS: Ten of the 40 patients (25%) developed CVE during a 12-month follow-up. Increased sST2 levels (p < 0.0001) as well as hs-cTnI and BNP are predictive of CVE. When analyzing biomarkers as binary variables for values above or below the normal range, the correlation remained significant only for sST2 (p = 0.001). A small variation in sST2 levels before and after HD sessions was found (-2.1 ng/mL). sST2 was correlated with left ventricular (LV) echocardiographic data: LV mass index (p = 0.0001), LV ejection fraction (p = 0.01), and diastolic bulging of septum (p = 0.015). BNP and sST2 combination increased the prediction of CVE in a statistical model. CONCLUSION: Our study confirms that sST2 is useful for stratifying CV risk in the HD population. sST2 can be evaluated simply as a dichotomous value higher or lower than the normal range, making it easily interpretable. Dialysis and residual diuresis did not affect significantly sST2. A multimarker approach that incorporates sST2 and BNP may improve the prediction of CVE.

Diagnostic efficacy of serum ST2 in patients with ASC.

BACKGROUND: Soluble suppression of tumorigenicity 2 (ST2) is closely related to the development of cardiovascular disease, but the level of acute coronary syndrome (ACS) and the relationship between ST2 and ACS are unclear. PATIENTS AND METHODS: Patients with the acute coronary syndrome were divided into the unstable angina pectoris (USAP) group (n = 65) and non-ST-segment elevation myocardial infarction (NSTEMI) group (n = 58), and the healthy population, without chest pain and with normal coronary CT, was included as a control group (n = 55). Laboratory index levels were collected from each participant. The baseline information was reviewed and analyzed. The binary logistic regression was used to explore the relation of ST2 levels with the occurrence of ACS and NSTEMI, and the diagnostic performance of ST2 for diagnosing ACS or NSTEMI was evaluated using a receiver-operating characteristic (ROC) curve. RESULTS: The level of ST2 was found significantly higher in NSTEMI than in USAP and was higher in USAP than in control (p < 0.01). ST2 levels were positively correlated with ALT, AST, and BNP in the control group, were negatively correlated with HGB and TG in the USAP group, and were positively correlated with WBC, GLU, BNP, and Gensini scores in the NSTEMI group. Multivariate analysis revealed that the occurrence of ACS was associated with ST2, BNP, GLU, TC, BUN, WBC, and PLT, and the occurrence of NSTEMI was associated with AST, WBC, LDL-C, and ST2. Meanwhile, ST2 levels achieved good performance for ACS and NSTEMI diagnostician. CONCLUSION: ST2 could be used as an auxiliary diagnostic indicator for the occurrence of ACS and NSTEMI.

Synergistic Effects of Weighted Genetic Risk Scores and Resistin and sST2 Levels on the Prognostication of Long-Term Outcomes in Patients with Coronary Artery Disease.

Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in RETN and IL1RL1 loci. We investigated candidate variants in the RETN locus for resistin levels and those in the IL1RL1 locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in RETN and IL1RL1 were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of RETN and IL1RL1 with resistin and sST2 levels were calculated. Kaplan-Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of RETN and IL1RL1, and their combinations. Three RETN variants (rs3219175, rs370006313, and rs3745368) and two IL1RL1 variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of RETN and IL1RL1 variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with RETN and IL1RL1 variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low RETN WGRS and those with high sST2 levels/low IL1RL1 WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not RETN and IL1RL1 variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of RETN and IL1RL1 genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding.

Louki Zupa decoction attenuates the airway inflammation in acute asthma mice induced by ovalbumin through IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway.

CONTEXT: Asthma is a common respiratory system disease. Louki Zupa decoction (LKZP), a traditional Chinese medicine, presents a promising efficacy against lung diseases. OBJECTIVE: To investigate the pathogenic mechanism of asthma and reveal the intervention mechanism of LKZP. MATERIALS AND METHODS: Forty-eight female Balb/c mice were randomly divided into 6 groups: normal control group (NC), ovalbumin (OVA)/saline asthma model group, OVA/LL group, OVA/LM group, OVA/LH group and OVA/DEX group (n = 8 per group). The asthmatic mice were modelled through intraperitoneal injecting and neutralizing OVA. LKZP decoction was administrated by gavage at the challenge stage for seven consecutive days (2.1, 4.2 and 8.4 g/kg/day). We investigated the change in lung function, airway inflammation, mucus secretion and TH-1/TH-2-related cytokines. We further verify the activated status of the IL-33/ST2/NF-κB/GSK3ß/mTOR signalling pathway. RESULTS: LKZP was proved to improve asthmatic symptoms, as evidenced by the down-regulated airway resistance by 36%, 58% and 53% (p < 0.01, p < 0.001 vs. OVA/saline group), up-regulated lung compliance by 102%, 114% and 111%, decreased airway inflammation and mucus secretion by 33%, 40% and 33% (p < 0.001 vs. OVA/saline group). Moreover, the content of cytokines in BALF related to airway allergy (such as IgE) and T helper 1/T helper 2 cells (like IL-2, IL-4, IL-5, IL-13, TNF-α and IFN-γ), were also markedly reduced by 13-65% on LKZP intervention groups compared with model group. Mechanistic research revealed that the IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway was activated in the OVA/saline group and LKZP significantly down-regulated this pathway. DISCUSSION AND CONCLUSION: LKZP improves lung function, airway inflammation, mucus secretion and correct immune imbalance by intervening with the IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway, presenting a promising therapeutic choice for asthma.

