Assessment of circulating biomarkers in patients with chronic thromboembolic pulmonary hypertension before and after surgical treatment

Introduction. The role of aseptic inflammation and disturbances in the hemostasis and fibrinolysis systems has been demonstrated in the pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH); however, the profile and direction of changes in circulating markers vary significantly across studies, reflecting the complexity of the molecular mechanisms underlying CTEPH development. Aim: To assess the dynamics of circulating markers of inflammation, hemostasis, and endothelial dysfunction during surgical treatment of patients with CTEPH. Material and Methods. The study included 205 patients with a newly diagnosed case of CTEPH (median age 56.0 [44.0; 67.0] years; 47% male) selected for pulmonary thromboendarterectomy or balloon pulmonary angioplasty (BPA) between January 1, 2014, and January 1, 2024. All assessments were performed at two time points: at the time of diagnosis and 3–6 months after surgical treatment. We investigated plasma markers of inflammation (CRP, IL-6, IL-8, IL-10, IL-18, MCP-1, IP-10, MPO), fibrosis (MMP-9, MIG, galectin-3, osteopontin), endothelial dysfunction and growth factors (TGF-β, PDGF-B, VEGF, ET-1, sRAGE, HIF-1), as well as markers of hemostasis and fibrinolysis (vWF:Ag, FVIII, D-dimer, t-PA, TAFI, PAI-1). The control group included 30 healthy volunteers (mean age 50.3 [31.2; 63.4] years; 48% men). Results. Baseline elevations were observed in the levels of fibrinogen (p=0.002), vWF:Ag (p<0.001), FVIII (p<0.001), t-PA (p<0.001), CRP (p=0.032), and IL-8 (p=0.040), as well as in the concentrations of IP-10 (р<0.001) and MCP-1 (р=0.002), compared to the control group. Weak correlations were found between IP-10 and t-PA levels and markers of CTEPH severity. Increases in MPO (p<0.001), MMP-9 (p=0.017), sRAGE (p=0.035), osteopontin (p<0.001), and galectin-3 (p=0.001) levels were recorded compared to controls. Following surgical treatment, significant reductions in FVIII (p<0.001) and t-PA (p<0.001) levels were observed; the vWF:Ag level decreased but did not reach the value seen in the control group (p<0.01). A positive correlation was demonstrated between Δ t-PA and the magnitude of the reduction in CTEPH severity markers, such as PVR and the RV/LV ratio. A decrease was also observed in the levels of CRP (p<0.001), IL-10 (p=0.001), IP-10 (p<0.001), galectin-3 (p<0.001), and sRAGE (p=0.023), although these did not reach the levels seen in the control group. Levels of MCP-1 (p=0.002) and MPO (p<0.001) decreased over time to match those of the control group. MMP-9 levels did not decrease significantly following surgical treatment (p=0.236) and remained higher than those of the donors. Conclusion. Several markers associated with CTEPH have been identified, reflecting endothelial activation/dysfunction (vWF:Ag, t-PA, sRAGE) and inflammation (CRP, MCP-1, IP-10). Among the circulating markers analyzed, t-PA appears promising for further study as a predictor of the development of obstructive pulmonary vasculopathy. It has been shown that mechanical relief of pulmonary artery obstruction leads to a reduction in systemic inflammation and endothelial activation but does not result in complete normalization of the disease's biological phenotype within the first 3–6 months.