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

<b>Rationale:</b> A subset of patients with group 1 pulmonary hypertension (PH) have superimposed left heart abnormalities with unclear metabolic implications. <b>Objectives:</b> To compare serum/transpulmonary metabolome between group 1 PH stratified by heart failure with preserved ejection fraction (HFpEF) probability. <b>Methods:</b> 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. <b>Measurements and Main Results:</b> Group 1 PH + high HFpEF probability (<i>n</i> = 131) was associated with a significant increase in 207 metabolites (false discovery rate [FDR] <i>P</i> < 0.05 and fold change >1) (<i>n</i> = 193, <i>t</i> test) and a significant decrease in 231 metabolites (FDR <i>P</i> < 0.05 and fold change <1) (<i>n</i> = 193, <i>t</i> test) compared with group 1 PH + low HFpEF probability (<i>n</i> = 62). Group 1 PH + high HFpEF probability was associated with enhanced tryptophan metabolism with higher downstream kynurenine metabolite concentrations and lower serotonin concentrations (FDR <i>P</i> < 0.002 for all, <i>n</i> = 193, <i>t</i> 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 <i>P</i> < 0.03 for all, <i>n</i> = 193, <i>t</i> test). Metabolome changes in group 1 PH + high HFpEF probability overlapped with clinical HFpEF (<i>n</i> = 240) but were abnormal relative to control subjects (<i>n</i> = 85) (<i>P</i> < 0.0001 for all, <i>n</i> = 456, <i>t</i> test). There was no evidence of differential transpulmonary uptake/release of most metabolites, suggesting probable nonpulmonary origin (except for serotonin, interaction <i>P</i> = 0.04; and kynurenine, interaction <i>P</i> = 0.03; <i>n</i> = 433, mixed model). <b>Conclusions:</b> 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.