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Soluble Suppression of Tumorigenicity 2: A Role in Biomarker-Guided Therapy of Heart Failure

Alexander E. Berezin1, MD, PhD; Alexander A. Berezin2, MD

1 Department of Internal Medicine, State Medical University of Zaporozhye, 26, Mayakovsky av., Zaporozhye, Ukraine
2 Department of Internal Medicine, Medical Academy of Postgraduate Education, Zaporozhye, Ukraine

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Alexander E. Berezin, Professor, MD, PhD, Senior Consultant of Therapeutic Unit, Internal Medicine Department, State Medical University of Zaporozhye, 26, Mayakovsky av., Zaporozhye, Ukraine.
Email: aeberezin@gmail.com; dr_berezin@mail.ru
Telephone: +966-12-2266666, ext. 25797
Fax: +380612894585

Received: May 31, 2019
Revised: May 31, 2019
Accepted: May 31 2019
Published online: July 3, 2019

ABSTRACT

Current clinical guidelines of European Society of Cardiology and American Heart Association regarding the diagnosis and treatment of acute and chronic HF recommend to use natriuretic peptides (NPs) as powerful diagnostic and predictive biomarker, while other biomarkers, such as galectin-3, cardiac troponins, and soluble suppressor of tumorigenisity (ST2) are embedded onto American Heart Association statement to improve a risk stratification, as well as NPs are considered for performing biomarker-guided therapy. The aim of the Editorial is to summarize knowledge among clinical efficacy of heart failure (HF) guidance care based on serial measure of sST2. Elevated levels of sST2 are established biomarker of high risk of all-cause and cardiovascular mortality, new diagnosed HF and re-admission due to HF decompensation, Therefore, a trend to declined serum levels of sST2 was associated with improved survival and decreased re-hospitalization in patients with different phenotypes of HF. It has shown that serial measure of sST2 concentrations in HF patients can predict poor clinical outcomes and personally optimize treatment care, especially in combination with repetitive measure of NT-proBNP levels. However, the role of combined biomarker approach (sST2 + NT-proBNP) in the clinical care of the HF patient is not yet partially defined and more large clinical trials are needed.

Key words: Heart failure; Biomarkers; Soluble ST2; Guided therapy; Prediction; Outcomes

© 2019 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Berezin AE, Berezin AA. Soluble Suppression of Tumorigenicity 2: A Role in Biomarker-Guided Therapy of Heart Failure. Journal of Cardiology and Therapy 2019; 6(1): 789-792 Available from: URL: http: //www.ghrnet.org/index.php/jct/article/view/2605

INTRODUCTION

The prevalence of heart failure (HF), which is associated with cardiovascular (CV) morbidity and mortality, is increasing worldwide[1]. Although during last decade there was rather an increase in prevalence of HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction (HFrEF), which remained stable for this period or even occurred to have declined in developed countries, the prognosis of HF regardless of phenotypes continued poor[2,3]. Patients with acute or actually decompensated heart failure (HF) are at high risk of cardiovascular (CV) death and even over next 30 days after discharged from the hospital expecting rate for HF-related outcomes remained to be extremely high[4,5]. Moreover, incidences for CV events and mortality in hemodynamically stable out-patients with overall types of HF have been widely recognized to be unchanged across last two decades[5]. It has been noted that majority of death causes in HFpEF out-patients are CV, whereas the proportion of non-CV deaths is higher in HFpEF than HFrEF. Perhaps, our understanding regarding optimal medication and risk factors control should be reappraised. In this context, circulating biomarkers, which reflect several pathogenetic stages of HF development, may be useful tool to revolutionize the diagnosis, prognosis and guidance in therapy of HF[6,7]. However, current clinical guidelines of European Society of Cardiology and American Heart Association regarding the diagnosis and treatment of acute and chronic HF recommend to use natriuretic peptides (NPs) as powerful diagnostic and predictive biomarker, while other biomarkers, such as galectin-3, cardiac troponins, and soluble suppressor of tumorigenisity (ST2) are embedded onto American Heart Association statement to improve a risk stratification, as well as NPs are considered for performing biomarker-guided therapy[8,9]. Table 1 is reported clinical relevance of circulating biomarkers for HF diagnosis, prediction, stratification and guided therapy. Previously, biomarker-guided therapy of HF has been found to be similarly efficient to clinical-guided care in routine practice, but nowadays there is a large number of evidence regarding new perspectives for biological markers in this field[10,11]. Indeed, changes in NPs (brain NP [BNP] and NT-proBNP) were significantly associated with risk of hospital stay for HF worsening [12], whereas increased biological variability, relation to body mass / obesity, decreased kidney clearance, other CV and non-CV disease, such as atrial fibrillation, diabetes mellitus, chronic obstructive pulmonary disease, pulmonary hypertension, and infections, shape serious problems in interpretations of data received[13]. It has been suggested that multiple biomarker models could be the best decision to improve an ability of longitudinal changes of circulating biomarkers to predict poor outcomes and modify personal care[14]. The aim of the Editorial is to summarize knowledge among clinical efficacy of HF guidance care based on serial measure of soluble ST2.

