Visit-to-visit Blood Pressure Variability and Cerebral White Matter Lesion Progression: A Pooled Individual Patient Data Analysis of 2 Trial

Background and objectives: Visit-to-visit blood pressure variability (BPV) may contribute to cerebral white matter lesions (WML) progression, but previous evidence has been inconsistent and limited by methodological heterogeneity. This study aimed to assess the association between BPV and WML progression and its mediating role in the neuroprotective effects of intensive blood pressure (BP) control. Methods: This post hoc individual participant data pooled analysis included the MRI substudies of ACCORD MIND and SPRINT MIND. Participants were eligible if they had both baseline and fo low-up MRI scans and at least three BP measurements from the 3-month visit onwards. Systolic BPV was calculated using multiple indices, with variation independent of mean (VIM) prespecified as the primary metric. WML progression was quantified as absolute and annualized changes in abnormal white matter (AWM) volume, with inverse hyperbolic sine (asinh)-transformed total change as the primary metric. Associations between systolic BPV and AWM volume changes were examined using multivariable linear regression, and causal mediation analysis assessed whether systolic BPV mediated the effects of intensive BP control. Results: A total of 952 participants (mean age 64.8 years SD 7.1; 400 42% women) were included, contributing a median of 12 (IQR 10-14) BP measurements. Median AWM volume increased from 1.69 mL to 2.58 mL (0.43 mL per year SD 0.84). Higher systolic BPV was independently associated with faster AWM volume progression (β=0.017, 95% CI 0.001 to 0.033). In raw annualized terms, participants in the highest tertile of SBP-VIM had 0.160 mL/year faster AWM progression than those in the lowest tertile. Intensive BP control was associated with slower AWM volume progression (β= 0.270, 95% CI -0.393 to -0.146). Mediation analysis indicated that systolic BPV partia ly mediated the association between intensive BP control and reduced AWM volume progression (average causal mediation effect 0.014, 95% CI 0.001 to 0.034), accounting for 9.15% of the total effect. Discussion: Higher visit-to-visit systolic BPV was independently associated with faster WML progression. The benefit of intensive BP lowering on white matter integrity was partly mediated by reduced BPV, suggesting BP stability as a modifiable target to prevent white matter injury.