Association between modifiable risk factors and bradyarrhythmia: A Mendelian randomization study

Background Bradyarrhythmia is associated with adverse outcomes; however, its primary prevention strategies remain undefined. Objective We aimed to evaluate the causal associations between modifiable risk factors and bradyarrhythmia using Mendelian randomization (MR). Methods Summary statistical data for modifiable risk factors and bradyarrhythmia were obtained from the European-ancestry genome-wide association study. Genetic instruments for each risk factor were derived from 2 datasets. Univariable, multivariable, and mediation MR analyses were conducted. Associations were considered significant at a Bonferroni-corrected threshold (<ani:em>P</ani:em> _adj <0.0023) and suggestive when 0.0023 ≤<ani:em>P</ani:em> _adj<0.05. Results In the discovery datasets, a suggestive positive association was found between genetically determined body mass index (BMI) (odds ratio [OR]: 1.19; 95% confidence interval [CI]: 1.06–1.34) and the risk of sick sinus syndrome. For conduction disorders (CD), genetic predisposition to higher BMI (OR: 1.27; 95% CI: 1.17–1.39), systolic blood pressure (SBP) (OR: 1.43; 95% CI: 1.26–1.63), diastolic blood pressure (DBP) (OR: 1.23; 95% CI: 1.08–1.40), and lipoprotein a (OR: 1.10; 95% CI: 1.04–1.16) were significantly associated with increased risk. When CD subtypes were used as independent outcomes, BMI and SBP exhibited significant associations with the risk of atrioventricular block, whereas SBP and DBP were associated with left bundle branch block. These results remained directionally consistent in replication analyses. Multivariable MR analysis revealed that BMI, SBP, and lipoprotein(a) were independent risk factors for CD. Mediation analysis showed that SBP and DBP explained 17.61% and 17.84% of the effect of BMI on CD. Conclusion This study identified distinct modifiable metabolic and lifestyle factors that are causally associated with different types of bradyarrhythmia.