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(Circulation. 1997;96:2438-2448.)
© 1997 American Heart Association, Inc.
Articles |
Percutaneous Treatment of Abdominal Aortic Aneurysm in a Swine Model
Understanding the Behavior of Aortic Aneurysm Closure Through a Serial Histopathological Analysis
From the Division of Cardiology, Loma Linda University Medical Center and Children's Hospital, Loma Linda (Calif) University School of Medicine, and The Heart Institute, Good Samaritan Hospital, Los Angeles, Calif (P.W.).
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background Previous studies used covered stent grafts to treat abdominal aortic aneurysms; however, such devices block flow into aortic side branches. We used uncovered stents with and without additional embolization coils to treat abdominal aortic aneurysm in a swine model and examined serial histological changes in the aneurysms over a 6-month period.
Methods and Results We examined aneurysms in 9 control and 9 treated pigs (5 received stents alone and 4 received stents and coils). Aneurysms were surgically created with abdominal fascia. Three days later, we percutaneously placed a self-expandable uncovered stent across the aneurysm. Coils were implanted through the stent into the aneurysm lumen. An aortogram immediately after stent placement showed no significant change in aneurysm lumen; however, in pigs that had aortograms between 6 weeks and 6 months after treatment, the diameter decreased (28% to 65%) in 4 of 5 pigs, and 1 had no discernible aneurysm. Three treated pigs died, but only 1 from rupture. In contrast, 7 untreated aneurysms ruptured (2 pigs died of other causes). Histological examination revealed that the aneurysm lumen was reduced after treatment by collagen production. This healing process was accelerated in aneurysms treated with both stents and coils. In contrast, only limited amounts of new collagen were found in untreated, ruptured aneurysms. Instead, the fascia was disrupted and there was evidence of collagen degradation.
Conclusions We found that uncovered stents reduce the likelihood of aneurysm rupture in a swine model without blocking arterial branches. The presence of coils enhanced filling of the lumen by collagen.
Key Words: aneurysm • aorta • collagen • stents • thrombus
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Ever since Dubost et al1 described surgical aneurysmectomy in 1952, this procedure has been the mainstay of treatment for abdominal aortic aneurysm (AAA). In recent years, transluminal implantation of endovascular grafts has been tested in animal models that may not fully replicate the pathophysiological conditions found in human aortic aneurysms.2 3 4 5 6 On the basis of such animal studies, investigators have initiated limited clinical trials, with mixed results.7 8 9 10 11 The majority experience in animals and humans has been accumulated with covered devices; however, radiological exclusion of an aneurysm may not be equivalent to an effective therapy. Furthermore, covered devices will interrupt blood flow into arteries covered by the graft.
In a previous study, we demonstrated the ability of uncovered stents to gradually exclude surgically created AAA during short-term follow-up in a canine model with no incidence of rupture.5 The canine fibrinolytic system is very active compared with that of humans,12 a potential disadvantage in the evaluation of aneurysm rupture after placement of uncovered devices. In the present study, we used swine as the experimental animal because their fibrinolytic and coagulation systems are closer to humans than are those of dogs.12 Our aim was to assess the long-term radiological and histological response to uncovered stents with and without the additional deployment of embolization coils in the aneurysm lumen.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Design
The study was conducted according to the principles outlined in the "Position of the American Heart Association on Research Animal Use," adopted November 11, 1984. The protocol was approved by the animal research committee of Loma Linda University.
Eighteen Yorkshire swine (15 to 31 kg) were assigned to two groups, 9 controls and 9 in the study group. In the study group, 5 pigs received stent alone, and 4 had embolization coils deployed in the aneurysm cavity in addition to stent placement. We first surgically created an "aneurysm" in the abdominal aorta in each pig and then deployed a stent in the study group 3 days after aneurysm creation. The study group animals were euthanized at 4 weeks, 6 weeks, 3 months, and 6 months after treatment. Tissue from control pigs was collected at the time of death.
Creation of Aneurysm Model
The surgical creation of AAA has been described
previously.13 Briefly, we took a piece of rectus abdominis
fascia about 80x100 mm and cut it in half. After exposing the
abdominal aorta, we sutured the two pieces of fascia on the external
surface of the aorta in a longitudinal fashion and then sutured them to
each other along their edges, which were left partially open. We placed
aortic cross-clamps below the renal arteries and at the aortic
bifurcation and proceeded to resect the entire aortic wall within the
pouch. We then clamped the pouch at a point adjacent to the aorta and
unclamped the aorta to allow blood flow through it while we sutured the
roof of the pouch. After closing the roof, we unclamped the pouch and
allowed blood flow into the aneurysm.
