|Year : 2018 | Volume
| Issue : 4 | Page : 148-153
Soluble ST2: A biomarker to monitor heart failure progression and treatment
Marin Nishimura MD, 1, Justin Sharim MD, 2, Yu Horiuchi MD, 3, Olga Barnett MD, 4, Nicholas Wettersten MD, 1, Alan S Maisel MD, 1
1 Division of Cardiovascular Medicine, University of California San Diego, San Diego, California, USA
2 Department of Medicine, University of California, San Diego, California, USA
3 Division of Cardiovascular Medicine, Veterans Affairs Medical Center, San Diego, California, USA
4 Department of Cardiology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
|Date of Web Publication||15-Oct-2018|
Dr. Marin Nishimura
9500 Gilman Dr Mc 7411C La Jolla, California 92093-7411
Source of Support: None, Conflict of Interest: None
Measurement of cardiac biomarkers has become routine for the care of patients with heart failure (HF). While troponin and natriuretic peptides are well-entrenched in the guidelines, soluble ST2 (sST2) is a novel biomarker that has shown consistent performance and is ready for clinical use. Multiple studies support the use of sST2 in both acute and chronic HF for prognostication. We suggest a novel scheme to guide HF management based on ambulatory sST2 levels.
Keywords: Biomarker, heart failure, ST2
|How to cite this article:|
Nishimura M, Sharim J, Horiuchi Y, Barnett O, Wettersten N, Maisel AS. Soluble ST2: A biomarker to monitor heart failure progression and treatment. J Clin Prev Cardiol 2018;7:148-53
|How to cite this URL:|
Nishimura M, Sharim J, Horiuchi Y, Barnett O, Wettersten N, Maisel AS. Soluble ST2: A biomarker to monitor heart failure progression and treatment. J Clin Prev Cardiol [serial online] 2018 [cited 2019 Mar 24];7:148-53. Available from: http://www.jcpconline.org/text.asp?2018/7/4/148/243257
| Introduction|| |
A multitude of complex signaling cascades involved in myocardial insult, remodeling, and neurohormonal activation are implicated in the development and progression of heart failure (HF). Various molecules found at each step of these intricate pathways have the potential to reveal important biological information regarding the failing heart. Assessment of cardiac biomarkers has established its role in the routine evaluation and treatment of HF patients. While troponin and natriuretic peptides (NP) are well-entrenched in the HF guidelines, many other proposed biomarkers have come and gone. Soluble ST2 (sST2) is one novel biomarker that holds great promise for HF management. In this review, we will highlight the current evidence for the use of sST2 in the management of HF and propose an algorithm for sST2-guided therapy.
| The Biology of Interleukin-33/ST2 Signaling|| |
ST2 is a member of the interleukin-1 (IL-1) receptor superfamily of proteins. Two distinct isoforms, ST2 L (the transmembrane form) and sST2 (the soluble form), are produced by alternative splicing of the ST2 gene. IL-33 has been identified as a ligand for ST2 L and IL-33/ST2 signaling is involved in T-cell mediated immune responses implicated in a number of inflammatory conditions including asthma, fibroproliferative diseases, autoimmune diseases, sepsis, and malignancy.,
In the heart, the IL-33/ST2 signaling pathway is upregulated in response to biomechanical stress and thought to play an important cardioprotective role in subsequent inflammatory response and fibrosis.,,, The interaction between IL-33 and ST2 L has been shown to reduce fibrosis, hypertrophy, and apoptosis, mitigating adverse remodeling seen in cardiac disease states.,, sST2, on the other hand, is thought to compete with ST2 L for IL-33 as a “decoy receptor,” attenuating the beneficial cardioprotective effects of the IL-33/ST2 signaling pathway [Figure 1]., Consequently, higher sST2 is associated with increased myocardial fibrosis and adverse cardiac remodeling.
|Figure 1: The interleukin-33/ST2 signaling pathway. (a) interleukin.33/ST2 L interaction leads to downstream cardio-protective effect. (b) Sequestration of interleukin-33 by soluble ST2, a decoy receptor. Without cardioprotective effects of the interleukin-33/ST2 L signaling pathway, fibrosis, hypertrophy, and apoptosis ensue, leading to cardiac remodeling|
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| Measurement of Soluble ST2|| |
sST2 can be found in the circulation – in contrast to its transmembrane counterpart – and its serum level can be measured with laboratory assays. The Presage™ ST2 assay (Critical Diagnostics, San Diego, CA) is currently the only sST2 approved assay by the US Food and Drug Administration and has received Conformité Européenne mark for clinical use. The assay measures sST2 in either serum or plasma via an ELISA. Good precision (coefficient of variation <4%) and high in vitro stability of the Presage™ assay have been demonstrated. The recommended cut point for sST2 is 35 ng/ml.
