Exploring the Lung-Liver Axis in Pulmonary Arterial Hypertension

Area of Science:

• Cardiovascular Research
• Hepatology
• Pulmonology

Background:

• The liver's role in the pathogenesis of pulmonary arterial hypertension (PAH) is not well understood.
• Inflammatory injury to pulmonary endothelium is a potential mechanism linking liver dysfunction to PAH.

Purpose of the Study:

• To investigate the hypothesis that the liver promotes inflammatory injury contributing to PAH pathogenesis.
• To explore the association between subclinical liver dysfunction and PAH severity in patients without diagnosed liver disease.

Main Methods:

• Unsupervised CART analysis of liver serologies in PAH patients to identify dysfunction clusters.
• Machine-learning models for differential gene expression and protein-protein interaction network analysis.
• Comparison of pulmonary artery endothelial cell transcriptomes with rat liver and lung data; assessment of liver fibrosis.

Main Results:

• CART analysis identified clusters with Model for End-Stage Liver Disease Sodium (MELD-Na) ≥ 12, associated with higher Fibrosis-4 scores and increased pulmonary vascular resistance.
• Patients with MELD-Na ≥ 12 exhibited reduced 6-minute walk distance.
• Protein-protein interaction network analysis highlighted IL-6 as a key hub in a module related to leukocyte migration in high MELD-Na patients; rat livers showed immune activation and a trend toward fibrosis.

Conclusions:

• A lung-liver axis may exist in PAH, even in the absence of overt liver disease.
• Subclinical liver dysfunction, indicated by MELD-Na scores, is linked to PAH severity and poorer outcomes.
• Further research is warranted to elucidate the mechanisms of this lung-liver interaction in PAH.