Description of Devices
We used a self-expandable uncovered stent made from
0.15-mm-diameter superelastic nitinol wire (Cook Inc). The stent was
constructed with 8 wires to form a woven mesh tube, and each cell size
was 2.03x4.72 mm (9.58 mm2). The wires at both
ends were rounded to prevent damage to the vessel wall. Three stent
diameters were used: 8, 10, and 12 mm. The unconstrained length of
all devices was 100 mm. The commercially available embolization
coils measured 50x5 mm (Cook Inc).
Stent Placement Procedure
All 9 pigs in the study group were taken to the
catheterization laboratory 3 days after AAA creation.
Under general anesthesia, an 8F (1 French unit=0.33
mm) sheath was placed percutaneously into the left
carotid artery. A 6F angiographic pigtail catheter, advanced over a
Benson wire (0.889 mm), was then placed in the descending aorta
50 mm above the aneurysm. Before stent implantation, we
documented the angiographic size and location of the created
aneurysm from an abdominal aortogram (30 mL of contrast at 20
mL/s). The stent, premounted on the delivery catheter, was then
advanced to the desired position and deployed under fluoroscopic
guidance. In the group of pigs treated with both stents and coils, the
coils were deployed with a 6F Judkins-type RCA catheter and pushed out
with a 0.889 mm Teflon stainless fixed wire. Two pigs received 1
coil, 1 pig received 5 coils, and another pig received 10 coils. An
aortogram was done after deployment of the stent or coils in all pigs.
No anticoagulants or antiplatelet drugs were used before, during,
or after this procedure.
Angiographic Measurement of Aneurysm Size
Aneurysm size was measured angiographically with a
computerized digital analytical system (AngioComm StatVIEW Digital
Recorder, ImageComm Systems, Inc). The largest transverse diameter
of the contrast-filled aneurysm was measured. The reference
aortic diameter was determined as the average of the normal aortic
diameter immediately above and below the aneurysm. Two
measurements were taken, and the mean value was calculated.
Follow-up
The control group animals were observed until death occurred, at
which time the abdominal aorta was removed. The study group pigs,
except for unexpected early deaths, were followed to 4 weeks, 6 weeks,
3 months, or 6 months after device implantation and then euthanized
under deep sodium pentobarbital anesthesia by injection of
potassium chloride solution. The entire descending aorta was then
removed.
Histological Study
After fixation in a solution of 10% neutral buffered formalin,
tissue from each aneurysm was processed for paraffin embedding
and sectioned at a thickness of 5 µm. In addition, we also cut
sections from the fascia used to construct the aneurysms. The
sections were stained with hematoxylin-eosin and with picrosirius
red.14
The hematoxylin-eosin–stained sections were examined by bright-field microscopy for the presence of inflammatory cells. The picrosirius red–stained sections were viewed with polarized light to examine the collagen fibers. We qualitatively assessed the thickness of the collagen fibers. The color of collagen fibers stained with picrosirius red and viewed with polarized light depends on the thickness of the fibers. As fiber thickness increases, the color changes from green to yellow to orange.15 In addition, we quantitatively examined three parameters: collagen fiber orientation, collagen content, and the optical properties of the collagen.
Collagen Fiber Orientation
Collagen fibers have been found to become, in time, increasingly
aligned in healing tissue. Such an increase in organization has been
reported in dermal wound healing16 and after acute
myocardial infarction.17 We speculated that the healing
process in our aneurysm model might be similar and therefore
that examination of collagen fiber organization in the
aneurysms could provide a method of assessing the progression
of healing. We measured the two-dimensional orientation of collagen
fibers in the aneurysm wall using a previously described
method.18 Briefly, picrosirius red–stained sections were
examined on the rotating stage of a polarizing microscope with a x40
objective lens. We measured the orientation of 50 collagen fibers at
three different locations in each sample. The fibers selected for
measurement were those intersected by the grid of an eyepiece reticule.
