This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Post, M. J. Articles by Kuntz, R. E. Search for Related Content PubMed PubMed Citation Articles by Post, M. J. Articles by Kuntz, R. E.

(Circulation. 1997;96:996-1003.)
© 1997 American Heart Association, Inc.

Articles

Arterial Remodeling After Balloon Angioplasty or Stenting in an Atherosclerotic Experimental Model

Mark J. Post, MD, PhD; Bart J. G. L. de Smet, MD; Yvonne van der Helm, BSc; Cornelius Borst, MD, PhD; ; Richard E. Kuntz, MD, MSc

From the Department of Cardiology, Utrecht University Hospital (M.J.P., B.J.G.L. de S., Y. van der H., C.B.), and the Interuniversity Cardiology Institute of the Netherlands (M.J.P., B.J.G.L. de S., Y. van der H.), Utrecht, and the Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School (M.J.P., R.E.K.), Boston, Mass.

Correspondence to Mark J. Post, MD, PhD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail mpost{at}bidmc.harvard.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Recent studies have indicated that coronary restenosis after balloon angioplasty is the sum of geometric remodeling and neointimal formation. A proportional relationship between acute gain and late lumen loss has been observed in clinical trials. The aims of this study were to evaluate (1) the contribution of geometric remodeling and neointimal formation to the proportional gain-loss relationship after PTA or stenting and (2) the relationship between geometric remodeling and neointimal formation.

Methods and Results In atherosclerotic iliac arteries of 29 Yucatan micropigs, PTA or stenting was performed, with serial intravascular ultrasound (IVUS) and quantitative angiography before and after intervention and at 2 or 42 days of follow-up, followed by histomorphometrical analysis. For PTA at 42 days, late lumen loss by IVUS correlated strongly with geometric remodeling, expressed as late media-bounded area (MBA) loss (R²=.843, P<.001, n=20), and correlated weakly with intimal hyperplasia area (R²=.214, P=.02). For stented arteries, however, late lumen loss correlated moderately with intimal hyperplasia (R²=.367, P=.01, n=18) and only weakly with geometric remodeling (R²=.195, P=.04). Late lumen loss and late MBA loss of reference segments were observed at 42 days, especially in PTA arteries. Intimal hyperplasia and geometric remodeling were not correlated.

Conclusions In this experimental model, the proportional relationship between acute gain and late lumen loss is mainly due to the proportional relationship between acute gain and geometric remodeling for PTA and between acute gain and intimal hyperplasia for stents. Finally, neointimal formation and remodeling seem to be unrelated processes.

Key Words: remodeling • balloon • angioplasty • stents • peripheral vascular disease

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Coronary restenosis after percutaneous transluminal coronary angioplasty, defined as excessive lumen narrowing of the treatment site, has long been considered to be primarily the consequence of excessive neointimal formation, leading to intimal hyperplasia. Recently, however, human¹ and animal studies^{2 3 4 5} have shown that in addition to neointimal formation, changes in the total arterial circumference (so-called geometric remodeling) also occur in response to arterial intervention. Once the vascular response to intervention has stabilized by 6 months, the final coronary lumen is the sum of geometric remodeling, either an increase or a decrease in the total arterial circumference, and the magnitude of neointimal formation.

The mechanism and time course of geometric remodeling and whether it is correlated with neointimal formation are unresolved.⁶ Whereas a proportional relationship between acute gain in lumen diameter provided by the coronary interventions and subsequent late loss of the coronary lumen has been observed in many randomized and nonrandomized clinical trials of coronary devices,^{7 8 9} an earlier PTA rabbit model was unable to show a specific correlation between acute gain or balloon dilation ratio and neointimal area.¹⁰ We therefore hypothesized that any proportional lumen gain-loss relationship observed might require significant involvement of geometric remodeling in addition to neointimal formation for PTA models. Because stents generally oppose geometric contraction,^{11 12} we hypothesized that the proportional gain-loss relationship in stent models was due primarily to intimal hyperplasia. To study these hypotheses, we developed an atherosclerotic Yucatan pig model and used serial IVUS, quantitative angiography, and histology to measure geometric dimensions after PTA or stenting. We also evaluated the potential of geometric remodeling to influence the reference segments adjacent to the treatment sites, because such reference remodeling might confound lumen-based interpretations, which assume that reference measurements remain unchanged.¹³

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Twenty-nine Yucatan micropigs (mean weight at death, 25 kg) were used for this study. All animals were started on an atherogenic diet at the age of 3 to 5 months. Two weeks and 6 weeks thereafter, they underwent Fogarty denudation of the internal iliac, external iliac, and femoral arteries and were continued on the atherogenic diet. Five to 8 months later, selected stenosed arterial segments underwent either balloon dilation or stenting. During the follow-up of either 2 days (n=5) or 6 weeks (n=24) after intervention, the animals were fed a regular diet. The protocol complied with the regulations of the Dutch Animals Act of 1977 and was approved by the Ethics Committee on Animal Experiments of the Faculty of Medicine, Utrecht University.