One of the strengths of sST2 is that unlike other cardiac biomarkers, sST2 appears to be minimally affected by patient characteristics such as age, obesity, etiology of HF, and anemia.,,,, In particular, renal impairment significantly affects the levels of NPs and cTn, whereas sST2 levels are affected to a lesser degree.,,,, Another notable strength of sST2 is its low intraindividual variation which is considerably lower than that of NPs. The low-biological variability of sST2 makes it an ideal biomarker for serial measurements to monitor disease course and response to therapy. Hence, there has recently been a surge of studies investigating the utility of sST2 in various HF clinical scenarios. We will review some of the notable studies in the following sections.
| Utility of Soluble ST2 in Acute Heart Failure|| |
sST2 is triggered by myocardial stress and is elevated during episodes of acute HF (AHF). In the PRIDE (Pro-Brain NP Investigation of Dyspnea in the Emergency Department) study, sST2 levels of 593 patients presenting to the emergency department with undifferentiated acute dyspnea were analyzed. Diagnosis of AHF was adjudicated by study physicians based on clinical history gathered by direct patient contact or by review of records. As a result, patients with an adjudicated diagnosis of AHF were found to have a significantly higher sST2 level compared to those without AHF, although N-terminal pro b-type natriuretic peptide (NT-proBNP) was still found to be superior to sST2 for the diagnosis of AHF. Importantly, sST2 measured during hospitalization was found to be strongly predictive of mortality at 1 year in dyspneic patients with and without AHF; the median concentration of sST2 was higher among decedents than survivors at 1 year (1.08 vs. 0.18 ng/ml, P < 0.001). In multivariate analysis, a sST ≥20 ng/ml predicted 1-year mortality among dyspneic patients as a whole (adjusted hazard ratio [HR] = 5.6, P < 0.001) as well as those with AHF (adjusted HR = 9.3, P = 0.03). The authors also found that the prognostic utility of sST2 was complementary to that of NT-proBNP; patients with elevation in both sST2 (≥20 ng/ml) and NT-proBNP (≥986 pg/ml) had the highest rate of 1-year mortality regardless if the dyspneic patients had AHF or not. Of note, those with low sST2 levels had low rates of 1-year mortality, irrespective of NT-proBNP levels. In fact, the majority of deaths in the PRIDE study occurred in those with elevated sST2, suggesting sST2 can reclassify risk of mortality beyond NT-proBNP. In a long-term follow-up analysis of the PRIDE study, sST2 obtained during AHF continued to significantly predict mortality at 4 years, even after adjustment for clinical, biochemical, and echocardiographic findings including left ventricular ejection fraction (LVEF) and logNT-proBNP (HR = 2.7; P = 0.003). In a recent meta-analysis including 10 studies with 4,835 patients, Aimo et al. also demonstrated that sST2 measured during AHF was predictive of cardiovascular outcomes at median follow-up of 13.5 months. Both admission and discharge sST2 levels were predictive of cardiovascular death (admission sST2, HR 2.29, P < 0.001; discharge sST2, HR 2.20, P < 0.001) and all-cause mortality (admission sST2, HR 2.46, P < 0.001; discharge sST2, HR 2.06, P < 0.001). Discharge sST2 also predicted HF rehospitalization (discharge sST2, HR 1.54, P = 0.007). Hence, robust recent evidence demonstrates the prognostic utility of sST2 assessment in patients admitted with AHF.
