ST2 Levels Research Articles

Combining Novel Biomarkers for Risk Stratification of Two-Year Cardiovascular Mortality in Patients with ST-Elevation Myocardial Infarction.

ST-elevation myocardial infarction (STEMI) is one of the main reasons for morbidity and mortality worldwide. In addition to the classic biomarker NT-proBNP, new biomarkers like ST2 and Pentraxin-3 (Ptx-3) have emerged as potential tools in stratifying risk in cardiac patients. Indeed, multimarker approaches to estimate prognosis of STEMI patients have been proposed and their potential clinical impact requires investigation. In our study, in 147 patients with STEMI, NT-proBNP as well as serum levels of ST2 and Ptx-3 were evaluated. During two-year follow-up (FU; 734.2 ± 61.2 d) results were correlated with risk for cardiovascular mortality (CV-mortality). NT-proBNP (HR = 1.64, 95% CI = 1.21–2.21, p = 0.001) but also ST2 (HR = 1.000022, 95% CI = 1.00–1.001, p < 0.001) were shown to be reliable predictors of CV-mortality, while the highest predictive power was observed with Ptx-3 (HR = 3.1, 95% CI = 1.63–5.39, p < 0.001). When two biomarkers were combined in a multivariate Cox regression model, relevant improvement of risk assessment was only observed with NT-proBNP+Ptx-3 (AIC = 209, BIC = 214, p = 0.001, MER = 0.75, MEV = 0.64). However, the highest accuracy was seen using a three-marker approach (NT-proBNP + ST2 + Ptx-3: AIC = 208, BIC = 214, p < 0.001, MER = 0.77, MEV = 0.66). In conclusion, after STEMI, ST2 and Ptx-3 in addition to NT-proBNP were associated with the incidence of CV-mortality, with multimarker approaches enhancing the accuracy of prediction of CV-mortality.

Pro-inflammatory cytokines, oxidative stress and diffuse coronary reocclusions in elderly patients after coronary stenting

BackgroundThe inflammation responses and oxidative stress were closely associated with coronary heart disease. We tried to evaluate the effects of multiple stents, long stents and small-diameter stents on inflammation responses and oxidative stress in the elderly patients with long diffuse reocclusions. MethodsThe blood samples were obtained after an overnight fast and we evaluated the expression levels of soluble ST2 (sST2), acrolein (ACR), aldosterone (ALD), angiotensin II (Ang II), toll-like receptor 4 (TLR4), tumour necrosis factor-α (TNF-α), malondialdehyde (MDA) and high sensitivity C-reactive protein (hs-CRP) in the elderly patients with long diffuse reocclusions after multiple stents, long stents, small-diameter stents implanted. Results: Levels of sST2, ACR, ALD, Ang II, TLR4, TNF-α, MDA and hs-CRP were remarkably increased (P < 0.001) in the elderly patients with long diffuse reocclusions after multiple stents, long stents, small-diameter stents implanted. The multiple stents, long stents and small-diameter stents may promote inflammatory response and oxidative stress, and led to long diffuse reocclusions in the elderly patients. The multiple stents, long stents and small-diameter stents may play the key roles in long diffuse reocclusions of the elderly patients. ConclusionsThe inflammatory and oxidative stress biomarkers could be considered as potential non-invasive diagnostic, predictive, prognostic and therapeutic molecular biomarkers for long diffuse reocclusions in the elderly patients after implantations of multiple stents, long stents and small-diameter stents.

ST2 PLASMA LEVEL IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION WITHOUT ST ELEVATION AND DIFFERENT CLINICAL CHARACTERISTICS

The aim. Estimation of ST2 plasma level in patients with acute myocardial infarction without ST elevation (NSTEMI) and its relationship with different clinical characteristics. Materials and methods. 165 patients aged from 35 to 79 (average of 60.7±0.8 years) with various forms of coronary artery disease (CAD) with and without arterial hypertension were examined. The variability of plasma ST2 level in different forms of CAD and in NSTEMI group was analyzed depending on gender-age and clinical characteristics and features of the disease course. Results: The results of the present investigation were that the ST2 level in the main cohort was in range from 5.5 to 233.9 (in the middle – 49.8±3.5 ng / ml (median indicator – 34.7 and the interquartile range – 21.9 and 59.1 respectively). Significantly higher ST2 levels were found in patients with NSTEMI, unlike the comparison group, in the median analysis (35.9 vs. 27.7 ng/ml, p=0.047) and no statistical differences were observed in the mean values. In patients with NSTEMI, a certain association of ST2 level in plasma with the MI course was detected. A higher level of neurohormone is registered with anterior unlike posterior ECG localization of MI; at high unlike moderate risk on the GRACE scale; when complicated unlike the uncomplicated course of MI; in the case of acute HF and cardiac arrhythmias unlike patients with the absence of these manifestations in the acute period of MI. Conclusions. High variability of ST2 level in plasma was demonstrated in patients with NSTEMI on the first day after destabilization (minimum and maximum values – 12.7 and 233.9 respectively, median – 35.9 and interquartile range – 25.9 and 55.7 ng / ml). It is shown that significantly higher ST2 level in plasma is determined in patients with acute MI regardless of its variant among different clinical forms of CAD. It is found that significantly higher level of ST2 in patients with NSTEMI is recorded in the case of concomitant HTN and type 2 diabetes, with smoking and heavy cardiovascular heredity. Proved influence of the character of MI course on the level of ST2 in plasma, significantly higher level of neurohormone was determined with anterior localization of MI, high risk on the GRACE scale (≥ 140 points), complicated course of MI, development of cardiac arrhythmias and HF in the acute period of MI.

