Arterial Stiffness and Cerebral Small Vessel Disease
The Rotterdam Scan Study
Mariëlle M.F. Poels, MD, PhD*; Kèren Zaccai, MSc*; Germaine C. Verwoert, MSc;
Meike W. Vernooij, MD, PhD; Albert Hofman, MD, PhD; Aad van der Lugt, MD, PhD;
Jacqueline C.M. Witteman, PhD; Monique, M.B. Breteler, MD, PhD;
Francesco U.S. Mattace-Raso, MD, PhD; M. Arfan Ikram, MD, PhD
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Background and Purpose—Aging and vascular risk factors contribute to arterial stiffening. Increased arterial stiffness
exposes the small vessels in the brain to abnormal flow pulsations and, as such, may contribute to the pathogenesis of
cerebral small vessel disease. In a population-based study, we investigated the association between arterial stiffness, as
measured by aortic pulse wave velocity (aPWV), and small vessel disease.
Methods—Overall, 1460 participants (mean age, 58.2 years) underwent aPWV measurement and brain MRI scanning. We
calculated aPWV by measuring time differences and distances between pulse waves in the carotid and femoral arteries.
Using automated MRI analysis, we obtained white matter lesion volumes. Infarcts and microbleeds were rated visually.
We used linear and logistic regression models to associate aPWV with small vessel disease, adjusting for age, sex, mean
arterial pressure, and heart rate and additionally for cardiovascular risk factors. Subsequently, we explored associations
in strata of hypertension.
Results—In the study group, higher aPWV was associated with larger white matter lesion volume (difference in volume
per SD increase in aPWV 0.07; 95% CI, 0.02– 0.12) but not with lacunar infarcts or microbleeds. In persons with
uncontrolled hypertension, higher aPWV was significantly associated with larger white matter lesion volume (difference
in volume per SD increase in aPWV 0.09; 95% CI, 0.00 – 0.18), deep or infratentorial microbleeds (OR, 2.13; 95% CI,
1.16 –3.91), and to a lesser extent also with lacunar infarcts (OR, 1.63; 95% CI, 0.98 –2.70). No such associations were
present in persons with controlled hypertension or without hypertension.
Conclusions—In our study, increased arterial stiffness is associated with a larger volume of white matter lesions. (Stroke.
2012;43:2637-2642.)
Key Words: arterial stiffness 䡲 epidemiology 䡲 pulse wave velocity 䡲 small vessel disease 䡲 vascular aging
A
ging, hypertension, and other cardiovascular risk factors
contribute to structural and functional changes of the
arterial wall.1,2 These changes result in decreased elasticity
and increased stiffness of the arteries. Arterial stiffness, as
measured by pulse wave velocity, has been associated with
increased risk of cardiovascular disease including clinical
stroke.3,4 It has further been suggested that arterial stiffening
exposes the small vessels in the brain to highly pulsatile
pressure and flow and, as such, may contribute to the
pathogenesis of cerebral small vessel disease.5 Several studies
have indeed shown an association between arterial stiffness
and subclinical cerebral small vessel disease, visualized on
MRI as white matter lesions (WMLs), lacunar infarcts, or
cerebral microbleeds (CMBs).6 –15 Some previous studies
furthermore suggested that arterial stiffness may be influenced differentially by blood pressure with the strongest
effects in subjects with hypertension.1,16 Most of the aforementioned studies, however, used proxy markers for arterial
stiffness, including the brachial–ankle pulse wave velocity
and arterial pulse waves,8,9,11–13 or were performed in selected
populations with high cardiovascular risk.6,7,10,14,15 Carotid–
femoral pulse wave velocity is considered as the “gold
standard” measurement of arterial stiffness and allows direct
investigation of the association between arterial stiffness and
small vessel disease.17
We investigated in the large population-based Rotterdam
Scan Study whether arterial stiffness, as measured by carotid–
femoral pulse wave velocity, was related to the presence of
Received October 18, 2011; final revision received July 1, 2012; accepted July 3, 2012.
From the Departments of Epidemiology (M.M.F.P., K.Z., G.C.V., M.W.V., A.H., J.C.M.W., M.M.B.B., F.U.S.M.-R., M.A.I.), Radiology (M.M.F.P.,
M.W.V., A.v.d.L., M.A.I.), and Internal Medicine (G.C.V., F.U.S.M.-R.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; and
DZNE, German Center for Neurodegenerative Diseases (M.M.B.B.), Bonn, Germany.
*Dr Poels and K. Zaccai, MSc contributed equally to this work.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.
642264/-/DC1.
Correspondence to M. Arfan Ikram, MD, PhD, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The
Netherlands. E-mail [email protected]
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.111.642264
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cerebral small vessel disease, that is, WML, lacunar infarcts,
and CMBs, and explored these associations in strata of
hypertension.
Methods
Study Population
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This study is embedded within the Rotterdam Study, a large
population-based cohort study in The Netherlands that started in
1990 and aims to investigate determinants of various chronic
diseases among elderly participants.18 The present study is based on
Rotterdam Study III, the second expansion of the Rotterdam Study.
