ST2: cardiac biomarker for risk stratification and prognosis of heart failure.

ST2 is a biomarker that is used for additive risk stratification and prognosis of patients with heart failure (HF). In contrast to BNP and NT-proBNP, ST2 is not affected by confounding factors such as age, body mass index, and impaired renal function.

ST2 is a member of the interleukin-1 receptor family, and it is also known as interleukin-1 receptor- like 1 (IL1RL-1). Unlike many other cardiac biomarkers, the levels of ST2 alter quickly in response to changes in the patient’s condition. This means that it helps physicians to take an appropriate course of action faster. Elevated levels of serum ST2 (sST2) in acute as well as chronic HF patients are strongly associated with the measures of HF severity, and they predict both recurrent hospitalization and mortality.

Measured levels of ST2 in chronic HF patients can be used for therapy evaluation and accordingly, decreased levels of sST2 that are responsive to medical treatment are associated with better outcomes for patients. The ST2 is an independent predictor of all-cause cardiac mortality, and it provides complementary prognostic information not only for NT-proBNP or BNP, but also for high-sensitivity cardiac troponin T (hs-cTnT) assays.

Anti-ST2 antibodies were obtained after immunization of various animal species (mice, rabbits, and rats) with recombinant human ST2. They have been well-characterized and can be used for the development of sensitive and precise immunoassays (see Figure 1).

Figure 1.  Performance of Anti-ST2 MAbs. Representative calibration curve for the ST2 prototype assay (S215-S103 sandwich ELISA, LoD 30 pg/ml). Recombinant human ST2 used as the antigen.

Figure 2.  ST2 concentrations obtained with the S215-S103 prototype immunoassay and a commercial ST2 assay. Correlation coefficient (Pearson) between prototype assay and commercial ST2 assay was 0.98 indicating excellent correlation between the assays.

Table 1. Recommended capture-detection pairs (prototype assays in sandwich ELISA format are marked in black, prototype assays in sandwich FIA format are marked in blue). Limit of detection (LoD) was determined as the mean of the blank (TBST buffer (ELISA)/assay buffer (FIA)) +2*SD. Recombinant ST2 (Cat.# 8-ST2) reconstituted in a corresponding buffer was used as an analyte.

ST2 exists in two isoforms: a transmembrane or cellular (ST2L) and soluble or circulating (sST2). ST2 is the receptor for interleukin-33 (IL-33), which is an IL-1-like cytokine that is secreted by living cells in response to cell damage. The IL-33 exerts its effects by binding to the transmembrane receptor ST2L isoform. The interaction of IL-33 and ST2L has been shown to be cardioprotective, reducing myocardial fibrosis, cardiomyocyte hypertrophy, apoptosis, and improving myocardial function. The IL-33/ST2 system is upregulated in cardiomyocytes and fibroblasts in response to cardiac injury. sST2 avidly binds to IL-33 and competes with ST2L. The interaction of the soluble ST2 with IL-33 blocks the IL-33/ST2L system and as a result eliminates the cardioprotective pathway of the IL-33/ST2L interaction. ST2L contains an extracellular domain of three immunoglobulin-like motifs, a transmembrane segment, and an intracellular cytoplasmic domain, whereas sST2 lacks the transmembrane and cytoplasmic domains.

Three linked immunoglobulinlike motifs of sST2 have a total length of 310 amino acid residues. The expression of sST2 is largely inducible and it is almost ubiquitous in living cells, such as resting fibroblasts. It has been suggested that sST2 is produced by both cardiac fibroblasts and cardiomyocytes in response to cardiac injury or cardiac stress, macrovascular (aortic and coronary artery), and heart microvascular endothelial cells in response to diastolic load.

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