DOI: 10.1111/eci.12482

ORIGINAL ARTICLE sST2 levels are associated with all-cause mortality in anticoagulated patients with atrial fibrillation rez-Cuellar†,‡,§, Francisco Marın‡,¶, Pilar Gallego**, Sergio ManzanoJuan A. Vılchez*,†, Montserrat Pe ‡,¶ ‡,¶ ndez , Mariano Valde s , Vicente Vicente‡,**, Jose  A. Noguera-Velasco†, Gregory Y. H. Lip††,‡‡,§§, Ferna †,‡,§ ‡,** n ~ ez-Llanos n Jordi Ordo and Vanessa Rolda *

Departments of Cardiology and Clinical Analysis, Clinic University Hospital Virgen de la Arrixaca, IMIB-Arrixaca, Murcia,  noma, Barcelona, Spain, ‡Red de Investigacio n Spain, †Department of Biochemistry and Molecular Biology, Universitat Auto § Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain, IIB-Sant Pau Biomedical Research Institute, Hospital Santa Creu i Sant Pau, Barcelona, Spain, ¶Department of Cardiology of Clinic University Hospital Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain, **Hematology and Medical Oncology Unit, General University Hospital Morales Meseguer, Murcia, Spain, †† Department of Clinical Analysis, Clinic University Hospital Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain, ‡‡Centre for Cardiovascular Sciences, University of Birmingham, City Hospital, Birmingham, UK, §§Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

ABSTRACT Background Atrial fibrillation (AF) is associated with high morbidity and mortality, even despite the use of oral anticoagulation (OAC). Soluble suppression of tumorigenicity-2 (sST2) is a member of the interleukin-1 receptor family [interleukin-1 receptor-like 1 (IL1RL1)], which has been associated with an increased risk of mortality and morbidity in heart failure or acute coronary syndrome. We assessed the predictive value of sST2 levels in an unselected ‘real-world’ cohort of anticoagulated AF patients. Methods We included 562 patients (49% male; median age 77 [IQR: 71–82]) with permanent AF who were stable (for at least 6 months) on OAC (INRs 20–30). sST2 levels were quantified by ELISA. Patients were followed-up for up to 4 years, and cardiovascular events and all-cause mortality were recorded. Results Median (IQR) of sST2 levels was 5123 (3909–6740) lg/L. Median follow-up was 1587 days [IQR 1482–1617], and during this period, 91 patients died (162%, 372%/year). The c-statistic for predicting mortality with sST2 was 058 + 003; P = 0017). On multivariate analysis, age [hazard ratio (HR) 109 (105–113); P < 0001], diabetes mellitus [176 (108–288); P = 0023], previous stroke [216 (129–360); P = 0003] and sST2 levels [1008 (1002–114); P = 0008] were independently associated with mortality. Concentrations of sST2 were also significantly associated with the risk of mortality, even after adjusting for the CHA2DS2–VASc score [HR: 1007 (1001–1013); P = 0014]. Conclusions In an anticoagulated AF patient’s cohort, sST2 levels are an independent predictive factor of all-cause mortality. sST2 levels could be a biomarker used to improve clinical risk assessment in anticoagulated AF patients. Keywords atrial fibrillation, biomarker, mortality, Soluble suppression of tumorigenicity-2. Eur J Clin Invest 2015; 45 (9): 899–905

Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia, which is associated with increased morbidity and mortality. AF increases the risk of stroke and death, and this risk of adverse events is increased by the coexistence of other cardiovascular risk factors [1]. Apart from stroke and thromboembolism, many patients with AF also have impaired cognitive function, poor quality of life and higher medical care costs [2]. Oral anticoagulation (OAC) reduces the risk of stroke and death in AF, but total and cardiovascular mortality still remains

generally high despite OAC [3]. Biomarkers could add significant prognostic information regarding mortality [2,4]. Suppression of tumorigenicity-2 (ST2) is a protein member of the IL-1 receptor family [5] with an immunomodulatory function as a cell surface marker of Th2 lymphocytes. ST2 plays a role in diseases marked by T-cell-mediated inflammation, such as asthma and rheumatoid arthritis [6]. The ligand for ST2 seems to be interleukin-33 (IL-33) and the latter exerts antihypertrophic, antifibrotic and anti-apoptotic actions. ST2 is a receptor existing in two forms: one as a transmembrane receptor and the other as a soluble, circulating receptor

