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Plasma Ceramides, Mediterranean Diet, and Incident Cardiovascular Disease in the PREDIMED Trial (Prevención con Dieta Mediterránea)
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Background: Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. Methods: The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ≤7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. Results: The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49–3.83, P trend <0.001), 1.91 (1.21–3.01, P trend =0.003), 1.97 (1.21–3.20, P trend =0.004), and 1.73 (1.09–2.74, P trend =0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% CI, 1.36–3.49; P trend <0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups ( P interaction =0.008). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up. Conclusions: Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. Clinical Trial Registration: URL: http://www.isrctn.com . Unique identifier: ISRCTN35739639.
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“It is well known that aberrant accumulation of ceramides, that frequently occurs because of excess saturated fat consumption, may lead to impaired cellular function, including impaired insulin function [55], while the MD has a favorable impact on CVD by diminishing ceramide concentration.”
From Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing (2021) · cites this paper as [55]
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“It is well known that aberrant accumulation of ceramides, that frequently occurs because of excess saturated fat consumption, may lead to impaired cellular function, including impaired insulin function [55], while the MD has a favorable impact on CVD by diminishing ceramide concentration.”
From Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing (2021) · cites this paper as [55]
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“The unsaturated fatty acids that are highly represented in the MD and especially in the extra virgin olive oil have been demonstrated, according to the PREDIMED Trial, to contribute to diminished ceramide accumulation and therefore to confer a cardioprotective effect.”
From Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing (2021) · cites this paper as [55]
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Metadata
- Authors
- Wang, D. D., Toledo, E., Hruby, A., Rosner, B. A., Willett, W. C., Sun, Q., Razquin, C., Zheng, Y., Ruiz-Canela, M., Guasch-Ferré, M., Corella, D., Gómez-Gracia, E., Fiol, M., Estruch, R., Ros, E., Lapetra, J., Fito, M., Aros, F., Serra-Majem, L., Lee, C.-H., Clish, C. B., Liang, L., Salas-Salvadó, J., Martínez-González, M. A., & Hu, F. B.
- Affiliations
- Harvard University (US)
- From Department of Nutrition (D.D.W., W.C.W., Q.S., Y.Z., M.G.-F., C.-H.L., F.B.H.); Department of Epidemiology (D.D.W., W.C.W., L.L., F.B.H.), Department of Biostatistics (B.A.R., L.L.), Department of Genetics and Complex Diseases (C.-H.L.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Nutrition (M.A.M.-G.), Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain (E.T., C.R., M.R.-C., M.A.M.-G.); Instituto de Investigación Sanitaria de...
- ORCID
- Venue
- Circulation
- Published
- 2017-05-23
- Volume
- 135
- Issue
- 21
- Pages
- 2028-2040
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC5496817
- OpenAlex
- W2890371182
- Cited by
- 327
- References
- 83
- Citations by year
- 2026: 29 · 2025: 33 · 2024: 30 · 2023: 38 · 2022: 44 · 2021: 50 · 2020: 42 · 2019: 34 · 2018: 21 · 2017: 6
- FWCI
- 11.51
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-10-14)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rovira & Virgili repository (submittedVersion, cc-by)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
- Funders
- U.S. Department of Agriculture
- American Heart Association
- Brigham and Women's Hospital
- Massachusetts Institute of Technology
- Harvard University
- Harvard T.H. Chan School of Public Health
- Universidad de Málaga
- Institut d'Investigació Sanitària Pere Virgili
- Broad Institute
- Generalitat de Catalunya
- Fundación Mapfre (Fundación Mapfre 2010)
- Generalitat Valenciana
- Universitat de València
- Universidad de Navarra
- Ministerio de Ciencia e Innovación
- Universitat de Barcelona
- Centro Nacional de Investigaciones Cardiovasculares
- Universidad de Las Palmas de Gran Canaria
- Universitat Rovira i Virgili
- Junta de Andalucía
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición
- Gobierno de Navarra
- National Institutes of Health
- Instituto de Salud Carlos III
- European Regional Development Fund
- Faculty of Medicine and Health, University of Sydney
- National Heart, Lung, and Blood Institute (R01HL118264)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- 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
- Keywords
- plasma ceramides, cardiovascular disease, Mediterranean diet, PREDIMED trial, extra virgin olive oil, nuts, cardiovascular risk, myocardial infarction, stroke, cardiovascular mortality, lipid metabolism, case-cohort design, metabolomics biomarkers
- MeSH terms
- Olive Oil, Aged, Cardiovascular Diseases, Ceramides, Chromatography, Liquid, Female, Humans, Male, Middle Aged, Nuts, Prospective Studies, Risk Factors, Spain, Time Factors, Biomarkers, Incidence, Multivariate Analysis, Linear Models, Proportional Hazards Models, Risk Assessment, Diet, Mediterranean, Risk Reduction Behavior, Tandem Mass Spectrometry, Metabolomics, Protective Factors
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