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(Circulation. 1996;94:1741-1745.)
© 1996 American Heart Association, Inc.

Articles

Influence of External Stent Size on Early Medial and Neointimal Thickening in a Pig Model of Saphenous Vein Bypass Grafting

Mohammad Bashar Izzat, MD, MCh, FRCS; Dheeraj Mehta, FRCS; Alan J. Bryan, DM, FRCS; Barnaby Reeves, DPhil; Andrew C. Newby, PhD; Gianni D. Angelini, MD, MCh, FRCS

the Bristol Heart Institute (M.B.I., D.M., A.J.B., A.C.N., G.D.A.) and Research and Development Support Unit (B.R.), University of Bristol, Bristol, UK.

Correspondence to Prof Dr G.D. Angelini, British Heart Foundation, Professor of Cardiac Surgery, Bristol Royal Infirmary, Bristol BS2 8HW, UK.

	Abstract

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Background Late saphenous vein graft failure results from intimal and medial thickening due to migration and proliferation of vascular smooth muscle cells and superimposed atheroma. These changes may represent an adaptation by the vein to its insertion into the arterial system. Using a porcine model of arteriovenous bypass grafting, we recently demonstrated that supporting the graft with a nonrestrictive external Dacron velour stent significantly reduced intimal hyperplasia and total wall thickness. In the present study, we investigated the influence of different external stent sizes on graft wall dimensions and cell proliferation.

Methods and Results Three stent sizes were tested: mildly restrictive, nonrestrictive, and oversized (5, 6, and 8 mm in diameter, respectively). Four weeks after grafting, total wall thickness was decreased 40% by 5-mm stents (P=.02), 66% by 6-mm stents (P=.0004), and 81% by 8-mm stents (P=.02 versus unstented grafts). Neointimal thickness was reduced almost 62% by 6-mm and 72% by 8-mm stents (both P=.01) but not by 5-mm stents. As a result, the encroachment of the intima into the lumen was reduced 70% by 6- or 8-mm stents (P=.02 and P=.01 versus unstented grafts, respectively). Both neointimal and medial cell proliferation were significantly reduced by all three stents compared with unstented grafts.

Conclusions External stenting of saphenous vein bypass grafts reduces early intimal and medial hyperplasia. Oversized stents give equally profound suppression of intimal thickening, obviating the need for precise size matching with the graft and greatly simplifying the surgical procedure.

Key Words: coronary disease • veins • grafts

	Introduction

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Late occlusion of autologous saphenous vein grafts occurs against a background of medial and neointimal thickening on migration and proliferation of smooth muscle cells and the later appearance of mature lipid-laden atherosclerotic plaques.¹ This vessel wall thickening may be regarded as an intrinsic adaptation of the vein to the increased wall tension, cyclic stretching, and high shear stress caused by the higher blood pressure and flow velocities in the arterial circulation.

Using our established porcine model of saphenous vein–into–carotid artery interposition grafting,² we demonstrated that supporting the vein graft with an external nonrestrictive Dacron (synthetic polyester textile fiber) velour stent significantly reduces intimal hyperplasia and total wall thickness. The aim of the present study was to investigate further the relation between stent size and the observed histological changes in vein grafts, since precise matching of stent size to the size of the graft would introduce significant practical obstacles into eventual clinical application.

	Methods

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Operative Procedure
Studies were performed with Large White pigs (n=30; weight, 20 to 25 kg), which received humane care according to the Home Office Animals (Scientific Procedures) Act of 1986.³ All animals underwent saphenous vein–into–carotid artery interposition grafting. Anesthesia was induced with ketamine (30 mg) and atropine (0.6 mg) administered intramuscularly. After endotracheal intubation, anesthesia was maintained with halothane and oxygen. Animals were allowed to ventilate spontaneously throughout the procedures. Heparin sodium (1 mg·kg^-1) was administered intravenously, and a single dose of 250 mg of benzyl penicillin was administered intramuscularly before skin incision.

A longitudinal incision was made on the outer aspect of the hind limb, and 10 cm of the vein was then dissected free of surrounding tissue using a "no touch" technique.⁴ All side branches were secured with a 6-0 Prolene ligature (Ethicon Inc). The vein was removed from the animal, rinsed in iso-osmotic sodium chloride solution (0.9 g·L^-1) containing 2 IU/mL heparin and 50 µg/mL glyceryl trinitrate, and stored in the same solution at room temperature (23°C) until needed. A segment of vein (ie, ungrafted vein) was pressure-fixed and processed as detailed below.

