© 1995 American Heart Association, Inc.
Articles |
Functional and Anatomic Evaluation of Carotid Atherothrombosis
A Combined Study of Indium 111 Platelet Scintigraphy and B-Mode Ultrasonography
From the Division of Nuclear Medicine (H.M., K.H., N.O.), the First Department of Internal Medicine (M.M., N.H., Y.I., T.K.), the Department of Neurology (M.M., M.N.), and the Department of Tracer Kinetics (T.N.), Osaka University Medical School, Suita, Japan.
Correspondence to Hiroshi Moriwaki, MD, First Department of Internal Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita 565, Japan.
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Abstract We examined the relation between in vivo thrombogenicity and the morphology of carotid lesions to clarify the role of platelet deposition in carotid atherothrombosis. We evaluated 60 subjects (120 carotid bifurcations) who had at least one established risk factor for atherosclerosis by using indium 111 platelet scintigraphy and high-resolution B-mode ultrasonography. We evaluated platelet accumulation in the carotid arterial wall by means of a dual-tracer method that used In 111–labeled platelets and technetium 99m–labeled human serum albumin. The tracer accumulation was assessed both visually and semiquantitatively by using the platelet accumulation index, ie, the ratio of radioactivity of the amount of In 111–labeled platelets deposited on the vascular wall to the amount of radioactivity in labeled platelets circulating in the blood pool. The morphology of the carotid lesions was analyzed with B-mode ultrasonography in terms of the presence of ulceration, the maximum percent stenosis, the echogenicity of plaque, and the plaque score, which indicates the severity of systemic atherosclerosis. Platelet accumulation increased with increase in plaque score (P<.01), and the magnitude of platelet accumulation was significantly greater in lesions with ulceration than in those without (P<.05). The platelet accumulation index in vessels with plaque showed a very weak but significant correlation with maximum percent stenosis (r=.28, P<.05) and a stronger correlation with the unilateral plaque score (r=.42, P<.0001). Analysis of the echogenicity of plaque showed that heterogeneous plaque had a high frequency of accumulating platelets. Platelet accumulation was related to the surface characteristics and severity of carotid lesions, especially in the presence of ulceration.
Key Words: atherosclerosis • platelet imaging • indium 111 • ultrasonography • carotid artery diseases
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Introduction |
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Extracranial carotid atherosclerosis is a major cause of ischemic CVD.1 2 3 Although CAG is the "gold standard" for morphological evaluation of carotid lesions, it is invasive, and its use is restricted to preselected patients. With advances in US techniques, high-resolution B-mode US has emerged as one of the best modalities for visualization of the carotid artery. B-mode US provides real-time information about the characteristics of the lumen and the vessel wall, and because it is noninvasive, it can be used for screening and/or crossover studies.2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Clinically, it is important to differentiate unstable carotid plaques with platelet deposition, which may produce symptoms, from stable plaques.20 Indium 111 (In 111)–labeled PSC is a useful and noninvasive technique for investigation of the in vivo platelet deposition of carotid atherosclerotic lesions.21 22 23 24 25 26 By using a dual-radiotracer method with In 111–labeled platelets and technetium 99m–labeled human serum albumin, we semiquantitatively evaluated thrombus formation27 28 29 and the effect of antithrombotic therapy on platelet deposition.28 29
Several studies have compared platelet deposition and morphological evaluation of carotid lesions,21 22 23 24 25 26 27 30 but most of them21 22 23 24 27 have evaluated carotid lesions by using the invasive CAG method. To our knowledge, there have been only a few studies25 30 that have compared PSC and B-mode imaging for evaluation of carotid lesions. Although these studies are valuable, they used only echogenicity in their B-mode imaging,25 30 included patients who were under antiplatelet therapy,30 or had a small number of subjects.25
We selected patients who were not receiving antithrombotic medication to exclude the influence of these drugs. By means of the noninvasive B-mode technique, we evaluated carotid morphology minutely by using the following four parameters in relation to the accumulation of plaques on the carotid artery: the plaque score, which indicates the severity of systemic atherosclerosis; the presence or absence of ulceration; the degree of maximum percent stenosis; and the echogenicity of plaque. Furthermore, we evaluated whether there were differences between symptomatic and asymptomatic groups in the US parameters and platelet accumulation.