In total, Rotterdam Study III comprised 3932 persons (ⱖ45 years of
age) of whom 1833 participants had arterial stiffness measurements
available. Missing information on arterial stiffness measurement was
almost entirely due to logistic reasons, in particular malfunctioning
equipment or unavailability of technicians. We excluded individuals
who were demented (n⫽7) or had MRI contraindications (including
claustrophobia, n⫽105). Consequently, 1644 persons were eligible
for brain MRI, of whom 1470 (89%) participated. Due to physical
inabilities (eg, back pain), imaging could not be performed or
completed in 10 individuals, yielding 1460 persons for the analyses.
The Medical Ethics Committee of Erasmus Medical Center approved
the study, and written informed consent was obtained from all
participants.
Measurement of Arterial Stiffness
Carotid–femoral pulse wave velocity (aPWV), a measure of arterial
stiffness, was measured with the subjects in the supine position.
After 5 minutes of rest, blood pressure was measured twice using an
automatic blood pressure recorder (Omron). Subsequently, aPWV
was measured. The time delay between the feet of simultaneously
recorded pulse waves in the carotid artery and the femoral artery was
measured using an automatic device (Complior Artech Medicla,
Pantin, France). The distance traveled by the pulse wave was
measured between the sternal notch and the femoral artery using a
tape measure. aPWV was calculated as the ratio of the distance
traveled by the pulse wave and the foot-to-foot time delay and was
expressed in meters per second. The average of 10 successive
measurements, to cover a complete respiratory cycle, was used in the
analyses.
Brain MRI
Brain MRI was performed on a 1.5-T scanner (GE Healthcare,
Milwaukee, WI) with an 8-channel head coil and included T1weighted, proton-density weighted, fluid-attenuated inversion recovery, and T2*-weighted gradient echo sequences.19
WML volume was quantified with a validated tissue classification
technique and was calculated by summing all voxels of the WML
class across the whole brain.20
Rating of CMBs and infarcts was performed according to a
previously described protocol.21 Infarcts were divided into cortical or
lacunar. CMBs were categorized into one of 3 locations: lobar, deep,
or infratentorial.21 We made separate categories of persons who had
one or more microbleeds restricted to a lobar location (strictly lobar
microbleeds) and persons with microbleeds in a deep or infratentorial
location with or without one or more lobar microbleeds (deep or
infratentorial microbleeds).21
Cardiovascular Risk Factors
Based on previous literature,6 –15 we considered the following cardiovascular risk factors as covariates in the models. Information on
medical history, smoking habits, and medication use was obtained
during the home interview. Smoking status was divided into 3
categories: current, former, and never smokers. The waist and hip
circumference were measured, and the waist– hip ratio was computed
(waist circumference divided by the hip circumference in centimeters). Blood pressure measurements were obtained as described
previously. Pulse pressure was defined as the difference between
systolic and diastolic blood pressure. We calculated mean arterial
pressure as diastolic blood pressure plus one third of the pulse
pressure. Diabetes mellitus was defined as a history of diabetes
mellitus and/or the use of blood glucose-lowering medication and/or
a fasting serum glucose level ⱖ7.0 mmol/L. Serum total cholesterol
and high-density lipoprotein cholesterol values were determined by
an automated enzymatic procedure (Boehringer Mannheim System).
Statistical Analysis
We investigated the association of aPWV per SD increase with
WML volume using linear regression models. WML volumes were
natural log transformed because of skewness of the untransformed
measure. Logistic regression models were used for the association of
aPWV per SD increase with lacunar infarcts, deep or infratentorial
microbleeds, and strictly lobar microbleeds.
All analyses were initially adjusted for age, sex, mean arterial
pressure, and heart rate and additionally for blood pressure-lowering
medication, diabetes mellitus, body mass index, current smoking
status, total cholesterol, high-density lipoprotein cholesterol, and
lipid-lowering medication. Analyses regarding WML volumes were
additionally adjusted for intracranial volume to correct for differences in individual head size.
In line with previous studies suggesting differential effects of
arterial stiffness according to blood pressure,1,16 we defined 3
categories of hypertension: (1) no hypertension (systolic blood
pressure ⬍140 mm Hg and a diastolic blood pressure ⬍90 mm Hg
without use of antihypertensive medication); (2) controlled hypertension (systolic blood pressure ⬍140 mm Hg and a diastolic blood
pressure ⬍90 mm Hg with use of antihypertensive medication); and
(3) uncontrolled hypertension (systolic blood pressure ⱖ140 mm Hg
or a diastolic blood pressure ⱖ90 mm Hg with or without use of
antihypertensive medication) and repeated the analyses stratified for
these categories.22
To create a more robust measure of cerebral small vessel disease,
we combined different markers of arteriolosclerotic small vessel
disease into one variable. Because it was previously shown that
CMBs in deep or infratentorial brain regions are indicative of
hypertensive or arteriolosclerotic vasculopathy,21,23 we included
microbleeds in these locations in this combined variable along with
the highest quartile of WML volume and presence of lacunar
infarcts. In the analysis using this combined variable as the outcome,
persons in the lowest quartile of arterial stiffness (indicating best
state of the arteries) were taken as the reference category.
