© 1996 American Heart Association, Inc.
Articles |
Role of Intimal Hyperplasia and Arterial Remodeling After Balloon Angioplasty
An Experimental Study in the Atherosclerotic Rabbit Model
From the Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Patrick L. Whitlow, MD, Department of Cardiology, F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195-5066.
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Abstract The arterial response to injury appears to be an important factor in the development of restenosis. Traditionally, intimal hyperplasia has been thought to be the primary mechanism responsible for restenosis. However, recent studies have found that arterial remodeling is a major determinant of lumen loss after balloon angioplasty. In this study, we evaluated the actual separate contributions of intimal hyperplasia and arterial remodeling to the restenotic process after balloon angioplasty in the atherosclerotic rabbit model. One month after induction of focal atherosclerotic lesions, femoral arteries were randomized to receive treatment with either two or six balloon inflations. One group of rabbits was euthanized immediately after angioplasty to evaluate the initial degree of injury with each dilatation strategy ("acute group"), and the rest were euthanized 28 days after angioplasty ("chronic group"). Arteries that had been treated with six inflations had a higher injury score than those treated with two (4.0±3.0 versus 1.9±1.5, P<.05). In the chronic group, there was a significant increase in intimal area in the six inflation–treated arteries compared with the two-inflation group (0.617±0.06 versus 0.432±0.05 mm2, P<.004). However, there was no significant difference in lumen cross-sectional area between groups. By multivariate analysis, the most important independent predictor of lumen area was the external elastic lamina (EEL) area, although the degree of intimal thickening was also a significant independent predictor. There was a strong, positive correlation between intimal area and EEL area: the larger the intimal area, the larger the EEL area (r=.703, P<.0001). The intimal area was similar in both restenotic and nonrestenotic lesions. In contrast, EEL area was significantly larger (due to remodeling) in nonrestenotic lesions. This study confirms previous findings that the degree of injury determines the degree of neointimal proliferation and supports recent findings that chronic arterial remodeling plays a major role in the final lumen area. Understanding and controlling the remodeling process rather than concentrating solely on intimal hyperplasia may yield better results after balloon angioplasty in the future.
Key Words: balloon angioplasty • restenosis • arterial remodeling • atherosclerotic rabbit model
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Percutaneous transluminal coronary angioplasty has become an important tool in the management of coronary artery disease. However, the effectiveness of this technique remains limited by a 30% to 50% restenosis rate within the first 6 months.1 2 Although technological advances and improvements in operator experience have increased the success rate and the feasibility of approaching more complex lesions, little progress has been made in reducing the rate of restenosis.
Arterial response to injury appears to be an important factor in the development of restenosis. Several human and animal studies suggest that the degree of vascular injury may play a major role in the development of restenosis.3 4 5 6 Most of these studies have assumed that neointimal formation resulting from smooth muscle cell proliferation, migration, and matrix synthesis is the primary mechanism responsible for the restenotic process. This assumption is based on several human necropsy studies and material obtained from atherectomy specimens.7 8 9 10
However, other reports have shown that the histological findings characteristic of neointimal proliferation are not always present. Waller et al,11 who analyzed 20 postmortem hearts at different times after balloon angioplasty, reported that 40% of the lesions did not exhibit the typical neointimal hyperplastic reaction. In another study, Isner12 analyzed 253 atherectomy specimens from restenotic lesions and found that 35% showed no distinctive histological evidence of restenosis. In addition, recent reports by Mintz et al,13 14 who used IVUS to assess the mechanism of restenosis in human coronary arteries, have shown that vascular remodeling is an important determinant of lumen restenosis after balloon angioplasty. They also found that even though intimal hyperplasia was present in most coronary arteries, the extent of hyperplasia was similar in arteries with and without restenosis.
In the present study, we evaluated varying degrees of response to injury to confirm or refute the hypothesis that greater vascular injury will induce more intimal proliferation in atherosclerotic lesions. In addition, we evaluated the actual separate contributions of intimal hyperplasia and arterial remodeling to the restenotic process after balloon angioplasty with reference to the hypothesis that intimal formation is not the only determinant of lumen renarrowing. We used the femoral artery angioplasty model in cholesterol-fed rabbits to test these hypotheses.
