ST2 for the clinician: the time is now

San Diego Veterans Affairs Medical Center and University of California, Division of Cardiology.

When we began using sST2 in the hospital and the heart failure clinic nearly two years ago, I would often be asked: Why should we use sST2 when our present way of managing heart failure is sufficient? The answer is both simple and complex. Take the example of patients presenting with acute heart failure. Most are treated exactly the same-meaning intravenous followed by oral diuretics followed by discharge. Some patients do fine; some are readmitted within 30 days; other die. The discouraging fact here that it is difficult up front to tell which patient will suffer which fate. High BNP levels (above the dry BNP) correlates with volume overload, which is often obvious to the physician. However, our experience thus far suggests that sST2 levels give us insight into the state of heart failure far beyond the state of intravascular volume or physical exam findings. While it is certainly additive to what NPs bring to the table, we believe that sST2 might potentially be looked at as the HbA1c of heart failure (figure one); in other words, the sST2 value has inputs from wall stress, inflammation, macrophage activation (fibrosis) and a number of still-to-be determined stimuli. Just as better glucose control drops HbA1c levels into a better prognostic range, better control of heart failure appears to lower sST2 levels.

Our experience with sST2 in the ADHF patient

Figure 2 depicts a patient whose sST2 levels decreased using a combination of diuretics and ACE inhibitors. This patient who was obese had low BNP levels at admission and throughout treatment. Thus, obesity precluded us using the NP level, but not the level of sST2

Figure 3 demonstrates that while sST2 levels decreased during hospitalization, they were still high (>35 ng/ml) at discharge and this was associated with a readmission ten days later, with even higher sST2 levels..

Finally figure 4 demonstrates the powerful predictive value of a high sST2 at admission. Even with a low BNP level, there was subsequent admissions and death.


 Lessons learned using sST2 in ADHF 

  1. sST2 levels when elevated in patients admitted for ADHF, point to a very sick patient, even when NP levels are either not high, or after they decrease during treatment. 

  2. sST2 levels will fall rapidly with hospital treatment, but if levels are still high at discharge they are still at risk.

  3. A level that falls less than 25% from admission may benefit from more aggressive treatment. We are beginning to drive sST2 levels down by adding medications such as spironolactone while in the hospital.

  4. Elevated sST2 levels are strongly predictive of future heart failure admissions, and characterize the “frequent fliers” better than NPs

  5. Potential uses of sST2 in Emergency Department ED)

The value of sST2 in the ED still needs validation, but there are hints that it may be extremely useful.  We have found the median sST2 level in our ED patients subsequently admitted for heart failure to be about 76 ng/ml, quite a bit higher than the 35ng/ml.  Here are some of the ways that sST2 testing may be useful in the emergency area.

  1. For patients with borderline criteria of admission to the hospital, an ssT2 level great than about 50ng/ml may be reason to admit the patient.
  2. A patient seen with heart failure in the ED who has a BNP level <35ng/ml is of very low risk and likely can be discharged from the ED, after a moderate diuresis is obtained.
  3. If a patient with acute heart is treated for 1-3 days in an observation unit associated with the ED, a dropping sST2 level by 25% or greater tends to portend a better prognosis.
  4. Hi sST2 levels respond well to MRA drugs like spironolactone, and thus, this medication may find greater use in patients with high sST2 levels.

Value of Soluble ST2 in Chronic Heart Failure and use in the Clinic.

Right now, in our clinical setting, we have the availability of not only BNP and sST2 but troponins as well. A recent study by Miller et al biomarkers were collected every 3 months over to years and analyzed in relation to death/cardiac transplantation and heart failure an hospitalization .Time dependent analysis demonstrated that BNP cTnT, and sST2, along with clinical variables demonstrated a relationship to the endpoints in all biomarkers but Galectin 3 .Interestingly, only serial measurements of sST2 demonstrated incremental value in reclassifying patients. Finally, we had data from own institution to go on  (Figure 5). We reported on 588 outpatients who were referred for echocardiography. High sST2 levels were independently associated with 1-year mortality, even among the subgroup of 429 patients with no history of HF. Importantly, no patient with an ST2 value below the median levels died in the first 6 months of follow-up (39).

A cut point of 35 ng/ml appears to separate high-risk from low-risk patients.

