© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Time course and importance of neoadventitial formation in arterial remodeling following balloon angioplasty of porcine coronary arteries
Department of Medicine, Vascular Biology Laboratory, University of Ottawa Heart Institute, 1053 Carling Avenue, Ottawa, Ontario, Canada KIY 4E9
* Corresponding author. Tel.: +1-613-761-5427; fax: +1-613-761-4690; e-mail: mlabinaz@heartinst.on.ca
Received 30 September 1997; accepted 7 May 1998
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Abstract |
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Objectives: Arterial remodeling has been suggested as the predominant factor in restenosis. However, the time course and morphometric factors that determine whether remodeling occurs remain unclear. We hypothesized that arterial remodeling does not occur in all arteries following balloon injury and is dependent on neoadventitial formation. Methods: Using single (SI) and double (DI) balloon injury of Yorkshire porcine coronary arteries we examined changes in morphometry 3, 7, 14, and 28 days following balloon injury. Results: In both SI and DI arteries, the neoadventitia (NAD) area expanded by day 3 and was the first compartment to increase following injury. In SI arteries lumen area (LA) decreased between day 3 and 14 while in DI arteries, there was significantly less loss in LA. In SI arteries, contracture of the area circumscribed by the external elastic lamina (EEL), which occurred predominantly between day 7 and 14, accounted for 67% of the loss of LA. Conclusions: Accumulation of NAD appears to be the earliest change in the vessel wall following balloon injury of normal or previously injured arteries and precedes the growth of the I+M (intima and media). The predominant mechanism for lumenal narrowing following single balloon injury of a normal artery is remodeling. In contrast, remodeling does not occur in DI arteries, possibly due to differences in the degree of adventitial fibrosis of normal and injured arteries.
KEYWORDS Restenosis; Vascular remodeling; Adventitia; Porcine
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1 Introduction |
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Despite the widespread use of percutaneous transluminal angioplasty for the treatment of obstructive coronary artery disease, the vascular response to severe balloon injury remains incompletely understood. Restenosis represents an extreme form of vascular repair and remains a significant problem despite recent advances in coronary interventional techniques [1]. Coronary stents significantly reduce, but do not eliminate, the occurrence of restenosis [2–4]. Numerous pharmacological agents have been clinically tested with generally unfavourable results [5–8]. Moreover, coronary artery biopsies obtained from human restenosis lesions show low levels of proliferation, challenging the importance of smooth muscle cell proliferation [9].
Some investigators have suggested that following balloon injury, the predominant mechanism for lumenal narrowing is the accumulation of neointimal mass [10–13]. However, recently, arterial remodeling, specifically arterial contracture, has been proposed as a more important process in restenosis [14, 15]. The term arterial remodeling has been applied to various conditions. For example, in atherosclerosis, remodeling has been equated with compensatory enlargement, the process by which arteries enlarge in order to accommodate increases in neointimal mass. The initial report of compensatory enlargement in coronary arteries was made in 1971 by Mann et al. [16]. They examined the coronary arteries of African Masai men and found that despite extensive atherosclerosis and intimal thickening, lumenal narrowing was rarely observed because of coronary artery enlargement. This process has been further described by Glagov et al., McPherson et al., Clarkson et al., and others in human coronary and peripheral arteries [17–19]. These investigators have used the term remodeling to explain lumenal narrowing in atherosclerosis that is due to the accumulation of neointimal mass without an adequate amount of arterial enlargement i.e. failure of remodeling or inadequate compensatory enlargement. The term remodeling has also been used to describe the process of arterial contracture in which lumenal narrowing occurs due to shrinkage of the artery. Recent data suggests that this process of arterial contracture may be the most important determinant of lumenal narrowing following coronary interventions in both animal models and humans [20–25].
