{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T09:08:47Z","timestamp":1781428127777,"version":"3.54.1"},"reference-count":83,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000308","name":"British Council","doi-asserted-by":"publisher","award":["172715657"],"award-info":[{"award-number":["172715657"]}],"id":[{"id":"10.13039\/501100000308","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000308","name":"British Council","doi-asserted-by":"publisher","award":["110256934230"],"award-info":[{"award-number":["110256934230"]}],"id":[{"id":"10.13039\/501100000308","id-type":"DOI","asserted-by":"publisher"}]},{"name":"COLCIENCIAS","award":["172715657"],"award-info":[{"award-number":["172715657"]}]},{"name":"COLCIENCIAS","award":["110256934230"],"award-info":[{"award-number":["110256934230"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe clinical form of chronic Chagas disease, representing one of the leading causes of morbidity and mortality in Latin America, and a growing global public health problem. There is currently no approved treatment for CCC; however, omics technologies have enabled significant progress to be made in the search for new therapeutic targets. The metabolic alterations associated with pathogenic mechanisms of CCC and their relationship to cellular and immunopathogenic processes in cardiac tissue remain largely unknown. This exploratory study aimed to evaluate the potential underlying pathogenic mechanisms in the failing myocardium of patients with end-stage heart failure (ESHF) secondary to CCC by applying an untargeted metabolomic profiling approach. Cardiac tissue samples from the left ventricle of patients with ESHF of CCC etiology (n = 7) and healthy donors (n = 7) were analyzed using liquid chromatography-mass spectrometry. Metabolite profiles showed altered branched-chain amino acid and acylcarnitine levels, decreased fatty acid uptake and oxidation, increased activity of the pentose phosphate pathway, dysregulation of the TCA cycle, and alterations in critical cellular antioxidant systems. These findings suggest processes of energy deficit, alterations in substrate availability, and enhanced production of reactive oxygen species in the affected myocardium. This profile potentially contributes to the development and maintenance of a chronic inflammatory state that leads to progression and severity of CCC. Further studies involving larger sample sizes and comparisons with heart failure patients without CCC are needed to validate these results, opening an avenue to investigate new therapeutic approaches for the treatment and prevention of progression of this unique and severe cardiomyopathy.<\/jats:p>","DOI":"10.3390\/ijms231810456","type":"journal-article","created":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T22:53:46Z","timestamp":1663023226000},"page":"10456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Metabolomic Profiling of End-Stage Heart Failure Secondary to Chronic Chagas Cardiomyopathy"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9448-8374","authenticated-orcid":false,"given":"Martha Luc\u00eda","family":"D\u00edaz","sequence":"first","affiliation":[{"name":"Grupo de Inmunolog\u00eda y Epidemiolog\u00eda Molecular, GIEM, Escuela de Microbiolog\u00eda, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga 680002, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Burgess","sequence":"additional","affiliation":[{"name":"Glasgow Polyomics, University of Glasgow, Glasgow G12 8QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1663-9004","authenticated-orcid":false,"given":"Richard","family":"Burchmore","sequence":"additional","affiliation":[{"name":"Glasgow Polyomics, University of Glasgow, Glasgow G12 8QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8792-1563","authenticated-orcid":false,"given":"Mar\u00eda Adelaida","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas-CIDEIM, Cali 760031, Colombia"},{"name":"Universidad Icesi, Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio Alejandro","family":"G\u00f3mez-Ochoa","sequence":"additional","affiliation":[{"name":"Cl\u00ednica de Falla Card\u00edaca, Fundaci\u00f3n Cardiovascular de Colombia, Floridablanca 681004, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Eduardo","family":"Echeverr\u00eda","sequence":"additional","affiliation":[{"name":"Cl\u00ednica de Falla Card\u00edaca, Fundaci\u00f3n Cardiovascular de Colombia, Floridablanca 681004, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Morillo","sequence":"additional","affiliation":[{"name":"Department of Cardiac Sciences, Cumming School of Medicine, Libin Cardiovascular Institute, University of Calgary, Calgary, AB T2N 1N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara Isabel","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Grupo de Inmunolog\u00eda y Epidemiolog\u00eda Molecular, GIEM, Escuela de Microbiolog\u00eda, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga 680002, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022, March 28). Chagas disease in Latin America: An epidemiological update based on 2010 estimates, Weekly Epidemiological Record, Available online: https:\/\/www.who.int\/wer\/2015\/wer9006.pdf?ua=1."