Pre-discharge risk stratification in unselected STEMI: Is there a role for ST2 or its natural ligand IL-33 when compared with contemporary risk markers? ☆ Onkar S. Dhillon ⁎, Hafid K. Narayan, Sohail Q. Khan, Dominic Kelly, Paulene A. Quinn, Iain B. Squire, Joan E. Davies, Leong L. Ng ⁎ Department of Cardiovascular Sciences, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK abstract article info Article history: Received 4 August 2011 Received in revised form 9 May 2012 Accepted 27 May 2012 Available online 24 July 2012 Keywords: Myocardial Infarction ST2 N-terminal B type natriuretic peptide prognosis GRACE score IL-33 Background: Soluble ST2 is a marker of cellular stress and injury whose natural ligand is interleukin-33. We investigate, for the first time, the relationship of IL-33 and ST2 with death at 30-days, 1-year and beyond in unselected STEMI patients. We assess the incremental value they offer over GRACE score and NT- proBNP. Secondary endpoints were heart failure readmission and re-infarction. Methods: ST2 and IL-33 were measured in 677 patients 3–5 days after admission. Median follow-up was 587 (134–2818) days during which 101 (15%) patients died. Results: ST2 was higher in those who died when compared to event-free survivors (median [range] 1125 [123–15781] vs. 630 [59–11729] pg/ml, p b 0.001) as was IL-33 (75 [5.4-17893] vs. 5.4 [5.4-16466] pg/mL, p = 0.006). Multivariate Cox regression analysis reveals that elevated ST2 is associated with increased risk of mortality at 30-days (HR 9.34, p b 0.001) and 1-year (HR 3.15, p = 0.001). These relationships continued after further adjustment for GRACE-RS and NT-proBNP. Combining ST2 (c-statistic 0.82, p b 0.001), GRACE- RS (0.82, p b 0.001) and NT-proBNP (0.84, p b 0.001) leads to a significant improvement in the c-statistic for 30-day mortality to 0.90 (p = 0.01). IL-33 above 5.4 pg/ml was independently associated with increased mor- tality at 30-days (HR 4.16, p = 0.007) and 1-year (HR 2.29, p = 0.008) but, did not add incremental prognostic value over using GRACE-RS and NT-proBNP. The ratio IL-33/ST2 was not associated with events. Conclusions: Elevated ST2 and IL-33 were both associated with increased mortality. ST2 demonstrated incre- mental value over contemporary risk markers but, IL-33 did not. ST2 has a potential role in risk stratification using a multi-marker approach. © 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The ST2 gene encodes 2 main isoforms. The first, termed ST2L, is a membrane bound receptor which when bound to its natural ligand, interleukin-33 (IL-33), acts to reduce the cardiac hypertrophic and fi- brotic responses to mechanical stress [1]. The second, termed ST2, is a truncated soluble version detectable in the serum which, conversely, may act as a decoy for IL-33 and thereby have a detrimental role [2,3]. Elevated soluble ST2 has been associated with an adverse 30-day prog- nosis in study populations with acute ST elevation myocardial infarction (STEMI) [4,5] but, relationship with more distant events has not been evaluated. Therefore, the first aim of the present study is to evaluate the association between soluble ST2 levels, taken prior to discharge, and adverse cardiac events at both 30-days, 1-year and beyond in unse- lected patients with STEMI. ST2 has shown additive value to the Throm- bolysis in Myocardial Infarction Risk Score (TIMI-RS) and NT-proBNP [4] but, has not yet been compared with the widely utilised Global Registry of Acute Coronary Events Risk Score (GRACE-RS) [6,7]. In accordance with benchmark criteria set by the American Heart Association (AHA) for the evaluation of novel biomarkers [8] our second aim is to evaluate whether ST2 yields any further value over GRACE-RS and NT-proBNP [9]. Third, we investigate the potential of utilising IL-33 levels as a prog- nostic marker for the first time in STEMI and also explore whether its ratio with ST2 relates to outcome. 2. Methods 2.1. Study Population We studied 677 consecutive patients admitted to the coronary care unit of Leices- ter Royal Infirmary presenting with ST-elevation myocardial infarction (STEMI). 500 patients were recruited between June 2004 and June 2006 and 177 patients between International Journal of Cardiology 167 (2013) 2182–2188 ☆ This work was supported by British Heart Foundation Junior Research Fellowships (grant numbers FS/03/028/15486, FS/05/004 and FS/09/040 for Dr. Dhillon, Dr. Khan and Dr. Narayan respectively) and Prof. Ng and Prof. Squire by the Leicester National Institute for Health Research Cardiovascular Biomedical Research Unit and the Van Geest Foundation. ⁎ Corresponding authors at: Department of Cardiovascular Sciences, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK. Tel.:+44 1162523132; fax: +44 1162523108. E-mail addresses: dhillonos@hotmail.com (O.S. Dhillon), lln1@le.ac.uk (L.L. Ng). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.073 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard