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Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension

Lookup NU author(s): Dr James Lordan


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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.

Publication metadata

Author(s): Rhodes CJ, Wharton J, Swietlik EM, Harbaum L, Girerd B, Coghlan JG, Lordan J, Church C, Pepke-Zaba J, Toshner M, Wort SJ, Kiely DG, Condliffe R, Lawrie A, Graf S, Montani D, Boucly A, Sitbon O, Humbert M, Howard LS, Morrell NW, Wilkins MR

Publication type: Article

Publication status: Published

Journal: American Journal of Respiratory and Critical Care Medicine

Year: 2022

Volume: 205

Issue: 9

Pages: 1102-1111

Print publication date: 01/05/2022

Online publication date: 26/01/2022

Acceptance date: 24/01/2022

ISSN (print): 1073-449X

ISSN (electronic): 1535-4970

Publisher: American Thoracic Society


DOI: 10.1164/rccm.202105-1118OC

PubMed id: 35081018


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