Abstract

Hypertension is the leading risk factor for stroke. Yet, it remains unknown whether blood pressure pulsatility (pulse pressure [PP]) causally affects stroke risk independently of the steady pressure component (mean arterial pressure [MAP]). It is further unknown how the effects of MAP and PP on stroke risk vary with age and stroke cause. Using data from UK Biobank (N=408 228; 38-71 years), we selected genetic variants as instruments for MAP and PP at age ≤55 and >55 years and across age deciles. We applied multivariable Mendelian randomization analyses to explore associations with ischemic stroke, intracerebral hemorrhage, and their subtypes. Higher genetically predicted MAP was associated with higher risk of ischemic stroke and intracerebral hemorrhage across the examined age spectrum. Independent of MAP, higher genetically predicted PP only at age >55 years was further associated with higher risk of ischemic stroke (odds ratio per-SD-increment, 1.23 [95% CI, 1.13-1.34]). Among subtypes, the effect of genetically predicted MAP on large artery stroke was attenuated, whereas the effect of genetically predicted PP was augmented with increasing age. Genetically predicted MAP, but not PP, was associated with small vessel stroke and deep intracerebral hemorrhage homogeneously across age deciles. Neither genetically predicted MAP nor PP were associated with lobar intracerebral hemorrhage. Beyond an effect of high MAP at any age on ischemic and hemorrhagic stroke, our results support an independent causal effect of high PP at older ages on large artery stroke. This finding warrants further investigation for the development of stroke preventive strategies targeting pulsatility in later life.