A MULTI-MARKER MODEL FOR PREDICTING DECOMPENSATED HEART FAILURE IN PATIENTS WITH PRIOR ACUTE MYOCARDIAL INFARCTION

The aim of the study was to assess the prognostic value of determining the plasma concentration of NT-proBNP and ST2 in the patients with decompensated HF and prior acute myocardial infarction and their combination in this category of patients. Materials and methods. There were examined 120 patients with acute myocardial infarction and stage II A-B decompensated chronic HF according to the classification proposed by Vasylenko V. Kh. and Strazhesko M.D., NYHA functional class (FC) III-IV. The patients with Q-QS wave MI (60 individuals) and non Q MI (60 individuals) were divided into 4 groups depending on the treatment methods. Study groups were homogenous by age, gender, disease severity, duration of the post-infarction period, clinical signs of decompensation, which served as a basis for inclusion of the patients in the study. All the patients underwent the six-minute walk test in a quiet 30-50-m long hospital corridor in the morning. N-terminal pro-B-type brain natriuretic peptide (NT-proBNP) and ST-2 were analyzed in all patients. Results. Promising biomarkers of HF decompensation in the post-infarction period were studied. In the patients with prior Q-QS MI and decompensated HF, NT-proBNP level was (950.38±3.15) pmol/l (p&lt;0.05); in the patients with prior MI without signs of decompensated HF, it was (580.15±3.03) pmol/l (p˂0.05); in apparently healthy individuals, the level of NT-proBNP was found to be (111.20±3.47) pmol/l. ST2 level was (14.80±1.61) ng/ml, (36.00±1.43) ng/ml and (49.22±1.40) ng/ml in the patients of Group 1, Group 2 and Group 3, respectively (p˂0.05). Similar changes were found in patients with decompensated HF in postinfarction period after non Q MI. Conclusions. The increase in plasma concentration of sST2 is associated with the activation of both neurohumoral and fibrous pathways and can help in detecting the patients with decompensated HF in the post-infarction period and predicting the risk of its development. Our results confirmed the results of other multiple studies reporting ST2 in combination with NT-proBNP to be valuable tools for prognosing the development of decompensated HF in the patients with prior MI. ST2, alongside with NT-proBNP, is a promising biomarker to be included in the diagnostic panel for detecting acute HF and can provide additional information on risk stratification for such patients during hospitalization and at the time of discharge from the hospital.

Характер анатомічного ураження коронарного русла в пацієнтів з гострим інфарктом міокарда без елевації сегменту ST залежно від рівня стимулюючого фактору росту, що експресується ґеном 2 в плазмі та ризику несприятливих подій

Aim.&nbsp;Assessment of the character of anatomical coronary lesions in patients with acute myocardial infarction without ST elevation depending on plasma level of gene 2 growth stimulating factor (ST2), and risk of adverse events.&nbsp; Materials and Methods.&nbsp;Ninety patients with acute myocardial infarction without ST elevation (NSTEMI) aged 38 to 79 (mean 61.3±1.1) years were examined. Among them, 60 (66.7%) patients were male. The study evaluated the risk of adverse events on the GRACE scale; the character of anatomical lesions of the coronary arteries using invasive coronary ventriculography; and the level of ST2 in the blood plasma by enzyme immunoassay. Results and Discussion.&nbsp;It was found that the severity of myocardial infarction without ST segment elevation, depending on the GRACE score, was associated with the nature of the coronary lesion. In most patients with a high GRACE score (&gt;140 points), prevalence of hemodynamically significant stenoses was found. In addition, these patients presented with a significant increase in three-vessel lesions of the coronary arteries. Instead, with less than 140 GRACE score, the number of patients without hemodynamically significant coronary artery stenoses increased significantly, and the number of patients with three-vessel lesions decreased. Conclusions.&nbsp;A connection of ST2 level with the severity of anatomical injury of coronary arteries in patients with NSTEMI was established. The total score of lesions of the coronary arteries increased &nbsp;according to the increase in the level of ST2. An association of the GRACE score was established with the risk of adverse events in patients with NSTEMI.

