Published online before print October 30, 2003, 10.1148/radiol.2293021485
(Radiology 2003;229:855-860.)
© RSNA, 2003
Endovascular Treatment of Internal Carotid Artery Stenosis: Effect of Primary Stent Application on Debris Particle Release in Human Cadaveric Specimens1
Oliver Wittkugel, MD,
Jens Fiehler, MD,
Christoph Koch, MD,
Bernd Eckert, MD,
Ergin Kilic, MD,
Mathias Frahm, MD and
Herrmann Zeumer, MD
1 From the Department of Neuroradiology (O.W., J.F., C.K., B.E., M.F., H.Z.) and Institute for Pathology (E.K.), University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Received November 14, 2002; revision requested January 16, 2003; revision received March 11; accepted April 14. Address correspondence to O.W. (e-mail: wittkuge@uke.uni-hamburg.de).
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ABSTRACT
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PURPOSE: To compare debris release with primary stent application (self-expanding stent application at stenosis and then balloon dilation through the opened stent) and that with secondary stent application (balloon angioplasty of stenosis and afterward additional stent application) for high-grade internal carotid artery stenosis in human cadaveric specimens.
MATERIALS AND METHODS: Fresh human cadaveric internal carotid artery specimens were attached to a tube system. High-grade stenoses (>66%) were selected, randomized for primary or secondary stent application, and then treated, with fluoroscopic guidance, while the system was rinsed in a pulsating flow. Fluid was collected and filtered, and debris particles were examined with a light microscope. Particles were analyzed according to those consecutively caught by 100 x 100-µm and 11 x 11-µm mesh filters. Results were evaluated in relation to stent application. For statistical analyses of group differences, the exact Mann-Whitney U test was used.
RESULTS: Thirteen high-grade human cadaveric internal carotid artery stenoses were analyzed. Five specimens were randomly assigned to secondary stent application, and eight were assigned to primary stent application. No significant difference could be demonstrated for debris release with primary or secondary stent application. P values ranged from .051 to .754.
CONCLUSION: The reported superiority of primary stent application may not be related to debris reduction.
© RSNA, 2003
Index terms: Carotid arteries, interventional procedures, 17.1269 • Carotid arteries, stenosis or obstruction, 17.721 • Experimental study
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INTRODUCTION
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Carotid endarterectomy is an effective stroke prophylaxis for treatment of high-grade symptomatic stenosis of the internal carotid artery (1,2). Most of the clinical neuroradiologic experience in regard to treatment of internal carotid artery stenosis with percutaneous transluminal angioplasty as an alternative to surgery has been gathered since the early 1990s, and surgery remains the standard, to date. Surgical guidelines for indications have been accepted for percutaneous transluminal angioplasty.
Besides numerous improvements to the catheter technique since the early 1990s, in 1997 the procedure for interventional recanalization of internal carotid artery stenosis in our department was modified. Until then, a stent was applied only if deemed necessary after therapeutic (6-mm) balloon dilation (ie, secondary stent application). The present procedure includes placement of a self-expanding stent at the stenosis without predilation before balloon dilation of the residual stenosis (ie, primary stent application). Patients receive therapy with a modified anticoagulation regimen. The regimen includes low-molecular-weight heparin, aspirin, and clopidogrel administered before and after intervention. The activated coagulation time is increased to a mean of 300 seconds ± 10% (SD) in patients treated with intravenous administration of unfractionated heparin during the intervention. Interventional protection systems such as filter systems or occlusion balloons are not used (3).
Before the technical modifications, the rate of thromboembolic strokes with lasting neurologic deficits in our department was 4% (four of 101). As reported elsewhere, the modified procedure that included primary stent application led to fewer thromboembolic strokes with lasting neurologic deficits (1.2% [two of 166]) than did the procedure that included secondary stent application (4). It remained unclear if the primary stent application or other treatment modifications (eg, the anticoagulation regimen) led to the improvement. It was assumed that the stents might affix intimal flaps and, thus, reduce the development of thrombi that form on them and also the amount of debris washout, since the intima covers the arteriosclerotic plug. Thus, the purpose of our study was to compare debris release with primary stent application (ie, self-expanding stent application at the stenosis and then balloon dilation through the opened stent) and that with secondary stent application (ie, balloon angioplasty of the stenosis and afterward additional stent application) for high-grade internal carotid artery stenosis in specimens obtained from human cadavers.
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MATERIALS AND METHODS
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Specimens and Preparation
According to the guidelines of our hospital concerning human research material, during a 24-month period pathologists who performed autopsies on cadavers refrigerated at 4°–6°C were requested to preselect all cases of extremely severe generalized arteriosclerosis. Epidemiologic factors such as age, sex, or cause of death were not considered important in the present laboratory trial. In 62 cadavers in which the pathologists identified this condition, carotid bifurcations were dissected en bloc and refrigerated at 4°–6°C. Within 24 hours after autopsy, they were transferred to our department for evaluation of the grade of stenosis and eventually for experimental treatment. The autopsies were performed 1.1–4.6 days (mean, 2.6 days ± 1.3) after the patients had died. The preparation of the specimens for radiologic examination was performed by one author (O.W.). In 20 cases, internal carotid arteries on both sides were examined. Special attention was paid to nontraumatic handling so that arteriosclerotic lesions would not be dislodged. Two specimens could not be examined because of damage during pathologic preparation. Eighty specimens were examined.
The prepared carotid bifurcation specimens were connected to a tube system as follows: The external carotid artery was first occluded; it was tied off with external cable ties. The opening of the internal carotid artery and of the common carotid artery were then fitted over custom-made stainless steel connecting fittings and were affixed with cable ties. The connecting fittings had varying diameters for the ends of the specimen and a 
-inch (0.95-cm) diameter on the ends that were to be connected to the silicone rubber tube system (Raumedic ECC-SIK; Rehau, Isernhagen, Germany). The internal carotid artery was perfused in the natural flow direction (Fig 1). Isotonic saline solution was pumped through the system in a pulsating flow by means of a roller pump (Stoeckert, Munich, Germany) at 0.5l L/min. Before the experimental treatment, the internal carotid arteries were rinsed for 6 minutes, during which diagnostic digital subtraction angiography (DSA) (Polystar; Siemens, Erlangen, Germany) was performed. The rinsing solution was then discarded. The degree of stenosis was measured in two projections according to guidelines of the North American Symptomatic Carotid Endarterectomy Trial. If stenosis of more than 66% was found compared with the poststenotic internal carotid artery lumen (North American Symptomatic Carotid Endarterectomy Trial evaluation criteria), the treatment condition (ie, primary or secondary stent application) was randomized, as will be stated later, and the vessel was immediately experimentally treated with percutaneous transluminal angioplasty with fluoroscopic guidance (Fig 2). Specimens with stenoses of less than 66% were discarded. Angiography and treatment were performed by the same author who prepared the specimens. The grade of stenosis was evaluated in consensus by that author and another (M.F.).
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Figure 1. Experimental setting. On the angiographic examination table, specimen is connected to the tube system. At left is roller pump, which pumps isotonic saline solution through the system in a pulsating flow. Inset shows a close-up of specimen connected to the tube system.
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Figure 2. DSA image of high-grade internal carotid artery stenosis (arrow 1) in one specimen before and immediately after experimental treatment. Specimen is attached to tube system with custom-made metal fittings (arrows 2).
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Experimental Treatment
The two experimental treatment conditions were randomly established with the toss of a coin. For secondary stent application, the stenosis was first dilated with a balloon, and then a self-expanding stent was placed as a splint. For primary stent application, the stenosis was first experimentally treated with the self-expanding stent and then dilated with a balloon through the opened stent. In either of the experimental conditions, the balloon (Penta 6-4.0; Medi-tech/Boston Scientific, Natick, Mass) and the stent (Carotid Wallstent; Boston Scientific), which was 5 F, were identical.
