(Stroke. 2001;32:719.)
© 2001 American Heart Association, Inc.
Original Contributions |
111In Platelet Scintigraphy for the Noninvasive Detection of Carotid Plaque Thrombosis
From the Divisions of Nuclear Medicine (G.M., R.B., G.B., M.G., R.B.) and Hematology (M.L.), University of Pisa, Pisa, Italy; Division of Neurosurgery (G.P.), Spedali Riuniti di Santa Chiara, Pisa, Italy; Division of Nuclear Medicine, Ospedali Civili di Livorno, Livorno, Italy (N.M.); and CNR Institute of Clinical Physiology (W.B., C.P., M.P., G.P., R. De C.), Pisa, Italy.
Correspondence to Raffaele De Caterina, MD, PhD, Chair of Cardiology, "G d’Annunzio" University, Chieti, and CNR Institute of Clinical Physiology, Area della Ricerca di S Cataldo, Via Alfieri, 1, I-56100 Pisa, Italy. E-mail rdecater{at}ifc.pi.cnr.it
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Thrombosis on atherosclerotic lesions in the large extracranial arteries is the main cause of embolization in the distal cerebral circulation and thus is involved in the pathogenesis of ischemic stroke. The assessment of biological characteristics of lesions that are predictive of thrombotic complications might help in stratification of the risk for stroke but is currently imperfect.
Methods—We compared the performance of 111In-platelet scintigraphy with blood pool subtraction, ultrasound-based tissue texture analyses, and transcranial Doppler techniques in their ability to predict the occurrence of superficial thrombosis or the presence of a lipid pool in carotid artery plaque specimens removed at the time of carotid endarterectomy in 22 patients with unilateral carotid artery stenosis of >70%.
Results—Positivity at 111In-platelet scintigraphy was present in 8 patients and correctly identified the presence of thrombosis superimposed on a complicated plaque. Neither tissue texture analysis nor emboli detection by transcranial Doppler, performed in 12 patients, significantly identified plaque thrombosis. None of the techniques used were able to detect the presence of a significant lipid pool inside the plaque.
Conclusions—Indium-platelet scintigraphy is an accurate noninvasive diagnostic tool to detect thrombotic complications in carotid plaques. Prospective studies should assess its ultimate value in risk stratification, possibly to guide the decision of whether to perform endarterectomy in selected patient categories.
Key Words: atherosclerosis • carotid stenosis • platelets • stroke assessment • thrombosis
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Atherosclerosis in the extracranial arteries has long been recognized as the most frequent pathological substrate of acute ischemic stroke.1 Although as many as 30% of persons over age 50 years have evidence of carotid artery disease,2 only some carotid stenoses carry an appreciable risk of stroke.1 3 4 Stenosis severity is one parameter that can help to identify such a risk. The North American Symptomatic Carotid Endarterectomy Trial (NASCET)5 and the European Carotid Surgery Trialists’ Collaborative Study6 have indicated the opportunity of carotid endarterectomy for patients with carotid stenoses of
70% in diameter at
angiography, with a previous recent transient ischemic attack
or stroke in the dependent territory. At the present time,
however, endarterectomy is not mandatory in
symptomatic patients with ipsilateral stenosis of
<70% in
diameter7 8 9
and in those with asymptomatic severe
stenosis,10 11
who amount to about one third of those who currently undergo the
procedure.12 The uncertainty
in the assignment of patients to surgery or medical therapy reflects at
least in part the variable fate of the carotid artery plaque, which
may "unstabilize" in many cases despite being diametrically mild or
may remain "stable" in many cases despite being severe. There is
therefore a need for techniques that can increase prediction of the
fate of carotid lesions.13
This need cannot be matched by the increasing diagnostic
accuracy in stenosis severity estimation with
ultrasonography,2 because it
is likely that stability depends little on severity and more on
additional parameters that reflect the pathobiology of the
plaque.14 15 In the coronary arteries, thrombosis on a fissured16 17 or superficially eroded18 19 plaque is currently considered the immediate precursor of acute ischemic syndromes. The positive results of stroke prevention studies with antiplatelet agents20 and, more recently, anticoagulants21 22 provide an argument that thrombosis on a plaque is in most cases the link between extracranial artery atherosclerosis and stroke.16 Therefore, techniques able to detect fissured plaques or superimposed thrombosis should expand the ability to stratify the risk of clinical complications and potentially guide therapeutic decisions.
Thrombosis superimposed on a plaque in a superficial vessel can be detected with nuclear medicine techniques. Tracers that bind to developing thrombi include radiolabeled platelets, fibrinogen, fibrin fragments, immunoglobulins, and peptides directed against platelet and fibrin components.23 Radiolabeled platelets are theoretically the best tool to image the platelet-rich thrombus developing on a lesion, because such thrombi may develop in high-shear regions even in the absence of notable fibrin deposition.17 Here, 111In-platelet scintigraphy has emerged as the technique of choice.24 25 However, initial enthusiasm with this technique has been tempered by a low signal-to-noise ratio with the circulating blood pool and the lack of documentation of the underlying pathology.23
We sought to define the potential value of platelet scintigraphy in the detection of carotid artery thrombosis. We used a blood pool subtraction procedure to maximize the scintigraphic signal (due to platelet deposition) over the blood pool noise and thus studied a series of patients who were candidates for endarterectomy to compare, for the first time, scintigraphic results with plaque histology and to seek correlations with thrombosis. In parallel, we performed a comparative evaluation of ultrasound-based analyses aimed at evaluation of plaque texture and the detection of peripheral embolization by transcranial Doppler.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Population
Twenty-two patients (16 men and 6 women), aged 48 to 77 years (median age 65 years), were recruited at the Neurosurgery Division of Pisa University Hospital from June 1996 to May 2000, and candidates for carotid endarterectomy were selected if they fulfilled the inclusion criterion of the presence of a unilateral >70%-diameter carotid artery stenosis on angiography. Exclusion criteria consisted of general contraindications to the procedure, such as severe ischemic heart disease, cancer, anemia, systemic infectious or inflammatory diseases, or interventions that were carried out soon after diagnosis and thus prevented study set-up. The clinical characteristics of the 22 patients recruited are summarized in Table 1
. Twelve of the patients underwent a full
protocol for comparative evaluations of noninvasive techniques with
respect to histologically detected thrombosis (study
1), and 10 patients underwent a confirmatory study of the predictive
value of platelet scintigraphy only (study 2). Twenty
patients were treated with low-dose acetyl salicylic acid or lysine
acetyl-salicylate (100 to 324 mg/d) at the time of surgery, whereas 2
were on ticlopidine
(Table 1). All symptomatic patients had a
cardiological work-up (ECG and 2-dimensional color Doppler
echocardiogram) to exclude the contribution of
cardioembolism to the reported
symptoms.
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Study Protocol
The 12 patients in study 1 underwent presurgical and
postsurgical procedures as described in
Figure 1. These included preoperative ex vivo separation and
111In labeling of autologous platelets,
reinjection, and performance 48 hours later of planar
scintigraphy of the neck region. This was immediately
followed, during the same session, by (1) scintigraphic acquisition
after imaging of the blood pool with
99mTc-human serum albumin, (2) a
complete ultrasonographic evaluation of the carotid artery region, with
derivatization of videodensitometric parameters of plaque
texture, and (3) a transcranial Doppler evaluation of
cerebromicroembolization. At the time of surgery, performed within 1
week after platelet scintigraphy, the carotid
endarterectomy specimen was saved for a subsequent
histological evaluation. The 10 additional patients in
study 2 underwent the same procedure with the exception of ultrasound
and Doppler studies. Study protocols were approved by the Pisa
University Hospital Ethical Committee.
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Angiography
Digital-subtraction carotid angiography was obtained
in the 15 days preceding patient recruitment through the
intravenous injection of a nonionic contrast medium
(iopamidol). Carotid artery stenosis was evaluated according to
the NASCET criteria as the ratio of luminal diameter (on 2 views) at
the point of the greatest stenosis and the normal portion of
the artery beyond the carotid
bulb.5
Ultrasound Quantitation of Carotid
Stenosis
Color-flow duplex investigation of the carotid
arteries was performed with a Diasonics Spectra apparatus
equipped with a 7.5-MHz transducer. The highest peak of
systolic velocity in the stenotic area was
recorded. Evaluation of the stenotic area was performed on
the basis of conventional
criteria26 27 and
with a curve of conversion from a linear index to stenosis
area, where a diameter reduction of 50% corresponds to a 75% area
reduction.28
Platelet Labeling
Platelet labeling was performed according to an
established protocol.29
Peripheral venous blood anticoagulated with acid-citrate
dextrose (blood-anticoagulant ratio of 6:1) was centrifuged at
150g for 10 minutes at 37°C
to obtain platelet-rich plasma (PRP). This was subsequently
separated into platelet-poor plasma (PPP) and a platelet pellet
through additional centrifugation at
1000g for 10 minutes at 37°C
in the presence of prostacyclin for human use (1 µmol/L final
concentration; Flolan; Glaxo-Welcome). The platelet pellet was then
sterilely resuspended twice in PBS without calcium and magnesium, pH
7.4, to a final count of 200 000/µL (platelet washing). Labeling
was performed with the addition of 55 Mbq of
111In-oxine (Byk Gulden Italia) for 30
minutes at 37°C. After the addition of more prostacyclin (1
µmol/L), the platelet suspension was centrifuged at
1000g for 10 minutes at 37°C
to wash out unbound indium, and the final resuspension of platelet
pellet was performed in autologous PPP. Labeling efficiency, calculated
from indium bound to platelets (B) and unbound (A) as B/(A+B)x100,
was always >70%.29 The
labeled platelet suspension was reinjected through an antecubital
vein within 5 minutes of the final preparation. Injected dose,
calculated from triplicate counting of a small aliquot of injected
suspension in a 
-counter as the weight of the injected dose (in mg)
multiplied by the average counts per minute per milligram of the
counted aliquots, was 37±10 Mbq, corresponding to a whole body
exposure of ~6 mSv.
Subtraction Carotid Imaging With
111In-Labeled Platelets and
99mTc-Labeled Human Serum
Albumin
Scintigraphy of the neck region was
performed 48 to 72 hours after the injection of
111In-platelets, with patients lying
supine. Planar scintigraphic images of the neck and upper chest were
acquired with a General Electric Starcam 3000 XC -camera fitted with
a medium-energy parallel-hole collimator and set at the 247-keV
111In photopeak. By keeping the patient
still, dynamic images (1 image/s for 1 minute) were also acquired
immediately after the intravenous injection of 555 Mbq of
99mTc-labeled human serum albumin
(Albutec; Sorin Biomedica), centering the
99mTc photopeak at 140 keV to detect carotid
arteries. Soon, static blood pool images were acquired in the same
position. A total of 500 000 counts were collected for both
tracers.
A normalization ratio
(Inref/Tcref) was
calculated for each patient according to the counts obtained from
regions of interest (ROIs) drawn in the
111In and 99mTc
images over a reference area taken on the ipsilateral subclavian
artery, where platelet deposition was expected to be negligible and
where no hot spots at the presubtraction acquisition were found. This
Inref/Tcref ratio
describes the relative activity of circulating platelets in the
blood pool; for any dimension of the ROI,
111In in the blood pool
(Inbp) can be
calculated as
 |
After image acquisition, elaborations and subtractions were performed offline by 2 experienced nuclear medicine physicians (G.M., R.C.B.) who were blinded to other results. Images were evaluated qualitatively (presence or absence of "hot spots" on carotid scintigrams after blood pool subtraction) and quantitatively by calculating a scintigraphic thrombus/blood index ("scintigraphic index"). In patients where a hot spot was detected visually, the index was obtained as the mean activity per pixel of the ROI placed on the hot spot (in the subtracted image) divided by the mean activity per pixel of the same ROI purely attributable to indium in the blood pool (Inbp), as defined earlier. When no hot spots were visually detected on the carotid subtraction image, the index was made equal to 0.
Transcranial Doppler Emboli
Detection
Embolizations in the intracranial circulation
("emboli detection") were detected with a DWL Multidop X-TCO7
apparatus with a pulsed-wave 2-MHz probe according to
previously described
principles.31 32
Acquisitions were performed for 1 hour in each
patient.
Videodensitometric Analysis of Carotid
Artery Plaque With Ultrasonic Parametric Imaging
To obtain tissue characterization
parameters, echo-tomography images were acquired in a
caudocranial direction at the site of the plaque, with the same
apparatus described for the ultrasound assessment of the
stenosis. In each patient, a total of 7 to 10 longitudinal and
transverse scans of the carotid axis, for a total of 47 images, spaced
0.5 to 2.5 cm, were obtained at the plaque level. The anatomic
bifurcation was the anatomic reference point. Selected frames were
digitized offline with an array processor–based computer for medical
image processing. Images that corresponded to the carotid plaque were
selected and converted into frames of 512x512 pixels of 256 gray
levels each (0 black, 255 white). For each selected frame, 1 ROI was
chosen to encompass a region that ranged in size from 0 to 255 pixels
within a plaque. For each ROI, a histogram of the echo gray-level
distribution was generated by plotting the gray level value on the
abscissa and the frequency of occurrence on the ordinate. Several
variables (first-order algorithms) were used to quantitatively
describe the shape of the histogram, as described
previously.33 The mean gray
level describes the average gray value distribution and allows the
objective ultrasonographic assessment of characters described visually
as "softness", "fibrosity," and
"calcification."34 In
addition, an attempt was made to relate the spatial distribution to
dependence among gray levels in an ROI. To quantify the spatial
interrelationship of the tonal distribution of echograms, algorithms
were applied to an ROI that encompassed the entire plaque (rather than
specific, smaller regions within the plaque, as for first-order
algorithms). A co-occurrence matrix is used to estimate the probability
that a couple of pixels, with their own gray levels and separated by a
displacement vector, occur in the considered ROI. Entropy reflects the
coarseness of the image, as its value increases when homogeneity is
reduced (ie, when co-occurrence matrix elements tend to be equal and
the diagonal concentration lowers). Entropy values were obtained
horizontally through scanning along the carotid axis and vertically
through scanning perpendicular to the main axis. Detailed descriptions
of the mathematics involved have been previously
published.34
Carotid
Endarterectomy
Endarterectomy was performed
through a lateral neck incision within 1 week from the scintigraphic
acquisition by a skilled neurosurgeon (G.P.). After exposure of the
carotid bifurcation and an assessment of the upper limit of the plaque,
the common, internal, and external carotid arteries were clamped. The
wall of the common carotid artery was incised, and the plaque was
excised. Attention was paid to the detection of pressure in the
internal carotid artery after clamping as an index of a good function
of intracranial collateral circles.
