Circulating ketone bodies, genetic susceptibility, with left atrial remodeling and atrial fibrillation: A prospective study from the UK Biobank

Background: Ketone bodies (KBs) are an important cardiac metabolic energy source. Metabolic remodeling has recently been found to play an important role in the pathological process of atrial fibrillation (AF). Objective: The purpose of this study was to evaluate the associations of circulating KB levels with incident AF risk in the general population. Methods: We studied 237,163 participants [mean age, 56.5 years; 129,472 women (55%)] from the UK Biobank who were free of AF at baseline and had data on circulating β-hydroxybutyrate (β-OHB), acetoacetate, and acetone. The associations of KBs with new-onset AF were evaluated using Cox regression in the general population and across the 3 genetic risk groups: low, moderate, and high polygenic risk score of AF. Results: During a median follow-up of 14.8 (13.8, 15.5) years, 16,638 participants (7.0%) developed AF. There was a U-shaped association of total KBs and β-OHB with incident AF, with nadirs at 60.6 and 40.8 μmol/L, respectively (P_nonlinear < .05), whereas there was a positive association of acetoacetate and acetone with AF (P_overall < .001; P_nonlinear > .05). Consistently, there was a U-shaped association of total KBs and β-OHB with left atrial (LA) volume parameters, including LA maximum volume, LA minimum volume, and their body surface area–indexed counterparts, and there was an inverted U-shaped association of total KBs and β-OHB with LA ejection fraction (P_nonlinear < .05 for all). The associations of KBs with AF were stronger in individuals with low genetic risk (P_interaction < .05), while the highest AF risk was in those with high genetic risk with high KB levels. Significant mediation effects of inflammatory markers on the associations between KBs and AF were identified. Conclusion: There was a U-shaped association of circulating total KBs and β-OHB with incident AF as well as a positive association of acetoacetate and acetone levels with AF risk in the general population.