Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension.
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Authors
Swietlik, Emilia M
Girerd, Barbara
Coghlan, J Gerry
Lordan, James
Church, Colin
Pepke-Zaba, Joanna
Toshner, Mark
Wort, Stephen J
Kiely, David G
Condliffe, Robin
Sitbon, Olivier
Howard, Luke S
Morrell, Nicholas W
Publication Date
2022-05-01Journal Title
Am J Respir Crit Care Med
ISSN
1073-449X
Publisher
American Thoracic Society
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Rhodes, C. J., Wharton, J., Swietlik, E. M., Harbaum, L., Girerd, B., Coghlan, J. G., Lordan, J., et al. (2022). Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension.. Am J Respir Crit Care Med https://doi.org/10.1164/rccm.202105-1118OC
Abstract
Rationale: NT-proBNP (N-terminal pro-brain natriuretic peptide), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH. Objectives: Identify prognostic proteins in PAH that complement NT-proBNP and clinical risk scores. Methods: An aptamer-based assay (SomaScan version 4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable, or drug-induced PAH from the UK National Cohort of PAH (n = 357) and the French EFORT (Evaluation of Prognostic Factors and Therapeutic Targets in PAH) study (n = 79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute-walk distance and NT-proBNP entered least absolute shrinkage and selection operator modeling, and the best combination in a single score was evaluated against clinical targets in EFORT. Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-minute-walk distance in the UK cohort. A weighted combination score of six proteins was validated at baseline (5-yr mortality; area under the curve [AUC], 0.73; 95% confidence interval [CI], 0.63-0.85) and follow-up in EFORT (AUC, 0.84; 95% CI, 0.75-0.94; P = 9.96 × 10-6). The protein score risk stratified patients independent of established clinical targets and risk equations. The addition of the six-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC 0.762 (0.702-0.821) to 0.818 (0.767-0.869) by receiver operating characteristic analysis (P = 0.00426 for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response.
Keywords
Proteomics, prognosis, biomarker, pulmonary arterial hypertension, PAH
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MR/K020919/1)
British Heart Foundation (None)
British Heart Foundation (SP/18/10/33975)
Identifiers
External DOI: https://doi.org/10.1164/rccm.202105-1118OC
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334440
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