34
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9.
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11.
STROKE
ease: a retrospective study of 769 patients. Acta Neurol Scand
Suppl 38: 1969
Lehman JF, DeLateur BJ, Fowler RS, etal: Stroke rehabilitation:
outcome and prediction. Arch Phys Med Rehab 56: 383-389, 1975
Miah K, von Arbin M, Britton M, et al: Prognosis in acute stroke
with special reference to some cardiac factors. J Chron Dis 36:
279-288, 1983
Oxbiiry JM, Greenhall RCD, Grainger KMR: Predicting the outcome of stroke: acute stage after cerebral infarction. Br Med J 3:
125-127, 1975
Britton M, de Faire U, Helmers C, Miah K: Prognostication in
acute cerebrovascular disease. Acta Med Scand 207: 37-42, 1980
Strand T, Asplund K, Eriksson S, et al: A randomized controlled
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VOL
16,
No
1, JANUARY-FEBRUARY
1985
trial of hemodilution therapy in ischemic stroke. Stroke 16: (in
press)
Feigenson JS, McCarthy ML: Stroke rehabilitation II. Guidelines
for establishing a stroke rehabilitation unit. N Y State J Med 77:
1430-1434, 1977
Feigenson JS, McDowell FH, Meese P, et al: Factors influencing
outcome and length of stay in a stroke rehabilitation unit. Part 1.
Analysis of 248 unscreened patients — medical and functional
prognostic indicators. Stroke 8: 651-656, 1977
Stern PH, McDowell F, Miller JM, et al: Factors influencing stroke
rehabilitation. Stroke 2: 213-218, 1971
Strand T, Asplund K, Eriksson S, Hagg E, Lithner F, Wester PO:
Stroke unit care — who benefits? (In manuscript)
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Serum HDL/Total Cholesterol Ratio and Blood
Pressure in Asymptomatic Atherosclerotic Lesions
of the Cervical Carotid Arteries in Men
TINY VAN MERODE, PAUL HICK, ARNOLD P.G.
HOEKS, AND ROBERT S.
RENEMAN
SUMMARY One hundred neurological!} asymptomatic male subjects (aged 50-69 years), randomly
selected through population registers, were screened for atherosclerotic lesions of the cervical carotid
arteries, using a high resolution multi-gate pulsed Doppler system. In 93 subjects serum was assayed for
total and HDL cholesterol. Besides, cuff arterial blood pressure measurements were made. Twenty-three of
these subjects (Group III) were classified as abnormal according to the Doppler investigation (degree of
narrowing < 50% in 78% of the cases). Seven of these 23 subjects also had a history of ischemic heart
disease or intermittent claudication. Of the 70 subjects with a normal Doppler examination 16 had a history
of ischemic heart disease and/or intermittent claudication (Group II). The remaining 54 subjects served as
controls (Group I). The frequency of asymptomatic atherosclerotic lesions of the cervical carotid arteries in
the population under investigation was 23%. The HDL/total cholesterol ratio was lower and the frequency
of high blood pressure higher in the Groups II and III than in Group I. The findings in this study support the
idea that a low serum HDL/total cholesterol ratio and high blood pressure have a high degree of association
with atherosclerotic lesions of the cervical carotid arteries. This association is already apparent at an early
stage of the disease, i.e. in asymptomatic subjects with a slight to moderate degree of carotid artery
narrowing.
Stroke Vol 16, No I, 1985
RISK FACTORS for carotid artery lesions have been
investigated extensively in the past decades. Especially high blood pressure, serum lipoprotein abnormalities and diabetes were found to be related to the risk of
cerebrovascular disorders like stroke and transient
ischemic attacks. 1 "" These investigations, however,
were performed on patients suffering from these disorders, which means that information has been obtained
about risk factors at a progressed stage of the disease.
Besides, in most of these investigations the control
subjects were assumed to be healthy, despite the fact
that asymptomatic carotid artery lesions may be present in the age groups studied.12"14
In the present investigation arterial blood pressure as
From the Departments of Physiology and Biophysics, Biomedical
Centre, University of Limburg, Maastricht, The Netherlands.
This work was supported by the Dutch Heart Foundation and Fungo
which is subsidized by the Netherlands Organization for the Advancement of Pure Research.
Address correspondence to: R.S. Reneman, M.D., Ph.D., Department of Physiology, Biomedical Center, University of Limburg, P.O.
Box 616, 6200 MD Maastricht, The Netherlands.
