Insight into the relationship between resting heart rate and atrial fibrillation: a Mendelian randomization study

AIMS: A low resting heart rate (RHR) implies a more efficient heart function and a lower risk of cardiovascular disease. However, observational studies have reported a U-shaped association between RHR and atrial fibrillation (AF). In contrast, Mendelian randomization (MR) studies have found an inverse causal association between RHR and AF. Hence, the causal nature of the relationship is not clear. The aim is to investigate the causal association and its shape between RHR on AF using linear and non-linear MR (NLMR). METHODS AND RESULTS: Linear and non-linear MR were performed on individual-level data in the Trøndelag Health Study (HUNT) and UK Biobank (UKB). HUNT consists of 69 155 individuals with 7,062 AF cases, while UKB provides data on 431 852 individuals with 20 452 AF cases. The linear MR found an inverse relationship between RHR and AF with an OR = 0.95 [95% confidence interval (CI): 0.93–0.98] and OR = 0.96 (95% CI: 0.95–0.97) per unit decrease in RHR in HUNT and UKB, respectively. The NLMR was supportive of an inverse linear relationship in both HUNT and UKB for RHR values <90 beats per minute (bpm). Several sensitivity analyses were also consistent. CONCLUSION: In contrast with the current observational knowledge of RHR and AF, an inverse causal association between RHR and AF was demonstrated in both linear and non-linear MR for RHR values up to 90 bpm. Further exploring the underlying mechanisms of the genetic instrument for RHR may shed light on whether pleiotropy is biasing this association.