We added interaction terms to the models to test differences
between categories of hypertension (aPWV⫻[un]controlled hypertension) regarding the association of arterial stiffness with small
vessel disease.
Previous studies have described an association between arterial
stiffness and large artery disease.3 Therefore, we performed additional analyses excluding persons with cortical infarcts (n⫽44) to
rule out that associations in our study are driven by cortical infarcts.
All analyses were performed using the statistical package SPSS
17.0 (SPSS Inc, Chicago, IL).
Results
Table 1 presents the characteristics of the study population.
Mean age of the study population was 58.2 years, and 809
(55%) were women. Carotid–femoral pulse wave velocity
increased with age (difference in aPWV per year increase in
age, 0.11; 95% CI, 0.10 – 0.12). Table 2 shows the association
between aPWV per SD increase and markers of cerebral
small vessel disease. Persons with higher aPWV had a larger
volume of WML (difference in WML volume per SD
increase in aPWV, 0.07; 95% CI, 0.02– 0.12) independent of
age, sex, mean arterial pressure, heart rate, intracranial
volume, and other vascular risk factors. No significant associations were found between aPWV and lacunar infarcts or
microbleeds (Table 2).
Poels et al
Table 1. Baseline Characteristics of the Study
Population (Nⴝ1460)
Age, y
58.2 (SD 7.2)
Women
809 (55.4%)
Aortic pulse wave velocity, m/s
9.0 (SD 1.6)
Mean arterial pressure, mm Hg
96.5 (SD 11.7)
Heart rate, beats/min
64.5 (SD 13.5)
Systolic blood pressure, mm Hg
130.0 (SD 17.6)
Diastolic blood pressure, mm Hg
79.8 (SD 9.7)
Blood pressure-lowering medication
1005 (69.3%)
Waist–hip ratio
0.86 (SD 0.09)
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Diabetes
111 (7.8%)
Serum total cholesterol, mmol/L
5.52 (SD 1.04)
Serum HDL cholesterol, mmol/L
1.43 (SD 0.42)
Lipid-lowering medication
320 (22.2%)
White matter lesions on MRI, mL, median
(interquartile range)
2.2 (1.4–3.8)
63 (4.3%)
Strictly lobar cerebral microbleeds on MRI
147 (10.1%)
Deep or infratentorial microbleeds on MRI
48 (3.3%)
Values are means with SD or numbers with percentages, unless specified
otherwise. Data are missing for smoking (n⫽10), waist– hip ratio (n⫽32),
diabetes (n⫽32), serum cholesterol (n⫽23), medication use (n⫽17), cerebral
microbleeds (n⫽6), lacunar infarcts (n⫽6), and white matter lesions (n⫽34).
HDL indicates high-density lipoprotein.
Studying the population in strata of hypertension, as shown
in Table 3, revealed that in persons with uncontrolled hypertension, high aPWV was associated both with larger WML
volume and with CMBs in deep or infratentorial locations.
Furthermore, although not significant, these persons also
tended to have a higher prevalence of lacunar infarcts when
arterial stiffness values were higher (OR per SD increase in
aPWV, 1.63; 95% CI, 0.98 –2.70). Among persons without
hypertension or persons with controlled hypertension, we did
not find any significant association between arterial stiffness
and cerebral small vessel disease (Table 3).
The Figure shows the association between quartiles of
aPWV and presence of cerebral small vessel disease. In
persons without hypertension or with controlled hyperten-
sion, no associations were found between arterial stiffness
and presence of cerebral small vessel disease (Figure A–B),
yet in persons with uncontrolled hypertension, we found that
those in the highest quartiles of aPWV had a higher prevalence of cerebral small vessel disease compared with the
reference group (Figure C). All statistical interaction terms
testing differential effects of (un)controlled hypertension
versus no hypertension were nonsignificant.
Repeating the analyses after excluding subjects with cortical infarcts did not change any of the results.
Discussion
In this cross-sectional population-based study, we found that
persons with high arterial stiffness, as measured by aPWV,
had a larger volume of WMLs.
Strengths of our study include the population-based setting,
the large sample size, and our focus on various subclinical
manifestations of cerebral small vessel disease, including
CMBs, which are a relatively new marker of cerebral vasculopathy. Furthermore, we measured arterial stiffness with
aPWV, which is generally accepted as the most simple,
noninvasive, robust, and reproducible method to determine
arterial stiffness.17,24
The present study, however, has also limitations. First, our
study has a cross-sectional design in which association does
not imply causation. Future studies are clearly needed to
further clarify the found association and elucidate possible
underlying mechanisms. Moreover, if reversible, arterial
stiffness may be a target for preventive therapies. Second,
information on measures of arterial stiffness was available for
somewhat less than half of the study cohort. When we
compared persons with and without arterial stiffness measurements, we found that persons with arterial stiffness
measurements were older and more often male, but other
characteristics did not differ significantly after correction for
differences in age and sex (online-only Data Supplement).
