Arginine catabolism metabolites and atrial fibrillation or heart failure risk: 2 case-control studies within the Prevención con Dieta Mediterránea (PREDIMED) trial

Abstract

Background: Arginine-derived metabolites are involved in oxidative and inflammatory processes related to endothelial functions and cardiovascular risks.

Objectives: We prospectively examined the associations of arginine catabolism metabolites with the risks of atrial fibrillation (AF) or heart failure (HF), and evaluated the potential modifications of these associations through Mediterranean diet (MedDiet) interventions in a large, primary-prevention trial.

Methods: Two nested, matched, case-control studies were designed within the Prevención con Dieta Mediterránea (PREDIMED) trial. We selected 509 incident cases and 547 matched controls for the AF case-control study and 326 cases and 402 matched controls for the HF case-control study using incidence density sampling. Fasting blood samples were collected at baseline and arginine catabolism metabolites were measured using LC-tandem MS. Multivariable conditional logistic regression models were applied to test the associations between the metabolites and incident AF or HF. Interactions between metabolites and intervention groups (MedDiet groups compared with control group) were analyzed with the likelihood ratio test.

Results: Inverse association with incident AF was observed for arginine (OR per 1 SD, 0.83; 95% CI: 0.73-0.94), whereas a positive association was found for N1-acetylspermidine (OR for Q4 compared with Q1 1.58; 95% CI: 1.13-2.25). For HF, inverse associations were found for arginine (OR per 1 SD, 0.82; 95% CI: 0.69-0.97) and homoarginine (OR per 1 SD, 0.81; 95% CI: 0.68-0.96), and positive associations were found for the asymmetric dimethylarginine (ADMA) and symmetric dimethlyarginine (SDMA) ratio (OR per 1 SD, 1.19; 95% CI: 1.02-1.41), N1-acetylspermidine (OR per 1 SD, 1.34; 95% CI: 1.12-1.60), and diacetylspermine (OR per 1 SD, 1.20; 95% CI: 1.02-1.41). In the stratified analysis according to the dietary intervention, the lower HF risk associated with arginine was restricted to participants in the MedDiet groups (P-interaction = 0.044).

Conclusions: Our results suggest that arginine catabolism metabolites could be involved in AF and HF. Interventions with the MedDiet may contribute to strengthen the inverse association between arginine and the risk of HF. This trial was registered at controlled-trials.com as ISRCTN35739639.

Keywords: Mediterranean diet; arginine catabolism metabolites; atrial fibrillation; case-control; heart failure; metabolomics.

FIGURE 1

Flowchart of the case-control design for incident AF within the PREDIMED trial. *Incidence density sampling with replacement was used as the control sampling method. Abbreviations: AF, atrial fibrillation; PREDIMED, Prevención con Dieta Mediterránea.

FIGURE 2

Flowchart of the case-control design for incident HF within the PREDIMED trial. *Incidence density sampling with replacement was used as the control sampling method. Abbreviations: HF, heart failure; PREDIMED, Prevención con Dieta Mediterránea.

FIGURE 3

Association (per SD) between arginine or N1-acetylspermidine and incident heart failure, stratified by intervention group. Adjusted for age, sex, smoking status (never, current, or former), BMI (kg/m²), physical activity (MET-min/day), prevalent chronic conditions at baseline (dyslipidemia, hypertension, and type 2 diabetes), and propensity scores predicting random assignment to account for small between-group imbalances at baseline. Abbreviation: MET, metabolic equivalent task.