Steele angioplasty-circ res-105

1524-4571
Copyright © 1985 American Heart Association. All rights reserved. Print ISSN: 0009-7330. Online ISSN:
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1985;57;105-112Circ. Res.
V Fuster
PM Steele, JH Chesebro, AW Stanson, DR Holmes, Jr, MK Dewanjee, L Badimon and
a pig model
Balloon angioplasty. Natural history of the pathophysiological response to injury in
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105
Balloon Angioplasty
Natural History of the Pathophysiological Response to Injury in a Pig
Model
Peter M. Steele, James H. Chesebro, Anthony W. Stanson, David R. Holmes, Jr.,
Mrinal K. Dewanjee, Lina Badimon, and Valentin Fuster
With the technical assistance of Holly B. Lamb, James M. Byrne, and Brenda I. Wendland
From the Division of Cardiovascular Diseases and Internal Medicine, Department of Diagnostic Radiology, and Section of Diagnostic
Nuclear Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
SUMMARY. The restenosis or occlusion that frequently follows balloon angioplasty is poorly
understood. Thus, the pathophysiological response to angioplasty of the common carotid artery
in 38 heparinized normal pigs was investigated by quantification of the ln
In-labeled platelet
deposition and histological and electron microscopic examination from 1 hour to 60 days after
angioplasty. At 1 hour, the following findings were noted: complete endothelial denudation in all
arteries, marked platelet deposition (44.7 ± 20.7 X 10'/cm2
), mural thrombus in seven of 10 pigs,
and a medial tear extending through the internal elastic lamina in nine of 18 arteries. All nine
arteries with tears had associated mural thrombus and severe platelet deposition (76 x 10'/cm2
);
in contrast, the nine arteries without a tear had no mural thrombus and much lower platelet
deposition (6 X 106/cm2
). Necrosis of medial smooth muscle cells was evident at 24 hours. Platelet
deposition remained high at 24 hours (40.5 ± 20.6 X 106
/cm2
), but was markedly reduced at 4
days (4.4 ± 1.5 X 106
/cm2
), coincident with partial regrowth of endothelium or periluminal lining
cells. No significant platelet deposition was noted at 7 days, when the endothelial cell type of
regrowth was largely complete. Intimal proliferation of smooth muscle cells was mild and patchy
at 7 days, significantly greater and more uniform at 14 days, and unchanged at 30 and 60 days
after angioplasty. Complete thrombotic occlusion occurred in four (11%) of the 38 pigs. A
significant stenosis present at 30 days after angioplasty was shown by histological examination
to be due to organization of mural thrombus. Thus, balloon angioplasty produced extensive
arterial damage and was a potent stimulus for acute platelet-thrombus deposition and subsequent
intimal hyperplasia. These results may have important clinical implications in the prevention of
restenosis and occlusion after angioplasty. (Circ Res 57: 105-112, 1985)
PERCUTANEOUS transluminal coronary angio-
plasty (PTCA) has rapidly gained acceptance as a
therapeutic option in the treatment of obstructive
coronary artery disease (Gruntzig et al., 1979; Kent
et al., 1982), even in the treatment of multivessel
disease (Vlietstra et al., 1983; Hartzler, 1983). The
mechanism by which angioplasty improves the pat-
ency of atherosclerotic arteries probably involves
plaque fracture and expansion of the external di-
ameter of the artery (Castaneda-Zuniga et al., 1980;
Block et al., 1981; Sanborn et al., 1983). Endothelial
denudation, platelet deposition, and mural throm-
bus formation have been observed in dogs after
angioplasty (Pasternak et al., 1980). The natural
history of platelet-thrombus deposition is unknown.
Platelet-thrombus deposition may be an important
cause of acute occlusion (Block et al., 1981) and
restenosis (Essed et al., 1983), which occurs within
6 months in 25%-35% of patients (Holmes et al.,
1984; Dangoisse et al., 1982).
We have established a model of arterial angio-
plasty in the pig and observed the pathophysiolog-
ical response up to 60 days after the procedure, with
particular reference to the relationship of the struc-
tural injury and repair of the artery to the platelet
deposition and mural thrombus formation.