A longitudinal neck incision was made just medial to the sternomastoid muscle, the muscle was retracted laterally, and the common carotid artery was carefully dissected from the internal jugular vein and vagus nerve within the carotid sheath. A 3-cm segment of the common carotid artery was isolated between vascular clamps and excised, beveling the cut ends obliquely to 45°. The saphenous vein was cut to the appropriate length, reversed, and similarly beveled, and an end-to-end anastomosis of the vein to common carotid artery was carried out using a continuous 7-0 Prolene suture. The graft was de-aired through the suture line before the suture of the second anastomosis was tied; then, the vascular clamps were removed, and the graft was perfused at arterial pressure. For stented grafts, the vein segment was passed through the stent before completion of the distal anastomosis. A stent comprised a continuous VP1200 polyester Locknit tube externally supported with helically wound polypropylene (a generous gift of Vascutek Ltd, Inchinnan, Renfrewshire, UK). Three stent sizes were tested: 5-mm, 6-mm, and 8-mm diameter. To reduce the total number of animals required for the study, 10 animals received bilateral grafts: a nonstented (control) graft on one side and a stented graft with a 6-mm stent on the opposite side. The remaining 20 animals received one unilateral graft each; 10 were stented with 5-mm stents and 10 with 8-mm stents. The use of the distal or proximal portions of the vein for unstented or stented grafts was randomized. Hemostasis was checked, neck and leg wounds were closed with 2-0 polyglycolic acid sutures (Dexon, Davis & Geck, Gosport), and inhalational anesthetic agents were discontinued. Animals were extubated and, when in a satisfactory condition, returned to their pens and fed a normal chow diet.

After 4 weeks, each animal was anesthetized as before, the neck wound was opened, and the graft was identified. The carotid artery was transected distal to the graft, and absence of blood flow was taken to indicate graft occlusion. Each graft was removed, including 1-cm segments of the proximal and distal carotid arteries. The proximal carotid segment was cannulated with a syringe attached to a mercury manometer, the distal carotid segment was also cannulated, and the cannula was clamped. Fixative, consisting of 10% formalin in 0.1 mol·L^-1 sodium phosphate buffer, pH 7.3, was infused into the lumen of the vessel for 10 minutes at a pressure of 100 mm Hg.² Perfusion-fixed specimens were further fixed in the same solution for 24 hours and then dehydrated, cleared, and embedded in paraffin wax with their axis perpendicular to the cutting plane. Transverse (5-µm-thick) sections were cut at four different levels, mounted onto glass slides, stained with Alcian blue Miller's elastic stain, and counterstained with van Gieson's stain.

Histological Techniques
Morphometric Analysis
Vessel wall dimensions were measured by computer-aided planimetry with an Olympus BH-2 microscope with a color video camera head (JVC TK-870E), Victor V386A computer (Victor Technologies), and MicroScale TM/TC image-analysis system (Digithurst Ltd). The area enclosed by the endothelium defined the lumen, the area between the endothelium and the internal elastic lamina defined the intima, and the area between the internal and external elastic laminae defined the media. Luminal encroachment was defined as the percentage of the area enclosed by the internal elastic lamina occupied by the intima. Luminal, intimal, and medial perimeters and areas were computed using the luminal boundary and internal and external elastic laminae as delimiters, and mean values were then calculated for all sections from the same graft. Average intimal, medial, and total vessel wall thicknesses were derived from the area and perimeter data for five sections from each graft on the basis of an assumption that the sections consisted of circular profiles, which was valid because the tissues were fixed at normal perfusion pressures.

Immunocytochemistry and Cell Proliferation Analysis
The presence of cells progressing through the cell cycle was detected with immunocytochemistry for proliferating cell nuclear antigen (PCNA).^{5 6} From randomly selected formalin-fixed, paraffin-embedded tissue samples (five for unstented and each of the stent sizes), 5-µm-thick sections were cut onto 3-aminopropyl-triethoxy-silane–coated slides. These were left to dry overnight before being dewaxed in Histoclear and hydrated in graded alcohols. Microwave pretreatment with 0.1 mol/L citric acid for 10 minutes was performed, and slides were left to cool for 30 minutes before being rinsed in 0.05 mol/L Tris-buffered saline (TBS). Sections were then incubated with normal rabbit blocking serum for 20 minutes, followed by a 1-hour incubation with PCNA antibody (PC10, DAKO) diluted 1:400. A secondary biotinylated rabbit anti-mouse antibody (DAKO) was then used at a dilution of 1:500 for 30 minutes, and visualization was achieved through the streptavidin-biotin HRP Detection system. TBS was used as the washing buffer between each incubation, and 3,3-diaminobenzidine was used as the chromagen. A light counterstain with elastin stain and hematoxylin was applied to permit visualization of morphology.

For quantification of PCNA labeling, the total number of cells and the number of PCNA-positive cells were counted in both the intima and media in five microscopic fields of viewing with a Leica Laborlux S microscope and a 40x objective. The number of PCNA-positive cells was expressed as a proportion of the total cell number (PCNA index).

