Is There a Side Predilection for Cerebrovascular Disease?
Sergio A. Rodríguez Hernández, Abraham A. Kroon, Martin P.J. van Boxtel, Werner H. Mess,
Jan Lodder, Jelle Jolles, Peter W. de Leeuw
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Abstract—In studies on carotid artery intima-media thickness and stroke, researchers implicitly assume that cerebrovascular abnormalities show a symmetrical distribution. To evaluate whether there is a difference in intima-media thickness
between the 2 carotids, we compared left and right common carotid artery intima-media thickness as measured by
B-mode ultrasonography in a group of 102 untreated hypertensive patients. This yielded a significant difference between
both sides (left, 0.75⫾0.11 mm; right, 0.71⫾0.11 mm; P⬍0.001). This was associated with a higher cross-sectional area
of the intima-media complex and a higher flow velocity at the left side. Arterial diameters, however, were not different.
We also assessed whether there is a side preference with respect to cerebrovascular accidents. To this end, we explored
our population-based Stroke Registry of 1843 subjects and indeed found a significantly higher incidence of nonlacunar
cerebrovascular stroke at the left side, whereas lacunar infarcts were symmetrically distributed. Our findings suggest a
predilection for cerebrovascular disease at the left side, which may be related to greater hemodynamic stress and intimal
damage in the left carotid artery. (Hypertension. 2003;42:56-60.)
Key Words: carotid arteries 䡲 atherosclerosis 䡲 cerebral arteries 䡲 stroke
A
n increase in carotid artery intima-media thickness
(IMT) not only coincides with other risk factors such as
hypercholesterolemia, hypertension, and diabetes mellitus but
also correlates independently with clinical end points such as
myocardial infarction and peripheral atherosclerosis.1–7 Recent data have confirmed the relationship between IMT and
stroke, especially of the nonlacunar subtype.8 Thus, an
increase in IMT can be considered as a marker of cardiovascular risk. Usually, one averages measurements from the left
and right common carotid artery for the determination of
IMT.9 However, it is not known whether this is justified, as
differences may exist in IMT between both arteries. Indeed,
during routine assessment, we frequently noted a left-right
difference in IMT. Other studies also suggest differences
between left and right IMT,5,9 but it is not clear whether there
is a systematic increase in favor of one side. This prompted us
to systematically compare left and right IMT in a group of
hypertensive patients who had been referred to our hospital
for evaluation of their elevated blood pressure. Although an
increased IMT of the internal carotid artery correlates well
with the risk of both myocardial infarction and stroke, a
higher IMT of the common carotid artery (CCA) is a good
predictor of stroke incidence as well as prevalent stroke.10,11
Moreover, Cupini and coworkers8 demonstrated that CCA
IMT values are higher in patients with nonlacunar stroke than
in those with lacunar stroke, thereby lending further support
to the notion that an increased IMT is a marker of atherosclerotic (ie, nonlacunar) cerebrovascular complications
rather than of microvascular (lacunar) lesions. For these
reasons and because they are easier to perform and more
reproducible, we restricted our measurements in the current
study to the CCA.
Because an increased IMT may develop in response to high
shear forces,12 any difference between the left and right
carotid artery IMT may reflect a differential effect of hemodynamic stress. Taking this a bit further, one could hypothesize that a left-right difference in the effects of hypertension
on the cerebral vasculature may lead to an asymmetrical
distribution of strokes as well. To examine this possibility, we
also performed a retrospective analysis of the Maastricht
Stroke Registry, which contains data on all stroke patients
admitted to our hospital since 1988. This was done to assess
whether there is a side preference in the occurrence of
nonlacunar stroke in patients known to have been hypertensive before their stroke.
Methods
Study 1: IMT Measurements
Patients were selected from the hypertension outpatient clinic of the
Department of Internal Medicine of the University Hospital of
Maastricht. As part of the local protocol, IMT measurements were
performed in all patients. For the current analysis, we selected 102
Received October 9, 2002; first decision November 12, 2002; revision accepted May 9, 2003.