Methods
Animals
The study animals, obtained from local farmers, were
normal pigs (average weight, 35 kg) of the Babcock 4-way
cross stock (mixture of Landrace, Yorkshire, Hampshire,
and Duroc breeds). All pigs were fed a normal chow diet.
Experimental Procedure and Angioplasty Technique
The pigs were sedated with ketamine, 300 mg, intra-
muscularly (Ketaject, Bristol), intubated after inhalation of
a small amount of ether (ether USP, J.T. Baker), and
mechanically ventilated with room air (Harvard respirator)
mixed with 0.5% halothane (Fluothane, Ayerst) to main-
tain anesthesia. Continuous electrocardiographic and ar-
terial pressure monitoring was performed with a Honey-
well multichannel recorder. All pigs were fully heparin-
ized immediately after insertion of the catheter, with a

106 Circulation Research/Vo/. 57, No. 1, July 1985
TABLE 1
Pathophysiological Response to Angioplasty over Time
Tune of
sacrifice
1hr
24 hr
4 days
7 days
14 days
30 days
60 days
Pigs
no.
10
6
5
4
5
4
4
Mural thrombus
(no./total)
7/10
3/6(1)J
1/5 (1»
2/4
V5 (1»
2/4 (1»
0/4
Platelets*
no. (x 10*/cm2
)
44.7 ± 20.7
40.5 ± 20.6
4.4 ± 1.5
1.2 ±0.6
0.2 ± 0.0
0.2 ±0.1
0.1 ±0.0
Endothelialf
regrowth
_
-
±
+
+
+
+
Thickness of
intima
(mm x 10"3
)
62.4 ± 6.5
85.6 ± 15.9
80.0 ± 22.8
84.8 ± 19.2
• Mean ± SE.
| Endothelium or periluminal lining cells: —, absent; +, complete; ±, incomplete.
j Complete thrombotic occlusion.
bolus of 100 USP units/kg given intravenously. The hep-
arin was not reversed at the end of the procedure, and no
farther doses of heparin were administered.
Through a right femoral cutdown, the balloon catheter
(Meditech 8 mm X 3 cm, polyethylene balloon) was ad-
vanced into the left and right common carotid arteries
under fluoroscopic visualization. The balloon was inflated
to 6 atmospheres (Meditech pressure manometer) for 30
seconds (these balloons inflate to a maximal diameter of
8 mm). Five inflations at 60-second intervals were per-
formed on both common carotid arteries (except for two
pigs, killed at 1 hour, in which only one artery was dilated
and the other served as a control). The average diameter
of the common carotid artery was 5-6 mm. Selective
carotid spot films were obtained before and immediately
after the dilation procedure by the manual injection of 6
ml of diatrizoate meglumine and diatrizoate sodium (Ren-
ografin-76, Squibb), and plain spot films were obtained
during dilation. Measurements taken from the spot films
taken before, during, and after balloon inflation demon-
strated that the diameter of the balloon inflated within
the artery was only 9.1 ± 6.1% (mean ± SD) more than
the diameter of the artery on the films obtained before
dilation.
Angioplasty was performed on 38 pigs that were killed
from 1 hour to 60 days after the procedure (Table 1).
Immediately after a lethal dose of sodium pentobarbital,
the carotid arteries were perfused in situ with 2% glutar-
aldehyde and 1% paraformaldehyde in 0.1 M cacodylate
(pH 7.25) at a pressure of 100 mm Hg for 15 minutes. The
arterial tissues then were removed, cleaned of all adven-
titia, and prepared for analysis.
Quantification of Platelet Deposition
Autologous platelets were labeled with '"In (tropo-
lone)3 (Dewanjee et al., 1981) by a modification of our
previously described method (Badimon et al., 1983), in
which the platelets were labeled in plasma instead of acid
citrate dextrose-saline. The platelets were injected 18-24
hours before sacrifice, in doses of 300-400 jtCi. The only
exceptions were pigs that were killed 24 hours after an-
gioplasty; in these cases, the platelets were labeled and
injected 48 hours before sacrifice. The platelet deposition
on each dilated artery (X 106
/cm2
) was calculated from
platelet counts and In activity on the arterial wall and
in blood by a method previously described by us (Dewan-
jee et al., 1984).
Tissue Analysis
The location of the dilated portion of the fixed artery
was identified easily because of the in situ fixation that
showed the almost invariable vasospasm proximal and
distal to the involved area. This finding was confirmed in
vivo by the films, as described previously. The dilated
portion was divided into two segments (1-1 Vi cm), and a
segment of similar size was taken from the distal unin-
volved artery. The tissue segments were examined under
low-power magnification (x2 lens, Sunnex Laboratories)
for the presence of mural thrombus formation.
From each arterial segment, 2- to 3-ring sections were
removed and stained with hematoxylin and eosin and
Lason's elastic-Van Gieson stain. The histological sections
were examined by two investigators and a consensus
evaluation was made. Histological sections were photo-
graphed. From these pictures, the thickness of the intima
from the surface to the internal elastic lamina was meas-
ured in six equidistant sections that were again divided
into 10 equal sections for a total of 60 measurements
around the circumference of the intima.
Two longitudinal specimens were cut from each seg-
ment, coated with carbon and gold-palladium alloy, and
examined with a scanning electron microscope (ETEC
Autoscan). Representative areas were photographed and
evaluated by at least two investigators, and a consensus
reading was made.
Selected specimens were thin-sectioned (600-700 A),
mounted on a 200-mesh copper grid, and stained with
uranyl acetate and lead citrate. Sections were examined
with a Philips 201 transmission electron microscope.
Statistics
Student's f-test or the x2
test w a
s used to determine
statistical significance.
Results
Arterial Injury and Repair
Balloon angioplasty produced complete endothe-
lial denudation in the dilated area (Figs. IB and 2A).
Four days after the procedure, there was partial
regrowth (Fig. 1C); by 7 days, the endothelium or
periluminal lining cells had largely regrown (Fig.

Steele et al./Balloon Angioplasty in a Pig Model 107
FIGURE 1. Scanning electron micro-
scopic views of the luminal surface of
the common carotid artery in the pig
(original magnification, l,000x). Panel
A: normal endothelium. Panel B: com-
pletely denuded endothelium replaced
by layer of adherent platelets 1 hour
after angioplasty. Panel G partial re-
growth of endothelium or periluminal
lining cells with a few platelets adhering
to uncovered subintima 4 days after an-
gioplasty. Panel D: endothelium or per-
iluminal lining cells largely regrown
with no adherent platelets 7 days after
angioplasty.
ID), except in focal areas overlying mural thrombus.
The nuclei of the smooth muscle cells in the media
frequently adopted a corkscrew shape (Castaneda-
Zuniga et al., 1980) 1 hour after angioplasty (Fig. 3).
By 24 hours, there often was necrosis of the smooth
muscle cells and damage to the normal architecture
of the elastic fibers.
Of the 18 arteries examined at 1 hour after angio-
plasty, nine (50%) showed a tear that extended
through the internal elastic lamina and into the
media to a variable depth (Fig. 4). The dilated arter-
ies without a tear were thinned and showed less of
a corkscrew pattern and less necrosis of the smooth
muscle cells than did the arteries with tears.
The reparative process in the media of the dilated
arteries was evident at 14 days after angioplasty
with connective tissue remodeling in an attempt to
restore the luminal contour to normal. Elastic stains
of histological sections showed loss or distortion of
normal elastic fibers with fibrocellular ingrowth into
areas of necrosis and into defects devoid of elastic
fibers that were probably created by a previous acute
tear.