PROGNOSTIC FACTORS OF CHRONIC CORONARY SYNDROME IN PATIENTS WITH CONCOMITANT TYPE 2 DIABETES MELLITUS

Introduction: Chronic coronary syndrome (CCS) with concomitant type 2 diabetes mellitus (T2DM) is still a major cause of disability and mortality. That is why studying the prognostic factors of combination of these diseases is very relevant. There are many researches regarding the inflammation component of the development of atherosclerosis in patients with CCS and T2DM. It is still unknown how exactly does chronic systemic inflammation influences cardiac remodeling in such patients. The Aim: Considering the aforementioned, the aim of our study was to asses the prognostic role of serum sST2, highsensitive C-reactive protein (hs-CRP) and TMAO as markers of chronic systemic inflammation and ins insulin resistance in patients with CCS and T2DM. Material and methods: 90 patients were enrolled, among them 30 patients with CCS: stable angina, class ІІ-ІІІ (group І) and 60 patients with CCS: stable angina, class ІІ-ІІІ and T2DM, non-insulin-requiring (group ІІ). The study was performed in Ivano-Frankivsk Central City Hospital and City Hospital No 1 (Ukraine) in accordance with the Helsinki Declaration and Good Clinical Practice Guideline. All patients gave written informed consent and the local ethics committee approved the study protocol. The patients were tested for the following: glycated hemoglobin (НbА1c), total plasma cholesterol (TC), triglycerides (TG), high density lipoproteins (HDL), low and very low density lipoproteins (LDL and VLDL), TMAO, sST2, hs-CRP. Results and discussion: Patients with CCS and concomitant T2DM have higher levels of markers of systemic inflammation response, including TMAO by 8.5 times, sST2 by 2.2, hs-CRP by 19.1, compared with healthy individuals. Conclusions: Patients with CCS and concomitant T2DM have more “atherogenic” dyslipidemia compared with the patients with isolated CCS, including statistically significant higher levels of triglycerides (р&lt;0.05), VLDL (р&lt;0.05), and atherogenicity index of plasma (AIP) (р&lt;0.05), and lower level of HDL(р&lt;0.05). Results of this study suggest the possible use of ST2 as diagnostic and prognostic marker in patients with stable angina, including patients with concomitant T2DM. ST2 level &gt; 35 ng/mL is negative prognostic marker concerning the development of chronic heart failure and testament for the need of more thorough examination of such patients. The level of TMAO can also be another credible predictor of negative prognosis of CCS.

Plasma Indoleamine 2,3-dioxygenase is predictive of left ventricular remodeling after myocardial infarction

Acute myocardial infarction (MI) is associated with an inflammatory response that may lead and/or worsen adverse left ventricular (LV) remodeling. Among inflammation markers is Indoleamine 2,3-dioxygenase (IDO), which production is induced upon inflammation. IDO catalyzes the transformation of tryptophane into kynurenine. We tested plasma IDO activity as a predictor of LV remodeling post-MI. The PREGICA cohort recruited prospectively patients with first MI. Blood samples, echocardiography and cardiac MRI were obtained at day 4 and at 6 months. To be included, the number of akinetic LV wall segments had to be ≥ 3 at day 4. IDO activity was the ratio between kynurenine and tryptophane measured by high-pressure liquid chromatography coupled with fluorimetric detection. Remodelers were identified as patients with a variation of end-diastolic left ventricular volume (EDLVV) between day 4 and 6 months post-MI ≥ 20%. Among the 292 patients studied (mean age 57 y, mean necrosis size 26% on MRI), the median increase in EDLVV was 16.7% and 137 (47%) were classified as remodelers. At day 4, IDO activity was significantly higher in remodelers (8.2 ± 4.2% vs. 5.3 ± 2.5% and 8.7 ± 5.7% vs. 5.6 ± 4.4%, p < 0.001) and remained higher at 6 months post-MI. IDO activity at day 4 was highly predictive of LV remodeling (AUC = 87% [95% CI 83–91%]);IDO threshold of 5.8 resulted in specificity = 81%, sensitivity = 89%, negative predictive value = 89%, positive predictive value = 80%. In contrast, plasma levels of NT-proBNP, ST2, Galectin 3 or CRP at day 4 were poorly predictive. In multivariate analysis including other predictive variables at day 4 (primary angioplasty, EDLVV, LVEF, necrosis size), increase in IDO activity was significantly associated with LV remodeling (OR 1.21 [95%CI 1.11–1.33]). IDO activity appears as a promising biomarker for the prediction of LV remodeling after MI. Its specific role in post-MI remodeling pathways requires further investigation.