From the Departments of Internal Medicine (S.A.R.H., A.A.K., P.W.d.L.), Clinical Neurophysiology (W.H.M.), and Neurology (J.L.), University
Hospital Maastricht, The Netherlands; the Department of Psychiatry and Neuropsychology, Maastricht University (S.A.R.H., M.P.J.v.B., J.J.); European
Graduate School of Neuroscience (EURON) (M.P.J.v.B., J.J.); and Cardiovascular Research Institute Maastricht (CARIM) (S.A.R.H., A.A.K., W.H.M.,
J.L., P.W.d.L.).
Correspondence to Peter W. de Leeuw, MD, PhD, Department of Internal Medicine, University Hospital Maastricht, Postbus 5800, 6202 AZ
Maastricht, The Netherlands. E-mail: [email protected]
© 2003 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000077983.66161.6F
56
Rodríquez Hernández et al
Side Predilection for Cerebrovascular Disease
57
Figure 1. Left-sided versus right-sided
carotid IMT (n⫽102). Left, Scatterplot of
data with regression line and 95% mean
confidence interval. Right, Bland-Altman
plot of the difference between left (L) and
right (R) IMT as a function of their
means.
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untreated hypertensive patients in whom no known cause for their
hypertension could be detected, who did not have any symptoms
suggestive of cerebrovascular disease or prior stroke and who
otherwise were also free of apparent cardiovascular complications.
This specific population was chosen because hypertension is a major
determinant of IMT and stroke13,14 and because the absence of
cardiovascular complications would render secondary changes of
IMT less likely. Blood pressure was measured before each IMT
measurement after 5 minutes of rest in sitting position. Measurements of the IMT of the posterior wall as well as of lumen diameters
of the left and right CCA were obtained 1 cm proximal to the bulb
from an anterolateral and posterolateral view (SONOS 5500;
Agilent-Philips; linear array transducer, 3 to 11 MHz). The left and
right arteries were investigated in random order.
End-diastolic B-mode images of the IMT were analyzed off-line
with an automated edge-tracking method (M’ath, version 2.0.1).15,16
The average IMT was measured over a length of 10 mm, and the
mean of both the anterolateral and posterolateral view at each side
was calculated and used for further analyses. In addition, flow
velocity indexes, that is, mean velocity (cm/s), pulsatility index [PI],
and resistance index [RI], were derived from the Doppler spectrum.
PI and RI were calculated as follows: PI⫽ (S⫺D)/MN and
RI⫽(S⫺D)/S, in which S and D indicate systolic and diastolic
velocity (cm/s), respectively, and MN mean velocity (cm/s). The
cross-sectional area of IMT (CSA⫺IMT) was calculated according
to the formula CSA⫺IMT⫽3.14⫻IMT⫻(IMT⫹D), in which D is
lumen diameter (mm).9
Measurements were performed in random order by 4 experienced
operators, none of whom was aware of the purpose of the study. In
addition, they were unaware of the left/right randomization of the
images. Although patients were informed about the purpose of the
IMT measurements, they did not know that this comprised evaluation of a left-right difference in IMT.
Study 2: Stroke Registry
The Maastricht Stroke Registry is a large database containing the
clinical, functional, and outcome data of all patients that have been
admitted to our hospital with a stroke.13 The Registry started in 1988
and at the time of this study had data on 1843 patients. We explored
the Registry and compared the prevalence of first-ever territorial
cerebral infarcts and cardio-embolic stroke in both hemispheres. In
addition, we looked at side differences for small deep lacunar
infarcts, because this type of infarct would not be expected to occur
more frequently on one side. Definitions to classify stroke subtypes
have been described before13 and are based on the Trial of Org 10172
in Acute Stroke Treatment (TOAST) criteria.17 Analyses were
performed for the whole group of patients with first-ever stroke as
well as for the subgroup of patients who were known to be
hypertensive.
The study was approved by the Medical Ethics Committee of
Maastricht University Hospital and performed according to the
institutional guidelines. All subjects or, if necessary, the next of kin,
gave written informed consent to use patient data for this type of
scientific evaluation.