Platelet-Thrombus Deposition
One hour after angioplasty, there was heavy
platelet deposition on the subintima (Figs. IB and
2B) that persisted to 24 hours (Table 1). The platelet
deposition in an artery at an untouched site distal
to the dilation was <0.5 X 106
/cm2
, which is the
same value obtained from normal arteries in 10
control pigs (unpublished data). One hour after the
angioplasty, 50% of the dilated arteries had a mac-
roscopic mural thrombus (Table 2) in addition to the
microscopic layer of platelets. A mural thrombus
and marked platelet deposition was seen only in
those arteries that had a medial tear (Figs. 2B and
4). Conversely, all arteries with tears had a mural
thrombus (Table 2).
At 4 days after angioplasty, the platelet deposition
was significantly reduced (P < 0.05); this decrease
coincided with the partial regrowth of an endothelial
cell type (Fig. 1C; Table 1). No significant platelet
deposition (Fig. ID) was noted at 7 days, at which
time the endothelial cell type of regrowth (perilu-
minal lining cells) was largely complete, as seen by

108 Circulation Research/Vol. 57, No. 1, July 1985
FIGURE 2. Transmission electron micrographs from site of dilation
1 hour after angwplasty. Panel A: monolayer ofdegranulated platelets
spread across subintima adjacent to internal elastic lamina (I) (original
magnification 10,5OOx). Panel B: thrombus (T) composed mainly of
aggregated and degranulated platelets attached to underlying medial
connective tissue and smooth muscle cells within a tear. Internal
elastic lamina is absent (original magnification, 3,0O0x.).
both scanning and transmission electron micros-
copy. Whether smooth muscle cells contribute in
part to this endothelial cell type of layer is uncertain.
In four (11%) of the 38 pigs, the mural thrombus
progressed to complete thrombotic occlusion, the
earliest of which was evident at 24 hours after the
procedure (Table 1).
The mural thrombi that were detected at 7 days
or later showed evidence of organization and even
simulated a significant stenosis by a fibrous plaque
(Fig. 5, A and B).
Intimal Proliferation of Smooth Muscle Cells
(Table 1)
At 7 days after angioplasty, intimal proliferation
of smooth muscle cells was seen, but it was patchy,
and the thickness of the intima (62.4 ± 6.5 mm X
10~3
) was significantly more (P < 0.05) than in
undamaged control arteries (31.0 ± 1.0 mm X 10~3
).
By 14 days, intimal proliferation was significantly
more (P < 0.05) than at 7 days, and was more
uniform around the circumference of the artery. At
30 and 60 days, the thickness of intimal proliferation
was not significantly greater than at 14 days.
Discussion
PTCA, particularly of the coronary arteries, has
made a significant impact in a short time on the
FIGURE 3. Sections of the common carotid artery in the pig at the site
of dilation. One hour after angioplasty, many nuclei of the smooth
muscle cells in the inner half of the media demonstrate characteristic
corkscrew appearance. Note absence of endothelium and presence of
intact internal elastic lamina 0) (hematoxylin and eosin; original
magnification, 20OX).
FIGURE 4. Sections of common carotid artery at site of dilation. Tear
(arrows) extending through internal elastic lamina (I) and almost
through entire media in association with mural thrombus (T) at
1 hour after angioplasty (hematoxylin and eosin; original magnifica-
tion, X64).

Steele et al./Balloon Angioplasty in a Pig Model
TABLE 2
Platelet-Thrombus Deposition According to Presence or
Absence of Medial Injury
Medial tear*
+
• +, present;
No. of
arteries
9
9
—, absent
Mural thrombus
(no./total)
9/9
0/9
Platelets
(x 107cm2
)
Mean no. Range
76 7-297
6 3-8
treatment of stenotic arterial disease (Gruntzig et al.,
1979; Kent et al., 1982; Vlietstra et al., 1983; Hart-
zler, 1983). Despite this development, many basic
questions concerning the pathophysiological events
after balloon injury remain unanswered. This study
addressed some of these questions.
