Metabolomic Differences in Connective Tissue Disease–Associated Versus Idiopathic Pulmonary Arterial Hypertension in the PVDOMICS Cohort

Abstract

ObjectivePatients with connective tissue disease‐associated pulmonary arterial hypertension (CTD‐PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in CTD‐PAH versus IPAH patients that might underlie these observed clinical differences.MethodsAdult subjects with CTD‐PAH (n=141) and IPAH (n=165) from the PVDOMICS (Pulmonary Vascular Disease Phenomics) Study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad‐based global metabolomic profiling of plasma samples. Subjects were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD‐PAH versus IPAH metabolomic profiles and to measure metabolite‐phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 subjects.ResultsMetabolomic profiles distinguished CTD‐PAH from IPAH, with CTD‐PAH patients demonstrating aberrant lipid metabolism, with lower circulating levels of sex steroid hormones and higher free fatty acids (FA) and FA intermediates in CTD‐PAH. Acylcholines were taken up by the right ventricular‐pulmonary vascular circulation, particularly in CTD‐PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and right ventricular measurements and with transplant‐free survival.ConclusionsCTD‐PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV‐pulmonary vascular FA metabolism may imply reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.

Metabolomics in Pulmonary Hypertension—A Useful Tool to Provide Insights into the Dark Side of a Tricky Pathology

“…In fact, patients with a connective tissue disease like systemic sclerosis and PAH had raised concentrations of fatty acid metabolites (including lignoceric acid and nervonic acid), eicosanoids/oxylipins, and sex hormone metabo-lites [71]. In fact, the main metabolomic feature of connective tissue disease-associated PAH is a dysregulated lipid metabolism (with reduced concentrations of sex steroid hormones and raised concentrations of free fatty acids), which implies a shifted metabolic substrate utilization and the downregulation of mitochondrial beta oxidation [72].…”