The orientation data obtained were analyzed by use of circular
statistics.19 Specifically, we calculated the mean
orientation and the angular deviation (the circular statistics
equivalent of SD) of each distribution. We expressed the orientation of
the fibers relative to the tangent angle to the aneurysm wall
at the point at which the measurements were taken.
Collagen Content
We measured the area occupied by collagen fibers in three
regions in which new collagen fibers were present (ie, not in the
fascia). This analysis was performed at a magnification of x20
on picrosirius red–stained sections according to previously published
methods.20 Briefly, we used an image analysis
system to subtract an image of the background (a field of view with no
tissue present) from a circularly polarized image of the tissue.
This has the effect of producing an image of gray collagen fibers on a
black background. The interstitial space was made black by
the subtraction process (pixel brightness in the image was expressed on
a 0 to 255 gray scale, with 0=black and 255=white). Thus, any pixel
with a gray level >0 represented collagen. Collagen
content was expressed as the area fraction of pixels with a gray-scale
level >0.
Optical Properties of the Collagen
In the same regions in which collagen content was measured, we
also measured the brightness of the fibers. Several groups have found
that collagen fiber brightness in scar tissue increases with
time.20 21 Thus, we anticipated that measurements of this
parameter would indicate the degree of healing. We examined
circularly polarized images of picrosirius red–stained tissue using a
x20 objective lens. Again, an image of the background was first
subtracted from the circularly polarized image, and then a histogram of
pixel intensity was plotted, from which we calculated the average gray
level of collagen fibers in the tissue. The average gray level of the
fibers in the three regions was then calculated.
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Results |
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Stent and Coil Placement
The stents were successfully deployed and placed across the aneurysms in all animals. In addition to stent placement, pigs 6 through 9 also received coil implantation. An aortogram taken before stent placement revealed an average aneurysm diameter of 61±15 mm (Table 1
; Figs 1
left and 2
left). The aortogram obtained immediately
after stent placement showed relatively faint contrast filling the
aneurysm cavity, but the angiographic cavity size was unchanged
or slightly decreased (Figs 1 middle and 2 middle). In one pig (pig 7),
an aortogram before stent placement revealed extensive retroperitoneal
extravasation of contrast, consistent with aneurysm
rupture (Fig 3A). A stent was immediately
placed across the aneurysm, followed by coil deployment. An
aortogram after placement of the stent and coil showed a significant
decrease in lumen size with no evidence of leaking and only residual
contrast stain retained in the retroperitoneal space (Fig 3B, 3C, and 3D). This pig survived the procedure and was euthanized 4 weeks
later.
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Follow-up
Control group. All pigs in the control group died. One
pig died of distal bowel perforation at 2 days after surgery, and
another died of undetermined cause (probably sepsis) at 3 days. The
remaining 7 pigs died of spontaneous aneurysm rupture between 4
and 43 days (median, 8 days) after the initial surgery. The rupture
site was found to be at the thinnest part of the aneurysm wall
and none at a suture line. The aneurysm size was much larger
(>200%) than that of the original fascia pouch, an observation
consistent with rapid expansion.
Study group. Pig 1 died of aneurysm rupture 8 days after stent placement. The aneurysm diameter in this animal at the time of stent implantation was 87 mm, six times larger than the reference aorta. Pig 2 died of sepsis secondary to intra-abdominal abscess 29 days after stent placement. Pig 6, which received both stent and coil, died of anesthesia complications 12 hours after the procedure.
Follow-up aortograms were performed on 5 pigs: at 6 weeks (pig 3), at 3
months (pigs 4 and 8), and at 6 months (pigs 5 and 9); however, no
follow-up aortogram was available in pig 7. In all cases, the lumen of
the stent was angiographically patent, with no filling defects, and all
arterial side branches were patent, with vigorous flow
through these arteries (Figs 1
right and 2 right). A decrease (28% to
65%) in aneurysm cavity size was observed in 4 of 5 pigs
undergoing repeat aortogram. The 1 remaining pig (pig 9) treated with
stent and coils had no angiographic evidence of an aneurysm at
6 months.
Gross Examination
No migration of the stent was observed after deployment in any of
the pigs. All stents were patent, with no fracture and no thrombus in
the lumen. The stents were either partially or entirely covered by
neointima; however, the orifice of aortic
arterial branches remained patent.