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(so-called soluble ST2 or sST2) [7]. sST2 concentrations are increased in inflammatory diseases and in heart disease and are considered a valuable prognostic marker in both. Importantly, expression of sST2 is mechanically induced in cardiomyocytes in response to stretch and the protein participates in the response to injury and remodelling of the heart [8]. In patients diagnosed with ACS or HF and having concentrations of sST2 > 30 lg/L (approximately the 85th percentile of normal), the risk of mortality within one year is higher than in patients with concentrations of sST2 below this level [9]. Furthermore, mortality risk increases with raising concentrations of sST2. Of note, sST2 has also been evaluated as a predictor of HF risk [10,11]. Soluble suppression of tumorigenicity-2 concentrations have never been evaluated in the context of patients with AF. Given the high mortality associated with AF, even despite OAC use, the aim of this study was to assess the predictive value of sST2 levels in an unselected ‘real-world’ cohort of anticoagulated AF patients seen in everyday clinical practice.

Methods Patients The current study included most selected patients. We recruited consecutive patients with permanent or paroxysmal AF on OAC from our outpatient anticoagulation clinics. To homogenize the cohort of patients, only patients who had an international normalized ratio (INR)_ between 20 and 30 during the previous 6 months were included, so the time within the therapeutic range (TTR) of this period was 100%. All patients were anticoagulated with acenocoumarol. Patients with prosthetic heart valves, acute coronary syndromes (ACS), stroke (ischaemic or embolic), valvular AF or any haemodynamic instability as well as patients who had hospital admission or surgical intervention in the preceding 6 months were excluded. A history of malignancy was allowed if the patient’s expected survival duration was more than 6 months and not receiving chemotherapy or radiotherapy at study entry. A complete medical history was recorded at inclusion. Follow-up was performed through visits to the anticoagulation clinic, the hospital electronic medical records system or, when unavailable or persisting doubts, by telephone interview. Baseline stroke risk was assessed using the Cardiac failure or dysfunction, Hypertension, Age over 75 years (Doubled), Diabetes, Stroke (Doubled) – Vascular disease, Age between 65 and 74 and Sex category (Female) (CHA2DS2–VASc) score, as described in recent guidelines. The bleeding risk using the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly (HAS–BLED) score was also recorded.

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Patients were followed-up for up to 4 years. Adverse cardiovascular endpoints (mainly thromboembolic) were defined as stroke/transient ischaemic attack (TIA), peripheral embolism, acute coronary syndrome, acute heart failure and cardiac death. Bleeding events were assessed by the 2005 International Society on Thrombosis and Haemostasis (ISTH) criteria. Finally, we recorded all-cause mortality and whether the cause of death was secondary to a cardiovascular event (stroke/TIA, peripheral embolism, acute coronary syndrome, acute heart failure and cardiac death) or a haemorrhagic one. The study protocol was approved by the Ethical Committee from Hospital Universitario Morales Meseguer, and patients gave informed consent to participation in the study.

Laboratory analysis Blood samples were collected atraumatically and without stasis into syringes preloaded with trisodium citrate (0011 M). Platelet-poor plasma fractions were obtained by centrifugation at 4 °C for 20 min at 2200 g. Aliquots were stored at 80 °C to allow batch analysis. Soluble ST2 levels were quantified by a quantitative sandwich monoclonal ELISA (Presage ST2 Assay; Critical Diagnostics, San Diego, SA, USA) that is FDAapproved. The kit is provided in microplate configuration with wells coated with mouse monoclonal anti-human sST2 antibodies (96 wells). We measured sST2 samples fully automated on a DSX System platform (DYNEX Technologies, Inc, Chantilly, VA, USA) in the laboratories of the IIB-Sant Pau Biomedical Research Institute (Sant Pau Hospital, Barcelona, Spain). The range of used standards was 31–2000 lg/L when used with specimens diluted in a 1 : 50 ratio. The intra-assay coefficient of variation (CV) was of 25% and total CV of 458 lg/L

