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

Identificador:  imarina:9292262

Handle: https://hdl.handle.net/20.500.11797/imarina9292262

Autors:  Santos, Jose L; Ruiz-Canela, Miguel; Razquin, Cristina; Clish, Clary B; Guasch-Ferre, Marta; Babio, Nancy; Corella, Dolores; Gomez-Gracia, Enrique; Fiol, Miquel; Estruch, Ramon; Lapetra, Jose; Fito, Montserrat; Aros, Fernando; Serra-Majem, Lluis; Liang, Liming; Martinez, Maria Angeles; Toledo, Estefania; Salas-Salvado, Jordi; Hu, Frank B; Martinez-Gonzalez, Miguel A

Resum:
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