Metabolomics of the tryptophan-kynurenine degradation pathway and risk of atrial fibrillation and heart failure: potential modification effect of Mediterranean diet

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 (Prevencion con Dieta MediterrAnea) 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 (P-interaction = 0.006), kynurenic acid (P-interaction = 0.008), and quinolinic acid (P-interection = 0.033) with HF and the association between kynurenic acid and AF (P-interection = 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.