Abstract
Background 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, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic 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 at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients.
Results Among the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of β-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort.
Conclusion The monitoring of β-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options.
Abstract
β-NGF, CXCL9 and TRAIL are independently associated with PAH prognosis at baseline and at follow-up. Prognostic value of the 3 cytokines is more powerful for predicting transplant-free survival than usual non-invasive variables (NYHA FC, 6MWD and BNP). http://bit.ly/3gnF0Vb
Footnotes
Conflict of interest: A. Boucly reports grants from Acceleron, Janssen and MSD, lecture honoraria from Janssen and Merck, and travel support from Janssen, outside the submitted work. C. Guignabert reports grants from Acceleron, Janssen, Merck and ShouTi, and lecture honoraria from Merck, outside the submitted work. C. Rhodes reports support for the present manuscript from BHF fellowship (FS/15/59/31839), Academy of Medical Sciences Springboard fellowship (SBF004\1095); consulting fees from United Therapeutics and Janssen, travel support from United Therapeutics, a patent submitted for prognostic protein model from Imperial Innovations, and advisory board participation with United Therapeutics and Janssen, outside the submitted work. P. De Groote reports consulting fees and lecture honoraria from Janssen, outside the submitted work. G. Prévot reports lecture honoraria from Boehringer Ingelheim, Sanofi and Jansen, and travel support from Boehringer Ingelheim, outside the submitted work. E. Bergot reports lecture honoraria and travel support from Janssen, Actelion and GSK, outside the submitted work. A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim, consulting fees, lecture honoraria and travel support from AstraZeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi, and advisory board participation with AB Science; outside the submitted work. A. Beurnier reports lecture honoraria and travel support from Sanofi, outside the submitted work. X. Jaïs reports grants from Acceleron, Janssen and MSD, lecture honoraria from Janssen and MSD, and travel support from Janssen, outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck, consulting fees from Acceleron, and lecture honoraria from Bayer, Janssen and Merck, outside the submitted work. M.R. Wilkins reports support for the current manuscript from the British Heart Foundation and National Institute for Health Research; outside the submitted work, consulting fees from MorphogenIX, Actelion and Novartis, a patent under consideration on “Biomarker panel for pulmonary hypertension based on blood biomarkers”, and participation on advisory boards with Acceleron and GSK. M. Humbert reports support for the current manuscript from Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC EFORT) and ANR-15-RHUS-0002 (RHU BIOART-LUNG 2020); outside the submitted work, grants and consulting fees from Acceleron, Janssen and Merck, lecture honoraria from Janssen and Merck, and advisory board participation for Acceleron, Janssen, Merck and United Therapeutics. O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD, consulting fees from Gossamer Bio, Janssen and MSD, lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD, and advisory board participation for Acceleron, Janssen, MSD and Ferrer, outside the submitted work. L. Savale reports grants from Acceleron, Janssen and Merck, and lecture honoraria from GSK and Janssen, outside the submitted work. All other authors have nothing to disclose.
This article has an editorial commentary: https://doi.org/10.1183/13993003.00018-2023
Support statement: This research was supported by grants from the Projet Hospitalier de Recherche Clinique (PHRC P081247) “EFORT” (AP-HP), grants from the French National Institute for Health and Medical Research (INSERM; “Contrat d'Interface”), the Université Paris-Saclay and in part by the French National Agency for Research (ANR) grant number ANR-15-RHUS-0002 (RHU BIOART-LUNG 2020) and grant number ANR-18-RHUS-0006 (RHU DESTINATION 2024). The UK study recognises the support of the Imperial NIHR Clinical Research Facility. M.R. Wilkins was supported by the BHF Imperial Research Centre of Excellence (RE/18/4/342215). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 16, 2022.
- Accepted November 12, 2022.
- Copyright ©The authors 2023. For reproduction rights and permissions contact permissions{at}ersnet.org
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