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Methods |
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Animals and Experimental Design
All animal experiments were performed according to the animal welfare policies of the American Heart Association and The Cleveland Clinic Foundation. The experimental protocol was approved by The Cleveland Clinic Foundation Animal Research Committee. Bilateral femoral artery atherosclerotic lesions were induced in 73 New Zealand White rabbits (weight, 3.5 to 3.7 kg; Mohigan Valley Rabbitry) by using the air-drying model followed by an atherogenic diet. One month after induction of focal atherosclerotic lesions, each rabbit underwent balloon angioplasty. To obtain different degrees of injury and evaluate the vascular response, femoral arteries were treated with strategies of six versus two inflations at 6 atm for 60 seconds. Only those rabbits that had both patent arteries at the time of angioplasty were included in the study, so that each animal served as its own control. Femoral arteries (right versus left) were randomized to receive treatments of two or six inflations. Before angioplasty, the animals were randomized to either immediate sacrifice to evaluate the initial degree of injury with each dilatation strategy ("acute group") or to sacrifice 28 days after angioplasty to evaluate the degree of development of intimal thickening ("chronic group").
Induction of Focal Atherosclerosis: the
Air-Drying Model
We used the original air-drying model of Fishman et
al15 with modification by Sarembock et al.16
In brief, anesthesia was induced with 5 mg/kg body wt
xylazine and 35 mg/kg body wt ketamine by intramuscular
injection. The proximal femoral arteries were exposed by cutdown to
below the level of the inguinal ligament, and the isolated
arterial segments were desiccated by air infusion delivered
at a rate of 80 mL/min for 8 minutes. After dessication was completed,
the ligatures were released and flow was restored. Local spasm was
treated topically with 1% lidocaine. The day after surgery, the
rabbits were started on a 2% cholesterol/6% peanut oil
diet (Zeigler Bros Inc) that continued for 1
month.17 18
Acetaminophen (Tylenol) 10 mg/kg body wt was given orally
for postoperative pain relief for 3 to 5 days. Penicillin G benzathine
(Ambipen) 3x105 U was given subcutaneously on
postoperative days 3 through 5.
Balloon Angioplasty Procedure
Each rabbit underwent balloon
angioplasty 1 month after
induction of focal atherosclerotic lesions. Anesthesia was
again induced with intramuscular injections of ketamine and
xylazine. The right common carotid artery was isolated, and via an
arteriotomy, a 5F introducer was placed and advanced to the junction of
the aortic arch. Heparin 150 U/kg body wt and lidocaine 20 mg were
injected intra-arterially. A control aortoiliofemoral
angiogram was performed via a 4F angiographic catheter that was
positioned above the aortic bifurcation. After verifying that both
femoral arteries in each rabbit were patent, we randomized the arteries
for treatment with two or six inflations. Under fluoroscopic guidance,
a 2.5-mm balloon angioplasty catheter (Advanced
Cardiovascular Systems) was introduced, advanced over a
0.014-in. guide wire, and positioned across the stenosis. The
balloon was inflated to 6 atm for 60 seconds with a handheld
indeflator, with 60-second intervals between inflations. After balloon
dilatation, the angioplasty catheter was withdrawn and a postprocedure
angiogram performed 10 minutes after the last inflation. To minimize
spasm, 20 mg lidocaine was given intra-arterially. A
0.6-cm lead marker was filmed to calculate magnification factors. The
right carotid artery was ligated with 3-0 silk and the skin wound
sutured. Penicillin G benzathine (Ambipen) 3x105 U and
acetaminophen were given as post–lesion induction
medications. After angioplasty, the rabbits were placed on a regular
rabbit chow diet until the end of the experiment. Rabbits in the acute
group were euthanized immediately after balloon angioplasty (see the
section below). A follow-up angiogram of the left carotid artery
was performed 4 weeks after angioplasty in the chronic group, as
described above.
Follow-up, Euthanasia, and Pressure Perfusion
After
angiography was completed the distal aorta was isolated
and tied off proximally, and a perfusion cannula was inserted to above
the level of the aortic bifurcation through a vertical abdominal
incision. The distal aorta was flushed with 100 mL saline. The rabbits
were then euthanized with an overdose of pentobarbital sodium (3 mL IV,
65 mg/mL). The distal aorta was fixed with 500 mL of 10% formaldehyde
solution that was infused over 15 minutes at 100 mm Hg. A 5-cm segment
of femoral artery was excised bilaterally, and the proximal and distal
ends were marked. This tissue was preserved in 10% formaldehyde for
light microscopy.
Histology
The femoral arteries were cut into serial 3- to
4-mm
sections from the proximal to the distal end. The sections were
embedded in paraffin, and duplicate slides were stained with
hematoxylin and eosin and van Gieson's stain to clearly identify the
IEL and EEL. Morphometric analysis was performed with the
Bioquant Program (R&M Biometric) to measure the cross-sectional
areas of the lumen, intima, media, and artery.