sST2 can also enhance risk prediction with other biomarkers in AHF. In a study by the GREAT network (Global Research on Acute Conditions Team), plasma biomarkers (sST2, mid-regional-pro adrenomedullin [MR-proADM], NT-proBNP, and C-reactive protein [CRP]), clinical characteristics and outcomes of 5306 patients admitted with AHF were analyzed. A clinical prediction model based on patient characteristics (age, gender, blood pressure, presence of estimated glomerular filtration rate <60 ml/min/1.73 m2, sodium and hemoglobin levels, and heart rate) was constructed, and individual plasma biomarker was assessed for improvement in the prediction model based on clinical risk factors. All biomarkers studied, with the exception of cardiac troponins, improved the model in predicting 30-day and 1-year mortality. Among the biomarkers, sST2 emerged as the best predictor of both 30-day and 1-year mortality. sST2 was also found to be the strongest biomarker with respect to its ability to reclassify death beyond a clinical model at both 30-days mortality (net reclassification improvement [NRI] 25.5%, P < 0.001) and 1-year mortality (NRI 10.3%, P < 0.05). An exception was MR-proADM, which was shown to have a better reclassification ability for 30-day mortality (NRI 28.7%, P < 0.001) although slightly lower regarding 90-day mortality (NRI 9.1%, P < 0.05).
Furthermore, in another analysis of the PRIDE study, cardiac structural and functional features of those patients presenting with dyspnea in relation to sST2 were analyzed. In this echocardiographic study, the authors revealed several associations between sST2 and echocardiographic features of more severely decompensated state and adverse cardiac remodeling. sST2 was associated with higher right ventricular systolic pressure (RVSP, r = 0.261, P = 0.005) and more severe tricuspid regurgitation, r = 0.284, P = 0.001. sST2 was also significantly correlated with higher LV end-systolic dimension (r = 0.181, P = 0.04) and inversely related to LVEF, r = − 0.367, P < 0.001 and RV fractional area change (r = − 0.175, P = 0.05). sST2 was also associated with RV hypokinesis (P < 0.001). In multivariate linear regression, independent predictors of sST2 levels included RVSP (t = 2.29, P = 0.002), LVEF (t = 2.15, P = 0.05), LV dimensions (end systolic, t = 2.57, P = 0.01; end diastolic, t = 2.98 m P = 0.005), log-transformed NT-proBNP (t = 3.31, P = 0.009), heart rate (t = 2.59, P = 0.01), and presence of jugular venous distension (t = 2.00, P = 0.05). Hence, measurement of sST2 during AHF has the potential to shed a light on many aspects of the patient's specific disease state including the diagnosis, short- and long-term prognosis, and severity of adverse remodeling, and it does this incrementally to other clinical characteristics and more widely utilized biomarkers.
| Change in Soluble ST during and After Acute Heart Failure Hospitalization|| |
Although we have thus far focused on isolated measurements of sST2 during AHF, our experience tells us that sST2 is a dynamic biomarker that could fall or remain elevated through a hospital course and beyond. As such, serial sST2 measurements during AHF hospitalization have also been investigated to determine their potential clinical implications.
In a study of patients hospitalized with AHF, Boisot et al. demonstrated the percent change in sST2 between admission to discharge was predictive of 90-day mortality. Patients whose sST2 levels decreased by 15.5% or more had a 7% 90-day mortality, whereas patients whose sST2 levels failed to decrease by at least 15.5% had a 33% 90-day mortality. In a similar study of 72 patients admitted with AHF, Manzano-Fernández et al. also identified the highest mortality (50% at 2 years) among patients admitted with an elevated sST2 (>76 ng/mL) that remained elevated during the course of the hospitalization (>46 ng/mL on hospital day 4). Furthermore, the C-index and reclassification analyses demonstrated that serial sST2 measurements improved mortality prediction beyond models based on other clinical risk factors (C-index of original model 0.76 vs. 0.88 with inclusion of sST2, P < 0.001; Intermittent dobutamine infusion 0.27, P < 0.001). Breidthardt et al. also measured sST2 on admission and at 48 h among patients with AHF and made similar observations. Patients that died within 1 year were noted to achieve lesser sST2 decrease during hospitalization compared to the survivors (median-25% among the deceased vs. − 42% among the survivors; P < 0.01). In a multivariate Cox regression analysis, change in sST2 during hospitalization independently predicted mortality at 1 year (adjusted HR 1.07 for every increase of 10%; P = 0.02). Hence, a decrease in sST2 during the AHF hospitalization appears to hold important prognostic implication as well.