Atherogenic Diet and Anesthesia
In addition to essential nutrients, vitamins, and salts, 1.5% cholesterol, 17.5% casein, 19.5% lard, and 0.5% bile salts were added to the diet (2400 kcal/d). This regimen results in a sustained 15-fold increase in cholesterol and a 2.5-fold increase in HDL level. Water intake was not restricted.

For all procedures, the animals were anesthetized with intravenous metomidate (4 mg/kg) and ventilated (Servo, EM 902) with O₂/N₂O 1:2 and 1% to 2% halothane. The animals were heparinized (100 IU/kg thromboliquine, Organon Technika) to an activated partial thromboplastin time >80 seconds. Every 15 minutes, 0.25 mg atropine was given intravenously. A nitroglycerin infusion (20 µg/min) and 10 mg nifedipine through the nasogastric tube were given to prevent arterial spasm. Dipyridamole 250 mg PO twice daily and acetylsalicylic acid (125 mg) were administered during follow-up for 2 weeks.

Procedures
For all procedures, the carotid artery was surgically exposed, and the aorta descendens was cannulated with an 8F guiding catheter under fluoroscopic guidance. Selective contrast (Telebrix, Laboratoire Guerbet) angiography was performed, and all other catheters were advanced, through this catheter. After the procedures, the carotid artery was sutured for future interventions. The initial and repeat denudation procedures were performed by triple withdrawal of a manually inflated 4F Fogarty catheter over 3 to 4 cm of the iliac and femoral arteries.

Five to 8 months after the second denudation, sites of arterial narrowing were either balloon dilated or stented. Because the presence of stenoses was inconsistent, from a total of 64 lesions (14 for 2 days and 50 for 42 days of follow-up, respectively), the selection of PTA and stenting was random if 2 matched stenoses were present (n=11). When 1 (n=5) or 3 (n=7) suitable stenoses were present, the unmatched stenoses were alternatively randomized between stent and PTA. For technical reasons, the Palmaz-Schatz coronary stent could not be used in arteries >4 mm in diameter, resulting in those cases in a loss of randomization (n=6) and also resulting in 5 animals in which only PTA was performed. Only one lesion per artery was treated with 8 femoral artery and 42 iliac artery lesions.

For balloon dilation, a standard peripheral (length, 2 cm; diameter, 2 to 4 mm) or coronary (length, 2 to 4 cm; diameter, 4 to 7 mm) balloon catheter was advanced over a guidewire. The mean dilation ratio (diameter of inflated balloon/diameter of the reference segment, both under fluoroscopy) was 1.2±0.2. The balloon was inflated three times to 10 atm. Palmaz-Schatz coronary stents (PS153, 15 mm, Johnson & Johnson Interventional Systems) were mounted on 3- to 4-mm PTA balloons, which were inflated to 10 atm. The mean dilation ratio was 1.2±0.2.

Termination
After follow-up, the animals were killed and the arteries harvested for histology after pressure (60 mm Hg) infusion with 3%/48.5%/48.5% wt/vol/vol agar-agar/contrast/water gel at 50°C that congealed at room temperature. Then, the arteries were submerged in situ under 4% formalin for 4 to 6 hours. By use of anatomic markers (side branches) on angiograms and agar/contrast postmortem fluoroscopy, the treated segments were identified and marked with sutures. The arterial tree was then taken out en bloc and postfixed for at least 24 hours.

Angiography and IVUS
Selective cine angiograms (12 images/s) were made before and after intervention and at follow-up with a digital C-arm (Philips). The image with the highest contrast was selected and stored on digital audio tape for later analysis.

The angiographic diameters were measured by a semiautomated program. The quantitative edge-detection algorithm was applied on the gray-value distribution of a proposed line perpendicular to the center axis of the lumen. The edges of the lumen were defined by the full-width–half-maximum points. The arterial diameter is the distance between these two points. In each artery, lumen diameters were measured at intervals of 0.5 cm. The reference segments were 1.5 cm removed from the treated segment. Serial measurements over time were performed at equal positions relative to an anatomic landmark. Angiography was calibrated with a radiopaque ruler. The mean lumen diameter and MLD of the lesion were determined. Acute gain was defined as MLD_post-MLD_pre, and late lumen loss was defined as MLD_post-MLD_FU, where FU is follow-up.¹⁴

IVUS recordings were made before and after intervention and at follow-up with a 30-MHz ultrasound transducer (Du-MED), which rotated up to 16 times per second within a 4.1F catheter. The axial resolution of the system was 0.1 mm. The images were recorded on VHS videotape (Fig 1) and later analyzed with a digital video analyzer as described previously.¹⁵ In the IVUS images, the area circumscribed by the interface between the echodense intimal layer and the echolucent media (MBA, Fig 2) and the LA were traced manually. Acute gain and late lumen loss (in areas) were defined as their angiographic counterparts. In addition to late lumen loss, late MBA loss was introduced to measure the geometric remodeling after angioplasty or stenting. Late MBA loss was defined as MBA_post-MBA_FU and the intimal area as MBA-LA. At follow-up, the intima is the sum of plaque and intimal hyperplasia; therefore, intimal hyperplasia was calculated as the difference between the intima at follow-up and before intervention. The lumen diameter (D) in ultrasound images was derived from the LA by the equation D=2x(LA/)^1/2.

