Clinical Science (2004) 106, 613–618 (Printed in Great Britain)
Increased arterial stiffening and thickening in the
paretic lower limb in patients with hemiparesis
Reiko OKABE∗ †, Masaaki INABA∗ , Shinrei SAKAI∗ †, Eiji ISHIMURA∗ ,
Atsushi MORIGUCHI†, Tetsuo SHOJI∗ and Yoshiki NISHIZAWA∗
∗
Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3,
Asahi-machi, Abeno-ku, Osaka 545-8585, Japan, and †Department of Internal Medicine, Hanwa Second Senboku Hospital,
3176, Fukai Kitamachi, Sakai City, Osaka 599-8271, Japan
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Atherosclerosis has two key components, thickening and stiffening of arterial wall. These
parameters are quantified ultrasonographically by IMT (intima-media thickness) and PWV (pulse
wave velocity). In the present study, we determined the FA IMT (IMT of the bilateral femoral
artery) and PWV of femoral–ankle (PWV fa) and brachial–ankle (PWV ba) segments in order
to examine whether the degree of atherosclerosis is different between paretic and non-paretic
lower limbs in 24 patients with hemiparesis. The values of PWV fa, PWV ba and FA IMT were all
significantly greater on the paretic than the non-paretic side. Furthermore, significant decreases in
masses of muscle, bone and fat, determined by dual-energy X-ray absorptiometry, were observed
in paretic lower limbs compared with the non-paretic side. PWV fa correlated significantly and
negatively with muscle mass (r = − 0.488, P = 0.0004) and tended to correlate negatively with
BMC (bone mineral content; r = − 0.264, P = 0.069) when statistical analyses were performed
with the paretic and non-paretic sides together. Multiple regression analysis elucidated that the
muscle mass was associated significantly with PWV fa and PWV ba, independent of age, duration
after cerebrovascular accident, gender, bone and fat mass and FA IMT. The muscle mass was
still associated with increased PWV fa and PWV ba when multivariate analysis was conducted
independently in the paretic and non-paretic sides. In summary, our results indicated that arterial
thickening and stiffening were greater on the paretic than the non-paretic side and suggested that
a decrease of muscle mass might be associated with increased arterial stiffening in the paretic
lower limb.
INTRODUCTION
It has been well documented that wasting of muscle and
bone masses in the paretic limb is a prominent feature
of hemiplegia and hemiparesis [1–4], because of longstanding disuse of the affected side [5–8]. Muscle wasting
in the affected side causes greater vascular resistance,
due to a decrease in venule density in skeletal muscle,
leading to lower muscle flow rates [9]. Since it has
been reported previously [10] that a decrease in muscle
blood flow in the paretic side is associated with the
development of insulin resistance and increased shear
stress, it is possible that muscle wasting may cause
the progression of local atherosclerosis in the paretic
side by increasing vascular injury. Alternatively, it is
known that bone loss is one of the major risk factors
for the exacerbation of atherosclerosis and that the
administration of a bone antiresorptive drug reverses
Key words: atherosclerosis, hemiparesis, intima-media thickness, osteoporosis, pulse wave velocity.
Abbreviations: BMC, bone mineral content; CV, coefficient of variation; CVA, cerebrovascular accident; IMT, intima-media
thickness; FA IMT, IMT of the femoral artery; PWV, pulse wave velocity; PWV ba, PWV of the brachial–ankle segment; PWV fa,
PWV of the femoral–ankle segment.
Correspondence: Dr Masaaki Inaba ([email protected]).
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the development of atherosclerosis in diabetic patients
[11].
The aim of the present study was to examine (i) whether
or not arterial stiffening and thickening progresses
preferentially in the paretic limb, and (ii) the correlation
between alterations in arterial properties and muscle
wasting or bone loss to elucidate the importance of these
factors in an acceleration of arterial stiffening and
thickening.