Therefore, we do not think that this has led to any selection
biases. Nevertheless, any residual selection bias due to
missing data cannot be fully ruled out. Third, WML volumes
were natural log transformed because of skewness of the
untransformed measure. When back transformed, we note
that the effect size seen of aPWV per SD increase in persons
with uncontrolled hypertension corresponds with a white
Table 2. The Association of Arterial Stiffness, as Measured by Aortic Pulse Wave Velocity, With Cerebral
Small Vessel Disease
Pulse Wave Velocity
2639
393 (27.2%)
Smoking, ever
Lacunar infarcts on MRI
Arterial Stiffness and Small Vessel Disease
White Matter Lesions*†
Differences in WML
Volume (95% CI)
Lacunar
Infarcts
OR (95% CI)
Deep or Infratentorial
Microbleeds‡
OR (95% CI)
Strictly Lobar
Microbleeds
OR (95% CI)
Per SD increase, Model I
0.08 (0.03– 0.13)
1.25 (0.92–1.69)
1.27 (0.91–1.76)
0.98 (0.79 –1.21)
Per SD increase, Model II
0.07 (0.02–0.12)
1.26 (0.92–1.73)
1.25 (0.90–1.75)
0.99 (0.79–1.23)
Values represent difference in white matter lesion (WML) volumes per SD increase in pulse wave velocity or ORs with 95% CIs.
Model I: adjusted for age, sex, mean arterial pressure, and heart rate. Model II: adjusted for age, sex, mean arterial pressure, heart
rate, smoking, waist– hip ratio, diabetes, cholesterol, high-density lipoprotein cholesterol, use of lipid-lowering drugs, and use of blood
pressure-lowering drugs. Values of white matter lesions are natural log-transformed. To obtain volumes in milliliters, back
transformation is needed.
*Ln-transformed.
†Additionally adjusted for intracranial volume.
‡With or without lobar microbleeds.
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Table 3. The Association of Arterial Stiffness, as Measured by Aortic Pulse Wave Velocity, With Cerebral
Small Vessel Disease in Strata of Hypertension
Pulse Wave Velocity
White Matter Lesions*†
Differences in WML
Volume (95% CI)
Lacunar
Infarcts
OR (95% CI)
Deep or Infratentorial
Microbleeds‡
OR (95% CI)
Strictly Lobar
Microbleeds
OR (95% CI)
Subjects without hypertension
(n⫽808)§
Per SD increase, Model I
0.07 (0.00 to 0.14)
0.91 (0.46 to 1.80)
1.24 (0.72 to 2.11)
0.84 (0.57 to 1.23)
Per SD increase, Model II
0.05 (⫺0.01 to 0.12)
0.97 (0.48 to 1.96)
1.20 (0.69 to 2.08)
0.83 (0.56 to 1.24)
Per SD increase, Model I
0.04 (⫺0.09 to 0.16)
1.05 (0.55 to 1.98)
0.59 (0.26 to 1.34)
0.83 (0.50 to 1.38)
Per SD increase, Model II
0.03 (⫺0.10 to 0.15)
1.24 (0.64 to 2.40)
0.50 (0.20 to 1.22)
0.86 (0.50 to 1.48)
Per SD increase, Model I
0.10 (0.01 to 0.19)
1.48 (0.93 to 2.34)
1.80 (1.05 to 3.07)
1.18 (0.85 to 1.62)
Per SD increase, Model II
0.09 (0.00 to 0.18)
1.63 (0.98 to 2.70)
2.13 (1.16 to 3.91)
1.18 (0.84 to 1.65)
Subjects with controlled
hypertension (n⫽226)§
Subjects with uncontrolled
hypertension (n⫽414)§
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Subjects without hypertension: systolic blood pressure ⬍140 mm Hg and a diastolic blood pressure ⬍90 mm Hg without use of
antihypertensive medication. Subjects with controlled hypertension: systolic blood pressure ⬍140 mm Hg and a diastolic blood
pressure ⬍90 mm Hg with use of antihypertensive medication. Subjects with uncontrolled hypertension: systolic blood pressure
ⱖ140 mm Hg or a diastolic blood pressure ⱖ90 mm Hg with or without use of antihypertensive medication. Values represent
difference in white matter lesion volumes per SD increase in pulse wave velocity or ORs with 95% CIs. Model I: adjusted for age, sex,
mean arterial pressure, and heart rate. Model II: adjusted for age, sex, mean arterial pressure, heart rate, smoking, waist– hip ratio,
diabetes, cholesterol, high-density lipoprotein cholesterol, use of lipid-lowering drugs, and use of blood pressure-lowering drugs.
Values of white matter lesions are natural log-transformed. To obtain volumes in milliliters, back transformation is needed.
*Ln-transformed.
†Additionally adjusted for intracranial volume.
‡With or without lobar microbleeds.
§Hypertension data missing for n⫽12.
matter volume increase of 1.1 mL. Lastly, a more integrative
measure of blood pressure over time will be more reliable
compared with a single or few measures due to regression to
the mean. Unfortunately, integrative measures were not
feasible in our population-based cohort.
