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Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:479-487

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:479-487.)
© 1996 American Heart Association, Inc.

Articles

Role of Intimal Hyperplasia and Arterial Remodeling After Balloon Angioplasty

An Experimental Study in the Atherosclerotic Rabbit Model

Luis A. Guzman; Mathew J. Mick; Anita M. Arnold; Farhad Forudi; Patrick L. Whitlow

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.


*    Abstract
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 *Abstract
down arrowIntroduction
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down arrowResults
down arrowDiscussion
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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


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
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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.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
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 1Down).


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  		Table 1. Angiographic Findings in the Acute and Chronic Study Groups

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 1Up 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 1Down). 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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  		Figure 1. Scatterplot showing the significant correlation between angiographic acute gain (immediately after balloon angioplasty) and late lumen loss during follow-up (y=0.81x+0.228).

Histological Results
Acute Group (Fig 2ADown and 2B)
Fig 3Down 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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  		Figure 2. Light photomicrographs of histological section of rabbit femoral arteries showing different degrees of injury after balloon angioplasty. Lawson's elastic—van Gieson's stain. A, Segment treated with two inflations (wall tear score 1 for this specific segment). B, Segment treated with six inflations (wall tear score 11 for this specific segment). Magnification x50.



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  		Figure 3. Individual histological injury scores of femoral arteries treated with two vs six inflations. Mean injury score for arteries treated with two inflations was 1.9±1.5 and for six inflations 4.0±3.0. Lines connect the values for two arteries in the same animal.

Chronic Group
Fig 4Down 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 5Down). 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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  		Figure 4. Histogram summarizing the morphometric cross-sectional areas of lumen, intima, media, and artery (EEL) 28 days after balloon angioplasty in both treatment groups.



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  		Figure 5. Individual histological intimal areas 28 days after balloon angioplasty of femoral arteries treated with two vs six inflations. Mean for arteries treated with two inflations was 32±3% and 43±3% for those treated with six inflations. Lines connect the values for two arteries in the same animal.

To determine the predictors of the final histological lumen cross-sectional area, univariate and multivariate analysis were performed (Table 2Down). 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 6Down).


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  		Table 2. Predictors of Histological Lumen Cross-sectional Area



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  		Figure 6. Scatterplot showing the highly significant correlation between histological intimal cross-sectional area and artery area cross-sectional area (EEL) (y=1.085x+1.153). The larger the intimal area, the bigger the artery.

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 3Down). 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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  		Table 3. Morphometric and Angiographic Results in Rabbits With and Without Restenosis by Angiographic and Histological Definitions

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 3Up). 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).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
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.


*    Selected Abbreviations and Acronyms
 
EEL = external elastic lamina
IEL = internal elastic lamina
IVUS = intravascular ultrasound
MLD = minimal lumen diameter


*    Acknowledgments
 
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.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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