View larger version (58K): [in this window] [in a new window]   Figure 1. Representative histological section of an iliac artery 42 days after PTA, EvG (A), and corresponding video still frame of an IVUS recording (B) at minimum LA in a femoral artery (identical to Fig 2C). A, Lesion is highly cellular. Artery retained a circular IEL (arrows) and EEL (arrowheads). Much of the intima (i) was preexistent, according to IVUS (Fig 2A). Perimeters of IEL (PIEL) and EEL (PEEL) and areas of media and intima (IA) were measured from digitized images. IEL area (=PIEL2/4), EEL area (=PIEL2/4), and LA (=IEL area-IA) were calculated. Bar=500 µm. B, From 5 to 12 o'clock positions, echolucent media is clearly seen. From 12 to 4 o'clock positions, media boundary is obscured but identifiable by life video. Lumen is sharply demarcated. Catheter, black circle in center of image; distance between indicators is 1 mm.

View larger version (97K): [in this window] [in a new window]   Figure 2. Representative serial IVUS images of atherosclerotic stenosis (A through C) and a proximal reference segment (D through F) before and after PTA and at follow-up (42 days). MBA (outer white line) and LA (inner white line) were manually traced for morphometry. Catheter, black circle in center of image; distance between indicators is 1 mm. Note increase in MBA (A, 11.4 mm2 vs B, 14.9 mm2) and LA after PTA and decrease during follow-up (B, 14.9 mm2 vs C, 11.7 mm2). Intimal hyperplasia accounted for 0.9 mm2 of late lumen loss. Reference segment of same artery has become slightly spastic after PTA of stenosis site (E). MBA of reference at follow-up (F, 10.9 mm2) was smaller than before angioplasty (D, 14.2 mm2), indicating shrinkage.

Histology and Histomorphometry
After they were harvested, the arteries were paraffin embedded. Serial sections (5 µm thick, 1-mm intervals) were stained with hematoxylin-eosin and with EvG. For morphometry, the EvG-stained sections were used. Images of the sections were recorded, digitized, and analyzed with Analyze (Biomedical Imaging Resource, Mayo Foundation). The lumen boundary and the IEL and EEL were traced manually, and their perimeters and areas were measured. To correct for form artifacts, the LA, IEL area, and EEL area were calculated from their perimeters, assuming circular geometry (Fig 1A). The intima was calculated as the difference between IEL area and LA. Lumen diameter was calculated as mentioned above.

Statistical Analysis
All data are presented as mean±SD. SPSS 6.1 software was used for statistical calculations. Pearson correlation coefficients were calculated when indicated. The comparison of angiographic, histological, and ultrasound measurements was performed with ANOVA for repeated measures, followed by paired t tests corrected for multiple comparisons to identify the differences between subsets. Differences in late lumen loss and late MBA loss between the treatments were evaluated with one-way ANOVA and Duncan's range test.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The analyses in this study for the 42 days of follow-up were based on 20 of 29 PTA arteries and 18 of 21 stented arteries in which a positive angiographic acute gain was achieved, and for the 2 days of follow-up, the analyses were based on 11 of 12 PTA arteries and 2 of 2 stented arteries. The negative gain in the remaining arteries resulted from spasm after PTA or insufficient stenting in arteries in which full stent expansion beyond the baseline MLD was prohibitive. To avoid expanding the coronary stent beyond its upper limit, stent placement was limited to vessels <4.0 mm. Consequently, angiographic and IVUS measurements (Tables 1 and 2) were smaller for stented arteries than for the control or PTA arteries. The postprocedure percent diameter stenosis (with the preprocedure reference diameter taken as the reference) was -6±18% in stented arteries and -9±13% in balloon-dilated arteries.

View this table: [in this window] [in a new window]   Table 1. Angiographic Parameters for 42-Day–Follow-up Group

View this table: [in this window] [in a new window]   Table 2. Intravascular Ultrasound Parameters for 42-Day–Follow-up Group

Remodeling at 42 and 2 Days With Serial IVUS
After 42 days, in the PTA arteries (n=20), the MBA on IVUS dropped by a mean value of 4.1 mm² (95% CI, 1.9 to 6.2 mm²), indicating a significant remodeling, resulting in shrinkage (Table 3, Figs 2 and 3). Neither the severity of stenosis (R²=.0008) nor the absolute MLD before PTA (R²=.055) correlated with remodeling.

View this table: [in this window] [in a new window]   Table 3. Contribution of Remodeling (Late MBA Loss) and Intimal Hyperplasia to Late Lumen Loss at 42-Day Follow-up

View larger version (20K): [in this window] [in a new window]   Figure 3. Box plot of remodeling 2 and 42 days after PTA (n=11 and 20, respectively), after stenting (n=2 and 18), and in control subjects (n=2 and 24). Remodeling is measured as late MBA loss on IVUS (see text). Boxes represent interquartile ranges; whiskers, maximum and minimum values; and horizontal line in box, median. Remodeling in PTA arteries after 42 days was significantly larger than in stented arteries and in control subjects (Wilcoxon rank sum test, P=.011). MBA loss 2 days after PTA was not different from zero (Wilcoxon rank sum test, P=.17).