Histology
Each endarterectomy sample was
embedded in paraffin and stained with both hematoxylin-eosin and
Mallory trichrome stain. Histological diagnosis was
performed by an expert pathologist (G.P.) who was blinded to other
study results. Based on a previously defined grading
system,35 each sample was
classified according to the 2 criteria of (1) the presence or absence
of thrombosis or intimal hemorrhage (with presence of any of
the 2 components being evidence of plaque fissuring or erosion) and (2)
the presence or absence of extensive lipid deposition (with plaques
classified as lipidic or fibrolipidic allocated into one group and
those classified as fibrous and calcific allocated into another
group).
Statistical Analysis
Quantitative data were described as mean±SD and
compared by the Student’s t
test for unpaired data. To assess the correspondence with histology,
all quantitative characteristics were dichotomized
(positivity/negativity or presence/absence), taking the median as the
cutoff value (dependent [y]
variables). They were analyzed for their coincidence with
the histology of the lesion (presence/absence or
thrombosis-hemorrhage, and presence/absence of extensive lipid
deposition) (independent [x]
variables). All characteristics were analyzed in a 2x2
statistical matrix by the Fisher’s exact test, giving absolute
probability values that relationships could be due to chance.
Bonferroni’s correction was introduced to account for the number of
repeated tests. A probability level of <0.02 was therefore
conservatively considered
significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Six of the 12 patients of study 1 had a clear-cut hot spot on 111In-platelet carotid scintigraphy after blood pool subtraction. The scintigraphic index in these patients ranged between 70 and 267 (Table 2
). In all these cases, evidence of plaque
thrombosis-hemorrhage was present at histology
(Table 2). On the other hand, when no hot spots were
present at the carotid subtraction image, in no case was luminal
thrombosis evident at the histological examination of
the endarterectomy specimen
(Table 2). Representative examples of these
situations are shown in
Figure 2. Histology revealed the presence of a
quantitatively important lipid core (fibrolipidic plaques) in 3 of the
6 patients with thrombosis, whereas the nature of the plaque was
determined to be fibrous in the remaining 3. In the additional series
of patients in study 2, 2 additional hot spots were detected, and these
again corresponded to the presence of thrombosis at histology. In this
last series, 1 case of thrombosis at histology was not accompanied by
positivity on platelet scintigraphy
(Table 2). Overall, in the 22 patients studied for this
purpose, specificity of platelet scintigraphy for the
detection of carotid plaque thrombosis was 100% and sensitivity was
89%. We found no obvious explanation for the discrepancy between
platelet scintigraphy and the
histological diagnosis of thrombosis in the only
patient with plaque thrombosis and negative scintigraphy
(patient 18,
Table 2).
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|
Transcranial Doppler emboli detection
revealed the occurrence of microembolization in 3 of 12 patients. In 2
of these, there was evidence of thrombosis-hemorrhage at
histology. Three patients with negative emboli detection at
transcranial Doppler examination had evidence of mural
thrombosis at histology
(Table 3).
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Videodensitometric analysis of carotid artery plaque
by ultrasonic parametric imaging showed no statistically
significant difference in plaque echogenicity (mean gray levels)
between plaques histologically proved to be fibrous
(mean±SD 35±22) and those classified as fibrolipidic (mean±SD
55±21). Mean gray levels analysis showed close-to-significance
higher values in plaques histologically described as
having thrombosis-hemorrhage (53.3±16.2) compared with plaques
described as not having thrombosis-hemorrhage (24.8±19.3)
(P=0.026)
(Table 3
).
Vertical dishomogeneity was not statistically different
between fibrous plaques (6.62±1.59) and fibrolipidic plaques
(6.09±2.08). Also, no difference in this parameter was
found with regard to plaques without thrombosis-hemorrhage
(6.95±0.90) compared with those with thrombosis-hemorrhage
(6.08±2.08) (P=NS) (data in
Table 3).
Horizontal dishomogeneity also did not differ between
fibrous plaques (6.16±1.09) and fibrolipidic plaques (6.39±1.71), as
well as between plaques without thrombosis-hemorrhage
(6.68±0.69) and plaques with thrombosis-hemorrhage
(5.85±1.44) (data in
Table 3).
When quantitative data were reduced to dichotomic
variables as being either below or above the median value, none of
these parameters were significantly coincident in 2x2
contingency tables with either the histology diagnosis of thrombosis
(Table 4) or the presence of a lipid core inside the plaque
(data not shown). Similarly, no predictive value of emboli detection,
with respect to the 2 histological
parameters considered, was found. However, there was a
highly significant coincidence between the positivity of carotid
subtraction scintigraphy and the diagnosis of
thrombosis-hemorrhage at histology
(Table 4), although the results of subtraction
scintigraphy did not predict the fibrous/fibrolipidic
nature of the plaque at histology.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The results of the present study demonstrate that 111In-labeled platelet scintigraphy with blood pool subtraction is an accurate method to detect thrombotic complications of carotid artery plaques, having, for the first time, the histology of the plaque as the gold standard. This technique proves to be much better than any of the other ultrasound-based methods used to assess either the occurrence of distal embolization (emboli detection by transcranial Doppler) or plaque texture parameters, as obtained through videodensitometric analysis of plaque ultrasound imaging. Our study also demonstrates that neither platelet scintigraphy nor the ultrasound-based methods used here are able to yield significant correlations with the presence of a discrete lipid pool inside the plaque at histology. However, because of the relation of carotid plaque fissuring and thrombosis with clinical complications16 that occur through distal embolization to the cerebral circulation,36 37 38 this study suggests the potential usefulness of platelet scintigraphy to identify plaques at risk of such clinical complications.
At variance from previous studies that investigated the ability to detect carotid artery stenoses with indium-platelet scintigraphy with blood pool subtraction,39 40 our study is the first to attempt a correlation with histology. This was carried out through the implementation of an accurate protocol of platelet labeling and carotid imaging immediately before the surgical removal of the plaque. Thus, we avoided the potential uncertainty in the definition of "ulceration" or "plaque complications" based on carotid ultrasound images, as used in the 2 largest previous studies of the relationship of these noninvasive echographic parameters with results of platelet carotid scintigraphy.39 40 Contrary to all previous studies, we used histology to identify the presence of mural thrombosis and plaque hemorrhage (2 markers of plaque fissuring) as the standard to which platelet scintigraphic results were compared. Our results thus confirm the findings by Moriwaki et al, who described the correlation of positivity at platelet scintigraphy with surface characteristics of complicated lesions,40 but differ from those in which lesion complications were not inferred indirectly from echographic indices, the reliability of which is open to question.27 41
The virtually complete superimposition of positive
results at platelet scintigraphy and evidence of
thrombosis-complicated plaque fissuring at histology in our study is
striking. A positive outcome of the present study may have been
favored (or determined) by at least 2 methodological factors. The first
is the injection of a relatively high dose of radioactivity (
1 mCi,
implying an even higher amount of radioactivity to be used at the
beginning of the ex vivo radiolabeling), still compatible, however,
with an acceptable patient exposure. To this purpose, we estimated
exposure to be in the same order of magnitude of other conventional
nuclear medicine examinations. The second factor is the careful control
of procedural details, ensuring an optimal functionality of injected
platelets, as assessed by the evaluation of platelet function
parameters and the response to aggregating agents after the
labeling procedure, procedural details that were carefully
optimized.29 Patient
selection also may have favorably influenced the outcome of the almost
complete correspondence between scintigraphic and
histological results. All of our patients were a
priori judged candidates for endarterectomy on the
basis of the angiographic findings of a significant (>70%) unilateral
stenosis, and the majority of them (12 of 22), by being
symptomatic, met the recognized international criteria for
a clear indication for
surgery.5 6
Moriwaki et al40 previously showed a
significant, albeit weak, correlation between the degree of
stenosis and scintigraphic evidence of platelet deposition.
The fact that all of our patients had a unilateral stenosis of
70% on both angiography and echo-Doppler analysis
indicates that patient selection likely contributed to a high
prevalence of scintigraphic positivity in the small patient population
studied. Regardless of the reasons, the technique appears to be, in our
hands, not only extremely specific in the detection of mural thrombosis
or intraplaque hemorrhage but also surprisingly (90%)
sensitive.
