Published Online
on January 13, 2003

A more recent version of this article appeared on February 11, 2003

This Article Full Text (PDF) All Versions of this Article: 107/5/721    most recent 01.CIR.0000047274.66749.FEv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weinberg, E. O. Articles by Lee, R. T. Search for Related Content PubMed PubMed Citation Articles by Weinberg, E. O. Articles by Lee, R. T. Related Collections Growth factors/cytokines Heart failure - basic studies

Submitted on August 28, 2002
Revised on October 22, 2002
Accepted on October 28, 2002

Identification of Serum Soluble ST2 Receptor as a Novel Heart Failure Biomarker

Ellen O. Weinberg PhD, Masahisa Shimpo MD, PhD, Shelley Hurwitz PhD, Shin-ichi Tominaga MD, PhD, Jean-Lucien Rouleau MD, and Richard T. Lee MD^*

From the Department of Medicine (E.O.W., M.S., S.H., R.T.L.), Brigham and Women's Hospital, Harvard Medical School, Cambridge, Mass; Department of Biochemistry (S.-i.T.), Jichi Medical School, Tochigi, Japan; and Division of Cardiology (J.-L.R.), Toronto General Hospital, Toronto, Ontario, Canada.

^* To whom correspondence should be addressed. E-mail: rlee{at}rics.bwh.harvard.edu.

Background--Using genomic technology, we previously identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes. The soluble receptor form of ST2 is secreted and detectable in human serum. This study tested the hypothesis that soluble ST2 levels in the serum of patients with severe chronic heart failure are increased in patients with neurohormonal activation.

Methods and Results--Serum samples, clinical variables, and neurohormone levels from the PRAISE-2 heart failure trial (NYHA functional class III-IV; end point, mortality or transplantation) were analyzed. ST2 serum measurements were performed with ELISA on samples from 161 patients obtained at trial enrollment and from 139 of the same patients obtained 2 weeks after trial enrollment. Baseline ST2 levels were correlated with baseline B-type natriuretic peptide (BNP) levels (r=0.36, P<0.0001), baseline proatrial natriuretic peptide (ProANP) levels (r=0.36, P<0.0001), and baseline norepinephrine levels (r=0.39, P<0.0001). The change in ST2 was significant as a univariate predictor of subsequent mortality or transplantation (P=0.048), as was baseline BNP (P<0.0001) and baseline ProANP (P<0.0001). In multivariate models including BNP and ProANP, the change in ST2 remained significant as a predictor of mortality or transplantation independent of BNP and ProANP.

Conclusions--Serum soluble ST2 is a novel biomarker for neurohormonal activation in patients with heart failure. In patients with severe chronic NYHA class III to IV heart failure, the change in ST2 levels is an independent predictor of subsequent mortality or transplantation.

Key words: heart failure • natriuretic peptides • norepinephrine • immune system

This article has been cited by other articles:

				D. A. Pascual-Figal, J. Ordonez-Llanos, P. L. Tornel, R. Vazquez, T. Puig, M. Valdes, J. Cinca, A. B. de Luna, A. Bayes-Genis, and on behalf of the MUSIC Investigators Soluble ST2 for Predicting Sudden Cardiac Death in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction. J. Am. Coll. Cardiol., December 1, 2009; 54(23): 2174 - 2179. [Abstract] [Full Text] [PDF]

				K. Seki, S. Sanada, A. Y. Kudinova, M. L. Steinhauser, V. Handa, J. Gannon;, and R. T. Lee Interleukin-33 Prevents Apoptosis and Improves Survival After Experimental Myocardial Infarction Through ST2 Signaling Circ Heart Fail, November 1, 2009; 2(6): 684 - 691. [Abstract] [Full Text] [PDF]

				S. Apostolakis, G. Y.H. Lip, and E. Shantsila Monocytes in heart failure: relationship to a deteriorating immune overreaction or a desperate attempt for tissue repair? Cardiovasc Res, October 28, 2009; (2009) cvp327v2. [Abstract] [Full Text] [PDF]

				R. V. Shah, A. A. Chen-Tournoux, M. H. Picard, R. R.J. van Kimmenade, and J. L. Januzzi Serum Levels of the Interleukin-1 Receptor Family Member ST2, Cardiac Structure and Function, and Long-Term Mortality in Patients With Acute Dyspnea Circ Heart Fail, July 1, 2009; 2(4): 311 - 319. [Abstract] [Full Text] [PDF]

				H. J. Bogaard, K. Abe, A. Vonk Noordegraaf, and N. F. Voelkel The Right Ventricle Under Pressure: Cellular and Molecular Mechanisms of Right-Heart Failure in Pulmonary Hypertension Chest, March 1, 2009; 135(3): 794 - 804. [Abstract] [Full Text] [PDF]

