White matter hyperintensities are independently associated with systemic vascular aging and cerebrovascular dysfunction

Background: In the Oxford Haemodynamic Adaptation to Reduce Pulsatility trial (OxHARP), sildenafil increased cerebrovascular reactivity but did not reduce cerebral pulsatility, a marker of vascular aging. This analysis of OxHARP tested whether these potentially causative mechanisms were independently associated with the severity of white matter hyperintensities (WMHs). Aims: The aims were to determine independence of the relationship between severity of WMHs with both cerebral pulsatility and cerebrovascular reactivity in the same population. Methods: OxHARP was a double-blind, randomized, placebo-controlled, crossover trial of phosphodiesterase inhibitors in patients with mild-to-moderate WMH and previous minor cerebrovascular events. It determined effects on cerebrovascular pulsatility and reactivity on transcranial ultrasound and reactivity on magnetic resonance imaging (MRI). Associations were determined between baseline ultrasound measures, and averaged MRI measures across follow-up, with the severity of WMH on clinical imaging (Fazekas or modified Blennow scores) and WMH volume in the MRI substudy, by ordinal and linear regression. Results: In 75/75 patients (median 70 years, 78% male), cerebral pulsatility was associated with age (p < 0.001) whereas reactivity on ultrasound was not (p = 0.29). Severity of WMH in all participants was independently associated with decreased cerebrovascular reactivity and increased cerebral pulsatility (pulsatility p = 0.016; reactivity p = 0.03), with a trend to a synergistic interaction (p = 0.075). Reactivity on ultrasound was still associated with WMH after further adjustment for age (p = 0.017), but pulsatility was not (p = 0.31). Volume of WMH in the MRI substudy was also independently associated with both markers on ultrasound (pulsatility p = 0.005; reactivity p = 0.029) and was associated with reduced cerebrovascular reactivity within WMH on MRI (p < 0.0001). Conclusion: WMHs are independently associated with cerebral pulsatility and reactivity, representing complementary potential disease mechanisms and treatment targets. Trial Registration: clinicaltrials.org: https://classic.clinicaltrials.gov/ct2/show/NCT03855332 .