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(Stroke. 1995;26:2075-2080.)
© 1995 American Heart Association, Inc.

Articles

Effect of Guglielmi Detachable Coils on Experimental Carotid Artery Aneurysms in Primates

Hiroshi Tenjin, MD, PhD; Shinji Fushiki, MD, PhD; Yoshikazu Nakahara, MD; Hiroto Masaki, MD; Takamasa Matsuo, RT; Christopher M. Johnson, MD Satoshi Ueda, MD, PhD

From the Departments of Neurosurgery (H.T., Y.N., H.M., S.U.), Dynamic Pathology, Research Institute for Neurological Diseases and Geriatrics (S.F.), and Radiology (T.M.), Kyoto Prefectural University of Medicine (Japan); and the Department of Pediatrics, Mayo Clinic and Foundation (C.M.J.), Rochester, Minn.

Correspondence to Hiroshi Tenjin, Department of Neurosurgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyoku, Kyoto 602, Japan.

	Abstract

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Background and Purpose Clinical experience has established that intravascularly placed metal coils can be a useful treatment for cerebral vascular aneurysms. However, the mechanism by which the coils induce occlusion of the aneurysm is unclear. Appropriate use of this promising treatment modality requires basic understanding of the occlusive process. We used an animal model system of experimentally induced carotid aneurysms to investigate the initial events induced by Guglielmi detachable coils (GDCs), as well as the subsequent vascular changes induced by the coils over time.

Methods We induced 23 aneurysms in the carotid arteries of 16 Japanese monkeys. Nineteen aneurysms were then occluded with GDCs placed via endovascular surgery; 4 aneurysms served as controls. We then used gross and microscopic pathological examination, angiography, and scanning electron microscopy to assess the effects of the GDC.

Results In the first few hours after placement of the GDC in the experimental aneurysms, we observed leukocyte attachment and deposition of fibrinlike materials and other proteins. By 4 days after coil placement, leukocytes and fibroblasts were observed in the thrombus. By 2 weeks after coil placement, there was evidence of an endothelial-like covering of the coils. At 3 months after coil placement, we observed development of an arterial media in the occluded aneurysms.

Conclusions The GDCs initiated a cellular response within several hours of aneurysm occlusion. By 2 weeks after coil placement, endothelialization was proceeding, and by 3 months after occlusion, remodeling of the aneurysm had progressed to produce a media-like structure in the former aneurysm.

Key Words: aneurysm • animal models • embolization • endovascular therapy • monkeys

	Introduction

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Cerebral aneurysms carry a high morbidity and mortality. In some instances, such aneurysms can be externally clipped at surgery. However, the location of many cerebral vascular aneurysms precludes a standard surgical approach. For these cases, an endovascular neurosurgical approach has been used to place metal coils in the aneurysm in an attempt to occlude the aneurysm and thereby prevent subsequent leakage and rupture. Although this technique has proved successful in many clinical cases,¹ the mechanism by which the coils may facilitate occlusion of the aneurysm is unknown. Appropriate use of this treatment modality requires an understanding of the cellular and biochemical events that occur after coil placement. Reorganization of an aneurysm is a complex process, and the cellular events that take place during healing may vary among different species. In these studies, we used an animal model system in primates to study both the immediate effects of coil placement and the long-term vascular remodeling that occurs in coil-treated aneurysms. We believe that our observations in this primate model are likely to mimic the events occurring in humans after Guglielmi detachable coil (GDC) treatment of clinical aneurysms. Our report is the first to describe the temporal sequence of histological and pathological events that follow GDC placement.

	Materials and Methods

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The primate model system for inducing experimental carotid aneurysms has been described elsewhere.² Briefly, 16 Japanese monkeys (Macaca fuscata) weighing between 5 and 12 kg were anesthetized with pentobarbital (5 mg/kg). The right femoral veins were exposed and resected. Outpouchings in the veins were then created with 5-0 nylon suture. Both carotid arteries in each monkey were then exposed and clipped for approximately 40 minutes while the aneurysms were created. This was accomplished by making 4-mm openings in the carotid arteries and sewing the vein pouches over the openings. The resultant aneurysms were approximately 5 mm in size (an example is illustrated in Fig 1). Two weeks later, with animals under pentobarbital anesthesia, carotid angiography was used to determine vascular patency and identify the aneurysms. Twenty-three aneurysms were successfully created in the 16 monkeys, and these aneurysms formed the basis for this study. The overall success rate in creating aneurysms identifiable at 2 weeks after the initial surgery was 74%. All animals survived the surgery.