During the experimental treatment procedure, 3 L of irrigation solution was flushed through the internal carotid artery, and the isotonic solution was collected for particle analysis. All 3 L of the solution was double filtered through a primary 100 x 100-µm mesh filter and a secondary 11 x 11-µm mesh filter (Millipore, Eschborn, Germany). The size and number of particles more than 100 x 100 µm could be evaluated, and those between 100 x 100 µm and 11 x 11 µm could be separately evaluated. The evaluation was conducted with light microscopic scanning of the entire filter surface. The particles were evaluated (ie, counted) microscopically by one author (M.F.). Particles that covered an estimated 50% of a single mesh opening of the filter were counted as one unit (Fig 3). The 100 x 100-µm size of the mesh filter was chosen because of its similarity to the size of common filter protection systems used in vivo. The 11 x 11-µm mesh filter was chosen as the finest available to ensure a thorough collection of particles washed through the larger filter.
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Figure 3. Microscopic image shows mesh of 100 x 100-µm filter with caught particle (*). Only the mesh opening was considered and not mesh width. Sizes of particles covering an estimated 50% of the opening were collected. At microscopic evaluation, depicted particle was considered to be 200 x 100 µm.
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The size and amount of collected debris were comparatively analyzed according to the two experimental conditions. With the first experimental condition, the focus of the investigation concerned the amount of debris that was larger than 100 x 100 µm, analogous with the size of debris captured with filter protection systems. With the second experimental condition, three clinically relevant debris particle sizes were differentiated and analyzed. The three sizes were based on the approximate diameter of brain vessels, such as those described in the literature, as follows (5): capillaries (diameter, <20 µm), arterioles (diameter, 20–200 µm), and arteries (diameter, >200 µm)
Statistical Analysis
For statistical analysis of group differences, the exact Mann-Whitney U test was used because of the skewed distribution of particles. All resulting P values were interpreted as descriptive measures in the sense of an explorative data analysis. Data are presented as the mean ± SD. Minimum and maximum values are presented where it was deemed of interest.
All calculations were performed with software (SPSS, version 10.0; SPSS, Chicago, Ill).
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RESULTS
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Clinical Data
Eighty carotid arteries from cadavers with severe general arteriosclerosis were examined. Thirteen high-grade internal carotid artery stenoses were found. Five of the specimens were randomly assigned to secondary stent application, and the other eight were assigned to primary stent application.
Analyses according to Filter Size
The distribution of debris revealed two peaks that corresponded to the pore width of the mesh filter used (Fig 4). The average number of particles equal to or larger than 100 x 100 µm was 89.6 for the specimens with the secondary stent application and 75.8 for those with the primary stent application (P = .284) (Fig 5, Table 1). The average size of debris particles in the group with particles more than 100 x 100 µm was 17,424 µm2 (mean length of sides, 132 µm), or 132 x 132 µm. The largest particle was 400 x 400 µm. The average number of particles that passed through the 100 x 100-µm filter and were caught with the 11 x 11-µm filter was 320.6 for the specimens with secondary stent application and 256.5 for those with primary stent application (P = .127) (Fig 5, Table 1). The average size of particles less than 100 x 100 µm and more than 11 x 11 µm was 225 µm2 (mean length of sides, 15 µm), or 15 x 15 µm; 165.4 (22.3%) of all 742.3 debris particles that were washed out during the procedure were captured in the 100 x 100-µm filter.
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Figure 4. Graph shows distribution of debris particles captured with 100 x 100-µm and 11 x 11-µm mesh filters and analyzed with a light microscope. Skewed distribution of debris particles was found. Distribution revealed two peaks that corresponded to the pore width of the mesh filter. Greater amount of smaller debris than larger debris was found in each filter system. Larger amount of pieces only slightly smaller than 100 x 100 µm was not found in the 11 x 11-µm filter.
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Figure 5. Graph shows distribution of number and size of debris particles according to primary or secondary stent application. At left, results of debris evaluation (ie, numbers of particles) are displayed according to size of the filters through which particles were filtered. At right, results of debris evaluation are displayed according to sizes that were based on three theoretically defined vessel diameters of arteries, arterioles, and capillaries.
