BACKGROUND: Previous observational studies have suggested a potential association between heart rate variability (HRV) and cerebrovascular disease. However, a causal relationship between the two has not yet been established. AIMS: The objective of this study was to determine the causal relationship between heart rate variability (HRV) and stroke through a two-sample Mendelian randomization analysis. METHODS: Three genetic predictive traits of heart rate variability standard deviation of the normal-to-normal interbeat intervals (SDNN), the root mean square of the successive differences of interbeat intervals (RMSSD), and the peak-valley respiratory sinus arrhythmia or high-frequency power (pvRSA/HF) were collected from publicly available genome-wide association studies (IEU Open GWAS). Additionally, stroke (STROKE) and its sub-types: ischemic stroke (IS), cardioembolic stroke (CES), small vessel stroke (SVS), large artery stroke (LAS), lacunar stroke (LS), and intracerebral hemorrhage (ICH)were also from this database. Two-sample Mendelian randomization and various sensitivity analyses were employed to explore the causal relationship between HRV and stroke and its sub-types. Inverse-variance weighted (IVW) was the primary method via which Mendelian randomization (MR) was conducted, and for the causal estimates determined by IVW, a series of sensitivity analyses were performed to assess the reliability of the results. (i) Four additional MR methods that complement IVW were utilized
(ii) Cochran's Q-test was employed for assessing heterogeneity
(iii) the MR-Egger's intercept test and MR-PRESSO global test were applied to assess the level of multivariate validity, and (iv) the "leave-one-out" method was utilized to assess stability. RESULTS: Two of the genetically predictive traits of HRV (standard deviation of the normal-to-normal interbeat intervals [SDNN]) and (the peak-valley respiratory sinus arrhythmia or high-frequency power [pvRSA/HF]) were associated with IS (OR 0.63,95 %CI 0.42-0.95, P = 0.03), (OR 0.84, 95 %CI: 0.72-1.00
P = 0.04), and LAS (OR 135.93, 95 %CI: 7.19-2569.22
P = 0.05), (OR 1.42, 95 %CI: 1.02-1.98
P = 0.04) were significantly correlated in addition to (pvRSA/HF) and LS (OR 0.84, 95 %CI: 0.72-1.00
P = 0.04) were also causally associated. Neither was causally associated with other sub-types of stroke or hemorrhagic stroke. Another genetically predictive trait of HRV (the root mean square of the successive differences of interbeat intervals [RMSSD]) was not found to be significantly associated with stroke, its subtypes, or Intracerebral hemorrhage. CONCLUSION: This study provides genetic evidence supporting the causal effects of HRV (SDNN) on ischemic stroke (IS) and large artery stroke (LAS), as well as (pvRSA/HF) on ischemic stroke (IS), large artery stroke (LAS), and lacunar stroke (LS).