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3389\/fpubh.2019.00166","article-title":"Chagas Disease: From Discovery to a Worldwide Health Problem","volume":"7","author":"Lidani","year":"2019","journal-title":"Front. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e004361","DOI":"10.1161\/CIRCHEARTFAILURE.117.004361","article-title":"Contemporary Characteristics and Outcomes in Chagasic Heart Failure Compared with Other Nonischemic and Ischemic Cardiomyopathy","volume":"10","author":"Shen","year":"2017","journal-title":"Circ. Heart Fail."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1146\/annurev-pathol-020117-043711","article-title":"Pathology and Pathogenesis of Chagas Heart Disease","volume":"14","author":"Bonney","year":"2019","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.idc.2018.10.015","article-title":"American Trypanosomiasis (Chagas Disease)","volume":"33","author":"Echeverria","year":"2019","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1056\/NEJMoa1507574","article-title":"Randomized Trial of Benznidazole for Chronic Chagas\u2019 Cardiomyopathy","volume":"373","author":"Morillo","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1586\/erc.12.115","article-title":"Device therapy in Chagas disease heart failure","volume":"10","author":"Bestetti","year":"2012","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_8","first-page":"112","article-title":"Left Ventricular Assist Device as a Bridge to Candidacy in End-stage Chagas Cardiomyopathy","volume":"111","author":"Atik","year":"2018","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/j.1525-1594.2007.00372.x","article-title":"Left Ventricular Circulatory Support as Bridge to Heart Transplantation in Chagas\u2019 Disease Cardiomyopathy","volume":"31","author":"Moreira","year":"2007","journal-title":"Artif. Organs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1111\/tmi.13487","article-title":"Circulating Trypanosoma cruzi load and major cardiovascular outcomes in patients with chronic Chagas cardiomyopathy: A prospective cohort study","volume":"25","author":"Rojas","year":"2020","journal-title":"Trop. Med. Int. Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.thromres.2021.02.025","article-title":"Coagulation disorders in Chagas disease: A pathophysiological systematic review and meta-analysis","volume":"201","author":"Rojas","year":"2021","journal-title":"Thromb. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e169","DOI":"10.1161\/CIR.0000000000000599","article-title":"Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement from the American Heart Association","volume":"138","author":"Nunes","year":"2018","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1080\/00034983.2000.11813580","article-title":"Systematic mapping of hearts from chronic chagasic patients: The association between the occurrence of histopathological lesions and Trypanosoma cruzi antigens","volume":"94","author":"Palomino","year":"2000","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S0002-9440(10)61741-5","article-title":"Modulation of Chagasic Cardiomyopathy by Interleukin-4: Dissociation between Inflammation and Tissue Parasitism","volume":"159","author":"Soares","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1086\/314889","article-title":"Parasite Persistence Correlates with Disease Severity and Localization in Chronic Chagas\u2019 Disease","volume":"180","author":"Zhang","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Giron\u00e8s, N., Carbajosa, S., Guerrero, N.A., Poveda, C., Chill\u00f3n-Marinas, C., and Fresno, M. (2014). Global Metabolomic Profiling of Acute Myocarditis Caused by Trypanosoma cruzi Infection. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0003337"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1161\/CIRCRESAHA.113.300376","article-title":"Cardiac Metabolism in Heart Failure: Implications Beyond ATP Production","volume":"113","author":"Doenst","year":"2013","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.21037\/jtd-21-22","article-title":"Narrative review of metabolomics in cardiovascular disease","volume":"13","author":"Bertsch","year":"2021","journal-title":"J. Thorac. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s11306-007-0082-2","article-title":"Proposed minimum reporting standards for chemical analysis. Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI)","volume":"3","author":"Sumner","year":"2007","journal-title":"Metabolomics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.ijcard.2007.07.151","article-title":"Cardiac remodeling and predictors for cardiac death in long-term follow-up of subjects with chronic Chagas\u2019 heart disease: A mathematical model for progression of myocardial damage","volume":"131","year":"2009","journal-title":"Int. J. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.3389\/fimmu.2018.01842","article-title":"Autoimmunity in Chronic Chagas Disease: A Road of Multiple Pathways to Cardiomyopathy?","volume":"9","author":"Lidani","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1586\/14779072.2015.1103648","article-title":"Developments in the management of Chagas cardiomyopathy","volume":"13","author":"Tanowitz","year":"2015","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4956016","DOI":"10.1155\/2019\/4956016","article-title":"Diet Alters Serum Metabolomic Profiling in the Mouse Model of Chronic Chagas Cardiomyopathy","volume":"2019","author":"Lizardo","year":"2019","journal-title":"Dis. Markers"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Dean, D.A., Gautham, G., Siqueira-Neto, J.L., McKerrow, J.H., Dorrestein, P.C., and McCall, L.-I. (2021). Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas Disease. PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009819"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/cbf.3173","article-title":"Large animal models of cardiovascular disease","volume":"34","author":"Tsang","year":"2016","journal-title":"Cell Biochem. Funct."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.jacbts.2016.11.009","article-title":"Metabolic Origins of Heart Failure","volume":"2","author":"Wende","year":"2017","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1258\/ebm.2012.012025","article-title":"Amino acids as metabolic substrates during cardiac ischemia","volume":"237","author":"Drake","year":"2012","journal-title":"Exp. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hakuno, D., Hamba, Y., Toya, T., and Adachi, T. (2015). Plasma Amino Acid Profiling Identifies Specific Amino Acid Associations with Cardiovascular Function in Patients with Systolic Heart Failure. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117325"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.1016\/j.amjcard.2008.02.074","article-title":"Hypercatabolic Syndrome: Molecular Basis and Effects of Nutritional Supplements with Amino Acids","volume":"101","author":"Pasini","year":"2008","journal-title":"Am. J. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1161\/CIRCHEARTFAILURE.114.001469","article-title":"Energy Metabolic Reprogramming in the Hypertrophied and Early Stage Failing Heart: A multisystems approach","volume":"7","author":"Lai","year":"2014","journal-title":"Circ. Heart Fail."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Aquilani, R., La Rovere, M.T., Corbellini, D., Pasini, E., Verri, M., Barbieri, A., Condino, A.M., and Boschi, F. (2017). Plasma Amino Acid Abnormalities in Chronic Heart Failure. Mechanisms, Potential Risks and Targets in Human Myocardium Metabolism. Nutrients, 9.","DOI":"10.3390\/nu9111251"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev.physiol.65.092101.142243","article-title":"Cardiac Hypertrophy: The Good, the Bad, and the Ugly","volume":"65","author":"Frey","year":"2003","journal-title":"Annu. Rev. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1093\/cvr\/cvr070","article-title":"Branched-chain amino acid metabolism in heart disease: An epiphenomenon or a real culprit?","volume":"90","author":"Huang","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5045","DOI":"10.1002\/ehf2.13572","article-title":"Plasma amino acid profiling improves predictive accuracy of adverse events in patients with heart failure","volume":"8","author":"Kouzu","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1007\/s00394-019-02108-z","article-title":"The effect of protein and essential amino acid supplementation on muscle strength and performance in patients with chronic heart failure: A systematic review","volume":"59","author":"Nichols","year":"2020","journal-title":"Eur. J. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17528","DOI":"10.1038\/s41598-017-17797-x","article-title":"Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues","volume":"7","author":"Sevostjanovs","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/j.1365-2125.2007.02926.x","article-title":"A pharmacokinetic model for L-carnitine in patients receiving haemodialysis","volume":"64","author":"Fornasini","year":"2007","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_38","first-page":"E1378","article-title":"Acylcarnitines activate proinflammatory signaling pathways","volume":"306","author":"Rutkowsky","year":"2014","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cmet.2009.02.002","article-title":"A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance","volume":"9","author":"Newgard","year":"2009","journal-title":"Cell Metab."