Advertisement

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

  • James L. JanuzziJr.
Article

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.

Keywords

Biomarker Prognosis Heart failure Acute myocardial infarction 

Notes

Disclosures

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

References

  1. 1.
    Daniels, L. B., & Maisel, A. S. (2007). Natriuretic peptides. Journal of the American College of Cardiology, 50(25), 2357–2368.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Braunwald, E. (2008). Biomarkers in heart failure. The New England Journal of Medicine, 358(20), 2148–2159.PubMedCrossRefGoogle Scholar
  6. 6.
    van Kimmenade, R. R., & Januzzi, J. L., Jr. (2012). Emerging biomarkers in heart failure. Clinical Chemistry, 58(1), 127–138.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.Google Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.From the Cardiology Division of the Department of MedicineMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations