• Francois Haddad, Kevin Contrepois, Myriam Amsallem, Andre Y Denault, Roberto J Bernardo, Alokkumar Jha, Shalina Taylor, Arthur AtaamJenniferJStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA., Olaf Mercier, Tatiana Kuznetsova, Anton Vonk Noordegraaf, Roham T Zamanian, and Andrew J Sweatt.
• Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA; Vera Moulton Wall Center for Pulmonary Disease at Stanford University, Stanford, CA. Electronic address: fhaddad@stanford.edu.
• Chest. 2022 May 1; 161 (5): 134713591347-1359.

BackgroundPrognosis in pulmonary arterial hypertension (PAH) is closely related to indexes of right ventricular function. A better understanding of their relationship may provide important implications for risk stratification in PAH.Research QuestionCan clinical network graphs inform risk stratification in PAH?Study Design And MethodsThe study cohort consisted of 231 patients with PAH followed up for a median of 7.1 years. An undirected, correlation network was used to visualize the relationship between clinical features in PAH. This network was enriched for right heart parameters and included N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP), comprehensive echocardiographic parameters, and hemodynamics, as well as 6-min walk distance (6MWD), vital signs, laboratory data, and diffusing capacity for carbon monoxide (Dlco). Connectivity was assessed by using eigenvector and betweenness centrality to reflect global and regional connectivity, respectively. Cox proportional hazards regression was used to model event-free survival for the combined end point of death or lung transplantation.ResultsA network of closely intertwined features centered around NT-proBNP with 6MWD emerging as a secondary hub were identified. Less connected nodes included Dlco, systolic BP, albumin, and sodium. Over the follow-up period, death or transplantation occurred in 92 patients (39.8%). A strong prognostic model was achieved with a Harrell's C-index of 0.81 (0.77-0.85) when combining central right heart features (NT-proBNP and right ventricular end-systolic remodeling index) with 6MWD and less connected nodes (Dlco, systolic BP, albumin, sodium, sex, connective tissue disease etiology, and prostanoid therapy). When added to the baseline risk model, serial change in NT-proBNP significantly improved outcome prediction at 5 years (increase in C-statistic of 0.071 ± 0.024; P = .003).InterpretationNT-proBNP emerged as a central hub in the intertwined PAH network. Connectivity analysis provides explainability for feature selection and combination in outcome models.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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