The ST2 protein belongs to the interleukin-1 receptor family (IL-1 RL-1) and exists in two isoforms, transmembrane (ST2L) and soluble (sST2). The specific ligand of the STL2 receptor is IL-33, which plays an anti-inflammatory, antihypertrophic, and antifibrotic role in the myocardium. The soluble ST2 receptor is the ST2L receptor, which, through specific proteases, undergoes a cut at the transmembrane and cytoplasmic domains with subsequent release into the extra cellular fluid. In the extracellular fluid and plasma, the sST2 protein can still bind its specific IL-33 high-affinity ligand, sequestering it and making it no longer available for binding to its membrane receptor. In this way, the sST2 receptor blocks the favorable effect of IL-33 on the myocardium by behaving as a decoy receptor.
High circulating levels of sST2 promote proinflammatory mechanisms leading to myocardial remodeling, cardiac fibrosis, and ventricular diastolic dysfunction. In accordance with this mechanism of action, many studies have shown that patients with heart failure have high circulating levels of sST2. However, as also pointed out for galectin-3, the measurement of sST2 does not always add significant prognostic information compared with other biomarkers, especially natriuretic peptides. Currently, it is impossible to measure sST2 by the most common automated platforms available in clinical laboratories, so its clinical use is limited to specialized centers, and, consequently, the results avail able in the literature are fewer than those related to galectin 3. sST2, however, provides better results than galectin-3 in evaluating patients with HFrEF than those with HFpEF. In addition, some authors have reported that sST2 can stratify the risk of progression of cardiac remodeling in patients with reduced left ventricular function (with or without symptoms of heart failure).
In conclusion, further prospective clinical cohort studies, with a sufficient number of heart failure patients, both with HFpEF and HFrEF, monitored for a significant number of years, are needed to evaluate and compare the possible prognostic relevance of galectin-3 and sST2 among themselves and concerning other biomarkers whose prognostic role is widely recognized, in particular natriuretic peptides and troponins, measured by methods with high analytical sensitivity.