METHODS
Subjects
Twenty-four patients, 10 females and 14 males, were
enrolled into the present study after written informed
consent was obtained. The protocol was approved by the
Ethics Committee of Hanwa Second Senboku Hospital.
The patients were selected from in-patients at Hanwa
Senboku Second Hospital, who had experienced an episode of CVA (cerebrovascular accident) at least 3 months
before and were stable with regards to physical ability
and daily activity. These patients were admitted to Hanwa
Senboku Second Hospital for physical and occupational
therapy. Hemiparesis affected the right side in 13 patients
and the left side in 11 patients. The mean +
− S.D. age was
68.9 +
1.8
years,
ranging
from
57–86
years.
The mean
−
period after the episode of CVA was 6.21 +
1.13
months
−
(range, 4–24 months). Age distribution did not differ
significantly between female and male patients.
Measurements of BMC (bone mineral
content), body fat mass and body muscle
BMC, muscle mass and fat mass of both legs were
measured by dual-energy X-ray absorptiometry using a
Hologic QDR-1000 instrument (Hologic Inc., Waltham,
MA, U.S.A.) [12]. The precision was performed by
measurement of the calibration phantom, with a CV
(coefficient of variation) of 0.54 % (n = 120). The CV of
BMC from 10 volunteers measured twice within the same
day was 0.65 %, as reported previously [13].
PWV (pulse wave velocity)
An automatic waveform analyser (model BP-203RPE;
Colin Co, Komaki, Japan) was used to measure PWV
simultaneously with blood pressure, ECG and heart
sounds as described previously [14,15]. Briefly, subjects
were examined in the supine position after 5 min of
bed rest, with ECG electrodes placed on both wrists, a
microphone for detecting hearts sounds placed on the
left edge of the sternum, and cuffs wrapped on both
the brachium and ankles. The cuffs were connected to
a plethymographic sensor that determines volume pulse
form and an oscillometric pressure sensor that measures
blood pressure. PWV was recorded using a semicon
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ductor pressure sensor (the sample acquisition frequency
for PWV was set at 1200 Hz). Volume waveforms for the
brachial and ankle arteries were stored, and the sampling
time was 10 s with automatic gain analysis and quality
adjustment.
The time interval between the wavefront of the brachial
waveform and that of the ankle waveform was defined as
T ba (the time interval between the brachial and ankle
arteries). Dba (distance between sampling points of the
brachial–ankle arteries) was calculated automatically on
the basis of the height of the subject. Lb (path length
from the suprasternal notch to the brachium) was obtained from superficial measurements and was expressed
using the following equation:
Lb = 0.2195 × height of the patient (cm) − 2.0734
La (path length from the suprasternal notch to the ankle)
was obtained from superficial measurements and was
expressed using the following equation:
La = 0.8129 × height of the patient (cm) + 12.328
Finally, the following equation was used to obtain the
PWV ba (PWV of the brachial–ankle segment)
PWV ba = (La − Lb )/Tba
In the same way, the time interval between the wavefront of the femoral waveform and that of the ankle
waveform was defined as T fa (the time interval
between the femoral and ankle arteries). The distance between sampling points of the PWV fa (PWV for the
femoral–ankle segment) was calculated automatically
according to the height of the subject. Lfa (path length
from the femoral to the ankle arteries) was obtained from
superficial measurements and was expressed using the
following equation:
Lfa = 0.2486 × height of the patient (cm) + 30.709
PWV fa was obtained by dividing Lfa by T fa .
Reproducibility of the PWV measurement was evaluated by repeating measurements in 17 healthy subjects
on two different occasions. CVs were 1.9 % and 3.3 %
for PWV ba and PWV fa respectively [15].