In the group of 5 pigs that received stent alone, one pig (pig 1) died
8 days after the procedure. On autopsy, we found that the
aneurysm had ruptured even though the stent had completely
crossed the aneurysm. In another pig (pig 2), the gross
external aneurysm diameter was 8 cm at 4 weeks after stent
placement, which was the same as the angiographic diameter (8 cm)
before stent placement. In the remaining 3 pigs (pigs 3 through 5), the
aneurysm wall increased in thickness over time, decreasing the
lumen volume (Fig 4).
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There was no aneurysm rupture in the 4 pigs that received stent
and coils. The aneurysm lumen in pig 6 (dead of
anesthesia complications 12 hours after the procedure) was
completely thrombosed, and the coil was embedded in the thrombus;
however, the intraluminal stent was patent and free of clots. In the
remaining 3 pigs (7 through 9), we found that the external size of the
aneurysms was smaller than that of the original pouch. The
aneurysm wall was thick at 4 weeks after stent and coil
placement (pig 7) (Fig 5 top) and even
thicker at 3 months (pig 8). We were unable to identify an obvious
aneurysm in pig 9 at 6 months after the procedure, and all that
remained was a small collagenous pouch containing the coils (Fig 5
bottom).
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Histological Study
The fascia used to construct the aneurysms consisted of
three layers of collagen fibers. The middle layer was wider than the
two outer layers and contained collagen fibers aligned perpendicular to
those in the outer layers (Fig 6 top).
This characteristic trilayered structure proved useful in
distinguishing the original fascia from new collagen fibers.
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Observations in untreated aneurysms. In the cases in
which rupture occurred within 1 week, we observed red blood cells,
macrophages, and neutrophils within the fascia. In addition,
the collagen bundles in the thick, middle layer of the fascia were
frequently separated by red blood cells. There was always a thrombus
adhering to the inside of the fascia; however, there was evidence of
new collagen in only one specimen (6 days after surgery). In two cases,
we observed collagen fibers in the fascia that were less bright than
normal (ie, they had reduced birefringence when viewed with circularly
polarized light) (Fig 7). Such a
reduction in birefringence is consistent with a breakdown of
the subcellular structure of the collagen.
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In two cases, rupture occurred relatively late, at 13 and 41 days. In both of these samples, we observed new collagen fibers. These fibers were green in the 13-day case, but some orange fibers were also present in the 41-day case. In both cases, we observed red blood cells, macrophages, and neutrophils within the wall.
Observations after stent placement. In the aneurysm
that ruptured 8 days after stent placement, we saw no collagen in the
aneurysm wall apart from that contained in the original fascia
patch. In addition, we observed red blood cells, macrophages,
and neutrophils that had infiltrated into the collagen of the fascia.
At 4 weeks after stent placement, we found a very small amount of new
collagen in the aneurysm wall. These fibers were green and were
located at the border between the fascia and the adherent thrombus. At
6 weeks and 3 months, we observed more new collagen fibers both on the
outside and on the inside of the fascia. These fibers were
predominantly green, and although generally aligned circumferentially
in the wall, were not particularly well organized (Fig 8 top
left). Fibroblasts could also be seen in
the region of the border between thrombus and fascia. In contrast, at 6
months we observed considerable numbers of fibroblasts throughout a
thick aneurysm wall. The collagen fibers were predominantly
orange and were highly aligned in the circumferential direction (Fig 8
top right). In addition, the collagen fibers were arranged in multiple
layers (Fig 8 top right).
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Observations after stent and coil placement. In the pig that
died 12 hours after placement of the stent and coil, there were red
blood cells, macrophages, and neutrophils within the fascia. At
4 weeks, we found extensive new collagen both inside and outside the
fascia layer. Most of these fibers were orange and were aligned in the
circumferential direction. Collagen fibers were also found within the
deepest regions of attached thrombus; however, these fibers were not so
highly aligned and were generally organized into a lattice-like
structure. We also observed fibroblasts and some neutrophils within the
wall. At 3 months, we observed even more fibroblasts. The
aneurysm wall was thick and contained several layers of
organized orange collagen fibers (Fig 8 bottom left). The
aneurysm at 6 months no longer had the appearance of an
aneurysm; instead, it consisted of a small nodule of connective
tissue containing the coils. The histology of tissue from this sample
revealed mainly highly aligned, orange collagen fibers (Fig 8 bottom
right).