For stents (n=18), no statistically significant tendency for either shrinkage or enlargement was seen (mean late MBA loss, -0.4 mm²; 95% CI, -2.1 to 1.1 mm²). In balloon-treated arteries, late lumen loss correlated strongly with late MBA loss (R²=.843, Fig 4A), but late lumen loss correlated only weakly with intimal hyperplasia (R²=.214, Fig 4B). In the stented arteries, however, the correlation between late lumen loss and late MBA loss was small (R²=.195, Fig 4C) and between late lumen loss and intimal hyperplasia, moderate (R²=.367, Fig 4D). Remodeling due to shrinkage (late MBA loss) accounted for 66% of late LA loss seen in the PTA arteries, compared with no significant remodeling in the stented arteries (Table 3). Two days after PTA or stenting, no remodeling was observed (Fig 3).

View larger version (24K): [in this window] [in a new window]   Figure 4. Linear regression of late lumen loss on late MBA loss (remodeling) and on intimal hyperplasia for PTA in A and B, respectively, and for stented arteries in C and D. Intimal hyperplasia was calculated as difference between intima at follow-up and before intervention, both measured by IVUS (see "Methods").

Remodeling in Reference Segments
In addition to remodeling seen in the lesion segments, significant late lumen loss (2.2±2.9 mm, P<.01, Table 4) and significant late MBA loss (1.6±3.7 mm², P<.05) was observed at 42 days of follow-up in the reference segments adjacent to the segments that had undergone PTA. The reference segments of stented arteries, conversely, showed no significant late lumen loss (-0.4±2.6 mm, P=NS) and no significant late MBA loss (-0.7±2.5 mm², P=NS).

View this table: [in this window] [in a new window]   Table 4. LA and MBA in Reference Segments of Treated and Control Arteries, Before (pre) and After (post) Intervention and at 42-Day Follow-up

Loss-Gain Relationship
Within both the stent and PTA arteries, late loss correlated strongly with acute gain expressed either as angiographic diameters or as ultrasound areas. For PTA arteries, the regression equation of angiographic late loss on acute gain was y=0.50x+0.28, R²=.203 (P<.01), and that for stent arteries was y=0.69x+0.0, R²=.482 (P<.01). The "loss index," ie, the proportion of the gain that is lost during follow-up, was therefore 0.5 after PTA. The regression equation of ultrasound late loss on acute gain (areas) was y=0.83x+2.39, R²=.65 (P<.01) for PTA, and that for stented arteries was y=0.60x-0.57, R²=.53 (P<.01). In PTA arteries, a strong correlation between late MBA loss and acute gain was seen (R²=.504, P<.001), whereas intimal hyperplasia correlated only weakly with acute gain (R²=.198, P=.037). In stented arteries, a correlation was seen between intimal hyperplasia and acute gain (R²=.394, P=.003) but not between late MBA loss and acute gain (R²=-.062, P=.918).

Relationship Between Intimal Hyperplasia and Late MBA Loss
No relationship was found between intimal hyperplasia and late MBA loss: R²=-.030, P=.464 for PTA (Fig 5). Since no significant late MBA loss was found in stented arteries, this relationship was not tested.

View larger version (13K): [in this window] [in a new window]   Figure 5. Relationship of intimal hyperplasia and late MBA loss for PTA arteries. Correlation coefficient R2=-.030, P=.464. Intimal hyperplasia was calculated as difference between intima at follow-up and before intervention, both measured by IVUS (see "Methods").

Correlation Between Angiographic, Ultrasound, and Histological Data
Intimal area at 2 and 42 days was composed of preexistent plaque and intimal hyperplasia. For stented arteries (n=20), the cross-sectional intimal area aver-aged for the entire stented segment was 6.4±2.0 mm² by IVUS and 4.4±3.0 mm² by histological morphometry. In PTA arteries (n=31), this average cross-sectional intimal area was 3.7±2.9 mm² by IVUS and 1.6±1.6 mm² by histological morphometry. The combined intimal area was 4.0±2.9 mm² by IVUS and 2.8±2.6 mm² by histological morphometry (P<.001, Table 5). The IVUS and histological measurements for each segment, however, were highly correlated (R²=.581).

View this table: [in this window] [in a new window]   Table 5. Comparison of Angiographic, Ultrasound, and Histological Data From All (Stent, PTCA) Arteries at 2- and 42-Day Follow-up

Angiography, ultrasound, and histology measurements of reference lumen diameters and MLDs were compared for all treated arteries (Table 5). The correlation coefficients (R²) ranged from .416 to .585, were higher for reference segments than for MLDs, and were the highest for IVUS and histology.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Arterial geometric remodeling, defined as a structural change in total arterial circumference during the restenosis period, is now recognized as a major component of the restenosis process.^{1 16} Remodeling can appear as enlargement or shrinkage and can thus reduce or increase lumen narrowing⁶ by neointimal formation. The mechanism of remodeling, its time course, and its relation to neointimal formation, however, are not known.

