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

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.

Keywords: Mediterranean diet; PREDIMED; atrial fibrillation; case–control; heart failure; kynurenine; metabolomics; tryptophan.

FIGURE 1

Flowchart of the case–control design for incident AF nested in the PREDIMED trial. *Incidence density sampling with replacement was used as the control sampling method. AF, atrial fibrillation; HILIC, hydrophilic interaction liquid chromatography; PREDIMED, Prevención con Dieta Mediterránea; Trp–Kyn, tryptophan–kynurenine.

FIGURE 2

Flowchart of the case–control design for incident HF nested in the PREDIMED trial. *Incidence density sampling with replacement was used as the control sampling method. HF, heart failure; HILIC, hydrophilic interaction liquid chromatography; PREDIMED, Prevención con Dieta Mediterránea; Trp–Kyn, tryptophan–kynurenine.

FIGURE 3

Matched ORs (95% CIs) for the association between baseline metabolites (1-SD increase) of the tryptophan–kynurenine pathway and incident heart failure (HF) within each PREDIMED (Prevención con Dieta Mediterránea) study intervention arm [both MedDiet intervention groups merged together (n = 516) compared with the control group (n = 301)]. The multivariable model adjusted for BMI (in kg/m²), smoking (never, current, former), leisure-time physical activity (metabolic equivalent tasks; min/d), prevalent chronic conditions at baseline (dyslipidemia, hypertension, and type 2 diabetes), family history of coronary artery disease, education level (primary or lower/secondary or higher), and propensity scores predicting random assignment to account for small between-group imbalances at baseline. MedDiet, Mediterranean diet.