Lipidomics of Pulmonary Vascular Disease

Project Summary/Abstract Pulmonary arterial hypertension (PAH) remains challenging to treat due to its complex pathobiology. The persistently high mortality observed in PAH, despite a recent evolution in available pulmonary vasodilator therapies, underscores a critical need to intervene upon fundamental disease biology. Our data show that abnormalities in long-chain fatty acid (LCFA) metabolism precede a clinical diagnosis of PAH in the at-risk scleroderma population. Despite increasing recognition of lipidomic aberrations in PAH, no studies have examined comprehensive high-resolution lipidomics in relation to measurements of right ventricular (RV) and pulmonary vascular (PV) function. Our preliminary single-center high-resolution lipidomic data show that lipid species with LCFA residues are associated with measures of RV-PV dysfunction. LCFAs are known to be biologically important mediators in the lung, and many are essential FAs obtained via dietary intake. The goal of the current proposal is to validate our single-center lipidomic observations in external cohorts with complementary data features and data structures. We hypothesize that the lipidomic signatures detected in our discovery cohort will reproducibly relate to specific RV-PV phenotypes and clinical outcomes, which will implicate biologically important aberrations in lipid metabolism that may be targetable via dietary or pharmacologic interventions. With Aim 1, we seek to validate lipidomic signatures in the larger, multi-center PVDOMICS cohort of patients with, or at risk for, pulmonary vascular disease, and to investigate lipid gradients across the pulmonary vasculature (e.g., differences in lipid abundance in blood samples collected from the mixed venous vs. wedged positions). Our second aim involves validating our preliminary lipidomic signatures in the ARIC cohort, a longitudinal study of initially healthy individuals followed forward in time. We will explore the relationships between dietary lipid intake, plasma lipid levels, and RV-PV function, hypothesizing that changes in LCFAs over time will predict RV-PV function. In Aim 3, we will prospectively follow patients newly diagnosed with PAH. We will investigate whether lipidomic aberrations, at baseline and in follow-up after initiation of standard PAH-specific therapy, can outperform traditional clinical measures of treatment response for predicting clinical worsening events. Completion of this project will yield a detailed understanding of lipid aberrations specific to phenotypes and outcomes in PH, which has the potential to identify novel biomarkers and therapeutic targets. Should our hypothesis be confirmed, the project stands to transform our approach to PH management via early identification of patients at high risk for experiencing poor outcomes, and potential early intervention based on lipidomic insights.