Data Analysis
Angiography
Luminal diameters and
percent stenosis were measured
with electronic calipers by two independent operators in a blinded
fashion, and the mean from both operators was reported.19
"Angiographic success" was defined as a >20% increment in lumen
diameter after treatment. Results were analyzed on a treatment
basis and included all treated arteries, whether or not treatment was
angiographically successful. "Acute gain" was defined as the
difference between the MLD before balloon angioplasty and the MLD
immediately after angioplasty. "Late loss" was defined as the
difference between the MLD immediately after angioplasty and the MLD at
follow-up. "Loss index" was defined as the proportion of
lumen lost during follow-up with respect to the initial
angiographic gain. A continuous definition of restenosis
was used, in which the mean follow-up MLD in each group was used
for comparison.20 In addition to a continuous definition,
restenosis was also defined as a >50% loss in lumen
diameter from the initial gain that was obtained due to
angioplasty.21
Histology
Morphometric
comparisons of cross-sectional areas of the
lumen, intima, media, and artery and percent cross-sectional areas
of the intima were analyzed between groups. The segment with
the most severe luminal narrowing was selected for quantitation.
Restenosis was defined histologically by
dividing the population of arteries at the median luminal area value.
Those arteries in which the lumen area was below the median were
considered restenotic, and those with a lumen area above
the median were considered nonrestenotic.
Wall Tear Score
A score for vessel injury based on the amount and length of tear
of the different wall structures was created to quantify the degree of
injury produced by each treatment modality of angioplasty (two versus
six inflations). The femoral arteries were sectioned every 3 mm, and
the three segments of each artery with the greatest injury were used to
determine the wall tear score. Each segment was divided into four
quadrants, and the degree of injury was quantified as follows. An
intact intima with no disruption of the IEL was given a score of 0 for
that quadrant. Lacerations of the intima, IEL, media, and EEL, with or
without adventitial laceration, were arbitrarily given a score of 1 for
each finding (maximum of 4 points per quadrant). The points for each
quadrant were added and the result represents the wall tear
score for that segment. Injury scores for each of the three segments
were averaged to obtain the final mean artery wall tear score. Thus,
the wall tear score ranged from 0 (minimal injury) to 16 (maximal
injury, representing laceration of all vessel layers in all
quadrants in all three arterial segments). The
reproducibility of our scoring method was tested in a subset of 40
segments by two independent observers. The interobserver correlation
was .953 and the mean interobserver difference 0.19±0.10; the
intraobserver correlation was .986 with a mean intraobserver difference
of 0.01±0.03.
The continuous quantitative angiographic data (luminal diameter, reference diameter, percent stenosis, acute gain, and late loss), histological morphometric data (cross-sectional areas), and wall tear scores were descriptively summarized as mean±SD. Analysis between two-inflation versus six-inflation groups was done in a paired manner with Student's two-tailed t test and in an unpaired manner for other comparisons. A nonparametric test was used when the observed values were not normally distributed. Values of P<.05 were considered significant. Linear regression analysis was used to evaluate the relationship between angiographic and histological data as well as the relationship between histological findings in the chronic group. Independent determinants of histological lumen area were constructed by using a stepwise multivariable regression technique, in which significant (P<.05) variables from a univariable model were entered into the multiple model.
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Results |
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Seventy-three rabbits underwent bilateral femoral artery lesion induction. Three rabbits died after lesion induction but before angioplasty. Fifteen rabbits (15/73, or 20%) were excluded from the study because of femoral artery occlusion at the time of the preangioplasty angiogram. Balloon angioplasty was attempted in all remaining 55 rabbits with patent bilateral femoral artery lesions. Thirteen animals died during the dilatation procedure or recovery. At the time of sacrifice, 42 animals and 84 patent arteries (60 in the chronic group and 24 in the acute group) were available for angiographic and histological evaluation.
Angiographic Results
In rabbits that were euthanized
immediately after angioplasty,
there were no differences in reference lumen diameter, preangioplasty
and postangioplasty MLD, and percent stenosis between arteries
treated with two inflations and those treated with six inflations.
However, there was a significantly greater acute gain in arteries
treated with six compared with two inflations (Table 1
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In rabbits that were euthanized 28 days after angioplasty, both
treatment groups had a significant increase in MLD after angioplasty.
