Fatty Acid and Oxylipin Metabolism Differentiate Isolated Postcapillary From Combined Pre- and Postcapillary Pulmonary Hypertension

BACKGROUND: Pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is the most common type of PH and comprises 2 subtypes with distinct clinical profiles and outcomes: isolated postcapillary PH and combined pre- and postcapillary PH (Cpc-PH). Bioactive lipid derivatives may underlie these divergent subphenotypes. This study aimed to investigate the molecular heterogeneity underlying Group 2 PH subtypes and identify shared pathways between Cpc-PH and pulmonary arterial hypertension (PAH). METHODS: In a cross-sectional study, we profiled plasma bioactive lipids using liquid chromatography-mass spectrometry in 128 patients with isolated postcapillary PH (n=21), Cpc-PH (n=69), or PAH (n=38), as well as in plasma samples from animal models of severe PH. RESULTS: <0.05. Of those, 28 were higher in Cpc-PH, particularly those in the polyunsaturated fatty acid and fatty acyl esters of hydroxy fatty acid pathways. Notably, 24 of these 28 did not differ from PAH, indicating a PAH-like bioactive lipid signature. Several metabolites, including adrenic acid, linoleic acid, docosatrienoic acid, palmitoleic acid, and fatty acyl esters of hydroxy fatty acids, were associated with increased mortality. These findings were corroborated in the Su/Hx rat model of PAH, where a subset of Cpc-PH-elevated metabolites was similarly increased. CONCLUSIONS: Cpc-PH exhibits a distinct, PAH-like metabolomic signature characterized by higher polyunsaturated fatty acids and fatty acyl esters of hydroxy fatty acids and lower pro-resolvin/vasodilatory oxylipins compared with isolated postcapillary PH. These findings have implications for PH classification, may inform diagnostic strategies, and nominate lipid pathways for therapeutic targeting.