# Physiologic relevance of the transpulmonary metabolome in connective tissue disease–associated pulmonary vascular disease

## TL;DR

This study shows that metabolite gradients in the lungs of patients with connective tissue disease-related PAH vary with exercise stages, offering new insights into disease mechanisms.

## Contribution

The study reveals exercise-specific transpulmonary metabolite gradients in CTD-PAH, linking them to disease progression and hemodynamics.

## Key findings

- Metabolite uptake and excretion across the pulmonary vascular bed differ by exercise stage.
- Glycolytic intermediates and lactate show physiological significance during peak exercise in advanced disease.
- Transpulmonary gradients correlate with hemodynamic endpoints during free-wheeling exercise.

## Abstract

Pathologic implications of dysregulated pulmonary vascular metabolism to pulmonary arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease–associated (CTD-associated) PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage–specific manner. Sixty-three CTD patients with established or suspected PAH underwent exercise right heart catheterization. Using mass spectrometry–based metabolomics, metabolites were quantified in plasma samples simultaneously collected from the pulmonary and radial arteries at baseline and during resistance-free wheeling, peak exercise, and recovery. We identified uptake and excretion of metabolites across the pulmonary vascular bed, unique and distinct from single vascular site analysis. We demonstrated the physiological relevance of metabolites previously shown to promote disease in animal models and end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, and tryptophan catabolites. Notably, pulmonary vascular metabolite handling was exercise stage specific. Transpulmonary metabolite gradients correlated with hemodynamic endpoints largely during free-wheeling. Glycolytic intermediates demonstrated physiologic significance at peak exercise, including net uptake of lactate in those with more advanced disease. Contribution of pulmonary vascular metabolism to CTD-PAH pathogenesis and therapeutic candidacy of metabolism modulation must be considered in the context of physiologic stress.

Connective tissue disease-associated pulmonary vascular disease is characterized by exercise stage-specific gradients of pathogenic metabolites across the pulmonary vascular bed.