ST2 and mortality in non–ST-segment elevation acute coronary syndrome

https://doi.org/10.1016/j.ahj.2010.02.022Get rights and content

Background

ST2 is a member of the interleukin-1 receptor family that is up-regulated in conditions associated with increased myocardial strain. ST2 has been shown to be independently predictive of adverse outcome in heart failure and ST-segment elevation myocardial infarction, but its prognostic value in non–ST-elevation acute coronary syndrome (NSTE-ACS) has not been established.

Methods

We measured ST2 at randomization and after 24, 48, and 72 hours in 403 NSTE-ACS patients from the GUSTO IV study, and studied its kinetics and its associations to clinical baseline factors and 1-year mortality.

Results

Median ST2 levels decreased from 28.4 U/mL at randomization to 21.8 U/mL at 72 hours (P < .001). Peak levels were noted 6 to 17 hours after symptom onset. Randomization ST2 levels were independently associated to N-terminal pro-B-type natriuretic peptide but otherwise exhibited only weak relations to cardiovascular risk factors and comorbidities, and biomarkers of myocardial necrosis or inflammation. ST2 was related to 1-year mortality independently of clinical risk indicators (odds ratio 2.3 [95% CI 1.1-4.6], P = .03) but lost its predictive value after additional adjustment for prognostic biomarkers, in particular N-terminal pro-B-type natriuretic peptide.

Conclusions

ST2 levels are elevated early in NSTE-ACS and predict 1-year mortality. Our data indicate that ST2 represents an interesting novel pathophysiologic pathway in the setting of ischemia-related myocardial dysfunction. However, future prospective evaluations in larger populations are needed before the clinical utility of ST2 can be determined.

Section snippets

Study population

The protocol and results of the GUSTO IV trial including 1-year follow-up data have been published previously.10, 11 This trial was a prospective multicenter study that for the first time evaluated the safety and efficacy of the glycoprotein IIb/IIIa inhibitor abciximab versus placebo on top of aspirin and unfractionated or low–molecular weight heparin as the primary treatment of NSTE-ACS. In brief, 7,800 patients were enrolled between 1999 and 2000 in GUSTO IV and randomized to 1 of 3

Patient characteristics and ST2 levels

The demographic data and clinical characteristics of the 403 patients included in the present analysis in relation to the median ST2 level at randomization are summarized in Table I. The median delay from symptom onset to randomization was 14.9 (25th-75th percentiles 9.4-19.9) hours. In total, 134 patients (33.3%) had been randomized to 24-hour treatment with abciximab, 135 patients (33.5%) to 48-hour treatment with abciximab, and 134 patients (33.3%) to placebo.

The median ST2 level at

Discussion

This is the first analysis assessing ST2 and its clinical implications in patients with NSTE-ACS. Our results demonstrate that ST2 levels are increased in NSTE-ACS and strongly predictive for mortality 1 year after the index event.

ST2 consists of a transmembrane receptor form (ST2L) restricted to the surface of T-helper type 2 cells and mast cells, and a truncated soluble receptor form (sST2). ST2L acts as a ligand for free IL-33 that exerts antihypertrophic, antifibrotic, and antiapoptotic

Conclusions

In conclusion, our results demonstrate that ST2 levels are increased in NSTE-ACS and indicate that the IL-33/ST2 system reflects a novel pathophysiologic mechanism in the setting of ischemia-related myocardial dysfunction, potentially as an on switch for downstream cardioprotective processes in the injured myocardium. Early ST2 levels were related to mortality independently of other clinical risk indicators. However, ST2 lost its predictive value after adjustment for other prognostic

Disclosures

This study was generously supported by Critical Diagnostics, providing the reagents and support for the conduction of the analyses of ST2. The GUSTO IV trial had been supported by a grant from Centocor Inc (Malvern, PA) and Eli Lilly and Company (Indianapolis, IN). None of these companies played a role in the design of study, interpretation of the data, or preparation or approval of the manuscript. None of the authors had conflicts of interest with respect to the present study.

Acknowledgements

We wish to thank James V. Snider from Critical Diagnostics for support with the conduction of the analyses of ST2 in the present study.

References (23)

  • BassandJ.P. et al.

    Guidelines for the diagnosis and treatment of non–ST-segment elevation acute coronary syndromes. The Task Force for the Diagnosis and Treatment of Non–ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology

    Eur Heart J

    (2007)
  • MorrowD.A. et al.

    National Academy of Clinical Biochemistry laboratory medicine practice guidelines: clinical characteristics and utilization of biochemical markers in acute coronary syndromes

    Clin Chem

    (2007)
  • BlakeG.J. et al.

    C-reactive protein and other inflammatory risk markers in acute coronary syndromes

    J Am Coll Cardiol

    (2003)
  • WeinbergE.O. et al.

    Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction

    Circulation

    (2002)
  • ShimpoM. et al.

    Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction

    Circulation

    (2004)
  • SabatineM.S. et al.

    Complementary roles of biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction

    Circulation

    (2008)
  • RehmanS.U. et al.

    Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure

    J Am Coll Cardiol

    (2008)
  • BoisotS. et al.

    Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure

    J Cardiac Fail

    (2008)
  • KakkarR. et al.

    The IL-33/ST2 pathway: therapeutic target and novel biomarker

    Nat Rev Drug Discov

    (2008)
  • SimoonsM.L. et al.

    Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early revascularisation: the GUSTO IV-ACS randomised trial

    Lancet

    (2001)
  • OttervangerJ.P. et al.

    Long-term results after the glycoprotein IIb/IIIa inhibitor abciximab in unstable angina. One-year survival in the GUSTO IV-ACS (Global Use of Strategies To Open Occluded Coronary Arteries IV–Acute Coronary Syndrome) trial

    Circulation

    (2003)

    • Cited by (76)

    View all citing articles on Scopus
    View full text
    Copyright © 2010 Mosby, Inc. All rights reserved.