Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease

作者：Darin Rosen, Todd M. Kolb, Stephen C. Mathai, Karthik Suresh, Rachel D’Amico, Steven Hsu, Ryan J. Tedford, Anna R. Hemnes, Jane A. Leopold, Evelyn M. Horn, Erika B. Rosenzweig, Franz Rischard, Robert P. Frantz, Serpil C. Erzurum, Gerald J. Beck, Nicholas S. Hill, John Barnard, Samar Farha, Gabriele Grünig, Christine Jellis, Deborah Kwon, Reena Mehra, Margaret Park, W.H. Wilson Tang, Paul M. Hassoun, Catherine E. Simpson, Nicholas S. Hill, L Xiao, Jeffrey Fessel, Yongping Fu, Lisa Postow, Barry Schmetter, R Sutliff, Xuefei Tian, Michael P. Gray, Elizabeth Joseloff, Brenda Wong, Jane A. Leopold, Aaron B. Waxman, Laurie Lawler, B Maron, David M. Systrom, David J. Brady, Wendy K. Chung, Gabriele Grünig, Jennifer Haythe, Udhay Krishnan, David A. Payne, Evelyn M. Horn, Geoffrey Bergman, K Bastert, Richard B. Devereux, Maria Karas, Ju Youn Kim, Udhay Krishnan, Julia Lohman, Alexandra C. Racanelli, Michelle L. Ricketts, Irina Sobol, Harsimran Singh, Jonathan W. Weinsaft, Paul M. Hassoun, S.C. Mathai, A. Balasubramanian, Kyle A. Carey, Rachel L. Damico, Blessing Enobun, Lei Gao, Marc K. Halushka, Steven Hsu, David A. Kass, Todd M. Kolb, Ting‐Tse Lin, Monica Mukherjee, Johannes Roth, Y Sanni, Catherine E. Simpson, Robert E. Weiss, Stefan L. Zimmerman, Robert P. Frantz, Atta Behfar, Barry A. Borlaug, Heinz Brock, Louise A. Durst, Denise Head, Thomas A. Foley, Benjamin R. Gochanour, H Halbach, Garvan C. Kane, Michael J. Krowka, David K. Menon, Gyu Tae Park, Margaret M. Redfield, Kristi Rohwer, T. Sands, Christopher G. Scott, André Terzic, Eric E. Williamson, Franz Rischard, Joe G. N. Garcia, R Vanderpool, Jason X.‐J. Yuan, C.S. Lim, Aiden Abidov, Akshay S. Desai, Harold Erickson, Lene Hansen, Anna R. Hemnes, Jamie E. Newman, Evan L. Brittain, James M. Cunningham, Meredith E. Pugh, Ivan M. Robbins, Gerald J. Beck, Serpil C. Erzurum, Micheala A. Aldred, Kewal Asosingh, Joan Aylor, John Barnard, B Beck, A Borowski, Clara Collart, Feixiong Cheng, S.A.A. Comhair, Francesco Di Filippo, Jeanne K. Drinko, Samar Farha, J. Emanuel Finet, Aisling M. Flinn, M Geraci, Bo Hu, Wael A. Jaber, Miriam Jacob, Christine Jellis, Alexandra Kanta, Deborah Kwon, Brett Larive, Jason K. Lempel, Minghui Li, Maite Velázquez Martín, J. MacKrell, Kevin McCarthy, Reena Mehra, D. Neumann, R Nawabit, Jill Odabashian, Mitchell A. Olman, M Park, Milena Radeva, José Ramos, R Renapurkar, Jacqueline Sharp, Stefan Sherer, Tang WHW, Jason Thomas, K Wadih, Simon P. Wells, Kerri L. Wiggins, Jane Wilcox, Belinda Willard, S Yu, Sharon Rounds, Raymond L. Benza, Todd Bull, John B. Cadigan, James C. Fang, Mardi Gomberg‐Maitland · 发表于：Journal of the American Heart Association · 年份：2025 · DOI：10.1161/jaha.124.041127 · 被引用次数：10 · 研究领域：Pulmonary Hypertension Research and Treatments、Cardiac Valve Diseases and Treatments、Chronic Obstructive Pulmonary Disease (COPD) Research

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...