Although the term arterial remodeling has been used extensively, several important issues including the mechanism(s) of remodeling, time course, and insights into why some arteries narrow while others do not remain unanswered. Recently, some investigators have focused on the importance of the adventitia in neointimal formation but the role of the adventitia in arterial contracture has not been carefully studied. We hypothesized that: (1) neoadventitial formation occurs in a stereotypical fashion following balloon injury and is part of the healing response to vessel wall injury, (2) in normal, uninjured arteries subjected to balloon injury, adventitial growth and fibrosis results in arterial contracture and subsequent lumenal narrowing, but (3) once a thickened neoadventitia has formed, the ability of the artery wall to remodel with repeat injury is attenuated. Therefore, we compared the changes in arterial wall dimensions following balloon injury in arteries without pre-existing adventitial fibrosis (SI) to arteries with pre-existing adventitial fibrosis (DI).
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2 Methods |
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All procedures were performed in accordance with the University of Ottawa Animal Ethics committee and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 8523, revised 1985). Yorkshire swine weighing approximately 20 kg were used. All animals were fed a standard nutritionally balanced pig chow (pig grower pellets 9110, Purina Mills, Richmond, IN, USA) without supplemental cholesterol.
2.1 Angioplasty
Animals were sedated with ketamine 25 mg/kg intramuscularly (IM) and and given atropine 1 mg IM to reduce orotracheal secretions. Animals were then intubated and ventilated and anesthesia was maintained throughout the surgery with isoflurane 1–3%. A standard femoral artery cutdown using sterile technique was performed and an 8 French (Fr) arterial sheath was inserted. A baseline hematocrit, blood gas and an activated clotting time (ACT) were obtained. Bretylium (10 mg/kg) and heparin (250 units/kg) were given prophylactically against ventricular arrhythmias and coronary thrombosis, respectively. The ACT was checked at baseline, 10 min following the initial bolus of heparin, and every 30 min during the procedure. Additional heparin was given to achieve an ACT of 300–350 s. Baseline rhythm and blood pressure measurements were obtained. The appropriate angioplasty guiding catheter was advanced to the coronary ostium and after administering 200 µg of intracoronary nitroglycerin, baseline coronary angiography in two orthogonal views using contrast media (MD 76: diatrizoate meglumine 66% and diatrizoate sodium 10%) was performed.
Single and repeat (double) injury was performed in porcine coronary arteries. We and others have previously demonstrated that adventitial fibrosis occurs following oversize balloon injury in this model [12, 13]. The proximal segment of a coronary artery was selected for balloon angioplasty and the initial injury was performed using a standard balloon angioplasty catheter 4.0 mm in diameter (Guidant, Santa Clara, CA, USA) to ensure a balloon–artery ratio of approximately 1.5:1. Following the final inflation, 200 µg of intracoronary nitroglycerin was administered and repeat angiography was performed. The arterial sheath was removed and the femoral artery ligated. Two weeks following the initial injury the animals returned to the animal catheterization laboratory for a second procedure using the same surgical technique as described above but using the contralateral femoral artery for vascular access. Baseline coronary angiography was performed. Oversize balloon injury of the originally injured artery (DI) and a second previously non-injured artery (SI) was performed. A third artery remained as a non-injured control.
Euthanasia, using an intravenous overdose of pentobarbital and KCl, was performed 3, 7, 14, and 28 days following the second injury (four animals in each group).
2.2 Tissue preparation and immunocytochemical staining
The heart was harvested and the coronaries were perfusion flushed with Ringers’ lactate at 100 mm Hg for 10 min and subsequently perfusion fixed with 10% neutral buffered formalin at 100 mm Hg for 60 min. In order to preserve the adventitia and the surrounding periadventitial tissue, the injured segment of coronary artery was carefully dissected and removed en bloc with the adjacent tissues (i.e. adipose tissue and myocardium). The arteries were placed in individual cassettes and fixed for at least 12 h in 10% neutral buffered formalin. The arteries were embedded in paraffin and cut at 5 µm intervals. Each representative arterial segment was stained with hematoxylin-phloxine- safranine (HPS), Movat pentachrome, Sirius red (collagen stain) and Alcian blue (proteoglycan stain). Sections were also immunolabeled for smooth muscle cell 
-actin using standard techniques. Briefly, slides were deparaffinized and rehydrated through a series of diluted ethanol solutions. Endogenous peroxidase activity was blocked with 3% hydrogen peroxide. After rinsing with PBS (pH 7.4), a monoclonal mouse antibody recognizing -smooth muscle actin (Boheringer Mannheim, Mannheim, Germany) at a dilution of 1:100 was applied at room temperature for 60 min. Biotinylated horse anti-mouse antibody was then applied for 30 min followed by an avidin–biotin peroxidase complex (ABC Elite Kit, Vector Laboratories, Burlingame, CA, USA) for 30 min. Slides were then placed in 0.05 M Tris containing the peroxidase enzyme substrate, 3,3'-diaminobenzidine (DAB) for 10 min at 37°C to yield a brown reaction product. Specimens were counterstained with hematoxylin.