165 (101–271); P = 0044

163 (106–262); P = 0043

Whilst a single measurement of sST2 provides important prognostic value, the response of sST2 appears to better predict prognosis, as is shown in a recent longitudinal study of 150 patients admitted with NYHA classes II–IV with acutely destabilized HF demonstrating the importance of serial measurement of sST2 [23]. The potential application of sST2 to patients with acutely destabilized HF was recently explored in the PRIDE study, demonstrating how sST2 was a biomarker of risk in patients presenting with dyspnoea [11], and concentrations of sST2 at presentation strongly predict 1-year mortality. The combination of elevated sST2 and NT-proBNP levels had the highest mortality risk, with highest AUC for sST2 in ROC analysis, and a higher hazard ratio in proportional hazards analysis [24]. These data were also confirmed in the study by Mueller et al. [9]. Comparative studies with other patients with AF and lower CHADS2VaSc score are needed to draw strong conclusions. But finally, sST2 may reflect both inflammation and cardiac stretch, being a strong and independent outcome predictor in our population of AF. Importantly, this evidence that sST2 provides additive prognostic value could add information to clinical variables and to other biomarkers as we recently published in a similar AF cohort [25,26]. This could be essential in clinical practice for clinicians who currently have to use clinical information with several scoring systems to manage their patients.

Limitations

166 (102–270); P = 0039

Selection bias could have occurred, because we recruited patients on stable OAC, so unstable patients who are more prone to adverse events were excluded. In addition, these were all patients experienced with coumarin treatment; that is, we recruited a population with good anticoagulation control at entry, which may have minimized bleeding and thrombotic outcomes due to ‘nonsteady’ OAC. Nonetheless, the event rates of thromboembolisms, major bleeds and mortality are comparable to other registries of elderly patients with AF taking OAC. Changes in sST2 may occur during follow-up, and these

Table 4 Cox regression analysis for the endpoint ‘mortality’ investigating sST2 levels as a dichotomized variable. Multivariate analysis HR (95% CI); P value

sST2 Cut-off ROC curve (4583 ng/mL)

sST2 25th percentile (3909 ng/mL)

sST2 50th percentile (5122 ng/mL)

sST2 75th percentile (6703 ng/mL)

Age

105 (105–113); P < 0001

109 (105–113); P < 0001

109 (106–113); P < 0001

109 (105–113); P < 0001

Diabetes

155 (098–245); P = 0058

155 (098–245); P = 0059

163 (104–256); P = 0033

159 (101–253); P = 0046

History of stroke or TIA

184 (111–298); P = 0013

187 (116–301); P = 0010

163 (104–256); P = 0033

178 (110–290); P = 0018

Coronary artery disease

160 (059–270); P = 0075

167 (099–281); P = 0054

167 (104–267); P = 0033

161 (095–271); P = 0072

Renal failure

103 (055–193); P = 091

107 (057–201); P = 0813

103 (055–192); P = 0923

099 (052–186); P = 0980

Current smoking habit

153 (088–265); P = 012

156 (098–270); P = 0813

171 (099–293); P = 0052

154 (089–186); P = 0122

sST2 lg/L

169 (104–274); P = 0032

183 (101–335); P = 0046

136 (087–211); P = 0169

155 (097–247); P = 0062

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modifications could give additional information. There are no data available on cardiovascular outcomes. We should recognize as another possible limitation the influence of cancer disease, as a history of malignancy was allowed if the patient’s expected survival duration was more than 6 months and not receiving chemotherapy or radiotherapy at study entry. Indeed, an association between sST2 and cancer as an immunomodulator has recently been observed [27,28].

Conclusion In an anticoagulated AF patient’s cohort, sST2 levels were an independent predictive factor of all-cause mortality. sST2 levels could be a biomarker used to improve clinical risk assessment in anticoagulated AF patient, especially for mortality risk. Sources of funding This work was partially supported by RD06/0014/039 (Red Cardiovascular, RECAVA) from Instituto de Salud Carlos III, Beca Cajamurcia-Fundaci on para la Formaci on e Investigaci on de la Regi on de Murcia (FFIS) 2010, and PI11/1256-Fondo Europeo de Desarrollo Regional (FEDER) from Instituto de Salud Carlos III. Dr. JA Vılchez received a grant ‘Rio Hortega’ by Instituto Carlos III, Madrid, Spain. Dra P Gallego holds a grant from the Spanish Foundation Alfonso Martın Escudero. Dr. Perez-Cuellar holds a contract from the Red de Investigaci on Cardiovascular, Instituto de Salud Carlos III. Disclosures There are no disclosures in relation to this article for all authors. Dr Roldan has received funding for consultancy and lecturing from Bristol-Myers Squibb (BMS), Bayer and Boehringer Ingelheim. Dr Marın has received funding for research, consultancy and lecturing from Abbott, Boston Scientific, Bayer, Astra Zeneca, Daiichi-Sankyo, BMS/Pfizer and Boehringer Ingelheim. Dr Lip has received funding for research, consultancy and lecturing from different manufacturers of drugs used for the treatment of AF, including Astra Zeneca, Bayer, Boehringer Ingelheim, Astellas, Sanofi-Aventis and Daiichi-Sankyo. Dr. Ordonez-Llanos has accepted honoraria for conferences/consultation from Abbott Laboratories, BioMerieux, Bio-Rad, Roche Diagnostics, Stat Diagnostics and Thermo Fisher and support for research from Abbott Laboratories, Alere Diagnostics, Astute Diagnostics, Critical Diagnostics, Roche Diagnostics, Siemens Healthcare Diagnostics and Thermo Fisher. Address Departments of Cardiology and Clinical Analysis, Clinic University Hospital Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain (J.A. Vılchez, F. Marın, S. Manzano-Fern andez,