Animal Model
It is extremely difficult to find an appropriate
animal model for experimental angioplasty. Rabbits
(Faxon DP et al., 1982; Sanborn et al., 1983) or dogs
(Castaneda-Zuniga et al., 1980; Pasternak et al.,
1980) have been used in previous studies. Neither
animal develops atherosclerosis naturally, although
a high-cholesterol diet (2%) after endothelial denu-
dation in the rabbit produces intimal thickening with
a large number of foam cells (Faxon et al., 1982;
Sanborn et al., 1982). The diet also induces very
high serum levels of cholesterol (1,476 ± 467 mg/
dl) (Sanbom et al., 1982). Thus, although a stenotic
lesion is produced by this model, there could be
major limitations in relating this pathophysiological
response to angioplasty to man because of the un-
natural situation of an excessive amount of lipid in
the arterial wall. Our study used pigs, animals that
spontaneously develop atherosclerosis without cho-
lesterol feeding (French et al., 1965; Fuster et al.,
1982b) and whose platelet-coagulation system is
more closely related to humans' (Folts and Rowe,
1983; Leach and Thorbum, 1982). Because they
were young, the pigs in this study did not have
atherosclerotic lesions, nor were they given a high-
cholesterol diet. The normal lipid levels may have
reduced the platelet-vessel wall interaction and de-
gree of smooth muscle cell proliferation. Pigs of this
age have a serum cholesterol of 101 ± 13 (SD) mg/
dl and triglycerides of 53 ± 19 mg/dl (Fuster et al.,
1982). The disadvantage of this model is the lack of
an atherosclerotic lesion to dilate. However, because
of the lack of lesion bulk, it might be expected to
result in a lesser expansion of the external diameter
(<10% average increase in diameter compared with
prediction) and lesser degTee or frequency of deep
arterial wall damage [tears into media in approxi-
mately 50% of normal arteries (Lam et al., 1985)
compared with nearly inevitable splitting of the
atherosclerotic plaque in a successful angioplasty
(Castaneda-Zuniga et al., 1980; Block et al., 1981)].
This decreased damage could decrease the stimulus
109
for and the amount of platelet-thrombus deposition.
Thus, this model probably underestimates the re-
sponse to angioplasty compared to the clinical situ-
ation. In addition, although continuous heparin in-
fusion in rats after air injury to the endothelium has
inhibited smooth muscle cell proliferation (Guyton
et al., 1980), the single dose of heparin used in this
study would not be expected to affect the smooth
muscle cell proliferation in these pigs.
Relation of Injury to Mechanism of Angioplasty
Balloon angioplasty produced endothelial denu-
dation in all arteries examined acutely, and major
mechanical damage to the arterial wall. The most
impressive feature was that a medial tear (Fig. 4)
was noted in 50% of arteries. These tears appeared
similar to the disruptive lesions of the media and to
atherosclerotic plaque reported in patients and in
atherosclerotic rabbits after angioplasty (Block et al.,
1981; Sanborn et'al., 1983; Essed et al., 1983). As
previously suggested (Castaneda-Zuniga et al.,
1980; Block et al., 1981; Sanborn et al., 1983), such
a tear or fracture of the intimal plaque and adjoining
media is usually necessary for a successful proce-
dure.
The frequent finding of smooth muscle necrosis
in the media at 24 hours after angioplasty is of
interest. This effect may be very desirable, essen-
tially making the artery an inert conduit (incapable
of vasospasm). In none of the arteries in these
animals did spasm occur in the dilated segment.
However, coronary spasm is usually multifocal;
thus, angioplasty would not be an appropriate treat-
ment, even in certain resistant patients with angio-
graphically documented coronary artery spasm.
Platelet-Thrombus Deposition
There is little information and no quantitative data
about platelet deposition after angioplasty. The
scanning electron microscopic appearance soon after
the procedure in a small number of dogs has been
described (Pasternak et al., 1980), but there is no
reported data about the natural history or determi-
nants of platelet-thrombus deposition.
This study confirmed the suspicion that angio-
plasty was a potent thrombogenic stimulus (Table
1). Endothelial regrowth seemed to protect against
de novo platelet deposition both quantitatively (Ta-
ble 1) and qualitatively (Fig. 1). Therefore, in this
model, the critical period for platelet-thrombus dep-
osition would include at least the first 4 days after
the procedure. This finding suggests that future
intervention studies should particularly involve
therapy that is started before the procedure in order
to achieve adequate blood levels of antithrombotic
therapy to prevent platelet-thrombus deposition that
begins during the procedure. In this model, therapy
should be most potent for the first 4-7 days after
the procedure, but this duration may differ in hu-
humans with atherosclerotic disease.