In this angiographic, serial ultrasound, and histological study of the atherosclerotic Yucatan micropig, remodeling explained 66% of late LA loss 42 days after PTA, which compares well with the reported 73% in human coronary arteries.¹⁷ Because no remodeling was observed 2 days after PTA, early elastic recoil can be ruled out as a cause for the decrease in arterial size. As expected in stented arteries, late lumen loss was entirely due to intimal hyperplasia. In accordance with clinical studies,^{11 12} no remodeling of the stent or the stented artery was observed. Thus, in this model, a major part of restenosis after PTA is determined by remodeling, which is prevented by stents. Remodeling develops between 2 and 42 days. The atherosclerotic Yucatan micropig may be a suitable model to study remodeling after PTA and to assess the effects of various drugs designed to reduce remodeling.

Comparison of Ultrasound and Histological Measurements
In our study, late lumen loss after stenting was due to neointimal formation, both by IVUS and by histology. Although we observed a discrepancy between tissue area found on IVUS and histomorphometry, these areas correlated strongly, and the offset was probably due to differences in methodology. First, stent struts that are incorporated in the intimal hyperplasia appear larger on IVUS and therefore lead to overestimation of the MBA. Second, even with pressure fixation, histological tissue shrinks 10% to 20% with dehydration, resulting in underestimation of histological MBA. Third, lumen measurements by IVUS were also larger than by histology or angiography, suggesting a systematic overestimation by IVUS, which has also been observed by other investigators.¹⁸

Relation Between Acute Gain, Late Lumen Loss, and Remodeling
In many trials of coronary devices, angiographic late lumen loss was proportional to the acute gain.^{7 8 9} These observations are supported by animal studies showing neointimal formation that was proportional to the injury imparted on the artery.^{19 20 21} In a previous study in rabbit femoral arteries using PTA balloons, however, we observed that intimal hyperplasia did not correlate with a wide range of dilatation ratios and areas of medial necrosis.¹⁰ Moreover, most of the former studies used a Fogarty balloon withdrawal technique that in our hands induces an aggressive healing response compared with PTA balloon dilatation.²² The relationship between acute gain and remodeling in PTA arteries found in this study suggests that this relationship is determined by remodeling rather than by neointimal formation. In stented arteries, on the other hand, the gain-loss relationship was based on proportional intimal hyperplasia, in accordance with Schwartz et al.¹⁹ Clinical trials for new coronary devices with serial IVUS will be needed to corroborate our findings.

Relationship Between Intimal Hyperplasia and Remodeling
In the present study, we found no correlation between the magnitude of intimal hyperplasia and remodeling. This suggests that the pathogeneses of the two are dissimilar. Lafont et al⁴ found adventitial changes to correlate with remodeling, and indeed, by its high collagen content, the adventitia is probably involved in remodeling.⁶ In a recent study, Mintz et al¹⁷ observed a weak correlation (R²=.204) between remodeling and change in intima+media for arteries that underwent a variety of interventions. The breakdown for the different interventions, however, is as yet unknown. In overstretched normal pig coronary arteries, a relation was found between intimal area and vessel size.²³ In this model, the overstretch resulted in a medial gap that was filled with neointima, producing an exact relation between neointimal area and the size of the gap. The gap by itself translates into the size of the artery. This model is essentially different from our model, in which mild overstretching left the media largely intact, and this difference most likely explains the contrasting results.

Remodeling and Late Lumen Loss in Reference Segments
In this study, we found a small but significant late lumen loss and remodeling in adjacent reference segments of balloon-dilated arteries and not of stented arteries or in control arteries. The reference late lumen loss has also been observed in PTA of human coronary arteries.²⁴ Although the reference segments were at least 1.5 cm from the treated segments, we cannot rule out that the balloons might have induced reference remodeling by longitudinal stretch of the artery. Late lumen loss of the reference artery leads to a reduction of the calculated percentage stenosis, and restenosis by many arbitrary definitions may therefore be underestimated. The observed remodeling in reference segments also implies that definitions of remodeling at the stenosis relative to the size of the reference may underestimate remodeling as well.^{13 25} The mechanism for remodeling of the reference is unknown, and it is intriguing that no reference remodeling occurs in stented arteries.

Limitations of the Study
This study was performed in peripheral arteries in an animal model of advanced atherosclerosis, and it remains to be determined how much of the late lumen loss in human coronary arteries is caused by remodeling. Separate serial IVUS studies in patients,^{1 16 17} however, indicate that remodeling contributes substantially to restenosis in human coronary arteries.

Because the selection of treatment was not strictly random and because for technical reasons, stents were placed predominantly in smaller arteries, direct comparison between the results in these groups may be inappropriate. The conclusions drawn from these data, however, are based on serial observations within the respective groups and did not depend on between-group comparisons.

Although the arteries contained considerable plaques (2.28±1.78 mm²), the angiographic stenoses were mild, and thus the acute gain was partly achieved by overdilation of the arteries. However, the dilation ratio in this study was 1.2 and similar to the dilation ratio in human coronary arteries. Moreover, the observed loss index of 0.50 was similar to that reported in clinical studies.⁷

Conclusions
From this serial IVUS study in an atherosclerotic Yucatan micropig model, it can be concluded that remodeling is an important determinant of late lumen loss after angioplasty, but remodeling is prevented by stenting. This remodeling occurs to a lesser extent also in reference segments of balloon-dilated arteries and not of stented arteries. For PTA, the proportional relation between acute gain and late lumen loss is caused by a proportional remodeling response, whereas in stented arteries, neointimal formation determines this proportionality. Finally, neointimal formation and remodeling seem to be unrelated processes.

