Skip to main content

Advertisement

SpringerLink
Log in

ST2 as a Cardiovascular Risk Biomarker: From the Bench to the Bedside

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

ST2 is a member of the interleukin (IL)-1 receptor family discovered in a classical translational science fashion, and exists in two forms, a trans-membrane receptor (ST2L) as well as a soluble decoy receptor (sST2). The ligand of ST2 is IL-33, which is involved in reducing fibrosis and hypertrophy in mechanically strained tissues. In in vitro and in vivo models, ST2L transduces the effects of IL-33, while excess sST2 or abnormalities in ST2 signaling leads to cardiac hypertrophy, fibrosis, and ventricular dysfunction. Clinically, in patients with symptomatic heart failure (HF), elevated concentrations of sST2 are strongly associated with severity of the diagnosis, and powerfully predict increased risk of complications, independent of other established or emerging biomarkers. sST2 testing has also been shown to predict onset of symptomatic HF in patients with acute myocardial infarction, while in community-based subjects, sST2 values independently predict future HF, cardiovascular disease events, and mortality.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Daniels, L. B., & Maisel, A. S. (2007). Natriuretic peptides. Journal of the American College of Cardiology, 50(25), 2357–2368.

    Article  PubMed  CAS  Google Scholar 

  2. Chen, A. A., Wood, M. J., Krauser, D. G., Baggish, A. L., Tung, R., Anwaruddin, S., et al. (2006). NT-proBNP levels, echocardiographic findings, and outcomes in breathless patients: results from the ProBNP Investigation of Dyspnoea in the Emergency Department (PRIDE) echocardiographic substudy. European Heart Journal, 27(7), 839–845.

    Article  PubMed  CAS  Google Scholar 

  3. Januzzi, J. L., Jr., Rehman, S., Mueller, T., van Kimmenade, R. R., & Lloyd-Jones, D. M. (2010). Importance of biomarkers for long-term mortality prediction in acutely dyspneic patients. Clinical Chemistry, 56(12), 1814–1821.

    Article  PubMed  CAS  Google Scholar 

  4. Januzzi, J. L., Jr., Sakhuja, R., O'Donoghue, M., Baggish, A. L., Anwaruddin, S., Chae, C. U., et al. (2006). Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department. Archives of Internal Medicine, 166(3), 315–320.

    Article  PubMed  CAS  Google Scholar 

  5. Braunwald, E. (2008). Biomarkers in heart failure. The New England Journal of Medicine, 358(20), 2148–2159.

    Article  PubMed  CAS  Google Scholar 

  6. van Kimmenade, R. R., & Januzzi, J. L., Jr. (2012). Emerging biomarkers in heart failure. Clinical Chemistry, 58(1), 127–138.

    Article  PubMed  Google Scholar 

  7. Weinberg, E. O., Shimpo, M., De Keulenaer, G. W., MacGillivray, C., Tominaga, S., Solomon, S. D., et al. (2002). Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation, 106(23), 2961–2966.

    Article  PubMed  CAS  Google Scholar 

  8. Januzzi, J. L., Jr., Peacock, W. F., Maisel, A. S., Chae, C. U., Jesse, R. L., Baggish, A. L., et al. (2007). 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. Journal of the American College of Cardiology, 50(7), 607–613.

    Article  PubMed  CAS  Google Scholar 

  9. Mueller, T., Dieplinger, B., Gegenhuber, A., Poelz, W., Pacher, R., & Haltmayer, M. (2008). Increased plasma concentrations of soluble ST2 are predictive for 1-year mortality in patients with acute destabilized heart failure. Clinical Chemistry, 54(4), 752–756.

    Article  PubMed  CAS  Google Scholar 

  10. Rehman, S. U., Mueller, T., & Januzzi, J. L., Jr. (2008). Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. Journal of the American College of Cardiology, 52(18), 1458–1465.

    Article  PubMed  CAS  Google Scholar 

  11. Iwahana, H., Yanagisawa, K., Ito-Kosaka, A., Kuroiwa, K., Tago, K., Komatsu, N., et al. (1999). Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells. European Journal of Biochemistry, 264(2), 397–406.

    Article  PubMed  CAS  Google Scholar 

  12. Coyle, A. J., Lloyd, C., Tian, J., Nguyen, T., Erikkson, C., Wang, L., et al. (1999). Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. The Journal of Experimental Medicine, 190(7), 895–902.

