Histidine and the risk of incident atrial fibrillation and post-ablation recurrence: evidence from two prospective cohorts

Objectives: To investigate the association between circulating histidine levels and the risk of atrial fibrillation (AF) onset and recurrence, and to explore potential underlying mechanisms. Methods: We analyzed data from 221,277 AF-free participants in the UK Biobank and from 44 patients with paroxysmal or persistent AF (PaAF/PeAF) undergoing catheter ablation, in whom histidine was measured in both peripheral and intracardiac blood. Associations with incident and recurrent AF were evaluated using Cox proportional hazards models, subgroup analyses, and sensitivity analyses. Receiver operating characteristic (ROC) analysis assessed the predictive value of histidine for AF recurrence. Mechanistic studies included a sheep AF model to examine the impact of electrical remodeling on atrial histidine metabolism, and neonatal rat cardiomyocyte experiments to assess histidine’s effects on cell viability and gene expression. Results: Over a median follow-up of 13.6 years, 14,427 participants developed new-onset AF. Higher histidine levels were associated with a lower risk of AF (hazard ratio [HR] per standard deviation: 0.95; 95% confidence interval [CI]: 0.94–0.97), with consistent findings across sensitivity analyses. In the ablation cohort, histidine predicted AF recurrence with 76% sensitivity and 77% specificity (area under the ROC curve [AUC] = 0.75; 95% CI: 0.59–0.90). In the sheep AF model, histidine levels remained stable despite increased 3-methylhistidine, indicating no effect of electrical remodeling on histidine metabolism. Histidine demonstrated a dose-dependent effect on cardiomyocyte viability, enhancing activity at nanomolar concentrations while reducing it at micromolar levels. The downregulation of oxidative phosphorylation genes at higher histidine doses, together with the reduction in relative MitoSOX intensity, suggests a dose-dependent modulation of mitochondrial function, potentially balancing energy production and oxidative stress. Conclusions: Histidine is inversely associated with AF risk and may serve as a predictive biomarker for AF recurrence. Experimental findings suggest that changes in histidine may precede AF development, supporting its potential as a modifiable metabolic target.