The Functional Molecular Biopsy: Exercise-Induced Transpulmonary Multi-Omic Profiling in Pulmonary Arterial Hypertension

Pulmonary hypertension (PH) is a disease in which diverse pathogenic drivers converge to promote inflammatory vascular remodeling, ultimately leading to right ventricular (RV) dysfunction and heart failure. Exercise right heart catheterization (RHC) reveals abnormal pulmonary vascular responses early in the disease course and improves diagnosis and risk stratification in PH. Despite major advances in PH research, direct access to the biological processes driving pulmonary vascular remodeling remains limited. Existing clinical assessments predominantly capture the consequences of disease rather than its causes, while tissue-based studies are constrained by limited access to early-stage human samples and the inability to perform serial measurements. This creates a critical need for methodologies capable of interrogating pulmonary vascular biology in vivo and across the disease continuum. We propose that combining exercise RHC with paired transpulmonary omics measurements may provide such an opportunity. The strategy of measuring the change in molecular concentrations across the pulmonary circulation during physiological stress has the potential to function as a dynamic molecular biopsy of the pulmonary vasculature, linking abnormal exercise hemodynamics to the biological pathways that drive disease, although current supporting evidence remains limited to small, heterogeneous proof-of-concept cohorts. In this review, we examine the physiological basis, technical framework, biological insights, and translational implications of this emerging approach for PH.