Jonathan Chacon-Barahona, Samuel J Chung, Jonah D Garry, Robert Frantz, Franz Rischard, Paul M Hassoun, Stephen C Mathai, Catherine E Simpson, Gerald Beck, Nicholas S Hill, Jane A Leopold, Aaron B Waxman, Erika B Rosenzweig, Barry A Borlaug, Monica Mukherjee, Rebecca Vanderpool, Miriam Jacob, Reena Mehra, Margaret M Park, J Emanuel Finet, Samar Farha, Gabriele Grunig, Deborah Kwon, Suzy Comhair, Serpil Erzurum, John Barnard, Bo Hu, Christine L Jellis, Alexandra Christin Racanelli, Jan Krumsiek, Evan L Brittain, Anna Hemnes, Evelyn Horn; PVDOMICS Study Group
Weill Cornell Medical College. Albert Einstein College of Medicine-Montefiore Health System. Vanderbilt University Medical Center. Mayo Clinic. University of Arizona. Johns Hopkins University. Cleveland Clinic. Tufts Medical Center. Brigham and Women’s Hospital. New York Medical College. Ohio State University. University of Washington Medical Center. Duke University. Weill Cornell Medical College.
United States
Circulation Research
Circ Res 2026;
DOI: 10.1161/CIRCRESAHA.125.327342
Abstract
Background: The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex.
Methods: We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed.
Results: There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in females compared with males. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores.
Conclusions: We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in females compared with males.
Category
Heart Dysfunction Associated with Pulmonary Vascular Disease (Right)
Diagnostic Testing for Pulmonary Vascular Disease. Non-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
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: No