It is interesting to note that the 10 asymptomatic patients who were enrolled in this study indeed had equivocal indications for endarterectomy. Two of them had evidence of platelet deposition at carotid scintigraphy, and both of them had evidence of mural thrombosis on the plaque surface. Thus, platelet scintigraphy results, because they correlated so strongly with the histology of a lesion "at risk," might well theoretically guide therapeutic decisions in patients similar to these 10 subjects in whom surgical treatment is debatable. The fact that all of our patients were studied on antiplatelet drugs (aspirin or ticlopidine), which, by reducing platelet function, may reduce surface platelet deposition, is compatible with the partial inefficacy of aspirin in the prevention of arterial thrombosis and stroke20 and contributes to ensure the transferability of the additional information provided by platelet scintigraphy into current medical practice.
Our study failed to demonstrate any relationship of histology (as evaluating both the presence of thrombosis and the presence of a detectable lipid pool inside the plaque) and a series of ultrasound-based parameters aimed at detecting microembolization into the cerebral circulation by transcranial Doppler (emboli detection) and analyzing the gray levels of the plaque at videodensitometry of echo images. Emboli detection by transcranial Doppler is an interesting noninvasive, simple-to-perform, and therefore increasingly popular technique to improve risk stratification by detecting signals of embolization into the cerebral circulation.31 32 42 43 44 45 Three of 12 patients of our complete protocol (study 1) underwent the detection of peripheral embolization, and 2 of them had histological evidence of thrombosis. Although the patients that we studied with this technique are few, one possible interpretation of the results is the incomplete overlapping of carotid thrombosis and peripheral embolization. Indeed, on the one hand, the source of embolization may be outside of the carotids, and on the other hand, thrombosis, when present, may be nonemboligenic. Practical problems in the reliability of the technique in detecting the target events may further complicate this evaluation.32 42
We also found discouraging results in the application of the performed videodensitometric analyses in an attempt to predict plaque histology. Although these analyses are better at the prediction of the presence of "soft," "lipid-rich,"34 and therefore possibly vulnerable15 plaques, and not of thrombosis, this was not the case in our series, with an almost random distribution of blindly measured videodensitometric parameters between fibrolipidic and fibrous plaques. Another consideration is that this technique would still be only indirectly related to the risk of fissuring and thrombosis. Its application to the specific goal of predicting mural thrombosis in the single subject would thus appear unlikely. Alternative ultrasonic parameters aimed at objective assessment of surface irregularities rather than structural features of the plaque might prove more useful clinically,40 46 but this needs to be practically tested.
The clinical transferability of our findings with platelet scintigraphy has to be viewed in perspective of the other techniques that are available to image thrombosis and atherosclerosis.23 Rival techniques for thrombosis imaging involve radiolabeled fibrinogen, fibronectin, and plasminogen activators (now mostly considered unpractical because of the risk of injecting nonautologous material); immunoglobulins against antigenic epitopes of activated platelets or fibrin; and peptides able to bind platelet activation receptors (for a review, see Vallabhajosula and Fuster23 ). For the imaging of atherosclerosis, refinement of echo-Doppler techniques, electron beam computed tomography, and magnetic resonance angiography appear to be the most promising.23 All of these techniques, with the notable exception of ultrasounds, are relatively "unavailable." Scintigraphy with radiolabeled platelets has probably been the most widely used functional imaging technique for atherosclerotic complications, because it uses a physiological cellular element as the carrier of the tracer and has clear pathophysiological background. The technique, however, lacks full validation. The present demonstration of the high specificity and sensitivity of platelet scintigraphy in the detection of mural thrombosis on a carotid artery plaque appears promising to start a thorough evaluation of the clinical potential of the technique in stratification of the thromboembolic risk in patients with carotid artery stenosis.
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Acknowledgments |
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This work was supported by 40% grants from the Ministero dell’Università e della Ricerca Scientifica (Drs Bellina, De Caterina, and Bianchi) and by Italian National Research Council grants to the CNR Institute of Clinical Physiology, Pisa, Italy (Dr De Caterina). The technical help of Sergio Suriano, MD, Salvatore Vargiu, Carmen Malvezzi, Fabiana Boldrini, Agnese Eschini, Francesca Morini, Daniele Fontanelli, Stefano Ginesi, and Michele Frattaruolo (Division of Nuclear Medicine, University of Pisa); Giovanni Bigalli and Carmela Morizzo (Vascular Laboratory, CNR Institute of Clinical Physiology); and Vittorio Gattai and Luciana Pozzolini (Histology Laboratory, CNR Institute of Clinical Physiology) is gratefully acknowledged. The authors also express special gratitude to Paolo Viacava, MD (Section of Pathology, Department of Oncology, University of Pisa) for further blind review of the histological slides.
Received September 1, 2000; revision received November 13, 2000; accepted November 15, 2000.