Ultrasonographical measurements of FA
IMT (femoral artery intima-media
thickness)
Ultrasonographical B-mode imaging of the femoral
artery was performed with a high-resolution real-time
ultrasonography with a 10 MHz in-line Sectascanner
(model SSD 650 CL; Aloka, Tokyo, Japan), as described
previously [16,17]. To avoid inter-observer variability,
all IMT measurements were performed by the same
examiner. Briefly, the femoral artery was scanned at the
level of the bifurcation on both sides. IMT was measured
in the far wall of the femoral artery at sites of the most
Increased arterial stiffening in paretic limb
advanced arterial thickening as diffuse and continuous
projection with the greatest distance between the lumen–
intimal interface and the media–adventitial interface, but
without an atherosclerotic plaque, which was defined as
localized lesions of thickness more than 2.0 mm, from
digitized still images of the arteries during scanning
[17–19]. These interfaces were manually traced. Three
still images from the same section of the artery were
measured from which the mean IMT value was calculated.
Reproducibility of FA IMT measurement was acceptable
as shown by a CV of 3.4 %.
Statistical analysis
Data were analysed using the StatView 5.0 J program
(Abacus Concepts, Inc., Berkeley, CA, U.S.A.). Values are
means +
− S.D. unless otherwise indicated. The differences
in the means between paretic and non-paretic sides were
analysed by Student’s t test. Correlation coefficients
were calculated by simple regression analysis. Multiple
regression analyses were performed to assess the
association of various clinical factors with PWV fa and ba.
P values < 0.05 were considered statistically significant.
Figure 1 PWV fa (a), PWV ba (b) and IMT (c) in the
paretic and non-paretic limbs of patients with hemiparesis/
hemiplegia
Open bars, paretic side; hatched bars, non-paretic side.
RESULTS
Comparison of arterial stiffening and
thickening and various body components
between paretic and non-paretic
lower limbs
The values of PWV fa, PWV ba and FA IMT were all
significantly increased (by 9.0 +
− 2.3, 10.5 +
− 2.2 and
10.3 +
3.0
%
respectively)
on
the
paretic side compared
−
with the non-paretic side (Figure 1). Figure 2 shows the
comparison of body components between the paretic
and non-paretic lower limbs. Muscle mass, BMC and fat
mass on the paretic side were all significantly decreased
by 10.7 +
− 2.4 %, 41.9 +
− 3.5 % and 5.4 +
− 1.8 % of the
respective values on the non-paretic side.
Correlations between muscle mass, BMC
and fat mass in lower limbs
Muscle mass in lower limbs correlated significantly and
positively with BMC (r = 0.568, P < 0.0001) and fat mass
(r = 0.41, P = 0.0161) in lower limbs when analysis was
performed together with the paretic and non-paretic
sides. However, BMC failed to correlate with fat mass
(r = 0.025, P = 0.865).
Correlations between markers of arterial
stiffening and thickening and body
components in lower limbs
Table 1 shows that PWV ba correlated significantly and
positively with PWV fa (r = 0.924, P < 0.0001), although
Figure 2 Muscle mass (a), bone mineral content (b) and
fat mass (c) in the paretic and non-paretic limbs of patients
with hemiparesis/hemiplegia
Open bars, paretic side; hatched bars, non-paretic side.
Table 1 Correlations between markers of arterial stiffening
and thickening and body components in lower extremities
(paretic plus non-paretic sides)
Values are standard regression coefficients. ∗ P < 0.05,
∗∗∗
P < 0.01.
PWV fa (cm/s)
PWV ba (cm/s)
FA IMT (mm)
∗∗
0.05 < P < 0.10 and
PWV ba
(cm/s)
FA IMT
(mm)
BMC
(g)
Muscle mass
(g)
Fat mass
(g)
0.924∗∗∗
–
–
0.092
0.099
–
− 0.264∗∗
− 0.342∗
0.023
− 0.488∗∗∗
− 0.589∗∗∗
0.095
− 0.153
− 0.158
0.109
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Figure 3 Correlation between PWV ba and muscle mass (a), bone mineral content (b) and fat mass (c) in patients with
hemiparesis/hemiplegia
Table 2 Multiple regression analysis of factors independently associated with PWV ba and PWV fa in both the paretic
plus non-paretic sides in hemiparetic patients
Table 3 Multiple regression analysis of factors independently associated with PWV fa and PWV ba in hemiparetic
patients
Values are standard regression coefficients. R2 , multiple coefficient of
determination. ∗ P < 0.05 and ∗∗ P < 0.01.