Statistical Analysis
The distribution of the planimetric data for medial and intimal thicknesses and luminal area was positively skewed and therefore transformed with the use of a square-root transformation to normalize the distributions before analysis. Comparison between control and 6-mm stent groups was carried out with a paired Student's t test. All other comparisons were carried out with unpaired Student's t tests.

	Results

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Morphometric Analysis
All grafts, stented or not, were patent 4 weeks after implantation. As illustrated in Fig 1 and summarized in Table 1, unstented and stented grafts, regardless of the stent size, had a similar total (lumen plus wall) cross-sectional area. This confirmed that none of the three stents significantly restricted the expansion of the vein graft in response to arterial pressure. There was a significant reduction in neointimal thickness compared with unstented grafts in the 6- and 8-mm stented grafts, although not in the 5-mm stented grafts (Tables 1 and 2). Indeed, the intimal thickness was significantly greater in the 5-mm stented grafts than in the 6- or 8-mm stented grafts (Table 2). There was, however, a significant reduction in medial thickness in each group of stented grafts compared with unstented grafts, with no difference in this reduction between the three stent sizes (Tables 1 and 2). As a result, the total wall thickness was significantly reduced in all of the stented grafts. The decrease in wall thickness from 0.77 mm in unstented grafts to 0.21 mm in 8-mm stented grafts corresponds to a decrease in wall cross-sectional area from 8.49 to 3.13 mm². There was a corresponding trend toward an increase in luminal area in stented compared with unstented grafts and with increasing stent size, although none of the comparisons between groups reached statistical significance (Table 2). Due to the large decreases in neointimal thickness and proportionally smaller increases in luminal area, the encroachment of the intima into the lumen was significantly reduced (P=.02 and .01, respectively) in either 6- or 8-mm stents (Table 1).

View larger version (123K): [in this window] [in a new window]   Figure 1. Histological appearance of (a) an ungrafted saphenous vein, (b) a representative unstented graft, (c) a representative stented graft with 5-mm stent, and (d) a representative stented graft with 8-mm stent (stent material removed before wax embedding). Closed triangles indicate the position of the internal elastic lamina; open triangles, the external elastic lamina. The scale bar represents 0.5 mm.

View this table: [in this window] [in a new window]   Table 1. Planimetry Results: Median Values and 95% Ranges for Unstented and 5-, 6-, and 8-mm Stented Grafts

View this table: [in this window] [in a new window]   Table 2. t and P Values for Pairwise Comparisons Between Planimetry Results of Unstented and 5-, 6-, and 8-mm Stented Groups

Immunocytochemistry and Cell Proliferation Analysis
PCNA-positive cells were rarely detected in ungrafted vein but were abundant in the media and the luminal aspect of the neointima of unstented grafts (Fig 2b). The percentage of PCNA-positive cells was reduced dramatically in each group of stented grafts (Fig 3). In contrast, PCNA labeling was frequently observed in the neoadventitia of both stented and unstented grafts (Fig 2b and 2c). The presence of microvessels penetrating the media of stented grafts was also noted in stented grafts (Fig 2c), but the microvessels were absent from the media of ungrafted vein or unstented grafts (Fig 2a and 2b). The luminal endothelial lining of all grafts, stented or not, was found to be intact through staining for Dolichos bifloros lectin (results not shown).

View larger version (123K): [in this window] [in a new window]   Figure 2. Immunocytochemistry for PCNA in (a) an ungrafted vein, (b) a representative unstented graft (note the presence of PCNA-positive cells in the neointima close to the luminal surface [long arrows]), and (c) a representative stented graft with 6-mm stent (note the presence of vasa vasorum [long arrows]). Closed triangles indicate the position of the internal elastic lamina; open triangles, the external elastic lamina. The scale bar represents 0.5 mm.

View larger version (26K): [in this window] [in a new window]   Figure 3. Distribution of PCNA indexes in unstented and 5-, 6-, and 8-mm stented grafts for (a) intima and (b) media (each n=5).

	Discussion

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Autologous saphenous vein continues to be one of the most widely used conduits for myocardial revascularization⁷ despite its disappointing long-term patency rate, with 50% of vein grafts occluded by 10 years after surgery.^{8 9} Late occlusion appears to result from both medial and neointimal thickening, caused by migration and proliferation of smooth muscle cells, and the late appearance of mature lipid-laden atherosclerotic plaques. These changes can compromise flow directly or promote thrombotic occlusion.^{1 10} Neither antiplatelet therapy nor avoidance of surgical preparative injury has been shown conclusively to eliminate medial and neointimal thickening in either experimental models or human vein grafts.^{1 2 8}

