Relationship between heart rate variability traits and stroke: A Mendelian randomization study

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.

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.

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.

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.

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).