Arteries that had been treated with two inflations increased their MLD
from 1.42±0.07 mm before to 1.69±0.07 mm after angioplasty
(P<.001). The MLD of arteries that had been treated with
six inflations increased from 1.34±0.05 mm before to 1.78±0.07
mm
after angioplasty (P<.0001). The overall angiographic
success rate was 87% (52 of 60 arteries), with no significant
difference between treatment groups (83% for two inflations versus
90% for six inflations; P=.44). The balloon-artery
ratio (ratio between balloon diameter and reference diameter) was
similar in both groups (1.18±0.04 for two inflations versus
1.19±0.04
for six inflations; P=.79). Table 1
summarizes
the
angiographic results. There were no differences in reference diameter,
MLD, and percent stenosis before angioplasty, after
angioplasty, or at follow-up between groups. However, arteries that
had been treated with six inflations showed a significantly greater
acute gain as well as a significant increase in late lumen loss
compared with the two inflation–treated arteries. The loss index,
however, was similar in both groups. Overall, there was a trend toward
a decrease in reference diameter over time (2.21±0.57 preangioplasty
versus 2.06±0.65 at follow-up; P=.10). There was a
significant correlation between acute gain and late loss: the greater
the gain during angioplasty, the larger the loss during follow-up
(r=.59, P<.0001; Fig 1).
Restenosis was present in 46 lesions (46/60, or 77%)
according to the definition of >50% loss of initial gain during
follow-up.
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Histological Results
Acute Group (Fig 2A
and 2B)
Fig 3 shows the wall tear score in both groups.
Arteries that had been treated with six inflations had a significantly
higher injury score (4.0±3.0 for six inflations versus 1.9±1.5
for
two inflations, P<.02). There were no statistical
differences in lumen cross-sectional area (1.06±0.1
mm2 for six inflations versus 1.12±0.1 mm2 for
two inflations, P=NS) or artery size (ie, EEL
cross-sectional area: 1.98±0.08 mm2 for six inflations
versus 1.89±0.1 mm2 for two inflations,
P=NS)
between groups. The lumen cross-sectional area for both groups
combined was 1.09±0.07 mm2 and for artery size,
1.93±0.07
mm2.
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Chronic Group
Fig 4
shows the morphometric analysis for
both treatment groups. There was a significant increase in intimal area
in those arteries treated with six inflations. When intimal area was
normalized to artery size, there was also a significant increase in
percent cross-sectional area of intima in the six
inflation–treated arteries compared with the two-inflation
group (Fig 5). Artery size (determined by measuring the
area encircled by the EEL) was similar in both groups. Despite a
significant increment in intimal area in arteries treated with six
inflations, there was a trend but not a statistically significant
difference in lumen cross-sectional area between groups. Overall,
there were no differences between artery size immediately after
angioplasty and at follow-up (1.93±0.31 mm2 versus
1.85±0.54 mm2, respectively;
P=.40).
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To determine the predictors of the final
histological
lumen cross-sectional area, univariate and
multivariate analysis were performed (Table 2). In the
univariate analysis,
lumen area correlated with the area encircled by the EEL, and there was
also a weak but significant correlation between intimal and luminal
area. By multivariate analysis, the most
important independent predictor of lumen area was EEL area, although
the degree of intimal thickening was also a significant independent
predictor. In addition, there was a strong, positive correlation
between intimal area and EEL area: the larger the intimal area, the
larger the EEL area (Fig 6).
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To further investigate the
role of intimal proliferation and vascular
remodeling in the restenotic process, we divided the
chronic group on the basis of restenosis development in
each animal by angiographic or histological criteria
(Table 3). By the angiographic definition of
restenosis, both the restenotic and
nonrestenotic groups had similar angiographic lumen
diameters before and after angioplasty. The
histological lumen area was significantly larger in
lesions without restenosis. Intimal area was slightly but
not statistically significantly larger in the restenotic
group. However, IEL as well as EEL areas were significantly larger in
the nonrestenotic group.
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Similar findings were noted when restenosis
was defined
histologically. Intimal area was very similar in both
the restenotic and nonrestenotic groups. The
main difference between groups was the size of the IEL and EEL areas:
both were significantly larger in the nonrestenotic group
(Table 3). Similar results were also found when only the
angiographically successful arteries (52 of 60 lesions, 87% of the
total group) were included in the analysis (data not
shown).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study shows that the degree of angioplasty-induced injury in this atherosclerotic rabbit model is strongly correlated with the degree of intimal proliferation, as shown by increases in wall tear score and intimal areas in those arteries that had been treated with six rather than two inflations. However, the very significant increment in intimal thickness did not result in a significant decrease in lumen area in the six-inflation group compared with the two-inflation group. The most important predictor of final lumen area in all animals was the area encircled by the EEL. This study has also shown that there was a significant, positive relationship between the degree of intimal thickening and EEL area: the greater the intimal thickness, the larger the EEL area. The most important difference between restenotic and nonrestenotic lesions, as defined both angiographically and histologically, was the significant increment in EEL size in the nonrestenotic group, with no significant difference in the degree of intimal hyperplasia. These results suggest that the degree of injury is a determinant of the extent of neointimal hyperplasia, but vascular remodeling also appears to play a dominant role in determining the final lumen area in this atherosclerotic rabbit model.
