Serum ST2 and hospitalization rates in Caucasian and African American outpatients with heart failure.

BACKGROUND: Limited data exist on the association between circulating suppression of tumorigenicity 2 (ST2) and recurrent hospitalizations and emergency department (ED) encounters in outpatients with heart failure (HF). In addition, data on ST2 in African American patients with HF are scarce. METHODS: We evaluated 307 outpatients with HF (age, 57 ±â€¯12 years; 64.2% men; 51.5% Caucasian, 45.6% African American; median ejection fraction, 35%; ischemic etiology, 41.4%). Median ST2 was 37.8 ng/mL (29.6-51.4). RESULTS: After a median of 3.1 years, there were 584 hospitalizations (224 for HF) and 335 ED visits (80 for HF). Patients (N = 176; 57.3%) with elevated (>35 ng/mL) ST2 had 2-fold higher hospitalization rates in adjusted models (rate ratio [RR] 1.97; 95% CI 1.38-2.82; P < 0.001), driven by 3.5-fold higher HF hospitalization rates (adjusted RR 3.56; 95% CI 1.69-7.49; P < 0.001). These associations persisted after adjusting for baseline B-type natriuretic peptide levels. Findings were similar for elevated ST2 and ED visit rates. Elevated ST2 was associated with the composite of death or HF hospitalization (109 patients; 3-year estimate: 35.4%); risk was 5-fold higher in the first 6 months but declined gradually. The higher hospitalization rates and composite endpoint risk associated with elevated ST2 was similar in African Americans and Caucasians. In landmark analyses in a subset of patients, 6-month (N = 112) and 12-month (N = 149) changes in ST2 levels from baseline added prognostic information. CONCLUSIONS: Elevated ST2 in outpatients with HF portends higher healthcare resources utilization and higher risk for accelerated disease progression, regardless of race, especially in the first 6 months.

Exercise-induced Changes in Soluble ST2 Concentrations in Marathon Runners.

PURPOSE: Previous studies have suggested that extreme endurance exercise may induce cardiac microdamage that could lead to subsequent myocardial fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a cardiac biomarker for assessment of myocardial fibrosis, inflammation, and strain. We evaluated baseline and exercise-induced sST2 concentrations in a heterogeneous cohort of marathon runners to identify predictors for sST2 concentrations. METHODS: Ninety-two runners supplied demographic data, health status, physical activity levels, and marathon experience. Before (baseline) and immediately after (finish) the marathon, blood was collected for analysis of sST2 and cardiac troponin I (cTnI). RESULTS: Eighty-two participants (45 ± 8 yr, 79% male) finished the race in 227 ± 28 min at 92% (88%-94%) of their predicted maximum heart rate (exercise intensity). sST2 concentrations increased in all runners, from 34 (25-46) ng·mL to 70 (53-87) ng·mL (P < 0.001), and cTnI increased from 9 (5-21) ng·L to 60 (34-102) ng·L (P < 0.001). sST2 concentrations were higher in the fastest marathon runners. Sex and marathon personal best time were associated with baseline sST2 (R = 0.27); baseline sST2, weight loss, and exercise intensity during marathon were associated with finish sST2 (R = 0.54); baseline sST2, height, sex, and weekly training hours were associated with the exercise-induced increase in sST2 (R = 0.47). We observed no association between sST2 and cTnI concentrations. CONCLUSION: An exercise-induced increase in sST2 was observed in all marathon runners with sST2 concentrations exceeding cutoff values both at baseline (48%) and finish (94%). Faster runners had higher sST2 concentrations. Our data suggest complex variables determine sST2 concentrations in marathon runners.

Soluble ST2 and Risk of Arrhythmias, Heart Failure, or Death in Patients with Mildly Symptomatic Heart Failure: Results from MADIT-CRT.

Soluble ST2 is an established biomarker of heart failure (HF) progression. Data about its prognostic implications in patients with mildly symptomatic HF eligible to receive cardiac resynchronization therapy defibrillators (CRT-D) are limited. In a cohort of 684 patients enrolled in Multicenter Automated Defibrillator Implantation Trial (MADIT)-CRT, levels of soluble ST2 (sST2) were serially assessed at baseline and 1 year (n = 410). In multivariable-adjusted models, elevated baseline sST2 was associated with an increased risk of death, death or HF, and death or ventricular arrhythmia (VA) even when adjusting for baseline brain natriuretic protein (BNP) levels. In addition, patients with lower baseline sST2 levels had greater risk reduction with CRT-D (p = 0.006). Serial assessment revealed increased risk of VA and death or VA (HR per 10 % increase in sST2 1.11 (1.04-1.20), p = 0.004). Among patients with mildly symptomatic HF and eligibility for CRT-D, baseline and serial assessments sST2 may provide important information for risk stratification.

Charting a roadmap for heart failure biomarker studies.

Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers.

Detection of soluble ST2 in human follicular fluid and luteinized granulosa cells.

Follicular fluid (FF) contains various cytokines that are involved with folliculogenesis, some of which have been shown to be associated with oocyte quality and the implantation potential of a resulting embryo. Several IL-1 family members have previously been identified in FF. This study investigates a newly identified member of the family, IL-33, and its receptor ST2, comparing values to those of FF Granulocyte-Colony Stimulating Factor (G-CSF)--a known predictor of Assisted Reproductive Technology (ART) success. FF was collected from patients undergoing in vitro fertilisation/intra-cytoplasmic sperm injection (IVF/ICSI) at oocyte retrieval to analyse IL-33 and sST2 expression in human follicles. sST2, but not IL-33, is highly increased in the FF compared to plasma levels (up to 7.9-fold), with higher levels in larger follicles (p<0.05). Furthermore, we identify that human luteinised granulosa cells are one possible source of the FF sST2, as these cells express and secrete sST2 when cultured ex vivo. FF associated with oocytes which when fertilised develop into good quality embryos have higher sST2 levels than those which are graded average (p<0.01). These embryos were transferred to the patient and levels of FF sST2 compared between successful and unsuccessful ICSI cycles. However unlike G-CSF, sST2 levels cannot be used to predict cycle outcome.