2.3 Morphometric analysis
A detailed morphometric analysis was performed on all arterial segments using a digitized images projected from an Olympus BX50 microscope via a colour camera (Iris CCD, Sony, Bravado Truevision-Capturing Software, Jandel, San Rafael, CA, USA) and analyzed using image analysis software (Mocha Image Analysis Software, Jandel) interfaced with SIGMAPLOT for Windows. The following parameters were measured on Movat pentachrome stained slides: (i) lumen area (LA), (ii) combined intimal plus medial area (I+M)=tissue area between the LA and the external elastic lamina. Because of interruptions of the internal elastic lamina post-balloon angioplasty, it was impossible to consider the intima and media as discrete entities, and therefore, a combined area was measured; (iii) external elastic lamina (EEL) area; (iv) neoadventitia (NAD)=area between EEL and the loose connective tissue or adipose tissue or myocardium surrounding the coronary artery (Fig. 1). The demarcation between the adventitia and the EEL (inner border) was readily identified on the sections stained with Movat pentachrome stain. The outer border of the NAD was also identified on Movat pentachrome slides since the sparse tissue in the outer adventitia stains very lightly and myocardium is easily identified by its characteristic histological appearance. In contrast, the NAD tissue is a dense collection of matrix and cells that stain with a dark colour when a Movat pentachrome stain is used. Other investigators have also used this method of measuring the adventitia, although different stains were used [13]. Morphometric analyses were performed by two independent investigators blinded to the time of sacrifice and to the type of injury.
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2.4 Angiographic analysis
Coronary angiograms were performed at the time of injury. No follow-up angiography was performed at the time of sacrifice. Quantitative coronary angiography was performed using a customized Siemens Digitron 3.61 analytical programme which we have previously described [26, 27]. The following angiographic measurements were made: (i) minimal lumen diameter (MLD) of the injured segment prior to balloon oversize injury (pre-balloon MLD), (ii) MLD immediately following balloon injury (post-balloon MLD), (iii) ratio of the balloon diameter to the pre-balloon MLD (balloon-to-artery ratio), (iv) the difference between the post-balloon and pre-balloon MLD (acute gain). One artery in each of the SI and DI groups could not be analyzed due to technical factors and therefore 15 arterial segments were available for analysis.
2.5 Statistical analysis
All results are reported as means±S.D. All control arteries were grouped together as no significant changes were observed over time in this group. The difference between the maximum and minimum LA and EEL area within each injury group were compared using an unpaired Student t-test. Differences between SI and DI arteries with respect to angiographic and morphometric data were also compared using an unpaired Student t-test. Temporal changes in the compartments of the arterial wall were compared to normal controls using a one-way ANOVA and if significant differences were noted a Dunnett t-test was used to compare each group to the normal control group. p<0.05 was considered statistically significant for all analyses.
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3 Results |
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All animals thrived during the experimental procedure. A total of 46 arteries from 16 animals were included in this study. One control artery in the 3-day group and one control artery in the 7-day group were excluded due to improper histologic processing.
3.1 Histology
Control arteries were devoid of an intima (Fig. 2a and b). A single layer of endothelial cells lined the lumen of the uninjured control arteries. The media consisted of several layers of circumferentially arranged smooth muscle cells while the adventitial layer was relatively acellular with sparse microvessels, nerves, adipose tissue and very little connective tissue.
