| Institution: | 1. University of Navarra, Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra), Pamplona, Spain;2. Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile;3. Broad Institute of MIT and Harvard University, Cambridge, MA, USA;4. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA;5. Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Institute of Health Carlos III, Madrid, Spain;6. Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnología, Unitat de Nutrició, Reus, Spain;7. University Hospital of Sant Joan de Reus, Nutrition Unit, Reus, Spain;8. Institut d''Investigació Sanitària Pere Virgili (IISPV), Reus, Spain;9. Department of Preventive Medicine, University of Valencia, Valencia, Spain;10. Department of Preventive Medicine, University of Málaga, Málaga, Spain;11. Health Research Institute of the Balearic Islands (IdISBa), Palma de Mallorca, Spain;12. Department of Internal Medicine, Biomedical Research Institute August Pi Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain;13. Centro de Salud San Pablo, Servicios de Atención Primaria, Servicio Andaluz de Salud, Sevilla, Spain;14. Cardiovascular and Nutrition Research Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain;15. Hospital Universitario de Araba, Vitoria, Spain;p. Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria and Service of Preventive Medicine, Complejo Hospitalario Universitario Insular Materno Infantil (CHUIMI), Canary Health Service, Las Palmas de Gran Canaria Spain;q. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA;r. Channing Division of Network Medicine, Department of Medicine, Brigham and Women''s Hospital and Harvard Medical School, Boston, MA, USA |
| Abstract: | Background and aimPlasma 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 resultsCase-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.ConclusionPlasma 2-hydroxyglutarate, fumarate and malate levels were prospectively associated with increased cardiovascular risk.Clinical trial numberISRCTN35739639 |
