Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension
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Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension. / Rhodes, Christopher J; Wharton, John; Swietlik, Emilia M; Harbaum, Lars; Girerd, Barbara; Coghlan, J Gerry; Lordan, James; Church, Colin; Pepke-Zaba, Joanna; Toshner, Mark; Wort, Stephen J; Kiely, David G; Condliffe, Robin; Lawrie, Allan; Gräf, Stefan; Montani, David; Boucly, Athénaïs; Sitbon, Olivier; Humbert, Marc; Howard, Luke S; Morrell, Nicholas W; Wilkins, Martin R; UK National PAH Cohort Study Consortium.
in: AM J RESP CRIT CARE, Jahrgang 205, Nr. 9, 01.05.2022, S. 1102-1111.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension
AU - Rhodes, Christopher J
AU - Wharton, John
AU - Swietlik, Emilia M
AU - Harbaum, Lars
AU - Girerd, Barbara
AU - Coghlan, J Gerry
AU - Lordan, James
AU - Church, Colin
AU - Pepke-Zaba, Joanna
AU - Toshner, Mark
AU - Wort, Stephen J
AU - Kiely, David G
AU - Condliffe, Robin
AU - Lawrie, Allan
AU - Gräf, Stefan
AU - Montani, David
AU - Boucly, Athénaïs
AU - Sitbon, Olivier
AU - Humbert, Marc
AU - Howard, Luke S
AU - Morrell, Nicholas W
AU - Wilkins, Martin R
AU - UK National PAH Cohort Study Consortium
PY - 2022/5/1
Y1 - 2022/5/1
N2 - 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.
AB - 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.
U2 - 10.1164/rccm.202105-1118OC
DO - 10.1164/rccm.202105-1118OC
M3 - SCORING: Journal article
C2 - 35081018
VL - 205
SP - 1102
EP - 1111
JO - AM J RESP CRIT CARE
JF - AM J RESP CRIT CARE
SN - 1073-449X
IS - 9
ER -