Several other studies have been performed in the general
population investigating the association between arterial stiffness and markers of cerebral small vessel disease.8,9,11–13 Our
finding that arterial stiffness is associated with WML volume
is in line with these studies.9,11,13 However, all of these studies
used the brachial–ankle pulse wave velocity as a proxy for
arterial stiffness. This is the first report on the association
between arterial stiffness and cerebral small vessel disease in
the general population using the carotid–femoral pulse wave
velocity, the “gold standard” measurement of arterial stiffness. Some of these studies also showed associations between
arterial stiffness and lacunar infarcts.8,9 We did not find a
higher prevalence of lacunar infarcts in persons with higher
arterial stiffness values. This may be explained by the
relatively young mean age (58.2 years) of our study population and hence a lower prevalence of lacunar infarcts (4.3%)
compared with other studies in community-dwelling elderly.8,9,11–13 Ochi et al12 furthermore found an association
between arterial stiffness and the presence of CMBs irrespective of their location in the brain. In contrast to their findings,
we did not observe an association with microbleeds in our
study population, yet in individuals with uncontrolled hypertension, we observed an association with deep or infratentorial microbleeds, but not with strictly lobar microbleeds. This
is in line with the hypothesis that deep or infratentorial
microbleeds are indicative of hypertensive vasculopathy,
whereas lobar microbleeds are thought to be a marker of
underlying amyloid angiopathy.25 Furthermore, again in participants with uncontrolled hypertension, but not in participants without hypertension, we found an association between
arterial stiffness and WML volume and nonsignificantly with
lacunar infarcts. Some other smaller studies performed in
hypertensive subjects reported similar results.1,16,26 However,
we note that in our study, formal tests of statistical interaction
were all nonsignificant. Possibly, our findings in this subgroup could be a chance finding due to multiple testing.
Several pathologies may contribute to the occurrence of
lacunes and WMLs. However, small vessel disease is the
major and most frequent underlying pathology. Conversely,
WMLs, lacunar infarcts, and CMBs are considered the best
available in vivo markers of cerebral small vessel disease.
When we analyzed these different markers of cerebral small
vessel disease separately, persons with higher aPWV had a
larger volume of WML, whereas no significant associations
were found between aPWV and lacunar infarcts or microbleeds. To create a more robust measure of cerebral small
vessel disease, we constructed an overall measure of cerebral
small vessel disease. This combined measure of cerebral
small vessel disease was significantly associated with arterial
stiffness. Nevertheless, even this combined measure may be
driven primarily by WMLs.
The associations found between arterial stiffness and markers of cerebral small vessel disease were independent of other
Poels et al
Arterial Stiffness and Small Vessel Disease
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Figure. A–C, The association between quartiles of arterial stiffness and presence of cerebral small vessel disease. Triangles represent
ORs adjusted for age, sex, mean arterial pressure, heart rate, smoking, waist– hip ratio, diabetes, cholesterol, high-density lipoprotein
cholesterol, use of lipid-lowering drugs, and use of blood pressure-lowering drugs. Error bars represent 95% CIs. Subjects without
hypertension: systolic blood pressure ⬍140 mm Hg and a diastolic blood pressure ⬍90 mm Hg without use of antihypertensive medication. Subjects with controlled hypertension: systolic blood pressure ⬍140 mm Hg and a diastolic blood pressure ⬍90 mm Hg with
use of antihypertensive medication. Subjects with uncontrolled hypertension: systolic blood pressure ⱖ140 mm Hg or a diastolic blood
pressure ⱖ90 mm Hg with or without use of antihypertensive medication.
vascular risk factors. This suggests that these associations are
probably not mediated by these risk factors. An explanation
could be that arterial stiffness reflects risk factors for cerebral
small vessel disease that we did not measure in our study, for
example, genetic factors or other biomarkers. For example,
there is an increasing interest in the cardiovascular effects of
plasma aldosterone levels. These biomarkers may give additional insights into the association of arterial stiffness with
cerebral small vessel disease. Alternatively, arterial stiffness
may be a better marker of small vessel disease than these
concomitantly measured cardiovascular risk factors.
Structural and functional changes of the arterial wall,
caused by aging and cardiovascular risk factors, result in
decreased elasticity and increased stiffness of the arteries.1,2
Vascular resistance and pulse wave reflections are very low in
the microcirculations of the brain and kidney.5 Arterial
stiffening exposes, therefore, especially the small vessels in
the brain and kidney, to highly pulsatile pressure and flow. It
is hypothesized that these abnormal flow pulsations contribute to the pathogenesis of cerebral small vessel disease.5
Shared underlying pathological mechanisms, however, may
also be a possible explanation for the associations we found
between arterial stiffness and markers of cerebral small vessel
disease.
The associations we found between arterial stiffness and
markers of cerebral small vessel disease were most pronounced in persons with uncontrolled hypertension. In the
presence of hypertension, structural and functional changes of
the arterial wall are thought to occur earlier.1,16 Moreover, it
is known that subjects with hypertension have a higher
prevalence of cerebral small vessel disease.21,27,28 Our results
suggest that within this group of subjects with uncontrolled
hypertension, those with stiffer large arteries are more prone
to develop cerebral small vessel disease.
Conclusions
We found that arterial stiffness is associated with WML and
that the associations were independent of cardiovascular risk
factors. Our study emphasizes the importance of identifying
persons with high arterial stiffness and to treat high blood
pressure in these persons appropriately.29 Longitudinal studies on reduction of arterial stiffness, however, are needed to
study whether this lowers the risk of cerebral small vessel
disease and ultimately decreases risk of symptomatic cerebrovascular disease.