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References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
- Busuttil RW, Baker JD, Davidson RK, Machleder HI. Carotid arterial stenosis: hemodynamic significance and clinical course. JAMA. 1981;245:1438–1445.[Abstract]
-
Barnett HJM,
Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of
ischemic stroke. N Engl
J Med. 1995;332:238–246.
[Free Full Text] - Sundt TMJ, Whisnant JP, Houser OW, Fode NC. Prospective study of the effectiveness and durability of carotid endarterectomy. Mayo Clin Proc. 1990;65:625–632.[Medline] [Order article via Infotrieve]
- Matchar DB. Decision making in the face of uncertainty: the case of carotid endarterectomy. Mayo Clin Proc. 1990;65:756–762.[Medline] [Order article via Infotrieve]
- North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–453.[Abstract]
- European Carotid Surgery Trialists’ Collaborative Group. MCR European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet. 1991;337:1235–1243.[Medline] [Order article via Infotrieve]
- European Carotid Surgery Trialists’ Collaborative Group. Endarterectomy for moderate symptomatic carotid stenosis: interim results from the MRC European Carotid Surgery Trial. Lancet. 1996;347:1591–1593.[Medline] [Order article via Infotrieve]
-
Barnett HJM,
Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN,
Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE, for the
North American Symptomatic Carotid
Endarterectomy Trial Collaborators. Benefit of
carotid endarterectomy in patients with
symptomatic moderate or severe stenosis.
N Engl J Med. 1998;339:1415–1425.
[Abstract/Free Full Text] -
Chassin MR.
Appropriate use of carotid endarterectomy.
N Engl J Med. 1998;339:1468–1469.
[Free Full Text] - Asymptomatic Carotid Atherosclerosis Study Group. Carotid endarterectomy for patients with asymptomatic internal carotid artery stenosis. JAMA. 1995;273:1421–1428.[Abstract]
- National Medical Advisory Committee. The Management of Patients With Stroke. Edinburgh, UK: HM Stationery Office; 1993.
-
Fode N,
Sundt TJ, Robertson J, Peerless S, Shields C. Multicenter retrospective
review of results and complications of carotid
endarterectomy in 1981.
Stroke. 1986;17:370–376.
[Abstract/Free Full Text] - Warlow C. Endarterectomy for asymptomatic carotid stenosis? Lancet 1995;345:1254–1255.
-
Davies MJ,
Bland JM, Hangartner JRW, Angelini A, Thomas AC. Factors
influencing the presence or absence of acute coronary artery
thrombi in sudden ischemic death.
Eur Heart J. 1989;10:203–208.
[Abstract/Free Full Text] - Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Med J. 1993;69:377–381.
- Falk E, Fernandez-Ortiz A. Role of thrombosis in atherosclerosis and its complications. Am J Cardiol. 1995;75:5B–11B.
-
Falk E,
Shah P, Fuster V. Coronary plaque disruption.
Circulation. 1995;92:657–671.
[Free Full Text] -
van der Wal
AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or
erosion of thrombosed coronary atherosclerotic plaques is
characterized by an inflammatory process irrespective of the dominant
plaque morphology. Circulation. 1994;89:36–44.
[Abstract/Free Full Text] -
Farb A,
Burke AP, Tang AL, Liang TY, Mannan P, Smialek J, Virmani R.
Coronary plaque erosion without rupture into a lipid core: a
frequent cause of coronary thrombosis in sudden
coronary death.
Circulation. 1996;93:1354–1363.
[Abstract/Free Full Text] -
Antiplatelet
Trialists’ Collaboration. Collaborative overview of randomised trials
of antiplatelet therapy, I: prevention of death, myocardial
infarction, and stroke by prolonged antiplatelet therapy in various
categories of patients. BMJ. 1994;308:81–106.
[Abstract/Free Full Text] - Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med. 1990;323:147–151.[Abstract]
- Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Effect of long term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet. 1994;343:499–503.[Medline] [Order article via Infotrieve]
-
Vallabhajosula
S, Fuster V. Atherosclerosis: imaging techniques and
the evolving role of nuclear medicine.
J Nucl Med. 1997;38:1788–1796.
[Abstract/Free Full Text] - Kritz H, Underwood SR, Sinzinger H. Imaging of atherosclerosis (part II). Wien Klin Wochenshr. 1996;108:87–97.[Medline] [Order article via Infotrieve]
- Smyth JV, Dodd PDF, Walker MG. Indium-111 platelet scintigraphy in vascular disease. Br J Surg. 1995;82:588–595.[Medline] [Order article via Infotrieve]
- Beach K, Lawrence R, Philips D, Primozich J, Strandness D. The systolic velocity criterion in quantifying internal carotid artery stenosis. J Vasc Technol. 1989;13:65–68.