	Selected Abbreviations and Acronyms

 

EEL = external elastic lamina EvG = elastin van Gieson stain IEL = internal elastic lamina IVUS = intravascular ultrasound LA = lumen area MBA = media-bounded area MLD = minimum lumen diameter PTA = percutaneous transluminal (balloon) angioplasty

	Acknowledgments

 
We gratefully acknowledge Johnson & Johnson Interventional Systems for the supply of stents and Jolanda van der Zande, BSc, and Evelyn Velema, BSc, for technical assistance.

Received October 16, 1996; revision received February 4, 1997; accepted February 11, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Mintz GS, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. Intravascular ultrasound comparison of restenotic and de novo coronary artery narrowings. Am J Cardiol. 1994;74:1278-1280.

2. 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.

3. 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.

4. Lafont A, Guzman LA, Whitlow PL, Goormastic M, Cornhill JF, Chisolm GM. Restenosis after experimental angioplasty: intimal, medial, and adventitial changes associated with constrictive remodeling. Circ Res. 1995;76:996-1002.

5. Nunes GL, Sgoutas DS, Redden RA, Sigman SR, Gravanis MB, King SB III, Berk BC. Combination of vitamins C and E alters the response to coronary balloon injury in the pig. Arterioscler Thromb Vasc Biol. 1995;15:156-165.

6. Post MJ, Pasterkamp G, Borst C. Arterial remodeling in atherosclerosis and restenosis: a vague concept of a distinct phenomenon. Atherosclerosis. 1995;118(suppl):S115-S123.

7. Kuntz RE, Gibson CM, Nobuyoshi M, Baim DS. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol. 1993;21:15-25.

8. Topol EJ, Leya F, Pinkerton CA, Whitlow PL, Hofling B, Simonton CA, Masden RR, Serruys PW, Leon MB, Williams DO, King SB III, Mark DB, Isner JM, Holmes DR Jr, Ellis SG, Lee KL, Keeler GP, Berdan LG, Hinohara T, Califf RM. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med. 1993;329:221-227.

9. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D, Teirstein PS, Fish RD, Colombo A, Brinker J, Moses J, Shaknovich A, Hirshfeld J, Bailey S, Ellis S, Rake R, Goldberg S. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994;331:496-501.

10. Van Erven L, Post MJ, Velema E, Borst C. In the normal rabbit femoral artery increasing arterial wall injury does not lead to increased intimal hyperplasia. J Vasc Res. 1993;31:153-162.

11. Gordon PC, Gibson CM, Cohen DJ, Carrozza JP Jr, Kuntz RE, Baim DS. Mechanisms of restenosis and redilation within coronary stents: quantitative angiographic assessment. J Am Coll Cardiol. 1993;21:1166-1174.

12. Painter JA, Mintz GS, Wong SC, Popma JJ, Pichard AD, Kent KM, Satler LF, Leon MB. Serial intravascular ultrasound studies fail to show evidence of chronic Palmaz-Schatz stent recoil. Am J Cardiol. 1995;75:398-400.

13. Post MJ, Kuntz RE, Borst C. Remodeling after PTCA: from shrinkage to compensatory enlargement. Circulation. 1995;92:2002. Letter.

14. 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.

15. Wenguang L, Gussenhoven WJ, Zhong Y, The SH, Di Mario C, Madretsma S, Van Egmond F, de Feyter P, Pieterman H, Van Urk H. Validation of quantitative analysis of intravascular ultrasound images. Int J Card Imaging. 1991;6:247-253.

16. Di Mario C, Gil R, Camenzind E, Ozaki Y, Von Birgelen C, Umans V, De Jaegere P, de Feyter PJ, Roelandt JR, Serruys PW. Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional coronary atherectomy. Am J Cardiol. 1995;75:772-777.

17. Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Wong SC, Hong MK, Kovach JA, Leon MB. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation. 1996;94:35-43.

18. De Scheerder I, De Man F, Herregods MC, Wilczek K, Barrios L, Raymenants E, Desmet W, De Geest H, Piessens J. Intravascular ultrasound versus angiography for measurement of luminal diameters in normal and diseased coronary arteries. Am Heart J. 1994;127:243-251.

19. Schwartz RS, Huber KC, Murphy JG, Edwards WD, Camrud AR, Vlietstra RE, Holmes DR Jr. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol. 1992;19:267-274.

20. Schwarcz TH, Dobrin PB, Mrkvicka R, Skowron L, Cole MB Jr. Early myointimal hyperplasia after balloon catheter embolectomy: effect of shear forces and multiple withdrawals. Surgery. 1988;7:495-499.

21. Indolfi C, Esposito G, Di Lorenzo E, Rapacciuolo A, Feliciello A, Porcellini A, Avvedimento VE, Condorelli M, Chiariello M. Smooth muscle cell proliferation is proportional to the degree of balloon injury in a rat model of angioplasty. Circulation. 1995;92:1230-1235.

