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Diastolic Carotid Artery Wall Shear Stress Is Associated

With Cerebral Infarcts and Periventricular White


Matter Lesions
Henri J.M.M. Mutsaerts, MD; Inge H. Palm-Meinders, MD, PhD; Anton J.M. de Craen, PhD;
Johan H.C. Reiber, PhD; Gerard J. Blauw, MD, PhD; Mark A. van Buchem, MD, PhD;
Jeroen van der Grond, PhD; Frieke M.A. Box, PhD; on behalf of the PROSPER Study Group
Background and PurposeLow wall shear stress (WSS) is an early marker in the development of vascular lesions. The
present study aims to assess the relationship between diastolic and systolic WSS in the internal carotid artery and
periventricular (PWML), deep white matter lesions, and cerebral infarcts (CI).
MethodsEarly, mid, and late diastolic and peak systolic WSS were derived from shear rate obtained by gradient echo
phase contrast magnetic resonance sequences multiplied by individually modeled viscosity.
PWML, deep white matter lesions, and CI were derived from proton density (PD), T2, and fluid attenuated inversion
recovery (FLAIR) MRI in 329 participants (70 82 years; PROSPER baseline). Analyses were adjusted, if appropriate,
for age, gender, intracranial volume, and multiple cardiovascular risk factors.
ResultsMid-diastolic WSS was significantly correlated with the presence of PWML (B10.15; P0.006) and CI
(B2.06; P0.044), but not with deep white matter lesions (B1.30; P0.050; adjusted for age, gender, WML,
and intracranial volume). After adjustment for cardiovascular risk factors, these correlations weakened but remained
significant. Systolic WSS was not correlated with any of the cerebrovascular parameters.
ConclusionsThis study is the first to our knowledge to present a cross-sectional correlation between carotid artery WSS
and cerebrovascular pathology such as PWML and CI in a large population. Furthermore, it shows that diastolic
hemodynamics may be more important than systolic or mean hemodynamics. Future studies exploring vascular
hemodynamic damage should focus on diastolic WSS. (Stroke. 2011;42:3497-3501.)
Key Words: carotid artery cerebral infarct hemodynamics wall shear stress white matter lesions

rom a hemodynamic point of view, wall shear stress


(WSS) is considered an important factor guarding vascular health. WSS is the frictional force exerted by the circulating blood on the endothelium. This force is the primary
stimulus for flow-mediated dilatation and modulates the
endothelial expression of all known atheroprotective and
atherogenic genes.1,2 In regions of low WSS, the vessel wall
shifts its production toward vasoconstrictive and inflammatory factors, creating a long-term tendency toward vascular
damage such as intimal hyperplasia and eventually atherosclerosis.1,3,4 Consequently, WSS has been shown to be
inversely correlated to a wide variety of systemic vascular
risk factors such as age, hypertension, body mass index,
hyperglycemia, renal failure, smoking, myocardial infarction,
and low physical exercise.3,57 Interestingly, these risk factors
lead to lesions on locations with a disturbed WSS.1,3,4 The
underlying interaction is still unclear. Possibly, WSS may
play a unique role in the explanation of the effects produced

by systemic risk factors. The possible function of WSS in the


early prediction of focal and distal susceptibility of vascular
pathology is still a matter of debate.1,4
WSS in the carotid bifurcation recently has been studied.
The complex and turbulent flow of the carotid bifurcation
creates regions of low or even oscillating WSS that are
notoriously prone to vascular damage.1,3,4
At present, no studies have been performed exploring
potential associations between disturbed carotid artery hemodynamics and cerebrovascular pathological changes occurring more distally. Because carotid artery WSS can be
regarded as a marker, representing the systemic vascular
hemodynamic condition (analog to intima-media thickness
measurements in the carotid artery), it may also represent
the overall hemodynamic condition of the cerebral vessels.
In addition, focal damage marked by WSS in the carotid
artery may have led to cerebrovascular pathology by
thromboembolism.

Received February 11, 2011; accepted June 21, 2011.


From the Department of Radiology (H.J.M.M.M., I.H.P.M., M.A.v.B., J.v.d.G., F.M.A.B.), Department of Gerontology & Geriatrics (A.J.M.d.C.,
G.J.B.), and Division of Image Processing, Department of Radiology, (J.H.C.R.), Leiden University Medical Centre, Leiden, the Netherlands.
Correspondence to Jeroen van der Grond, PhD, Department of Radiology, C3-Q, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden,
the Netherlands. E-mail J.van_der_Grond@lumc.nl
2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.111.614453

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pants refrained from smoking for at least 90 minutes before the
examination. Measurements from both internal carotid arteries were
averaged.

