The diagnostic value of sST2 for myocardial fibrosis in idiopathic inflammatory myopathies in subclinical stage of cardiac involvement.

OBJECTIVE: Myocardial fibrosis occurs in the early subclinical stage of cardiac involvement in idiopathic inflammatory myopathies (IIMs). Soluble suppression of tumorigenicity 2 (sST2) is known to have an immunomodulatory impact during autoimmune disease development. The current study investigated the diagnostic value of sST2 for myocardial fibrosis during early stage of cardiac involvement in IIM. METHODS: A total of 44 IIM patients with normal heart function and 32 age- and gender-matched healthy controls (HCs) were enrolled. Serum sST2 levels were measured by ELISA and cardiac magnetic resonance (CMR) parameters for myocardial fibrosis [native T1, extracellular volume (ECV), late-gadolinium enhancement (LGE)] and oedema (T2 values) were analysed. RESULTS: IIM patients had significantly higher sST2 levels than HCs [67.5 ng/ml (s.d. 30.4)] vs 14.4 (5.5), P < 0.001] and levels correlated positively with diffuse myocardial fibrosis parameters, native T1 (r = 0.531, P = 0.000), ECV (r = 0.371, P = 0.013) and focal myocardial fibrosis index and LGE (r = 0.339, P = 0.024) by Spearman's correlation analysis. sST2 was an independent predictive factor for diffuse and focal myocardial fibrosis after adjustment for age, gender, BMI and ESR. Risk increased ≈15.4% for diffuse [odds ratio (OR) 1.154 (95% CI 1.021, 1.305), P = 0.022] and 3.8% for focal [OR 1.038 (95% CI 1.006, 1.072), P = 0.020] myocardial fibrosis per unit increase of sST2. Cut-off values for diagnosing diffuse and focal myocardial fibrosis were sST2 ≥51.3 ng/ml [area under the curve (AUC) = 0.942, sensitivity = 85.7%, specificity = 98.9%, P < 0.001] and 53.3 ng/ml (AUC = 0.753, sensitivity = 87.5%, specificity = 58.3%, P < 0.01), respectively. CONCLUSION: sST2 showed a marked elevation during the subclinical stage of cardiac involvement in IIM and has potential as a biomarker for predicting diffuse and focal myocardial fibrosis in IIM.

Evaluation of soluble suppression of tumorigenicity 2 (sST2) as serum marker for liver fibrosis.

BACKGROUND & AIMS: With the increase in patients at risk of advanced liver disease due to the obesity epidemic, there will be a need for simple screening tools for advanced liver fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a serum biomarker for fibrotic processes. The aim of this study was to evaluate sST2 as marker for liver fibrosis in patients successfully treated for chronic hepatitis C. METHODS: 424 patients from the Swiss Hepatitis C Cohort Study were screened for inclusion in this post-hoc cohort study. Inclusion criteria were sustained virological response (SVR), available elastography (VCTE) and serum samples for biomarker analysis before and after treatment. For the validation of sST2, values were compared to VCTE, FIB-4 and APRI using Spearman's correlation and AUROC analyses. RESULTS: Data of 164 subjects were finally analyzed. Median sST2 values slightly increased with VCTE-derived fibrosis stages and remained stable after reaching SVR within the respective fibrosis stage, suggesting that sST2 is not influenced by liver inflammation. However, correlation of sST2 pre- and post-treatment with VCTE was fair (Spearman's rho = 0.39 and rho = 0.36). The area under the curve (AUROC) for sST2 in detecting VCTE-defined F4 fibrosis (vs. F0-F3) before therapy was 0.74 (95%CI 0.65-0.83), and 0.67(95%CI 0.56-0.78) for the discrimination of F3/F4 fibrosis vs. F0-F2. Adding sST2 to either APRI or FIB-4, respectively, increased diagnostic performance of both tests. CONCLUSIONS: sST2 can potentially identify patients with advanced fibrosis as a single serum marker and in combination with APRI and FIB-4.

