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

Abstract

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.

An Overview of Circulating Pulmonary Arterial Hypertension Biomarkers

“…Finally, concerning specific PAH subgroups, IPAH was correlated with elevated levels of LMPs—specifically derived from T-cells ( 173 ), and PMPs (CD42a and CD42b + ) ( 174 ). Raised EMPs (CD31 + /CD42b − ) have been found in both IPAH and SSc-PAH, and variation in measurements taken before and after treatment initiation did not reflect clinical improvement, suggesting this as a marker of endothelial injury ( 175 ). Regarding SSc-PAH in particular, elevated VE-cadherin + MPs have also been reported, which measurements appear to independently predict PAH in SSc patients without PH ( 176 ).…”

Biomarkers in Pulmonary Arterial Hypertension

“…Cellular biomarkers can provide essential information about vascular endothelial function. These markers include circulating microvesicles and progenitor cells (PCs) [ 146 ]. These endothelial microvesicles (EMVs) are <0.1 μm in size.…”

“…These endothelial microvesicles (EMVs) are <0.1 μm in size. They are released by the endothelium in response to damage or apoptosis [ 146 ]. Circulating EMVs can be identified and quantified in peripheral blood vessels through flow cytometry [ 147 ].…”

“…Circulating EMVs can be identified and quantified in peripheral blood vessels through flow cytometry [ 147 ]. Healthy individuals show only small amounts of EMVs; however, in PAH, increased levels of EMVs may be correlated with disease severity [ 146 ], especially in IPAH. It is therefore suggested that EMVs might play a role in the pathogenesis of PAH [ 146 ].…”

“…Healthy individuals show only small amounts of EMVs; however, in PAH, increased levels of EMVs may be correlated with disease severity [ 146 ], especially in IPAH. It is therefore suggested that EMVs might play a role in the pathogenesis of PAH [ 146 ]. Progenitor cells are small immature cells produced in the bone marrow and released into circulation to replace damaged endothelial cells [ 148 ].…”