Black yeast beta glucan for insulin resistance prevention through IL-33, ST2 and leptin Level: An In vivo study of an obesity model using Sprague dawley rats

Black yeast beta glucan for insulin resistance prevention through IL-33, ST2 and leptin Level: An In vivo study of an obesity model using Sprague dawley rats

The Correlation between sST2 and Atrial Fibrillation and Its Clinical Significance

Objective: To explore the level of soluble growth-stimulated expression gene 2 (sST2) in patients with atrial fibrillation (AF) and its relationship with atrial remodeling. Methods: From December 2018 to July 2019, 86 patients were enrolled in the cardiovascular department of Jingzhou Central Hospital in Hubei Province. AF group was 60 patients with AF diagnosed according to the diagnostic criteria of electrophysiology and pacing branch of Chinese Medical Association, while the control group was 26 normal ECG patients with sinus rhythm examined by ECG and/or DCG. Clinical data, NT proBNP and birth rate of all patients were collected chemical indicators. All the patients in the groups were examined by ECG and color Doppler echocardiography. The serum level of ST2 was detected by enzyme-linked immunosorbent assay (ELISA), and the indexes related to atrial remodeling in echocardiography, left atrial diameter (LAD), were collected, compared and analyzed. Results: Serum sST2 levels and LAD and RAD values in the AF group were higher than those in the control group (P < 0.05 or P < 0.01). Serum sST2 levels were higher in the AF group than in the paroxysmal atrial fibrillation group (P = 0.031). 1) The sST2 level was positively correlated with LAD and RAD measured by cardiac ultrasound (r = 0.388, P = 0.029). Conclusion: Serum sST2 levels have early recognition value in patients with high-risk atrial fibrillation, which contributes to the stratification of risk of atrial fibrillation and the prediction of disease activity. Elevated serum sST2 levels may be associated with atrial remodeling. sST2 may be an objective biomarker that predicts the risk of emergency admission in patients with atrial fibrillation. Elevated sST2 levels may be associated with atrial fibrillation progression.

Dynamic changes of soluble ST2 levels predicted fatality and were involved in coagulopathy in dengue fever in the elderly.

BackgroundSevere dengue virus (DENV) infection involves plasma leakage and vascular collapse, and leads to significant morbidity and death. Serum soluble ST2 (sST2 [interleukin (IL)-1 receptor like-1 protein: IL-1-RL-1]) levels are high in pediatric cases of DENV infection, and the disease progresses. However, the correlation between serum sST2 levels and the outcomes of DENV infection in the elderly (≥65 years) is unclear. We thus explored the mechanisms of serial sST2 level changes involved in the coagulopathy and bloodstream infections of elderly patients in Taiwan’s 2015 DENV outbreak.MethodsThis retrospective study was done in a tertiary medical center in southern Taiwan during the outbreak. All DENV-infected patients who, between July 1, 2015, and December 31, 2015, provided a written informed consent for at least two blood sample analyses were enrolled and reviewed. The serum levels of sST2 were quantified. ΔsST2 is defined as the “changes of sST2 levels in serially paired samples”. Receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) analyses were used to evaluate the prognostic ability of ΔsST2.ResultsForty-three patients with DENV infection were enrolled. Mean patient age was 75.0 ± 12.2 years and the case fatality rate was 44.2% (19/43). Significantly more non-survivors than survivors had increased ST2 level (78.9% vs. 12.5%, p < 0.001). The AUC value for serum ΔsST2 level was 0.857 for predicting DENV fatality. Moreover, patients given frozen fresh plasma (FFP) transfusions were significantly (p = 0.025) more likely to have higher serum ST2 level changes than were those who had not. DENV-infected patients with early bloodstream infections (BSIs) seemed to have higher ST2 levels than those who did not have BSIs.ConclusionsSerum ST2 levels increased in the elderly (≥ 65 years of age) with DENV infection. The changes in serum sST2 levels might be a critical indicator of DENV infection severity for the elderly; sST2 is an important modulator of coagulopathy in severe DENV infections.

ST2 levels increased and were associated with changes in left ventricular systolic function during a three-year follow-up after adjuvant radiotherapy for breast cancer

ObjectivesTo search for biomarkers of RT-induced cardiotoxicity, we studied the behavior of ST2 during RT and three years after RT, and the associations with echocardiographic changes. Materials and methodsWe measured soluble ST2 (ng/ml) in serum samples from 63 patients receiving RT for early breast cancer. Sampling and echocardiography were performed at baseline, after RT and at the three-year follow-up. Patients were grouped by >15% (group 1) and ≤15% (group 2) relative worsening in global longitudinal strain (GLS). ResultsST2 levels tended to increase during RT, from a median (interquartile range; IQR) of 17.9 (12.4–22.4) at baseline to 18.2 (14.1–23.5) after RT (p = 0.075). By the three-year follow up, ST2 levels increased to 18.7 (15.8–24.2), p = 0.018. The increase in ST2 level was associated with worsening cardiac systolic function at three-year follow-up, GLS (rho = 0.272, p = 0.034) and left ventricular ejection fraction (LVEF) (rho = ─0.343, p = 0.006). Group 1 (n = 14) had a significant increase in ST2 levels from 17.8 (12.3–22.5) at baseline to 18.4 (15.6–22.6) after RT, p = 0.035 and to 19.9 (16.0–25.1) three years after RT, p = 0.005. ST2 levels were stable in group 2 (n = 47): 17.8 (12.3–22.0) at baseline, 17.7 (12.6–23.5) after RT and 18.0 (15.5–22.4) at three years. ConclusionST2 may be useful for determining which patients are at risk for long-term cardiovascular toxicity following adjuvant breast cancer RT, but prospective clinical studies are needed to confirm this hypothesis.