Serum levels of interleukin-33, soluble ST2 and IgE in patients with asthma: a case-control study.

INTRODUCTION: Interleukins play a very important role in the pathophysiology of asthma. Interleukin-33 (IL-33) is a partially explored cytokine in asthma. It binds with a specific receptor called suppression of tumorigenicity 2 (ST2). The study aims to evaluate the serum levels of IL-33, sST2 and IgE in asthmatic patients and healthy controls and its further association with the forced expiratory volume in one second (FEV 1%) and absolute eosinophil count. MATERIALS AND METHODS: We enrolled 100 asthmatic patients and 57 healthy subjects for the study. We measured serum levels of IgE, IL-33, and sST2. Based on serum IgE levels, patients were divided into allergic and non-allergic groups. Statistical analysis was done by using Graph pad prism software 8. RESULTS: We found significantly elevated levels of IL-33 and IgE in asthmatic patients as compared to healthy subjects. However, sST2 levels were significantly lower in asthmatic patients than in healthy subjects. FEV1% values were decreased in uncontrolled asthmatic patients. In addition, serum levels of IL-33 were significantly correlated with the IgE. Furthermore, we found a significant correlation between IL-33 and AEC in allergic asthmatic patients. CONCLUSION: In this study, we reported elevated IL-33 and IgE levels and decreased sST2 levels in asthmatic patients compared to healthy controls. IL-33 and sST2 may act as inflammatory biomarkers for allergic diseases such as asthma.

Circulating Markers of Necroptosis in Acute Pancreatitis.

OBJECTIVES: Necroptosis, a programmed inflammatory cell death, is involved in the pathogenesis of acute pancreatitis (AP). We compared levels of interleukin (IL)-33 (released upon necroptosis), sST2 (soluble IL-33 receptor), MLKL, RIPK1 and RIPK3 (necroptosis executioner proteins), and proinflammatory cytokines IL-6, TNF and IL-1ß at various severity categories and stages of AP. METHODS: Plasma from 20 patients with early mild AP (MAP) (symptom onset < 72 h), 7 with severe AP (SAP) without and 4 with persistent organ failure (OF) at sampling, 8 patients with late SAP and 20 healthy controls (HC) were studied by ELISAs. RESULTS: Early sST2 and IL-6 levels predicted the development of SAP and were higher in both MAP and early and late SAP than in HC. RIPK3 levels were higher than in HC in the patients who had or would later have SAP. MLKL levels were associated with the presence of OFs, particularly in the late phase, but were also higher in MAP than in HC. CONCLUSIONS: sST2, RIPK3 and IL-6 levels may have prognostic value in AP. Elevated MLKL levels are associated with OF in AP. Better understanding of necroptosis in AP pathophysiology is needed to evaluate whether inhibiting and targeting necroptosis is a potential therapeutic option in AP.

Possibilities of predicting adverse cardiovascular events based on the analysis of clinical and instrumental research methods, as well as sST2 in patients after myocardial infarction.

OBJECTIVE: Aim: To determine the possibility of predicting adverse cardiovascular events based on the analysis of clinical and instrumental research methods, as well as sST2 in patients after myocardial infarction. PATIENTS AND METHODS: Materials and Methods: The study included 64 patients who suffered an acute myocardial infarction and underwent PCI with balloon angioplasty and stenting of the infarct-related vessel in the acute period. The predictors of adverse cardiovascular events were assessed events during 1 year of observation. Indicators of echocardiography and coronary angiography were assessed and concentrations sST2. RESULTS: Results: A worse prognosis was associated with intermediate ejection fraction (EF) (odds ratio (OR)=3.981, p<0.05), left aneurysm ventricle (LV) (OR=29.5, p<0.05), high concentrations of sST2 (OR=1.017, p<0.05) and scores on the Syntax scale (OR=1.001, p<0.05). CONCLUSION: Conclusions: In patients who underwent percutaneous coronary intervention for myocardial infarction, adverse outcome during the next 2 years is associated with coronary and echocardiographic parameters, as well as biochemical indicators of myocardial stress and fibrosis. HF patients with intermediate EF, LV aneurysm, high sST2 concentrations, and high Syntax scores have the worst prognosis.

