Plasma Arginine/Asymmetric Dimethylarginine Ratio and Incidence of Cardiovascular Events: A Case-Cohort Study
Open accessAbstract
Context: 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. Objective: To examine the association between baseline and 1-year concentrations of urea cycle metabolites and cardiovascular disease (CVD) in a case-cohort setting. Design: 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). Setting: Multicenter randomized trial in Spain. Participants: Participants were 984 participants accruing 231 events over 4.7 years' median follow-up. Main Outcome Measure: Incident CVD. Results: 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. Conclusions: 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.
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NADPH is the preferred substrate for all NOX isoforms, with the NOX2 isoform being particularly NADPH specific.
“NADPH is the preferred substrate for all NOX isoforms, with the NOX2 isoform being particularly NADPH specific (48, 63, 177, 1047).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1047]
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- Authors
- Yu, E., Ruiz-Canela, M., Hu, F. B., Clish, C. B., Corella, D., Salas-Salvadó, J., Hruby, A., Fitó, M., Liang, L., Toledo, E., Ros, E., Estruch, R., Gómez-Gracia, E., Lapetra, J., Arós, F., Romaguera, D., Serra-Majem, L., Guasch-Ferré, M., Wang, D. D., & Martínez-González, M. A.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Universitat de València (ES)
- Tufts University (US)
- Instituto de Salud Carlos III (ES)
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2017-03-02
- Volume
- 102
- Issue
- 6
- Pages
- 1879-1888
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC6283443
- OpenAlex
- W2624081701
- Cited by
- 30
- References
- 43
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 1 · 2021: 5 · 2020: 2 · 2019: 2 · 2018: 1
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rovira & Virgili repository (submittedVersion, cc-by)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion)
- Funders
- Universidad de Navarra
- International Nut and Dried Fruit Council
- National Heart, Lung, and Blood Institute (R01HL118264)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- asymmetric dimethylarginine, L-arginine, cardiovascular disease incidence, cardiovascular risk, arginine availability, ornithine, citrulline, Mediterranean diet, cardiovascular mortality, myocardial infarction, stroke
- MeSH terms
- Aged, Arginine, Cardiovascular Diseases, Chromatography, Liquid, Citrulline, Female, Humans, Male, Middle Aged, Myocardial Infarction, Ornithine, Prospective Studies, Risk Factors, Cohort Studies, Incidence, Multivariate Analysis, Proportional Hazards Models, Case-Control Studies, omega-N-Methylarginine, Stroke, Tandem Mass Spectrometry
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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