IL-33/ST2 axis promotes glioblastoma cell invasion by accumulating tenascin-C

Tenascin-C (TNC), a very large multimeric glycoprotein, is overexpressed in human glioblastomas, leading to a highly motile and invasive phenotype of glioma cells. However, the regulation of TNC expression in glioma has remained unclear until now. Our data suggest that interleukin-33 (IL-33) may promote the accumulation of TNC protein by autocrine or paracrine modes of action in glioma. In the present study, the expression levels of TNC, IL-33, and ST2 were measured in glioma tissue specimens, and the impact of altered IL-33 expression on TNC was investigated in vitro and in vivo. In contrast with control treatment, IL-33 treatment increased TNC expression, and knockdown of IL-33 attenuated TNC expression in glioma cells. Furthermore, IL-33 induced the activation of nuclear factor κB (NF-κB) and increased the expression of TNC in U251 cells. In addition, blockage of the IL-33-ST2-NFκB pathway resulted in downregulation of TNC production. IL-33 promoted glioma cell invasion by stimulating the secretion of TNC. Similarly, knockdown of TNC inhibited the invasiveness of glioma cells. These findings provide a novel perspective on the role of the IL-33/NF-κB/TNC signalling pathway in supporting cancer progression. Thus, targeting the IL-33/NF-κB/TNC signalling pathway may be a useful therapeutic approach in glioma.

Low Levels of Plasmacytoid Dendritic Cells at the Time of Engraftment Are a Valuable Severe aGVHD Indicator in Children Undergoing Allogeneic Stem Cell Transplantation

Graft-versus-host-disease (GVHD) remains a leading cause of transplant-related mortality (TRM) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients who do not respond to GVHD therapy are at high risk for death without relapse. Strategies that can predict the development of severe GVHD in transplant patients may improve risk stratification for steroids treatment refractory GVHD and TRM. Dendritic cells (DCs) play nonredundant roles in regulating both immunity and tolerance. Clinical and pre-clinical studies suggest that GVHD causes dysregulated development of functional DCs and impaired reconstitution of donor DCs is associated with increased risk of severe GVHD. We demonstrate that donor plasmacytoid DC (pDC) reconstitution around the engraftment time is a useful predictor for the development of severe GVHD in children after allo-HSCT. We examined reconstitution of donor DCs, including total DCs (lineage-negative (LIN-)HLADR+), pDCs (LIN-HLADR+CD123+CD1c-) and CD1c+DCs (LIN-HLADR+CD123-CD1c+), in peripheral blood of patients undergoing allo-HSCT, using age-matched healthy children as controls. The median time for engraftment was 14 days (range, 13.0~17 days), whereas clinical signs of GVHD occurred approximately 10 days later (median time, 24 days;range, 18~35 days). Thus, measuring the number and frequency of circulating blood DCs early at the engraftment time allowed us to evaluate the subsequent occurrence of GVHD. Transplant patients were followed up for 6 months after allo-HSCT. Of evaluable 45 transplant patients, 27 patients had no GVHD (grade 0) or mild GVHD (grade I), and 18 patients developed severe GVHD (grade II-IV GVHD). Patients who developed grade II-IV GVHD had no significant difference in frequency ( median, 0.2%; range, 0.04~0.35%) and number (median, 1.6 cell/ml; range, 1~3.8 cell/ml) of total DCs than patients with grade 0-I GVHD (median frequency, 0.41%; range, 0.15~0.63%, P&lt;0.05; and median number, 2.6 cell/ml , range, 1~6.7 cell/ml,Figure1A,1B). Both pDCs and CD1c+DCs represent the major DC populations in human peripheral blood. Patients with grade II-IV GVHD showed significantly lower frequency and number of pDCs (median frequency, 3.4%; range, 0.64~14%, median number, 0.06/ml, range, 0.02~0.25 cell/ml) than patients with grade 0-I GVHD median frequency, 29.1%, range, 20.3%~39.2%, P&lt;0.01; mediate number, 0.5 cell/ml, range, 0.2~1.9 cell /ml, P&lt;0.01Figure1A,1B). In contrast, there was no significant difference in frequency and number of CD1c+DC between the two groups. These data suggest that the reconstitution of donor pDCs is linked to the occurrence of severe GVHD. Using Receiver operating characteristic (ROC) curve analysis, we explored thresholds of pDCs as a discriminator for grade II-IV GVHD patients versus grade 0-I GVHD patients. The median pDC level in all tested patients was 0.25 cell/ml (range, 0.1~0.9 cell/ml,Figure1C) at the engraftment time. We chose the threshold of pDC level at 0.3 cell/ml to evaluate the difference in patients with high (above the threshold) versus low (below the threshold) pDC levels. Of these 45 patients, 21 (46.7%) patients had high pDCs and 24 (53.3%) were low pDCs. Patients with low pDCs had a significantly higher probability of developing grade II-IV GVHD (p&lt;0.01). The sensitivity of discriminating severe GVHD versus no/mild GVHD was 75% and the specificity was 94%. In addition, low engraftment pDC patients had higher TRM compared to high pDC patients (12.5% versus 0%) for median follow-up time 300 days (range, 210-465 days) after transplantation. However, there was no significant difference in overall survival rate between high pDC- and low pDC-group. Furthermore, the serum level of REG3α and ST2 at the engraftment time was not associated with the incidence of severe GVHD in these patients. Collectively, our findings identify that quantitation of pDCs at the engraftment time is a valuable prognostic predicator for severe GVHD in patients undergoing allo-HSCT. Given the importance of pDCs in modulating GVH reactions, it will be important to further determine whether impaired reconstitution of donor DCs may contribute to dysregulated immune tolerance against host tissues after allo-HSCT. Disclosures No relevant conflicts of interest to declare.