},{"key":"ref_40","first-page":"E990","article-title":"Long-chain acylcarnitines activate cell stress and myokine release in C2C12myotubes: Calcium-dependent and -independent effects","volume":"308","author":"McCoin","year":"2015","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25133","DOI":"10.1074\/jbc.M116.754978","article-title":"Novel Molecular Interactions of Acylcarnitines and Fatty Acids with Myoglobin","volume":"291","author":"Chintapalli","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1161\/CIRCULATIONAHA.115.017545","article-title":"Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure","volume":"133","author":"Bedi","year":"2016","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.cardfail.2006.06.005","article-title":"Decreased Myocardial Free Fatty Acid Uptake in Patients with Idiopathic Dilated Cardiomyopathy: Evidence of Relationship with Insulin Resistance and Left Ventricular Dysfunction","volume":"12","author":"Tuunanen","year":"2006","journal-title":"J. Card. Fail."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s12265-010-9223-5","article-title":"Assessment of Metabolic Phenotypes in Patients with Non-ischemic Dilated Cardiomyopathy Undergoing Cardiac Resynchronization Therapy","volume":"3","author":"Obrzut","year":"2010","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1073\/pnas.96.5.2356","article-title":"Mutations in the organic cation\/carnitine transporter OCTN2 in primary carnitine deficiency","volume":"96","author":"Wang","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"eaaz2015","DOI":"10.1126\/sciadv.aaz2015","article-title":"Mapping of host-parasite-microbiome interactions reveals metabolic determinants of tropism and tolerance in Chagas disease","volume":"6","author":"Hossain","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10414","DOI":"10.1021\/acs.analchem.7b02423","article-title":"Mass Spectrometry-Based Chemical Cartography of a Cardiac Parasitic Infection","volume":"89","author":"McCall","year":"2017","journal-title":"Anal. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jacc.2015.10.079","article-title":"Long-Chain Acylcarnitine Metabolites are Associated with Adverse Outcomes and Reversible with Mechanical Circulatory Support in Systolic Heart Failure","volume":"67","author":"Ahmad","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s12933-021-01353-z","article-title":"Circulating long chain acylcarnitines and outcomes in diabetic heart failure: An HF-ACTION clinical trial substudy","volume":"20","author":"Truby","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_50","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_51","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1161\/01.CIR.94.11.2837","article-title":"Fatty Acid Oxidation Enzyme Gene Expression Is Downregulated in the Failing Heart","volume":"94","author":"Sack","year":"1996","journal-title":"Circulation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1161\/CIRCULATIONAHA.119.044452","article-title":"The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure","volume":"142","author":"Badolia","year":"2020","journal-title":"Circulation"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/BF00240038","article-title":"Regulation of and intervention into the oxidative pentose phosphate pathway and adenine nucleotide metabolism in the heart","volume":"160\u2013161","author":"Zimmer","year":"1996","journal-title":"Mol. Cell. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1007\/BF02137950","article-title":"The role of the pentose-phosphate pathway in adjustment of the heart to a high load and the development of myocardial hypertrophy","volume":"23","author":"Meerson","year":"1967","journal-title":"Experientia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"H709","DOI":"10.1152\/ajpheart.00783.2013","article-title":"Beneficial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart","volume":"306","author":"Vimercati","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"11534","DOI":"10.1038\/ncomms11534","article-title":"ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto \u03b1-dystroglycan","volume":"7","author":"Gerin","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3448","DOI":"10.1038\/s41467-018-05990-z","article-title":"Ribitol restores functionally glycosylated \u03b1-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice","volume":"9","author":"Cataldi","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1161\/CIRCRESAHA.109.199489","article-title":"Dystroglycan Matrix Receptor Function in Cardiac Myocytes Is Important for Limiting Activity-Induced Myocardial Damage","volume":"105","author":"Michele","year":"2009","journal-title":"Circ. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.nmd.2013.06.371","article-title":"Increased levels of expression of dystroglycan may protect the heart","volume":"23","author":"Brancaccio","year":"2013","journal-title":"Neuromuscul. Disord."