{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:18:02Z","timestamp":1793089082159,"version":"4.5.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:sec id=\"jah310989-sec-0001\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec id=\"jah310989-sec-0002\" xml:lang=\"en\">\n            <jats:title>Methods<\/jats:title>\n            <jats:p xml:lang=\"en\">We performed global untargeted metabolomics on plasma from 55 patients who underwent gold\u2010standard RV\u2010PA coupling measurements using multibeat pressure volume loop assessment in a single\u2010center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex\u2010adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares\u2013discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec id=\"jah310989-sec-0003\" xml:lang=\"en\">\n            <jats:title>Results<\/jats:title>\n            <jats:p xml:lang=\"en\">RV\u2010PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma \u03b1\u2010ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec id=\"jah310989-sec-0004\" xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">We identify an association between circulating TCA cycle intermediate levels and RV\u2010PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV\u2010targeted therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.041127","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T10:38:03Z","timestamp":1747910283000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5352-9288","authenticated-orcid":false,"given":"Darin T.","family":"Rosen","sequence":"first","affiliation":[{"name":"Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0524-7400","authenticated-orcid":false,"given":"Todd 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