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Methods |
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Subjects
We recruited 52 men and 8 women (age, 60.3±8.2 years) from among inpatients and outpatients at the First Department of Internal Medicine, Osaka University Medical School Hospital, who had at least one established risk factor for atherosclerosis (ie, hypertension, hypercholesterolemia, diabetes mellitus, obesity, or cigarette smoking). Of these 60 patients, 22 were without CVD. The remaining 38 had ischemic CVD referable to the carotid system31 ; of these, 10 had experienced transient ischemic attacks and 28 had a history of brain infarction. Patients were excluded if they were neurologically unstable or had cardioembolic risk factors such as atrial fibrillation, valvular heart disease, or myocardial infarction. Antiplatelet medication or anticoagulant medication was given to 30 of the 38 CVD patients and 5 of the 22 non-CVD patients initially, but all patients gave informed consent and stopped receiving any anticoagulant or platelet-active drugs (ie, warfarin, aspirin, ticlopidine, dipyridamole, heparin, or other nonsteroidal anti-inflammatory drugs) during the 3 weeks that preceded the PSC study. No strokes, transient ischemic attacks, or other cardiovascular events occurred during the present study.
PSC and US were performed to determine the functional and morphological characteristics of the carotid systems. CAG was performed in 28 of the 38 CVD patients for clinical reasons, and US findings were compared with CAG findings. Each of these examinations was performed at least 4 weeks after the patient's last CVD episode, and the intervals between these examinations were within 6 weeks.
The study protocol was in accordance with the standard ethical guidelines of Osaka University Medical School, and informed consent was obtained from all subjects.
PSC
Autologous platelets were labeled with In 111–tropolone
according to the method of Dewanjee et al.32 The mean
injected dose was 32.6±6.8 MBq, and the final labeling efficiency was
72.2±12.7%. Anterior scintigrams of the head and neck, including the
upper thorax, were obtained 48 hours after injection of the labeled
platelets. After the platelet study, 555 MBq Tc
99m–labeled human serum albumin was injected
intravenously, and blood-pool images of the same area
were obtained. Scintigrams for In 111 and Tc 99m containing 200 000
counts were obtained by using a large-field-of-view gamma
camera equipped with a medium-energy, parallel-hole
collimator.27
Platelet accumulation was evaluated visually and semiquantitatively
(Table 1
). Two experienced observers who were unaware of
the patients' clinical data visually assessed the focal accumulation
of platelets at each carotid bifurcation. Scintigrams were graded
as positive, equivocal, or negative; regions that showed obviously
greater activity in platelet images than in blood-pool images
were classified as positive; regions that showed slightly greater
activity were classified as equivocal. Regions that did not show an
increase in platelet radioactivity were classified as negative. The
observers initially disagreed on assessments of 7 of 120 regions, but
reached agreement through discussion. Subjects were classified into
three groups based on the results of visual analysis: group 1,
negative bilateral carotid; group 2, at least one equivocal side; and
group 3, at least one positive side.
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For semiquantitative analysis, we determined the PAI, which was defined as the ratio of the amount of radioactivity in In 111–labeled platelets deposited on the vascular wall to the amount of radioactivity in circulating labeled platelets. Square ROIs (20x20 mm) were drawn over the aortic arch and both carotid bifurcations by using the same locations for both tracers. The ROIs at the carotid bifurcations were placed in a blinded fashion (without the knowledge of the US data) by using the human serum albumin images referred to the initial arterial phase,33 after which the same ROIs were traced on the platelet images. The ROI at the aortic arch served as the reference region with absent or minimal platelet deposition. PAI values were calculated as follows27 : PAI=(InCB/InAA)/(TcCB/TcAA)-1, where InCB represents the In 111 radioactivity at the carotid bifurcation, InAA represents the In 111 radioactivity at the aortic arch, and TcCB and TcAA represent the Tc 99m radioactivity at the carotid bifurcation and aortic arch, respectively. We have found adequate reproducibility of PAI values.27
High-Resolution B-Mode US
Carotid B-mode imaging was performed with a 7.5-MHz transducer
with an axial resolution of <0.4 mm (EUB-450, Hitachi). Subjects were
examined in the seated position, and the carotid system was imaged from
three longitudinal views and the transverse view. In our earlier
study,2 the maximum thickness of the intima-media
complex of healthy Japanese subjects was 
1.0 mm. Therefore, we
defined atherosclerotic lesions as plaques when the axial thickness of
the intima-media complex was >1.0 mm.
