Exploratory Study of Prognostic Plasma Biomarkers in Patients with Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular lumen occlusion, ultimately leading to right ventricular failure and death. Risk stratification is essential for the management of patients with PAH. So far, B-type natriuretic peptide and its N-terminal pro-form are the only circulating biomarkers used as part of composite PAH risk assessment tools. Identification of other biomarkers of vascular or systemic origin may be valuable to provide additional information on disease severity and prognosis. Using proximity extension assay, >700 proteins related to oncology and neurology were measured in the plasma of 60 patients with PAH and 28 age- and sex-matched controls. Among the 114 proteins significantly up-regulated in patients with PAH, 14 were independently associated with death/lung transplantation after adjustment for the 2015 European Society of Cardiology/European Respiratory Society, the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk scores, and the refined four-stratum risk assessment model. Among them, ectodysplasin A2 receptor (EDA2R), WAP four-disulfide core domain 2 (WFDC2), and tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) displayed incremental prognostic value on top of these predictive models. Combining previously published proteomic data sets generated from different panels with the same cohort, a set of 23 proteins was identified, many of which are strongly associated with chronological age, that predict outcome of patients with PAH after adjusting for risk assessment tools. In conclusion, proteins likely involved in the pathophysiology of the disease and potential candidates for prognostic enrichment were identified in this study.