{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T17:35:39Z","timestamp":1794591339284,"version":"4.9.1"},"reference-count":110,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pulmonary hypertension (PH) is a multifaceted illness causing clinical manifestations like dyspnea, fatigue, and cyanosis. If left untreated, it often evolves into irreversible pulmonary arterial hypertension (PAH), leading to death. Metabolomics is a laboratory technique capable of providing insights into the metabolic pathways that are responsible for a number of physiologic or pathologic events through the analysis of a biological fluid (such as blood, urine, and sputum) using proton nuclear magnetic resonance spectroscopy or mass spectrometry. A systematic review was finalized according to the PRISMA scheme, with the goal of providing an overview of the research papers released up to now on the application of metabolomics to PH\/PAH. So, eighty-five papers were identified, of which twenty-four concerning PH, and sixty-one regarding PAH. We found that, from a metabolic standpoint, the hallmarks of the disease onset and progression are an increase in glycolysis and impaired mitochondrial respiration. Oxidation is exacerbated as well. Specific metabolic fingerprints allow the characterization of some of the specific PH and PAH subtypes. Overall, metabolomics provides insights into the biological processes happening in the body of a subject suffering from PH\/PAH. The disarranged metabolic pathways underpinning the disease may be the target of new therapeutic agents. Metabolomics will allow investigators to make a step forward towards personalized medicine.<\/jats:p>","DOI":"10.3390\/ijms241713227","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T01:56:57Z","timestamp":1693187817000},"page":"13227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Metabolomics in Pulmonary Hypertension\u2014A Useful Tool to Provide Insights into the Dark Side of a Tricky Pathology"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8374-0260","authenticated-orcid":false,"given":"Pier Paolo","family":"Bassareo","sequence":"first","affiliation":[{"name":"Mater Misercordiae University Hospital, D07 R2WY Dublin, Ireland"},{"name":"Children\u2019s Health Ireland at Crumlin, D12 N512 Dublin, Ireland"},{"name":"School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5729-1038","authenticated-orcid":false,"given":"Michele","family":"D\u2019Alto","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Unit, Dipartimento di Cardiologia, Universit\u00e0 della Campania \u201cLuigi Vanvitelli\u201d, Ospedale Monaldi, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Novoyatleva, T. (2023). Pulmonary Hypertension: New Insights and Recent Advances from Basic Science to Translational Approaches. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108462"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1164\/rccm.202109-2079PP","article-title":"Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial Hypertension?","volume":"205","author":"Vizza","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1093\/eurheartj\/ehac237","article-title":"2022 ESC\/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension","volume":"43","author":"Humbert","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3820","DOI":"10.1080\/14767058.2019.1695770","article-title":"Pulmonary hypertension in pediatrics. A feasible approach to bridge the gap between real world and guidelines","volume":"34","author":"Calcaterra","year":"2021","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s00441-016-2539-y","article-title":"Pulmonary vascular remodeling in pulmonary hypertension","volume":"367","author":"Tuder","year":"2017","journal-title":"Cell. Tissue Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.ccm.2013.08.009","article-title":"Pathology of pulmonary hypertension","volume":"34","author":"Tuder","year":"2013","journal-title":"Clin. Chest Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1183\/09031936.00038410","article-title":"Pulmonary hypertension and pulmonary arterial hypertension: A clarification is needed","volume":"36","author":"Palazzini","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_8","first-page":"e201627","article-title":"Systems biology: An emerging strategy for discovering novel pathogenetic mechanisms that promote cardiovascular disease","volume":"2016","author":"Maron","year":"2016","journal-title":"Glob. Cardiol. Sci. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s12931-017-0631-9","article-title":"Using omics approaches to understand pulmonary diseases","volume":"18","author":"Kan","year":"2017","journal-title":"Respir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ferrasi, A.C., Puttini, R., Galvani, A.F., Hamamoto Filho, P.T., Delafiori, J., Argente, V.D., de Oliveira, A.N., Dias-Audibert, F.L., Catharino, R.R., and Silva, O.C. (2023). Metabolomics Approach Reveals Important Glioblastoma Plasma Biomarkers for Tumor Biology. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108813"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bassareo, P.P., and McMahon, C.J. (2022). Metabolomics: A New Tool in Our Understanding of Congenital Heart Disease. Children, 9.","DOI":"10.3390\/children9121803"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"800","DOI":"10.2459\/JCM.0b013e32834a658f","article-title":"Metabolomics: A new era in cardiology?","volume":"12","author":"Mercuro","year":"2011","journal-title":"J. Cardiovasc. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.jacc.2022.01.022","article-title":"Eisenmenger Syndrome: JACC State-of-the-Art Review","volume":"79","author":"Arvanitaki","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1086\/677369","article-title":"The emerging role of metabolomics in the development of biomarkers for pulmonary hypertension and other cardiovascular diseases (2013 Grover Conference series)","volume":"4","author":"Lewis","year":"2014","journal-title":"Pulm. Circ."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3389\/fmed.2018.00157","article-title":"Using Omics to Understand and Treat Pulmonary Vascular Disease","volume":"5","author":"Hemnes","year":"2018","journal-title":"Front. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e12205","DOI":"10.1002\/pul2.12205","article-title":"Transpulmonary amino acid metabolism in the sugen hypoxia model of pulmonary hypertension","volume":"13","author":"Philip","year":"2023","journal-title":"Pulm. Circ."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Luo, L., Yin, H., and Gou, D. (2023). Gut Microbiota and Metabolome Changes in Three Pulmonary Hypertension Rat Models. Microorganisms, 11.","DOI":"10.3390\/microorganisms11020472"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"640718","DOI":"10.3389\/fimmu.2021.640718","article-title":"Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension","volume":"12","author":"Li","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41598-019-57200-5","article-title":"Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment","volume":"10","author":"Sanders","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"20458940211054325","DOI":"10.1177\/20458940211054325","article-title":"Metabolic endophenotype associated with right ventricular glucose uptake in pulmonary hypertension","volume":"11","author":"Farha","year":"2021","journal-title":"Pulm. Circ."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1900005","DOI":"10.1183\/13993003.00005-2019","article-title":"Still puzzling about a clear definition of pulmonary arterial hypertension in newborns","volume":"53","author":"Calcaterra","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"L870","DOI":"10.1152\/ajplung.00283.2017","article-title":"Umbilical cord blood metabolomics reveal distinct signatures of dyslipidemia prior to bronchopulmonary dysplasia and pulmonary hypertension","volume":"315","author":"Fahrmann","year":"2018","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"L770","DOI":"10.1152\/ajplung.00469.2020","article-title":"Gestational long-term hypoxia induces metabolomic reprogramming and phenotypic transformations in fetal sheep pulmonary arteries","volume":"320","author":"Leslie","year":"2021","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hautbergue, T., Antigny, F., Bo\u00ebt, A., Haddad, F., Masson, B., Lambert, M., Delaporte, A., Menager, J.B., Savale, L., and Pavec, J.L. (2021). Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure. Cells, 10.","DOI":"10.3390\/cells10061559"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sen, P., Shashikadze, B., Flenkenthaler, F., Van de Kamp, E., Tian, S., Meng, C., Gigl, M., Fr\u00f6hlich, T., and Merkus, D. (2023). Proteomics- and Metabolomics-Based Analysis of Metabolic Changes in a Swine Model of Pulmonary Hypertension. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202301.0014.v1"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tremblay-Gravel, M., Fortier, A., Baron, C., David, C., Mehanna, P., Ducharme, A., Hussin, J., Hu, Q., Tardif, J.C., and Des Rosiers, C. (2021). Long-Chain Acylcarnitines and Monounsaturated Fatty Acids Discriminate Heart Failure Patients According to Pulmonary Hypertension Status. Metabolites, 11.","DOI":"10.3390\/metabo11040196"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1086\/690554","article-title":"Plasma acylcarnitines are associated with pulmonary hypertension","volume":"7","author":"Luo","year":"2017","journal-title":"Pulm. Circ."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1186\/1752-1947-4-395","article-title":"Morgagni\u2019s diaphragmatic hernia mimicking a severe congenital heart disease in a newborn: A case report","volume":"4","author":"Bassareo","year":"2010","journal-title":"J. Med. Case Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Romero-Lopez, M.D.M., Oria, M., Watanabe-Chailland, M., Varela, M.F., Romick-Rosendale, L., and Peiro, J.L. (2021). Lung Metabolomics Profiling of Congenital Diaphragmatic Hernia in Fetal Rats. Metabolites, 11.","DOI":"10.3390\/metabo11030177"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/s11306-021-01845-9","article-title":"Identification of novel metabolic signatures potentially involved in the pathogenesis of COPD associated pulmonary hypertension","volume":"17","author":"Choudhury","year":"2021","journal-title":"Metabolomics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"114342","DOI":"10.1016\/j.ab.2021.114342","article-title":"Protection function of 18\u03b2-glycyrrhetinic acid on rats with high-altitude pulmonary hypertension based on 1H NMR metabonomics technology","volume":"631","author":"Yang","year":"2021","journal-title":"Anal. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3302","DOI":"10.1021\/acs.jproteome.0c00219","article-title":"Macitentan Attenuates Chronic Mountain Sickness in Rats by Regulating Arginine and Purine Metabolism","volume":"19","author":"Gao","year":"2020","journal-title":"J. Proteome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13244-019-0695-9","article-title":"Pathophysiology of right ventricular failure in acute pulmonary embolism and chronic thromboembolic pulmonary hypertension: A pictorial essay for the interventional radiologist","volume":"10","author":"Bryce","year":"2019","journal-title":"Insights Imaging"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1021\/pr400872j","article-title":"Metabolomics reveals metabolite changes in acute pulmonary embolism","volume":"13","author":"Bujak","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2045894019890553","DOI":"10.1177\/2045894019890553","article-title":"Plasma metabolomic profile in chronic thromboembolic pulmonary hypertension","volume":"10","author":"Heresi","year":"2020","journal-title":"Pulm. Circ."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107157","DOI":"10.1016\/j.vph.2023.107157","article-title":"Histone deacetylase inhibitors synergize with sildenafil to suppress purine metabolism and proliferation in pulmonary hypertension","volume":"149","author":"Zhang","year":"2023","journal-title":"Vascul. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.prostaglandins.2015.03.005","article-title":"Effects of thyroid hormone status on metabolic pathways of arachidonic acid in mice and humans: A targeted metabolomic approach","volume":"118\u2013119","author":"Yao","year":"2015","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Alamri, A., Burzangi, A.S., Coats, P., and Watson, D.G. (2018). Untargeted Metabolic Profiling Cell-Based Approach of Pulmonary Artery Smooth Muscle Cells in Response to High Glucose and the Effect of the Antioxidant Vitamins D and E. Metabolites, 8.","DOI":"10.3390\/metabo8040087"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1093\/ehjci\/jey175","article-title":"Metabolic pathways associated with right ventricular adaptation to pulmonary hypertension: 3D analysis of cardiac magnetic resonance imaging","volume":"20","author":"Attard","year":"2019","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Peng, J., Lu, C., Hsin, M., Mura, M., Wu, L., Chu, L., Zamel, R., Machuca, T., and Waddell, T. (2014). Metabolomic heterogeneity of pulmonary arterial hypertension. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088727"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, X., Shults, N.V., and Suzuki, Y.J. (2017). Oxidative profiling of the failing right heart in rats with pulmonary hypertension. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176887"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Bujak, R., Mateo, J., Blanco, I., Izquierdo-Garc\u00eda, J.L., Dudzik, D., Markuszewski, M.J., Peinado, V.I., Laclaustra, M., Barber\u00e1, J.A., and Barbas, C. (2016). New Biochemical Insights into the Mechanisms of Pulmonary Arterial Hypertension in Humans. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160505"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Swinarew, A.S., Gabor, J., Kusz, B., Skoczy\u0144ski, S., Raif, P., Skoczylas, I., Jonas, K., Grabka, M., Mizia-Szubryt, M., and Bula, K. (2022). Exhaled Air Metabolome Analysis for Pulmonary Arterial Hypertension Fingerprints Identification-The Preliminary Study. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20010503"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"L723","DOI":"10.1152\/ajplung.00058.2018","article-title":"Mesenchymal stromal cell-derived exosomes improve mitochondrial health in pulmonary arterial hypertension","volume":"316","author":"Hogan","year":"2019","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zhao, Y.D., Chu, L., Lin, K., Granton, E., Yin, L., Peng, J., Hsin, M., Wu, L., Yu, A., and Waddell, T. (2015). A Biochemical Approach to Understand the Pathogenesis of Advanced Pulmonary Arterial Hypertension: Metabolomic Profiles of Arginine, Sphingosine-1-Phosphate, and Heme of Human Lung. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134958"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1161\/CIRCULATIONAHA.116.024602","article-title":"Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension","volume":"135","author":"Rhodes","year":"2017","journal-title":"Circulation"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1136\/thoraxjnl-2018-212144","article-title":"Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension","volume":"74","author":"Harbaum","year":"2019","journal-title":"Thorax"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1038\/s41440-022-00898-0","article-title":"Metabolomics-based mechanism exploration of pulmonary arterial hypertension pathogenesis: Novel lessons from explanted human lungs","volume":"45","author":"Ding","year":"2022","journal-title":"Hypertens. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"201","DOI":"10.4103\/2045-8932.97606","article-title":"Metabolomic analysis of bone morphogenetic protein receptor type 2 mutations in human pulmonary endothelium reveals widespread metabolic reprogramming","volume":"2","author":"Fessel","year":"2012","journal-title":"Pulm. Circ."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Wakasugi, T., Shimizu, I., Yoshida, Y., Hayashi, Y., Ikegami, R., Suda, M., Katsuumi, G., Nakao, M., Hoyano, M., and Kashimura, T. (2019). Role of smooth muscle cell p53 in pulmonary arterial hypertension. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212889"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"110910","DOI":"10.1016\/j.biopha.2020.110910","article-title":"Sera and lungs metabonomics reveals key metabolites of resveratrol protecting against PAH in rats","volume":"133","author":"Sun","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3389\/fcvm.2018.00110","article-title":"Metabolic Reprogramming in the Heart and Lung in a Murine Model of Pulmonary Arterial Hypertension","volume":"5","author":"Arias","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"127205","DOI":"10.1016\/j.micres.2022.127205","article-title":"Microbiome and metabolome dysbiosis of the gut-lung axis in pulmonary hypertension","volume":"265","author":"Chen","year":"2022","journal-title":"Microbiol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1161\/CIRCRESAHA.122.321923","article-title":"Metabolomic Signatures Associated with Pulmonary Arterial Hypertension Outcomes","volume":"132","author":"Pi","year":"2023","journal-title":"Circ. Res."},{"key":"ref_55","first-page":"308","article-title":"Osthole attenuates pulmonary arterial hypertension by the regulation of sphingosine 1-phosphate in rats","volume":"18","author":"Yao","year":"2020","journal-title":"Chin. J. Nat. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"114662","DOI":"10.1016\/j.jpba.2022.114662","article-title":"Integrated metabolomics and mechanism to reveal the protective effect of kaempferol on pulmonary arterial hypertension","volume":"212","author":"Yi","year":"2022","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.jacbts.2021.09.004","article-title":"With No Lysine Kinase 1 Promotes Metabolic Derangements and RV Dysfunction in Pulmonary Arterial Hypertension","volume":"6","author":"Prisco","year":"2021","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"10695","DOI":"10.1039\/D2FO01424F","article-title":"Targeted metabolomics combined with network pharmacology to reveal the protective role of luteolin in pulmonary arterial hypertension","volume":"13","author":"Song","year":"2022","journal-title":"Food Funct."