Collagen fiber orientation. The average angular deviation of
the collagen fiber orientation distributions decreased with time (Table 2), which indicates that the fibers
became progressively more aligned. Representative
orientation distributions from the stent-treated cases are shown in Fig 9. The average angular deviations of the
distributions obtained from aneurysms treated with stents and
coils were similar to or smaller than those obtained from
aneurysms treated with stents alone (Table 2). The average
difference in orientation between the mean of each distribution and the
tangent angle to the wall at the site at which the measurements were
taken was 20±4° in the stent-treated aneurysms and 18±2°
in the aneurysms treated with stents and coils. Therefore, the
collagen fibers were generally aligned circumferentially in the
aneurysm wall.
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Collagen content. There was a progressive increase in the
collagen content of the tissue with time in both stent-treated and
stent-plus-coil–treated aneurysms (Table 2). However, the
collagen content in the aneurysms treated with both stents and
coils was always higher, at any given time point, than in those treated
with stents alone.
Optical properties of the collagen. The average fiber
brightness increased in both groups with time after treatment and, as
with collagen content, the values were consistently higher at
any given time point in the group treated with both stents and coils
(Table 2). There was a significant correlation between collagen content
and average fiber brightness in both groups (P<.01, data
not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We have demonstrated the effectiveness of endovascular uncovered stent placement, with and without additional embolization coil, for treatment of an animal model of AAA. In contrast to previous methods,2 3 4 5 6 7 8 9 10 11 we used a stent with no covering material. We also demonstrated, through serial histological analysis, that the aneurysm lumen was gradually replaced by scar tissue after stent deployment. Furthermore, the combination of stent placement plus embolization of the aneurysm lumen with coils appeared to accelerate this healing process.
Animal Model of AAA
To test the effectiveness of any aneurysm treatment, it is
desirable to do so in a model in which rupture is likely. Our finding
of a 78% (7 of 9; the other 2 pigs died of other causes, but the
aneurysm size significantly increased) incidence of rupture in
the untreated pigs indicates the applicability of our fascia pouch
model. However, we used exactly the same method to create
aneurysms in canine aortas and found no rupture (although the
aneurysms increased in size). We speculate that the difference
between the two studies results from structural differences in the
fascia. Although the fascias in the two models were similar in
thickness and were composed of three distinct collagen layers, the
collagen fibers in the middle layer were more organized and tightly
packed in the dog fascia than in the pig (Fig 6 bottom). Such
organization in the dog probably confers greater structural integrity
than that of the pig fascia, in which we found the collagen fibers of
the middle layer to be disrupted and pulled apart by infiltration of
red blood cells. Thus, we propose that the precise structural
configuration of the material in the wall of the model aneurysm
is a crucial determinant of outcome.
Even though we were able to create an animal model in which aneurysm rupture did occur, rupture of the aneurysm presents a paradox. Collagen is a strong and stiff material that should, under normal circumstances, be expected to easily withstand the hemodynamic forces exerted on it in the model. How could an aneurysm constructed of collagen expand and rupture? We observed collagen fibers in several ruptured aneurysms that had reduced birefringence when viewed with polarized light (they appeared less bright). This optical property is an indicator of the subcellular structure of a material; a material with an anisotropic subcellular structure is birefringent and therefore appears bright when viewed with polarized light, whereas isotropic materials appear dark. Thus, a reduction in collagen birefringence indicates a breakdown of its normal anisotropic structure. Similar optical changes have been found after in vitro degradation of collagen,22 and the presence of collagen fibers with reduced or no birefringence was associated with ventricular expansion after myocardial infarction.23 Therefore, we propose that our observation is consistent with collagen degradation and may explain the propensity for expansion and rupture in our model. Although our model was designed to evaluate stent treatment, it may also provide an opportunity to study the pathophysiology of aneurysm growth and rupture.
Aneurysm Treatment With Uncovered Stents
Deployment of the uncovered stent across the mouth of the
aneurysm decreased the incidence of rupture in pigs from 78%
to 20% (1 of 5; the angiographic size of this aneurysm was
87 mm). One major advantage of the uncovered stent is that it
permits blood flow through all arterial branches crossed by
the stent, and so there is no risk of preventing flow to vital organs.
