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To determine whether creation of a carotid-jugular arteriovenous fistula, (AVF) to induce remodeling of the right common carotid artery (RCCA) results in larger elastase-induced aneurysms in rabbits.
RCCA-right jugular AVFs were created in 6 New Zealand white rabbits (Group 1), followed by elastase-induced aneurysm creation 4 weeks later. Follow up Digital subtractive angiography (DSA) was performed to assess AVF patency and aneurysm sizes. Six other elastase-induced aneurysms created in regular way were used as control (Group 2). Diameters of right common carotid artery (RCCA) and left common carotid artery (LCCA) in Group 1, and aneurysm sizes in both groups were measured from DSA images and compared using the Student’s t test.
The patency of AVFs in Group 1 was confirmed in all the six (100%) cases. Mean RCCA diameter in Group 1 was larger than contralateral LCCA (3.6 ± .7 mm versus 2.0 ± .1 mm, from 1.8 to 2.2 mm, p < .01). The mean aneurysm neck diameter, width, and height for Group 1 was larger than that of Group 2 (4.6 ± .9 mm versus 3.5 ± .7 mm, p< .05; 4.7 ± 1.1 mm versus 3.4 ± .5 mm, p< .05; 13.8 ± 3.2 mm versus 8.1 ± 1.3 mm, p < .05, respectively). Aneurysm volume for Group 1 was significantly larger than that of Group 2 (273 ± 172mm3 versus 77 ± 32 mm3, p < .05).
Carotid-jugular AVFs result in RCCA remodeling that yields relatively larger elastase-induced aneurysms.
The elastase-induced aneurysm model in rabbits has been widely used in basic and pre-clinical research, especially in evaluation of neuroendovascular devices (1-14). The advantage if this model is that it closely simulates the morphology and hemodynamics of human, intracranial aneurysms (1, 10). However, unlike surgically created aneurysm models, the maximum size of rabbit elastase induced model aneurysms is relatively small (15-17). As such, the model does not show high rates of recurrence after coil embolzation, which would be a desirable trait for testing new endovascular devices (11, 18, 19).
Various modifications have been made to the elastase aneurysm model to alter its size and morphology including such aspects as the location of carotid artery ligation (20-25). Although not previously applied in aneurysm research, surgically created arteriovenous fistulae (AVF) have been used to stimulate arterial remodeling in animal models (26). Such remodeling acts in response to elevated arterial flow, with well-defined molecular signaling pathways (27, 28) and resultant chronic enlargement of arterial diameter.
We hypothesized that the size of elastase induced aneurysms in rabbits could be increased if such aneurysms were created in the setting of a chronic AVF, which would act to remodel and enlarge the carotid artery prior to elastase injury and aneurysm creation. In the current study we report our preliminary experience with elastase aneurysm creation following AVF creation to determine whether resultant aneurysms are larger in the setting of successful, patent AVF as compared to aneurysms created in regular way (1).
Following approval from our Instituional Animal Care and Use Committee, carotid-jugular AVFs were created in 6 (Group 1) New Zealand white rabbits. The right common carotid artery (RCCA) and right external jugular vein (REJV) were exposed and dissected. An arteriotomy of the RCCA was performed and aneurysm clips were used to temporally occlude proximal and distal side of arteriotomy. The REJV was cut into two segments, the proximal side of REJV was used for end-to-side anastomosis to RCCA using 7-0 prolene suture. The distal RCCA was permanently ligated using 4-0 silk. An end-to-side anastomosis of REJV and RCCA was performed and the AVF was created. Animals were allowed to recover and were maintained for at least four weeks prior to aneurysm creation.