    Article  PubMed  CAS  Google Scholar 

  13. Yin, H., Li, X. Y., Jin, X. B., Zhang, B. B., Gong, Q., Yang, H., et al. (2010). IL-33 prolongs murine cardiac allograft survival through induction of TH2-type immune deviation. Transplantation, 89(10), 1189–1197.

    Article  PubMed  CAS  Google Scholar 

  14. Turnquist, H. R., Sumpter, T. L., Tsung, A., Zahorchak, A. F., Nakao, A., Nau, G. J., et al. (2008). IL-1beta-driven ST2L expression promotes maturation resistance in rapamycin-conditioned dendritic cells. Journal of Immunology, 181(1), 62–72.

    CAS  Google Scholar 

  15. Brint, E. K., Xu, D., Liu, H., Dunne, A., McKenzie, A. N., O'Neill, L. A., et al. (2004). ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nature Immunology, 5(4), 373–379.

    Article  PubMed  CAS  Google Scholar 

  16. Liu, J., Buckley, J. M., Redmond, H. P., & Wang, J. H. (2010). ST2 negatively regulates TLR2 signaling, but is not required for bacterial lipoprotein-induced tolerance. Journal of Immunology, 184(10), 5802–5808.

    Article  CAS  Google Scholar 

  17. Sanada, S., Hakuno, D., Higgins, L. J., Schreiter, E. R., McKenzie, A. N., & Lee, R. T. (2007). IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. The Journal of Clinical Investigation, 117(6), 1538–1549.

    Article  PubMed  CAS  Google Scholar 

  18. Seki, K., Sanada, S., Kudinova, A. Y., Steinhauser, M. L., Handa, V., Gannon, J., et al. (2009). Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling. Circulation. Heart Failure, 2(6), 684–691.

    Article  PubMed  CAS  Google Scholar 

  19. Miller, A. M., Xu, D., Asquith, D. L., Denby, L., Li, Y., Sattar, N., et al. (2008). IL-33 reduces the development of atherosclerosis. The Journal of Experimental Medicine, 205(2), 339–346.

    Article  PubMed  CAS  Google Scholar 

  20. Dieplinger, B., Januzzi, J. L., Jr., Steinmair, M., Gabriel, C., Poelz, W., Haltmayer, M., et al. (2009). Analytical and clinical evaluation of a novel high-sensitivity assay for measurement of soluble ST2 in human plasma—the Presage ST2 assay. Clinica Chimica Acta, 409(1–2), 33–40.

    Article  CAS  Google Scholar 

  21. Coglianese, E. E., Larson, M. G., Vasan, R. S., Ho, J. E., Ghorbani, A., McCabe, E. L., et al. (2012). Distribution and clinical correlates of the interleukin receptor family member soluble ST2 in the Framingham Heart Study. Clinical Chemistry, 58(12), 1673–1681.

    Article  PubMed  CAS  Google Scholar 

  22. Oshikawa, K., Kuroiwa, K., Tago, K., Iwahana, H., Yanagisawa, K., Ohno, S., et al. (2001). Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. American Journal of Respiratory and Critical Care Medicine, 164(2), 277–281.

    Article  PubMed  CAS  Google Scholar 

  23. Martinez-Rumayor, A., Camargo, C. A., Green, S. M., Baggish, A. L., O'Donoghue, M., & Januzzi, J. L. (2008). Soluble ST2 plasma concentrations predict 1-year mortality in acutely dyspneic emergency department patients with pulmonary disease. American Journal of Clinical Pathology, 130(4), 578–584.

    Article  PubMed  Google Scholar 

  24. Manzano-Fernandez, S., Mueller, T., Pascual-Figal, D., Truong, Q. A., & Januzzi, J. L. (2011). Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction. The American Journal of Cardiology, 107(2), 259–267.

    Article  PubMed  CAS  Google Scholar 

  25. Pascual-Figal, D. A., Manzano-Fernandez, S., Boronat, M., Casas, T., Garrido, I. P., Bonaque, J. C., et al. (2011). Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure. European Journal of Heart Failure, 13(7), 718–725.

    Article  PubMed  CAS  Google Scholar 

  26. Bettencourt, P., Azevedo, A., Pimenta, J., Frioes, F., Ferreira, S., & Ferreira, A. (2004). N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation, 110(15), 2168–2174.

    Article  PubMed  CAS  Google Scholar 

  27. Januzzi, J. L., Jr., Rehman, S. U., Mohammed, A. A., Bhardwaj, A., Barajas, L., Barajas, J., et al. (2011). Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction. Journal of the American College of Cardiology, 58(18), 1881–1889.