Received December 8, 1983; revision #2 accepted June 14, 1984.
well as serum total cholesterol and high density lipoprotein (HDL) cholesterol levels were assessed in
asymptomatic subjects with atherosclerotic lesions of
the cervical carotid arteries and in healthy subjects
without cervical carotid artery lesions. The subjects
were randomly selected through the population registers of small, average and large urban and rural towns,
and screened for cervical carotid artery lesions using a
high resolution multi-gate pulsed Doppler system.15"17
Arterial lesions were diagnosed, using the criteria of
spectral broadening as developed for pulsed Doppler
systems18-l9 and adapted to the characteristics of the
multi-gate device. The study was limited to men above
the age of 50 years because cervical carotid artery
lesions are likely to occur infrequently below this
age.20 Men were selected since differences in HDLcholesterol levels between patients and control subjects are often more pronounced in males than in females. 4 6 The serum HDL cholesterol level and the
HDL/total cholesterol ratio were used as indicators for
dyslipoproteinemia because a low HDL-cholesterol
level is considered to be an independent risk factor for
RISK FACTORS AND CAROTID ARTERY LESIONS/ww Merode et al
atherosclerosis.4"8 Moreover, overnight fasting is not
required for accurate assessment of these biochemical
variables21-22 which is a major advantage in studies on
non-hospitalized subjects.
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Materials and Methods
The study was performed on 100 male volunteers
from the Maastricht area, varying in age between 50
and 69 years. Their names and addresses were randomly selected from the population registers of small, average and large urban and rural towns. Two hundred and
fifty subjects were contacted once to obtain 100 volunteers. All respondents were included in the study.
From all volunteers informed consent was obtained
before they entered the study. A history was taken on
symptoms related to atherosclerosis. They all had a
physical examination, including cuff blood pressure
measurements in the supine position. In case of hypertensive blood pressure readings (see below), the measurements were repeated 2-3 times and the lowest value
was taken as the subject's reading.
The cervical carotid arteries were screened for disease, using a high resolution multi-gate pulsed Doppler system15"17 with the following characteristics: emission frequency 6.1 MHz, pulse repetition frequency 18
KHz, emission duration 1.0 [x. s, sample interval 0.5
mm and number of gates 64. The sample volume of
this system as measured in vitro (23) is 1.2 mm3 at a
range of 15 mm and 1.7 mm3 at a range of 20 mm (20).
The Doppler examinations were performed with the
volunteers in the supine position with the head in the
mid-position. Doppler spectra were recorded midstream at various sites in the common, internal and
external carotid arteries. The site of sampling was localized through a velocity image of the bifurcation. All
spectra were stored on a 4-channel tape recorder (Racal; 0-10 KHz-3dB) and analyzed off-line with a Nicolet spectrum analyzer (100 frequency bins, each 100
Hz), providing amplitude as a function of frequency.
For display the amplitude of the spectrum was scaled
with respect to the peak amplitude. The spectra were
classified according to the criteria of spectral broadening as developed for pulsed Doppler systems18- " and
adapted to the characteristics of our multi-gate device
(table 1). Since doubt has been raised whether B classifications always represent cervical carotid artery lesions, even when small sample volumes are used,20
only B classifications associated with disturbed flow
patterns as indicated by other criteria, were considered
to be representative of vessel disease. These criteria
include asymmetry of the velocity profile and/or disturbed instantaneous velocity waveforms along the ultrasound beam, locally or along the whole vessel diameter. Velocity profiles at discrete time intervals during
the cardiac cycle and instantaneous velocity waveforms at various sites along the ultrasound beam can be
recorded on-line with our multi-gate pulsed Doppler
system.24-25 In prospective studies the pulsed Doppler/
spectrum analysis method to detect atherosclerotic lesions of the cervical carotid arteries has been compared
with biplane arteriography. l8 - l9 These studies revealed
that cervical carotid artery lesions associated with a
35
TABLE 1 Grading of Artery Narrowing from the Degree of Spectral Broadening according to Langlois et al's and Breslau'9 and
Adapted to the Characteristics of our Multi-gate Pulsed Doppler
System
Normal
(A) no spectral broadening; max. frequency
<6 kHz*
<15% stenosist
(B) spectral broadening in deceleration phase
of systole; max. frequency <6 kHz
16-49% stenosis
(C) spectral broadening throughout systole;
max. frequency <6 kHz
50-99% stenosis
(D) spectral broadening throughout systole/
increased frequencies in diastole; max. frequency >6 kHz
Total occlusion
(E) No signal
T h e maximum systolic peak frequency for our system was considered to be 6 kHz because of the higher emission frequency and
the slightly steeper angle between vessel and probe in our multi-gate
device than in the ATL Duplex scanner as used by Langlois et al and
Breslau.
tDiameter reduction.
degree of artery narrowing of 16-49% (C classification) and 50-99% (D classification) can be diagnosed
accurately, provided that the sample volume of the
Doppler system is small, as is the case in the present
investigation. In our hands these lesions can be diagnosed with a sensitivity of 89%, a specificity of 83%
and a diagnostic accuracy of 87% as compared to arteriography (unpublished results of a prospective study).