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Following injury a number of changes occurred as part of the process of vascular repair. Although the intimal reaction was minimal and no significant re-endothelialization was observed 3 days following injury, an increase in NAD area was noted at this early time point (Fig. 3a). At day 3 the NAD was composed of fibroblasts with a few cells exhibiting
-actin immunostaining (Fig. 4a). There was some increase in collagen and proteoglycans in the NAD demonstrated by Sirius red and Alcian blue staining, respectively, compared to uninjured controls (Fig. 5a,b). Further expansion of the NAD area was noted by day 7, and this coincided with the development of a neointima. There was prominent -actin immunoreactivity in the NAD as well as some in the neointima at this interval. The neointima formed at sites where the media had been disrupted and was composed of smooth muscle cells and proteoglycans. Further collagen staining in the NAD was evident at this time. Fourteen days following SI, the NAD was well developed and numerous -actin immunolabelled cells were present (Fig. 4b). In addition to these cellular changes a dense layer of collagen in the NAD was circumferentially arranged around the artery (Fig. 3c). The neointima consisted predominantly of -actin staining cells and abundant proteoglycans with relatively little collagen (Fig. 6). Except for a decrease in -actin immunoreactivity in the NAD, there were no other important differences seen between days 14 and 28.
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Although qualitatively similar histological changes were observed in the vessel wall following the second balloon injury, some differences were noted. Three days following DI, significant circumferential adventitial fibrosis was already present due to the initial SI (Fig. 3c). At day 3 some of the NAD cells were immunolabelling with
-actin but significant -actin immunoreactivity was evident by day 7 and 14 (Fig. 4c and d). Fourteen days following DI, there was a well-developed neointima and the NAD was markedly thickened (Fig. 3d). In contrast to SI arteries, there was more collagen demonstrated by Sirius red histochemical staining in the NAD in DI compared to SI arteries particularly at days 3, 7 and 14 (Fig. 5). No substantial differences were seen between SI and DI arteries with respect to the distribution of proteoglycans.
3.2 Acute angiographic data
There were no differences seen between the SI and DI arteries following oversize balloon injury (Table 1). Specifically the immediate post-balloon MLD in SI arteries was 3.27±0.39 mm, while in DI arteries the MLD was 3.41±0.44 mm. The balloon-to-artery ratio was also similar between SI and DI arteries suggesting a comparable degree of oversize injury.
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3.3 Changes in arterial dimensions
Image analysis was used to measure the LA and EEL area. Lumenal narrowing was seen following SI and to a lesser degree following DI. In SI arteries, the maximum LA was seen at day 3 while the minimum LA was seen at day 14. In SI arteries the mean LA decreased from 5.06±2.12 mm2 at day 3 to 1.41±0.30 mm2 (p=0.01) at day 14 representing a mean loss of 3.65 mm2 (72% reduction in area) (Fig. 7). The loss of LA was due to both an increase in I+M area as well as a decrease in EEL area, but these factors appeared to be operating at different time intervals. Between days 3 and 7, an increase in I+M area (Fig. 9) was responsible for the majority of lumenal narrowing while a significant decrease in EEL area occurred primarily between day 7 and 14 (Fig. 8). Nevertheless, contracture of the EEL area was responsible for 67% of the loss of LA decreasing from 6.58±2.32 mm2 to 3.29±0.34 mm2 (p=0.03) between day 3 and 14 respectively, representing a mean loss of 3.29 mm2. No changes in LA, EEL or I+M area were noted beyond day 14.
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Double injured arteries also demonstrated loss of LA. The maximum LA was seen at day 3 (2.72±0.71 mm2) while the minimum LA was seen at 14 (1.49±0.51 mm2; p=0.03) (Fig. 7). During the same interval, there were no changes in the EEL area (Fig. 8) and therefore the loss of LA was entirely due to increases in I+M area (Fig. 9).
3.4 Neoadventitial formation
There were no changes seen in the adventitia of normal control arteries over time. The first compartment to undergo an increase following oversize balloon injury in SI arteries was the adventitia and this occurred prior to the development of arterial contracture. The NAD area expanded to 2.22±1.65 mm2 at day 3 (p=0.02 vs. controls) but no further growth was noted over time (Fig. 10). The NAD was also the first compartment to increase in the DI group and although the difference was not statistically significant, the area tended to be larger in DI compared to SI arteries at day 3 (2.22±1.65 vs. 6.40±3.96 mm2; p=0.09) as well as at later time points. As in the SI arteries, no further changes in the area of NAD occurred over time. Despite this increase in NAD no changes in EEL area was observed in the DI group.
