Blood Pressure Variability and Cerebral Perfusion Decline: A Post Hoc Analysis of the SPRINT MIND Trial

Abstract

Background Blood pressure variability (BPV) is predictive of cerebrovascular disease and dementia, possibly though cerebral hypoperfusion. Higher BPV is associated with cerebral blood flow (CBF) decline in observational cohorts, but relationships in samples with strictly controlled blood pressure remain understudied. We investigated whether BPV relates to change in CBF in the context of intensive versus standard antihypertensive treatment. Methods and Results In this post hoc analysis of the SPRINT MIND (Systolic Blood Pressure Intervention Trial–Memory and Cognition in Decreased Hypertension) trial, 289 participants (mean, 67.6 [7.6 SD] years, 38.8% women) underwent 4 blood pressure measurements over a 9‐month period after treatment randomization (intensive versus standard) and pseudo‐continuous arterial spin labeling magnetic resonance imaging at baseline and ≈4‐year follow‐up. BPV was calculated as tertiles of variability independent of mean. CBF was determined for whole brain, gray matter, white matter, hippocampus, parahippocampal gyrus, and entorhinal cortex. Linear mixed models examined relationships between BPV and change in CBF under intensive versus standard antihypertensive treatment. Higher BPV in the standard treatment group was associated with CBF decline in all regions (ß comparing the first versus third tertiles of BPV in whole brain: −0.09 [95% CI, −0.17 to −0.01]; P =0.03), especially in medial temporal regions. In the intensive treatment group, elevated BPV was related to CBF decline only in the hippocampus (ß, −0.10 [95% CI, −0.18, −0.01]; P =0.03). Conclusions Elevated BPV is associated with CBF decline, especially under standard blood pressure–lowering strategies. Relationships were particularly robust in medial temporal regions, consistent with prior work using observational cohorts. Findings highlight the possibility that BPV remains a risk for CBF decline even in individuals with strictly controlled mean blood pressure levels. Registration URL: http://clinicaltrials.gov . Identifier: NCT01206062.

Blood pressure variability, central autonomic network dysfunction and cerebral small vessel disease in APOE4 carriers

“…There are also open questions regarding the causal directionality of BPV-associated risk for cerebrovascular disease. Many have hypothesized that BPV elevation is a modifiable risk factor that is causally linked to vascular brain injury since increased BPV precedes and predicts future longitudinal decline in medial temporal cerebral blood flow (18), accelerated neurodegeneration (4,15,16) and decline in cognitive ability (19,20). However, causal directionality has been questioned by some (21) since BPV is partly determined by the baroreflex (22), and both neurodegeneration and white matter damage due to CSVD may be associated with autonomic dysfunction (23).…”

The interactive effect of intra-beat and inter-beat blood pressure variability on neurodegeneration in older adults

“…The mechanisms underlying the adverse independent effects of increased inter-beat BPV on cerebrovascular and neurodegenerative disease remain unclear, but may be related to the ability of the cerebrovasculature to adapt to chronic fluctuations in pressure and flow while sustaining cerebral perfusion 21 , blood-brain barrier integrity 22 and clearance of brain waste products 23 .…”

“…Thus, higher inter-beat BPV in the presence of arterial stiffness may promote transmission of even greater blood pressure fluctuations, both within (intra-beat) and between (inter-beat) cardiac cycles. The transmission of these fluctuating pressure waves deep into the brain could promote brain injury and neurodegeneration by interfering with cerebral perfusion 21 , blood brain barrier integrity 22 , and waste clearance 23,38 mechanisms ( Figure 2 ).…”

“…Thus, higher inter-beat BPV in the presence of arterial stiffness may promote transmission of even greater blood pressure fluctuations, both within (intra-beat) and between (inter-beat) cardiac cycles. The transmission of these fluctuating pressure waves deep into the brain could promote brain injury and neurodegeneration by interfering with cerebral perfusion 21 , blood brain barrier integrity 22 , and waste clearance 23,38 mechanisms (Figure 2). To our knowledge, no studies to date have addressed the potential interaction between inter-beat BPV (ARV) and intra-beat BPV (ASI) relating to neurodegeneration markers on MRI (e.g., MTL atrophy) and in plasma [e.g., neurofilament light (NfL) 39 and glial fibrillary acidic protein (GFAP)] 40 .…”

“…Prior studies have variously quantified ARV and arterial stiffness and identified them separately as risk factors for age-related cognitive decline 14,15 , dementia risk 16,17 , and cerebral small vessel disease 18–20 . The mechanisms underlying the adverse independent effects of increased inter-beat BPV on cerebrovascular and neurodegenerative disease remain unclear, but may be related to the ability of the cerebrovasculature to adapt to chronic fluctuations in pressure and flow while sustaining cerebral perfusion 21 , blood-brain barrier integrity 22 and clearance of brain waste products 23 .…”