A number of studies all point to this level as the proverbial “magic number” to strive for, much the same way we strive for NTproBNP levels < 1000 pg/ml and BNP levels < 100 pg/ml. Januzzi et al determined in the PROTECT trial that the more time a patient spent with levels > 35 ng/ml the more cardiac remodeling was felt to occur . In the Valsartan Heart Failure Trial (VAL-HeFT) an increase in sST2 concentrations from baseline to 12 months was an excellent predictor of events. Finally, the effects of medications on sST2 serial measurements in the PROTECT study were assessed . Those with elevated baseline sST2 concentrations who achieved higher beta-blocker doses had significantly lower risk of events than those titrated to lower beta-blocker dose. Those with low ST2 levels and high beta-blocker doses experienced the lowest rate of events.

Examples of sST2 and BNP in our outpatient clinic

Figure 6 demonstrates a patient whose discharge sST2 level was extremely high. He was placed on high doses of beta-blocker and hydralazine was started. His sST2 level has dropped significantly and within that time period did not have a readmission.

In figure 7, adding Spironolactone decreased sST2 to less than 35 ng/ml and the patient has been free of complications and readmission

Figure 8 demonstrates that a high sST2 level in the clinic predicted subsequent admission, despite a relatively low BNP level.

Finally Figure 9 demonstrates a patient where a high sST2 predicted two early readmissions. Once in clinic medications were added that decreased sST2 from 167 ng/ml to 73 ng/ml (greater than 50% response) and as of August 2015, has not had another admission.

Lessons learned using sST2 in ambulatory heart failure clinic

  1. sST2 levels measured in the outpatient setting, will decrease as effective treatment is added.
  2. A level <35 ng/ml or a response of >50% decrease appears to be associated with improvement in symptoms and prognosis
  3. High sST2 levels in the outpatient setting are predictive of events, even when NP levels are low.

The future of sST2 levels.

If sST2 indeed turns into the HbA1c of heart failure, its value should increase exponentially in our management of patients with heart failure.  Serial sST2 levels should allow us to titrate therapy and monitor the clinical state of the patient . In addition, since sST2 is such a strong marker of the risk of death, it would not be surprising to see a level be used to make decisions when patients are on the cusp of such therapies as ICD, CRT, CardioMems implantation, and even left ventricular assist devices.

A discussion about the use of biomarkers would not be complete without mentioning the issue of surrogates for determining the therapy effectiveness of some of the newer heart failure drugs. Novartis’s Entresto®, the brand name for its recently CE marked and FDA approved ARNI1 drug (previously known as LCZ696) and Servier’s ivabradine drug Corlanor® (marketed by Amgen in the U.S.), also CE marked and FDA approved, while offering exciting potential benefits to heart failure patients – even being hailed ‘game-changer’ drugs by some – raises the thorny issue of cost versus benefit. These new drugs are several times the cost of the generics that have become the mainstay of heart failure treatment, i.e., ACE inhibitors, ARBs, beta-blockers, etc. Pushback is therefore expected from payers.

Because sST2 changes rapidly with the underlying condition of the patient, is not affected by normal confounding factors, and has a single cut point, it may be ideally suited to help clinicians determine if these newer mediations are effective for each patient, are improving quality of life, and whether dosing needs to be titrated or changed.

The new reality of heart failure care is that while more treatment options have opened up, which can literally be a lifesaver for millions of patients, the burden on healthcare systems has skyrocketed. Biomarkers, and particularly sST2, could offer physicians and payors payers a way to bring treatment down to an individual patient level, providing good, affordable care to those in need and can benefit from these breakthroughs. For that and the many real-world examples shown above, sST2 has a very bright future in heart failure care.


