Mitral stenosis severity and the hypoxic response: potential role of hypoxia-inducible factor-2α - a cross-sectional study

Mitral stenosis (MS) causes chronic pressure overload and secondary pulmonary hypertension, which are associated with activation of hypoxia-inducible pathways. This study investigated the circulating levels of hypoxia-inducible factor-2α (Endothelial PAS domain protein 1-EPAS1) in patients with MS and their relationship with disease severity. This prospective study included 69 patients diagnosed with rheumatic MS and an equal number of age- and sex-matched healthy individuals. Hypoxia-inducible factor-2α (HIF-2α) levels were assessed using an enzyme-linked immunosorbent assay (ELISA) along with conventional biomarkers, and all patients underwent echocardiographic assessments. Statistical comparisons were performed using appropriate parametric or non-parametric tests, and relationships were evaluated using Spearman’s rank correlation coefficients. HIF-2α levels were significantly higher in patients with MS than in the controls (median 5.2 vs. 4.7; p = 0.0275). Patients with MS also had higher high-sensitivity cardiac troponin T levels (median 7.7 vs. 4.9, p = 0.0328) than controls. HIF-2α was weakly positively correlated with systolic pulmonary artery pressure (ρ = 0.28, p = 0.001), left atrial diameter (ρ = 0.22, p = 0.012), and N-terminal pro-B-type natriuretic peptide level (ρ = 0.29, p = 0.014). HIF-2α levels did not significantly correlate with the mitral valve area or mean transmitral gradient. Elevated HIF-2α levels in patients with MS are correlated with pulmonary hypertension and cardiac stress. These findings support the involvement of hypoxia-inducible pathways in the pathophysiology of MS. However, HIF-2α elevation is modest and its clinical utility as a biomarker for MS is currently limited.