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A two-sample Mendelian randomization analysis of heart rate variability and cerebral small vessel disease.

ABSTRACT: Cerebral small vessel disease (cSVD) is correlated with a high risk of stroke and cognitive impairment. Previous studies between heart rate variability (HRV) and cSVD revealed paradoxical results. The authors aimed to investigate the relationship between HRV and cSVD using Mendelian randomization analysis. Genetic instruments for HRV were obtained from previous genome-wide association studies. They applied inverse variance-weighted analysis, weighted median analysis, simple median analysis, and Mendelian randomization-Egger regression to evaluate the associations of HRV with white matter hyperintensity (WMH) and small vessel stroke (SVS) in the UK Biobank neuroimaging dataset and the MEGASTROKE genome-wide association study dataset. Two genetically predicted traits of HRV (the root mean square of the successive differences of inter beat intervals [RMSSD] and the peak-valley respiratory sinus arrhythmia or high frequency power [pvRSA/HF]) were suggestively associated with WMH (β 0.26, 95% confidence interval [CI] 0.04-0.49, p = .02; β 0.14, 95% CI 0.02-0.27, p = .03, respectively). Genetically predicted traits of HRV were not significantly associated with SVS. This study provides genetic support for a suggestive causal effect of HRV (RMSSD, pvRSA/HF) on WMH but not SVS.

SUBMITTER: Tian D

PROVIDER: S-EPMC8678680 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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A two-sample Mendelian randomization analysis of heart rate variability and cerebral small vessel disease.

Tian Danyang D Zhang Linjing L Zhuang Zhenhuang Z Huang Tao T Fan Dongsheng D

Journal of clinical hypertension (Greenwich, Conn.) 20210701 8

Cerebral small vessel disease (cSVD) is correlated with a high risk of stroke and cognitive impairment. Previous studies between heart rate variability (HRV) and cSVD revealed paradoxical results. The authors aimed to investigate the relationship between HRV and cSVD using Mendelian randomization analysis. Genetic instruments for HRV were obtained from previous genome-wide association studies. They applied inverse variance-weighted analysis, weighted median analysis, simple median analysis, and ...[more]

PMID: 34196464

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Project description:BackgroundObservational studies have suggested that women's reproductive factors (age at menarche (AAM), age at first birth (AFB), age at first sexual intercourse (AFS), age at natural menopause (ANM), and pregnancy loss) may influence the risk of cerebral small-vessel disease (CSVD) although the causality remains unclear.MethodsWe conducted two-sample univariable Mendelian randomization (UVMR) and multivariable MR (MVMR) to simultaneously investigate the causal relationships between five women's reproductive traits and CSVD clinical [intracerebral hemorrhage (ICH) by location or small-vessel ischemic stroke (SVS)] and subclinical measures [white matter hyperintensities (WMH), fractional anisotropy (FA), and mean diffusivity (MD)], utilizing data from large-scale genome-wide association studies of European ancestry. For both UVMR and MVMR, the inverse-variance-weighted (IVW) estimates were reported as the main results. The MR-Egger, weighted median, generalized summary-data-based MR (GSMR), and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods for UVMR and MVMR-Egger, and the MVMR-robust methods for MVMR were used as sensitivity analyses. Sex-combined instruments for AFS and AFB were used to assess the impact of sex instrumental heterogeneity. Positive control analysis was implemented to measure the efficacy of selected genetic instruments.ResultsWe found no evidence to support causal associations between genetic liability for women's reproductive factors and the risk of CSVD in UVMR (all P-values > 0.05). Using MVMR, the results were consistent with the findings of UVMR after accounting for body mass index and educational attainment (all P-values > 0.05). Sensitivity analyses also provided consistent results. The putative positive causality was observed between AAM, ANM, and ovarian cancer, ensuring the efficacy of selected genetic instruments.ConclusionOur findings do not convincingly support a causal effect of women's reproductive factors on CSVD. Future studies are warranted to investigate specific estrogen-related physiological changes in women, which may inform current researchers on the causal mechanisms involved in cerebral small-vessel disease progression.

Project description:ObjectiveThis study aimed to investigate the relationships of heart rate variability (HRV) with the presence, severity, and individual neuroimaging markers of cerebral small vessel disease (CSVD).MethodA total of 4676 participants from the Third China National Stroke Registry (CNSR-III) study were included in this cross-sectional analysis. CSVD and its markers, including white matter hyperintensity (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMBs), and brain atrophy (BA), were evaluated. Two common HRV parameters, including the square root of the mean of the sum of the squares of differences between adjacent N-N intervals (RMSSD) and the standard deviation of all N-N intervals (SDNN), were used to evaluate the function of the autonomic nervous system (ANS). Binary or ordinal logistic regression analyses were performed to investigate the association between HRV and CSVD. In addition, two-sample mendelian randomization (MR) analyses were performed to investigate the causality of HRV with CSVD.ResultsRMSSD was significantly associated with total burden of CSVD (Wardlaw's scale, common odds ratio [cOR] 0.80, 95% confidence interval [CI] 0.67-0.96, p = 0.02; Rothwell's scale, cOR 0.75, 95% CI 0.60-0.93, p = 0.008) and the presence of CSVD (Rothwell, OR 0.75, 95% CI 0.60-0.93, p = 0.008). However, no significant associations between SDNN and the presence or total burden of CSVD were observed. Moreover, RMSSD was related to WMH burden (OR 0.80, 95% CI 0.66-0.96, p = 0.02), modified WMH burden (cOR 0.82, 95% CI 0.69-0.97, p = 0.02), and Deep-WMH (OR 0.75, 95% CI 0.62-0.91, p = 0.003), while SDNN was related to Deep-WMH (OR 0.80, 95% CI 0.66-0.96, p = 0.02) and BA (cOR 0.80, 95% CI 0.68-0.95, p = 0.009). Furthermore, adding HRV to the conventional model based on vascualr risk factors enhanced the predictive performance for CSVD, as validated by the integrated discrimination index (p < 0.05). In addition, no causality between HRV and CSVD was observed in two-sample MR analyses.ConclusionDecreased HRV may be a potential risk factor of CSVD, implying the possible role of the ANS in the pathogenesis of CSVD.

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A two-sample Mendelian randomization analysis of heart rate variability and cerebral small vessel disease.

Publications

A two-sample Mendelian randomization analysis of heart rate variability and cerebral small vessel disease.

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