Sources of Funding
The Rotterdam Study is supported by the Erasmus MC University
Medical Center and Erasmus University Rotterdam, the Netherlands
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Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMW), the
Research Institute for Diseases in the Elderly (RIDE), The Netherlands Genomics Initiative, the Ministry of Education, Culture and
Science, the Ministry of Health, Welfare and Sports, the European
Commission (DG XII), and the Municipality of Rotterdam.
Disclosures
None.
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Arterial Stiffness and Cerebral Small Vessel Disease: The Rotterdam Scan Study
Mariëlle M.F. Poels, Kèren Zaccai, Germaine C. Verwoert, Meike W. Vernooij, Albert Hofman,
Aad van der Lugt, Jacqueline C.M. Witteman, Monique M.B. Breteler, Francesco U.S.
Mattace-Raso and M. Arfan Ikram
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Stroke. 2012;43:2637-2642; originally published online August 9, 2012;
doi: 10.1161/STROKEAHA.111.642264
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SUPPLEMENTAL MATERIAL
Table A. Baseline characteristics of the study population stratified according to hypertension status.
Subjects without
Subjects with controlled
Subjects with uncontrolled
hypertension
hypertension
hypertension
(n=808)*
(n=226)*
(n=414)*
Age, years
56.9 (SD 6.4)
60.1 (SD 7.6)
60.1 (SD 7.8)
Women
469 (58.0%)
120 (53.1%)
210 (50.7%)
Aortic Pulse Wave Velocity, m/s
8.5 (SD 1.3)
9.1 (SD 1.5)
10.0 (SD 1.7)
Mean arterial pressure, mmHg
90.3 (SD 7.7)
93.4 (SD 7.0)
110.6 (SD 7.9)
Heart rate, bpm
65.0 (SD 11.9)
61.3 (SD 16.1)
65.4 (SD 14.8)
Systolic blood pressure, mmHg
120.4 (SD 10.7)
124.6 (SD 9.3)
151.8 (SD 12.1)
Diastolic blood pressure, mmHg
75.2 (SD 7.0)
77.7 (SD 7.1)
90.1 (SD 7.9)
--
226 (100.0%)
167 (40.8%)
Diuretics
--
57 (25.2%)
42 (10.1%)
Betablocking agents
--
117 (51.8%)
81 (19.6%)
Calcium blockers
--
43 (19.0%)
29 (7.0%)
ACE-inhibitors
--
110 (48.7%)
91 (22.0%)
Other antihypertensives
--
1 (0.4%)
2 (0.5%)
Smoking, ever
562 (69.7%)
161 (71.2%)
276 (67.2%)
Waist-hip ratio
0.8 (SD 0.1)
0.9 (SD 0.1)
0.9 (SD 0.1)
32 (4.0%)
31 (13.7%)
48 (11.9%)
Serum total cholesterol, mmol/L
5.6 (SD 1.0)
5.2 (SD 1.2)
5.6 (SD 1.0)
Serum HDL cholesterol, mmol/L
1.5 (SD 0.4)
1.3 (SD 0.4)
1.4 (SD 0.4)
Lipid lowering medication
112 (13.9%)
107 (47.3%)
101 (24.7%)
1.9 (IR 1.3-3.3)
2.9 (IR 1.6-4.9)
2.5 (IR 1.6-4.5)
Lacunar infarcts on MRI
22 (2.7%)
17 (7.5%)
23 (5.6%)
Strictly lobar cerebral microbleeds
59 (7.3%)
26 (11.5%)
60 (14.5%)
22 (2.7%)
10 (4.4%)
16 (3.9%)
Blood pressure lowering medication
Diabetes
White matter lesions on MRI, mL,
median (interquartile range)
on MRI
Deep or infratentorial microbleeds on
MRI
* Hypertension data missing for n=12.
Subjects without hypertension: Systolic blood pressure <140 mmHg and a diastolic blood pressure <90 mmHg
without use of antihypertensive medication.
Subjects with controlled hypertension: Systolic blood pressure <140 mmHg and a diastolic blood pressure <90
mmHg with use of antihypertensive medication.
Subjects with uncontrolled hypertension: Systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90
mmHg with or without use of antihypertensive medication.
Values are means with standard deviation (SD) or numbers with percentages (%), unless specified otherwise.
Data are missing for medication use (n=17), smoking (n=10), diabetes (n=32), serum cholesterol (n=23),
cerebral microbleeds (n=6), lacunar infarcts (n=6), and white matter lesions (n=3).
Table B. Baseline characteristics of the study population stratified according to presence or absence of
cerebral small vessel disease.