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.

Do Heart Failure Biomarkers Influence Heart Failure Treatment Response?

PURPOSE OF REVIEW: Heart failure (HF) is one of the leading causes of cardiac morbidity and mortality around the world. Our evolving understanding of the cellular and molecular pathways of HF has led to the identification and evaluation of a growing number of HF biomarkers. Natriuretic peptides remain the best studied and understood HF biomarkers, with demonstrated clinical utility in the diagnosis and prognostication of HF. Less commonly understood is the utility of HF biomarkers for guiding and monitoring treatment response. In this review, we outline the current HF biomarker landscape and identify novel biomarkers that have potential to influence HF treatment response. RECENT FINDINGS: An increasing number of biomarkers have been identified through the study of HF mechanisms. While these biomarkers hold promise, they have not yet been proven to be effective in guiding HF therapy. A more developed understanding of HF mechanisms has resulted in an increased number of available pharmacologic HF therapies. In the past, biomarkers have been useful for the diagnosis and prognostication of HF. Future evaluation on their use to guide pharmacologic therapy is ongoing, and there is promise that biomarker-guided therapy will allow clinicians to begin personalizing treatment for their HF 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.

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.

Postmortem biochemical analysis of soluble ST2 in the pericardial fluid of patients with sudden cardiac death caused by ischemic heart disease: a pilot study.

Soluble growth stimulation expressed gene 2 protein (sST2) is a myocardial protein induced by biomechanical stress. sST2 is widely present in the serum of patients with heart failure and is recommended as an important indicator to predict adverse outcomes in these patients. However, no postmortem biochemical analysis of sST2 in forensic practice has been reported. The present pilot study aimed to investigate the expression of sST2 in the pericardial fluid of patients with sudden cardiac death (SCD) caused by ischemic heart disease (IHD). In addition, to explore the relationship of sST2 with CK-MB, cTnT, and NT-proBNP, which have been proven to be auxiliary biomarkers for the diagnosis of SCD, we analyzed CK-MB, cTnT, NT-proBNP, and sST2 levels in twenty-one pericardial fluid samples from the Center of Forensic Investigation, China Medical University, with a Roche cobas e 411 electrochemiluminescence automatic immunoassay system and ST2/IL-33R Valukine™ enzyme-linked immunosorbent assay kit. The levels of sST2 in the pericardial fluid of patients with SCD caused by IHD were significantly increased (P < 0.01) and positively correlated with CK-MB and NT-proBNP (P < 0.0001). Receiver operating characteristic curve analysis indicated that the combined measurement of sST2 and NT-proBNP has a higher diagnostic value for SCD caused by IHD than the measurement of either indicator alone. This study preliminarily demonstrated that sST2 in the pericardial fluid was significantly increased in patients with SCD caused by IHD and might be used as a novel auxiliary biomarker for postmortem diagnosis of SCD in forensic practice.

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.

Biomarkers for the diagnosis and management of heart failure.

Heart failure (HF) is a significant cause of morbidity and mortality worldwide. Circulating biomarkers reflecting pathophysiological pathways involved in HF development and progression may assist clinicians in early diagnosis and management of HF patients. Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload. The roles of B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) for diagnosis and risk stratification in HF have been extensively demonstrated, and these biomarkers are emerging tools for population screening and as guides to the start of treatment in subclinical HF. On the contrary, conflicting evidence exists on the role of NPs as a guide to HF therapy. Among the other biomarkers, high-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification, with independent value to NPs. Other biomarkers evaluated as predictors of adverse outcome are galectin-3, growth differentiation factor 15, mid-regional pro-adrenomedullin, and makers of renal dysfunction. Multi-marker scores and genomic, transcriptomic, proteomic, and metabolomic analyses could further refine HF management.