    Article  PubMed  CAS  Google Scholar 

  28. Boisot, S., Beede, J., Isakson, S., Chiu, A., Clopton, P., Januzzi, J., et al. (2008). Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure. Journal of Cardiac Failure, 14(9), 732–738.

    Article  PubMed  Google Scholar 

  29. Manzano-Fernandez, S., Januzzi, J. L., Pastor-Perez, F. J., Bonaque-Gonzalez, J. C., Boronat-Garcia, M., Pascual-Figal, D. A., et al. (2012). Serial monitoring of soluble interleukin family member ST2 in patients with acutely decompensated heart failure. Cardiology, 122(3), 158–166.

    Article  PubMed  CAS  Google Scholar 

  30. Zilinski, J. L., Shah, R. V., Gaggin, H. K., Gantzer, M. L., Wang, T. J., & Januzzi, J. L., Jr. (2012). Measurement of multiple biomarkers in advanced stage heart failure patients treated with pulmonary artery catheter guided therapy. Critical Care, 16(4), R135.

    Article  PubMed  Google Scholar 

  31. Shah, R. V., Chen-Tournoux, A. A., Picard, M. H., van Kimmenade, R. R., & Januzzi, J. L. (2009). Serum levels of the interleukin-1 receptor family member ST2, cardiac structure and function, and long-term mortality in patients with acute dyspnea. Circulation. Heart Failure, 2(4), 311–319.

    Article  PubMed  CAS  Google Scholar 

  32. Ky, B., French, B., McCloskey, K., Rame, J. E., McIntosh, E., Shahi, P., et al. (2011). High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circulation. Heart Failure, 4(2), 180–187.

    Article  PubMed  Google Scholar 

  33. Pascual-Figal, D. A., Ordonez-Llanos, J., Tornel, P. L., Vazquez, R., Puig, T., Valdes, M., et al. (2009). Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction. Journal of the American College of Cardiology, 54(23), 2174–2179.

    Article  PubMed  CAS  Google Scholar 

  34. Sabatine, M. S., Morrow, D. A., Higgins, L. J., MacGillivray, C., Guo, W., Bode, C., et al. (2008). Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction. Circulation, 117(15), 1936–1944.

    Article  PubMed  CAS  Google Scholar 

  35. Shimpo, M., Morrow, D. A., Weinberg, E. O., Sabatine, M. S., Murphy, S. A., Antman, E. M., et al. (2004). Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation, 109(18), 2186–2190.

    Article  PubMed  CAS  Google Scholar 

  36. Weinberg, E. O., Shimpo, M., Hurwitz, S., Tominaga, S., Rouleau, J. L., & Lee, R. T. (2003). Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation, 107(5), 721–726.

    Article  PubMed  Google Scholar 

  37. Weir, R. A., Miller, A. M., Murphy, G. E., Clements, S., Steedman, T., Connell, J. M., et al. (2010). Serum soluble ST2: a potential novel mediator in left ventricular and infarct remodeling after acute myocardial infarction. Journal of the American College of Cardiology, 55(3), 243–250.

    Article  PubMed  CAS  Google Scholar 

  38. Kohli, P., Bonaca, M. P., Kakkar, R., Kudinova, A. Y., Scirica, B. M., Sabatine, M. S., et al. (2012). Role of ST2 in non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 trial. Clinical Chemistry, 58(1), 257–266.

    Article  PubMed  CAS  Google Scholar 

  39. Wang, T. J., Wollert, K. C., Larson, M. G., Coglianese, E., McCabe, E. L., Cheng, S., et al. (2012). Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation, 126(13), 1596–1604.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosures

Dr. Januzzi has received grant support from Critical Diagnostics, Roche Diagnostics, Siemens, BG Medicine, and Thermo-Fisher.

Author information

Authors and Affiliations

  1. From the Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 32 Fruit Street, Yawkey 5984, Boston, MA, 02114, USA

    James L. Januzzi Jr.

Authors
  1. James L. Januzzi Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James L. Januzzi Jr..

Additional information

Clinical significance

The biomarker ST2 has been increasingly recognized as a predictor of risk for heart failure complications across a wide spectrum of patients, from apparently well, to those with myocardial infarction, as well as those with heart failure.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Januzzi, J.L. ST2 as a Cardiovascular Risk Biomarker: From the Bench to the Bedside. J. of Cardiovasc. Trans. Res. 6, 493–500 (2013). https://doi.org/10.1007/s12265-013-9459-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-013-9459-y

Keywords

Search

Navigation