In the same subjects detailed above, elastase-induced, saccular aneurysms were created. Intra-venous digital subtraction angiography (IVDSA) was performed before aneurysm creation to evaluate patency of the AVF and to determine diameters of the carotid arteries using procedures described previously by our group (29). Briefly, 7cc of iodinated contrast material (Omnipaque 300) was injected into the left ear-vein catheter at approximately 2cc/sec during DSA and the X-ray exposure rate was 2 frames per second. The diameter of RCCA and control LCCA four weeks after AVF creation were determined in comparison to external sizing devices. Following IVDSA, aneurysms were created. Detailed procedures for aneurysm creation have been described previously (1). Briefly, anesthesia was induced with an intramuscular injection of ketamine, xylazine and acepromazine (75, 5, and 1mg/kg, respectively). Using sterile technique, the RCCA was re-exposed and isolated. The AVF was disconnected at the surgical anastomotic site. A 1-2 mm bevelled arteriotomy was made and a 5F vascular sheath (Cordis Endovascular, Miami Lakes, FL) was advanced retrograde in the RCCA to a point approximately 3 cm cephalad to the origin of RCCA. A roadmap image was obtained by injection of contrast through the sheath retrograde in the RCCA, in order to identify the junction between the RCCA and the subclavian and brachiocephalic arteries (Advantx; General Electric Company; Milwaukee, Wisconsin). A 3F Fogarty balloon (Baxter Healthcare Corporation, Irvine, CA) was advanced through the sheath to the level of the origin of the RCCA with fluoroscopic guidance and was inflated with iodinated contrast material. Porcine elastase (5.23 μ/mgP, 40.1 mgP/ml, approximate 200 U/mL; Worthington Biochemical Corporation, Lakewood, NJ) was incubated within the lumen of the common carotid artery above the inflated balloon for 20 minutes, after which the catheter, balloon and sheath were removed, and the RCCA was ligated below the sheath entry site. Six elastase-induced aneurysms randomly selected from the aneurysms we created previously using regular way (1) without fistula (Group 2) were used for comparison of aneurysm sizes with Group 1. Ligation positions of RCCA in Group 1 and 2 were similar, which were approximately 3 cm cephalad to the origin of RCCA.
Three weeks after aneurysm creation the width, height and neck diameters of the aneurysm cavities were determined with IVDSA using the same external sizing device as reference. Intra-arterial digital subtractive angiography (IADSA) was performed in Group 2 three weeks after aneurysm creation. Details of IADSA procedure were demonstrated previously (29). The aneurysm volume was calculated as: Volume=3.14(width/2)2(height)
The diameter of RCCA at initial follow up, immediately prior to aneurysm creation surgery, was compared to that of the LCCA in Group 1, and the aneurysm dimensions three weeks following aneurysm creation, were compared between groups using the Student’s t test.
Six (100%) AVFs remained patent in Group 1. Time period between two procedures (AVF and aneurysm creation) and aneurysm sizes were shown in Table 1. Mean RCCA diameter (3.6 ± .7 mm, from 2.6 to 4.2 mm) was larger than contralateral LCCA (2.0 ± .1 mm, from 1.8 to 2.2 mm) at initial follow-up in Group 1 (p < .01) (Figure 1A).
The mean aneurysm neck diameter for Group 1 (4.6 ± .9 mm, from 3.5 to 5.5 mm) was larger than that of Group 2 (3.5 ± .7 mm, from 2.5 to 4.3 mm) (p< .05). Differences in aneurysm width between Group 1 (4.7 ± 1.1 mm, from 3.4 to 6.4 mm) and Group 2 (3.4 ± .5 mm, from 2.9 to 4.3 mm) were also significant (p > .05). Mean aneurysm height was greater in Group 1 (13.8 ± 3.2 mm, from 8.6 to 16.8 mm) compared to Group 2 (8.1 ± 1.3 mm, from 6.4 to 9.5 mm) (p < .05). Aneurysm volume in Group 1 (273 ± 172 mm3, from 77 to 369 mm3) was significantly larger than that of Group 2 (77 ± 32 mm3, from 44 to 138 mm3) (p < .05) (Figure 1 B-C).
The elastase aneuruysm is widely applied for both basic research and for testing of neuroendovascular devices (30-34). Unlike vein pouch models, in which large diameter veins can be harvested in order to create large aneurysms, the ultimate size of the elastase induced model aneurysms likely are limited by the initial size of the RCCA (1, 35-37). In an attempt to increase the size of elastase-induced aneurysms we induced arterial remodeling using chronic AVF prior to aneurysm creation surgery. We have demonstrated positive remodeling in patent AVF cases, indicating, as expected, that chronic elevation of flow results in arterial luminal enlargement.
Previous studies have shown that elastase aneurysm dimensions can be modified using specific surgical techniques. For example, aneurysm neck can be controlled by adjusting the position of inflated balloon during elastase incubation (20, 23), and the aneurysm height can be controlled by adjusting the position of ligation of RCCA (25). Other researchers also reported the aneurysm height can be controlled by adjusting the position of the sheath in RCCA (21). The current work expands our knowledge regarding optimal methods for elastase-induced aneurysm creation by suggesting that larger aneurysms can be induced following chronic AVF creation.
This study suffers several limitations. First, small numbers of subjects were included. Second, no test of the value of the aneurysms created after AVF creation on the frequency of recurrences was performed in current study. We recognize those limitations and are doing more study to valid this model.
Patent carotid-jugular AVFs result in RCCA remodeling that yields relatively large elastase-induced aneurysms.
Supported by NIH R01 NS46246