Effects of liraglutide vs. lifestyle changes on soluble suppression of tumorigenesis-2 (sST2) and galectin-3 in obese subjects with prediabetes or type 2 diabetes after comparable weight loss.

BACKGROUND: Soluble suppression of tumorigenesis-2 (sST2) and galectin (Gal)-3 are two biomarkers related to inflammation, metabolic disturbances and to myocardial fibrosis that characterize several cardiac pathological conditions. Increased circulating levels of these molecules have been associated with risk of cardiovascular death. Treatment with liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We wanted to assess (I) potential differences between subjects with prediabetes or type 2 diabetes mellitus (T2DM) and healthy controls in sST2 and Gal-3 circulating levels, and their relationship with glycemic control and markers of beta cell function and myocardial injury; (II) whether liraglutide treatment modulates these markers in subjects with prediabetes or early T2DM independently of weight loss; (III) whether baseline levels of any of these two molecules may predict the response to liraglutide treatment. METHODS: Forty metformin-treated obese subjects (BMI ≥ 30) with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n = 23)] or newly diagnosed T2DM (n = 17), were randomized to liraglutide or lifestyle counseling until achieving a comparable weight loss (7% of initial body weight). Thirteen subjects were enrolled as healthy controls for baseline sST2 and Gal-3 levels. RESULTS: Baseline sST2 levels were comparable between controls and obese patients (p = 0.79) whereas Gal-3 levels were significantly higher in patients as compared to controls (p < 0.001). Liraglutide treatment, but not weight loss achieved by lifestyle counseling, decreased plasma sST2 levels (- 9%, beta = - 14.9, standard deviation 6.9, p = 0.037) while Gal-3 levels did not change. A reduction in serum hs-Troponin I was observed after intervention, due to a 19% (p = 0.29) increase in the lifestyle arm, and a 25% decrease (p = 0.033) in the liraglutide arm (between-group difference p = 0.083). Lower baseline Gal-3 levels predicted a better improvement in beta cell function after liraglutide treatment. CONCLUSIONS: Liraglutide-induced reduction in sST2 and possibly hs-TnI suggests that in obese patients with prediabetes or early T2DM this drug may have a positive effect on (cardiac) fibrosis, whereas plasma level of Gal-3 before liraglutide initiation may predict response to the drug in terms of beta cell function improvement. Trial registration Eudract: 2013-001356-36.

IL33 and sST2 serum level in systemic sclerosis microvascular involvement.

AIM: Endothelial dysfunction and microvascular damage are hallmarks of systemic sclerosis (SSc). Objective of this study was to evaluate IL33 and ST2 serum levels in SSc patients and healthy controls (HC). Secondary aim was to evaluate the IL33 axis in the SSc microvascular manifestation. METHODS: IL33 and sST2 have been assessed in 46 SSc patients and 24 HC matched for sex and age. Main clinimetric indexes were assessed. Skin perfusion of hands was evaluated by Laser Speckle Contrast Analysis (LASCA) and echocolordoppler ultrasound of renal arteries was performed to evaluate subclinical renal involvement. RESULTS: SSc patients had higher serum level of IL33 and sST2 than HC. IL33 and sST2 were significantly higher in SSc patient with digital ulcers (DUs) compared to SSc patients without DUs. SSc patients with late nailfold videocapillaroscopy (NVC) pattern had higher serum levels of sST2 than SSc patients with active NVC pattern. SSc patients without proximal-distal gradient (PDG) at LASCA had significantly higher sST2 serum level compared to SSc patients with PDG. SSc patients with renal resistive index (RRI) ≥ 0.70 had higher serum levels of sST2 than SSc patients with RRI < 0.70. A positive linear correlation was shown between sST2 and RRI, between sST2 and intrarenal S/D and between sST2 and PI. Kaplan-Meier curves show a significantly reduced free survival from DUs in patients with increased sST2 (p = 0.025). In multivariate analysis, sST2 is associated with the development of new DUs. CONCLUSION: IL33 and sST2 are increased in SSc patients and ST2 might be a marker of microvascular damage.