				J. Bartunek, L. Delrue, F. Van Durme, O. Muller, F. Casselman, B. De Wiest, R. Croes, S. Verstreken, M. Goethals, H. de Raedt, et al. Nonmyocardial production of ST2 protein in human hypertrophy and failure is related to diastolic load. J. Am. Coll. Cardiol., December 16, 2008; 52(25): 2166 - 2174. [Abstract] [Full Text] [PDF]

				S. U. Rehman, T. Mueller, and J. L. Januzzi Jr Characteristics of the Novel Interleukin Family Biomarker ST2 in Patients With Acute Heart Failure J. Am. Coll. Cardiol., October 28, 2008; 52(18): 1458 - 1465. [Abstract] [Full Text] [PDF]

				J. Diez Serum Soluble ST2 as a Biochemical Marker of Acute Heart Failure: Future Areas of Research J. Am. Coll. Cardiol., October 28, 2008; 52(18): 1466 - 1467. [Full Text] [PDF]

				W.H. W. Tang The ongoing search for a stratified medicine approach in heart failure. J. Am. Coll. Cardiol., June 17, 2008; 51(24): 2310 - 2312. [Full Text] [PDF]

				E. Braunwald Biomarkers in Heart Failure N. Engl. J. Med., May 15, 2008; 358(20): 2148 - 2159. [Full Text] [PDF]

				T. Mueller, B. Dieplinger, A. Gegenhuber, W. Poelz, R. Pacher, and M. Haltmayer Increased Plasma Concentrations of Soluble ST2 are Predictive for 1-Year Mortality in Patients with Acute Destabilized Heart Failure Clin. Chem., April 1, 2008; 54(4): 752 - 756. [Abstract] [Full Text] [PDF]

				A. M. Miller, D. Xu, D. L. Asquith, L. Denby, Y. Li, N. Sattar, A. H. Baker, I. B. McInnes, and F. Y. Liew IL-33 reduces the development of atherosclerosis J. Exp. Med., February 18, 2008; 205(2): 339 - 346. [Abstract] [Full Text] [PDF]

				J. L. Januzzi Jr, W. F. Peacock, A. S. Maisel, C. U. Chae, R. L. Jesse, A. L. Baggish, M. O'Donoghue, R. Sakhuja, A. A. Chen, R. R.J. van Kimmenade, et al. Measurement of the Interleukin Family Member ST2 in Patients With Acute Dyspnea: Results From the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) Study J. Am. Coll. Cardiol., August 14, 2007; 50(7): 607 - 613. [Abstract] [Full Text] [PDF]

				W.H. Wilson Tang, G. S. Francis, D. A. Morrow, L. K. Newby, C. P. Cannon, R. L. Jesse, A. B. Storrow, R. H. Christenson, COMMITTEE MEMBERS, R. H. Christenson, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure Circulation, July 31, 2007; 116(5): e99 - e109. [Full Text] [PDF]

				M. Mirotsou, V. J. Dzau, R. E. Pratt, and E. O. Weinberg Physiological genomics of cardiac disease: quantitative relationships between gene expression and left ventricular hypertrophy Physiol Genomics, January 12, 2007; 27(1): 86 - 94. [Abstract] [Full Text] [PDF]

				J. J. Saris, P. A.C. 't Hoen, I. M. Garrelds, D. H.W. Dekkers, J. T. den Dunnen, J. M.J. Lamers, and A.H. Jan Danser Prorenin Induces Intracellular Signaling in Cardiomyocytes Independently of Angiotensin II Hypertension, October 1, 2006; 48(4): 564 - 571. [Abstract] [Full Text] [PDF]

				R. R. van Kimmenade, J. L. Januzzi Jr, P. T. Ellinor, U. C. Sharma, J. A. Bakker, A. F. Low, A. Martinez, H. J. Crijns, C. A. MacRae, P. P. Menheere, et al. Utility of Amino-Terminal Pro-Brain Natriuretic Peptide, Galectin-3, and Apelin for the Evaluation of Patients With Acute Heart Failure J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1217 - 1224. [Abstract] [Full Text] [PDF]

				H. Huang, R. D. Kamm, and R. T. Lee Cell mechanics and mechanotransduction: pathways, probes, and physiology Am J Physiol Cell Physiol, July 1, 2004; 287(1): C1 - C11. [Abstract] [Full Text] [PDF]

				M. Shimpo, D. A. Morrow, E. O. Weinberg, M. S. Sabatine, S. A. Murphy, E. M. Antman, and R. T. Lee Serum Levels of the Interleukin-1 Receptor Family Member ST2 Predict Mortality and Clinical Outcome in Acute Myocardial Infarction Circulation, May 11, 2004; 109(18): 2186 - 2190. [Abstract] [Full Text] [PDF]

				D. W. Kamp Idiopathic Pulmonary Fibrosis: The Inflammation Hypothesis Revisited Chest, October 1, 2003; 124(4): 1187 - 1190. [Full Text] [PDF]