The degree of injury has previously been claimed to be the major predictor of neointimal response. Steele et al22 showed that deeper injury was associated with an increased degree of mural thrombosis. Platelets and thrombin have been recognized in a number of animal models to be important mediators in the development of restenosis after balloon angioplasty.23 24 Schwartz et al,6 using the porcine coronary artery injury model, have shown that the degree of injury is strongly correlated with the level of intimal proliferation. However, those experiments were performed in a normal coronary artery rather than in atherosclerotic lesions as in the present study. In addition, stent wires, which are a chronic source of injury, may represent a different scenario compared with conventional balloon angioplasty, in which injury is produced exclusively at the time of initial dilation. The present study has found, using an atherosclerotic rabbit model and a balloon angioplasty procedure, that deeper injury is produced by increasing the number of inflations and that this increased injury is correlated with a greater proliferative response, thus confirming prior findings.6 16
Intimal hyperplasia has been assumed to be responsible for restenosis, and suppression of this "healing" response has been postulated to reduce the restenosis rate.24 25 26 However, most clinical trials that have been designed to decrease intimal hyperplasia in humans have failed to decrease the rate of restenosis.27 28 29 30 31 32 33 The relationship between the actual magnitude of intimal hyperplasia and the restenotic process has recently been questioned. Post et al,34 using different species and animal models, have found that intimal hyperplasia contributes little to late lumen loss but that remodeling (artery constriction) accounts for 50% to 90% of late lumen loss. Kakuta et al,35 using an animal model very similar to ours, have found that arterial enlargement (vascular remodeling) is the most important determinant of final lumen size. In addition, Kakuta et al also found that intimal thickness was similar in arteries with and without restenosis. These findings are consistent with those of the present study: final histological lumen area is mainly determined by the size of the IEL and EEL. In addition, the degree of intimal hyperplasia in restenotic lesions is similar to that in nonrestenotic lesions, with arterial enlargement being an important determinant of final lumen area. The present study also shows that EEL area is correlated with intimal area: the greater the intimal area, the larger the EEL area. The same observations have also been made by Kakuta et al, thus confirming that arterial remodeling plays a major role in restenosis. Gertz et al,36 using the same animal model as ours, have recently reported that arterial remodeling is not the principal process in restenosis. Although this report appears to disagree with ours, when only balloon angioplasty–treated arteries are considered (as in our study), there was a 60% to 80% increment in artery size compared with that of the noninjured adjacent (remodeled) segment. Conversely, for those arteries in which intimal hyperplasia was inhibited by a pharmacological agent, lumen loss during follow-up was mainly due to a decrease in artery size (remodeling). This agrees with our finding that arterial remodeling and intimal hyperplasia are both important and probably interrelated players in restenosis.
There is recent evidence that vascular remodeling also occurs after balloon angioplasty in human coronary arteries. Mintz et al13 14 recently reported on a quantitative coronary IVUS series, that arterial dilatation does occur in a subgroup of patients and that arterial enlargement appears to be a compensatory response to the increase in intimal proliferation. In addition, they found that the degree of intimal hyperplasia was similar in both restenotic and nonrestenotic lesions and that failure of the arteries to enlarge was associated with restenosis in almost all cases. However, in those studies, "late recoil" was the principal determinant of late lumen loss. In our study, we have not definitively determined that late recoil is a significant part of the remodeling process. The size of restenotic arteries in the present study appears to be smaller than those from animals that were euthanized immediately after angioplasty (1.78±0.07 mm2 versus 1.93±0.07 mm2, P<.21), suggesting that chronic recoil may also play a role in this process. In a recent report, Lafont et al37 have shown that chronic recoil plays a significant role in this animal model. However, recoil was not observed by Kakuta et al35 using a very similar animal model. Studies utilizing serial IVUS in the same lesion over time may help determine the relative roles of recoil and enlargement in restenosis.
Glagov et al38 39 and Zarins et al40 have presented data consistent with the hypothesis that human arteries tend to enlarge as plaque forms to preserve the lumen cross-sectional area. In addition, arteries tend to adapt to maintain stability with respect to flow and shear stress. Once shear stress increases, eg, due to atherosclerotic plaque, the radius of the artery will increase until the wall shear stress returns to normal. The angioplasty procedure as well as the proliferative process with thickening of the intima both produce changes in flow and shear stress that stimulate adaptive reactions of the arterial wall, ie, remodeling.
