The Liver is an Inflammatory Mediator of Pulmonary Arterial Hypertension

Inflammation is central to pulmonary arterial hypertension (PAH) pathogenesis. The liver regulates systemic immunity, yet its contribution to PAH remains unclear. To characterize hepatic involvement in experimental and human PAH. We hypothesized the liver promotes inflammation and pulmonary endothelial injury through endocrine crosstalk. PAH patients without liver disease with pulmonary artery endothelial cell (PAEC) biopsies were included. Liver serologies and imaging were included in unsupervised classification and regression tree (CART) analysis to identify subclinical liver dysfunction clusters. The union of two machine learning models predicted cluster assignment and informed differential expression. PAEC gene expression was compared to liver and lung transcriptomes from monocrotaline (MCT) and Sugen-Hypoxia (SuHx) rats using Ingenuity Pathway Analysis. Hepatic fibrosis was assessed in rat and human PAH livers. Among 25 PAH patients (76% female, median age 61 [range 30 – 84] years), CART identified clusters distinguished by Model for End-Stage Liver Disease Sodium (MELD-Na) score ≥12, which predicted higher pulmonary vascular resistance (PVR)(ß=0.5 Wood units, 95% CI 0.2-0.8, p=0.005) after adjustment for right atrial pressure. Subjects with MELD-Na ≥12 had decreased 6-minute walk distance (353 m [120 – 576] vs. 411 m [300 – 600] m, p=0.03), with upregulation of apelin, beta-catenin, and immune pathway signaling. Similarly, rat lung ECs demonstrated survival and hepatic growth factor signaling, while rat livers showed immune activation. Both rat (3.5 vs 2.2 % area stained, p=0.01) and human PAH livers revealed fibrosis despite absent right ventricular failure. Hepatic inflammation and fibrosis accompany pulmonary endothelial activation, supporting a pathogenic lung-liver axis in PAH.