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pulse pressure
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received October 29, 2012; first decision February 28, 2013; revision accepted March 3, 2013.
From the Departments of Epidemiology (B.F.J.V., M.W.V., A.H., M.A.I.), Radiology (B.F.J.V., M.W.V., R.d.B., W.J.N., A.v.de.L., M.A.I.), and Medical
Informatics (R.d.B., W.J.N.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; and Faculty of Applied Sciences, University of
Technology, Delft, The Netherlands (W.J.N.).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
111.00430/-/DC1.
Correspondence to M. Arfan Ikram, Department of Epidemiology, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The
Netherlands. E-mail m.a.ikram@erasmusmc.nl
2013 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.111.00430
Methods
2005-2006
Visit 2. N=865
- Random subset of full cohort
- Dementia-free
- Stroke-free
- No MRI contraindication
2008-2010
Visit 3. N=731
MRI-scan 2
BP measurement 2 and
MRI-scan 1
Statistical Analyses
We investigated how systolic blood pressure, diastolic blood pressure,
and pulse pressure were related to WML volume cross-sectionally
and annual WML progression longitudinally, using linear regression
models, adjusted for age, sex, and intracranial volume in model I, and
additionally for cardiovascular risk factors (antihypertensive medication, total cholesterol, high-density lipoprotein cholesterol, triglycerides, body mass index, alcohol consumption, smoking, and diabetes
mellitus) in model II. For the analyses regarding WML progression,
we also applied a model III with adjustments for baseline WML
volume, to assess whether possible associations were explained by
WML accumulated before the first scan.
Additionally, the following exploratory analyses were conducted.
We evaluated additional adjustments for cardiovascular disease and
ApoE-4 carriership and tested for interaction of ApoE-4 carriership
with systolic blood pressure, diastolic blood pressure, or pulse pressure. In addition, we adjusted pulse pressure for the presence of hypertension to see whether pulse pressure had additional value beyond
hypertension. We evaluated the addition of quadratic terms of systolic
blood pressure, diastolic blood pressure, and pulse pressure to explore whether J-shaped relationships were present. We repeated all
analyses with waist/hip ratio as covariate instead of body mass index.
Finally, we evaluated the relationship between hypertension
treatment and WML progression by constructing 4 mutually
exclusive groups of people: normotensives, controlled treated
hypertensives, uncontrolled treated hypertensives, and uncontrolled
untreated hypertensives. These 4 groups were defined as follows
based on the mean blood pressure of visits 1 and 2, and the use
1356HypertensionJune 2013
Table 1. Characteristics of the Study Population
Variable
Results
P Value for
Difference
Visit 1
Visit 2
Visit 3
Age, y
61.6 (5.0)
66.9 (5.0)
70.4 (5.0)
NA
Female
52%
52%
NA
52%
Systolic blood
pressure, mmHg
138 (19)
143 (18)
<0.01
Diastolic blood
pressure, mmHg
78 (10)
81 (10)
<0.01
60 (14)
62 (15)
<0.01
Anithypertensive
medication
22%
34%
<0.01
Total cholesterol,
mmol/L
5.84 (0.95)
5.73 (0.93)
<0.01
High-density
lipoprotein, mmol/L
1.39 (0.37)
1.44 (0.38)
<0.01
Triglycerides, mmol/L
1.33 [0.80]
NA
26.8 (3.5)
27.5 (3.6)
<0.01
Alcohol, units/wk
6 [14]
NA
Current smoker
16%
11%
<0.01
Diabetes mellitus*
8%
9%
<0.01
Cardiovascular disease
6%
7%
0.03
Model I*
Model II
Model III
Systolic blood
pressure
Diastolic blood
pressure
Pulse pressure
Values are white matter lesion progression in mL/y (95% CI) per SD increase
of blood pressure (mean of the measures at visit 1 and 2), derived from
linear regression models. CI indicates confidence interval; HDL, high-density
lipoprotein; and WML, white matter lesion.
*Model I: adjustments for age, sex, and intracranial volume.
Model II: adjustments for age, sex, intracranial volume, antihypertensive
medication, total cholesterol, HDL-cholesterol, triglycerides, body mass index,
alcohol consumption, smoking, and diabetes mellitus.
Model III: as model II, but additional adjustment for WML volume on scan 1.
Discussion
In this longitudinal MRI study, we found that high systolic blood pressure and high diastolic blood pressure were
WML
Baseline WML volume progression
2
0
1.00 mL
1.04 mL
1.39 mL
1.59 mL
2
4
6
8
Persistent
normotensives
Controlled
Uncontrolled
treated
treated
hypertensives hypertensives
Uncontrolled
untreated
hypertensives
1358HypertensionJune 2013
we found that hypertension treatment is associated with less
WML progression. Our study therefore further establishes
high blood pressure as a strong risk factor for WMLs and
implies that treatment of hypertension could lead to less
WML progression in the general population. Further studies
are needed to assess whether preventing WML development is
also relevant to prevent cognitive decline and clinical disease.
Perspectives
The results of our study suggest that antihypertensive treatment would be beneficial in preventing WML progression in
the general population. To further elucidate the relationship
between blood pressure and WML, additional studies with >2
longitudinal measures of blood pressure and WMLs are desirable. Examination of interactions between blood pressure and
other risk factors could possibly detect deleterious risk profiles.
Including change in cognition as an outcome measure could
throw light on the clinical implications of change in blood
pressure and WML volume. Still, clinical trials are the best
way to establish that blood pressure control is beneficial in the
slowing or prevention of WML progression.
Sources of Funding
This study was funded by Erasmus MC, University Medical Center
Rotterdam, and Erasmus University Rotterdam; The Netherlands
Organisation of Scientific Research (NWO); The Netherlands
Organisation for Health Research and Development (ZonMw); The
Research Institute for Diseases in the Elderly; the Ministry of Education,
Culture, and Science; the Ministry of Health, Welfare, and Sports; the
European Commission (DG-XII); and the Municipality of Rotterdam.
Grants: NWO 918-46-615, 948-00-010 and 916.13.054, Alzheimers
Association New Investigator Research Grant-09-13168, and Medische
Research Advies Commissie grant from the Erasmus MC. Drs Ikram
and Verhaaren received funding from the Dutch Heart Foundation
(Nederlandse Hartstichting), grant 2009B102.
Disclosures
None.
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Summary
Our study provides strong and much needed confirmatory evidence that
high blood pressure is a risk factor for progression of cerebral white matter lesion in the aging general population.
What Is Relevant?
Our study further adds to the evidence, suggesting that treatment of hypertension may decrease the risk of white matter lesions.
SUPPLEMENTARY TABLE
Table S1. Blood pressure and cross-sectional WML volume
Variable
Scan 1
Scan 2
Pulse pressure