22. Doornekamp FNG, Borst C, Haudenschild CC, Post MJ. Fogarty and PTCA balloon injury induce comparable damage to the arterial wall but lead to different healing responses. J Vasc Surg. 1996;24:843-850.

23. Andersen HR, Mæng M, Thorvest M, Falk E. Remodeling rather than neointimal formation explains luminal narrowing after deep vessel wall injury. Circulation. 1996;93:1716-1724.

24. Beatt KJ, Luijten HE, de Feyter PJ, Van den Brand M, Reiber JH, Serruys PW. Change in diameter of coronary artery segments adjacent to stenosis after percutaneous transluminal coronary angioplasty: failure of percent diameter stenosis measurement to reflect morphologic changes induced by balloon dilation. J Am Coll Cardiol. 1988;12:315-323.

25. Gertz SD, Gimple LW, Banai S, Ragosta M, Powers ER, Roberts WC, Perez LS, Sarembock IJ. Geometric remodeling is not the principal pathogenetic process in restenosis after balloon angioplasty: evidence from correlative angiographic-histomorphometric studies of atherosclerotic arteries in rabbits. Circulation. 1994;90:3001-3008.

This article has been cited by other articles:

				W. E. Hellings, F. L. Moll, J.-P. P. M. De Vries, R. G. A. Ackerstaff, K. A. Seldenrijk, R. Met, E. Velema, W. J. M. Derksen, D. P. V. De Kleijn, and G. Pasterkamp Atherosclerotic Plaque Composition and Occurrence of Restenosis After Carotid Endarterectomy JAMA, February 6, 2008; 299(5): 547 - 554. [Abstract] [Full Text] [PDF]

				W. Alvarez Jr and N. K. Kapur Drug Eluting Stent Technology: A Paradigm Shift in the Treatment and Prevention of Restenosis Journal of Pharmacy Practice, December 1, 2005; 18(6): 461 - 478. [Abstract] [PDF]

				O. D. Defawe, R. D. Kenagy, C. Choi, S. Y.C. Wan, C. Deroanne, B. Nusgens, N. Sakalihasan, A. Colige, and A. W. Clowes MMP-9 regulates both positively and negatively collagen gel contraction: A nonproteolytic function of MMP-9 Cardiovasc Res, May 1, 2005; 66(2): 402 - 409. [Abstract] [Full Text] [PDF]

				L. Mauri, E. J. Orav, A. J. O'Malley, J. W. Moses, M. B. Leon, D. R. Holmes Jr, P. S. Teirstein, J. Schofer, G. Breithardt, D. E. Cutlip, et al. Relationship of Late Loss in Lumen Diameter to Coronary Restenosis in Sirolimus-Eluting Stents Circulation, January 25, 2005; 111(3): 321 - 327. [Abstract] [Full Text] [PDF]

				G. Pasterkamp, Z. S. Galis, and D. P.V. de Kleijn Expansive Arterial Remodeling: Location, Location, Location Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 650 - 657. [Abstract] [Full Text] [PDF]

				P. H. Stone, A. U. Coskun, S. Kinlay, M. E. Clark, M. Sonka, A. Wahle, O. J. Ilegbusi, Y. Yeghiazarians, J. J. Popma, J. Orav, et al. Effect of Endothelial Shear Stress on the Progression of Coronary Artery Disease, Vascular Remodeling, and In-Stent Restenosis in Humans: In Vivo 6-Month Follow-Up Study Circulation, July 29, 2003; 108(4): 438 - 444. [Abstract] [Full Text] [PDF]

				I.-M. o Chung, H. K. Gold, S. M. Schwartz, Y. Ikari, M. A. Reidy, and T. N. Wight Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2072 - 2081. [Abstract] [Full Text] [PDF]

				G. Theilmeier, R. Quarck, P. Verhamme, M.-L. Bochaton-Piallat, M. Lox, H. Bernar, S. Janssens, M. Kockx, G. Gabbiani, D. Collen, et al. Hypercholesterolemia impairs vascular remodelling after porcine coronary angioplasty Cardiovasc Res, August 1, 2002; 55(2): 385 - 395. [Abstract] [Full Text] [PDF]

				K. Kozuma, M.A. Costa, W.J. van der Giessen, M. Sabate, J.M.R. Ligthart, V.L.M.A. Coen, I.P. Kay, A.J. Wardeh, A.H.M. Knook, P.J de Feyter, et al. Initial observation regarding changes in vessel dimensions after balloon angioplasty and stenting followed by catheter-based {beta}-radiation. Is stenting necessary in the setting of catheter-based radiotherapy? Eur. Heart J., April 2, 2002; 23(8): 641 - 649. [Abstract] [Full Text] [PDF]

				H. Okura, M. Hayase, S. Shimodozono, H. N. Bonneau, P. G. Yock, and P. J. Fitzgerald Impact of pre-interventional arterial remodeling on subsequent vessel behavior after balloon angioplasty: a serial intravascular ultrasound study J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2001 - 2005. [Abstract] [Full Text] [PDF]