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11306-016-0956-2","article-title":"A targeted metabolomics assay for cardiac metabolism and demonstration using a mouse model of dilated cardiomyopathy","volume":"12","author":"West","year":"2016","journal-title":"Metabolomics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0261-5614(98)80308-7","article-title":"Glutamate metabolism of the heart during coronary artery bypass grafting","volume":"17","author":"Pietersen","year":"1998","journal-title":"Clin. Nutr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1172\/JCI116657","article-title":"Effects of amino acids on substrate selection, anaplerosis, and left ventricular function in the ischemic reperfused rat heart","volume":"92","author":"Jessen","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1042\/cs1010573","article-title":"The effect of glutamate infusion on cardiac performance is independent of changes in metabolism in patients undergoing routine coronary artery bypass surgery","volume":"101","author":"Langenberg","year":"2001","journal-title":"Clin. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Durante, W. (2019). The Emerging Role of l-Glutamine in Cardiovascular Health and Disease. Nutrients, 11.","DOI":"10.3390\/nu11092092"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9570325","DOI":"10.1155\/2021\/9570325","article-title":"Cardiac Aging: From Basic Research to Therapeutics","volume":"2021","author":"Yan","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"a025148","DOI":"10.1101\/cshperspect.a025148","article-title":"The Aging Heart","volume":"5","author":"Chiao","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"583","DOI":"10.18632\/aging.101181","article-title":"Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging","volume":"9","author":"Zhou","year":"2017","journal-title":"Aging"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1111\/acel.12203","article-title":"Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart","volume":"13","author":"Dai","year":"2014","journal-title":"Aging Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.yjmcc.2021.04.005","article-title":"Branched chain amino acids selectively promote cardiac growth at the end of the awake period","volume":"157","author":"Latimer","year":"2021","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1093\/cvr\/cvab207","article-title":"Chronically elevated branched chain amino acid levels are pro-arrhythmic","volume":"118","author":"Portero","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e002157","DOI":"10.1161\/CIRCGEN.118.002157","article-title":"Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women","volume":"11","author":"Tobias","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"101198","DOI":"10.1016\/j.arr.2020.101198","article-title":"Branched chain amino acids, aging and age-related health","volume":"64","author":"Cogger","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1161\/CIRCULATIONAHA.121.054204","article-title":"Dysregulated Phenylalanine Catabolism Plays a Key Role in the Trajectory of Cardiac Aging","volume":"144","author":"Czibik","year":"2021","journal-title":"Circulation"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/0735-1097(94)00557-7","article-title":"Dilated cardiomyopathy is associated with an increase in the type I\/type III collagen ratio: A quantitative assessment","volume":"25","author":"Marijianowski","year":"1995","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"107424","DOI":"10.1016\/j.carpath.2022.107424","article-title":"The application of autopsy and explanted heart samples in scientific research","volume":"59","author":"Liu","year":"2022","journal-title":"Cardiovasc. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1093\/bioinformatics\/btx499","article-title":"PiMP my metabolome: An integrated, web-based tool for LC-MS metabolomics data","volume":"33","author":"Gloaguen","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"D521","DOI":"10.1093\/nar\/gkl923","article-title":"HMDB: The Human Metabolome Database","volume":"35","author":"Wishart","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1097\/01.ftd.0000179845.53213.39","article-title":"METLIN: A metabolite mass spectral database","volume":"27","author":"Smith","year":"2005","journal-title":"Ther. Drug Monit."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"W486","DOI":"10.1093\/nar\/gky310","article-title":"MetaboAnalyst 4.0: Towards more transparent and integrative metabolomics analysis","volume":"46","author":"Chong","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1093\/bioinformatics\/btq418","article-title":"MetPA: A web-based metabolomics tool for pathway analysis and visualization","volume":"26","author":"Xia","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Ihnatova, I., Popovici, V., and Budinska, E. (2018). A critical comparison of topology-based pathway analysis methods. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191154"},{"key":"ref_83","unstructured":"World Medical Association (2013, January 16\u201319). Wma Declaration of Helsinki\u2014Ethical Principles for Medical Research Involving Human Subjects. Proceedings of the 64th WMA General Assembly, Fortaleza, Brazil."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:28:25Z","timestamp":1760142505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,9]]},"references-count":83,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231810456"],"URL":"https:\/\/doi.org\/10.3390\/ijms231810456","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,9]]}}}