{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T12:16:28Z","timestamp":1781784988183,"version":"3.54.5"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Defects in fatty acid (FA) utilization have been well described in group 1 pulmonary hypertension (PH) and in heart failure (HF), yet poorly studied in group 2 PH. This study was to assess whether the metabolomic profile of patients with pulmonary hypertension (PH) due HF, classified as group 2 PH, differs from those without PH. We conducted a proof-of-principle cross-sectional analysis of 60 patients with chronic HF with reduced ejection fraction and 72 healthy controls in which the circulating level of 71 energy-related metabolites was measured using various methods. Echocardiography was used to classify HF patients as noPH-HF (n = 27; mean pulmonary artery pressure [mPAP] 21 mmHg) and PH-HF (n = 33; mPAP 35 mmHg). The profile of circulating metabolites among groups was compared using principal component analysis (PCA), analysis of covariance (ANCOVA), and Pearson\u2019s correlation tests. Patients with noPH-HF and PH-HF were aged 64 \u00b1 11 and 68 \u00b1 10 years, respectively, with baseline left ventricular ejection fractions of 27 \u00b1 7% and 26 \u00b1 7%. Principal component analysis segregated groups, more markedly for PH-HF, with long-chain acylcarnitines, acetylcarnitine, and monounsaturated FA carrying the highest loading scores. After adjustment for age, sex, kidney function, insulin resistance, and N-terminal pro-brain natriuretic peptide (NT-proBNP), 5\/15 and 8\/15 lipid-related metabolite levels were significantly different from controls in noPH-HF and PH-HF subjects, respectively. All metabolites for which circulating levels interacted between group and NT-proBNP significantly correlated with NT-proBNP in HF-PH, but none with HF-noPH. FA-related metabolites were differently affected in HF with or without PH, and may convey adverse outcomes given their distinct correlation with NT-proBNP in the setting of PH.<\/jats:p>","DOI":"10.3390\/metabo11040196","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T13:17:53Z","timestamp":1616764673000},"page":"196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Long-Chain Acylcarnitines and Monounsaturated Fatty Acids Discriminate Heart Failure Patients According to Pulmonary Hypertension Status"],"prefix":"10.3390","volume":"11","author":[{"given":"Maxime","family":"Tremblay-Gravel","sequence":"first","affiliation":[{"name":"Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H1T1C8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annik","family":"Fortier","sequence":"additional","affiliation":[{"name":"Montreal Health Innovations Coordinating Center Institute, Montr\u00e9al, QC H1T1C8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cantin","family":"Baron","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00e9","family":"David","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Mehanna","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anique","family":"Ducharme","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3T1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Hussin","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3T1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Claude","family":"Tardif","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3T1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Des Rosiers","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"},{"name":"Department of Nutrition, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3T1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"Dupuis","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3T1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute, Montr\u00e9al, QC H1T1C8, Canada"},{"name":"Department of Nutrition, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3T1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.15420\/cfr.2016:25:2","article-title":"Global Public Health Burden of Heart Failure","volume":"3","author":"Savarese","year":"2017","journal-title":"Card. Fail. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.hfc.2018.02.006","article-title":"Pulmonary Hypertension and Heart Failure: A Dangerous Liaison","volume":"14","author":"Guazzi","year":"2018","journal-title":"Heart Fail. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1056\/NEJMra063052","article-title":"The failing heart\u2014An engine out of fuel","volume":"356","author":"Neubauer","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1161\/CIRCHEARTFAILURE.113.000521","article-title":"Plasma free fatty acids and risk of heart failure: The Cardiovascular Health Study","volume":"6","author":"Djousse","year":"2013","journal-title":"Circ. Heart Fail."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/j.1365-2796.2011.02384.x","article-title":"Fatty acid composition in chronic heart failure: Low circulating levels of eicosatetraenoic acid and high levels of vaccenic acid are associated with disease severity and mortality","volume":"270","author":"Oie","year":"2011","journal-title":"J. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jacc.2015.10.079","article-title":"Prognostic Implications of Long-Chain Acylcarnitines in Heart Failure and Reversibility with Mechanical Circulatory Support","volume":"67","author":"Ahmad","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e000542","DOI":"10.1161\/JAHA.113.000542","article-title":"A plasma long-chain acylcarnitine predicts cardiovascular mortality in incident dialysis patients","volume":"2","author":"Kalim","year":"2013","journal-title":"J. Am. Heart Assoc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"H768","DOI":"10.1152\/ajpheart.00820.2016","article-title":"Circulating acylcarnitine profile in human heart failure: A surrogate of fatty acid metabolic dysregulation in mitochondria and beyond","volume":"313","author":"Ruiz","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1161\/CIRCULATIONAHA.114.006979","article-title":"Emerging concepts in the molecular basis of pulmonary arterial hypertension: Part I: Metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension","volume":"131","author":"Ryan","year":"2015","journal-title":"Circulation"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hemnes, A.R., Luther, J.M., Rhodes, C.J., Burgess, J.P., Carlson, J., Fan, R., Fessel, J.P., Fortune, N., Gerszten, R.E., and Halliday, S.J. (2019). Human PAH is characterized by a pattern of lipid-related insulin resistance. JCI Insight, 4.","DOI":"10.1172\/jci.insight.123611"},{"key":"ref_11","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_12","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_13","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.redox.2013.12.009","article-title":"Circulating levels of linoleic acid and HDL-cholesterol are major determinants of 4-hydroxynonenal protein adducts in patients with heart failure","volume":"2","author":"Asselin","year":"2014","journal-title":"Redox Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hunter, W.G., Kelly, J.P., McGarrah, R.W., Khouri, M.G., Craig, D., Haynes, C., Ilkayeva, O., Stevens, R.D., Bain, J.R., and Muehlbauer, M.J. (2016). Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure. J. Am. Heart Assoc., 5.","DOI":"10.1161\/JAHA.115.003190"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1161\/CIRCULATIONAHA.115.019351","article-title":"Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension","volume":"133","author":"Brittain","year":"2016","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1161\/CIRCHEARTFAILURE.111.966127","article-title":"Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension","volume":"6","author":"Mizuno","year":"2013","journal-title":"Circ. Heart Fail."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1097\/TP.0b013e3181e49b83","article-title":"Analysis of the lung allocation score estimation of risk of death in patients with pulmonary arterial hypertension using data from the REVEAL Registry","volume":"90","author":"Benza","year":"2010","journal-title":"Transplantation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/BF03261931","article-title":"Carnitine and acylcarnitines: Pharmacokinetic, pharmacological and clinical aspects","volume":"51","author":"Reuter","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1097\/00005344-200007000-00002","article-title":"Long-chain acylcarnitine induces Ca2+ efflux from the sarcoplasmic reticulum","volume":"36","author":"Yamada","year":"2000","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1161\/01.CIR.100.22.2248","article-title":"Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children","volume":"100","author":"Bonnet","year":"1999","journal-title":"Circulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1111\/j.2042-7158.1991.tb03553.x","article-title":"The synthesis, and structure-activity relationships of some long chain acyl carnitine esters on the coronary circulation of the rat isolated heart","volume":"43","author":"Criddle","year":"1991","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/j.1476-5381.1990.tb12953.x","article-title":"The effects of novel vasodilator long chain acyl carnitine esters in the isolated perfused heart of the rat","volume":"99","author":"Criddle","year":"1990","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1002\/acr.24013","article-title":"Associations of Amino Acid and Acylcarnitine Profiles With Incident Hyperuricemia in Middle-Aged and Older Chinese Individuals","volume":"72","author":"Wang","year":"2020","journal-title":"Arthritis Care Res. (Hoboken)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1161\/CIRCULATIONAHA.106.645184","article-title":"Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure","volume":"114","author":"Tuunanen","year":"2006","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S0008-6363(01)00406-0","article-title":"Longchain n-3 polyunsaturated fatty acids and blood vessel function","volume":"52","author":"Abeywardena","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.plefa.2010.02.020","article-title":"N-3 vs. saturated fatty acids: Effects on the arterial wall","volume":"82","author":"Sudheendran","year":"2010","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"403","DOI":"10.4196\/kjpp.2019.23.5.403","article-title":"Differential effects of saturated and unsaturated fatty acids on vascular reactivity in isolated mesenteric and femoral arteries of rats","volume":"23","author":"Vorn","year":"2019","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.echo.2010.05.010","article-title":"Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography","volume":"23","author":"Rudski","year":"2010","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Simonneau, G., Montani, D., Celermajer, D.S., Denton, C.P., Gatzoulis, M.A., Krowka, M., Williams, P.G., and Souza, R. (2019). Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur. Respir. J., 53.","DOI":"10.1183\/13993003.01913-2018"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.echo.2015.11.001","article-title":"Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography","volume":"29","author":"Amsallem","year":"2016","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.echo.2013.01.006","article-title":"Derivation of mean pulmonary artery pressure from noninvasive parameters","volume":"26","author":"Steckelberg","year":"2013","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4058","DOI":"10.1016\/j.ijcard.2013.07.005","article-title":"Accuracy and precision of echocardiography versus right heart catheterization for the assessment of pulmonary hypertension","volume":"168","author":"Romeo","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pang, Z., Chong, J., Li, S., and Xia, J. (2020). MetaboAnalystR 3.0: Toward an Optimized Workflow for Global Metabolomics. Metabolites, 10.","DOI":"10.3390\/metabo10050186"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1053\/j.ajkd.2012.01.014","article-title":"Serum metabolite concentrations and decreased GFR in the general population","volume":"60","author":"Goek","year":"2012","journal-title":"Am. J. Kidney Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2337\/db12-0466","article-title":"Acylcarnitines: Reflecting or inflicting insulin resistance?","volume":"62","author":"Schooneman","year":"2013","journal-title":"Diabetes"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/4\/196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:41:29Z","timestamp":1760161289000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/4\/196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,26]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["metabo11040196"],"URL":"https:\/\/doi.org\/10.3390\/metabo11040196","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,26]]}}}