				T. Christen, V. Verin, M.-L. Bochaton-Piallat, Y. Popowski, F. Ramaekers, P. Debruyne, E. Camenzind, G. van Eys, and G. Gabbiani Mechanisms of Neointima Formation and Remodeling in the Porcine Coronary Artery Circulation, February 13, 2001; 103(6): 882 - 888. [Abstract] [Full Text] [PDF]

				M. J. Sierevogel, G. Pasterkamp, E. Velema, P. P. T. de Jaegere, B. J. G. L. de Smet, J. H. Verheijen, D. P. V. de Kleijn, and C. Borst Oral Matrix Metalloproteinase Inhibition and Arterial Remodeling After Balloon Dilation : An Intravascular Ultrasound Study in the Pig Circulation, January 16, 2001; 103(2): 302 - 307. [Abstract] [Full Text] [PDF]

				M A Costa, K Kozuma, A L Gaster, W J van der Giessen, M Sabaté, D P Foley, I P Kay, J M R Ligthart, P Thayssen, M J van den Brand, et al. Three dimensional intravascular ultrasonic assessment of the local mechanism of restenosis after balloon angioplasty Heart, January 1, 2001; 85(1): 73 - 79. [Abstract] [Full Text]

				Y. Cottin, M. Kollum, R. Chan, B. Bhargava, Y. Vodovotz, and R. Waksman Vascular repair after balloon overstretch injury in porcine model effects of intracoronary radiation J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1389 - 1395. [Abstract] [Full Text] [PDF]

				M. R. Ward, G. Pasterkamp, A. C. Yeung, and C. Borst Arterial Remodeling : Mechanisms and Clinical Implications Circulation, September 5, 2000; 102(10): 1186 - 1191. [Full Text] [PDF]

				B. J. G. L. de Smet, D. de Kleijn, R. Hanemaaijer, J. H. Verheijen, L. Robertus, Y. J. M. van der Helm, C. Borst, and M. J. Post Metalloproteinase Inhibition Reduces Constrictive Arterial Remodeling After Balloon Angioplasty : A Study in the Atherosclerotic Yucatan Micropig Circulation, June 27, 2000; 101(25): 2962 - 2967. [Abstract] [Full Text] [PDF]

				G. Pasterkamp, D. P.V de Kleijn, and C. Borst Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications Cardiovasc Res, March 1, 2000; 45(4): 843 - 852. [Abstract] [Full Text] [PDF]

				S. G. Worthley, G. Helft, V. Fuster, A. G. Zaman, Z. A. Fayad, J. T. Fallon, and J. J. Badimon Serial In Vivo MRI Documents Arterial Remodeling in Experimental Atherosclerosis Circulation, February 15, 2000; 101(6): 586 - 589. [Abstract] [Full Text] [PDF]

				C. M. Dollery, J. R. McEwan, M. Wang, Q. A. Sang, Y. E. Liu, and Y. E. Shi TIMP-4 Is Regulated by Vascular Injury in Rats Circ. Res., March 19, 1999; 84(5): 498 - 504. [Abstract] [Full Text] [PDF]

				J. Binko, S. Meachem, and H. Majewski Endothelium removal induces iNOS in rat aorta in organ culture, leading to tissue damage Am J Physiol Endocrinol Metab, January 1, 1999; 276(1): E125 - E134. [Abstract] [Full Text] [PDF]

				A. Lafont and D. Faxon Why do animal models of post-angioplasty restenosis sometimes poorly predict the outcome of clinical trials? Cardiovasc Res, July 1, 1998; 39(1): 50 - 59. [Full Text] [PDF]

				B.J.G.L de Smet, J van der Zande, Y.J.M van der Helm, R.E Kuntz, C Borst, and M.J Post The atherosclerotic Yucatan animal model to study the arterial response after balloon angioplasty: the natural history of remodeling Cardiovasc Res, July 1, 1998; 39(1): 224 - 232. [Abstract] [Full Text] [PDF]

				B. J. G. L. de Smet, G. Pasterkamp, Y. J. van der Helm, C. Borst, and M. J. Post The Relation Between De Novo Atherosclerosis Remodeling and Angioplasty-Induced Remodeling in an Atherosclerotic Yucatan Micropig Model Arterioscler Thromb Vasc Biol, May 1, 1998; 18(5): 702 - 707. [Abstract] [Full Text] [PDF]

				T. Kakuta, M. Usui, W. D. Coats Jr, J. W. Currier, F. Numano, and D. P. Faxon Arterial Remodeling at the Reference Site After Angioplasty in the Atherosclerotic Rabbit Model Arterioscler Thromb Vasc Biol, January 1, 1998; 18(1): 47 - 51. [Abstract] [Full Text] [PDF]

				M. J. Sierevogel, E. Velema, P. P. de Jaegere, D. P. de Kleijn, C. Borst, and G. Pasterkamp Minimal Duration of Oral Matrix Metalloproteinase Inhibition to Prevent Constrictive Arterial Remodeling after Balloon Dilation in the Pig Radiology, February 1, 2002; 222(2): 468 - 473. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Post, M. J. Articles by Kuntz, R. E. Search for Related Content PubMed PubMed Citation Articles by Post, M. J. Articles by Kuntz, R. E.