Metabolomic Evidence of Biological Overlap with Heart Failure with Preserved Ejection Fraction in a Subset of Pulmonary Arterial Hypertension
Year: 2025
Type: article
Study design: Observational Study
Abstract: Rationale A subset of patients with group 1 pulmonary hypertension (PH) have superimposed left heart abnormalities with unclear metabolic implications. Objectives To compare serum/transpulmonary metabolome between group 1 PH stratified by heart failure with preserved ejection fraction (HFpEF) probability. Methods Patients with group 1 PH were stratified into low (<25%) and high (⩾75%) HFpEF-ABA (age, body mass index, and atrial fibrillation) probability, with healthy control subjects and subjects with clinical HFpEF used for comparison of venous and transpulmonary metabolomics. Measurements and Main Results Group 1 PH + high HFpEF probability (n = 131) was associated with a significant increase in 207 metabolites (false discovery rate [FDR] P < 0.05 and fold change >1) (n = 193, t test) and a significant decrease in 231 metabolites (FDR P < 0.05 and fold change <1) (n = 193, t test) compared with group 1 PH + low HFpEF probability (n = 62). Group 1 PH + high HFpEF probability was associated with enhanced tryptophan metabolism with higher downstream kynurenine metabolite concentrations and lower serotonin concentrations (FDR P < 0.002 for all, n = 193, t test). Linoleate (precursor to arachidonic acid and prostaglandins) and arginine and homoarginine (precursors to nitric oxide) were all lower in group 1 PH + high HFpEF probability (FDR P < 0.03 for all, n = 193, t test). Metabolome changes in group 1 PH + high HFpEF probability overlapped with clinical HFpEF (n = 240) but were abnormal relative to control subjects (n = 85) (P < 0.0001 for all, n = 456, t test). There was no evidence of differential transpulmonary uptake/release of most metabolites, suggesting probable nonpulmonary origin (except for serotonin, interaction P = 0.04; and kynurenine, interaction P = 0.03; n = 433, mixed model). Conclusions Patients with group 1 PH + high HFpEF probability have a unique metabolome characterized by enhanced tryptophan-kynurenine pathway breakdown, deficiency of amino acids (such as glycine and serine), lower serotonin, and decreased prostaglandin and nitric oxide precursors. Despite fulfilling clinical criteria for group 1 PH, these metabolome changes were comparable with clinical HFpEF, supporting biological overlap between these two forms of PH.
Authors: Yogesh N. V. Reddy, Aneesh K. Asokan, Robert P. Frantz, Anna Hemnes, Paul M. Hassoun, John Barnard, Evelyn Horn, Jane A. Leopold, Franz Rischard, Erika B. Rosenzweig, Nicholas S. Hill, Serpil C. Erzurum, Gerald J. Beck, J. Emanuel Finet, Gabriele Grunig, Christine L. Jellis, Stephen C. Mathai, Catherine E. Simpson, W. H. Wilson Tang, K. Sreekumaran Nair, Barry A. Borlaug
Institutions: Mayo Clinic, Vanderbilt University, Vanderbilt University Medical Center, Johns Hopkins University, Johns Hopkins Medicine, Cleveland Clinic, Weill Cornell Medicine, Brigham and Women's Hospital, Harvard University, University of Arizona, Westchester Medical Center, Columbia University, Tufts Medical Center, New York University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G13618882, Pulmonary Vascular Disease Phenomics Program (PVDOMICS) Data Coordinating Center, HL-Inorganic Nitrite to Enhance Benefits from Exercise Training in Heart Failure with preserved Ejection Fraction, Hopkins Clinical Center for Pulmonary Vascular Disease Phenomics Program, Intergrated Endothelial Phenotyping to Redefine Pulmonary Hypertension, G4106935645, PVDOMICS Defining the Future Fingerprints of Pulmonary Vascular Disease, Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics: Clinical Centers (CC) (U01)., Phenomic and genomic study to subphenotype Hispanics with pulmonary hypertension, Mayo Clinic HeartShare Clinical Center, Pulmonary Hypertension in Left Heart Disease
OpenAlex ID: W4411266175