Cytokines as prognostic biomarkers in pulmonary arterial hypertension

Introduction: Risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, B-type natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) is the only marker for right ventricular dysfunction used in clinical practice in association with echocardiographic and invasive hemodymamic variables to predict outcome in patients with PAH. Methods: This study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable, or drug-induced PAH at baseline and first follow-up. Results: Among the 20 biomarkers studied with the multiplex EllaTM platform, we identified a 3-biomarker panel composed of ß-NGF, CXCL9 and TRAIL that was independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after PAH therapy initiation. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (functional class, 6-minute walking distance and BNP/NT-proBNP level). The results were validated in a fully independent external validation cohort. Conclusion: The monitoring of ß-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options.