Using the plasma proteome for risk stratifying patients with pulmonary arterial hypertension

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Title: Using the plasma proteome for risk stratifying patients with pulmonary arterial hypertension
Authors: Rhodes, C
Wharton, J
Swietlik, E
Harbaum, L
Girerd, B
Coghlan, G
Lordan, J
Church, C
Pepke-Zaba, J
Toshner, M
Wort, SJ
Kiely, D
Condliffe, R
Lawrie, A
Graf, S
Montani, D
Boucly, A
Sitbon, O
Humbert, M
Howard, LS
Morrell, NW
Wilkins, MR
Item Type: Journal Article
Abstract: Rationale: N-terminal pro-brain natriuretic peptide (NT-proBNP), 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 which complement NT-proBNP and clinical risk scores. Methods: An aptamer-based assay (SomaScan-V4) 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 study (n=79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute walk distance (6-MWD) and NT-proBNP entered LASSO modelling 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-MWD in the UK Cohort. A weighted combination score of 6 proteins was validated at baseline (5-year mortality, AUC:0.73, 95%CI:0.63-0.85) and follow-up in EFORT (AUC:0.84, 95%CI:0.75-0.94, p=9.96x10-6). The protein score risk-stratified patients independent of established clinical targets and risk equations. The addition of the 6-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 ROC 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.
Issue Date: 1-May-2022
Date of Acceptance: 9-Dec-2021
ISSN: 1073-449X
Publisher: American Thoracic Society
Start Page: 1102
End Page: 1111
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 205
Issue: 9
Copyright Statement: © 2022 by the American Thoracic Society.
Sponsor/Funder: British Heart Foundation
The Academy of Medical Sciences
Funder's Grant Number: FS/15/59/31839
Keywords: biomarkers
clinical outcomes
Area Under Curve
Familial Primary Pulmonary Hypertension
Natriuretic Peptide, Brain
Peptide Fragments
Pulmonary Arterial Hypertension
Natriuretic Peptide, Brain
Peptide Fragments
Area Under Curve
Familial Primary Pulmonary Hypertension
Pulmonary Arterial Hypertension
Respiratory System
11 Medical and Health Sciences
Publication Status: Published
Embargo Date: 2023-01-25
Online Publication Date: 2022-01-26
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine