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, the PVDOMICS Study Group
Johns Hopkins University. University of Miami, Medical University of South Carolina. Vanderbilt University. Brigham and Women’s Hospital. Cornell University Medical Center. Westchester Medical Center and New York Medical College Valhalla. University of Arizona College of Medicine. Mayo Clinic. Cleveland Clinic. Tufts University. New York University Grossman School of Medicine. University of Washington Medical Center.
United States
Journal of the American Heart Association
J Am Heart Assoc 2025;
DOI: 10.1161/JAHA.124.041127
Abstract
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.
Category
Right Heart Dysfunction Associated with Pulmonary Vascular Disease
Diagnostic Testing for Pulmonary Vascular Disease. Invasive Testing
Potential Biomarkers Associated with Pulmonary Vascular Disease
Age Focus: Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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