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Soluble ST2 and Risk of Arrhythmias, Heart Failure, or Death in Patients with Mildly Symptomatic Heart Failure: Results from MADIT-CRT

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Abstract

Soluble ST2 is an established biomarker of heart failure (HF) progression. Data about its prognostic implications in patients with mildly symptomatic HF eligible to receive cardiac resynchronization therapy defibrillators (CRT-D) are limited. In a cohort of 684 patients enrolled in Multicenter Automated Defibrillator Implantation Trial (MADIT)-CRT, levels of soluble ST2 (sST2) were serially assessed at baseline and 1 year (n = 410). In multivariable-adjusted models, elevated baseline sST2 was associated with an increased risk of death, death or HF, and death or ventricular arrhythmia (VA) even when adjusting for baseline brain natriuretic protein (BNP) levels. In addition, patients with lower baseline sST2 levels had greater risk reduction with CRT-D (p = 0.006). Serial assessment revealed increased risk of VA and death or VA (HR per 10 % increase in sST2 1.11 (1.04–1.20), p = 0.004). Among patients with mildly symptomatic HF and eligibility for CRT-D, baseline and serial assessments sST2 may provide important information for risk stratification.

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References

  1. Rea, T. D., Pearce, R. M., Raghunathan, T. E., Lemaitre, R. N., Sotoodehnia, N., Jouven, X., & Siscovick, D. S. (2004). Incidence of out-of-hospital cardiac arrest. The American Journal of Cardiology, 93, 1455–1460.

    Article  PubMed  Google Scholar 

  2. Disertori, M., Gulizia, M. M., Casolo, G., Delise, P., Di Lenarda, A., Di Tano, G., Lunati, M., Mestroni, L., Salerno-Uriarte, J., & Tavazzi, L. (2016). Improving the appropriateness of sudden arrhythmic death primary prevention by implantable cardioverter-defibrillator therapy in patients with low left ventricular ejection fraction. Point of view. Journal of Cardiovascular Medicine (Hagerstown, Md.), 17, 245–255.

    Article  Google Scholar 

  3. Vest, R. N., 3rd, & Gold, M. R. (2010). Risk stratification of ventricular arrhythmias in patients with systolic heart failure. Current Opinion in Cardiology, 25, 268–275.

    Article  PubMed  Google Scholar 

  4. Engels, E. B., Mafi-Rad, M., van Stipdonk, A. M., Vernooy, K., & Prinzen, F. W. (2016). Why QRS duration should be replaced by better measures of electrical activation to improve patient selection for cardiac resynchronization therapy. Journal of Cardiovascular Translational Research, 9, 257–265.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bose, A., Truong, Q. A., & Singh, J. P. (2015). Biomarkers in electrophysiology: role in arrhythmias and resynchronization therapy. Journal of Interventional Cardiac Electrophysiology, 43, 31–44.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Spinale, F. G., & Stolen, C. M. (2013). Biomarkers and heart disease: what is translational success? Journal of Cardiovascular Translational Research, 6, 447–448.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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, 1538–1549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Anand, I. S., Rector, T. S., Kuskowski, M., Snider, J., & Cohn, J. N. (2014). Prognostic value of soluble ST2 in the valsartan heart failure trial. Circulation. Heart Failure, 7, 418–426.

    Article  CAS  PubMed  Google Scholar 

  9. Bayes-Genis, A., de Antonio, M., Galan, A., Sanz, H., Urrutia, A., Cabanes, R., Cano, L., Gonzalez, B., Diez, C., Pascual, T., Elosua, R., & Lupon, J. (2012). Combined use of high-sensitivity ST2 and NT-pro-BNP to improve the prediction of death in heart failure. European Journal of Heart Failure, 14, 32–38.

    Article  CAS  PubMed  Google Scholar 

  10. Ky, B., French, B., McCloskey, K., Rame, J. E., McIntosh, E., Shahi, P., Dries, D. L., Tang, W. H., Wu, A. H., Fang, J. C., Boxer, R., Sweitzer, N. K., Levy, W. C., Goldberg, L. R., Jessup, M., & Cappola, T. P. (2011). High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circulation. Heart Failure, 4, 180–187.

    Article  PubMed  Google Scholar 

  11. Felker, G. M., Fiuzat, M., Thompson, V., Shaw, L. K., Neely, M. L., Adams, K. F., Whellan, D. J., Donahue, M. P., Ahmad, T., Kitzman, D. W., Pina, I. L., Zannad, F., Kraus, W. E., & O’Connor, C. M. (2013). Soluble ST2 in ambulatory patients with heart failure: association with functional capacity and long-term outcomes. Circulation. Heart Failure, 6, 1172–1179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pascual-Figal, D. A., Ordonez-Llanos, J., Tornel, P. L., Vazquez, R., Puig, T., Valdes, M., Cinca, J., de Luna, A. B., & Bayes-Genis, A. (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, 2174–2179.

    Article  CAS  PubMed  Google Scholar 

  13. Moss, A. J., Brown, M. W., Cannom, D. S., Daubert, J. P., Estes, M., Foster, E., Greenberg, H. M., Hall, W. J., Higgins, S. L., Klein, H., Pfeffer, M., Wilber, D., & Zareba, W. (2005). Multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT): design and clinical protocol. Annals of Noninvasive Electrocardiology, 10, 34–43.

    Article  PubMed  Google Scholar 

  14. Moss, A. J., Hall, W. J., Cannom, D. S., Klein, H., Brown, M. W., Daubert, J. P., Estes, N. A., 3rd, Foster, E., Greenberg, H., Higgins, S. L., Pfeffer, M. A., Solomon, S. D., Wilber, D., & Zareba, W. (2009). Cardiac-resynchronization therapy for the prevention of heart-failure events. The New England Journal of Medicine, 361, 1329–1338.