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M. Valdes, J. A. Noguera-Velasco); Red de Investigaci on Cardiovascular. Instituto de Salud Carlos III. Madrid. Spain (M. Perez-Cuellar, F. Marın, S. Manzano-Fern andez, M. Valdes, V. ~ ez-Llanos, V. Roldan); IIB-Sant Pau BiomediVicente, J. Ord on cal Research Institute, Hospital Santa Creu i Sant Pau (M. ~ ez-Llanos), Department of Biochemistry Perez-Cuellar, J. Ord on and Molecular Biology, Universitat Aut onoma, Barcelona, ~ ez-Llanos); Hematology and Spain (M. Perez-Cuellar, J. Ord on Medical Oncology Unit, General University Hospital Morales Meseguer, Murcia, Spain (P. Gallego, V. Roldan); University of Birmingham. Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK (G.Y.H. Lip); Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark (G.Y.H. Lip). Correspondence to: Francisco Marın, Department of Cardiology, Hospital Clınico Universitario Virgen de la Arrixaca, Ctra Madrid-Cartagena s/n, Murcia, Spain 30011. Tel./fax: +34 968 398115; e-mail: [email protected] Received 29 November 2014; accepted 14 June 2015 References 1 Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 2007;69:546–54. 2 Kornej J, Apostolakis S, Bollmann A, Lip GY. The emerging role of biomarkers in atrial fibrillation. Can J Cardiol 2013;29:1181–93. 3 Jover E, Roldan V, Gallego P, Hernandez-Romero D, Valdes M, Vicente V et al. Predictive value of the CHA2DS2-VASc score in atrial fibrillation patients at high risk for stroke despite oral anticoagulation. Rev Esp Cardiol (Engl Ed) 2012;65:627–33. 4 Vilchez JA, Roldan V, Hernandez-Romero D, Valdes M, Lip GY, Marin F. Biomarkers in atrial fibrillation: an overview. Int J Clin Pract 2014;68:434–43. 5 Weinberg EO, Shimpo M, De Keulenaer GW, MacGillivray C, Tominaga S, Solomon SD et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 2002;106:2961–6. 6 Barksby HE, Lea SR, Preshaw PM, Taylor JJ. The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders. Clin Exp Immunol 2007;149:217–25. 7 Shah RV, Januzzi JL Jr. ST2: a novel remodeling biomarker in acute and chronic heart failure. Curr Heart Fail Rep 2010;7:9–14. 8 Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 2003;107:721–6. 9 Mueller T, Dieplinger B, Gegenhuber A, Poelz W, Pacher R, Haltmayer M. Increased plasma concentrations of soluble ST2 are predictive for 1-year mortality in patients with acute destabilized heart failure. Clin Chem 2008;54:752–6. 10 Ky B, French B, McCloskey K, Rame JE, McIntosh E, Shahi P et al. High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circ Heart Fail 2011;4:180–7. 11 Januzzi JL Jr, Peacock WF, Maisel AS, Chae CU, Jesse RL, Baggish AL et al. Measurement of the interleukin family member ST2 in

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sST2 levels are associated with all-cause mortality in anticoagulated patients with atrial fibrillation.

Atrial fibrillation (AF) is associated with high morbidity and mortality, even despite the use of oral anticoagulation (OAC). Soluble suppression of t...
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