Statistical Analysis
Differences in IMT between the left and right CCA were determined
by means of t tests for paired samples. The concordance between left
and right IMT was analyzed by linear regression. Bland-Altman
analysis was used to assess systematic differences between both
sides.18 Proportional differences between stroke subgroups were
determined by means of ␹2 tests. Data are shown as mean⫾SD,
unless indicated otherwise. A probability value ⬍0.05 was considered statistically significant.
Results
Study 1
The mean age of the 102 hypertensive subjects was 56⫾11
years, 60% were men, and body mass index averaged 29⫾6
kg/m2. Office systolic and diastolic blood pressures were
165⫾7 and 94⫾8 mm Hg, respectively. A close relationship
was found between the IMT of both sides (regression equation y⫽0.5755x⫹0.2844; R2⫽0.4528; P⬍0.001; Figure 1, left
panel). Table 1 shows the IMT of the left and right carotid
artery: 0.75⫾0.11 mm and 0.71⫾0.11 mm, respectively
(P⬍0.001). The mean left-right difference was
0.03⫾0.09 mm, with no systematic deviation at any level of
average IMT (Figure 1, right panel). Although both left and
right IMT tended to increase with age and with the level of
systolic blood pressure, none of the relationships reached
statistical significance in simple regression analysis. However, when patients were divided in quartiles by age, the
left-right difference appeared to increase with age in subjects
younger than 60 years; thereafter, the difference became
again smaller (Figure 2). There was no significant difference
in lumen diameter between both carotids (Table 1). Differences in IMT between the left and right side remained
significant after correction for the luminal diameter. As
shown in Table 1, the cross-sectional area of the intima-media
complex was greater at the left side as well. Mean blood flow
velocities in the left and right carotid artery at the side where
the IMT measurements were done were 41.1⫾9.4 cm/s
versus 39.3⫾9.8 cm/s, respectively (P⫽0.004). No differTABLE 1. Echo Doppler Characteristics of Left and Right
Common Carotid Artery
Variable
Left
Right
IMT, mm
0.75⫾0.11
0.71⫾0.11
Lumen, mm
P
⬍0.001*
7.5⫾1.0
7.6⫾1.0
NS
PI
1.18⫾0.39
1.19⫾0.40
NS
RI
0.64⫾0.09
0.64⫾0.10
NS
Mean velocity, cm/s
41.1⫾9.4
39.3⫾9.8
0.004*
CSA-IMT, mm2
10.6⫾3.0
9.9⫾2.7
0.001*
IMT indicates intima media thickness; PI, pulsatility index; RI, resistance
index; CSA-IMT, cross sectional area of IMT; and NS, not significantly different.
*t test for paired samples.
58
Hypertension
July 2003
Figure 2. Mean difference and 95% confidence intervals for difference between left and right IMT by quartiles of age. Q1–Q4
indicates quartile 1 to 4; *P⬍0.01 compared with quartile 1.
ences between left and right arteries could be found with
respect to PI and RI (Table 1). Results were similar for all 4
observers.
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Study 2
The median age of all patients (n⫽1843) in this database was
72 years (range, 25 to 99), 51% of patients were men, and
50% had known hypertension (systolic blood pressure
ⱖ160 mm Hg and/or diastolic blood pressure ⱖ90 mm Hg).
Lacunar infarcts appeared to be symmetrically distributed
(Table 2). In contrast, for nonlacunar strokes, we found a
predilection for side: both atherosclerotic and cardio-embolic
stroke subtypes were significantly more frequent in the left
hemisphere: ␹2⫽9.81; OR, 1.39 (95% CI, 1.13 to 1.70), and
␹2⫽7.49; OR, 1.46 (95% CI, 1.11 to 1.92), respectively
(Table 2). Stroke severity, based on the Renkin classification,
was not different for left-sided and right-sided strokes. When
the analyses were run separately for the subgroup of patients
with known hypertension and for the normotensive patients,
similar results were obtained in both subgroups.
