Yogesh N V Reddy, Aneesh K Asokan, Robert P Frantz, Anna Hemnes, Paul M Hassoun, John Barnard, Evelyn Horn, Jane A Leopold, Franz Rischard, Erika B Rosenzweig, Nicholas S Hill, Serpil C Erzurum, Gerald J Beck, J Emanuel Finet, Gabriele Grunig, Christine L Jellis, Stephen C Mathai, Catherine E Simpson, W H Wilson Tang, K Sreekumaran Nair, Barry A Borlaug
{"title":"在肺动脉高压亚群中与HFpEF生物学重叠的代谢组学证据。","authors":"Yogesh N V Reddy, Aneesh K Asokan, Robert P Frantz, Anna Hemnes, Paul M Hassoun, John Barnard, Evelyn Horn, Jane A Leopold, Franz Rischard, Erika B Rosenzweig, Nicholas S Hill, Serpil C Erzurum, Gerald J Beck, J Emanuel Finet, Gabriele Grunig, Christine L Jellis, Stephen C Mathai, Catherine E Simpson, W H Wilson Tang, K Sreekumaran Nair, Barry A Borlaug","doi":"10.1164/rccm.202501-0034OC","DOIUrl":null,"url":null,"abstract":"<p><p><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.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"1701-1713"},"PeriodicalIF":19.4000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432440/pdf/","citationCount":"0","resultStr":"{\"title\":\"Metabolomic Evidence of Biological Overlap with Heart Failure with Preserved Ejection Fraction in a Subset of Pulmonary Arterial Hypertension.\",\"authors\":\"Yogesh N V Reddy, Aneesh K Asokan, Robert P Frantz, Anna Hemnes, Paul M Hassoun, John Barnard, Evelyn Horn, Jane A Leopold, Franz Rischard, Erika B Rosenzweig, Nicholas S Hill, Serpil C Erzurum, Gerald J Beck, J Emanuel Finet, Gabriele Grunig, Christine L Jellis, Stephen C Mathai, Catherine E Simpson, W H Wilson Tang, K Sreekumaran Nair, Barry A Borlaug\",\"doi\":\"10.1164/rccm.202501-0034OC\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><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.</p>\",\"PeriodicalId\":7664,\"journal\":{\"name\":\"American journal of respiratory and critical care medicine\",\"volume\":\" \",\"pages\":\"1701-1713\"},\"PeriodicalIF\":19.4000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432440/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of respiratory and critical care medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1164/rccm.202501-0034OC\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CRITICAL CARE MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of respiratory and critical care medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1164/rccm.202501-0034OC","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
Metabolomic Evidence of Biological Overlap with Heart Failure with Preserved Ejection Fraction in a Subset of Pulmonary Arterial Hypertension.
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.
期刊介绍：
The American Journal of Respiratory and Critical Care Medicine focuses on human biology and disease, as well as animal studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients. Papers that are solely or predominantly based in cell and molecular biology are published in the companion journal, the American Journal of Respiratory Cell and Molecular Biology. The Journal also seeks to publish clinical trials and outstanding review articles on areas of interest in several forms. The State-of-the-Art review is a treatise usually covering a broad field that brings bench research to the bedside. Shorter reviews are published as Critical Care Perspectives or Pulmonary Perspectives. These are generally focused on a more limited area and advance a concerted opinion about care for a specific process. Concise Clinical Reviews provide an evidence-based synthesis of the literature pertaining to topics of fundamental importance to the practice of pulmonary, critical care, and sleep medicine. Images providing advances or unusual contributions to the field are published as Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences.
A recent trend and future direction of the Journal has been to include debates of a topical nature on issues of importance in pulmonary and critical care medicine and to the membership of the American Thoracic Society. Other recent changes have included encompassing works from the field of critical care medicine and the extension of the editorial governing of journal policy to colleagues outside of the United States of America. The focus and direction of the Journal is to establish an international forum for state-of-the-art respiratory and critical care medicine.
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