Background: Glutamate metabolism may play a role in the pathophysiology of cardiometabolic disorders. However, there is limited evidence on the association between glutamate-related metabolites and, moreover, changes in these metabolites, and risk of cardiovascular disease (CVD).
Methods and Results: Plasma levels of glutamate and glutamine were measured at baseline and 1-year follow-up in a case-cohort study including 980 participants (mean age: 67 years; 46% male) from the PREDIMED randomized trial, which assessed a Mediterranean diet intervention in the primary prevention of CVD. During median 4.8 years of follow-up, there were 229 incident CVD events (non-fatal stroke, non-fatal myocardial infarction, or CVD death). In fully-adjusted models, per 1-SD, baseline glutamate was associated with 43% (95% CI: 16-76%) and 81% (39-137%) increased risk of composite CVD and stroke alone, respectively, and baseline glutamine-to-glutamate ratio with 25% (6-40%) and 44% (25-58%) decreased risk of composite CVD and stroke alone, respectively. Associations appeared linear for stroke (both Plinear trend≤0.005). Among participants with high baseline glutamate, the interventions lowered CVD risk by 37% compared to the control diet; the intervention effects were not significant when baseline glutamate was low (Pinteraction=0.02). No significant effect of the intervention on year-1 changes in metabolites was observed, and no effect of changes themselves on CVD risk was apparent.
Conclusions: Baseline glutamate was associated with increased CVD risk, particularly stroke, and glutamine-to-glutamate ratio was associated with decreased risk. Participants with high glutamate levels may obtain greater benefits from the Mediterranean diet than those with low levels.