The activin pathway in chronic thromboembolic pulmonary hypertension: a potential biomarker for residual pulmonary hypertension after endarterectomy.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by persistent pulmonary vascular obstruction due to unresolved thromboembolic lesions and distal pulmonary vascular remodelling. Despite the recognised role of the activin pathway in pulmonary vascular remodelling, its involvement in CTEPH remains insufficiently explored. This study aimed to investigate the presence of activin pathway components in CTEPH-related microvasculopathy and evaluate their potential as biomarkers. Methods: Plasma levels of activin pathway biomarkers and key inflammatory mediators were assessed in controls and operable CTEPH patients pre- and post-surgery. The study enrolled 69 patients (mean age 62±13 years, 51% male), among whom 29 exhibited residual pulmonary hypertension (PH) after surgery, and two died following post-endarterectomy (PEA). Results: CTEPH patients demonstrated elevated levels of activin-A, activin-B, FSTL3, C-X-C motif chemokine ligand 9 (CXCL9), β-nerve growth factor, C-reactive protein (CRP) and pro-brain natriuretic peptide (compared to controls). Pre-operative activin-A levels were associated with an increased risk of residual PH or mortality post-surgery (odds ratio 2.469, 95% CI 1.011-5.487; p=0.027), following adjustments for age, mean pulmonary arterial pressure before PEA, and CRP. Histological analysis of lung specimens from CTEPH patients revealed nuclear accumulation of phosphorylated Smad 2 and upregulation of inhibin-βA, inhibin-βB, activin receptor type IIB (ACTRIIB) and FSTL3 in muscularised pulmonary arterioles. Conclusions: These findings suggest a potential role for activin-A as a predictive biomarker for residual PH following pulmonary endarterectomy in CTEPH. Further investigation into the activin pathway may uncover therapeutic targets for managing CTEPH-associated vascular remodelling.