Implication of heart rate variability on cerebral small vessel disease: A potential therapeutic target

Objective: This 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). Method: A 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. Results: RMSSD 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. Conclusion: Decreased HRV may be a potential risk factor of CSVD, implying the possible role of the ANS in the pathogenesis of CSVD.