Values are standard regression coefficients. R2 , multiple coefficient of
determination. ∗ P < 0.05 and ∗∗ 0.05 < P < 0.1.
Dependent variable
Dependent variable
Independent variable
PWV fa
PWV ba
Age
Duration after CVA
Muscle mass
BMC
Fat mass
FA IMT
R2
− 0.050
− 0.126
− 0.627∗∗
0.045
− 0.025
− 0.031
0.259∗
0.178
− 0.059
− 0.670∗∗
0.069
0.067
− 0.078
0.382∗
neither PWV ba nor PWV fa correlated significantly
with FA IMT. PWV ba correlated significantly and
negatively with muscle mass (r = − 0.589, P < 0.0001)
and BMC (r = − 0.342, P = 0.017), but not with fat
mass (r = − 0.158, P = 0.283) (Figure 3). PWV fa had
a significant and negative correlation with muscle mass
(r = − 0.488, P = 0.0004), a tendency towards a negative
correlation with BMC (r = − 0.264, P = 0.069), but no
correlation with fat mass (r = − 0.153, P = 0.1154). FA
IMT did not correlate significantly with muscle mass,
BMC or fat mass.
Multiple regression analysis of factors
independently associated with PWV ba
and PWV fa in hemiparetic patients
Table 2 shows the multiple regression performed with
the paretic and non-paretic sides together. Muscle mass
was associated significantly with increased PWV ba
and PWV fa, independent of age, duration after CVA,
BMC, fat mass and FA IMT when the analysis was
conducted in both paretic and non-paretic limbs. Even
when the association of those parameters with PWV
fa and PWV ba were examined independently in the
paretic and non-paretic limbs, muscle mass was again
significantly and independently associated with PWV ba
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Paretic side
Non-paretic side
Independent variable
PWV fa
PWV ba
PWV fa
PWV ba
Age
Duration after CVA
Muscle mass
BMC
Fat mass
FA IMT
R2
− 0.153
− 0.364
− 0.507∗
− 0.067
0.109
− 0.180
0.395
0.080
− 0.244
− 0.564∗
− 0.060
0.162
− 0.151
0.463
0.018
− 0.157
− 0.485∗∗
− 0.328
0.055
− 0.065
0.395
0.226
− 0.030
− 0.538∗
− 0.105
0.027
− 0.115
0.463
on either side. Likewise, PWV fa was also significantly
and independently associated in the paretic limb, and
tended to be associated with PWV fa in the non-paretic
limb (Table 3).
DISCUSSION
A marked decrease in blood flow in the affected limb
is commonly observed in the patients with hemiplegia/
hemiparesis following CVA [20]. In the present study, we
have elucidated structural abnormalities of the femoral
artery in the paretic limb characterized by increased
arterial stiffening and thickening, as shown by increased
PWV ba, PWV fa and FA IMT. Since IMT and PWV
provide a relevant assay for quantifying arterial thickening and stiffening respectively, our data clearly indicated
that arterial thickening and stiffening were both increased
in paretic lower limbs compared with the non-paretic
side. Furthermore, we have demonstrated that decreased
muscle mass may be one of the major factors for increased
arterial stiffening of paretic lower limbs in patients with
hemiparesis/hemiplegia.