Venous blood was taken from each person in a nonfasting condition for the estimation of total cholesterol
and HDL cholesterol in whole serum. The concentration of total cholesterol in serum was measured after
direct addition of Liebermann-Burchard reagent and
the results were calibrated with human serum pools
with known cholesterol concentrations as described by
Katan and co-investigators.26 Reproducibility for blind
control sera provided by the Centers for Disease Control, Atlanta USA, was within 0.9% and the accuracy
was within 1.6% of the true (target) values. The concentration of cholesterol in HDL was measured after
the precipitation of low and very low density lipoproteins by heparin- MnCl2.27 Reproducibility for blind
control sera as obtained in the Center for Disease Control Survey of HDL-measurements28 was within ±
2.2% and this, with regard to the overall survey mean,
was an average of 0-1%. Blood samples were taken
scattered over the day. This is allowed because previous studies have shown that there are no detectable
differences in the concentrations of total and HDL cholesterol with time of the day and the time interval since
the last meal.21-22 Differences between the mean values
of the variables in the various groups were evaluated
for statistical significance (p < 0.05) in an one-way
analysis of variance as implemented in a standard computer program (BMDP statistical software 1981, p.
106).
Results
In 5 of the 100 volunteers the serum lipid concentrations could not be assessed for technical reasons. Two
subjects were excluded from the study because of insulin-dependent diabetes mellitus.
STROKE
36
TABLE 2 Arteries Involved and the Degrees of Artery Narrowing
in the 23 Subjects with Abnormal Doppler Findings
internal
- <50% stenosis (C)*t
carotid
(n = 18)
artery
(n = 21)
(n = 3)
carotid
artery
lesions
(n = 23)
external
carotid
50-99% stenosis (D)
artery
(n = 2)
*Diameter reduction.
tlncluding 5 patients with multi carotid artery disease.
t
patients with multi carotid artery disease.
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Twenty-three of the remaining 93 subjects had an
abnormal Doppler investigation (30% in the 6th age
decade and 18% in the 7th age decade, a non-significant difference; Pearson x2 test). The arteries involved
and the degree of narrowing are given in table 2. In 21
cases lesions were found in the internal carotid artery,
while the external carotid artery was involved in 2
cases. In 5 subjects multi-vessel disease was observed.
All volunteers were asymptomatic for carotid artery
disease, which means a negative history of stroke,
transient ischemic attacks or amaurosis fugax. The
Doppler examination was normal in the subjects that
were excluded from the serum lipid estimation (see
above). Hence, the frequency of asymptomatic carotid
artery disease in the population under investigation
was 23%. Of the 70 subjects with normal Doppler
findings, 16 had a positive history of angina pectoris,
myocardial infarction and/or intermittent claudication.
Based upon these findings three groups were formed.
One group of normal subjects, consisted of 54 volunteers with normal Doppler findings and no history of
atherosclerotic disease (Group I). A second group consisted of 16 volunteers with normal Doppler findings,
but with a positive history of atherosclerotic disease
(Group II). The third group consisted of the 23 subjects
with abnormal Doppler findings (Group III). Seven of
these subjects had a positive history of angina pectoris
or intermittent claudication. Beta blocking agents were
taken by one subject in Group I (Lopresor (metoprolol)), 9 subjects in group II (6 Inderal (propranolol), 2
Trasicor (oxprenolol), 1 Aptine (alprenolol)) and 2
subjects in Group III (Trasicor). Two subjects in each
group took thiazides (Esidrex).
