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

• Published in: Nutrition, metabolism, and cardiovascular diseases metabolism, and cardiovascular diseases, 2023-04, Vol.33 (4), p.835-843
• Main Authors: Santos, José L., Ruiz-Canela, Miguel, Razquin, Cristina, Clish, Clary B., Guasch-Ferré, Marta, Babio, Nancy, Corella, Dolores, Gómez-Gracia, Enrique, Fiol, Miquel, Estruch, Ramón, Lapetra, José, Fitó, Montserrat, Aros, Fernando, Serra-Majem, Lluis, Liang, Liming, Martínez, María Ángeles, Toledo, Estefanía, Salas-Salvadó, Jordi, Hu, Frank B., Martínez-González, Miguel A.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Cardiovascular disease; Cardiovascular Diseases - diagnosis; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - prevention & control; Case-Control Studies; citrates; Citric Acid Cycle; Cohort Studies; death; Diet, Mediterranean; Female; fumarates; Humans; lactic acid; liquid chromatography; Malates; Male; Mediterranean diet; metabolism; metabolites; Metabolomics; Middle Aged; myocardial infarction; nutritional intervention; pyruvic acid; regression analysis; risk; Risk Factors; standard deviation; Stroke; succinic acid; tandem mass spectrometry; tricarboxylic acid cycle; Tricarboxylic cycle
• ISSN: 0939-4753; 1590-3729; 1590-3729
• DOI: 10.1016/j.numecd.2023.01.002

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. 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