Plasma soluble suppression of tumorigenicity 2 and depression after acute ischemic stroke.

BACKGROUND AND PURPOSE: Soluble suppression of tumorigenicity 2 (sST2) might be related to stroke and depression, but the association of sST2 with poststroke depression (PSD) is unclear. The study aimed to prospectively assess the association between plasma sST2 levels and PSD. METHODS: A total of 635 acute ischemic stroke patients with sST2 measurements from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this analysis. We used the 24-item Hamilton Rating Scale for Depression to assess depression at 3 months, and PSD was defined as a score of ≥8. Logistic regression analysis was performed to estimate the risk of PSD associated with sST2, and net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to assess the predictive value of sST2. RESULTS: Two hundred fifty (39.4%) patients developed depression at 3 months after ischemic stroke. Patients with PSD had higher sST2 levels than patients without PSD (172.7 vs. 153.8 pg/ml; p = 0.003). After adjustment for age, sex, education, National Institutes of Health Stroke Scale score, and other covariates, the odds ratio for the highest quartile of sST2 compared with the lowest quartile was 1.84 (95% confidence interval, 1.10-3.08) for PSD. Adding sST2 to a conventional model notably improved risk prediction for PSD (category-free NRI = 19.34%, 95% confidence interval = 4.39%-34.28%, p = 0.017; IDI = 1.20%, 95% confidence interval = 0.25%-2.15%, p = 0.014). CONCLUSIONS: Increased plasma sST2 levels in the acute phase of ischemic stroke were significantly associated with the increased risk of PSD, independently of conventional risk factors.

Long-Term and Short-Term Prognostic Value of Circulating Soluble Suppression of Tumorigenicity-2 Concentration in Chronic Heart Failure: A Systematic Review and Meta-Analysis.

INTRODUCTION: Soluble suppression of tumorigenicity-2 (sST2) has been considered as a prognostic factor of cardiovascular disease. However, the prognostic value of sST2 concentration in chronic heart failure remains to be summarized. METHODS: We searched PubMed, Embase, and Web of Science for eligible studies up to January 1, 2020. Data extracted from articles and provided by authors were used in agreement with the PRISMA statement. The endpoints were all-cause mortality (ACM), cardiovascular mortality (CVM)/heart failure-related hospitalization (HFH), and all-cause mortality (ACM)/heart failure-related readmission (HFR). RESULTS: A total of 11 studies with 5,121 participants were included in this analysis. Higher concentration of sST2 predicted the incidence of long-term ACM (hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 1.02-1.04), long-term ACM/HFR (HR: 1.42, CI: 1.27-1.59), and long-term CVM/HFH (HR: 2.25, CI: 1.82-2.79), regardless of short-term ACM/HFR (HR: 2.31, CI: 0.71-7.49). CONCLUSION: Higher sST2 concentration at baseline is associated with increasing risk of long-term ACM, ACM/HFR, and CVM/HFH and can be a tool for the prognosis of chronic heart failure.

Increased ratio of sST2/LVMI predicted cardiovascular mortality and heart failure rehospitalization in heart failure with reduced ejection fraction patients: a prospective cohort study.

BACKGROUND: Inflammation is one of the principal triggering mechanisms for left ventricular fibrosis and remodeling in heart failure, leading to adverse clinical outcomes. Soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, is assumed to play a significant role in the fibrotic response to inflammation. Left ventricular mass index (LVMI) is a parameter of the prefibrotic inflammatory phase of heart failure preceding remodeling. The present study aimed to investigate the prognostic value of the sST2/LVMI ratio in heart failure with reduced ejection fraction. METHODS: This was a prospective cohort study. A total of 45 consecutive patients with heart failure with reduced ejection fraction, treated between September 2015 and December 2016, were enrolled. The sST2/LVMI ratio was measured at baseline. The primary endpoint was a composite of cardiovascular mortality and readmission for heart failure. The prognostic impact of the sST2/LVMI ratio was evaluated using a multivariable Cox proportional hazards regression model. RESULTS: Forty-five patients were enrolled in this study. Their average age was 48 ± 14 years, and approximately 20% of them were men. Patients were followed for 9 months, during which the primary outcome occurred in 15 patients. Kaplan-Meier analysis showed that patients with a high sST2/LVMI ratio (≥ 0.39) had shorter event-free survival than those with intermediate (between 0.39 and 0.24) and low ratios (< 0.24) (log-rank, P = 0.022). The fully adjusted multivariable Cox regression analysis showed that the sST2/LVMI ratio was positively associated with the composite outcome in patients with heart failure with reduced ejection fraction after adjusting for confounders (hazard ratio 1.64, 95% confidence interval 1.06 to 2.54). By subgroup analysis, a stronger association was found with age between 40 and 55 years, systolic blood pressure < 115 or ≥ 129 mmHg, diastolic blood pressure < 74 mmHg, hematocrit < 44.5%, and interventricular septum thickness ≥ 8.5 mm. CONCLUSION: In patients with heart failure with reduced ejection fraction, the relationship between the sST2/LVMI ratio and the composite outcome was linear. A higher baseline ratio of sST2/LVMI was associated with an increased risk of cardiovascular mortality and heart failure rehospitalization in the short-term follow-up.