Plasma Arginine/Asymmetric Dimethylarginine Ratio and Incidence of Cardiovascular Events: A Case-Cohort Study.
Arginine, its methylated metabolites, and other metabolites related to the urea cycle have been independently associated with cardiovascular risk, but the potential causal meaning of these associations (positive for some metabolites and negative for others) remains elusive due to a lack of studies measuring metabolite changes over time.



To examine the association between baseline and 1-year concentrations of urea cycle metabolites and cardiovascular disease (CVD) in a case-cohort setting.



A case-cohort study was nested within the Prevención con Dieta Mediterránea trial. We used liquid chromatography-tandem mass spectrometry to assess metabolite levels at baseline and after 1-year follow-up. The primary CVD outcome was a composite of myocardial infarction, stroke and cardiovascular death. We used weighted Cox regression models (Barlow weights) to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs).



Multicenter randomized trial in Spain.



Participants were 984 participants accruing 231 events over 4.7 years' median follow-up.



Incident CVD.



Baseline arginine/asymmetric dimethylarginine ratio [HR per standard deviation (SD) = 0.80; 95% CI, 0.67 to 0.96] and global arginine availability [arginine / (ornithine + citrulline)] (HR per SD = 0.83; 95% CI, 0.69 to 1.00) were significantly associated with lower risk of CVD. We observed no significant association for 1-year changes in these ratios or any effect modification by the Mediterranean diet (MD) intervention.



A higher baseline arginine/asymmetric dimethylarginine ratio was associated with lower CVD incidence in a high cardiovascular risk population. The intervention with the MD did not change 1-year levels of these metabolites.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.
Edward
E
Yu
Department of Preventive Medicine and Public Health, University of Navarra, and Instituto de Investigacion Sanitaria de Navarra (IdiSNA), University of Navarra, 31008 Pamplona, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Miguel
M
Ruiz-Canela
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.|Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Frank B
FB
Hu
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142.
Clary B
CB
Clish
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Department of Preventive Medicine, University of Valencia, 46010 Valencia, Spain.
Dolores
D
Corella
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Human Nutrition Unit, Institut d'Investigació Sanitària Pere Virgili (IISPV), University Hospital of Sant Joan de Reus, Universitat Rovira i Virgili, 43201 Reus, Spain.
Jordi
J
Salas-Salvadó
Jean Mayer United States Department of Agriculture (USDA) Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111.
Adela
A
Hruby
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, 08028 Barcelona, Spain.
Montserrat
M
Fitó
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.
Liming
L
Liang
Department of Preventive Medicine and Public Health, University of Navarra, and Instituto de Investigacion Sanitaria de Navarra (IdiSNA), University of Navarra, 31008 Pamplona, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Estefanía
E
Toledo
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, 08007 Barcelona, Spain.
Emilio
E
Ros
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Department of Internal Medicine, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, 08007 Barcelona, Spain.
Ramón
R
Estruch
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Department of Preventive Medicine, University of Malaga, 29016 Malaga, Spain.
Enrique
E
Gómez-Gracia
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Department of Family Medicine, Research Unit, Primary Care Division of Sevilla, 41004 Sevilla, Spain.
José
J
Lapetra
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Department of Cardiology, University Hospital Araba, 01009 Vitoria, Spain.
Fernando
F
Arós
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain.
Dora
D
Romaguera
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.|Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, 35001 Las Palmas, Spain.
Lluís
L
Serra-Majem
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.
Marta
M
Guasch-Ferré
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.
Dong D
DD
Wang
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.|Department of Preventive Medicine and Public Health, University of Navarra, and Instituto de Investigacion Sanitaria de Navarra (IdiSNA), University of Navarra, 31008 Pamplona, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Miguel A
MA
Martínez-González
D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood* / Q000401:mortality; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D002956:Citrulline / Q000097:blood; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000097:blood* / Q000453:epidemiology; D009952:Ornithine / Q000097:blood; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000097:blood* / Q000453:epidemiology; D053719:Tandem Mass Spectrometry; D019323:omega-N-Methylarginine / Q000097:blood
D019323:omega-N-Methylarginine; D002956:Citrulline; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D009952:Ornithine