Association of TREM-1, IL-1β, IL-33/ST2, and TLR Expressions With the Pathogenesis of Ocular Toxoplasmosis in Mouse Models on Different Genetic Backgrounds.

Ocular toxoplasmosis (OT) is one of the most common causes of posterior uveitis. The signaling of triggering receptor expressed on myeloid cells (TREM)-1 amplifies inflammation, whereas TREM-2 signaling is anti-inflammatory. IL-1β is a major driver of inflammation during infection. Toll-like receptors (TLRs) play important roles in protective immune response during Toxoplasma gondii infection, and interleukin (IL)-33 receptor (T1/ST2) signaling prevents toxoplasmic encephalitis in mice. However, the pathogenic mechanisms of OT are not yet well elucidated. To investigate the role of TREM-1, TREM-2, IL-1β, IL-33/ST2, and TLRs in OT of susceptible C57BL/6 (B6) and resistant BALB/c mice, both strains of mice were intravitreally infected with 500 tachyzoites of the RH strain of T. gondii. Histopathological analysis showed that T. gondii-infected B6 mice had more severe ocular damage observed by light microscopy, higher number of neutrophil elastase-positive cells in the eyes detected by immunohistochemical staining, more T. gondii tachyzoites in the eyes observed by transmission electron microscopy, and higher mRNA expression levels of tachyzoite-specific surface antigen 1 detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) in comparison of T. gondii-infected BALB/c mice. Detected by using qRT-PCR, the mRNA expression levels of TREM-1, IL-1β, IL-33, ST2, TLR11, TLR12, and TLR13 were significantly higher in the eyes of T. gondii-infected B6 mice than those of T. gondii-infected BALB/c mice, whereas the mRNA expression levels of TLR3 and TLR9 were significantly higher in the eyes of T. gondii-infected BALB/c mice than those of T. gondii-infected B6 mice. Correlation analysis showed that significant positive correlations existed between TREM-1 and IL-1β/IL-33/ST2/TLR9/TLR11 in the eyes of B6 mice and existed between TREM-1 and IL-33/ST2/TLR3/TLR9/TLR13 in the eyes of BALB/c mice after ocular T. gondii infection. Our data revealed that, compared with T. gondii-resistant BALB/c mice, ocular T. gondii infection can stimulate higher production of TREM-1, IL-33, ST2, TLR11, TLR12, and TLR13 in the eyes of T. gondii-susceptible B6 mice, however, whether those lead to more severe ocular pathology in the susceptible B6 mice remain to be further studied.

2232Circulating levels of ST2 are associated with myocardial injury, left ventricular function and future adverse clinical events in patients with ST-elevation myocardial infarction

Abstract Background Soluble ST2, a member of the IL-1 receptor family, seems to be associated with adverse outcome in acute myocardial infarction and heart failure (HF), and is suggested to be involved in left ventricular (LV) remodelling. Purpose To elucidate a possible role of ST2 in LV injury, remodelling and prognosis in ST-elevation myocardial infarction (STEMI) patients. The main objectives of the study were to investigate whether circulating ST2 levels were associated with infarct size, LV function, adverse remodeling and clinical outcome in a cohort of patients with STEMI. Methods 270 patients with clinically stable first-time STEMI treated with primary percutaneous coronary intervention (PCI) were included. Blood samples were drawn before and immediately after the PCI procedure, at day 1 (median 18.3 hours after PCI) and after 4 months. Cardiac magnetic resonance (CMR) was performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12 months' and 70 months' follow-up, respectively. A composite endpoint was defined as death, MI, unscheduled revascularisation &gt;3 months after the index infarction, rehospitalisation for HF or stroke. Associations between ST2 and CMR parameters and clinical events were evaluated with linear regression and logistic regression, respectively. Results There was a significant increase in ST2 levels from the PCI procedure to day 1 with a subsequent decline from day 1 to 4 months in the POSTEMI cohort. Patients with high ST2 levels (&gt;median) at all sampling points during hospitalisation had significantly larger infarct size, lower myocardial salvage, lower LVEF, larger increase in EDV and higher frequency of MVO. After adjustment for relevant clinical variables, peak CRP and peak troponin T, ST2 measured at day 1 remained associated with infarct size (β 2.0 per SD of ST2, p&lt;0.001) and LVEF (β −1.8 per SD of ST2, p=0.02) at 4 months. High levels of ST2 measured at day 1 (&gt;75th percentile) were associated with increased risk of having an adverse clinical event during the first year and with long-term all-cause mortality (Figure). High levels of ST2 measured in a stable phase 4 months after STEMI were also associated with an increased risk of all-cause mortality (Figure). Figure 1 Conclusions High levels of ST2 in STEMI patients were associated with large infarct size, impaired recovery of LV function, and adverse clinical outcome in patients with STEMI. ST2 measured 4 months after STEMI remained associated with all-cause mortality.

