The emergency department (ED) evaluation of potential acute coronary syndrome patients is limited by the initial sensitivity of cell injury biochemical markers. Increased ST2, a protein thought to participate in the response to cardiovascular injury, has been noted to be prognostic in patients with acute myocardial infarction. We hypothesize that ST2 would be increased at presentation in ED chest pain patients with myocardial ischemia, thus allowing for the early identification of acute myocardial infarction, acute coronary syndrome, and 30-day adverse cardiovascular events, with an area under the receiver operator characteristic curve (AUC) for each outcome of greater than 0.7.
Patients aged 25 years or older and presenting to the ED with chest pain prompting an ECG were prospectively enrolled. ST2 was measured at presentation. Main outcomes were acute myocardial infarction, acute coronary syndrome, and 30-day events (death, acute myocardial infarction, or revascularization). Median ST2 values were calculated for patients with and without each outcome. The AUCs were calculated for each outcome. In a post hoc analysis, patients with outlying increased ST2 values were examined to determine possible alternative causes for ST2 expression.
There were 348 patients enrolled. The outcomes were acute myocardial infarction 17 patients (4.9%), acute coronary syndrome 39 (11.2%), and 30-day events 23 (6.6%). The AUCs for acute myocardial infarction, acute coronary syndrome, and 30-day events were 0.636, 0.630, and 0.579, respectively. ST2 did not predict acute myocardial infarction, acute coronary syndrome, or 30-day events. It was increased in a small number of patients with pulmonary disease, notably, pulmonary emboli, systemic infection or inflammation, and alcohol abuse.
ST2 was not of value in the evaluation of ED patients with potential acute coronary syndrome.
[Show abstract][Hide abstract] ABSTRACT: Asthma is a chronic disease characterised by variable airflow obstruction, bronchial hyperresponsiveness and airways inflammation. At an immunological level Th2 inflammation and the presence of activated eosinophils and mast cells are key features of asthma. ST2, the receptor for the novel cytokine IL-33, is expressed upon Th2 lymphocytes and mast cells but its role in clinical and experimental asthma remains unclear. IL-33 has been shown to induce local and systemic eosinophilia when administered to the peritoneum of mice. In this thesis I have set out to test the hypothesis that the activation of mast cells by IL-33 acting on cell surface ST2 plays a critical role in allergic airways inflammation. I began by studying the function of ST2 on mast cells in vitro. I found that ST2 was expressed at an early stage of development, and correlated closely with the expression of the stem cell factor receptor (c-kit), a marker present on mast cells from a progenitor stage. Despite this mast cells generated form ST2 gene deleted mice proliferated and matured normally. When mast cells were activated by IL-33, acting in an ST2-dependent manner, pro-inflammatory cytokines and chemokines were released that have potential roles in asthma, specifically IL-6, IL-13, MIP-1α and MCP-1. To extend these findings I looked at the role of ST2 in allergic airways inflammation. I first optimised and validated an ovalbumin and adjuvant based ‘short’ twelve day model of murine asthma and demonstrated that ST2 gene deletion results in attenuated eosinophilic inflammation. In addition to being ST2 dependent it is possible that this adjuvant based short model is mast cell dependent, unlike longer adjuvant based models which are mast cell and ST2 independent. Therefore I went on to study an adjuvant-free model of asthma which has been demonstrated to be mast cell dependent. In this adjuvant-free model of asthma the airway inflammation was attenuated in ST2 gene deficient mice compared with wild type mice, while AHR was unaffected. There was an associated reduction in IgE production and thoracic lymph node recall Th2 cytokine responses. I then examined the effect of ST2 activation in the lungs. When IL-33 was administered directly to the airways of naïve mice it induced the features of experimental asthma. There was extensive eosinophilic inflammation within the lung tissue and airspaces. The Th2 cytokines IL-5 and IL-13, and the eosinophil chemoattractant chemokines eotaxin-1 and eotaxin-2 were detected at increased concentrations. Significant airways hyperresponsiveness was also generated. Using ST2 gene deleted mice I demonstrated that these effects were ST2 specific. Although I have shown that mast cells are activated by IL-33 in vitro, I