Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease
Background 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. Methods We performed global untargeted metabolo...
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2025-06-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.041127 |
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| author | Darin T. Rosen Todd M. Kolb Stephen C. Mathai Karthik Suresh Rachel Damico Steven Hsu Ryan J. Tedford Anna R. Hemnes Jane A. Leopold Evelyn M. Horn Erika S. Berman‐Rosenzweig Franz Rischard Robert P. Frantz Serpil C. Erzurum Gerald J. Beck Nicholas S. Hill John Barnard Samar Farha Gabriele Grunig Christine Jellis Deborah H. Kwon Reena Mehra Margaret M. Park W. H. Wilson Tang Paul M. Hassoun Catherine E. Simpson |
| author_facet | Darin T. Rosen Todd M. Kolb Stephen C. Mathai Karthik Suresh Rachel Damico Steven Hsu Ryan J. Tedford Anna R. Hemnes Jane A. Leopold Evelyn M. Horn Erika S. Berman‐Rosenzweig Franz Rischard Robert P. Frantz Serpil C. Erzurum Gerald J. Beck Nicholas S. Hill John Barnard Samar Farha Gabriele Grunig Christine Jellis Deborah H. Kwon Reena Mehra Margaret M. Park W. H. Wilson Tang Paul M. Hassoun Catherine E. Simpson |
| author_sort | Darin T. Rosen |
| collection | DOAJ |
| description | Background 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. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted 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–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate 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. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA 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‐targeted therapies. |
| format | Article |
| id | doaj-art-35d01d36d86c4dc2b406fbfa303d875a |
| institution | Kabale University |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-35d01d36d86c4dc2b406fbfa303d875a2025-08-20T03:31:07ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-06-01141110.1161/JAHA.124.041127Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular DiseaseDarin T. Rosen0Todd M. Kolb1Stephen C. Mathai2Karthik Suresh3Rachel Damico4Steven Hsu5Ryan J. Tedford6Anna R. Hemnes7Jane A. Leopold8Evelyn M. Horn9Erika S. Berman‐Rosenzweig10Franz Rischard11Robert P. Frantz12Serpil C. Erzurum13Gerald J. Beck14Nicholas S. Hill15John Barnard16Samar Farha17Gabriele Grunig18Christine Jellis19Deborah H. Kwon20Reena Mehra21Margaret M. Park22W. H. Wilson Tang23Paul M. Hassoun24Catherine E. Simpson25Division of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD USADivision of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD USADivision of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD USADivision of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD USADivision of Pulmonary, Critical Care and Sleep Medicine University of Miami FL USADivision of Cardiology Johns Hopkins University Baltimore MD USADivision of Cardiology, Department of Medicine Medical University of South Carolina Charleston SC USADivision of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine Vanderbilt University Nashville TN USADivision of Cardiovascular Medicine, Department of Medicine Brigham and Women’s Hospital Boston MA USADivision of Cardiology, Department of Medicine Cornell University Medical Center New York NY USADepartment of Pediatrics Westchester Medical Center, New York Medical College Valhalla NY USADivision of Pulmonary, Allergy, Critical Care, and Sleep Medicine University of Arizona College of Medicine Tucson AZ USADivision of Circulatory Failure, Department of Cardiovascular Medicine Mayo Clinic Rochester MN USACleveland Clinic Lerner Research Institute Cleveland OH USACleveland Clinic Lerner Research Institute Cleveland OH USAPulmonary, Critical Care and Sleep Division Tufts University Boston MA USACleveland Clinic Lerner Research Institute Cleveland OH USACleveland Clinic Lerner Research Institute Cleveland OH USANew York University Grossman School of Medicine New York NY USAHeart, Vascular and Thoracic Institute, Cleveland Clinic Cleveland OH USAHeart, Vascular and Thoracic Institute, Cleveland Clinic Cleveland OH USADivision of Pulmonary, Critical Care and Sleep Medicine University of Washington Medical Center Seattle WA USAHeart, Vascular and Thoracic Institute, Cleveland Clinic Cleveland OH USACleveland Clinic Lerner Research Institute Cleveland OH USADivision of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD USADivision of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD USABackground 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. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted 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–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate 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. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA 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‐targeted therapies.https://www.ahajournals.org/doi/10.1161/JAHA.124.041127global untargeted metabolomicsright ventricular maladaptationright ventricular–pulmonary artery couplingtricarboxylic acid cycle |
| spellingShingle | Darin T. Rosen Todd M. Kolb Stephen C. Mathai Karthik Suresh Rachel Damico Steven Hsu Ryan J. Tedford Anna R. Hemnes Jane A. Leopold Evelyn M. Horn Erika S. Berman‐Rosenzweig Franz Rischard Robert P. Frantz Serpil C. Erzurum Gerald J. Beck Nicholas S. Hill John Barnard Samar Farha Gabriele Grunig Christine Jellis Deborah H. Kwon Reena Mehra Margaret M. Park W. H. Wilson Tang Paul M. Hassoun Catherine E. Simpson Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease global untargeted metabolomics right ventricular maladaptation right ventricular–pulmonary artery coupling tricarboxylic acid cycle |
| title | Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease |
| title_full | Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease |
| title_fullStr | Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease |
| title_full_unstemmed | Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease |
| title_short | Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease |
| title_sort | dysregulated tricarboxylic acid cycle metabolism is associated with right ventricular maladaptation in pulmonary vascular disease |
| topic | global untargeted metabolomics right ventricular maladaptation right ventricular–pulmonary artery coupling tricarboxylic acid cycle |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.041127 |
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