Cardiovascular biomarkers in acute Kawasaki disease.

BACKGROUND: Endomycocardial biopsies have demonstrated that subclinical myocarditis is a universal feature of acute Kawasaki disease (KD). METHODS: We investigated biochemical evidence of myocardial strain, oxidative stress, and cardiomyocyte injury in 55 acute KD subjects (30 with paired convalescent samples), 54 febrile control (FC), and 50 healthy control (HC) children by measuring concentrations of cardiovascular biomarkers. RESULTS: Levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble ST2 (sST2) were elevated in acute vs. convalescent KD, FC, and HC (p≤0.002), while γ-glutamyl transferase and alanine amino transferase as measures of oxidative stress were increased in acute vs. FC (p≤0.0002). Cardiac troponin I (cTnI) levels, using a highly sensitive assay, were elevated in 30% and 40% of paired acute and convalescent KD subjects, respectively, and normalized within two years of disease onset. NT-proBNP and sST2 negatively correlated with deceleration time, but only NT-proBNP correlated with MV E:A ratio and internal diameter of the coronary arteries (RCA/LAD Zworst). CONCLUSIONS: NT-proBNP and sST2 were elevated in acute KD subjects and correlated with impaired myocardial relaxation. These findings, combined with elevated levels of cTnI, suggest that both cardiomyocyte stress and cell death are associated with myocardial inflammation in acute KD.

Measurement of sST2 is comparable to PlGF in the diagnosis of early-onset pre-eclampsia.

A diagnostic test to confirm pre-eclampsia would be beneficial for the clinical management of the syndrome. The Triage PlGF test is able to confirm pre-eclampsia with high accuracy, with the greatest efficacy at <35weeks gestation. We recently found that the anti-inflammatory protein sST2 is elevated in the plasma of pre-eclamptic women compared to normal controls. Here sST2 and PlGF are compared in early-onset and late-onset pre-eclamptic women. sST2 was found to be an equally good diagnostic tool for early-onset (sST2 AUC 0.944 versus PlGF AUC 0.995; not significant) but not late-onset disease.

ST2 and IL-33 in pregnancy and pre-eclampsia.

Normal pregnancy is associated with a mild systemic inflammatory response and an immune bias towards type 2 cytokine production, whereas pre-eclampsia is characterized by a more intense inflammatory response, associated with endothelial dysfunction and a type 1 cytokine dominance. Interleukin (IL)-33 is a newly described member of the IL-1 family, which binds its receptor ST2L to induce type 2 cytokines. A soluble variant of ST2 (sST2) acts as a decoy receptor to regulate the activity of IL-33. In this study circulating IL-33 and sST2 were measured in each trimester of normal pregnancy and in women with pre-eclampsia. While IL-33 did not change throughout normal pregnancy, or between non-pregnant, normal pregnant or pre-eclamptic women, sST2 was significantly altered. sST2 was increased in the third trimester of normal pregnancy (p<0.001) and was further increased in pre-eclampsia (p<0.001). This increase was seen prior to the onset of disease (p<0.01). Pre-eclampsia is a disease caused by placental derived factors, and we show that IL-33 and ST2 can be detected in lysates from both normal and pre-eclampsia placentas. ST2, but not IL-33, was identified on the syncytiotrophoblast layer, whereas IL-33 was expressed on perivascular tissue. In an in vitro placental perfusion model, sST2 was secreted by the placenta into the 'maternal' eluate, and placental explants treated with pro-inflammatory cytokines or subjected to hypoxia/reperfusion injury release more sST2, suggesting the origin of at least some of the increased amounts of circulating sST2 in pre-eclamptic women is the placenta. These results suggest that sST2 may play a significant role in pregnancies complicated by pre-eclampsia and increased sST2 could contribute to the type 1 bias seen in this disorder.

Establishment of reference intervals for soluble ST2 from a United States population.

BACKGROUND: Soluble ST2 (sST2) is a protein in the interleukin-1 receptor family secreted by myocytes in response to mechanical strain. Elevated sST2 is strongly prognostic in patients with heart failure. METHODS: sST2 was measured using the Presage ST2 ELISA. Evaluation included imprecision, linearity, recovery, analytical sensitivity, limit of quantification, stability, and sample type comparisons. Gender-specific reference intervals were established from 245 male and 245 female serum specimens. RESULTS: At sST2 concentrations of 11.6, 26.9, and 88.0 ng/mL, the within-day CV was 7.6, 2.4, and 3.8%, respectively and the total CV was 11.5, 14.0, and 6.3%, respectively. The assay was linear over a concentration range of 2.8-161.1 ng/mL (y=0.95x+2.25; R(2)=0.997; Sy.x=3.03). The limit of quantification was 3.3 ng/mL. sST2 was stable for 2 days at room temperature, 10days at 4 °C, and 30 days at -20 °C. Concentrations of sST2 were significantly higher in males compared to females (24.9 vs. 16.9 ng/mL; p<0.0001) but were not correlated by age in either gender (r=-0.07; p=0.14). Reference intervals for sST2 were determined to be 8.6-49.3 and 7.2-33.5 ng/mL for males and females, respectively. CONCLUSION: The Presage ST2 ELISA had acceptable performance characteristics for quantifying sST2 in serum or plasma. The assay is precise and linear over a wide sST2 concentration range and can measure low sST2 concentrations. Concentrations of sST2 are unaffected by age but are higher in males compared to females.