Exploring the Lung-Liver Axis in Pulmonary Arterial Hypertension

The liver's contribution to pulmonary arterial hypertension (PAH) pathogenesis remains unclear. We hypothesized that the liver promotes inflammatory injury to the pulmonary endothelium. PAH patients without liver disease with pulmonary artery endothelial cell (PAEC) biopsies were included. Unsupervised CART analysis of liver serologies identified subclinical dysfunction clusters; machine-learning models informed differential expression and protein-protein interaction network assembly. PAEC transcriptomes were compared to liver and lung data from monocrotaline and Sugen-Hypoxia rats. Liver fibrosis was assessed in rat and human PAH livers. Among 25 PAH patients (76% female, median age 61 [30-84] years), CART identified clusters distinguished by Model for End-Stage Liver Disease Sodium (MELD-Na) ≥ 12, which was associated with higher Fibrosis-4 scores and higher pulmonary vascular resistance (ß = 0.5 Wood units per point increase in MELD-Na, 95% CI 0.2-0.8, p = 0.005) after adjustment for right atrial pressure. Subjects with MELD-Na ≥ 12 had decreased 6-min walk distance (353 [120-576] m vs. 411 [300-600] m, p = 0.03). In comparing the two clusters, a protein-protein interaction network analysis identified IL-6 as the primary hub of a transcriptional module enriched for leukocyte chemotaxis and myeloid leukocyte migration (all FDR < 0.05) among the High-MELD-Na group. Rat livers demonstrated immune activation and a trend toward increased fibrosis (20.8 vs. 16.6% area stained, p = 0.09), and human PAH livers without liver disease showed an intermediate fibrotic phenotype between controls and portopulmonary hypertension, though this did not reach statistical significance. Our observations support a lung-liver axis in PAH even in the absence of liver disease, warranting further study.