Effect of Guglielmi Detachable Coils on Experimental Carotid Artery Aneurysms in Primates
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.
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
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.
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 ×200 and ×1000 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.
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⇓.
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).
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 surgery14 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.
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.
- Copyright © 1995 by American Heart Association
Tenjin H, Ueda S, Fushiki S, Ohmori Y, Nakahara Y, Masaki H, Matsuo T. Experimental production of the carotid artery aneurysms in Japanese monkey. J Kyoto Pref Univ Med. 1994;103:715-720.
Ahnja AA, Hergenrother RW, Strother CM, Rappe AA, Cooper SL, Graves VB. Platinum coil coatings to increase thrombogenicity: a preliminary study in rabbits. AJNR Am J Neuroradiol. 1993;14:794-798.
Graves VB, Partington CR, Rufenacht DA, Rappe AH, Strother CM. Treatment of carotid artery aneurysms with platinum coils: an experimental study in dogs. AJNR Am J Neuroradiol. 1990;11:249-252.
Mawad ME, Mawad JK, Cartwright J Jr, Gokaslan Z. Long-term histopathologic changes in canine aneurysms embolized with Guglielmi detachable coils. AJNR Am J Neuroradiol.. 1995;16:7-13.
Hawkey C. Hemostasis in mammals. In: Dodds WJ, ed. Animal Models of Thrombosis and Hemorrhagic Disease. Bethesda, Md: US Dept of Health, Education, and Welfare, Public Health Service, National Institutes of Health; 1976:69-86.
Kalman PG, Rotstein OD, Niven J, Glynn MFX, Romaschin AD. Differential stimulation of macrophage procoagulant activity by vascular grafts. J Vasc Surg. 1993:17:531-537.
Dirrenberger RA, Deen GH, Sundt TM. Temporal profile of the healing process following endoarterectomy. In: Sundt TM, ed. Occlusive Cerebrovascular Disease: Diagnosis and Surgical Management. Philadelphia, Pa: WB Saunders Co; 1987:232-242.