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We sought to identify differential metabolism in patients with CTD\u2010PAH versus patients with IPAH that might underlie these observed clinical differences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Adult participants with CTD\u2010PAH (n\u00a0=\u00a0141) and IPAH (n\u00a0=\u00a0165) from the Pulmonary Vascular Disease Phenomics (PVDOMICS) study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad\u2010based 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\u2010PAH versus IPAH metabolomic profiles and to measure metabolite\u2010phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 participants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Metabolomic profiles distinguished CTD\u2010PAH from IPAH, with patients with CTD\u2010PAH 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\u2013pulmonary vascular (RV\u2010PV) circulation, particularly in CTD\u2010PAH, 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\u2010free survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CTD\u2010PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV\u2010PV FA metabolism may imply a reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42632","type":"journal-article","created":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T14:35:10Z","timestamp":1687185310000},"page":"2240-2251","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Metabolomic Differences in Connective Tissue Disease\u2013Associated Versus Idiopathic Pulmonary Arterial Hypertension in the <scp>PVDOMICS<\/scp> Cohort"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2388-5660","authenticated-orcid":false,"given":"Catherine E.","family":"Simpson","sequence":"first","affiliation":[{"name":"Johns Hopkins University  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna R.","family":"Hemnes","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Griffiths","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center  Dallas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Grunig","sequence":"additional","affiliation":[{"name":"New York University Grossman School of Medicine  New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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