Subjects with absence of
Subjects with presence
cerebral small vessel disease
cerebral small vessel disease
(n=1048)
(n=412)*
Age, years
56.8 (SD 6.0)
62.1 (SD 8.5)
Women
574 (54.8%)
235 (57.0%)
Aortic Pulse Wave Velocity, m/s
8.8 (SD 1.4)
9.6 (SD 1.8)
Mean arterial pressure, mmHg
96.0 (SD 11.6)
97.8 (SD 12.0)
Heart rate, bpm
64.7 (SD 13.0)
64.1 (SD 14.8)
Systolic blood pressure, mmHg
128.7 (SD 17.2)
133.2 (SD 18.2)
Diastolic blood pressure, mmHg
79.7 (SD 9.7)
80.0 (SD 9.9)
Blood pressure lowering medication
244 (23.6%)
149 (36.5%)
Smoking, ever
699 (67.3%)
306 (74.3%)
Waist-hip ratio
0.9 (SD 0.1)
0.9 (SD 0.1)
71 (6.9%)
40 (9.9%)
Serum total cholesterol, mmol/L
5.5 (SD 1.0)
5.5 (SD 1.1)
Serum HDL cholesterol, mmol/L
1.4 (SD 0.4)
1.4 (SD 0.4)
Lipid lowering medication
204 (19.7%)
116 (28.4%)
1.7 (IR 1.2-2.5)
5.7 (IR 4.2-9.0)
--
63 (15.3%)
96 (9.2%)
51 (12.4%)
--
48 (11.7%)
Diabetes
White matter lesions on MRI, mL, median
(interquartile range)
Lacunar infarcts on MRI
Strictly lobar cerebral microbleeds on
MRI
Deep or infratentorial microbleeds on
MRI
* Presence of small vessel disease (n=412) was defined as persons in the highest quartile of white matter lesion
volume, or presence of lacunar infarcts, or presence of deep or infratentorial microbleeds.
Values are means with standard deviation (SD) or numbers with percentages (%), unless specified otherwise.
Data are missing for medication use (n=17), smoking (n=10), diabetes (n=32), serum cholesterol (n=23),
cerebral microbleeds (n=6), lacunar infarcts (n=6), and white matter lesions (n=34).
Table C. Baseline characteristics of Rotterdam Study III (n=3932) stratified according to presence or
absence of arterial stiffness measurements.
Subjects without arterial
Subjects with arterial
stiffness measurements
stiffness measurements
(n=2099)
(n=1833)
Age, years
56.1 (SD 6.6)
58.3 (SD 7.6)*
Women
1212 (57.7%)
1040 (56.7%)*
Systolic blood pressure, mmHg
131.7 (SD 18.2)
133.6 (SD 20.0)
Diastolic blood pressure, mmHg
82.3 (SD 10.8)
82.9 (SD 11.2)
Blood pressure lowering medication
560 (26.7%)
516 (28.2%)
Smoking, ever
1497 (71.6%)
1267 (69.5%)
Waist-hip ratio
0.9 (SD 0.1)
0.9 (SD 0.1)
Serum total cholesterol, mmol/L
5.6 (SD 1.1)
5.5 (SD 1.0)
Serum HDL cholesterol, mmol/L
1.4 (SD 0.5)
1.4 (SD 0.4)
*Age and sex-adjusted (when applicable) difference between groups is P<0.05.
Values are means with standard deviation (SD) or numbers with percentages (%).
Data are missing for blood pressure (n=290), blood pressure lowering medication (n=38), smoking (n=18), and
cholesterol (n=378).
SUPPLEMENTAL MATERIAL
Table A. Baseline characteristics of the study population stratified according to hypertension status.
Subjects without
Subjects with controlled
Subjects with uncontrolled
hypertension
hypertension
hypertension
(n=808)*
(n=226)*
(n=414)*
Age, years
56.9 (SD 6.4)
60.1 (SD 7.6)
60.1 (SD 7.8)
Women
469 (58.0%)
120 (53.1%)
210 (50.7%)
Aortic Pulse Wave Velocity, m/s
8.5 (SD 1.3)
9.1 (SD 1.5)
10.0 (SD 1.7)
Mean arterial pressure, mmHg
90.3 (SD 7.7)
93.4 (SD 7.0)
110.6 (SD 7.9)
Heart rate, bpm
65.0 (SD 11.9)
61.3 (SD 16.1)
65.4 (SD 14.8)
Systolic blood pressure, mmHg
120.4 (SD 10.7)
124.6 (SD 9.3)
151.8 (SD 12.1)
Diastolic blood pressure, mmHg
75.2 (SD 7.0)
77.7 (SD 7.1)
90.1 (SD 7.9)
--
226 (100.0%)
167 (40.8%)
Diuretics
--
57 (25.2%)
42 (10.1%)
Betablocking agents
--
117 (51.8%)
81 (19.6%)
Calcium blockers
--
43 (19.0%)
29 (7.0%)
ACE-inhibitors
--
110 (48.7%)
91 (22.0%)
Other antihypertensives
--
1 (0.4%)
2 (0.5%)
Smoking, ever
562 (69.7%)
161 (71.2%)
276 (67.2%)
Waist-hip ratio
0.8 (SD 0.1)
0.9 (SD 0.1)
0.9 (SD 0.1)
32 (4.0%)
31 (13.7%)
48 (11.9%)
Serum total cholesterol, mmol/L
5.6 (SD 1.0)
5.2 (SD 1.2)
5.6 (SD 1.0)
Serum HDL cholesterol, mmol/L
1.5 (SD 0.4)
1.3 (SD 0.4)
1.4 (SD 0.4)
Lipid lowering medication
112 (13.9%)
107 (47.3%)
101 (24.7%)
1.9 (IR 1.3-3.3)
2.9 (IR 1.6-4.9)
2.5 (IR 1.6-4.5)
Lacunar infarcts on MRI
22 (2.7%)
17 (7.5%)
23 (5.6%)
Strictly lobar cerebral microbleeds
59 (7.3%)
26 (11.5%)
60 (14.5%)
22 (2.7%)
10 (4.4%)
16 (3.9%)
Blood pressure lowering medication
Diabetes
White matter lesions on MRI, mL,
median (interquartile range)
on MRI
Deep or infratentorial microbleeds on
MRI
* Hypertension data missing for n=12.
