Findings seen with blood pressure increases or decreases

Small vessel disease (SVD), lower whole brain volumes, and worse white matter integrity were more common when blood pressure variation was high regardless of the direction of change from mean blood pressure values, analysis of data from the Rotterdam prospective cohort study found.

Large variation in systolic blood pressure (SBP; defined as >3.3% per year) was associated with higher odds of having multiple markers of SVD in adjusted analysis:

  • Severe white matter hyperintensities (WMH; OR 1.32, 95% CI 1.21-1.43).
  • Progression of WMH (rate ratio 1.14, 95% CI 1.02-1.27).
  • Lacunes (OR 1.25, 95% CI 1.04-1.48).
  • Microbleeds (OR 1.16, 95% CI 1.03-1.31).

Those in the large variation group also had a 30% higher chance of reaching a composite outcome of any WMH, lacune, or microbleeds (OR 1.30, 95% CI 1.18-1.45).

A higher burden of these findings was seen with large variation whether SBP rose or fell, and similar findings were seen with diastolic blood pressure (DBP) variation.

“Elevated blood pressure variation was associated with a wide range of subclinical brain structural changes, including MRI markers of cerebral small vessel disease, smaller brain tissue volumes, and worse white matter microstructural integrity,” wrote Yuan Ma, MD, PhD, of Harvard University and coauthors in Journal of the American College of Cardiology. “These subclinical brain changes could be the underlying mechanisms linking BP variation to dementia and stroke.”

In an accompanying editorial, Costantino Iadecola, MD, and Neal Parikh, MD, MS, both of Weill Cornell Medicine in New York City, wrote: “These data suggest that the magnitude of long-term BP variation is independently associated with SVD and its progression over time, regardless of the direction of BP change and even after adjusting for mean blood pressure.”

Alternative explanations should also be considered, they added, noting that “in addition to the possibility that BP variability is a result of SVD induced damage to central autonomic pathways (reverse causation), unmeasured confounders, such as medication nonadherence, alcohol overuse, and obstructive sleep apnea, might account for observed associations between BP variability and SVD.”

Extant and progressing but subclinical vascular brain disease has received increasing attention as a common ground for acute events like stroke as well as neurodegenerative disease like Alzheimer’s dementia, and vascular risk factors, including chronic hypertension, increase the risk for Alzheimer’s disease.

A link between chronic BP elevation and neurodegeneration is suspected through SVD, with characteristic MRI findings including lacunes, cerebral microbleeds, and progressive WMH. Chronic hypertension leads to dysfunction of endothelial cells, the blood brain barrier, and cerebral autoregulation along with vascular stiffening. These changes also expose the brain to increased BP variability compared with a functional, flexible system that normally minimizes the variation in pressures experienced by brain tissue. Recurrent mechanical stress in vascular structures changes oxidative stress, nitric oxide availability, and remodeling in ways that may in turn link BP variability to small vessel disease, though the picture is not as clear as for chronic hypertension.

To further explore the connection between blood pressure variation and subclinical brain disease, Ma and colleagues turned to the Rotterdam Study, a prospective, population-based cohort study begun in 1990 to study disease determinants. The study enrolled >11,000 participants age 55 and over with followup every 3-4 years, including blood pressure measurements and, since 2005, one or optionally more brain MRIs (completed in about 77% of participants by September 2015). The authors included 2,348 participants with no history of dementia or stroke; of those, 1,109 participants had two or more MRIs and were assessed for progression.

BP was measured after 5 minutes of seated rest. Variation of both systolic and diastolic pressures was calculated as absolute BP difference divided by the mean from 2 sequential visits, then expressed as percentage change. BP variation was interpreted in three tertiles as low (<1.4%/year; this tertile was used as the reference group for the other two), moderate (1.4%-3.3%/year), or high (>3.3%/year).

Available MRI data was used to identify WMH burden, lacunes, cerebral microbleeds, and brain tissue volumes; white matter integrity was evaluated with fractional anisotropy and diffusivity sequences.

Mean age was 61 years, and 56% were women, with hypertension prevalence of 45%. Systolic BP, measured every 3 to 4 years, varied by 2.2% per year on average, and the median time from BP variation assessment to first MRI was 7 years.

Volume data showed an association of high SBP variability with smaller total brain, white matter, gray matter, and hippocampal volumes (all P for trend <0.05), as well as worse white matter microstructural integrity reflected in lower global fractional anisotropy and higher mean diffusivity.

Adjusted analysis included antihypertensive medication, age, sex, baseline hypertension, and length of followup. With sensitivity analysis adjusted for mean BP level (the reference for fluctuation direction), these secondary analyses did not alter the conclusions.

“Although efforts to mitigate SVD and dementia in hypertensive individuals should undoubtedly focus on lowering BP, the current report by Ma et al., together with a growing body of literature, support the need for randomized trials to determine whether reducing BP variability adds value above and beyond the benefits of BP normalization,” the editorialists concluded.

Limitations include BP variation assessed over two visits with no statistical modeling, which risked measurement error. Also, those with two or more MRIs, in whom progression analysis was done, may have differed from those with one scan.

  1. Small vessel disease, lower whole brain volumes, and worse white matter integrity were more common when blood pressure variation was high regardless of the direction of change from mean blood pressure values, analysis of data from the Rotterdam prospective cohort study found.

  2. A higher burden of these findings was seen with large variation whether systolic blood pressure rose or fell, and similar findings were seen with diastolic blood pressure variation.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. This work was partially supported by an unrestricted grant from the Janssen Prevention Center.

The researchers reported no relevant relationships.

Iadecola is a member of the Scientific Advisory Board for Broadview Ventures. Parikh reported no relevant relationships.

Cat ID: 130

Topic ID: 82,130,730,102,6,130,192,916,925