Cristina Razquin1,2,3, Miguel Ruiz-Canela1,2,3, Estefania Toledo1,2,3, Pablo Hernández-Alonso3,4,5,6, Clary B Clish7, Marta Guasch-Ferré8,9, Jun Li8, Clemens Wittenbecher8,10,11, Courtney Dennis7, Angel Alonso-Gómez3,12, Montse Fitó3,13, Liming Liang14,15, Dolores Corella3,16, Enrique Gómez-Gracia3,17, Ramon Estruch3,18, Miquel Fiol3,19, Jose Lapetra3,20, Lluis Serra-Majem3,21, Emilio Ros3,22, Fernando Aros3,12, Jordi Salas-Salvadó3,4,6, Frank B Hu8,9, Miguel A Martínez-González1,2,3,8. 1. Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain. 2. Navarra Health Research Institute (IdiSNA), Pamplona, Spain. 3. CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Carlos III Institute of Health, Madrid, Spain. 4. Human Nutrition Unit, Department of Biochemistry and Biotechnology, Rovira i Virgili University, Reus, Spain. 5. Endocrinology and Nutrition Clinical Management Unit, Virgen de la Victoria Hospital, Málaga Biomedical Research Institute (IBIMA), Málaga, Spain. 6. Pere Virgili Health Research Institute (IISPV), San Joan de Reus University Hospital, Reus, Spain. 7. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. 8. Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA. 9. Channing Division for Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 10. Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 11. German Center for Diabetes Research (DZD), Neuherberg, Germany. 12. Bioaraba Health Research Institute, Osakidetza Basque Health Service, Araba University Hospital; University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain. 13. Unit of Cardiovascular Risk and Nutrition, Hospital del Mar Institute for Medical Research (IMIM), Barcelona, Spain. 14. Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA. 15. Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA. 16. Department of Preventive Medicine, University of Valencia, Valencia, Spain. 17. Department of Preventive Medicine, University of Málaga, Málaga, Spain. 18. Department of Internal Medicine, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain. 19. Clinical Trials Platform, Balearic Islands Health Research Institute (IdISBa), Son Espases University Hospital, Palma de Mallorca, Spain. 20. Research Unit, Department of Family Medicine, Seville Primary Care Health District, Sevilla, Spain. 21. Nutrition Research Group, Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. 22. Lipid Clinic, Department of Endocrinology and Nutrition, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain.
Abstract
BACKGROUND: The tryptophan-kynurenine pathway is linked to inflammation. We hypothesize that metabolites implicated in this pathway may be associated with the risk of heart failure (HF) or atrial fibrillation (AF) in a population at high risk of cardiovascular disease. OBJECTIVES: We aimed to prospectively analyze the associations of kynurenine-related metabolites with the risk of HF and AF and to analyze a potential effect modification by the randomized interventions of the PREDIMED (Prevención con Dieta Mediterránea) trial with Mediterranean diet (MedDiet). METHODS: Two case-control studies nested within the PREDIMED trial were designed. We selected 324 incident HF cases and 502 incident AF cases individually matched with ≤3 controls. Conditional logistic regression models were fitted. Interactions with the intervention were tested for each of the baseline plasma metabolites measured by LC-tandem MS. RESULTS: Higher baseline kynurenine:tryptophan ratio (OR for 1 SD: 1.20; 95% CI: 1.01, 1.43) and higher levels of kynurenic acid (OR: 1.19; 95% CI: 1.01, 1.40) were associated with HF. Quinolinic acid was associated with AF (OR: 1.15; 95% CI: 1.01, 1.32) and HF (OR: 1.25; 95% CI: 1.04, 1.49). The MedDiet intervention modified the positive associations of kynurenine (Pinteraction = 0.006), kynurenic acid (Pinteraction = 0.008), and quinolinic acid (Pinteraction = 0.033) with HF and the association between kynurenic acid and AF (Pinteraction = 0.02). CONCLUSIONS: We found that tryptophan-kynurenine pathway metabolites were prospectively associated with higher HF risk and to a lesser extent with AF risk. Moreover, an effect modification by MedDiet was observed for the association between plasma baseline kynurenine-related metabolites and the risk of HF, showing that the positive association of increased levels of these metabolites and HF was restricted to the control group.
BACKGROUND: The tryptophan-kynurenine pathway is linked to inflammation. We hypothesize that metabolites implicated in this pathway may be associated with the risk of heart failure (HF) or atrial fibrillation (AF) in a population at high risk of cardiovascular disease. OBJECTIVES: We aimed to prospectively analyze the associations of kynurenine-related metabolites with the risk of HF and AF and to analyze a potential effect modification by the randomized interventions of the PREDIMED (Prevención con Dieta Mediterránea) trial with Mediterranean diet (MedDiet). METHODS: Two case-control studies nested within the PREDIMED trial were designed. We selected 324 incident HF cases and 502 incident AF cases individually matched with ≤3 controls. Conditional logistic regression models were fitted. Interactions with the intervention were tested for each of the baseline plasma metabolites measured by LC-tandem MS. RESULTS: Higher baseline kynurenine:tryptophan ratio (OR for 1 SD: 1.20; 95% CI: 1.01, 1.43) and higher levels of kynurenic acid (OR: 1.19; 95% CI: 1.01, 1.40) were associated with HF. Quinolinic acid was associated with AF (OR: 1.15; 95% CI: 1.01, 1.32) and HF (OR: 1.25; 95% CI: 1.04, 1.49). The MedDiet intervention modified the positive associations of kynurenine (Pinteraction = 0.006), kynurenic acid (Pinteraction = 0.008), and quinolinic acid (Pinteraction = 0.033) with HF and the association between kynurenic acid and AF (Pinteraction = 0.02). CONCLUSIONS: We found that tryptophan-kynurenine pathway metabolites were prospectively associated with higher HF risk and to a lesser extent with AF risk. Moreover, an effect modification by MedDiet was observed for the association between plasma baseline kynurenine-related metabolites and the risk of HF, showing that the positive association of increased levels of these metabolites and HF was restricted to the control group.
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