Abstract
SummaryBackgroundIdiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification.MethodsIn this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint.Findings20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2·5 years' follow-up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff-based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0·83 (for REVEAL risk score, 95% CI 0·77–0·89; p<0·0001) to 0·91 (for panel and REVEAL 0·87–0·96; p<0·0001) and improving reclassification indices without detriment to calibration. Poor survival was preceded by an adverse change in panel score in paired samples from 43 incident patients with pulmonary arterial hypertension in cohort 3 (p=0·0133). The protein panel was validated in 93 patients with idiopathic or heritable pulmonary arterial hypertension in cohort 4, with 4·4 years' follow-up and improved risk estimates, providing complementary information to the clinical risk equation.InterpretationA combination of nine circulating proteins identifies patients with pulmonary arterial hypertension with a high risk of mortality, independent of existing clinical assessments, and might have a use in clinical management and the evaluation of new therapies.FundingNational Institute for Health Research, Wellcome Trust, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, Inserm, Université Paris-Sud, and Agence Nationale de la Recherche.
Highlights
Idiopathic and heritable pulmonary arterial hypertension constitute a rare disease group characterised by an imbalance in endothelial-derived vasoactive factors, inflammation, and structural remodelling of pulmonary vessels.[1]
The incidence of pulmonary arterial hypertension is estimated at 1–7·6 per million per year and cases of idiopathic or heritable pulmonary arterial hypertension account for 0·9–2·6 per million per year.[3]
Concentrations of 134 proteins were associated with overall survival in cohort 1. 40 of these proteins were validated as able to differentiate between survivors and non-survivors in cohort 2. 20 prognostic proteins, including brain natriuretic peptide (BNP), were prioritised by random sampling analysis as the most robust
Summary
Idiopathic and heritable pulmonary arterial hypertension constitute a rare disease group characterised by an imbalance in endothelial-derived vasoactive factors, inflammation, and structural remodelling of pulmonary vessels.[1]. Regular assessment of disease severity and prognosis is necessary to guide clinical management. The existing guidelines recommend a combination of established prognostic parameters on the basis of clinical assess ment, imaging, and biochemistry.[6] These clinical parameters are not always available for each patient visit and existing risk assessments have poor accuracy (with C statistics ranging between 0·57 for the US National Institutes of Health,7 0·59 for the French Registries,[2] and 0·77 for the REVEAL equation8), leaving considerable scope for improvement.[3]
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