Circulating Cell Biomarkers in Pulmonary Arterial Hypertension: Relationship with Clinical Heterogeneity and Therapeutic Response

Biomarcadores; Disfunción endotelial; Células progenitoras Biomarcadors; Disfunció endotelial; Cèl·lules progenitores Biomarkers; Endothelial dysfunction; Progenitor cells Background: Endothelial dysfunction is central to PAH. In this study, we simultaneously analysed circulating levels of endothelial microvesicles (EMVs) and progenitor cells (PCs) in PAH and in controls, as biomarkers of pulmonary endothelial integrity and evaluated differences among PAH subtypes and as a response to treatment. Methods: Forty-seven controls and 144 patients with PAH (52 idiopathic, 9 heritable, 31 associated with systemic sclerosis, 15 associated with other connective tissue diseases, 20 associated with HIV and 17 associated with portal hypertension) were evaluated. Forty-four patients with scleroderma and 22 with HIV infection, but without PAH, were also studied. Circulating levels of EMVs, total (CD31+CD42b−) and activated (CD31+CD42b−CD62E+), as well as circulating PCs (CD34+CD133+CD45low) were measured by flow cytometry and the EMVs/PCs ratio was computed. In treatment-naïve patients, measurements were repeated after 3 months of PAH therapy. Results: Patients with PAH showed higher numbers of EMVs and a lower percentage of PCs, compared with healthy controls. The EMV/PC ratio was increased in PAH patients, and in patients with SSc or HIV without PAH. After starting PAH therapy, individual changes in EMVs and PCs were variable, without significant differences being observed as a group. Conclusion: PAH patients present disturbed vascular homeostasis, reflected in changes in circulating EMV and PC levels, which are not restored with PAH targeted therapy. Combined measurement of circulating EMVs and PCs could be foreseen as a potential biomarker of endothelial dysfunction in PAH. This research was funded by grants PI12/00510, PI15/00582 and PI18/00960 from the Institute of Health Carlos III (ISCiii), Spain, co-funded by the European Union (ERDF/ESF); the Catalan Society of Respiratory Medicine (SOCAP); and the Fundación Contra la Hipertensión Pulmonar (FCHP). OTC is the former recipient of a Marie Curie Post-Doctoral Fellowship Award BIOTRACK-IDIBAPS, and the current recipient of a Miguel Servet contract from ISCiii (CP17/00114).