The role of vascular remodeling after coronary angioplasty in humans remains to be determined. Interaction between local circulatory stimuli and the tissue response to maintain basal conditions of flow and stress may be key factors in the process of remodeling, although the basic mechanisms of arterial remodeling remain unclear. Plaque, arterial wall composition, and compliance probably play a major role in determining the tissue response to changes in flow and shear stress and therefore in determining the final outcome of balloon angioplasty.
Limitations
The relevance of animal models of experimental
atherosclerosis and balloon angioplasty to human
restenosis has been questioned. No single model has yet
been shown to reliably mimic and predict the human
restenotic process. However, animal studies may provide a
better understanding of the pathophysiology of the process. The rabbit
atherosclerotic model in this study is well characterized and has a
well-established lesion consistency and
reproducibility.16 41 The histological
characteristics are similar to those of fibroproliferative
atherosclerotic lesions in humans, without the predominant foam cells
that are usually seen in most other atherosclerotic
models.16 17 42 Nevertheless, these
results are derived
from an animal model, and extrapolation to the treatment of
restenosis in humans remains speculative. Another
limitation of the study is that we have not shown an actual change in
arterial size over time after balloon angioplasty, because
serial measurements in the same artery were not made. As stated above,
probably the best way to make precise comparisons would be to utilize
serial IVUS measurements in the same lesion over time.
In conclusion, this study confirms previous findings that the degree of injury determines the degree of neointimal proliferation. In addition, the study supports recent findings that chronic arterial remodeling plays a major role in final lumen area and that the role of intimal proliferation in restenosis may have been overestimated in the past. Understanding and controlling the remodeling process rather than concentrating solely on intimal hyperplasia may yield better control of restenosis after balloon angioplasty in the future. However, eliminating restenosis will require attention to both arterial remodeling and intimal hyperplasia as responses to injury.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors thank Joy Brown for performing the histology; Robert Lewis, Ronald Porter, and James Howard for technical assistance; and Kathryn Brock for editorial assistance.
Received May 19, 1995; accepted December 11, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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1. Califf RM, Ohman EM, Frid DJ, Fortin DF, Mark DB, Hlatky MA, Herndon JE, Bengtson JR. Restenosis: the clinical issue. In: Topol EJ, ed. Textbook of Interventional Cardiology. Philadelphia, Pa: WB Saunders Co; 1990:363-394.
2.
Popma JJ, Califf RM, Topol EJ. Clinical trials
of restenosis after coronary angioplasty.
Circulation. 1991;84:1426-1436.
3. Kuntz R, Gibson C, Nobuyoshi M, Baim D. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol. 1993;21:15-25. [Abstract]
4. Kuntz RE, Safian RD, Levine MJ, Reis GJ, Diver DJ, Baim DS. Novel approach to the analysis of restenosis after the use of three new coronary devices. J Am Coll Cardiol. 1992;19:1493-1499. [Abstract]
5. Beatt KJ, Serruys PW, Luijten HE, Rensing BJ, Suryapranata H, de Feyter P, van den Brand M, Laarman GJ, Roelandt J. Restenosis after coronary angioplasty: the paradox of increased lumen diameter and restenosis. J Am Coll Cardiol. 1992;19:258-266. [Abstract]
6. Schwartz RS, Huber KC, Murphy JG, Edwards WD, Camrud AR, Vlietstra RE, Holmes DR. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol. 1992;19:267-274. [Abstract]
7. Nobuyoshi M, Kimura T, Ohishi H, Horiuchi H, Nosaka H, Hamasaki N, Yokoi H, Kim K. Restenosis after percutaneous transluminal coronary angioplasty: pathologic observations in 20 patients. J Am Coll Cardiol. 1991;17:433-439. [Abstract]
8.
Ueda M, Becker AE, Tsukada T, Numano F, Fujimoto
T. Fibrocellular tissue response after
percutaneous transluminal coronary
angioplasty. Circulation. 1991;83:1327-1332.
9. Garratt KN, Holmes DR, Bell MR, Bresnahan JF, Kaufmann UP, Vlietstra RE, Edwards WD. Restenosis after directional coronary atherectomy: differences between primary atheromatous and restenotic lesions and influence of subintimal tissue resection. J Am Coll Cardiol. 1990;16:1665-1671. [Abstract]
10. Austin GE, Ratliff NB, Hollman J, Tabei S, Phillips DF. Intimal proliferation of smooth muscle as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol. 1985;6:369-375. [Abstract]
11. Waller BF, Pinkerton CA, Orr CM, Slack JD, Van Tassel JW, Peters T. Restenosis 1 to 24 months after clinically successful coronary balloon angioplasty: a necropsy study of 20 patients. J Am Coll Cardiol. 1991;17:58B-70B.