Twenty-five of the volunteers were hypertensive according to the criteria of the W.H.O. (blood pressure
> 140/90). The frequency of hypertension was significantly higher in the Groups II (4%) and III (35%) than
in Group I (19%). No significant difference could be
detected between the frequency in Group II and Group
III. Diastolic blood pressure was significantly higher
in Group II (87.6 ± 9.9 mmHg; x ± sd) and Group III
(86.0 ± 10.6 mmHg) than in Group I (81.5 ± 8.7
mmHg). The diastolic blood pressure readings in the
Groups II and III were not significantly different. No
VOL
16, No
1, JANUARY-FEBRUARY
1985
TABLE 3 Serum Total and HDL Cholesterol Concentrations
(mmol/l) and HDLITotal Cholesterol Ratio in Normal Subjects
(Group I), Subjects with a Positive History of Atherosclerosis, but
without Detectable Cervical Carotid Artery Lesions (Group II) and
Subjects with Asymptomatic Cervical Carotid Artery Lesions
(Group HI), x ± SD
Group I
(n = 54)
6.02 ±0.85
1.30±0.39
Total cholesterol
HDL cholesterol
HDL/total
cholesterol ratio 0.22 ±0.06
Group II
(n = 16)
6.25 ±0.93
1.05±0.22t
Group III
(n = 23)
6.61 ±1.04*
1.18±0.27
0.17±0.06t
O.18±O.O5t
*Significantly higher than in Group 1.
tSignificantly lower than in Group I.
significant differences could be detected between the
systolic blood pressure readings in the three groups. In
all hypertensive subjects in Group I blood pressure was
lower than 160/95 and hence their hypertensive status
could be considered borderline. Three subjects in
Group II and 3 subjects in Group III were definitely
hypertensive (blood pressure > 160/95). There was no
significant difference in the frequency of hypertension
between the 6th and 7th age decade in the Groups I and
III, but a higher frequency of hypertension in the 6th
age decade in Group II (Pearson x2 test). The groups
were comparable as far as age and heart rate are
concerned.
The serum total and HDL cholesterol concentrations
as well as the HDL/total cholesterol ratio in the various
groups are shown in table 3. The total cholesterol level
was significantly higher in Group III than in Group I,
while the HDL cholesterol level was significantly lower in Group II than in Group I. The HDL/total cholesterol ratio was significantly lower in the Groups II and
III than in Group I. No significant differences could be
detected between the Groups II and HI. The serum
total and HDL cholesterol concentrations, and the
HDL/total cholesterol ratio were similar for hypertensive and non-hypertensive subjects (table 4).
Discussion
In the present study serum total cholesterol was
found to be higher and the serum HDL/total cholesterol
ratio lower in subjects with asymptomatic cervical carotid artery lesions than in age matched subjects devoid
of obvious atherosclerosis as evidenced by a normal
Doppler examination and a negative history of symptoms related to atherosclerosis. In the former subjects
the frequency of hypertension and the diastolic blood
pressure level were higher than in the control subjects.
These findings support the idea that at least in men a
TABLE 4 Serum Total and HDL Cholesterol Concentrations
(mmol/l) and HDL/Total Cholesterol Ratio in Normotensive and
Hypertensive Subjects (x ± SD)
Normotensive
Hypertensive
(n = 25)
(n = 68)
6.14±0.83
Total cholesterol
6.20±1.10
HDL cholesterol
1.23±0.38
1.21 ±0.29
HDL/total cholesterol ratio
0.20 ±0.06
0.20 + 0.06
RISK FACTORS AND CAROTID ARTERY LESIONS/vcm Merode et al
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low serum HDL/total cholesterol ratio3"8 and high
blood pressure 29 -" can be considered as risk factors
for atherosclerotic lesions of the cervical carotid arteries, especially since these aberrations are already observed at an early stage of the disease. In the present
investigation, after all, all subjects were asymptomatic
for cerebrovascular disease, while 78% of the lesions
were associated with less than 50% narrowing of the
artery (table 2). That these risk factors are related to
atherosclerosis is supported by the finding that the
serum lipid disturbances, the frequency of high blood
pressure and the diastolic blood pressure level were
similar in the group with asymptomatic cervical carotid artery lesions (Group III) and in the group of subjects with a history of ischemic heart disease and/or
intermittent claudication (Group II), but with a normal
Doppler examination. Furthermore, 30% of the subjects in Group III also had a history of ischemic heart
disease or intermittent claudication. These findings
also imply that the risk factors under investigation are
indiscriminate as far as the localization of atherosclerosis is concerned. A major advantage of the use of the
serum HDL/total cholesterol ratio as risk factor in epidemiologic studies over other lipids is that overnight
fasting is not required to estimate this ratio accurately. 2122 Several subjects, especially in Group II, were
taking beta-blocking agents or thiazides. Whether this
has influenced the results as obtained in the present
investigation is not known because the effect of these
compounds on serum lipids is still a matter of
debate.5-29"32
In the present investigation the Doppler spectral
classifications A and classifications B with normal velocity profiles and instantaneous velocity waveforms
were grouped and assumed to be representative of normal arteries, despite the fact that B classifications per
se have been considered to be associated with very
minor lesions. In a recent study, however, it was indicated that B classifications per se do not necessarily
reflect cervical carotid artery disease, especially in the
internal carotid artery20 where the flow conditions are
rather complicated, even under normal circumstances.33 On the other hand, the inclusion of subjects
with very minor carotid artery lesions in the group of
normals cannot be excluded when A and some B classifications are combined.