View larger version (14K): [in this window] [in a new window]   Figure 1. Diagrams show angiographic appearance of aneurysms. The animals in the various groups are identified by number with either right (R) or left (L) carotid aneurysms. Although all samples showed aneurysms at 2 weeks after surgery, there was some variability in the specific sizes and morphologies of the aneurysms.

The GDCs were positioned in the aneurysms through a Tracker-18 microcatheter (both supplied by Target Therapeutics Inc) and subsequently detached by applying 1 mA of positive direct electrical current for 3 to 15 minutes. For short-term studies, the anesthetized animals were then killed with pentobarbital at either 1 hour (3 aneurysms in 3 monkeys) or 3 hours (3 aneurysms in 3 monkeys) after placement of the coils. Before death, the region of the carotid artery containing the aneurysm was cleared with 100 mL heparinized saline and then perfusion-fixed with 50 mL PBS/4% paraformaldehyde to preserve cellular ultrastructure for scanning electron microscopy. For long-term studies, animals underwent repeated carotid angiography at 2 days (3 aneurysms in 3 monkeys), 4 days (3 aneurysms in 2 monkeys), 14 days (4 aneurysms in 3 monkeys), and 3 months (3 aneurysms in 3 monkeys) after coil placement and were then killed as above. The 4 control animals underwent angiography, perfusion fixation, and death as above without placement of coils at 2 weeks (3 aneurysms in 3 monkeys) and 4 weeks (1 aneurysm in 1 monkey) after creation of the aneurysms.

After perfusion in situ, the tissues were removed, and the fixation was continued in the same fixative for 24 hours. The vessels were then opened, and the luminal surface including the aneurysmal orifices was evaluated macroscopically. The samples were then dehydrated in graded ethanol and dried with HCP-2 (Hitachi Ltd); the dried tissue was mounted on an aluminum stub by use of silver conductive paint (Dotite D-550, Fujikura Kasei Co Ltd). The samples were then sputter-coated with platinum-palladium (Hitachi E-1030) and observed and photographed at x200 and x1000 magnifications in a scanning electron microscope at an accelerating voltage of 15 kV (Hitachi S-520LB). After electron microscopy, the specimens were fixed again in absolute ethanol and embedded in polyester plastic resin. Sections of 10 µm were then made using a diamond knife, and the sections were stained with hematoxylin-eosin and von Gieson's stains.

These studies were approved by the Experimental Animals Committee, Kyoto Prefectural University of Medicine, and conducted in accordance with the relevant regulations regarding animal care and use.

	Results

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Angiography of control animals showed patency of the aneurysms at both 2 weeks (3 monkeys) and 4 weeks (1 monkey) after creation of the aneurysms.² Microscopically, control aneurysms showed complete reendothelialization between the border of the aneurysm and the vessel wall. Fig 1 illustrates the angiographic appearance of the aneurysms after coil placement in the various experimental groups. Angiography after coil placement typically showed no entry of contrast material into the aneurysm after coil placement. This is illustrated in Fig 2.

View larger version (124K): [in this window] [in a new window]   Figure 2. Representative angiogram 3 hours after coil placement.

Our macroscopic and microscopic findings are summarized in the Table. Thrombus formation occurred immediately after endovascular surgery (Fig 3, top left), accompanied by deposition of proteinaceous material and cellular components (Fig 4A, 4B, and 4C). Fibroblasts were observed to be infiltrating the aneurysms 4 days after coil placement (Fig 5, top left). Macroscopic observations made 14 days after coil placement showed a thin membrane covering the aneurysmal orifice in all but one sample (Fig 3, bottom left). This membrane was observed by scanning electron microscopic examination to consist of endothelial-appearing cells covering the coils across the borders of the aneurysms (Fig 4E and 4F). In one 14-day sample, we observed an aneurysmal "shoulder" macroscopically (Fig 3, top right), which scanning electron microscopic examination showed to lack discernible cellular boundaries (Fig 4D). Macroscopic examination of the aneurysms 3 months after coil placement showed the aneurysmal orifices to be covered by a thick membrane (Fig 3, bottom right). Light microscopy of the 3-month samples showed tissue resembling vascular media in the organizing aneurysm (Fig 5, top right and bottom).

View this table: [in this window] [in a new window]   Table 1. Gross and Microscopic Findings of All Experimental Aneurysms Receiving Endovascular Guglielmi Detachable Coil Treatment

View larger version (84K): [in this window] [in a new window]   Figure 3. Macroscopic findings. Top left, Three hours after endovascular surgery, the coil and a thrombus can be seen in the aneurysm (arrowheads); top right, at 14 days after coil placement, this sample showed persistence of an aneurysmal "shoulder" (arrowhead); bottom left, at 14 days after coil placement, this sample showed a thin membrane covering the aneurysmal orifice; bottom right, at 3 months after coil placement, this sample showed a thick membrane covering the aneurysmal orifice (arrowheads).