  1. Maisel A. Biomonitoring and biomarker-guided therapy: the next step in heart failure and biomarker research. Journal of the American College of Cardiology. Oct 25 2011;58(18):1890-1892.
  2. Maisel AS, McCord J, Nowak RM, Hollander JE, Wu AH, Duc P, Omland T, HC, Storrow AB, Krishnaswamy P, Abraham WT, Clopton P, Steg G, Aumont MC, Westheim A, Knudsen CW, Perez A, Kamin R, Kazanegra R, Herrmann HC, McCullough PA; Breathing Not Properly Multinational Study Investigators.  Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction.  Results from the Breathing Not Properly Multinational Study.  J Amer Coll Cardiol. Jun 4;41(11):2010-7, 2003.
  3. Maisel A, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AHB, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.    347(3):161-167, July 18, 2002.
  4. Maisel, A, Mueller, C, Adams, K, Anker, SD, Aspromonte, N, Cleland, JG, Cohen-Solal, A, Dahlstrom, U, DeMaria, A, Di Somma, S, Filippatos, GS, Fonarow, GC, Jourdain, P, Komajad, M, Liu, PP, McDonagh, T, McDonald, K, Mebazaa, A, Nieminen, MS, Peacock, WF, Tubaro, M, Valle, R, Vanderhyden, M, Yancy, CW, Zannad, F, Brunwald, E.(2008). State of the art: Using natriuretic peptide levels in clinical practice. European journal of heart failure, 2008 Aug 28
  5. Daniels, LB, & Maisel, AS. (2006). Natriuretic peptides as diagnostic test: lessons from the first 5 years of clinical application. Heart failure clinics, 2(3), 299-309.
  6. Maisel, AS, Peacock, WF, McMullin, N, Jesse, R, Fonarow, GC, Wynne, J, Mills, RM. (2008). Timing of immunoreactive B-type natriuretic peptide levels and treatment delay in acute decompensated heart failure: an ADHERE (Acute Decompensated Heart Failure National Registry) analysis. Journal of the American College of Cardiology, 52(7), 534-40.
  7. Xue Y, Clopton P, Peacock WF, Maisel AS. Serial changes in high-sensitive troponin I predict outcome in patients with decompensated heart failure. Eur J Heart Fail. 2011 Jan;13(1):37-42
  8. Januzzi JL, Jr., Filippatos G, Nieminen M, Gheorghiade M. Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section. European heart journal. Sep 2012;33(18):2265-2271.
  9. Peacock WFt, De Marco T, Fonarow GC, et al. Cardiac troponin and outcome in acute heart failure. The New England journal of medicine. May 15 2008;358(20):2117-2126.
  10. Schuetz P, Mueller B.The role of immune and metabolic biomarkers for improved management of sepsis patients.Expert Rev Clin Immunol. 2014 Sep;10(9):1255-62. doi: 10.1586/1744666X.2014.932250. Epub 2014 Jul 29
  11. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective.Clin Chem Lab Med. 2015 Mar;53(4):583-92. doi: 10.1515/cclm-2014-1015.
  12. Maisel A, Neath SX, Landsberg J, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Möckel M, Hogan C, Wu AH, Richards M, Clopton P, Filippatos GS, Di Somma S, Anand I, Ng LL, Daniels LB, Christenson RH, Potocki M, McCord J, Terracciano G, Hartmann O, Bergmann A, Morgenthaler NG, Anker SD.  Use of procalcitonin for the diagnosis of pneumonia in patients presenting with a chief complaint of dyspnoea: results from the BACH (Biomarkers in Acute Heart Failure) trial. Eur J Heart Fail. 2012 Mar;14(3):278-86.
  13. Daniels LB, Bayes-Genis, A. Using ST2 in cardiovascular patients: a review. Fute Cardiol (2014) 10 (4). 525-539
  14. Muelller T, Zimmerman M, Dieplinger B, Ankersmit HF, Haltmayer M. Comparison of plasma concentrations of soluble ST2 measured by three different commercially abalible assays: the MBL ST2 assay, the Presage ST2 assay and the R and D ST2 assay. Clin Chim Acta 413 (19-20), 1493-1494. 2012
  15. Pascual-Figal DA, Januzzi JL. The biology of ST2: The International ST2 Consensus Panel. Am J Cardiol 2015;115[suppl]:3B-7B.
  16. Tominaga S. A putative protein of a growth specific cDNA from BALB/c-3T3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor. FEBS Lett 1989;258:301-304.
  17. Weinberg EO, Shimpo M, De Keulenaer GW, MacGillivray C, Tominaga S, Solomon SD, ET al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 2002;106:2961-2966.