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3.5 Morphometric correlations
In SI arteries, the LA correlated with the area of the EEL (r=0.69, p=0.003) but it did not correlate with the I+M area (r=–0.16, p=0.56). Furthermore, the I+M area also correlated with the EEL area (r=0.60, p=0.01). These data suggest that the area of the EEL rather than the growth of the neointima determine LA in SI arteries. In contrast, the LA of DI arteries did not correlate with EEL area (r=0.33, p=0.2). However, there was a strong positive correlation between I+M area and EEL area (r=0.92, p<0.001).
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4 Discussion |
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From this experiment, we conclude that the predominant mechanism for lumenal narrowing following SI of a normal artery is contracture while increases in the I+M play a less significant role. However, the process of contracture does not occur ubiquitously following balloon injury. In DI contracture does not occur and lumenal narrowing is therefore dependent on increases in the area of the I+M. Accumulation of mass in the NAD appears to be the earliest change in the vessel wall following balloon injury and occurs with both SI and DI. The growth of the NAD area precedes the development of arterial contracture in SI arteries and ultimately may be responsible for this process. However, in DI arteries the presence of a pre-existing fibrotic NAD appears to act like a ‘biological stent’ and attenuates arterial contracture despite further increases in NAD area. In both SI and DI arteries, the growth of the NAD precedes increases in I+M area.
Arterial remodeling has been previously recognized as an important process in atherosclerosis [17–20]. More recently, Mintz et al., using serial intravascular ultrasound examinations in humans undergoing coronary angioplasty, have demonstrated that the late lumen loss following angioplasty is primarily due to arterial contracture rather than neointimal growth [20]. Several, but not all, investigators using various animal models of arterial injury have also suggested that the late lumen loss following balloon injury is primarily due to arterial ‘remodeling'. Interestingly, in both human studies and the various animal models of arterial injury, approximately two-thirds of the late lumen loss appears to be due to arterial contracture while the remaining third is due to intimal growth [20, 22, 23]. We observed similar results in our single injury experiment in which 68% of the late lumen loss was due to contracture of the EEL area while growth in the I+M accounted for the remainder of the loss.
Although other investigators have described arterial contracture in animal models of vascular injury, the time course for this process has not been clearly delineated. In our study, arterial contracture occurred primarily between day 7 and 14 following SI. During this time interval, abundant collagen deposition and -actin immunoreactive cells are present in the NAD suggesting that these structural changes may be responsible for arterial contracture. Our data is consistent with others but more clearly identifies the time interval for vascular contracture. Kakuta et al. using a hypercholesterolemic rabbit model observed arterial contracture by 4 weeks but earlier time points were not examined [22]. Andersen et al. using a porcine coronary injury model found no change in LA between week 2 and 4 [21]. Recently, Geary et al. [28]observed that following angioplasty in atherosclerotic iliac arteries of non-human primates, both lumen and EEL areas returned to baseline by 7 days [29]. Although the time interval for contracture is longer in our study, this may be due to differences in species and the use of an atherogenic diet in the monkeys that were studied by Geary et al. [28]. The delineation of the time course for remodeling may have important therapeutic implications since the application of an ‘anti-contracture’ agent may be required for a prolonged period of time following an intervention but not indefinitely.