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2003201","DOI":"10.1183\/13993003.03201-2020","article-title":"Plasma metabolomics exhibit response to therapy in chronic thromboembolic pulmonary hypertension","volume":"57","author":"Swietlik","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1086\/683810","article-title":"Profiling the role of mammalian target of rapamycin in the vascular smooth muscle metabolome in pulmonary arterial hypertension","volume":"5","author":"Kudryashova","year":"2015","journal-title":"Pulm. Circ."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Bassareo, P.P., Argiento, P., McMahon, C.J., Dunne, E., Walsh, K.P., Russo, M.G., and D\u2019Alto, M. (2023). Idiopathic Pulmonary Arterial Hypertension in Paediatrics Represents Still a Serious Challenge: A Case Series Study. Child, 10.","DOI":"10.3390\/children10030518"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2000522","DOI":"10.1183\/13993003.00522-2020","article-title":"Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension","volume":"56","author":"He","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kurdyukov, S., Eccles, C.A., Desai, A.A., Gonzalez-Garay, M., Yuan, J.X., Garcia, J.G.N., Rafikova, O., and Rafikov, R. (2018). New cases of Glucose-6-Phosphate Dehydrogenase deficiency in Pulmonary Arterial Hypertension. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203493"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"L508","DOI":"10.1152\/ajplung.00165.2020","article-title":"Glucose-6-phosphate dehydrogenase deficiency contributes to metabolic abnormality and pulmonary hypertension","volume":"320","author":"Varghese","year":"2021","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1111\/jcmm.14937","article-title":"Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China","volume":"24","author":"Chen","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"L810","DOI":"10.1152\/ajplung.00167.2020","article-title":"Protein biomarkers and risk scores in pulmonary arterial hypertension associated with ventricular septal defect: Integration of multi-omics and validation","volume":"319","author":"Yuan","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"940784","DOI":"10.3389\/fmed.2022.940784","article-title":"Altered Lung Microbiome and Metabolome Profile in Children with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease","volume":"9","author":"Ma","year":"2022","journal-title":"Front. Med."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Xu, B., Huang, C., Zhang, C., Lin, D., and Wu, W. (2022). NMR-Based Metabolomic Analysis of Plasma in Patients with Adult Congenital Heart Disease and Associated Pulmonary Arterial Hypertension: A Pilot Study. Metabolites, 12.","DOI":"10.3390\/metabo12090845"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Jin, N., Yu, M., Du, X., Wu, Z., Zhai, C., Pan, H., Gu, J., and Xie, B. (2023). Identification of potential serum biomarkers for congenital heart disease children with pulmonary arterial hypertension by metabonomics. BMC Cardiovasc. Disord., 23.","DOI":"10.1186\/s12872-023-03171-5"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1038\/s41401-021-00804-3","article-title":"Plasma metabolomics in the perioperative period of defect repair in patients with pulmonary arterial hypertension associated with congenital heart disease","volume":"43","author":"He","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.chest.2022.08.2230","article-title":"Metabolomic Profiles Differentiate Scleroderma-PAH From Idiopathic PAH and Correspond with Worsened Functional Capacity","volume":"163","author":"Alotaibi","year":"2023","journal-title":"Chest"},{"key":"ref_72","first-page":"204","article-title":"Metabolomic differences in connective tissue disease-associated versus idiopathic pulmonary arterial hypertension in the PVDOMICS cohort","volume":"163","author":"Simpson","year":"2023","journal-title":"Arthritis Rheumatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"L363","DOI":"10.1152\/ajplung.00212.2011","article-title":"The monocrotaline model of pulmonary hypertension in perspective","volume":"302","author":"Farkas","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5803031","DOI":"10.1155\/2016\/5803031","article-title":"(1)H NMR-Based Analysis of Serum Metabolites in Monocrotaline-Induced Pulmonary Arterial Hypertensive Rats","volume":"2016","author":"Lin","year":"2016","journal-title":"Dis. Markers"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"834179","DOI":"10.3389\/fmolb.2022.834179","article-title":"Proteomic and Metabolomic Analyses of Right Ventricular Failure due to Pulmonary Arterial Hypertension","volume":"9","author":"Qin","year":"2022","journal-title":"Front. Mol. Biosci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Rafikova, O., Meadows, M.L., Kinchen, J.M., Mohney, R.P., Maltepe, E., Desai, A.A., Yuan, J.X., Garcia, J.G., Fineman, J.R., and Rafikov, R. (2016). Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150480"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s12931-018-0800-5","article-title":"Metabolic reprogramming of the urea cycle pathway in experimental pulmonary arterial hypertension rats induced by monocrotaline","volume":"19","author":"Zheng","year":"2018","journal-title":"Respir. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1093\/ajh\/hpz121","article-title":"Circulating Plasma Metabolomic Profiles Differentiate Rodent Models of Pulmonary Hypertension and Idiopathic Pulmonary Arterial Hypertension Patients","volume":"32","author":"Zhao","year":"2019","journal-title":"Am. J. Hypertens."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1042\/CS20190142","article-title":"NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy","volume":"133","author":"Zhou","year":"2019","journal-title":"Clin. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e008574","DOI":"10.1161\/CIRCHEARTFAILURE.121.008574","article-title":"Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility","volume":"15","author":"Prisco","year":"2022","journal-title":"Circ. Heart Fail."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"935423","DOI":"10.3389\/fcvm.2022.935423","article-title":"Comparative analysis of right ventricular metabolic reprogramming in pre-clinical rat models of severe pulmonary hypertension-induced right ventricular failure","volume":"9","author":"Banerjee","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"11954","DOI":"10.18632\/aging.202898","article-title":"Influence of atorvastatin on metabolic pattern of rats with pulmonary hypertension","volume":"13","author":"Luo","year":"2021","journal-title":"Aging"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5173","DOI":"10.1080\/21655979.2021.1952365","article-title":"Changes in the gut microbiome and metabolome in a rat model of pulmonary arterial hypertension","volume":"12","author":"Hong","year":"2021","journal-title":"Bioengineered"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.ijcard.2017.04.024","article-title":"Distinctive metabolomic fingerprint in scleroderma patients with pulmonary arterial hypertension","volume":"241","author":"Deidda","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1021535","DOI":"10.3389\/fphar.2023.1021535","article-title":"Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416\/hypoxia rat model","volume":"14","author":"Barreira","year":"2023","journal-title":"Front. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"13284","DOI":"10.1038\/s41598-022-17374-x","article-title":"An explorative metabolomic analysis of the endothelium in pulmonary hypertension","volume":"12","author":"Carlsen","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s11306-014-0653-y","article-title":"De novo synthesize of bile acids in pulmonary arterial hypertension lung","volume":"10","author":"Zhao","year":"2014","journal-title":"Metabolomics"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1901700","DOI":"10.1183\/13993003.01700-2019","article-title":"Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: A hyperglycaemic clamp and metabolomics study","volume":"55","author":"Mey","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e018349","DOI":"10.1161\/JAHA.120.018349","article-title":"Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension","volume":"9","author":"Brittain","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"L836","DOI":"10.1152\/ajplung.00003.2023","article-title":"Metabolic profiling of in vivo right ventricular function and exercise performance in pulmonary arterial hypertension","volume":"324","author":"Simpson","year":"2023","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/978-3-319-63245-2_19","article-title":"Redox Signaling in the Right Ventricle","volume":"967","author":"Suzuki","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1164\/rccm.201507-1444OC","article-title":"Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle","volume":"194","author":"Talati","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3892\/ijmm.2022.5124","article-title":"Multi-omics