Discussion
The current study shows that in untreated essential hypertensive patients, a difference exists between IMT of the left and
right common carotid artery, with higher values on the left
side. Although the difference is small, it is statistically
significant and of the same magnitude as that observed during
aggressive lipid-lowering therapy.19 Also, cross-sectional
area (as a marker of vascular mass) of the intima-media
complex was larger on the left than on the right side. In most
published studies, IMT values are seldom reported for the left
and right carotid separately. However, in reports in which
data are actually given for both sides, the IMT of the left CCA
tends, on average, to be larger than on the right.9,20 Further
TABLE 2. Distribution of Stroke Subtypes in the Maastricht
Stroke Registry
Subtypes
Number
Left (%)
Right (%)
Lacunar
721
357 (49.9)
364 (50.1)
Cardioembolic
319
188 (58.9)*
131 (41.1)
Atherosclerotic
803
463 (57.7)*
340 (42.3)
All strokes
1843
*P⬍0.001 for left/right difference.
1008 (54.7)
835 (45.3)
analysis revealed that the difference in IMT between both
carotids tends to increase up to an age of about 60 years and
to decline again thereafter. The latter phenomenon may be
due to selection bias, because we deliberately excluded in our
first study patients with overt cerebrovascular disease, and it
may be that those with the highest IMT difference already had
symptoms. Although the clinical significance of the asymmetry in IMT is not yet apparent, the phenomenon should be
taken into account when evaluating the association between
the results of IMT measurements and the occurrence of
cardiovascular complications. Presently, it is common practice to use the average of the left and right carotid IMT in
such associations, but the relationships may run a steeper
course when only the left one is used for analysis.
Whether an increased IMT in hypertensive patients is
indicative of an endothelial abnormality or merely reflects
medial hypertrophy remains a matter of debate.21,22 Certainly,
hypertension is a major determinant of CCA IMT, as demonstrated in various studies.20,22,23 Since medial hypertrophy
typically is an adaptive response to an elevated pressure, a
larger IMT at a certain segment of the vasculature in a
hypertensive patient would point toward a higher transmural
pressure gradient at that site if indeed IMT predominantly
represents medial structures. In that case, one would also
expect a greater number of lacunar infarcts in the same
vascular territory because these lesions are related to microvascular disease for which hypertension is a risk factor. This,
however, is not borne out by our findings, which showed a
symmetrical distribution of lacunar infarcts. Therefore, our
data suggest that the left-right difference in IMT should
probably be interpreted in terms of intimal changes rather
than medial hypertrophy. Nevertheless, whether the increased
IMT in the left carotid artery is due to greater intimal
hyperplasia or to more extensive medial hypertrophy, both
conditions could be viewed as a sequel of increased hemodynamic stress at that side. If these differential effects of
hemodynamic forces were to be a general phenomenon, one
could then expect a side preference for the occurrence of
nonlacunar stroke as well. This is, indeed, supported by our
observation of an anatomic predilection of nonlacunar strokes
in the left hemisphere. Nonlacunar strokes can be divided into
atherosclerotic and cardio-embolic subtypes. Generally, lacunar strokes are caused by local obstruction and not by
embolism, whereas most cardio-embolic strokes occur in the
absence of carotid disease. Therefore, the similarity between
cardio embolic and atherosclerotic strokes with regard to
predilection to the left hemisphere in our study suggests again
a role for hemodynamic factors. These may cause more
cardiac emboli to enter the left carotid system and more often
affect the left carotid artery structure.
The preferential occurrence of cerebrovascular pathology
at the left side could be due to hemodynamic effects related
to the specific anatomy of the carotid vessels. Whereas the
right common carotid artery arises from the brachiocephalic
trunk (generally at a right angle to the flow of the innominate
artery), the left one stems directly from the aortic arch and
runs more in an even line with the ascending aorta. As a
corollary, energy transfer from systolic emptying forces may
be greater in the left carotid than in the right one, where part
Rodríquez Hernández et al
Side Predilection for Cerebrovascular Disease
59
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of the flow vector energy will be reduced by the innominate
artery. This is further supported by our observation that mean
flow velocity was significantly higher in the left than in the
right carotid artery. Consequently, high or oscillating shear
forces, which are strong determinants of adaptive intimal
thickening,12 will be different in both arteries. Whereas
intimal thickening at sites of high shear stress does not in
itself proceed to atherosclerosis, marked oscillations in the
direction of wall shear may enhance atherogenesis at more
distally located sites.24 From a different perspective, however,
we also need to consider the possibility that blood flow
through the aortic arch could play a role, as ulcerated plaques
at this side may cause embolic stroke.25
To the best of our knowledge, no data have been published
with regard to side predilection of cerebrovascular disease.