In contrast, a covered stent cannot be allowed to cross major arteries;
otherwise, severe complications will develop. In an animal study,
Mirich et al2 found that a covered device caused renal
artery occlusion and death after the stent migrated in a canine aorta.
In a human trial, Dake et al7 reported one death secondary
to paraplegia (probably because of spinal artery occlusion) after using
a covered stent graft to treat thoracic aortic aneurysm. Of
course, this advantage also means that the aneurysm is not
immediately excluded from the circulation, and there is still blood
flow into the lumen. However, the amount of flow into the lumen
decreased, as shown by the reduced density of contrast in the
aneurysm lumen. Such a decrease would be accompanied by a
reduction in the pulsatile hemodynamic forces acting on
the aneurysm wall, which would lessen the likelihood of
rupture.
Over the 6-month follow-up period, the aneurysm lumen was first filled with thrombus and finally by fibrosis. The appearance of a thrombus is consistent with the reduced flow into the aneurysm lumen suggested by the aortograms. However, the presence of large amounts of thrombus has been associated with a greater likelihood of rapid expansion.24 Vorp et al25 speculated that the thrombus would limit the amount of oxygen reaching the aneurysm wall by increasing the diffusion distance. Such a lack of oxygen might then lead to smooth muscle necrosis and hence make the wall less resistant to distension. However, our stent-treated aneurysms all contained extensive thrombus, and only one huge aneurysm ruptured. The lack of rupture in our model with extensive thrombus may be because of the previously mentioned reduction of pulsatile forces after stent placement.
Aneurysm Treatment With a Combination of Stent and
Embolization Coils
The deployment of coils after the stent was in position was
feasible because the stent was uncovered and the size of the individual
stent cells was sufficiently large to allow easy catheter-mediated
placement. The rationale for the addition of coils was that their
presence would accelerate thrombus formation and hence quickly
eliminate the aneurysm lumen from the
circulation.26 In fact, an extensive thrombus was found as
early as 12 hours after treatment. Furthermore, the acute rupture that
occurred in one pig (indicated by the leaking contrast media; Fig 3)
was successfully treated by stent and coil placement. There was no
incidence of rupture in any of the four aneurysms subjected to
this combined therapy, which further suggests that the presence of
thrombus within the aneurysm lumen is not necessarily
associated with an adverse outcome.
Long-term Histological Changes in Treated
Aneurysms
We measured the orientation, content, and birefringence of the new
collagen fibers that we observed to first infiltrate and then replace
the thrombus. These parameters are known to increase in
cases of wound healing; for example, in scar formation after acute
myocardial infarction and in healing after tendon
injury.17 21 In the treated aneurysms, the new
collagen fibers became increasingly aligned, more densely packed, and
thicker (denoted by both the color changes and the increased brightness
seen with circularly polarized light). All of these changes will reduce
the likelihood of rupture. An increase in fiber alignment will increase
wall stiffness, whereas an increase in fiber content and thickness will
increase wall strength. Furthermore, as the new fibers mature, there is
an increase in intermolecular and intramolecular collagen
cross-linking, leading to increase in tensile strength. In addition, as
the wall thickens, there will be a decrease in wall stress according to
Laplace's law. Thus, we propose that our aneurysm treatment
not only prevented early rupture but also allowed initiation of a
healing process that further reduces the chances of expansion and
rupture and will eventually result in complete replacement of the
aneurysm lumen by fibrosis, as seen in one pig at 6-month
follow-up. Although our sample size was too small to permit statistical
comparison, the progression of healing appeared to be more advanced in
aneurysms treated with stents and coils at all time points
examined than in aneurysms treated with stents alone. This may
indicate that early thrombus formation allows earlier onset of the
repair process.
Even though healing was evident, the process appeared to be slow
in comparison with other examples of wound healing. After acute
myocardial infarction, complete replacement of the necrotic tissue by a
firm, fibrous scar has occurred, even in large-animal models, after
6 weeks. We speculate that a lack of oxygen supply to the
aneurysm, caused in part by limitation of oxygen diffusion from
the circulation by the thrombus, is responsible. Similar slow healing
has been reported in human aneurysms treated with coils. In two
patients examined at necropsy 2 and 6 months after treatment, the
resolution of thrombus within giant cerebral aneurysms (25 to
35 mm in diameter) was not complete.27 The authors
speculated that the slow rate of healing was the result of the
avascular nature of the aneurysm wall. Healing might be even
slower in our model because the fascia lacks the vasa vasorum that
would likely be present in a structure that contains former
arterial tunica adventitia.