110
As has been observed in other models of endo-
thelial injury (Fishman et al., 1975; Groves et al.,
1979; Fuster et al., 1983), the platelets were depos-
ited on the subinrima as a thin layer (usually a
monolayer). In addition, a mural thrombus was
noted in half of the arteries from pigs killed within
an hour, was related to the presence of a medial
tear, and contributed greatly to the measured plate-
let deposition (Fig. 2B; Table 2). The exposed media
seemed to be an overwhelming stimulus for platelet
deposition and thrombus formation, even in fully
heparinized animals. We would expect that the tear
or fracture of a plaque produced by angioplasty in
humans (Block et al., 1981) would be no less throm-
bogenic.
The reasons that deeper arterial injury caused a
greater thrombotic stimulus are not clear but may in
part be related to both the enhancement of throm-
bosis with the exposure of fibrillar collagen found
predominantly in the media and adventitia (Baum-
gartner and Haudenschild, 1972) and the destruc-
tion of two nahiral antithrombotic systems present
in intact endothelial and subendothehal arterial lay-
ers, namely, the prostaglandin system with prosta-
cyclin production and the fibrinolyric system
(Kwaan and Astrup, 1967; Moncada et al., 1977;
Cragg et al., 1983). Prostacyclin production varies
by the site in the arterial wall; as the arterial wall
layers approach the luminal surface, the prostacyclin
production increases (Moncada et al., 1977). Loss of
the antithrombotic mechanisms noted above is also
accompanied by a greater thrombotic stimulus from
the exposure of collagen to circulating blood. Expo-
sure of platelets, to the basement membrane alone
may result in platelet spreading without release
(Baumgartner et al., 1976), whereas platelet adher-
ence to fibrillar collagen results in both spreading
and release of proaggregating substances from
within the platelet granules (Baumgartner et al.,
1976; Kinlough-Rathbone et al., 1980). In addition,
thrombin generation via the intrinsic or extrinsic
coagulation pathways promotes both platelet aggre-
gation and the production of fibrin which stabilizes
platelet thrombi (Nemerson and Nossel, 1982). The
exposure of collagen to circulating factor XII or factor
XI can activate the intrinsic pathway (Wilner et al.,
1968; Walsh, 1972) and, thus, stimulate thrombin
generation. Likewise, the acutely damaged area of
the arterial wall can generate tissue thromboplastin,
which activates the extrinsic pathway and thus pro-
motes thrombin. generation and further thrombosis
(Nemerson and Pitlick, 1972). Cells from the deeper
layers of the arterial wall, fibroblasts and smooth
muscle cells, generate greater peak thromboplastic
activity than the cells at the luminal surface, the
endothelial cells (Maynard et al., 1977). All of these
factors may contribute to the greater frequency and
severity of platelet-thrombus deposition with deeper
arterial wall injuiy.
In 11% of the pigs, the mural thrombus pro-
gressed to complete thrombotic occlusion (Table 1).
Although the timing of this occlusion is uncertain,
Circulation Research/Vo/. 57, No. 1, July 1985
since no observation was possible before the time of
sacrifice, the histological appearance was that of old
and organizing thrombus, suggesting that this
started during the acute phase. In a larger series of
control pigs, we observed acute occlusion within
1 hour of angioplasty in two of 48 (4%) arteries
(Lam et al., 1985). It is uncertain whether contin-
uation of heparin beyond the acute period would
have influenced this development. No thrombi were
apparent on the monoplane angiograms obtained
soon after the angioplasty; however, angiography is
not sensitive for the detection of mural thrombi. Our
preliminary studies with in vivo imaging using n
'In-
labeled platelets suggest that this is a much more
sensitive method of detecting mural thrombi in ar-
teries (Steele et al., 1984a). Thus, the process of
mural thrombus formation probably starts during
the procedure, and may be present immediately after
PTCA in man [similar to observations in iliofemoral
angioplasty (Ezekowitz et al., 1983)] but may not be
evident angiographically.