P5456The role of ST2 as an early marker of endothelial dysfunction in hypertensive patients

Abstract Background The association between endotelial dysfunction and progression of diastolic dysfunction suggests that endotelial and myocardial impairment might have similar pathogenic pathways. Moreover, in hypertensive diabetics the endotelial function is worse in those with impaired diastolic performance compared to normal diastolic performance. ST2 provides additional data to echocardiography in early detection of diastolic performance alteration in hypertension (HT) and is a prominent predictive marker of worse clinical outcome in hypertensive patients. There is scarce data on ST2 role in detection of early vascular involvement in hypertensive patients. Purpose The aim of the study is to evaluate whether ST2 levels correlate with impaired endotelial function in hypertensive patients. Methods Our prospective study included 84 hypertensive patients (mean age 52.9±14.4 yrs, 54.3% males and 45.7% females), after they signed an informed consent. All patients underwent clinical and laboratory (including ST2) evaluation. To investigate endothelial function, we performed ultrasound measurement of the brachial artery diameter both at rest and during reactive hyperemia in the muscle distal to the brachial artery (BA) which causes endothelium-dependent vasodilatation. The study methodology was approved by the Ethical Committee and statistical data processing was performed with SPSS. Results Patients were assigned to group A – those without left ventricular hypertrophy (LVH) and group B – those with LVH. There were no significant differences regarding gender, age and HT stage between groups A and B. Patients in group A had lower ST2 levels [18.83 (13.98 - 42.05) vs 55.63 (48.6 - 100.21) vs, p&lt;0.001] and fewer risk factors (1.4 vs 2.6, p&lt;0.01) compared to group B. We found significant differences regarding diastolic performance parameters between the groups. The relative increase in diameter (% FMD; DD = D 100) was significantly higher in group A than group B (6.67±0.43% vs 3.10±0.33%, p&lt;0.01). ST2 levels were greater in group B and correlated with the degree of endotelial dysfunction evaluated by flow-mediated dilatation (FMD) (r=0.411, p&lt;0.01). Multiple regression analysis showed that ST2 had a significant negative correlation with the relative increase in arterial diameter while multivariate Cox regression analysis showed ST2 was an independent predictor of endothelial dysfunction severity in hypertensive patients (hazard ratio: 4.012, 95% confidence interval: 1.207–31.24, P=0.031). Conclusions ST2 levels correlate with cardiovascular risk and are a significant predictive marker of endothelial dysfunction in hypertensive patients regardless of diastolic dysfunction.

P5444Plasma Indoleamine 2,3-dioxygenase is highly predictive of cardiac remodeling after myocardial infarction

Abstract Background Acute myocardial infarction (MI) is associated with a strong inflammatory response resulting from the cardiac insult. On the other hand, such an inflammation may lead and/or worsen adverse left ventricular (LV) remodeling after MI. Among the markers of inflammation is Indoleamine 2,3-dioxygenase (IDO), which production is induced upon inflammation. IDO catalyzes the transformation of tryptophane into kynurenine. Purpose We tested plasma IDO activity as a predictor of LV remodeling post-MI. Methods The PREGICA cohort recruited prospectively patients who were admitted because of first acute myocardial infarction. Blood samples were collected on admission, at day 4 and at day 6. Echocardiography and cardiac MRI were obtained at day 4 and at 6 months. To be included, the number of akinetic LV wall segments had to be ≥3 on 17 at day 4. IDO activity was the ratio between kynurenine and tryptophane measured by high pressure liquid chromatography coupled with fluorimetric detection. Remodelers were identified as patients with a variation of end-diastolic left ventricular volume (EDLVV) between day 4 and 6 months post-MI &gt;20%. Results Among the 292 patients studied (mean age 57y, mean necrosis size 26% on MRI), the median increase in EDLVV was 16.7% and 137 (47%) were classified as remodelers. On admission as well as at day 4, IDO activity was significantly higher in remodelers (8.2±4.2% vs 5.3±2.5% and 8.7±5.7% vs 5.6±4.4%, p&lt;0.001) and remained higher at 6 months post-MI. IDO activity at day 4 was highly predictive of LV remodeling (Figure): AUC = 87% [95% CI 83–91%]; IDO threshold of 5.8% resulted in specificity = 81%, sensitivity = 89%, negative predictive value = 89%, positive predictive value = 80%. In contrast, blood levels of NTproBNP, ST2, Galectin 3 or CRP at day 4 were poorly predictive. In multivariate analysis including other predictive variables at day4 (primary angioplasty, EDLVV, LVEF, necrosis size), increase in IDO activity was significantly associated with LV remodeling (OR 1.21 [95% CI 1.11–1.33]. Conclusions IDO activity appears as a promising biomarker for the prediction of LV remodeling after MI. Its specific role in postMI remodeling pathways requires further investigation. Acknowledgement/Funding PHRC national