analysis of right ventricles in rat models of pulmonary arterial hypertension: Consideration of mitochondrial biogenesis by chrysin","volume":"49","author":"Kobayashi","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1021\/acsomega.1c05895","article-title":"Metabolic Reprogramming of the Right Ventricle and Pulmonary Arteries in a Flow-Associated Pulmonary Arterial Hypertension Rat Model","volume":"7","author":"Liu","year":"2021","journal-title":"ACS Omega"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"227","DOI":"10.3892\/mmr.2021.11866","article-title":"Metabolic remodeling in the right ventricle of rats with severe pulmonary arterial hypertension","volume":"23","author":"Sakao","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1136\/heartjnl-2019-315900","article-title":"Trans-right ventricle and transpulmonary metabolite gradients in human pulmonary arterial hypertension","volume":"106","author":"Chouvarine","year":"2020","journal-title":"Heart"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2045894019882623","DOI":"10.1177\/2045894019882623","article-title":"Metabolomics of exercise pulmonary hypertension are intermediate between controls and patients with pulmonary arterial hypertension","volume":"9","author":"Sanders","year":"2019","journal-title":"Pulm. Circ."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1165\/rcmb.2018-0095OC","article-title":"Vascular Adaptation of the Right Ventricle in Experimental Pulmonary Hypertension","volume":"59","author":"Graham","year":"2018","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e022722","DOI":"10.1161\/JAHA.121.022722","article-title":"Intermittent Fasting Enhances Right Ventricular Function in Preclinical Pulmonary Arterial Hypertension","volume":"10","author":"Prisco","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_100","unstructured":"Chaudhry, R., and Varacallo, M. (2023, June 25). Biochemistry, Glycolysis, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK482303\/."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"838657","DOI":"10.3389\/fcvm.2022.838657","article-title":"The Role of Glutamine and Glutaminase in Pulmonary Hypertension","volume":"9","author":"Wang","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1086\/679720","article-title":"Arginine metabolic endotypes in pulmonary arterial hypertension","volume":"5","author":"Kao","year":"2015","journal-title":"Pulm. Circ."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2045894018759125","DOI":"10.1177\/2045894018759125","article-title":"The serotonin hypothesis in pulmonary hypertension revisited: Targets for novel therapies (2017 Grover Conference Series)","volume":"8","author":"MacLean","year":"2018","journal-title":"Pulm. Circ."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.pupt.2005.07.001","article-title":"Prodrug of proline analogue reduces hypoxic pulmonary hypertension in rats","volume":"19","author":"Simon","year":"2006","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Poyatos, P., Gratac\u00f3s, M., Samuel, K., Orriols, R., and Tura-Ceide, O. (2023). Oxidative Stress and Antioxidant Therapy in Pulmonary Hypertension. Antioxidants, 12.","DOI":"10.3390\/antiox12051006"},{"key":"ref_106","unstructured":"Edwards, M., and Mohiuddin, S.S. (2023, June 25). Biochemistry, Lipolysis, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK560564\/."},{"key":"ref_107","unstructured":"Dhillon, K.K., and Gupta, S. (2023, June 25). Biochemistry, Ketogenesis, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK493179\/."},{"key":"ref_108","unstructured":"Aziz, N., and Jamil, R.T. (2023, June 25). Biochemistry, Xanthine Oxidase, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK545245\/."},{"key":"ref_109","first-page":"168","article-title":"Precision medicine: The future of diagnostic approach to pulmonary hypertension?","volume":"22","author":"Kedzierski","year":"2019","journal-title":"Anatol. J. Cardiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/bph.15056","article-title":"The application of \u2018omics\u2019 to pulmonary arterial hypertension","volume":"178","author":"Harbaum","year":"2021","journal-title":"Br. J. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13227\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:39:22Z","timestamp":1760128762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,25]]},"references-count":110,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713227"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713227","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,25]]}}}