We evaluated carotid lesions in terms of four parameters:
the plaque score, the presence of ulceration, the maximum percent
stenosis, and the echogenicity of the plaque (Table 1
). All
plaques within 60 mm of the carotid bifurcation, from the common
carotid artery 45 mm below the bifurcation to the internal and external
carotid arteries 15 mm above the bifurcation, were evaluated
separately. To quantify the severity of carotid
atherosclerosis, the plaque score was obtained by
summing the maximum axial thickness of all plaques in both carotid
systems.2 The length of individual plaques was not
considered in determining the plaque score. We classified the subjects
into four groups according to the plaque score: none, 0; mild, 1.1 to
5.0; moderate, 5.1 to 10.0; and severe, >10.0. The unilateral plaque
score represented the plaque score for each carotid
artery and was classified into four groups: none, 0; mild, 1.1 to 2.5;
moderate, 2.6 to 5.0; and severe, >5.0. Ulceration was defined as the
presence of large, obvious excavations, multiple cavities, or a
cavernous appearance.4 The maximum percent
stenosis was calculated from the ratio of the residual lumen to
the original diameter.5 Vessels were classified as having
no stenosis (without plaques), low-grade stenosis
(<50% maximum percent stenosis), or high-grade
stenosis (
50% maximum percent stenosis). Lesions
were classified as homogeneous or heterogeneous
on the basis of the echogenicity of the plaque according to the
classification of Reilly et al.6 Homogeneous
lesions were characterized by a uniform echo level and
heterogeneous lesions by a combination of high-, medium-,
and low-level echoes. If more than two plaques were present in
one vessel, the tissue character of the plaque with highest maximum
thickness in the vessel was evaluated.
CAG
In the 28 patients who underwent both US and CAG, carotid
lesions were evaluated in terms of the presence of ulceration and the
maximum percent stenosis. The CAG parameters were
determined according to the recommendations of the North American
Symptomatic Carotid Endarterectomy
Trial (NASCET).34 35 Carotid angiograms were evaluated
blindly by two neuroradiologists in a double-check manner.
Statistical Analysis
Data were analyzed by 
2 and
Student's t tests. Parametric comparisons of
measured data obtained in more than three groups were performed by
ANOVA. Scheffé's multiple comparison test was used to examine
the relationship between variables. A difference of
P<.05 was considered significant. Results are mean±SD.
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Results |
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Visual analysis identified 13 positive vessels, 30 equivocal vessels, and 77 negative vessels. Fig 1
shows
a comparison between visual and semiquantitative analyses. The
mean PAI value was significantly higher in vessels with positive
scintigraphic findings (19.5±10.7%) than in vessels with equivocal
(9.8±6.5%; P<.01) or negative (2.1±6.3%;
P<.001) findings. The PAI value was significantly higher in
equivocal than in negative vessels (P<.001).
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Plaques were present on at least one side of the carotid arteries
in 48 of 60 (80%) subjects. Subjects were classified by plaque score
as follows: none in 12 (20%) patients, mild in 15 (25%), moderate in
20 (33%), and severe in 13 (22%). An increased plaque score was
associated with an increase in the percentage of subjects with an
equivocal (group 2) or positive (group 3) plaque accumulation
(P<.001) (Fig 2). The subjects with moderate
to severe plaque scores had a higher incidence of group 3 than those
with plaque scores of none to mild (P<.05).
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CAG and US assessments of maximum percent stenosis in 28 patients (56 vessels) were significantly correlated (r=.89, P<.01). CAG and US identifications of ulceration were in agreement in 53 of 56 (95%) vessels (P<.01).
Plaques were present on 81 of 120 vessels; 11 were classified as
homogeneous and 70 were classified as
heterogeneous. Ulcers were found on 16 vessels. All
ulcerated plaques showed heterogeneous echogenicity. Fig 3 compares the PAI values with the US characteristics of
carotid lesions. The mean PAI value in vessels with ulceration
(15.8±11.8%) was significantly higher than that of the other three
groups, ie, vessels without plaque (1.9±7.0%; P<.001),
vessels with homogeneous plaque (4.5±5.3%;
P<.05), and vessels with heterogeneous plaque
without ulcer formation (6.2±7.7%; P<.05). The mean PAI
value of the vessels with homogeneous plaque (4.5±5.3%)
was lower than that of all heterogeneous plaques
(8.4±9.6%) and heterogeneous plaque without ulcer
formation (6.2±7.7%), although without statistical significance. Fig 4 shows imaging findings in a
representative patient.
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Fig 5 shows the relation between the severity of carotid
lesions and platelet imaging by visual analysis.