Relevance of the Fascia Pouch Model to Real Aneurysms
The fascia pouches, like actual aneurysms, have the
capability of both expansion and rupture. In addition, the later
appearance of the pouch, modified by the production of new
collagen, is similar to that seen in human aneurysms.
Specifically, unlike the normal artery wall, both the pouch model and
real aneurysms are composed almost exclusively of collagen with
little elastin or smooth muscle.28 The organization of
this collagen into multiple distinct layers is also a common feature.
Multiple layers of generally circumferentially aligned collagen fibers
have been found in human cerebral aneurysms.29 30
We are unaware of published data regarding the organization of collagen
fibers in human aortic aneurysms; however, in tissue obtained
from two cases of aortic aneurysm resection, we found multiple
layers of collagen fibers (Fig 10 top).
In addition, one of the pigs in our study was found to have a natural
aortic aneurysm, which had a histological
structure similar to that seen in the later stages of the treated model
aneurysms (Fig 10 bottom). These apparent similarities in
structure indicate that our model may allow examination of the
expansion, rupture, and healing phases of aneurysm. However,
the dissimilarity between the pouch and normal aorta, which contains
significant amounts of elastin and smooth muscle,28 means
that the model has little relevance to the initiation of
aneurysm formation.
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Limitations of the Model
Despite the structural similarities described above, there are
potentially important differences between human aneurysms and
our model. Although we attempted to create a fusiform aneurysm
to mimic the common appearance of human AAAs, their angiographic
appearance tended to be more saccular in nature. Whether such
differences will influence the effectiveness of stent treatment is
unknown.6 Similarly, aneurysm size may be an
important limitation of stent effectiveness. Although we substantially
reduced the incidence of aneurysm rupture with stent treatment,
it was not eliminated, and the one aneurysm that did rupture
was very large. The addition of coils appeared to enhance stent
treatment; however, our sample size was too small to definitively
answer such questions. Even though our model appears to possess some
features of human AAAs, no model can fully duplicate the human disease;
for example, macrophages and lymphocytes rather than
neutrophils are predominant in human AAAs.31 Thus,
although our results are encouraging, an even longer follow-up period
in a larger number of animals may be necessary. However, the
limitations of the animal model may mean that once feasibility has been
demonstrated, perhaps the only reasonable progression is evaluation in
humans.6
Conclusions
Our study documents that uncovered stents, with and without
additional embolization coils, can be used to effectively treat large
AAAs in a swine model. In the untreated model aneurysms, the
fascia pouch was disrupted and there was evidence of collagen
degradation. Although we found some collagen fibers in the cases of
late rupture, the degree of healing was minimal. In contrast, placement
of stents prevented aneurysm expansion, reduced the incidence
of rupture, and allowed healing to proceed so that the aneurysm
wall became reinforced by multiple layers of highly aligned collagen
fibers (Fig 11). We speculate that the
stents stabilize the aneurysms sufficiently to provide enough
time for this relatively slow healing process to eventually fill the
aneurysm lumen with fibrosis. The use of uncovered stents
permits continued blood flow through arterial branches
crossed by the stent and allows the additional deployment of
embolization coils into the aneurysm lumen. This combination
allowed us to successfully treat an acutely leaking aneurysm.
Furthermore, the presence of embolization coils appeared to accelerate
the rate of healing. We conclude that the long-term patency of both the
uncovered stents and the arterial branches crossed by the
stents, plus the reduction in the incidence of rupture via enhanced
healing, support the initiation of clinical trial of this approach.
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Acknowledgments |
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We thank Cook Inc, Bloomington, Ind, for both their grant support of the study and their contribution to the publication of the color photographs.
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Footnotes |
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Reprint requests to Dr Carlos E. Ruiz, Division of Cardiology, Department of Medicine, Loma Linda University Medical Center and Children's Hospital, Room 4002, 11234 Anderson St, PO Box 2000, Loma Linda, CA 92354-0200.
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 11-14, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-59).
Received February 18, 1997; revision received April 15, 1997; accepted April 18, 1997.
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