Schistosoma mansoni infection decreases IL-33-mRNA expression and increases CXCL9 and CXCL10 production by peripheral blood cells.

Schistosoma mansoni infections, particularly egg antigens, induce Th2-dominant granulomatous responses accompanied by remarkable immunoregulatory mechanisms that avoid intense fibrosis. Interleukin (IL)-33 is a cytokine that stimulates the early activation of Th2 responses, and its soluble ST2 receptor (sST2) avoids granulomatous response, as well as CXCL9 and CXCL10 chemokines that have antifibrotic activity. However, in schistosomiasis, these molecules have not been suitably studied. Therefore, this study aimed to measure IL-33 and sST2 RNA, cytokines, and chemokines in peripheral blood cultures from individuals living in schistosomiasis-endemic areas. Peripheral blood cells from individuals with S. mansoni (n = 34) and non-infected individuals (n = 31) were cultured under mitogen stimulation. Supernatant chemokines and cytokines were evaluated using a cytometric bead array, and IL-33 and sST2 mRNA expression was measured using qPCR. Infected individuals showed higher levels of CXCL8, CXCL9, CXCL10, IFN-γ, TNF-α, IL-6, IL-2, IL-4, and IL-10; there was a lower expression of IL-33 mRNA and similar expression of sST2mRNA in infected than non-infected individuals. In conclusion, for the first time, we demonstrated lower IL-33mRNA expression and high levels of the antifibrotic chemokines CXCL9 and CXCL10 in schistosomiasis mansoni, which could control exacerbations of the disease in individuals from endemic areas.

Role of altered IL-33/ST2 immune axis in the immunobiology of Guillain-Barré syndrome.

BACKGROUND: The IL-33/ST2 immune axis plays crucial roles in infection and immunity. A dysregulated IL-33/ST2 axis can induce autoimmune reaction and inflammatory responses. Guillain-Barré syndrome (GBS) is an acute peripheral neuropathy, mostly caused by post-infection autoimmunity. The role of IL-33/ST2 axis is not known in GBS. This study aimed to explore the role of IL-33/ST2 axis in GBS. METHODS: Three single nucleotide polymorphisms (SNPs) of Il33 gene (rs16924159, rs7044343, rs1342336) and three SNPs of Il1rl1 gene (rs10192157, rs1041973, rs10206753) coding for suppressor of tumorigenicity 2 (ST2) were genotyped in 179 GBS patients and 186 healthy controls by TaqMan Allelic Discrimination Assay. Plasma levels of IL-33 and sST2 were measured in a subset of GBS patients (n = 80) and healthy controls (n = 80) by ELISA. RESULTS: The frequencies of CC genotype of rs10192157 (p = 0.043) and TT genotype of rs10206753 (p = 0.036) SNPs of Il1rl1 gene differed significantly between GBS patients and healthy controls. Gene-gene interaction between Il33 and Il1rl1 genes also conferred significant risk for GBS. In addition, the plasma sST2 levels were significantly elevated in GBS patients compared to healthy subjects (24,934.31 ± 1.81 pg/ml vs. 12,518.97 ± 1.51 pg/ml, p < 0.001). Plasma sST2 levels showed a significant correlation with the disability scores at the peak of neurological deficit in GBS patients. CONCLUSIONS: The IL-33/ST2 axis is suggested to influence the immunopathogenesis of GBS. Genetic variants of Il1rl1 gene might serve as a risk determinant of GBS and plasma sST2 levels might emerge as a biomarker of severity of GBS, if replicated further by other studies.

Persistently elevated levels of sST2 after acute coronary syndrome are associated with recurrent cardiac events.