The frequency of asymptomatic cervical carotid artery lesions of 23% as found in this study compares
favorably with the results obtained by Martin and coinvestigators13 in post-mortem studies, but is significantly higher than the incidence of 5.9% found by
Hennerici and his colleagues12 in neurologically
asymptomatic at-risk patients. The latter investigators,
however, only considered patients with a degree of
carotid artery narrowing of more than 50%. The incidence of lesions in this category was 5% in our study, a
value in close agreement with the one described by
Hennerici.
In summary the findings of the present study support
the idea that a low serum HDL/total cholesterol ratio
and high blood pressure have a high degree of associ-
37
ation with atherosclerotic lesions of the cervical carotid arteries. This association is already apparent at an
early stage of the disease.
Acknowledgments
The authors are greatly indebted to Astrid Dingjan for her help in
collecting and processing the blood samples, and to Mr. Z. Kruyswijk
and Dr. C.E. West (Agriculture University, Wageningen) for the estimation of the serum total and HDL cholesterol concentrations. The heip
of Jos Heemskerk and Mariet de Groot in preparing the manuscript is
kindly acknowledged.
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Modification of Cerebral Ischemia With Fluosol
S. J. PEERLESS, M . D . , F.R.C.S.(C), R. NAKAMURA, M . D . ,
A. RODRIGUEZ-SALAZAR, M . D . , AND I. G. HUNTER, B . S C .
SUMMARY Fluosol-DA (Perfluorochemical Blood Substitute) was investigated in a previous study and
found to provide some protection from ischemia and possible usefulness in limiting the size of infarction. In
the present study, larger doses over longer periods of acute focal cerebral ischemia were used. Twenty four
cats had transorbital ligation of the middle cerebral artery (MCA). The 12 experimental animals were given
20% Fluosol-DA. The control group of 12 received isotonic saline solution. Twenty-four hours after the
MCA occlusion, the cats were perfused with saline and phosphate-buffered formalin. The brains were
removed and immersed in 10% formalin for 2 weeks. The results of macroscopic and histological examination suggested that, although Fluosol-DA did not provide complete protection from ischemic injury to the
brains of the cats treated, it may have helped to slow the development of the pathological changes.
Stroke Vol 16, No 1, 1985
SINCE CLARK AND GOLAN 1 pioneered the experimental use of perfluorochemicals as blood substitutes,
there has been much investigation of the oxygen-carrying capability of these substances.
The most promising of these componds, FluosolDA, was developed by the Green Cross Corporation as
an artificial blood substitute which could act as both a
plasma volume-expander and an oxygen carrier. It is
much less toxic than former preparations and has been
used clinically for hemorrhagic shock, extracorporeal
circulation, and elective surgery in Jehovah's Witness
patients. 2
In a previous study, we introduced the idea that the
small fluorocarbon particles (0.1 yum) might infiltrate
the microcirculation, carrying oxygen (O2) to otherwise ischemic cerebral tissue. 3 Our data indicated that
From the Division of Neurosurgery, The University of Western Ontario, London, Ontario, Canada.
Address correspondence to: S. J. Peerless, M.D., Division of Neurosurgery, The University of Western Ontario, London, Ontario, Canada.
Received June 2, 1983; revision # 2 accepted June 15, 1984.
Fluosol-DA did provide some protection from ischemia and might be useful in limiting the size of infarction. The present report is based on further investigation of the effectiveness of Fluosol-DA, using larger
doses over longer periods of acute focal cerebral ischemia.
Material and Methods
Implantation of Occlusive Device (Tourniquet)
Twenty-four cats were anesthetized with intraperitoneal injection of ketamine-HCl (30 mg/kg). Intubation was done for the security of airway and the head
was immobilized in an operating apparatus.
As described in our previous study, the microtourniquet was surgically placed in position, around the
proximal portion of the left MCA. 3 The tourniquet was
not tightened at this time.
During the recovery period of four or five days following the operation, the cats were kept under observation and showed no apparent neurological deficit.
Following this period, each animal was anesthetized
Serum HDL/total cholesterol ratio and blood pressure in asymptomatic atherosclerotic
lesions of the cervical carotid arteries in men.
T van Merode, P Hick, P G Hoeks and R S Reneman
Stroke. 1985;16:34-38
doi: 10.1161/01.STR.16.1.34
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