1.4

Wall Shear Stress Computation


WSS is defined as viscosity multiplied by shear rate (ie, the gradient
of blood velocity with respect to the vessel wall). Shear rate values
were extracted from flow measurements fit on the previously
described 3-dimensional paraboloid method, within semiautomatically delineated vessels, using the in-house developed software
package FLOW (Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands).12 Viscosity and its shearthinning properties (ie, the decrease of viscosity after an increase of
shear rate) were modeled by the Carreau-Yasuda model. Values from
the well-tested blood-mimicking KSCN-X solution were individually adjusted for hematocrit with the following equation13,14:

WSS (Pa)

1.2

1.0

0.8

(1)
0

10 11 12 13 14 15

Cardiac phases

y/x

Figure. Mean wall shear stress (WSS) and 95% confidence


interval of the cardiac phases. The brown circle represents early
diastolic, the pink circle represents mid-diastolic, and the red
circle represents late diastolic WSS. The blue rectangle represents peak systolic WSS. The overall mean (0.98 Pa) is depicted
with a green line. The dynamic change, the increase in WSS in
each phase, is illustrated with a triangle on the right.

The present study aims to evaluate whether WSS in the


internal carotid artery is associated with white matter lesions
(WML) and cerebral infarcts (CI), 2 neuroradiological markers that are frequently found on cranial MRI.8,9 In addition to
mean WSS, we analyzed diastolic and systolic WSS
separately.

Materials and Methods


Participants
Data for this study were drawn from the baseline of the Dutch MRI
substudy of the PROspective Study of Pravastatin in the Elderly at
Risk (PROSPER).10 This randomized controlled trial examines the
effect of pravastatin on cardiovascular and cerebrovascular events in
elderly individuals, aged 70 to 82 years, with vascular disease or at
high vascular risk. The inclusion and exclusion criteria of PROSPER
and its MRI substudy have been described in detail elsewhere.10,11 At
baseline, 329 of the PROSPER participants underwent MRI of both
the internal carotid artery and cranium. Our Institutional Review
Board approved the protocol for the MRI substudy. All participants
gave informed consent and agreed with future retrospective analyses.
All imaging was performed on a 1.5-T system with a standard head
coil (Gyroscan ACS-NT 15; Philips Medical Systems).

Blood Flow Measurement


Blood flow measurements in both internal carotid arteries were
performed with a gradient echo phase-contrast technique: repetition
time, 14.7 ms; echo time, 9.1 ms; flip angle, 7.5 degrees; slice
thickness, 5 mm; matrix, 256154; field of view, 250188 mm; and
velocity encoding 100 cm/s and 1 number of signal averages. By
retrospective gating, a peripheral pulse unit divided the average
cardiac cycle length into 16 discrete phases. These phases are
clustered into and analyzed as diastolic and systolic phases according
to similarity of mean WSS and 95% confidence intervals, increasing
reproducibility.12 The Figure illustrates how diastole (phases 4 to 12)
and systole (phases 14 to 1) are subdivided into early (4 6), mid
(79), and late diastolic (10 12) and peak systolic (15 to 0) cardiac
phases.
The scans were performed in a plane perpendicular to the internal
carotid arteries 3 cm cranial to the carotid bifurcation. All partici-

Viscosity2.2(222.2)*
(1(0.11*shear rate)0.644)(hematocrit1)/0.644

Individual hematocrit values were obtained from 4 mL blood


withdrawn from the antecubital vein of sober participants and
collected in a 7.2-mg K2EDTA sterile collecting tube using a
Sysmex XE-2100 Automated Hematology Analyzer (TOA Medical
Electronics).

Cerebral Pathology
Quantification of WML volumes was performed by in-house developed automated lesion detection software.10 For postprocessing, PD,
FLAIR, and T2-weighted MRI were transferred to an offline workstation. By combining fuzzy clustering, connectivity rules, and
mathematical morphology, WML segmentations were generated
automatically. WML were defined as regions being hyperintense on
both proton density-weighted MRI and T2-weighed MRI. Lesions
were divided into periventricular WML (PWML) and deep WML
(DWML) based on their connection to the lateral ventricles. To
correct for incidental inclusion of cerebrospinal fluid and gray
matter, the automatically generated WMH segmentations were edited manually by a trained rater with 20 years of neuroradiological
experience (M.A.v.B.). FLAIR scans were used as a reference to rule
out other pathogenesis or the entanglement of WMH with VirchowRobin spaces. Infratentorial lesions (brain stem and cerebellum)
were excluded.
Infarcts were identified by an experienced neuroradiologist
(M.A.v.B.) with 20 years of neuroradiological experience and
defined as a parenchymal defect: (1) having the same signal intensity
as cerebrospinal fluid on all pulse sequences; (2) surrounded by a
tissue rim with increased signal intensity on PD, T2, and FLAIR; (3)
with a vascular distribution; and (4) without a mass effect. Hemorrhagic infarcts were excluded based on the presence of hemosiderin
in the wall of the parenchymal defect on the susceptibility-weighed
scan. All measurements were performed blinded to participant
identity, age, and gender.