    Article  PubMed  Google Scholar 

  15. Harrell, F. (2001). Regression modeling strategies: with applications to linear models, logistic and ordinal regression, and survival analysis. New York: Springer.

    Book  Google Scholar 

  16. Januzzi, J. L., Jr. (2013). ST2 as a cardiovascular risk biomarker: from the bench to the bedside. Journal of Cardiovascular Translational Research, 6, 493–500.

    Article  PubMed  Google Scholar 

  17. Weinberg, E. O., Shimpo, M., De Keulenaer, G. W., MacGillivray, C., Tominaga, S., Solomon, S. D., Rouleau, J. L., & Lee, R. T. (2002). Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation, 106, 2961–2966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ho, J. E., de Filippi, C. R., & Wang, T. J. (2015). Soluble ST2 testing in the general population. The American Journal of Cardiology, 115, 22B–25B.

    Article  PubMed  Google Scholar 

  19. Ahmad, T., Fiuzat, M., Neely, B., Neely, M. L., Pencina, M. J., Kraus, W. E., Zannad, F., Whellan, D. J., Donahue, M. P., Pina, I. L., Adams, K. F., Kitzman, D. W., O’Connor, C. M., & Felker, G. M. (2014). Biomarkers of myocardial stress and fibrosis as predictors of mode of death in patients with chronic heart failure. JACC Heart Failure, 2, 260–268.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vondrakova, D., Malek, F., Ostadal, P., Vranova, J., Sedlackova, L., Sediva, L., Petru, J., Skoda, J., & Neuzil, P. (2012). Short term effect of CRT on biomarkers of cardiac remodelling and fibrosis: NT-pro-BNP, sST2, galectin-3, and a marker of oxidative stress—ceruloplasmin—a pilot study. International Journal of Cardiology, 159, 159–160.

    Article  PubMed  Google Scholar 

  21. Broch, K., Ueland, T., Nymo, S. H., Kjekshus, J., Hulthe, J., Muntendam, P., McMurray, J. J., Wikstrand, J., Cleland, J. G., Aukrust, P., & Gullestad, L. (2012). Soluble ST2 is associated with adverse outcome in patients with heart failure of ischaemic aetiology. European Journal of Heart Failure, 14, 268–277.

    Article  CAS  PubMed  Google Scholar 

  22. Gaggin, H. K., Szymonifka, J., Bhardwaj, A., Belcher, A., De Berardinis, B., Motiwala, S., Wang, T. J., & Januzzi, J. L., Jr. (2014). Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure. JACC Heart Failure, 2, 65–72.

    Article  PubMed  Google Scholar 

  23. Januzzi, J. L., Pascual-Figal, D., & Daniels, L. B. (2015). ST2 testing for chronic heart failure therapy monitoring: the international ST2 consensus panel. The American Journal of Cardiology, 115, 70B–75B.

    Article  PubMed  Google Scholar 

  24. Knappe, D., Pouleur, A. C., Shah, A. M., Cheng, S., Uno, H., Hall, W. J., Bourgoun, M., Foster, E., Zareba, W., Goldenberg, I., McNitt, S., Pfeffer, M. A., Moss, A. J., & Solomon, S. D. (2011). Dyssynchrony, contractile function, and response to cardiac resynchronization therapy. Circulation. Heart Failure, 4, 433–440.

    Article  PubMed  Google Scholar 

  25. Kutyifa, V., Goldenberg, I., & Moss, A. J. (2016). Lessons learned from the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT). Trends in Cardiovascular Medicine, 26, 137–146.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St., Boston, MA, 02115, USA

    Hicham Skali & Scott D. Solomon

  2. Critical Diagnostics, San Diego, CA, USA

    Robert Gerwien & James V Snider

  3. Boston Scientific, St. Paul, MN, USA

    Timothy E. Meyer & Craig M. Stolen

Authors
  1. Hicham Skali
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  2. Robert Gerwien
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  3. Timothy E. Meyer
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  4. James V Snider
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  5. Scott D. Solomon
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  6. Craig M. Stolen
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Corresponding authors

Correspondence to Hicham Skali or Craig M. Stolen.

Ethics declarations

Funding

Boston Scientific funded the MADIT-CRT trial and the specimen collection. Critical Diagnostics funded the ST2 measurements.

Conflict of Interest

HS has no conflicts to disclose. CMS and TEM are employed by Boston Scientific and have stock ownership in Boston Scientific. RG and JVS are employed by Critical Diagnostics, and JVS has ownership interest in Critical Diagnostics. SDS has received research support (>$10,000) and consulting fees (<$10,000) from Boston Scientific.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and with the 1964 Helsinki declaration and its later amendments. This article does not contain any studies with animals performed by any of the authors.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Editor-in-Chief Enrique Lara-Pezzi oversaw the review of this article

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

Baseline characteristics of the cohorts with and without sST2 assessment. (PDF 1.33 MB)

Supplementary Table 2

(PDF 1.33 MB)

Supplementary Table 3

(DOCX 20 kb)

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Skali, H., Gerwien, R., Meyer, T.E. et al. Soluble ST2 and Risk of Arrhythmias, Heart Failure, or Death in Patients with Mildly Symptomatic Heart Failure: Results from MADIT-CRT. J. of Cardiovasc. Trans. Res. 9, 421–428 (2016). https://doi.org/10.1007/s12265-016-9713-1

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  • DOI: https://doi.org/10.1007/s12265-016-9713-1

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