View larger version (165K): [in this window] [in a new window]   Figure 4. Scanning electron microscopic findings. A, At 1 hour after coil placement, the coil surface was covered by proteinaceous material and cellular components (magnified x200); B, a higher magnification view (x1000) of the sample seen in panel A shows that most of the cellular components appear to be leukocytes; C, at 3 hours after coil placement, platelets and other cells are seen to be enmeshed in a fibrillar network (x1000); D, at 14 days the coil shown in Fig 3, top right, is covered by a membrane without discernible cellular boundaries (x200); E, at 14 days after coil placement, endothelial-appearing cells cover the coils across the border of the aneurysm (arrows, x200); F, a higher magnification view (x1000) of the sample seen in panel E shows the cellular covering to be composed of fusiform-appearing cells in a continuous monolayer. The shape and the continuation from normal artery strongly suggest endothelialization of aneurysm.

View larger version (0K): [in this window] [in a new window]   Figure 5. Light microscopic findings. Top left, At 4 days after coil placement, fibroblasts (arrows) are seen to be infiltrating the aneurysm (x100, hematoxylin-eosin stain); top right, at 3 months after coil placement, tissue resembling vascular media can be seen to be forming (arrow) in the organizing aneurysm (x40, hematoxylin-eosin stain); bottom, higher power view of the same tissue shown in the top right panel demonstrates (arrows) the media-like region (van Gieson's stain, x100).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Ruptured cerebral aneurysm is one of the most frequent fatal disorders encountered in neurosurgical practice. Additionally, nonlethal cases often carry a high morbidity. The traditional approach to aneurysmal surgery, placement of a surgical clip, is not feasible in many patients because of the location of the aneurysm. For such patients, the use of an endovascular surgical approach for the placement of coils (such as the GDC¹ ) offers the potential for ablation of the aneurysm. Previous investigators have studied the usefulness of coils using animal systems in pigs,³ rabbits,⁴ and dogs.^{5 6} No previous studies using primates have been reported. The monkey model used in the present studies should prove useful in assessing the effectiveness and natural history of coil therapy for cerebral aneurysm.

In general, a foreign body placed intravascularly induces clot formation. The extent of this clot formation depends on the chemical composition, electrical charge, and surface texture of the foreign body as well as on the relationship between the foreign body and adjacent structures and the extent of intimal injury.⁷ In this regard, we note that the coagulation system of the monkey is quite similar to that of humans.⁸ Early thrombus formation involves attachment of platelets and leukocytes to the injured vessel surface, followed by fibrin formation⁹ ; our observations at 1 hour after coil insertion are consistent with this sequence of events (Fig 4A).

Vascular remodeling is a complex process involving contributions of many cytokines and growth factors.^{10 11} Intravascularly placed coils could facilitate the organization of the occluded aneurysm by inducing thrombus formation. Two weeks after coil placement, we observed fusiform cells covering the orifice of the aneurysm. The shape of these fusiform cells and the continuation with the normal artery strongly suggest that endothelialization of the aneurysm was occurring. We observed fibroblast invasion of the site at 4 days after coil placement as well as formation of tissue resembling arterial media at 3 months after coil placement. Our finding of media-like regions in the healing aneurysm may be particularly important for interrupting regrowth of the aneurysm.^{12 13} Mawad and colleagues⁶ have observed similar results in a canine model system. Cerebral aneurysms may reoccur after endovascular surgery^{14 15} ; a "water hammer effect" has been postulated as contributing to this regrowth.¹⁵ A bed of fibrous tissue on the aneurysmal site may be key to preventing regrowth.¹⁶ If the coil fails to induce formation of a thrombus in the aneurysm, a "packing effect" may occur whereby the coils progressively occupy less and less of the aneurysmal sac over time. Such an effect appeared to have occurred in our sample 9L, in which we noted incomplete endothelialization.

We believe that this model offers the capability to study the macroscopic and cellular events that follow endovascular placement of GDCs. Such information should aid in the proper clinical application of this promising treatment for cerebral aneurysms.

	Acknowledgments

 
The authors thank Dr David N. Fass and Dr Guido Guglielmi for their helpful suggestions; Dr Yoshio Ohmori, Mayumi Murakami, and Yurimi Ogawa for technical assistance; and Target Therapeutics Inc for supply of materials.

Received March 20, 1995; revision received June 26, 1995; accepted June 30, 1995.

	References

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tenjin, H. Articles by Ueda, S. Search for Related Content PubMed PubMed Citation Articles by Tenjin, H. Articles by Ueda, S.