used mast cell deficient mice to demonstrate that the eosinophilic inflammation generated by IL-33 is unaffected by the absence of mast cells. These data show that IL-33 can induce in the lungs the cardinal pathological characteristics of asthma, and that it appears to act upstream of other important mediators such as IL-13 and the eotaxins. Furthermore the IL-33 receptor ST2 is required in an adjuvant free model of asthma, which is more akin to human disease. Placing these findings in the context of recent evidence that IL-33 is released by structural cells in response to damage or injury suggests that IL-33 may play a key role in initiating the immunological features of clinical asthma. As a consequence of this position in the hierarchy of inflammation IL-33 offers a promising direct target for novel biological therapies in asthma.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the association between ST2 concentrations and mortality at 1 year in 231 acutely dyspneic patients with pulmonary diseases seen in the emergency department. Blood concentrations of ST2 were ascertained; using 1-year survival as the reference standard, receiver operating characteristic curves with resultant area under the curve (AUC) were measured. Cox proportional hazards models identified independent predictors of 1-year death. Hazard curves compared rates of death as a function of ST2 concentration. Concentrations of ST2 were significantly higher in patients with pulmonary diseases compared with 153 subjects without cardiopulmonary disease (0.23 vs 0.11 ng/mL; P = .01). Among patients with pulmonary diseases, concentrations of ST2 were higher among decedents compared with survivors (1.14 ng/mL vs 0.19 ng/mL; P < .001). ST2 had an AUC of 0.72 as a predictor of death (P < .0001). An ST2 of 0.20 ng/mL had a hazard ratio for death of 6.1 (95% confidence interval, 1.8-21.0; P = .004). Compared with patients with lower ST2 concentrations, mortality rates for patients with an enrollment ST2 of 0.20 ng/mL or more diverged early and rose progressively in 1 year (P < .001). ST2 concentrations are frequently elevated in acute pulmonary diseases and are markedly prognostic for death by 1 year.
American Journal of Clinical Pathology 11/2008; 130(4):578-84. DOI:10.1309/WMG2BFRC97MKKQKP · 2.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was designed to investigate: 1) relationships between serum ST2 levels and hemodynamic/neurohormonal variables; 2) myocardial ST2 production; and the 3) expression of ST2, membrane-anchored ST2L, and its ligand, interleukin (IL)-33, in myocardium, endothelium, and leukocytes from patients with left ventricular (LV) pressure overload and congestive cardiomyopathy.
Serum levels of ST2 are elevated in heart failure. The relationship of ST2 to hemodynamic variables, source of ST2, and expression of ST2L and IL-33 in the cardiovascular system are unknown.
Serum ST2 (pg/ml; median [25th, 75th percentile]) was measured in patients with LV hypertrophy (aortic stenosis) (n = 45), congestive cardiomyopathy (n = 53), and controls (n = 23). ST2 was correlated to N-terminal pro-brain natriuretic peptide, C-reactive protein, and hemodynamic variables. Coronary sinus and arterial blood sampling determined myocardial gradient (production) of ST2. The levels of ST2, ST2L, and IL-33 were measured (reverse transcriptase-polymerase chain reaction) in myocardial biopsies and leukocytes. The ST2 protein production was evaluated in human endothelial cells. The IL-33 protein expression was determined (immunohistochemistry) in coronary artery endothelium.
The ST2 protein was elevated in aortic stenosis (103 [65, 165] pg/ml, p < 0.05) and congestive cardiomyopathy (194 [69, 551] pg/ml, p < 0.01) versus controls (49 [4, 89] pg/ml) and correlated with B-type natriuretic peptide (r = 0.5, p < 0.05), C-reactive protein (r = 0.6, p < 0.01), and LV end-diastolic pressure (r = 0.38, p < 0.03). The LV ST2 messenger ribonucleic acid was similar in aortic stenosis and congestive cardiomyopathy versus control (p = NS). No myocardial ST2 protein gradient was observed. Endothelial cells secreted ST2. The IL-33 protein was expressed in coronary artery endothelium. Leukocyte ST2L and IL-33 levels were highly correlated (r = 0.97, p < 0.001).
In human hypertrophy and failure, serum ST2 correlates with the diastolic load. Though the heart, endothelium, and leukocytes express components of ST2/ST2L/IL-33 pathway, the source of circulating serum ST2 is extra-myocardial.
Journal of the American College of Cardiology 01/2009; 52(25):2166-74. DOI:10.1016/j.jacc.2008.09.027 · 16.50 Impact Factor
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