Table 1 Clinical relevance of circulating biomarkers for HF diagnosis, prediction, stratification and guided therapy.
BiomarkersHeart failure
diagnosisoutcomesguided therapyrisk stratification
hs-troponin T/I҂-++--+
NPs#҂++++++++
MR-proADM++++-++
Galectin-3҂-+-+
sST2҂--+++-
Copeptin+++-+
GDF15--++-+
hs-CRP--+--
IL-1β--+-+
IL-6--+-+
MMP-2--+----
MMP-9--+----
CTPpC-I--+--+
APpC-III--+--+
miRNAs--+++
Notes: “-“ mild disagree; “--“ moderate disagree; “+” mild agree; ”++” moderate agree; ”+++” strong agree; #, approved by European Society of Cardiology (2016); ҂ approved by American College of Cardiology/American Heart Association (2017).Abbreviations; hs, high sensitive; HF, heart failure; NPs, natriuretic peptides; sST2, soluble suppression of tumorigenicity-2; MR-proADM, mid-regional pro-adrenomedullin; GDF, growth / differential factor; CRP, C-reactive protein; miRNAs, micro-ribonucleic acids; MMP, matrix metalloproteinase; CTPpC-I, carboxytelopeptides of procollagen type I; APpC-III, aminopeptide of procollagen type III.