The mechanism of arterial contracture remains unclear [25]. Acute elastic recoil has been proposed by some investigators but appears to be limited to the first 24 h following angioplasty [30–34]. While the vascular response to changes in flow and shear stress may be very important determinants of remodeling, the structure of the vessel wall is likely an important pre-determinant of how an artery might respond to injury [35–37]. In SI arteries, in which there is no previous injury, significant arterial contracture is observed. However, in DI arteries the adventitia is thickened and a neointima is present prior to the second injury and no significant contracture is observed. The earliest changes in the vessel wall following balloon injury are seen in the adventitia where a significant increase in mass is observed by day 3 in both SI and DI arteries. As also demonstrated by Scott et al. and Sci et al., many of the neoadventitial cells are myofibroblasts that are capable of collagen synthesis and tissue contraction as seen in wound healing [12, 13]. Therefore, it is interesting to postulate that myofibroblasts of the NAD may be responsible for arterial wall contracture following balloon injury. Our data would support this hypothesis since significant expansion of the adventitia is seen early at day 3 and proceeds the period of arterial contracture in SI arteries. However in DI arteries, there is also an increase in the area of the adventitia as well as the number of -actin smooth muscle cells but no significant contracture is observed. In fact, the area of the NAD in DI arteries is significantly larger than SI arteries at most time points and therefore more contracture should occur. Additional differences in the architecture of the vessel wall of SI and DI likely account for the differences in ‘remodeling'. For example, an artery's inability to undergo compensatory enlargement may be finite and once a critical degree of vessel wall thickening has been reached further expansion is impossible. Lafont et al. also found no correlation between adventitial growth alone and arterial contracture [25]. They hypothesized that changes between the relative sizes of the I+M and adventitia favoring a larger adventitia may result in contracture. Other investigators have also demonstrated that balloon injury results in growth of the adventitia and have suggested that it may play a role in arterial remodeling [12, 13]. Perhaps future studies aimed at attenuating neoadventitial formation after balloon injury may help uncover the mechanism(s) by which this arterial layer may contribute to remodeling.
The results of the present study may help to reconcile some of the debate regarding the role of arterial contracture in restenosis following balloon angioplasty. Gertz et al. suggested that arterial contracture was not the principal process in restenosis using an atherosclerotic rabbit model while several other investigators, including ourselves, have found that it is likely the predominant mechanism for lumenal renarrowing, at least after first injury [21–25, 29]. The current study demonstrates that arterial contracture does not occur in all cases and in our study appears to be attenuated in arteries with significant adventitial fibrosis. Therefore, the group of arteries included in the study by Gertz et al. may simply have been more ‘diseased’ and unable to contract, similar to the DI arteries in our experiment. Also the variation in remodeling observed by Mintz et al. may be due to a different ‘disease-state’ of the initial lesion, such that, concentrically diseased vessels may not be able to change dimensions while contracture may be seen in vessels with less plaque burden [20]. Pasterkamp et al. also noted that arterial remodeling in the femoral artery varied among individuals and suggested that there may be a relationship between remodeling and lesion eccentricity [38].
Our study is not without limitations. As with any animal model, direct extrapolation to human coronary arteries with advanced, complicated atherosclerosis that has developed over years may not be appropriate. Also, the lack of follow-up angiography in this study did not allow for serial examinations of the arterial lumen in the same animal. Despite examining a minimum of ten cross-sections per arterial segment, lesion morphology likely varies along the length of the injury and therefore the selected segments are not always representative of the entire injured segment.
In summary, late lumen loss following single oversize balloon injury is primarily caused by contracture while the growth of the I+M appears to play a lesser role. The degree of lumenal narrowing following repeat balloon injury is less pronounced than that of SI arteries and is primarily due a modest growth of I+M without arterial contracture. Therefore, in arteries with no pre-existing disease, the early development of a NAD is associated with arterial contracture and significant lumenal narrowing. However, once significant circumferential adventitial fibrosis has occurred repeat balloon injury fails to result in further contracture despite further increases in NAD. These data suggest that architectural changes in the vessel wall and specifically in the adventitia appear to be important determinants of arterial contracture. Further study of the biology of the adventitia will be important for understanding the mechanisms involved in remodeling and restenosis.
Time for primary review 24 days.
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Acknowledgements |
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This work was supported in part by grants NA3089, NA2915, and B3154 of the Heart and Stroke Foundation of Canada and the J.P. Bickell Foundation. E. O'B. is a research scholar of the Heart and Stroke Foundation of Canada. K.P. is a research fellow (Pe-598/1-2) of the Deutsche Forschungsgemeinschaft (DFG) of Germany. We are also indebted to Dr. Lyall Higginson for his support and critical review of the manuscript. The authors would also like to thank Valerie Duffin for her secretarial assistance and the Animal Care workers at the University of Ottawa Heart Institute for their expert care.
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