  18. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, ET al. IL-33, an interleukin-1-like cytokyne that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokynes. Immunity 2005;23:479-490.
  19. Wu AH, Wians F, Jaffe A. Biologic variation of galectin-3 and soluble ST2 for chronic Health failure: implication on interpretation of test results. Am Heart J 2013;165:995-999.
  20. Felker GM, Fiuzat M, Thompson V, Shaw LK, Neely ML, Adams KF. Soluble ST2 in ambulatory patients with heart failure: association with functional capacity and long-term outcomes. Circ Heart Fail 2013;6:1172-1179.
  21. Anand IS, Rector TS, Kuskowski M, Snider J, Cohn JN. Prognostic value of soluble ST2 in the Valsartan Heart Failure trial. Circ Heart Fail 2014;7:418-426.
  22. Januzzi JL Jr, Peacock WF, Maisel AS, Chae CU, Jesse RL, Baggish AL 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 2007;50:607-613.
  23. Lassus J, Gayat E, Mueller C, Peacock WF, Spinar J, Harjola VP et al. Incremental value of biomarkers to clinical variables for mortality prediction in acutely decompensated heart failure: the Multinational Observational Cohort on acute heart failure (MOCA) Study. Int J Cardiol 2013;168:2186-2194.
  24. Maisel AS, Richards AM, Pascual-Figual D, Mueller C. Serial ST2 testing in hospitalized patients with acute heart failure. Am J Cardiol 2015;105[suppl]:32B-37B.
  25. Manzano-Fernández S, Januzzi JL, Pastor-Pérez FJ, Bonaque-Gonzales JC, Boronat-Garcia M, Pascual-Figal DA. Serial monitoring of soluble interleukin family member ST2 in patients with acutely decompensated heart failure. Cardiology 2012;122:158-166.
  26. Breidthardt T, Balmelli C, Twenrenbold R, Mosimann T, Espinola J, Haaf P, et al. Heart failure therapy-induced early ST2 changes may offer long-term therapy guidance. J Card Fail 2013;19:821-828.
  27. Mueller t, Dieplinger B, The Presage ST2 Assay: analytical conidertation and clinical applications for a high-sensitivity assay for measurement of soluble ST2. Expert Rev Mol. Diagn 13 (1) 1-18, 2013
  28. Rifai N, Watson ID, Miller, WG Commercial Immunoassays in biomarkers studies: researchers beward! Clinical Chemistroy 58:10 13-87-88, 2012
  29. Daniels LB, Bayes-Genis A.Using ST2 in cardiovascular patients: a review.Future Cardiol. 2014 Jul;10(4):525-39. doi: 10.2217/fca.14.36. Review.
  30. Felker GM, Fiuzat M, Thompson V, Shaw LK, Neely ML, Adams KF. Soluble ST2 in ambulatory patients with heart failure: association with functional capacity and long-term outcomes. Circ Heart Fail 2013;6:1172-1179.
  31. Broch K, Ueland T, Nymo SH, Kjekshus J, Hulthe J, Muntendam P, et al. Soluble ST2 is associated with adverse outcome in patients with heart failure of ischaemic aetiology. Eur J Heart Fail 2012;14:268-277.
  32. Gruson D, Lepoutre T, Ahn SA, Rousseau MF. Increased soluble ST2 is a stronger predictor of long-term cardiovascular death than natriuretic peptides in heart failure patients with reduced ejection fraction. Int J Cardiol 2014;172:e250-e252.
  33. Daniels LB, Clopton P, Iqbal N, Tran K, Maisel AS. Association of ST2 levels with cardiac structure and function and mortality in outpatients. Am Heart J 2010;160:721-728.
  34. Bayes-Genis A, Zhang Y, Ky B. St2 and patient prognosis in chronic heart failure. Am J Cardiol 2015;115[suppl]:64B-69B.
  35. Gagging HK, Szymonifka J, Bhardwaj A, Belcher A, De Berardinis B, Motiwala S, et al. Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitivity troponin T measurements in patients with chronic heart failure. JACC Heart Fail 2014;2:65-72.
  36. Bayes-Genis A, De Antonio M, Villa J, Peñafiel J, Galan A, Barallat J, et al. Head-to-head comparison of 2 myocardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 versus galectine-3. J Am Coll Cardiol 2014:63:159-166.)
  37. Miller, saenger, Grill, Slusser et al  Prognostic value of serial measurements of sST2 and Galectin3 in Ambulatory Chronic heart Failure patients . J of Cardiac Failure )
  38. Daniels LB, Clopton P, Iqbal N, Tran K, Maisel AS. Association of ST2 levels with cardiac structure and function and mortality in outpatients. Am Heart J 2010;160:721-728.