Soluble ST2 in HF diagnosis, prediction and stratification

ST2 is the receptor for interleukin-33 (IL-33), which is presented in two isoforms including soluble (sST2) isoform and the transmembrane receptor ST2L isoform[15]. ST2 belongs to the IL-1 receptor family and is released by several cells (fibroblasts, cardiac myocytes, macrophages, mononuclears, progenitor precursors, endothelial cells) due to inflammatory activation, necrosis / apoptosis and ischemia[16]. Recent studies have shown that IL-33/ST2L signaling mechanism had cardioprotective capabilities that are mediated through binding sST2 with IL-33. The result of this interaction is an improvement of cell viability after ischemia / injury due to suppression of nuclear factor kappa-B in fibroblasts and immune cells, preventing mitochondrial dysfunction and oxidative stress, unleash to up-expression of the anti-apoptotic factors (XIAP, cIAP1) and hypoxia induce factor-1, and preventing fibrosis and inflammation[17,18]. There is a large body of evidence regarding predictive capability of elevating levels of sST2 in general population for CV mortality and disease, as well as a high risk of poor prognosis in patients with established HF[19,20]. There is data clarifying that acute HF in-patients with low sST2 (< 35 ng/mL) also presented better probability to short-term survival and less hospital stay than individuals with high sST2 concentration (≥35 ng/mL) regardless of NP levels[21]. Moreover, measure of sST2 levels can help to stratify acute and acutely decompensated HF patients as higher risk of death and re-admission at discharge[22,23]. sST2 can be valuable for improvement of the diagnostic and predictive of acute myocardial infarction and adverse cardiac remodeling leading to HF I patients underwent percutaneous coronary intervention (PCI) regardless of numerous co-morbidities including diabetes mellitus, abdominal obesity, atrial fibrillation, kidney dysfunction[24]. Yet, elevated levels of sST2 were found to be superior NPs for assay of an increased risk of readmission or 30-days mortality after cardiac surgery and PCI[25]. Overall, face-to-face comparison of sST2 and NT-proBNP in HF individuals for prediction of long-term HF-related outcomes has revealed superiority of sST2, whereas NPs were most optimal for prediction of in-hospital stay long and re-admission[6]. Another advantage of sST2 in comparison with traditional biomarkers (NPs, cardiac troponins and galectin-3) is an ability to predict clinical outcomes in patients with different phenotype of HF[26]. Once the diagnosis of HF has been established, a potential approach should implement to a panel of biomarkers to identify the HF phenotypes (HFrEF, HFpEF, HFmrEF), guiding towards more appropriate therapeutic strategies. Interestingly, serum levels of sST2 can be modified during treatment that opens perspectives for optimized therapy in HF patients under control of biomarker levels. Indeed, the TRIUMPH (TRanslational Initiative on Unique and novel strategies for Management of Patients with Heart failure) study has revealed that serial sST2 measurements appeared to be a strong predictor of poor clinical outcome in acute HF patients independent of serial measured NT-pro brain NP[27]. Overall, measure of serum sST2 levels appears to be promising tool to HF prognosis and perhaps treatment monitoring, while evidence regarding serial sST2 measures for guidance therapy of HF gave controversial results.

Soluble ST2 as potential target of intervention in HF patients

Early clinical trials have shown that continuous monitoring of sST2 concentrations in acute and chronic HF patients were associated with impending cardiac failure to reduce filling pressures and 90-day impending events that was accompanied to benefit from specific HF therapy changes[28-30]. For instance, the results of the MUSIC study have been yielded that declined serum sST2 (< 0.23 ng/mL) was able to predict lowered risk of sudden death[30]. Additionally, the MOCA (Multinational Observational Cohort) study has revealed an ability to the trend of sST2 concentration to suggest all-cause mortality[31]. These findings were extremely important, because they have shown a benefit of serial measure of the biomarker despite the biological variability[32,33]. Finally, serum levels of sST2 defined as 35ng/mL were suggested as a target for the personified therapy of patients with acute and acutely decompensated HF[34]. Moreover, sST2 values, which were complementary to serum levels of NPs, may shape a new approach for serial testing in the acutely admitted HF patient to predict poor outcomes[35]. Indeed, HF patients who were attained lowered levels of sST2 (< 35ng/mL) and NT-proBNP (< 1000 pg/mL) in contrast to those have haven higher levels of both biomarkers (≥35ng/mL and ≥1000 pg/mL, respectively) during treatment had been found improved survival and decreased need for re-admission[36,37]. In fact, multiple biomarker model based on both sST2 and NT-pro-BNP was able not just predict clinical outcomes during HF therapy, but yet to improve accuracy of prognostication for both HFpEF and HFrEF[38]. Although circulating levels of sST2 were predominantly associated with all-cause mortality and non-CV death in HF out-patients showing strong association with systemic inflammation and malnutrition, while NT-proBNP levels were associated with CV death and re-admission[39], the combined use of both biomarkers for personifying optimization of HF care appears to be promising. Large clinical trials with adequate sample size are required to shape the most optimal strategy of biomarker-guided therapy in patients with several phenotypes of HF.

Conclusion

Serial measure of sST2 concentrations in HF patients can help to predict clinical outcomes and personally optimize treatment strategy, especially in combination with repetitive measure of NT-proBNP levels, but their role in the clinical care of the HF patient is not yet partially defined and more large clinical trials are needed.

Acknowledgments

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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