Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study

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dc.contributor.authorSantos Martín, José Luis
dc.contributor.authorRuiz Canela, Miguel
dc.contributor.authorRazquin, Cristina
dc.contributor.authorClish, Clary B.
dc.contributor.authorGuasch-Ferré, Marta
dc.contributor.authorBabio, Nancy
dc.contributor.authorCorella, Dolores
dc.contributor.authorGómez-Gracia, Enrique
dc.contributor.authorFiol, Miquel
dc.contributor.authorEstruch, Ramón
dc.contributor.authorLapetra, José
dc.contributor.authorFitó, Montserrat
dc.contributor.authorAros, Fernando
dc.contributor.authorSerra-Majem, Lluis
dc.contributor.authorLiang, Liming
dc.contributor.authorMartínez, María Ángeles
dc.contributor.authorToledo, Estefanía
dc.contributor.authorSalas-Salvadó, Jordi
dc.contributor.authorHu, Frank B.
dc.contributor.authorMartínez González, Miguel Ángel
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.departmentInstitute on Innovation and Sustainable Development in Food Chain - ISFOODen
dc.date.accessioned2025-04-14T08:35:51Z
dc.date.available2025-04-14T08:35:51Z
dc.date.issued2023-01-12
dc.date.updated2025-04-14T08:28:29Z
dc.description.abstractBackground and aim: Plasma citric acid cycle (CAC) metabolites might be likely related to cardiovascular disease (CVD). However, studies assessing the longitudinal associations between circulating CAC-related metabolites and CVD risk are lacking. The aim of this study was to evaluate the association of baseline and 1-year levels of plasma CAC-related metabolites with CVD incidence (a composite of myocardial infarction, stroke or cardiovascular death), and their interaction with Mediterranean diet interventions. Methods and results: Case-cohort study from the PREDIMED trial involving participants aged 55¿80 years at high cardiovascular risk, allocated to MedDiets or control diet. A subcohort of 791 participants was selected at baseline, and a total of 231 cases were identified after a median follow-up of 4.8 years. Nine plasma CAC-related metabolites (pyruvate, lactate, citrate, aconitate, isocitrate, 2-hydroxyglutarate, fumarate, malate and succinate) were measured using liquid chromatography-tandem mass spectrometry. Weighted Cox multiple regression was used to calculate hazard ratios (HRs). Baseline fasting plasma levels of 3 metabolites were associated with higher CVD risk, with HRs (for each standard deviation, 1-SD) of 1.46 (95%CI:1.20¿1.78) for 2-hydroxyglutarate, 1.33 (95%CI:1.12-1.58) for fumarate and 1.47 (95%CI:1.21¿1.78) for malate (p of linear trend <0.001 for all). A higher risk of CVD was also found for a 1-SD increment of a combined score of these 3 metabolites (HR = 1.60; 95%CI: 1.32-1.94, p trend <0.001). This result was replicated using plasma measurements after one-year. No interactions were detected with the nutritional intervention. Conclusion: Plasma 2-hydroxyglutarate, fumarate and malate levels were prospectively associated with increased cardiovascular risk.en
dc.description.sponsorshipSupported by NIH grant HL118264 (to FBH, MAM). The PREDIMED trial was supported by grants of the Spanish National Institute of Health (Instituto de Salud Carlos III) and other minor grants (see extended funding information and acknowledgments in appendix).
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/msworden
dc.identifier.citationSantos, J. L., Ruiz-Canela, M., Razquin, C., Clish, C. B., Guasch-Ferré, M., Babio, N., Corella, D., Gómez-Gracia, E., Fiol, M., Estruch, R., Lapetra, J., Fitó, M., Aros, F., Serra-Majem, L., Liang, L., Martínez, M. A., Toledo, E., Salas-Salvadó, J., Hu, F. B., Martínez-González, M. A. (2023). Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study. Nutrition, Metabolism and Cardiovascular Diseases, 33(4), 835-843. https://doi.org/10.1016/j.numecd.2023.01.002.
dc.identifier.doi10.1016/j.numecd.2023.01.002
dc.identifier.issn0939-4753
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/53969
dc.language.isospa
dc.publisherElsevier
dc.relation.ispartofNutrition, Metabolism and Cardiovascular Diseases (2023), vol. 33, núm. 4
dc.relation.publisherversionhttps://doi.org/10.1016/j.numecd.2023.01.002
dc.rights© 2023 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY-NC-ND license.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCitric acid cycleen
dc.subjectTricarboxylic cycleen
dc.subjectMetabolomicsen
dc.subjectCardiovascular diseaseen
dc.subjectStrokeen
dc.titleCirculating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED studyen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dspace.entity.typePublication
relation.isAuthorOfPublicationa52c0775-f788-4e86-bfbb-a94121c2fbd4
relation.isAuthorOfPublication.latestForDiscoverya52c0775-f788-4e86-bfbb-a94121c2fbd4

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