Reddy Yogesh N V, Asokan Aneesh K, Frantz Robert P, Hemnes Anna, Hassoun Paul M, Barnard John, Horn Evelyn, Leopold Jane A, Rischard Franz, Rosenzweig Erika B, Hill Nicholas S, Erzurum Serpil C, Beck Gerald J, Finet J Emanuel, Grunig Gabriele, Jellis Christine L, Mathai Stephen C, Simpson Catherine E, Tang W H Wilson, Nair K Sreekumaran, Borlaug Barry A
Department of Cardiovascular Medicine and.
Division of Endocrinology, Diabetes, and Nutrition, Mayo Clinic, Rochester, Minnesota.
Am J Respir Crit Care Med. 2025 Sep;211(9):1701-1713. doi: 10.1164/rccm.202501-0034OC.
A subset of patients with group 1 pulmonary hypertension (PH) have superimposed left heart abnormalities with unclear metabolic implications. To compare serum/transpulmonary metabolome between group 1 PH stratified by heart failure with preserved ejection fraction (HFpEF) probability. 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. Group 1 PH + high HFpEF probability ( = 131) was associated with a significant increase in 207 metabolites (false discovery rate [FDR] < 0.05 and fold change >1) ( = 193, test) and a significant decrease in 231 metabolites (FDR < 0.05 and fold change <1) ( = 193, test) compared with group 1 PH + low HFpEF probability ( = 62). Group 1 PH + high HFpEF probability was associated with enhanced tryptophan metabolism with higher downstream kynurenine metabolite concentrations and lower serotonin concentrations (FDR < 0.002 for all, = 193, 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 < 0.03 for all, = 193, test). Metabolome changes in group 1 PH + high HFpEF probability overlapped with clinical HFpEF ( = 240) but were abnormal relative to control subjects ( = 85) ( < 0.0001 for all, = 456, test). There was no evidence of differential transpulmonary uptake/release of most metabolites, suggesting probable nonpulmonary origin (except for serotonin, interaction = 0.04; and kynurenine, interaction = 0.03; = 433, mixed model). 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.
1型肺动脉高压（PH）患者的一个亚组存在叠加的左心异常，其代谢影响尚不清楚。为了比较按射血分数保留的心力衰竭（HFpEF）概率分层的1型PH患者的血清/经肺代谢组。将1型PH患者分为HFpEF-ABA（年龄、体重指数和心房颤动）概率低（<25%）和高（⩾75%）的两组，以健康对照受试者和临床HFpEF受试者作为静脉和经肺代谢组学比较的对象。与1型PH+低HFpEF概率组（n = 62）相比，1型PH+高HFpEF概率组（n = 131）有207种代谢物显著增加（错误发现率[FDR]<0.05且变化倍数>1）（n = 193, t检验），231种代谢物显著减少（FDR<0.05且变化倍数<1）（n = 193, t检验）。1型PH+高HFpEF概率组与色氨酸代谢增强有关，下游犬尿氨酸代谢物浓度较高，血清素浓度较低（所有P<0.002，n = 193, t检验）。亚油酸（花生四烯酸和前列腺素的前体）以及精氨酸和高精氨酸（一氧化氮的前体）在1型PH+高HFpEF概率组中均较低（所有P<0.03，n = 193, t检验）。1型PH+高HFpEF概率组的代谢组变化与临床HFpEF（n = 240）有重叠，但相对于对照受试者（n = 85）则是异常的（所有P<0.0001，n = 456, t检验）。没有证据表明大多数代谢物有经肺摄取/释放差异，提示可能起源于非肺组织（血清素除外，交互作用P = 0.04；犬尿氨酸除外，交互作用P = 0.03；n = 433，混合模型）。1型PH+高HFpEF概率组患者有独特的代谢组特征，表现为色氨酸-犬尿氨酸途径分解增强、氨基酸（如甘氨酸和丝氨酸）缺乏、血清素降低以及前列腺素和一氧化氮前体减少。尽管符合1型PH的临床标准，但这些代谢组变化与临床HFpEF相当，支持这两种形式的PH之间存在生物学重叠。