P778Valsartan reduces level of soluble ST2 and left ventricle remodeling in patients with dual chamber pacemaker

Abstract Introduction Permanent right ventricle pacing leads to left ventricle remodeling, its systolic dysfunction and symptomatic heart failure in the long run. Valsartan is well known for its preventive anti-remodeling function in the post infarction heart remodeling. Objectives To assess the effect of valsartan on left ventricle remodeling in patients with second and third degree atrioventricular block with first-time implantation of dual chamber pacemaker. Methods This was a randomized, double-blind, placebo controlled single center study. One hundred eligible patients were assigned in a 1:1:1 fashion to receive placebo, valsartan 80mg or 160mg once daily, respectively. Echocardiographic assessment of left ventricle geometry, its systolic and diastolic function was performed at baseline and at twelve months. One patient from placebo group suffered stroke. We present the baseline date for 100 enrolled patients and follow-up data for 88 patients who have completed the study. Data in valsartan arms are pooled in one group. Concentration of soluble ST2 was measured in duplicates with Aspect Reader (Critical Diagnostics). Results Results are presented in table. Data are presented as mean and standard deviation. Table 1 Placebo (n=28) Valsartan (n=60) ANOVA Baseline 12 mths Baseline 12 mths sST2, ng/mL 36.0±16.0 39.4±15.3 35.1±15.2 19.9±6.5 0.01 LVEF, % 60±8 55±9 60±8 58±8 0.01 LVEDD, mm 48±5 50±4 48±6 49±5 NS LVESD, mm 29±4 32±5 29±5 31±4 NS LVEDV, mL 79±12 84±13 80±12 81±13 NS LVESV, mL 32±5 38±7 31±5 34±6 0.01 E/A 0.94±0.12 0.92±0.13 0.94±0.15 0.95±0.15 NS DecT, ms 211±38 226±43 223±45 218±37 0.01 IVRT, ms 98±14 108±17 101±17 99±18 0.01 Conclusion Valsartan has protective effect of left ventricle remodeling and function. It may be useful in prevention of pacing induced heart failure. Decrease in soluble ST2 concentration may help explain the alternative mechanism for protective role of valsartan. (NCT01805804)

Modern approaches to evaluating the effectiveness of treatment of chronic heart failure

The efficacy of therapy for patients with chronic heart failure, a new combination drug valsartan/sacubitrile according to the levels of biomarkers ST2 and NT-proBNP was evaluated. In all patients of the study group, valsartan/sacubitrile therapy improved the NYHA functional class, in the control group - only in 75%. The dynamics of indicators of biomarkers ST2 and NT-proBNP coincided with the improvement of the clinical status of patients against the background of therapy, and to a greater extent this trend reflects the indicator NT-proBNP.

Using Soluble ST2 to Predict Adverse Postoperative Outcomes in Patients with Impaired Left Ventricular Function Undergoing Coronary Bypass Surgery.

Background and Objectives: The aim of this study was to investigate the prognostic value of soluble ST2 (sST2) in predicting postoperative adverse events in patients with impaired left ventricular (LV) function undergoing coronary artery bypass graft (CABG) surgery. Materials and Methods: This study included 80 consecutive patients with stable coronary artery disease (CAD) and impaired LV function (ejection fraction ≤ 45%) undergoing on-pump coronary artery bypass graft surgery. The patients were divided into the “high” or “low” group according to their ST2 levels (≥35 or <35 ng/mL). Results: Postoperative adverse events were more common in patients with high sST2 levels than in patients with low sST2 levels (100% vs 26%, p < 0.0001). Multivariate analysis showed that sST2 level was an independent predictor of the presence of postoperative adverse events (OR: 1.117 (95% CI: 1.016–1.228), p = 0.022). The receiver operating characteristic curve (ROC) analysis of sST2 revealed an area under the curve (AUC) of 0.812 (95% CI: 0.710–0.913, p < 0.001) in predicting postoperative adverse events. An sST2 level of 26.50 ng/ml was identified as the optimal cut-off value, with a sensitivity and specificity of 74.1% and 75.3%, respectively. Conclusion: Higher sST2 levels were associated with adverse outcomes after CABG in patients with impaired LV and stable CAD.