- Bornstein N, Norris J. The value of carotid Doppler ultrasound in asymptomatic extracranial disease. Can J Neurol Sci. 1988;15:378–383.[Medline] [Order article via Infotrieve]
-
Alexandrov
A, Bladin C, Maggisano R, Norris J. Measuring carotid stenosis:
time for a reappraisal. Stroke. 1993;24:1292–1296.
[Abstract/Free Full Text] - Giannessi D, Bernini W, Puccetti P, De Caterina R. Platelet radiolabeling with 111Indium for in vivo studies: a methodological reappraisal. Nucl Med Biol. 1995;22:399–403.[Medline] [Order article via Infotrieve]
- Bergmann SR, Lerch RA, Mathias CJ. The detection of acute coronary thrombosis in patients with In-111 labeled platelets. J Nucl Med. 1983;24:59.
- Markus HS, Droste D, Brown MM. Ultrasonic detection of cerebral emboli in carotid stenosis. Lancet. 1993;341:1606.
-
Markus HS,
Harrison MJ. Microembolic signal detection using
ultrasound. Stroke. 1995;26:1517–1519.
[Free Full Text] - Pinamonti B, Picano E, Ferdeghini E. Quantitative texture analysis in two-dimensional echocardiography: application to the diagnosis of myocardial amyloidosis. J Am Coll Cardiol. 1989;14:666–669.[Abstract]
- Mazzone A, Urbani M, Picano E, Paterni M, Borgatti E, De Fabritiis A, Landini L. In vivo ultrasonic parametric imaging of carotid atherosclerotic plaque by videodensitometric technique. Angiology. 1995;46:663–672.
- Robbins S, Cotran R. The Pathological Basis of Disease: Philadelphia, Pa: WB Saunders; 1979:593–642.
-
Awad I,
Modic M, Little JR, Furlan AJ, Weinstein M. Focal parenchymal lesions
in transient ischemic attacks: correlation of computed
tomography and magnetic resonance imaging.
Stroke. 1986;17:399–403.
[Abstract/Free Full Text] - DeBono DP, Warlow CP. Potential source of emboli in patients with presumed transient cerebral or retinal ischemia. Lancet. 1981;1:343–345.[Medline] [Order article via Infotrieve]
-
Sitzer M,
Muller W, Siebler M, Hort W, Kniemeyer HW, Jancke L, Steinmetz H.
Plaque ulceration and lumen thrombus are the main source of cerebral
microemboli in high-grade internal carotid artery stenosis.
Stroke. 1995;26:1231–1233.
[Abstract/Free Full Text] -
Minar E,
Ehringer H, Dudzak R, Schofl R, Jung M, Koppensteiner R, Ahmadi R,
Kretschmer G. Indium-111-labeled platelet scintigraphy
in carotid atherosclerosis.
Stroke. 1989;20:27–33.
[Abstract/Free Full Text] -
Moriwaki H,
Matsumoto M, Handa N, Isaka Y, Hashikawa K, Oku N, Nakamura M, Kamada
T, Nishimura T. Functional and anatomic evaluation of carotid
atherosclerosis: combined study of indium-111
platelet scintigraphy and B-mode ultrasonography.
Arterioscler Thromb. 1995;15:2234–2240.
[Abstract/Free Full Text] -
Eliasziw M,
Rankin RN, Fox AJ, Haynes RB, Barnett HJ. Accuracy and prognostic
consequences of ultrasonography in identifying severe carotid artery
stenosis. North American Symptomatic Carotid
Endarterectomy Trial (NASCET) Group.
Stroke. 1995;26:1747–1752.
[Abstract/Free Full Text] - Grosset DG, Georgiadis D, Hillis WS, Lees KR. Clinical significance of cerebral emboli signals. Lancet. 1993;342:559.
-
Markus H,
Loh A, Brown M. Computerized detection of cerebral emboli and
discrimination from artifact using Doppler ultrasound.
Stroke. 1993;24:1667–1672.
[Abstract/Free Full Text] - Markus HS, Droste TW, Brown MM. Detection of asymptomatic cerebral embolic signals with Doppler ultrasound. Lancet. 1994;343:1011–1012.[Medline] [Order article via Infotrieve]
- Georgiadis D, König M, Zunker P, Nabavi D, Stögbauer F, Ringelstein EB. Microembolic signals in patients referred for echocardiography. Stroke. 1995;26:525. Letter.
-
Urbani MP,
Picano E, Parenti G, Mazzarisi A, Fiori L, Paterni M, Pelosi G, Landini
L. In vivo radiofrequency-based ultrasonic tissue characterization of
the atherosclerotic plaque.
Stroke. 1993;24:1507–1512.
[Abstract/Free Full Text]
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