Abstract
BACKGROUND: Pulmonary arterial hypertension (PAH) is a disease of progressive right ventricular (RV) failure with high morbidity and mortality. Our goal is to investigate proteomic features and pathways associated with RV-focused outcomes including mortality, RV dilation, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in PAH. METHODS: Participants in a single-institution cohort with 3 years of follow-up underwent proteomic profiling of their plasma using 7288 aptamers (targeting 6467 unique human proteins). Partial least squares discriminant analysis was performed to assess global protein variation associated with mortality, RV dilation, and NT-proBNP levels. Differentially abundant proteins and enriched pathways associated with outcomes were identified following baseline adjustments. RV vulnerability models estimated associations for individuals with similar afterload following adjustment for pulmonary vascular resistance. RESULTS: A total of 117 participants with PAH were included. Partial least squares discriminant analysis of the proteome showed clear separation between survivors and nonsurvivors, participants with dilated versus nondilated RVs, and across NT-proBNP levels. Proteins and pathways involving the ECM (extracellular matrix) were upregulated in participants who died during follow-up, those with severe RV dilation, and those with higher levels of NT-proBNP. Pulmonary vascular resistance adjustment reinforced the importance of ECM proteins in the association with RV vulnerability, independent of afterload. These findings were confirmed in independent PAH cohorts with available plasma proteomics and RV tissue gene and protein expression. CONCLUSIONS: Distinct plasma proteomic profiles are associated with mortality, RV dilation, and NT-proBNP in PAH. Proteins and pathways governing tissue remodeling are strongly associated with poor outcomes, may mediate RV vulnerability to right heart failure, and represent promising candidates as biomarkers and potential therapeutic targets.