Fig. 6: Multivariable Mendelian randomization reveals pulse pressure and atrial fibrillation as potential mediators of the association of genetically predicted RHR with ischemic and cardio-embolic stroke, respectively.

Forestplots of the results of the two-sample multivariable Mendelian randomization analyses of resting heart rate on a any stroke (Ncases = 67,162; Ncontrols = 454,450), b ischemic stroke (Ncases = 60,341; Ncontrols = 454,450) and c cardio-embolic stroke (Ncases = 9006; Ncontrols = 403,807), when using atrial fibrillation, systolic, diastolic and pulse pressure as secondary exposures. Shown in red are the univariable Mendelian randomization estimates which represent the total estimates of resting heart rate on the outcome. In black are the multivariable Mendelian randomization estimates, which show the direct effect of RHR when corrected for the secondary exposure. These results indicate that atrial fibrillation attenuates the beneficial effect of a higher resting heart rate on cardio-embolic stroke, while pulse pressure attenuates the beneficial effect on any ischemic stroke. MR-Steiger sensitivity analysis indicated that the association between the RHR-associated genetic variants and pulse pressure is unlikely mediated through RHR entirely and biological pleiotropic effects are therefore more likely to cause the attenuation of the association between RHR and stroke when correcting for pulse pressure. Odds ratios and 95% confidence intervals are shown. The X-axis shows odds ratio’s on a log₁₀ scale, the center as indicated by a gray line depicts an odds ratio of 1. RHR resting heart rate; MV multivariable, Nsnp number of SNPs.