Taken together, however, our 2 studies support the notion that
such a predilection exists. Whereas study 1 suggests that the
higher IMT in the left carotid reflects greater hemodynamic
stress in the left cerebrovascular system, the results from
study 2 suggest (by extrapolation) that the higher frequency
of left-sided stroke may the consequence of this greater
sensibility of the left cerebrovascular system to hypertensive
stress.
relationship. Only prospective follow-up studies would be
able to assess whether a higher IMT at one side predicts
future stroke in the same vascular territory. Moreover, despite
the fact that some investigators have found significant associations between CCA IMT and atherosclerosis elsewhere in
the carotid system,28,29 so far no evidence is available that
changes in IMT are causally related to plaque formation and
stroke. Nevertheless, the current results allow us to conclude
that the left cerebrovascular system probably is affected
adversely more from the hypertensive process than the right
one.
Limitations
This work was supported by grants from the University Hospital
Maastricht (code No. T88), Maastricht, The Netherlands, and from
the Dutch Brain Foundation.
Obviously, several limitations apply to our 2 studies. First,
the increased IMT at the left side probably reflects a higher
hemodynamic stress in large conduit arteries but not necessarily in small resistance arteries. Our observation that lacunar infarcts do not show a side preference provides indirect
support for the hypothesis that greater hemodynamic stress
manifests itself primarily at the level of the greater arteries.
Second, our IMT studies have focused only on the CCA.
Although several studies have shown that a thicker intimamedia complex of the internal carotid artery is a valid marker
of atherosclerotic complications,10,26 a higher IMT of the
CCA remains a good predictor of stroke incidence,10 and
patients with brain infarction have a greater IMT of the far
wall of both common carotid arteries than control subjects.27
For these reasons and because they are easier to perform and
more reproducible, we restricted our measurements in the
current study to the CCA. Third, one could argue that the
differences in the site of strokes may have resulted from
admission bias in this particular cohort of patients: left
hemispheric infarcts may be more symptomatic and rated by
physicians as more severe. However, the initial stroke severity in our Registry was similar between left and right
hemispheric infarcts, which make such a bias less likely.
Finally, we compared stroke rates in a different population
than the one in which we obtained IMT measurements, and,
contrary to study 1, only half of the patients in study 2 had
hypertension. Although this may confound the potential
influence of hypertension on stroke in the study 2 population,
our data are still in accordance with the assumption that the
cerebral vasculature is more susceptible to damage at the left
side.28 In addition, we want to emphasize that the higher IMT
in the left CCA and the more frequent occurrence of stroke in
the left hemisphere do not necessarily reflect a common
pathophysiological mechanism or even a cause-and-effect
Perspectives
We have shown an increased susceptibility of the left cerebral
vessels in hypertensive patients. Further prospective studies
investigating the relationship of IMT and stroke in the same
cohort are necessary to evaluate whether an increased IMT at
the left side predisposes to nonlacunar infarcts at the same
side. Furthermore, our findings may set the stage for an early,
differential preventive strategy for left or right carotid artery
disease. This may be highly relevant, as the left hemisphere is
dominant in most people.
Acknowledgments
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Is There a Side Predilection for Cerebrovascular Disease?
Sergio A. Rodríguez Hernández, Abraham A. Kroon, Martin P.J. van Boxtel, Werner H. Mess,
Jan Lodder, Jelle Jolles and Peter W. de Leeuw
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Hypertension. 2003;42:56-60; originally published online June 16, 2003;
doi: 10.1161/01.HYP.0000077983.66161.6F
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