PURPOSE: Higher soluble ST2 (sST2) levels at admission are associated with adverse outcome in acute coronary syndrome (ACS) patients. We studied the dynamics of sST2 over time in post-ACS patients prior to a recurrent ACS or cardiac death. METHODS: We used the BIOMArCS case cohort, consisting of 187 patients who underwent serial blood sampling during one-year follow-up post-ACS. sST2 was batch-wise quantified after completion of follow-up in a median of 8 (IQR: 5-11) samples per patient. Joint modelling was used to investigate the association between longitudinally measured sST2 and the endpoint, adjusted for gender, GRACE risk score and history of cardiovascular diseases. RESULTS: Median age was 64 years and 79% were men. The 36 endpoint patients had systematically higher sST2 levels than those that remained endpoint free (mean value 29.6 ng/ml versus 33.7 ng/ml, p-value 0.052). The adjusted hazard ratio for the endpoint per standard deviation increase of sST2 was 1.64 (95% confidence interval: 1.09-2.34; p = 0.019) at any time point. We could not identify a steady or sudden increase of sST2 in the run-up to the combined endpoint. CONCLUSION: Asymptomatic post-ACS patients with persistently higher sST2 levels are at higher risk of recurrent ACS or cardiac death during one-year follow-up.

Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers.

PURPOSE: Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. METHODS: A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. RESULTS: Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. CONCLUSIONS: Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. TRIAL REGISTRATION: NCT03276858, registered September 8, 2017, retrospectively registered.

Galectin-3 and sST2: associations to the echocardiographic markers of the myocardial mechanics in systemic sclerosis - a pilot study.

BACKGROUND: Progressive cardiac fibrosis is the central aspect of the myocardial involvement in systemic sclerosis (SSc). We hypothesized that circulating biomarkers of the cardiac fibrosis may be useful in the early diagnosis of the cardiac manifestation in this disease. Thus, we investigated the potential correlations between the levels of galectin-3, soluble suppression of tumorigenicity-2 (sST2) and the echocardiographic markers of the myocardial mechanics in SSc patients. METHODS: Forty patients (57.3 ± 13.7 years, 36 female) were investigated. In addition to the conventional echocardiography, tissue Doppler and speckle tracking-derived strain techniques were used to assess the function of both ventricles and atria. To estimate the correlations between galectin-3 and sST2 levels and the echocardiographic variables, partial correlation method was used with age as correcting factor. RESULTS: In age adjusted analysis galectin-3 level showed significant correlation with left ventricular global longitudinal strain (r = 0.460, p = 0.005); grade of left ventricular diastolic dysfunction (r = 0.394, p = 0.013); septal e' (r = - 0.369, p = 0.021); septal E/e' (r = 0.380, p = 0.017) and with the grade of mitral regurgitation (r = 0.323, p = 0.048). No significant correlation was found between sST2 levels and the echocardiographic variables. CONCLUSIONS: Galectin-3 levels, but not sST2 levels show significant correlation with the parameters of the left ventricular systolic and diastolic function. Galectin-3 may be a useful biomarker for the screening and early diagnosis of SSc patients with cardiac involvement.

Prognostic Role of sST2 in Acute Heart Failure and COVID-19 Infection-A Narrative Review on Pathophysiology and Clinical Prospective.

The importance of cardiovascular biomarkers in clinical practice increased dramatically in the last years, and the interest extends from the diagnosis purpose to prognostic applications and response to specific treatment. Acute heart failure, ischemic heart failure, and COVID-19 infection represent different clinical settings that are challenging in terms of the proper prognostic establishment. The aim of the present review is to establish the useful role of sST2, the soluble form of the interleukin-1 receptor superfamily (ST2), physiologically involved in the signaling of interleukin-33 (IL-33)-ST2 axis, in the clinical setting of acute heart failure (HF), ischemic heart disease, and SARS-CoV-2 acute infection. Molecular mechanisms associated with the IL33/ST2 signaling pathways are discussed in view of the clinical usefulness of biomarkers to early diagnosis, evaluation therapy to response, and prediction of adverse outcomes in cardiovascular diseases.