Subjects without hypertension: Systolic blood pressure <140 mmHg and a diastolic blood pressure <90 mmHg
without use of antihypertensive medication.
Subjects with controlled hypertension: Systolic blood pressure <140 mmHg and a diastolic blood pressure <90
mmHg with use of antihypertensive medication.
Subjects with uncontrolled hypertension: Systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90
mmHg with or without use of antihypertensive medication.
Values are means with standard deviation (SD) or numbers with percentages (%), unless specified otherwise.
Data are missing for medication use (n=17), smoking (n=10), diabetes (n=32), serum cholesterol (n=23),
cerebral microbleeds (n=6), lacunar infarcts (n=6), and white matter lesions (n=3).
Table B. Baseline characteristics of the study population stratified according to presence or absence of
cerebral small vessel disease.
Subjects with absence of
Subjects with presence
cerebral small vessel disease
cerebral small vessel disease
(n=1048)
(n=412)*
Age, years
56.8 (SD 6.0)
62.1 (SD 8.5)
Women
574 (54.8%)
235 (57.0%)
Aortic Pulse Wave Velocity, m/s
8.8 (SD 1.4)
9.6 (SD 1.8)
Mean arterial pressure, mmHg
96.0 (SD 11.6)
97.8 (SD 12.0)
Heart rate, bpm
64.7 (SD 13.0)
64.1 (SD 14.8)
Systolic blood pressure, mmHg
128.7 (SD 17.2)
133.2 (SD 18.2)
Diastolic blood pressure, mmHg
79.7 (SD 9.7)
80.0 (SD 9.9)
Blood pressure lowering medication
244 (23.6%)
149 (36.5%)
Smoking, ever
699 (67.3%)
306 (74.3%)
Waist-hip ratio
0.9 (SD 0.1)
0.9 (SD 0.1)
71 (6.9%)
40 (9.9%)
Serum total cholesterol, mmol/L
5.5 (SD 1.0)
5.5 (SD 1.1)
Serum HDL cholesterol, mmol/L
1.4 (SD 0.4)
1.4 (SD 0.4)
Lipid lowering medication
204 (19.7%)
116 (28.4%)
1.7 (IR 1.2-2.5)
5.7 (IR 4.2-9.0)
--
63 (15.3%)
96 (9.2%)
51 (12.4%)
--
48 (11.7%)
Diabetes
White matter lesions on MRI, mL, median
(interquartile range)
Lacunar infarcts on MRI
Strictly lobar cerebral microbleeds on
MRI
Deep or infratentorial microbleeds on
MRI
* Presence of small vessel disease (n=412) was defined as persons in the highest quartile of white matter lesion
volume, or presence of lacunar infarcts, or presence of deep or infratentorial microbleeds.
Values are means with standard deviation (SD) or numbers with percentages (%), unless specified otherwise.
Data are missing for medication use (n=17), smoking (n=10), diabetes (n=32), serum cholesterol (n=23),
cerebral microbleeds (n=6), lacunar infarcts (n=6), and white matter lesions (n=34).
Table C. Baseline characteristics of Rotterdam Study III (n=3932) stratified according to presence or
absence of arterial stiffness measurements.
Subjects without arterial
Subjects with arterial
stiffness measurements
stiffness measurements
(n=2099)
(n=1833)
Age, years
56.1 (SD 6.6)
58.3 (SD 7.6)*
Women
1212 (57.7%)
1040 (56.7%)*
Systolic blood pressure, mmHg
131.7 (SD 18.2)
133.6 (SD 20.0)
Diastolic blood pressure, mmHg
82.3 (SD 10.8)
82.9 (SD 11.2)
Blood pressure lowering medication
560 (26.7%)
516 (28.2%)
Smoking, ever
1497 (71.6%)
1267 (69.5%)
Waist-hip ratio
0.9 (SD 0.1)
0.9 (SD 0.1)
Serum total cholesterol, mmol/L
5.6 (SD 1.1)
5.5 (SD 1.0)
Serum HDL cholesterol, mmol/L
1.4 (SD 0.5)
1.4 (SD 0.4)
*Age and sex-adjusted (when applicable) difference between groups is P<0.05.
Values are means with standard deviation (SD) or numbers with percentages (%).
Data are missing for blood pressure (n=290), blood pressure lowering medication (n=38), smoking (n=18), and
cholesterol (n=378).