Possible Mechanisms of Restenosis
Restenosis remains a challenging clinical problem
that affects 25%-35% of patients within 6 months
after PTCA (Dangoisse et al., 1982; Holmes et al.,
1984). Although some clinical features are associated
with an increased risk of restenosis (Holmes et al.,
1984), the cause is unknown. The data from this
study suggest that restenosis may occur via two
mechanisms, both of which are instrumental in the
development and progression of atherosclerosis
(Ross and Glomset, 1976; Fuster and Chesebro,
1982).
First, platelet deposition on the damaged arterial
wall can form a mural thrombus, which may
undergo organization and cause restenosis. In this
study, we have shown that a medial tear is a very
potent stimulus for thrombus formation. Mural
thrombi can organize over a period of weeks and
result in an obstructive lesion (Fig. 5) that eventually
is indistinguishable from a fibrous plaque (Jorgensen
et al., 1967). In our study, the frequency of mural
thrombi immediately after angioplasty despite full
heparinization suggests that these thrombi may be
a very important mechanism for restenosis in man.
Second, the platelets deposited early after angio-
plasty may, by the release of platelet-derived growth
factor, induce the smooth muscle cells in the media
to migrate to the intima and proliferate. This intimal
proliferation of smooth muscle cells may contribute
to restenosis. This mechanism is essentially the re-
sponse to injury hypothesis of atherogenesis (Ross
and Glomset, 1976). We observed this intimal pro-
liferation in pigs, and it also has been reported
recently in a patient who died 5 months after angio-
plasty (Waller et al., 1983).
The contribution of these mechanisms to resten-
osis may vary, depending on a number of features:
composition and distribution of the atherosclerotic
plaque, blood lipid levels, balloon size, and pressure

Steele et al./Balloon Angioplasty in a Pig Model 111
FIGURE 5. Artery at site of dilation 30
days after angioplasty. Panel A- macro-
scopic appearance of significant stenotic
lesion. Panel B: histological section of
same lesion showing that obstruction is
due to organization of mural thrombus
(Lason's elastic-Van Gieson; original
magnification, 64x).
and duration of inflation, presence and degree of
exposed media, degree of smooth muscle cell necro-
sis, platelet deposition and thrombus formation, re-
coil and degree of fibrous tissue ingrowth in the
arterial wall, and vasospasm. Despite the multiplic-
ity of possible contributing factors, this study
strongly suggests that the early platelet-thrombus
deposition after angioplasty plays a pivotal role in
the pathophysiological response to balloon injury
and may be closely involved with the process of
restenosis (Fig. 5). Thus, although this model does
not reproduce the human situation of dilating a
high-grade lesion and probably underestimates the
clinical response to angioplasty, it may provide a
basis for screening potential antithrombotic and
platelet-inhibitor agents for use in future drug trials
for the prevention of acute occlusion and restenosis
after arterial angioplasty (Steele et al., 1984b, 1984c),
as suggested by the negative response to low molec-
ular weight dextran in our animal model and the
negative response in patients (Steele et al., 1984b;
Swanson et al., 1985).
We appreciate the secretarial expertise of Carol A. Stocker.
Doctor Steele was supported by the National Heart Foundation of
Australia. His current address is Cardiac Clinic, Royal Adelaide
Hospital, Adelaide, South Australia.
Doctor Fuster's current address is Division of Cardiology, Mount
Sinai Medical Center, New York, New York 10029.
Address for reprints: James H. Chesebro, M.D., Mayo Clinic, 200
First Street, S.W., Rochester, Minnesota 55905.
Received August 30, 1984; accepted for publication April 4, 1985.
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INDEX TERMS: Angioplasty • Platelet deposition • Thrombus
• Endothelial damage • Smooth muscle cell proliferation • Arterial
injury

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