Finally, in a recent Translational Initiative on Unique and novel strategies for Management of Patients with HF clinical cohort study, 496 patients admitted with AHF were subsequently followed with serial measurements of sST2 after hospital discharge for 1 year. After adjustment, they too found an association between baseline sST2 and risk for the composite outcome of mortality and HF readmission (adjusted HR per 1 standard deviation increase in sST2 on the log2 scale 1.30, P = 0.005). Adding to the previous data, the authors demonstrated a significant association between a rising sST2 during follow-up after AHF hospitalization and the composite outcome of mortality and HF readmission (aHR per 1 ST increase in sST2 1.85, P = 0.044). Hence, ambulatory sST2 trajectory even following AHF hospitalization may play an important role in patient risk stratification.
| Soluble ST2 in Chronic Heart Failure|| |
In addition to the use in patients with AHF, studies have consistently supported clinical utility of sST2 monitoring in the ambulatory setting in patients with chronic HF. Daniels et al. investigated sST2 levels in 588 outpatients with HF referred for echocardiography and demonstrated that among stable HF patients, there was a significant association between sST2 and 1-year mortality risk (log sST2, adjusted HR 15.11, P < 0.01). Survival analysis of these patients showed an incremental risk of 1-year mortality with increasing sST2 quartile (P = 0.01 for linear trend). In fact, no patient with an sST2 level below the median (19.8 ng/mL) died within the first 6 months of follow-up. Of note, although BNP was a significant predictor of 1-year mortality in univariate analysis (HR 2.88, P = 0.004), the effect attenuated after adjustment for sST2 and other confounding factors. Felker et al. similarly observed a significant association between ambulatory sST2 and a long-term composite outcome of death or HF readmission (adjusted HR 1.48, P < 0.0001). The prognostic utility of sST2 was also demonstrated in ischemic HF patients. In the cohort of Controlled Rosuvastatin Multinational Trial in HF (CORONA) study including 1,449 elderly patients with LVEF ≤40% due to ischemic heart disease, sST2 was predictive of death and hospitalization due to worsening HF after adjustment for confounders including NTpro-BNP and CRP. In a recent meta-analysis of sST2 measurement in chronic HF, seven studies with 6372 patients were analyzed for all-cause mortality, and five studies with 5,051 patients were analyzed for cardiovascular mortality. A significant association between ambulatory sST2 and all-cause mortality (adjusted HR 1.75, P < 0.001) as well as cardiovascular mortality (adjusted HR 1.79, P < 0.001) was observed, further supporting the use of sST2 in ambulatory patients with stable HF.
In clinical practice, management decisions are not often made solely based on an isolated lab value. As such, the utility of sST2 in a biomarker panel or risk score has also been investigated. Bayes-Genis et al. investigated the value of a multibiomarker panel which included NT-proBNP, hs-TnT, and sST2 in ambulatory HF patients and found the panel of all three was superior to any of the three biomarkers alone or in combination at identifying patients at elevated risk for recurrent hospitalization. Lupón et al. suggested optimal risk stratification of chronic HF patients using the ST2-R2 (reverse remodeling) score, which incorporated sST2, non-ischemic etiology, absence of left bundle branch block (LBBB), HF duration, baseline LVEF, and beta-blocker treatment. The ST2-R2 score was shown to predict reverse LV remodeling in chronic HF patients; improvement in the score resulted in LVEF recovery (from + 5.6% to 17.3%, P < 0001), percentage reduction in LV end-systolic volume index (from −6.1% to −32.1%, P < 0.001), and LV end-systolic diameter index (from −1.1% to −18.6%, P < 0.001). The ST2-R2 score also predicted mortality at 4 years.
| Serial Soluble ST2 in Chronic Heart Failure|| |
Serial ambulatory sST2 levels can also be monitored in patients with chronic HF to assess disease course. In a post hoc analysis of the PROTECT study (proBNP Outpatient Tailored Chronic HF Study), sST2, as well as NT-proBNP, growth determination factor-15 (GDF-15), and hsTnT were measured in 151 outpatients with chronic HF at 0, 3, 6, and 9 months. Baseline levels of all three biomarkers independently predicted time to cardiovascular event after adjustment for covariates including NT-proBNP. Beyond baseline measurements, however, serial measurements of only sST2 (but not GDF-15 or hs-cTnT) demonstrated incremental benefit in predicting cardiac outcome. Change in sST2 from ≤35 ng/mL to >35 ng/mL during the study was associated with increased risk of cardiovascular event (HR 3.64, P = 0.009). Furthermore, the percentage of time spent below the threshold of 35 ng/mL also predicted improved cardiovascular outcomes (adjusted OR 0.86 for each 10% time spent below 35 ng/mL). In the cohort of Valsartan HF Trial, prognostic values of sST2 were evaluated at baseline, 4 months, and 12 months; increases in sST2 for 12 months, but not decreases, were significantly associated with subsequent outcomes of HF readmission and mortality.
| Directing Therapy Based on Soluble ST2|| |
If an elevated sST2 portends worse outcome for patients with HF, can we specifically target these at-risk patients with pharmacotherapy to mitigate the risk?