Statistical Analysis
All statistical analyses were performed with the statistical software
package SPSS for Windows, release 17.0 (SPSS). Relations between
gender and age and WSS and the cerebrovascular parameters were
investigated by linear regression analysis. Relations between the
WSS clusters and cerebrovascular pathology parameters were
investigated by 2 linear regression models. Model 1 only adjusted
for age, gender, and total intracranial volume, and model 2
additionally adjusted for the cardiovascular risk factors of alcohol
use, systolic and diastolic blood pressure, low-density lipoprotein,
high-density lipoprotein, total and total/high-density lipoprotein
cholesterol, triglycerides, history of vascular disease, history of
hypertension or history of diabetes mellitus, and glucose. The
exact measurement methods of these parameters are previously
described in the PROSPER study setup.11

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Mutsaerts et al
Table 1.

Characteristics of Study Participants (n329)


Findings

Age, median (25%, 75% interquartile ranges in y)

74 (7277)

Men

184 (56%)

PWML volume (mL)

4.158.84

DWML volume (mL)

1.001.56

CI (n)

1.051.95

Total count of CI

324

Intracranial volume (mL)

1399148

CI indicates cerebral infarct; DWML, deep white matter lesion; PWML,


periventricular white matter lesion.
Of continuous variables, the meanSD are shown. For the categorical
variable gender, findings are presented in count of men with percentages
shown in parentheses.

The level of significance was set at P0.05. No violations of the


usual regression assumptions were detected.

Results
Of the enrolled participants, 184 (56%) were men. Age
ranged from 70 to 82 years, with a median of 74 years, with
25% and 75% interquartile ranges of 72 and 77 years. These
and other characteristics are shown in Table 1. Men had
higher WSS values than women in all cardiac phases (from
B0.081, P0.02 for peak-systolic WSS to B0.061,
P0.01 for mid-diastolic WSS). Men were on average 1 year
older (B0.838; P0.017) and had more CI than women
(B0.482; P0.027). Gender was not correlated with
PWML or DWML. Age was correlated with all WSS phases
(from B0.013, P0.01 for peak systolic WSS to
B0.015, P0.01 for mid-diastolic WSS). Age was correlated with PWML (B0.651; P0.01) and DWML
(B0.120; P0.01). Age was not correlated with CI. The
associations of WSS with PWML, DWML, and CI are shown
in, respectively, Tables 2, 3, and 4.
Mean WSS was correlated with total WML volume
(B7.83; P0.025), PWML (B7.02; P0.022), and
CI (B1.53; P0.031), but not with DWML (B0.77;

Wall Shear Stress

3499

P0.165; Tables 2 and 3). All WSS clusters were significantly and inversely correlated with PWML, but none was
correlated with DWML. The strongest correlation with
PWML was shown in mid-diastole (B10.15; P0.006)
and the weakest was shown in peak systole (B4.03;
P0.044). After adjustment for cardiovascular risk factors,
only peak systolic WSS lost its significance. The highest
correlation with DWML was found in mid-diastole, which
was borderline significant (B1.30; P0.050). All WSS
clusters except for peak systolic WSS were associated with
CI (Table 4). Mid-diastolic WSS showed the highest correlation (B2.06; P0.015), where peak systolic WSS
showed the weakest correlation (B0.79; P0.089). After
adjustment for cardiovascular risk factors, this correlation of
both mean and early diastolic WSS lost significance.