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Analyses according to Size
The average number of particles found is summarized as follows: Eight particles of artery size were found for specimens with the secondary stent application, and 10.6 were found for those with the primary stent application (P = .139). A total of 130.8 particles of arteriole size were found for the specimens with the secondary stent application; and 122.9 particles of that size, for the specimens with the primary stent application (P = .754). A total of 271.8 particles of capillary size were found for the specimens with the secondary stent application; and 198.9 particles of that size, for the specimens with the primary stent application (P = .051) (Fig 5, Table 2).
Histologic Analysis
With the light microscope, the histologic analyses of the washed out debris particles revealed that the debris consisted of amorphous, noncalcified, and fat-rich material, as seen in atheromas of blood vessels. Neither cells nor cellular components were seen.
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DISCUSSION
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It was of interest that a skewed distribution of debris, according to size and amount, was found. More small debris than large debris was found in each of the filter systems, and the expected collection of pieces only slightly smaller than 100 x 100 µm was not found in the 11 x 11-µm filter. In our view, this can be explained as a technical artifact that occurs because of fragmentation (breaking) of particles little more than 100 x 100 µm in size at the grid of the mesh filter. This phenomenon could also occur with in vivo protection devices, which have 100-µm pores. In the present study, the decision as to which filter size to use was based on clinical practice, since according to the manufacturers’ information, the pore size of neuroradiologically implemented filter protection systems ranges between 80 and 150 µm (80 µm: Epi-Filter, Boston Scientific; 100 µm: Angioguard, Cordis/Johnson & Johnson, Miami, Fla; 150 µm: MedNova Neuroshield, MedNova, Galway, Ireland). The smallest available mesh filter size was 11 x 11 µm.
It has been reported elsewhere that transcranial Doppler ultrasonography (US) can show high-intensity signals during angioplasty of the carotid artery (6,7), but an accurate classification of particles with this technique is not possible. Thus, the experimental setting with cadaveric specimens was deemed appropriate. Debris has not yet been analyzed with such delicate filters, so the large amount of very small debris found in the present study was established for the first time, to our knowledge. Ohki et al (8) performed an ex vivo experiment with 120-µm filters in which a mean particle size of 338 µm ± 344 was found. In an experiment with a 130-µm filter in which Ohki et al (9) analyzed the efficiency of a protection filter system ex vivo, the mean particle size was 226.5 µm ± 130.7, and the largest particle was 1,100 µm. The reported debris in both studies was larger than it was in the present study. In another postmortem study, particles of more than 1 mm were found (10).
In the present study, the average size of debris smaller than 100 x 100 µm was 15 µm (225 µm2). In the present study, the average size of debris of 100 x 100 µm or larger was 132 µm (17,424 µm2), with a maximum particle size of 400 x 400 µm. To our knowledge, particles smaller than 100 x 100 µm were not analyzed in any other study. The divergence from the results of Ohki et al (8,9) and Rapp et al (10) may be explained by major experimental differences: In the present study, clinical procedures were simulated, whereas the other authors intraoperativly obtained plug specimens from internal carotid artery stenoses and remodeled vessels by inserting the specimens in a tissue graft. In the studies of Ohki et al (8,9), the experimental vessel was totally submerged in a bath, and the fluid was later analyzed. Larger debris particles could have been detached during the intraoperative manipulation or the preparation of the graft. Extraluminal contamination also could have influenced the result. Martin et al (11), who analyzed debris particles gained during an in vivo treatment with a balloon protection system, reported maximum sizes of debris between 389 and 594 µm, and these sizes are more comparable with the present results, in which the largest washed out debris particle was 400 x 400 µm.
Manninen et al (12) mainly analyzed intimal "stripes" (fragments) and cellular constituents as washed out particles in a postmortem experiment. The authors associated their results with the intravascular US findings of intimal flaps. Such flaps might have been aggravated by their use of a retrograde intravascular US examination performed before the vessel treatment. In the present experiment, no such particles were found for specimens with primary or secondary stent application. This could be explained by the careful handling of the specimens. Varying postmortem specimen ages could be another explanation, but this has not been analyzed in detail in any study, as far as we know.
