SST2 as a marker of severely reduced exercise capacity in heart failure with reduced ejection fraction

Background Exercise capacity is a key prognostic indicator in heart failure (HF). Peak oxygen uptake (VO₂), assessed during maximal exercise through cardiopulmonary exercise testing (CPET), is the gold standard for evaluating exercise capacity and guiding therapy adjustments in HF. Soluble suppression of tumorigenicity 2 (sST2) has emerged as a novel biomarker reflecting myocardial stress and remodelling. However, its utility in identifying patients with severely impaired functional capacity, objectively assessed by cardiopulmonary exercise testing, remains inadequately explored. Purpose To determine a specific sST2 cut-off value associated with severe exercise intolerance, defined as a relative peakVO₂ below 12 mL/kg/min, in patients with heart failure with reduced ejection fraction. Methods This prospective analysis included 135 stable patients (LVEF≤40%) receiving guideline-based treatment. All subjects underwent symptom-limited cardiopulmonary exercise testing to measure relative peakVO₂. Circulating sST2 was quantified using a commercially available immunoassay, and an optimal cut-off for predicting a relative peakVO₂ under 12 mL/kg/min was established by receiver operating characteristic curve analysis. Results The mean sST2 concentration was 45.5 ± 39.2 ng/mL. In patients whose relative peak VO₂ was below 12 mL/kg/min, sST2 concentrations were significantly higher (70.7 ± 57.4 vs. 40.6 ± 32.7 ng/mL, p < 0.001). The determined sST2 threshold was 52.377 ng/mL (AUC=0.692, 95% CI: 0.567–0.816). Patients with sST2 levels ≥ 52.377 ng/mL had a lower LVEF, higher heart rate at discharge (p = 0.002), and more frequent AF (p = 0.01). They also presented with more advanced HF symptoms assessed as NYHA III and ambulatory IV class (69.4% vs. 42.4%, p = 0.005). Patients with lower sST2 levels had higher PETCO2 (p < 0.001) and higher oxygen pulse (p = 0.011). In contrast, participants with higher sST2 concentrations showed a significantly higher VE/VCO2 slope (p = 0.002). Conclusions An sST2 concentration is significantly associated with severe exercise intolerance in heart failure with reduced ejection fraction. Incorporating sST2 measurements into routine assessment may enhance the early identification of patients at risk of advanced disease and support timely therapeutic interventions.