Vessel wall thickening may be regarded as an intrinsic adaptation of the vein to arterial pressure,^{1 10} and grafting per se was recently shown to stimulate the production of endogenous growth factors from pig saphenous vein, which may account for the platelet independence of graft wall thickening.¹¹ Factors that are potentially responsible for these changes include increased wall tension, cyclic stretching, and shear stress due to the higher pressure and flow velocities in the arterial circulation.^{12 13} Indeed, vein grafts develop medial wall thickening, which corresponds in its distribution to that of wall stress and appears to come to a halt when this stress is reduced to values similar to those of the grafted artery.^{10 14 15} In addition, an increase in the magnitude of cyclic deformation of a vein graft in vivo has been shown to result in accelerated myointimal hyperplasia.¹⁶

Support of the graft with an external stent has the theoretical potential to reduce or even eliminate wall stress and prevent the cyclic stretching of medial and endothelial cells, all of which might be expected to reduce wall thickening. However, placement of a nonporous or restrictive stent around vein grafts or native arteries has been shown to promote neointimal formation and reduce the final luminal size.^{17 18 19} The use of a nonporous Silastic cuff interrupts flow through the vasa vasorum and may provoke intimal thickening through hypoxia-induced increases in the production of growth factors.^{19 20} The diminished fluid efflux from the vessel wall due to increased wall thickness and disruption of vasa vasorum is likely to increase the effective concentration of such endogenously produced mitogens.^{19 20 21 22}

We previously used a microporous polytetrafluoroethylene tube to externally stent vein grafts in our pig model, and this stimulated neointimal thickening and reduced luminal size.²³ In contrast, our group recently demonstrated in the same pig model that external support of arteriovenous bypass grafts with nonrestrictive, highly porous Dacron velour stents significantly decreased smooth muscle cell proliferation and both medial and intimal thickening.²⁴ The results of this study confirm our previous findings. Taken together, our results imply that the structure of the stent material rather than the experimental model is crucial in determining the outcome. Dacron velour is a macroporous fabric material, which is therefore unlikely to restrict fluid outflow. Furthermore, loops of yarn from the velour extend out into the fibrous tissue layer, allowing physical binding of fibrous tissues to the fabric and stimulating capillaries to traverse graft interstices. One possibility, supported by our histological observations, is that this particular stent material stimulates the development of an adventitial reaction and facilitates the formation of new vasa vasorum. These new vessels may improve smooth muscle cell oxygen and nutrient supply in the vessel wall. The ability of the stent to encourage the formation of adventitial vessels and reduce neointimal and medial thickening should increase fluid flux and thereby decrease accumulation of growth factors and lipoproteins in the grafts. Consistent with this hypothesis, local infusion of basic fibroblast growth factor into a rat model of carotid balloon angioplasty has been shown to stimulate the formation of vasa vasorum, which in turn reduced smooth muscle cell proliferation.²⁵

A second variable likely to influence the outcome of external stenting of grafts is the size of the stent. In previous studies,^{17 23} the use of a restrictive stent, although it somewhat reduced total wall thickness, promoted neointimal thickening and reduced final luminal size. This study was carried out to investigate systematically the effect of varying stent diameter on the reduction in wall thickening. Results with the 6-mm stent confirmed our previous data²⁴ showing a reduction in neointimal and medial thickening. In this study, all stented groups showed a significant reduction in medial thickening and cell proliferation that was independent of stent size; however, there appeared to be an inverse relationship between stent size and neointimal thickening. The differences between the 5-mm and the 6- or 8-mm stented grafts were highly significant and reproducible, even though for reasons of economy not all graft sizes were compared directly in the same pigs and therefore analyses had to be carried out with the use of multiple t tests rather than regression or ANOVA methods. The significantly lesser benefit in terms of neointimal thickening of the smaller stent size is consistent with the data obtained with similarly sized stents of other materials.^{17 23}

The equal efficacy of 6- and 8-mm stents in reducing neointimal and medial thickening, as demonstrated in the present study, indicates that it is not crucial to match the diameter of the graft and stent precisely. Oversized stents appear to favor equally profound suppression of intimal thickening. These results are of considerable surgical significance since they highlight the potential importance of oversizing the stent while greatly simplifying the surgical procedure if it were applied to humans.

The type of stenting material and procedure used here are readily applicable to human saphenous vein grafts. A decrease in intimal encroachment into the lumen in stented grafts would be expected to favor unrestricted flow and thereby reduce thrombotic occlusion. Decreased wall thickness also implies a reduced risk of lipoprotein and macrophage accumulation and therefore less vein graft atheroma. Longer-term experimental studies aimed at testing these predictions are in progress. The impact of this kind of stent on wall thickness and patency also needs to be tested directly in clinical studies.

	Acknowledgments

 
This work was supported by grants from the British Heart Foundation and The Garfield Weston Trust.

Received August 9, 1995; revision received March 28, 1996; accepted April 11, 1996.

	References

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