Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study
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Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study. / 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.
In: Nutrition, Metabolism & Cardiovascular Diseases, Vol. 33, No. 4, 2023, p. 835-843.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study
AU - Santos, José L
AU - Ruiz-Canela, Miguel
AU - Razquin, Cristina
AU - Clish, Clary B
AU - Guasch-Ferré, Marta
AU - Babio, Nancy
AU - Corella, Dolores
AU - Gómez-Gracia, Enrique
AU - Fiol, Miquel
AU - Estruch, Ramón
AU - Lapetra, José
AU - Fitó, Montserrat
AU - Aros, Fernando
AU - Serra-Majem, Lluis
AU - Liang, Liming
AU - Martínez, María Ángeles
AU - Toledo, Estefanía
AU - Salas-Salvadó, Jordi
AU - Hu, Frank B
AU - Martínez-González, Miguel A
N1 - Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
PY - 2023
Y1 - 2023
N2 - BACKGROUND 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.CLINICAL TRIAL NUMBER: ISRCTN35739639.
AB - BACKGROUND 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.CLINICAL TRIAL NUMBER: ISRCTN35739639.
KW - Humans
KW - Cardiovascular Diseases/diagnosis
KW - Citric Acid Cycle
KW - Cohort Studies
KW - Diet, Mediterranean
KW - Malates
KW - Risk Factors
KW - Male
KW - Female
KW - Middle Aged
KW - Aged
KW - Aged, 80 and over
KW - Case-Control Studies
U2 - 10.1016/j.numecd.2023.01.002
DO - 10.1016/j.numecd.2023.01.002
M3 - Journal article
C2 - 36739229
VL - 33
SP - 835
EP - 843
JO - Nutrition, Metabolism & Cardiovascular Diseases
JF - Nutrition, Metabolism & Cardiovascular Diseases
SN - 0939-4753
IS - 4
ER -
ID: 347795864