Platelet accumulation increased in association with increases in
the maximum percent stenosis (P<.0001) and the
unilateral plaque score (P<.0001). To examine the direct
effect of stenosis and unilateral plaque score, we compared the
numerical values of these indexes with the PAI values of the vessels
with plaque formation. The PAI value showed a very weak but significant
positive correlation with maximum percent stenosis
(r=.28, P<.05) and a stronger correlation with
the unilateral plaque score (r=.42, P<.0001)
(Fig 6).
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There were no significant differences between CVD patients (n=38) and
non-CVD patients (n=22) in the incidence of risk factors for
atherosclerosis. The mean age in CVD patients was
significantly (P<.05) younger than that in non-CVD patients
(Table 2).
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Table 3 shows the US characteristics of carotid lesions
and platelet imaging in each carotid artery ipsilateral to the
symptomatic and asymptomatic hemispheres.
Seven of 38 CVD patients showed symptoms referable to the bilateral
carotid systems. We classified all 120 vessels as either
symptomatic (ipsilateral to the symptomatic
hemisphere; n=45) or asymptomatic (n=75). The
prevalence of plaque formation did not differ between the two groups.
Ulceration was significantly more frequent in the
symptomatic group (P<.05). The average maximum
percent stenosis was significantly higher in the
symptomatic group (P<.05). Positive
platelet accumulation was significantly more frequent in the
symptomatic group (P<.001), and the mean PAI
value of the symptomatic group was significantly higher
than in the asymptomatic group (P<.05).
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Platelets play an important role in the initial steps of atherosclerosis as they interact with or adhere to subendothelial connective tissue and release their constituents.36 The progression and spontaneous regression of carotid atherosclerosis are multifactorial, and the exact role of platelets remains to be clarified.7 20 37 Although a number of studies21 22 23 24 25 26 27 have shown that PSC is useful for evaluation of carotid lesions, others30 38 have found it of little value. Problems associated with the methods used to evaluate function and morphology may be responsible for these conflicting results. As a functional evaluation, qualitative assessment with In 111–labeled platelets alone may not be sensitive enough to detect small foci of platelet deposition due to interference from the radioactivity of circulating labeled platelets. CAG has been used in most studies as a morphological evaluation, but CAG cannot give information about vessel wall characteristics. In addition, it is clear that antithrombotic medication influences the outcome of PSC.28 29 To minimize these problems in the present study, we selected patients who were not receiving antithrombotic medication and examined the relation between platelet deposition as obtained by dual-tracer PSC and morphological characteristics as obtained by US.
We evaluated the results of PSC by using visual and semiquantitative analyses and showed that parameters obtained by both analyses correlated well with US parameters. Appropriate use of visual analysis is important in the daily clinical situation, but semiquantitative analysis offers a more precise and objective evaluation.
Platelet accumulation increased with increases in plaque score,
especially when the plaque score was >5.0 (Fig 2). Crouse et
al39 have proposed a scoring system for extracranial
carotid atherosclerosis and have shown a positive
relationship with atherosclerotic risk factors.8 The
plaque score is a clinically useful index for quantification of total
carotid atherosclerosis.2 9 10 The
incidence of symptomatic11 and
asymptomatic12 cerebral infarctions
increases as the plaque score increases, especially when the score is
>5.0. Carotid atherosclerosis is a part of systemic
atherosclerosis, and platelet adhesion and
accumulation cause it to progress. The results cited above indicate
that the classification of our grading system of the plaque score was
valid.
The morphological findings obtained by CAG and US in the present study were in close agreement. For maximum percent stenosis, our results were consistent with those of O'Donnell et al,13 who report that both CAG and US show good agreement with pathological findings. On the other hand, for the diagnosis of ulceration, the accuracy of CAG or US compared with pathological examinations is controversial, ranging from 60% to 95%.6 14 15 16 35 40 This discrepancy may result from differences in radiological and pathological criteria. Moore et al41 classify the angiographic appearance of ulcerations into three groups: type A (small minimal excavations), type B (large obvious excavations), and type C (multiple cavities or cavernous appearance) ulcers. In our US study, type B and/or C ulcers were evaluated simply as ulcers. We have reported an 85% accuracy of US diagnosis of ulcer formation when comparing pathological and US findings,4 which is similar to the results of Jones et al14 (95%) and Reilly et al6 (71%). O'Leary et al,15 who report 60% accuracy, may have primarily evaluated the type B ulcer of Moore et al41 without considering the type C ulcer. On the other hand, due to the limited spatial resolution of B-mode imaging compared with microscopic findings, we may have missed small shallow ulcers, such as Moore's type A ulcer.