Discussion
The most important findings of this study are that WSS in the
internal carotid artery is inversely correlated with PWML and
CI, but not with DWML. Overall, diastolic WSS showed
more significant correlations than systolic WSS.
The association between carotid and cerebrovascular pathology has been elaborately studied.8,15 However, only a
limited number of studies investigated the influence of WSS
on cerebrovascular pathology. One study reported an association between unilateral ischemic stroke and lower mean
WSS in the ipsilateral common carotid artery.16 Likewise,
low internal carotid and basilar artery WSS have been related
to mild cognitive impairment and Alzheimer disease.17 Intracranially, both lower and higher intracranial WSS were
correlated with intracranial stenoses and aneurysm growth
and rupture.18 Apart from associations with focal and distal
vascular damage, WSS was previously associated with a
variety of systemic vascular risk factors.1,37 The associations
described in this study could have their origin in a direct
effect that carotid artery hemodynamics have on the incidence of cerebrovascular pathology, such as artery-to-artery
microemboli. Still, a relationship of disrupted cerebrovascular hemodynamics that develops in an equal trend when

Table 2. Cross-Sectional Associations of Early, Mid, and Late Diastolic and Peak Systolic
Wall Shear Stress With Periventricular White Matter Lesions
Periventricular White Matter Lesion
Volume (mL) Model 1

Model 2

CI

CI

Mean WSS (Pa)

7.02

13.150.90

0.022*

6.76

13.040.47

0.035*

Early diastolic WSS (Pa)

7.39

13.900.89

0.026*

7.09

13.850.32

0.040*

Mid-diastolic WSS (Pa)

10.15

17.412.89

0.006

9.36

16.851.86

0.015*

Late diastolic WSS (Pa)

8.63

16.271.00

0.027*

8.55

16.440.66

0.034*

Peak systolic WSS (Pa)

4.03

7.940.11

0.044*

3.96

8.070.17

0.060

Associations were assessed by linear regression models. Model 1 adjusted for age, gender, and total
intracranial volume. Model 2 also adjusted for cardiovascular risk factors.
Each estimate presents the cross-sectional association of WSS with white matter lesions. WSS represents
carotid artery wall shear stress. B is a regression coefficient. CI represents lower and upper 95% confidence
intervals of B.
CI indicates confidence interval; WSS, wall shear stress.
*P0.05.
P0.01.

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Table 3. Cross-Sectional Associations of Early, Mid, and Late Diastolic and Peak Systolic
Wall Shear Stress With Deep White Matter Lesions
Deep White Matter Lesion
Volume (mL) Model 1

Model 2

CI

CI

Mean WSS (Pa)

0.77

1.850.32

0.165

0.78

1.890.34

0.170

Early diastolic WSS (Pa)

0.92

2.080.24

0.121

0.94

2.140.26

0.123

Mid-diastolic WSS (Pa)

1.30

2.600.00

0.050

1.25

2.580.07

0.064

Late diastolic WSS (Pa)

1.19

2.550.18

0.087

1.20

2.590.20

0.093

Peak systolic WSS (Pa)

0.37

1.070.33

0.301

0.40

1.130.33

0.283

Associations were assessed by linear regression models. Model 1 adjusted for age, gender, and total
intracranial volume. Model 2 also adjusted for cardiovascular risk factors.
Each estimate presents the cross-sectional association of WSS with white matter lesions. WSS represents
carotid artery wall shear stress. B is a regression coefficient. CI represents lower and upper 95% confidence
intervals of B.
CI indicates confidence interval; WSS, wall shear stress.

exposed to identical systemic risk factors cannot be excluded.3,57,19 Moreover, any causal correlation between carotid hemodynamics and cerebrovascular pathology could be
confounded by similar worsening hemodynamics in the
cardiac, vertebrobasilar, or cerebral arteries.20
In this study PWML, but not DWML, were associated with
WSS. Interestingly, previous investigators have found a
similar distinction as PWML, but not DWML, were associated with total cerebral blood flow, intima-media thickness,
plaques in the carotid artery, and atrial fibrillation.15,21,22 An
explanation may be found in their suspected dissimilar
etiology. PWML are large, diffuse, and symmetrical, suggesting global vascular damage. DWML, however, are typically
small and asymmetrical, which suggests focal perfusion
disturbances.21,22 The association of carotid artery WSS with
PWML may be mainly explained from a systemical relationship of carotid and cerebrovascular hemodynamics worsening
in an equal trend.
CI are typically linked to a direct relationship, and carotid
artery WSS may predict atherosclerotic pathology that directly leads to thromboembolic processes responsible for
CI.1,4,8,23 Cross-sectional associations of WSS with CI have
not, to our knowledge, been demonstrated before. Still, 1
study reported a lower mean WSS in the common carotid