In a post hoc analysis of the aforementioned PROTECT study, Gaggin et al. demonstrated that elevation in sST2 may identify patients who are more likely to benefit from higher beta-blocker dosage. To investigate the relationship between sST2 levels and beta blocker dosing, the authors stratified the study population based on sST2 (low versus high, cut-off = 35 ng/mL) and the achieved dose of beta blocker with time (high >50 mg versus low <50 mg daily equivalent of metoprolol succinate). Although beta-blocker therapy had dose-related benefits across all participants regardless of baseline sST2 levels, patients with high baseline sST2 treated with low-dose beta-blockade had the highest cardiovascular event rate. These high-risk patients can particularly benefit from higher dose beta-blocker therapy. Breidthardt et al. also found that the association of beta-blockers with survival differed significantly according to sST2 levels, with beneficial effects restricted to those with sST2 levels that failed to respond through the hospital stay (P = 0.04). Thus, vigilant targeting of beta-blocker therapy to subgroups of patients with elevated sST2 may afford a particular survival advantage from this perspective. Similarly, elevated sST2 may identify patients that may especially benefit from the addition of a mineralocorticoid receptor antagonist. In a study on the effect of spironolactone in patients with AHF, patients with elevated sST2 were noted to derive significant benefit from spironolactone therapy regarding mortality and rehospitalization risk (P = 0.007), in contrast to those without elevated sST2 (P > 0.05). Mineralocorticoid-receptor antagonists are thought to exert their effect on sST2 via a reduction of cardiac fibrosis and subsequent remodeling. Renin-angiotensin-aldosterone system inhibitors have been previously shown to enhance IL-33/ST2 signaling and lower expression of fibrosis and inflammatory markers,, thus preventing increased collagen synthesis.
Taken together, we propose the following clinical algorithm for the use of sST2 in guiding clinical HF management [Figure 2].
|Figure 2: Use of soluble ST2 in outpatients with heart failure. (a) Patients with heart failure with reduced ejection fraction. (b) Patients with heart failure with preserved ejection fraction|
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Of note, our model suggests the use of sST2 for treatment guidance in patients with HF with Preserved EF (HFpEF); however, definitive evidence is still conflicting in regards to whether sST2 levels differ between HFpEF and HF with Reduced EF (HFrEF)., Nonetheless, it has been shown that sST2 levels significantly correlate both with the severity of HF symptoms and 1-year all-cause mortality in HFpEF. Moreover, Wang et al. have previously demonstrated the diagnostic role of sST2 in HFpEF, showing that sST2 levels were superior to those of NT-proBNP regarding both identifying patients with HFpEF as well as increasing proportionally to E/e'. Zile et al. later corroborated these findings, also showing a significant and direct relationship between sST2 and indices of HFpEF severity, including E/e' and left atrial volume on echocardiography. In HFpEF, elevated sST2 levels may result from elevated left ventricular filling pressures and subsequent myocardial stress, as evidenced by direct correlations of sST2 levels with diastolic load., We thus propose the use of sST2 under the current algorithm in both HFrEF as well as HFpEF given its association with cardiac remodeling and its subsequent strong prognostic utility.
| Conclusion|| |
sST2 is a novel biomarker that has shown its immense potential for HF management and is ready for clinical use. Robust evidence supports the prognostic utility of sST2 in both acute and chronic HF. sST2 elevation in patients with HF identifies at-risk patients who will derive the most benefit from intensive pharmacotherapy. As such, sST2 can be used as a biomarker in an ambulatory setting to target pharmacotherapy for optimal, more personalized medical management of patients with HF.
Financial support and sponsorship
Conflicts of interest
Dr Alan S Maisel reports receiving research grants from Roche and consulting for Critical Diagnostics.
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[Figure 1], [Figure 2]