12.
Isner JM. Vascular remodeling: Honey, I think I
shrunk the artery. Circulation. 1994;89:2937-2941.
13. Mintz GS, Kovach JA, Pichard AD, Kent KM, Satler LF, Popma JJ, Painter JA, Morgan K, Leon MB. Geometric remodeling is the predominant mechanism of clinical restenosis after coronary angioplasty. J Am Coll Cardiol. 1994:138A. Abstract.
14. Mintz GS, Matar FA, Kent KM, Pichard AD, Satler LF, Harvey M, Ditrano JC, Prunka N, Popma JP, Leon MB. Chronic compensatory arterial dilatation following coronary angioplasty: an intravscular ultrasound study. J Am Coll Cardiol. 1994:139A. Abstract.
15. Fishman J, Ryan GB, Karnovsky MJ. Endothelial regeneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of intimal thickening. Lab Invest. 1975;32:339-351. [Medline] [Order article via Infotrieve]
16.
Sarembock IJ, La Veau PJ, Sigal SL, Timms I, Sussman J,
Haudenschild C, Ezekowitz MD. Influence of inflation pressure
and balloon size on the development of intimal hyperplasia after
balloon angioplasty. Circulation. 1989;80:1029-1040.
17. LeVeen RF, Wolf GL, Villanueva TG. New rabbit atherosclerosis model for the investigation of transluminal angioplasty. Invest Radiol. 1982;17:470-475. [Medline] [Order article via Infotrieve]
18. Kritchevsky D, Tepper SA, Kim HK, Story JA, Vesselinovitch D, Wissler RW. Experimental atherosclerosis in rabbits fed cholesterol-free diets: comparison with peanut, corn, butter and coconut oils. Exp Mol Pathol. 1976;24:375-391. [Medline] [Order article via Infotrieve]
19. Scoblionko DP, Brown BG, Mitten S, Caldwell JH, Kennedy JW, Bolson EL, Dodge HT. A new digital electronic caliper for measurement of coronary arterial stenosis: comparison with visual estimates and computer-assisted measurements. Am J Cardiol. 1984;53:689-693. [Medline] [Order article via Infotrieve]
20. Califf RM, Fortin DF, Frid DJ, Harlan WR, Ohman EM, Bengtson JR, Nelson CL, Tcheng JE, Mark DB, Stack RS. Restenosis after coronary angioplasty: an overview. J Am Coll Cardiol. 1991;17:2B-13B.
21. Holmes DR, Vlietstra RE, Smith HC, Vetrovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF, Detre KM, van Raden MJ, Mock MB. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA registry of the National Heart, Lung, and Blood Institute. Am J Cardiol. 1984;53:77C-81C. [Medline] [Order article via Infotrieve]
22.
Steele PM, Chesebro JH, Stanson AW, Holmes DR Jr,
Dewanjee MK, Badimon L, Fuster V. Balloon angioplasty: natural
history of the pathophysiological response to
injury in a pig model. Circ Res. 1985;57:105-112.
23.
Fingerle J, Johnson R, Clowes A, Majesky MW, Reidy
MA. Role of platelets in smooth muscle cell proliferation
and migration after vascular injury in rat carotid artery.
Proc Natl Acad Sci U S A. 1989;86:8412-8416.
24.
Sarembock IJ, Gertz D, Gimple LW, Owen RM, Powers ER,
Roberts WC. Effectiveness of recombinant desulphatohirudin in
reducing restenosis after balloon angioplasty of
atherosclerotic femoral arteries in rabbits.
Circulation. 1991;84:232-243.
25. Villa A, Guzman L, Chen W, Golomb G, Levy R, Topol E. Local delivery of dexamethasone for prevention of neointimal proliferation in a rat model of balloon angioplasty. J Clin Invest. 1994;93:1243-1249.
26.
Ferns G, Raines E, Sprugel K, Motani A, Reidy M,
Ross R. Inhibition of neointimal smooth muscle
accumulation after angioplasty by an antibody to PDGF.
Science. 1991;253:1129-1132.
27.