artery ipsilateral to unilateral ischemic stroke, accompanied


by more evident atherosclerotic plaques at the same side.16
A major strength of this study is its individually modeled
viscosity values as opposed to a fixed value used by other
studies.14 Another major strength of the methods used in this
study are the 4-dimensional (3-dimensionaltime) MR measurements of WSS requiring minimal manual interference.12
The dynamics of WSS in 1 cardiac cycle are illustrated in the
Figure. Unfortunately, whereas MR has a high spatial resolution for WSS computations, it has a low temporal resolution
compared to duplex ultrasonography. Moreover, by retrospectively averaging the heart rate, temporal variations in and
between individuals, such as differences in vessel lengths and
vessel compliances, are not taken into account. As a consequence, distinct WSS values of cardiac phases fade as they
mix with neighboring phases. This disadvantage may especially burden systolic WSS because it experiences the fastest
dynamic shear stress changes. Interestingly, mid-diastolic
WSS experiences the slowest dynamic changes in WSS and
showed the highest correlations. This may partly explain the
absence of correlations found in systole as compared to
diastole. Likewise, other studies have found most or best
correlations with diastolic WSS.6,17,24 Maybe diastolic WSS
is a more sensitive parameter for detecting vascular pathol-

Table 4. Cross-Sectional Associations of Early, Mid, and Late Diastolic and Peak Systolic
Wall Shear Stress With Confidence Intervals
CI (n) Model 1

Model 2

CI

Mean WSS (Pa)

1.53

2.920.14

0.031*

0.78

1.890.34

CI

0.170

Early diastolic WSS (Pa)

1.50

2.990.02

0.047*

1.41

2.930.12

0.070

Mid-diastolic WSS (Pa)

2.06

3.720.40

0.015*

1.89

3.580.20

0.028*

Late diastolic WSS (Pa)

2.00

3.740.25

0.025*

1.84

3.620.06

0.043*

Peak systolic WSS (Pa)

0.79

1.690.12

0.089

0.90

1.830.03

0.057

Associations were assessed by linear regression models. Model 1 adjusted for age, gender, and total
intracranial volume. Model 2 also adjusted for cardiovascular risk factors.
Each estimate presents the cross-sectional association of WSS with CI. WSS represents carotid artery wall
shear stress. B is a regression coefficient. CI represents 95% confidence intervals of B.
CI indicates confidence interval; WSS, wall shear stress.
*P0.05.

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Mutsaerts et al
ogy. Another possible explanation, previously hypothesized
by Irace et al,5 is a WSS threshold value. We also hypothesized the existence of a threshold level of WSS, below which
vascular pathology only occurs. This would explain why a
decrease of peak systolic WSS does not, but diastolic WSS
does, increase vulnerability.

Conclusions
This study is the first to our knowledge to present a
cross-sectional correlation between carotid artery WSS and
cerebrovascular pathology such as periventricular WML and
CI in a large population. It shows that diastolic hemodynamics may be more important than systolic or mean hemodynamics. Disturbed WSS may present early atherogenesis and
may predict possible damage in an earlier stage than current
markers for large vessel disease. The results of the present
study should encourage new longitudinal WSS studies to test
the clinical predictive value of WSS measurements in relation
to current standards.

Appendix
In the present study, only subjects were included who were
participants from the nested MRI substudy of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).
The PROSPER Study Group consists of: (Glasgow) J. Shepherd (chairman and principal investigator), S.M. Cobbe, I.
Ford, A. Gaw, P.W. Macfarlane, C.J. Packard, and D.J. Stott;
(Leiden) G.J. Blauw (principal investigator), E.L.E.M. Bollen, A.M. Kamper, and R.G.J. Westendorp; (Cork) M.B.
Murphy (principal investigator), B.M. Buckely, M. Hyland,
and I.J. Perry.

Acknowledgments
The authors are grateful to Jan Schoones (Information Specialist,
Walaeus Library, Leiden University Medical Center) for aiding with
literature searches.

Sources of Funding
This work was financed by the Dutch Heart Foundation Grant
2000.119. The PROspective Study of Pravastatin in the Elderly at
Risk (PROSPER) study was sponsored by Bristol Myers-Squibb,
Princeton, NJ, who had no role in the study design, data collection,
analyses or interpretation.

Disclosures
None.

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Diastolic Carotid Artery Wall Shear Stress Is Associated With Cerebral Infarcts and
Periventricular White Matter Lesions
Henri J.M.M. Mutsaerts, Inge H. Palm-Meinders, Anton J.M. de Craen, Johan H.C. Reiber,
Gerard J. Blauw, Mark A. van Buchem, Jeroen van der Grond and Frieke M.A. Box
Stroke. 2011;42:3497-3501; originally published online September 8, 2011;
doi: 10.1161/STROKEAHA.111.614453
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