Metabolomic Evidence of Biological Overlap with HFpEF in a Subset of Pulmonary Arterial Hypertension.
Academic Article
Overview
abstract
RATIONALE: A subset of 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 probability, with healthy controls and clinical HFpEF for comparison of venous and transpulmonary metabolomics Measurements and Main results: Group 1 PH+high HFpEF probability(n=131) was associated with significant increase in 207 metabolites(false discovery rate(FDR) p<0.05 and Fold change>1)(n=193,T-test) and decrease in 231 metabolites (FDR p<0.05 and Fold change<1)(n=193,T-test) compared to 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 levels and lower serotonin levels(FDR p<0.002 for all,n=193,T-test). Linoleate(precursor to arachidonic acid and prostaglandins), 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 controls(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 non-pulmonary 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 to clinical HFpEF, supporting biological overlap between these two forms of pulmonary hypertension.