Weintraub WS, Boccuzzi SJ, Klein JL, Kosinski AS, King
SB, Ivanhoe R, Cedarholm JC, Stillabower ME, Talley JD, DeMaio SJ,
O'Neill NW, Frazier JE, Cohen-Bernstein CL, Robbins DC, Brown CL,
Alexander RW. Lack of effect of lovastatin on
restenosis after coronary angioplasty:
lovastatin restenosis trial study
group. N Engl J Med. 1994;331:1331-1337.
28.
Serruys PW, Rutsch W, Heyndrickx GR, Danchin N, Mast
EG, Wijns W, Rensing BJ, Vos J, Stibbe J, for the Coronary
Artery Restenosis Prevention on Repeated
Thromboxane-Antagonism Study Group (CARPORT). Prevention of
restenosis after percutaneous transluminal
coronary angioplasty with thromboxane A2-receptor
blockade—a randomized, double-blind, placebo-controlled
trial. Circulation. 1991;84:1568-1580.
29.
The Multicenter European Research Trial with Cilazapril
After Angioplasty to Prevent Transluminal Coronary Obstruction
and Restenosis (MERCATOR) Study Group. Does the new
angiotensin converting enzyme inhibitor
Cilazapril prevent restenosis after
percutaneous transluminal coronary angioplasty?
Results of the MERCATOR Study. Circulation. 1992;86:100-110.
30. Kent KM, Williams DO, Cassagneau B, Broderick T, Chapekis A, Simpfendorfer C, Cote G, Bates E, Tauscher G, Kuntz RE, Popma JJ, Foegh M. Double blind, controlled trial of the effect of angiopeptin on coronary restenosis following balloon angioplasty. Circulation. 1993;88(suppl I):I-506. Abstract.
31.
Thornton MA, Gruentzig AR, Hollman J, King SB III,
Douglas JS. Coumadin and aspirin in prevention of
recurrence after transluminal coronary angioplasty: a
randomized study. Circulation. 1984;69:721-727.
32. Whitworth HB, Roubin GS, Hollman J, Meier B, Leimgruber PP, Douglas JS, King SB, Gruentzig AR. Effect of nifedipine on recurrent stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol. 1986;8:1271-1276. [Abstract]
33. O'Keefe JH, McCallister BD, Bateman TM, Kuhnlein DL, Ligon RW, Hartzler GO. Ineffectiveness of colchicine for the prevention of restenosis after coronary angioplasty. J Am Coll Cardiol. 1992;19:1597-1600. [Abstract]
34.
Post MJ, Borst C, Kuntz RE. The relative
importance of arterial remodeling compared with intimal
hyperplasia in lumen renarrowing after balloon angioplasty: a study in
the normal rabbit and the
hypercholesterolemic Yucatan Micropig.
Circulation. 1994;89:2816-2821.
35.
Kakuta T, Currier JW, Haudenschild CC, Ryan TJ, Faxon
DP. Differences in compensatory vessel enlargement, not intimal
formation, account for restenosis after angioplasty in the
hypercholesterolemic rabbit model.
Circulation. 1994;89:2809-2815.
36.
Gertz S, Gimple L, Benai S, Ragosta M, Powers E,
Roberts W, Perez L, Sarembock I. Geometric remodeling is not a
principal pathogenetic process in restenosis after balloon
angioplasty: evidence from correlative
angiographic-histomorphometric studies of atherosclerotic arteries
in rabbits. Circulation. 1995;90:3001-3008.
37.
Lafont A, Guzman L, Whitlow P, Goormastic M, Cornhill
J, Chisolm G. Restenosis after experimental
angioplasty: intimal, medial, and adventitial changes associated with
constrictive remodeling. Circ Res. 1995;76:996-1002.
38. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371-1375. [Abstract]
39. Glagov S, Zarins CK, Masawa N, Xu CP, Bassiouny H, Giddens DP. Mechanical functional role of non-atherosclerotic intimal thickening. Front Med Biol Eng. 1993;5:37-43. [Medline] [Order article via Infotrieve]
40. Zarins CK, Weisenberg E, Kolletis G, Stankunavicius R, Glagov S. Differential enlargement of artery segments in response to enlarging atherosclerotic plaque. J Vasc Surg. 1988;7:386-394. [Medline] [Order article via Infotrieve]
41.
LaVeau PJ, Sarembock IJ, Sigal SL, Yang TL, Ezekowitz
MD. Vascular reactivity after balloon angioplasty in an
atherosclerotic rabbit. Circulation. 1990;82:1790-1801.
42.
Faxon DP, Weber VJ, Haudenschild C, Gottsman SB,
MacGovern WA, Ryan TJ. Acute effects of transluminal angioplasty
in three experimental models of
atherosclerosis.
Arteriosclerosis. 1982;2:125-133.
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