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J Am Heart Assoc. 2016 Sep 15;5(9). pii: e003755. doi: 10.1161/JAHA.116.003755.

Metabolites of Glutamate Metabolism Are Associated With Incident Cardiovascular Events in the PREDIMED PREvención con DIeta MEDiterránea (PREDIMED) Trial.

Author information

1
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA.
2
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
3
Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain IDISNA (Instituto de Investigación Sanitaria de Navarra), Pamplona, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
4
Broad Institute of MIT and Harvard University, Cambridge, MA.
5
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Human Nutrition Department, IISPV, Universitat Rovira i Virgili, Reus, Spain.
6
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA.
7
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Department of Preventive Medicine, University of Valencia, Spain.
8
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Lipid Clinic, Departments of Endocrinology and Nutrition, Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
9
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain.
10
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Department of Preventive Medicine, University of Malaga, Spain.
11
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Department of Cardiology, University Hospital of Alava, Vitoria, Spain.
12
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Palma Institute of Health Research (IdISPa), Hospital Son Espases, Palma de Mallorca, Spain.
13
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Research Unit, Department of Family Medicine, Distrito Sanitario Atencion Primaria Sevilla, Sevilla, Spain.
14
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Las Palmas, Spain.
15
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain Department of Internal Medicine, Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
16
Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain IDISNA (Instituto de Investigación Sanitaria de Navarra), Pamplona, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain mamartinez@unav.es.

Abstract

BACKGROUND:

Glutamate metabolism may play a role in the pathophysiology of cardiometabolic disorders. However, there is limited evidence of an 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 68 years; 46% male) from the PREvención con DIeta MEDiterránea (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 (nonfatal stroke, nonfatal myocardial infarction, or CVD death). In fully adjusted models, per 1-SD, baseline glutamate was associated with 43% (95% CI: 16% to 76%) and 81% (39% to 137%) increased risk of composite CVD and stroke alone, respectively, and baseline glutamine-to-glutamate ratio with 25% (6% to 40%) and 44% (25% to 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.

CLINICAL TRIAL REGISTRATION:

URL: www.controlled-trials.com. Unique identifier: ISRCTN 35739639.

KEYWORDS:

cardiovascular disease; diet; dietary clinical trial; epidemiology; glutamate; glutamine; incidence; stroke

PMID:
27633391
PMCID:
PMC5079035
DOI:
10.1161/JAHA.116.003755
[Indexed for MEDLINE]
Free PMC Article

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