Year: 2025
Type: preprint
Study design: Observational Study
Abstract: 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. Liver serologies and imaging were analyzed by unsupervised classification and regression tree (CART) to identify subclinical liver dysfunction clusters. Two machine-learning models predicted cluster assignment and informed differential expression. 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, predicting 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-minute walk distance (353 [120 - 576] m vs. 411[300 - 600] m, p=0.03), with upregulation of apelin, beta-catenin, and immune signaling. Rat lung ECs demonstrated survival and hepatic growth-factor signaling, while rat livers showed immune activation. Rat (20.8 vs 16.6 % area stained, p=0.09) and human PAH livers revealed fibrosis despite absent right ventricular failure, supporting a pathogenic lung-liver axis in PAH.
Authors: Navneet Singh, Jordan Lawson, Ashok Ragavendran, Somanshu Banerjee, Andy Hon, Alejandro Vega, Jason Hong, Christopher J. Mullin, Mandy Pereira, Allyson Sherman-Roe, Alexander T. Jorrin, Tiffaney Cayton, Gregory Fishbein, James R. Klinger, William Oldham, Zhiyu Dai, Michael Fallon, Elizabeth O. Harrington, Olin D. Liang, Soban Umar, Corey E. Ventetuolo
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: CardioPulmonary Vascular Biology COBRE, G5490037263, Effects of DHEA in Pulmonary Hypertension (DiPH), G9000225961, Advance Clinical and Translational Research (Advance-CTR), Brown Respiratory Research Training Program, Pulmonary Artery Endothelial Cell Endotypes and the Role of Anoikis Resistance in Pulmonary Hypertension, Integrative Multiomics to Uncover Novel Genes and Networks in Pulmonary Arterial Hypertension, Investigating the molecular mechanisms of right ventricular failure in pulmonary hypertension, Digital Twins from the Atom to the Rhythm, SOX17/RUNX1 Axis Regulates Endothelial Cell Fate in the Pathogenesis of Pulmonary Arterial Hypertension
OpenAlex ID: W4414854762