Platelet accumulation was significantly greater in ulcerated
plaques, as assessed by semiquantitative analysis (Fig 3). Our
results are consistent with those of Goldman et
al,21 Henningsen,26 and Isaka et
al,27 who report that the activity of radiolabeled
platelets was greater in ulcerated plaques than in nonulcerated
stenosis. Endothelial injury in the ulcerated
lesion is believed to play a central role in platelet
activation.36
Heterogeneous plaque showed a nonsignificant tendency to
accumulate more platelets than homogeneous plaque (Fig 3). When Reilly et al6 compared pathological findings
obtained at the carotid endarterectomy with
preoperative US findings, they found that heterogeneous
plaque was associated with a higher frequency of intraplaque
hemorrhage, whereas homogeneous plaque consisted
mainly of fibrous lesions. US-assessed heterogeneous plaque
is associated with the occurrence of neurological
symptoms.17 18 These results suggest that the increase of
platelet accumulation in heterogeneous plaques may lead
to clinical symptoms. It is possible that occult ulcers, such as the
type A ulcer of Moore et al,41 which are difficult to
diagnose and may be overlooked by US, may be concealed by
heterogeneous lesions.42 The nature of these
lesions, including their potential embolic character, should be
considered when a remedial plan for carotid artery disease is
established.
Platelet accumulation was weakly but significantly correlated with maximum percent stenosis (r=.28), which is consistent with the results of Powers et al22 and Kessler et al.23 The correlation between the PAI and the unilateral plaque score (r=.42) was somewhat stronger. These results suggest the possibility that platelet accumulation is related to total carotid atherosclerosis rather than to the maximum stenosis at a single site. However, the magnitude of these values was at best modest. This result may arise partly from a difference in characteristics between platelet accumulation and US parameters. Though both stenosis and plaque score are influential factors in platelet accumulation, there are, of course, other factors that affect platelet accumulation.
Except for age, risk factors did not differ between CVD and non-CVD patients. The results of our comparison of symptomatic and asymptomatic groups suggest the possibility that ulceration and maximum percent stenosis affect platelet accumulation and clinical symptoms. The NASCET study43 has demonstrated that high-grade stenosis and ulceration are associated with a high risk of stroke. To evaluate whether and to what extent US parameters and platelet accumulation affect the prediction of CVD, additional prospective studies are needed.
The main limitation of this study is due to methodological problems with PSC. The first problem is the limited resolution of a gamma imaging system. Goldman et al21 report from a theoretical phantom study that a certain number of platelets are necessary for a positive scintigram, and it is clear that PSC has inherently poor spatial and contrast resolution.22 26 30 The second problem is the ROI setting needed to calculate the PAI. The ROI used in this study (20x20 mm) was too wide for the carotid bifurcation, which contains the vessel wall and surrounding soft tissues. However, ROIs that are too small cannot contain statistically adequate counts. The third problem is the difficulty of an appropriate choice of reference region. Powers et al44 report that the vascular region with the minimal ratio of In 111 to Tc 99m, such as the aortic arch, is considered to represent the area with minimal or absent In 111 platelet deposition. However, atherosclerotic changes and platelet accumulation in the aortic arch may result in an underestimation of the PAI.
As a morphological diagnostic device, US also has clear limitations. For example, US may miss up to 40% of ulcers due to the lack of well-developed criteria for the US appearance of ulceration and limitations in image resolution.15
Another limitation of our results is the distribution of PAIs, which
overlapped widely among vessels in each group (Fig 3). One possible
explanation is that the group of ulcerated vessels included ulcerations
of various sizes. Thiele et al19 report that the embolic
potential changes with differences in the size of the ulceration.
Another possibility is that in some ulcerated vessels, platelet
thrombi are present only transiently and are no longer present
when PSC is performed.30
In conclusion, by using noninvasive PSC and B-mode US, we evaluated the relation between in vivo thrombogenicity and the morphology of carotid atherothrombotic lesions. Platelet accumulation was related to the presence of ulceration and the severity of carotid atherosclerosis. For the evaluation of carotid lesions, noninvasive and widespread B-mode imaging may be useful in predicting thrombogenicity, which can be visually estimated by platelet imaging.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a research grant for cardiovascular diseases from the Japanese Ministry of Health and Welfare and was also supported in part by the Smoking Research Foundation. The authors thank Y. Kusumi, H. Ohmori, and Y. Nakamura for their technical assistance. The authors also thank M. Shimomura and R. Manabe for their invaluable secretarial assistance.
Received March 15, 1995; accepted September 25, 1995.
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