Wasting of muscle is a prominent feature of hemiplegia/hemiparesis. Previous reports demonstrated that
Increased arterial stiffening in paretic limb
the muscle blood flow, measured using a radioisotope
(133 Xe)-clearance method [21], was decreased significantly in the paretic limb. As muscle mass decreases,
vascular resistance becomes greater, leading to lower
muscle flow rates in the affected limbs [22]. Increased
shear stress, due to increased vascular resistance, may
contribute to the progression of local atherosclerosis in
the paretic side by increasing vascular injury [23].
An increase in basal vascular resistance in the hindlimb
of the sedentary spontaneously hypertensive rats is
significantly decreased after training [24]. Its mechanism
is explained by training-induced increase of venule
density in skeletal muscle. Alternatively, physical exercise
may exert its effect on vascular function by decreasing
insulin resistance. Asymmetrical training of the upper
limbs is accompanied by a greater distensibility of the
middle-sized arteries of the more trained side [25].
Previous studies have reported improved vascular endothelial function in the upper limb after hand-grip exercise
training in the patients with congestive heart failure
[26,27], suggesting that the beneficial effect of training
on vascular endothelial function may be localized to the
side where muscle mass is increased.
Previous work has demonstrated that hindlimb unloading rapidly diminishes blood flow to the femoral and
tibial metaphysis (cancellous bone), diaphysis (cortical
bone), and marrow [28] that appears to coincide with a
diminished mineral apposition rate, density and mass of
both cortical and cancellous bone observed in hindlimb
unloading in rats [29–35]. The hypothesis was proposed
that the hindlimb-unloading-induced decrease in blood
perfusion to bone leads to bone loss by both stimulating
bone resorption and inhibiting bone formation. It is
possible that the hindlimb-unloading-induced decreases
in blood flow and increases in shear stress alter vascular
endothelial cell release of NO (nitric oxide) and PGI2
(prostaglandin I2 ), which could subsequently modify the
focal balance between osteoblast and osteoclast activity.
Furthermore, the acute increase in blood flow to the
bones of the forelimb, shoulder and head appears to
coincide with some reports of increased bone mass in
hindlimb unloading in rats [33]. Therefore a correlation
between PWV and BMC may suggest that decreased
blood flow may cause bone loss in the affected side of
hemiparetic patients. Another possibility is that enhanced
release of calcium from bone in the paretic lower limb may
enhance atherosclerosis locally, since etidronate, a bone
antiresportive bisphosphoante, was reported to reverse
atherosclerosis in diabetic patients [36].
Multiple regression analysis elucidated that the muscle
mass was significantly associated with PWV fa and PWV
ba, independent of age, duration after CVA, bone and
fat mass and FA IMT (Table 2). Furthermore, even
when multiple regression analysis was performed independently in the paretic and non-paretic sides, muscle
mass still emerged as an independent factor associated
with PWV fa and PWV ba (Table 2). However, bone mass
failed to appear as an independent factor associated with
PWV fa and PWV ba. These data clearly indicated that the
decrease of muscle mass may be a factor independently
associated with accelerated atherosclerosis in paretic
limbs of hemiparetic patients.
The limitation of the present study is that it is purely
observational, since it is possible that increased PWV
may cause a decrease in muscle blood flow, resulting
in the decrease of muscle mass. Furthermore, since the
alteration of arterial properties demonstrated in the present study only increased arterial thickening and
stiffening in paretic lower limbs, as reflected by increased
IMT and PWV, there is no direct histopathological
evidence that increased IMT or PWV in paretic lower
limbs is due to atherosclerosis. Therefore it is possible
that the arterial stiffening and thickening of the femoral
artery in paretic lower limbs might be the result of another
non-atherosclerotic arteriopathy.
In summary, our results indicated that the decrease
in muscle mass is a major factor independently associated
with the local increase in arterial thickening and stiffening
in paretic limbs of hemiparesis/hemiplegia patients.
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Received 24 November 2003/26 January 2004; accepted 5 February 2004
Published as Immediate Publication 5 February 2004, DOI 10.1042/CS20030387
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2004 The Biochemical Society