Metabolomic Evidence of Biological Overlap with Heart Failure with Preserved Ejection Fraction in a Subset of Pulmonary Arterial Hypertension

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.