The method suggested by the North American Symptomatic Carotid Endarterectomy Trial for determination of the degree of stenoses was chosen because it is used by the reporting department. Even though a parallel alignment of the poststenotic vessel walls was always visible during the experiment, it cannot be maintained that this would be the case in vivo. The same method for estimation of the degree of stenosis was applied in all cases. As in other experiments (8–10,12), only a two-dimensional plane of the observed particles was analyzed, and not the volume. An alleged inaccuracy that occurs for technical reasons should not influence or reduce the relative results of the experiment, since the same evaluation technique was applied for both primary and secondary stent application. It does, however, weaken the generalization of the results.
From a clinical point of view, the role of atherosclerotic debris as a risk factor during carotid revascularization is a key question that has been discussed since the onset of use of carotid artery angioplasty. It has been shown that debris can lead to neurologic deficits such as amaurosis fugax (13). The risk of thromboembolic stroke is controversial. To the present, many authors have argued that plaque debris plays a major role in the evolution of periprocedural stroke (11,14–16). The predominant change in the angioplasty technique in our treatment center since July 1997 entailed the primary application of a self-expanding stent at the stenosis (without predilation) and the dilation of the residual stenosis through the stent that was performed afterward. Cautious predilation with a 3-mm balloon to prevent vessel wall dissection was unavoidable in only four of 161 clinical cases (4). We assumed that the use of stents would affix intimal flaps and reduce the risk of formation of thrombi. Thrombi, adherent to intimal flaps, were no longer observed after procedural changes. We also assumed that the primary stent at least partially sheathed the ruptured plaque covered by intima and reduced the amount of debris being washed out. On the basis of the results of the present experiment, our theory concerning debris washout reduction could not be confirmed.
After the therapeutic changes, the rate of thromboembolic strokes with lasting neurologic deficits markedly decreased from 4% to 1.2%. In angioplasty cases, after introduction of the new method, the most common complications with severe neurologic deficits were not thromboembolic strokes but hyperperfusion hemorrhages, which were seen in 1.8% of cases, and this percentage is still comparable with the results after the earlier procedure. This rate also is comparable with the 0.3%–1.2% bleeding rate reported after carotid endarterectomy (17), despite that during and after carotid endarterectomy, the anticoagulation treatment is less aggressive. It remains uncertain whether the observed improvements were caused by newer catheter technology, a better anticoagulation regimen, avoidance of dissections, or all of these.
Practical application: Our negative finding, that the treatment modality (primary stent application or not) does not affect the amount of debris washout, leads us to the conclusion that the improvement in our clinical results since July 1997 was not caused by debris reduction. Findings of the experiment also demonstrated that 100 x 100-µm filter protection devices caught only 22.3% of the analyzed debris. Hence, the influence of debris concerning the development of embolic stroke may have been overevaluated. In consideration of the small stoke risk involved with our unprotected percutaneous transluminal angioplasty technique and the great amount of presumed risky particles that common filter systems let pass, it becomes necessary to assess the benefit-risk ratio of protection systems. As long as the inherent risk of in vivo filter systems remains unknown, such devices cannot be recommended as being unequivocally necessary.
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ACKNOWLEDGMENTS
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We thank V. Schoder, MS, Institute of Mathematics and Computer Science in Medicine, University Hospital, Hamburg-Eppendorf, Germany, for the helpful discussions and J. Knispel, PhD, Hamburg, Germany, for his language advice.
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FOOTNOTES
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Abbreviation: DSA = digital subtraction angiography
Author contributions: Guarantors of integrity of entire study, O.W., H.Z.; study concepts, O.W.; study design, O.W., B.E., C.K., J.F., M.F.; literature research, O.W., C.K.; experimental studies, O.W., E.K., J.F., M.F.; data acquisition and analysis/interpretation, O.W., E.K., J.F.; statistical analysis, O.W.; manuscript preparation, O.W., E.K.; manuscript definition of intellectual content, O.W., H.Z.; manuscript editing, O.W., C.K., M.F.; manuscript revision/review, H.Z., C.K., J.F.; manuscript final version approval, all authors
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ABSTRACT
INTRODUCTION
