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Objective: Patients 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 patients with CTD‐PAH versus patients with IPAH that might underlie these observed clinical differences. Methods: Adult participants with CTD‐PAH (n = 141) and IPAH (n = 165) from the Pulmonary Vascular Disease Phenomics (PVDOMICS) study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad‐based global metabolomic profiling of plasma samples. Participants 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 participants. Results: Metabolomic profiles distinguished CTD‐PAH from IPAH, with patients with CTD‐PAH demonstrating aberrant lipid metabolism with lower circulating levels of sex steroid hormones and higher free fatty acids (FAs) and FA intermediates. Acylcholines were taken up by the right ventricular–pulmonary vascular (RV‐PV) 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 RV measurements and with transplant‐free survival. Conclusions: CTD‐PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV‐PV FA metabolism may imply a reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation. [ABSTRACT FROM AUTHOR]

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