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Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study
José L Santos1, Miguel Ruiz-Canela2, Cristina Razquin2
1University of Navarra, Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra), Pamplona, Spain; Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Insights
Plasma levels of 2-hydroxyglutarate, fumarate, and malate are linked to a higher risk of cardiovascular disease (CVD). These findings were consistent at baseline and after one year, regardless of diet intervention.
Area of Science:
- Metabolomics
- Cardiovascular Disease Research
- Nutritional Science
Background:
- Circulating citric acid cycle (CAC) metabolites may influence cardiovascular disease (CVD) risk.
- Longitudinal studies on CAC metabolites and CVD risk are limited.
- This study investigates CAC metabolites in relation to CVD incidence.
Purpose of the Study:
- To assess the association of baseline and 1-year plasma CAC metabolite levels with CVD incidence.
- To explore potential interactions between CAC metabolites and Mediterranean diet interventions.
- To identify specific CAC metabolites predictive of future cardiovascular events.
Main Methods:
- A case-cohort study design was employed within the PREDIMED trial.
- Nine plasma CAC metabolites were quantified using liquid chromatography-tandem mass spectrometry.
- Weighted Cox multiple regression analysis was used to determine hazard ratios.
Main Results:
- Elevated baseline plasma levels of 2-hydroxyglutarate, fumarate, and malate were associated with increased CVD risk.
- A combined score of these three metabolites also predicted higher CVD incidence.
- These associations remained significant when assessed using 1-year follow-up plasma measurements.
Conclusions:
- Plasma 2-hydroxyglutarate, fumarate, and malate levels are prospectively associated with heightened cardiovascular risk.
- The predictive value of these metabolites for CVD risk was confirmed at both baseline and 1-year follow-up.
- No significant interactions were found between these metabolite levels and the dietary interventions studied.
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.
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