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Ann Thorac Surg 1998;66:1948-1952
© 1998 The Society of Thoracic Surgeons

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Original Articles

Sustained reduction of neointima with c-myc antisense oligonucleotides in saphenous vein grafts

^a Cardiovascular Research Center, Jefferson Medical College, Philadelphia, Pennsylvania, USA
^b Departments of Surgery and Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA

Address reprint requests to Dr. Mannion, Jefferson Medical College, 1025 Walnut Street, 607 College Building, Philadelphia, PA 19107
e-mail: (john.mannion{at}mail.tju.edu)

Presented at the Poster Session of the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Treatment of saphenous veins with c-myc antisense oligomers during preparation for grafting reduces medial cellular proliferation and macrophage infiltration, and preserves medial smooth muscle content at 3 days. Accordingly, the purpose of this study was to examine whether c-myc antisense oligomers have an impact on late vein graft remodeling.

Methods. Sixty-two pigs underwent unilateral saphenous vein-carotid artery interposition grafting. Harvested veins were incubated either in saline (control group) or 20-µmmol/L or 200-µmmol/L concentrations of c-myc antisense oligomers (treated groups) for 30 minutes intraoperatively. Three months after surgery, vein graft histology was assessed.

Results. Forty-five of 62 randomized animals survived the experiment; no differences in animal survival or graft patency among the groups were observed (p = NS, ²). C-myc antisense oligomers significantly decreased neointimal and wall thickness, as well as increased lumenal index, in treated groups (p < 0.04, p < 0.03, and p < 0.001, respectively, analysis of variance). In contrast, there was no difference in medial thickness or perivascular wound healing.

Conclusion. Intraoperative treatment of saphenous veins with c-myc antisense oligomers decreased neointimal formation at 3 months after grafting. In conjunction with our previous reports, these findings suggest that early inhibition of cellular proliferation and inflammatory infiltration results in a sustained reduction in neointimal formation and favorable graft remodeling.

	Introduction

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Prevention of vein graft disease remains an important therapeutic goal. The process of saphenous vein arterialization invariably induces remodeling responses, including the formation of neointima, which can lead to conduit disease and graft attrition. Although the neointima contributes to a normalization of wall stress [1], it also causes lumenal narrowing in up to 30% of patients within 18 months of surgery [2], and over the long-term, remains the substrate for accelerated graft atherosclerosis [3].

Neointima formation can be viewed as a result of a tissue response to injury, which invariably involves mesenchymal cell proliferation, migration, and extracellular matrix production. As a consequence of arterialization, the vein graft is subject to changes in its cytokine milieu [4], a vigorous inflammatory infiltration, and stimulation by abundant growth factors such as PDGF, bFGF, and TGFß, among others [5]. All of these events increase the expression of cell-cycle regulatory genes, which results in cell proliferation. Recent findings suggest a heterogeneous proliferative response, with fibroblasts, as well as smooth muscle cells, participating in vein graft repair [6]. Although cell proliferation represents only one aspect of the vascular response to injury, its inhibition has been shown to reduce early neointimal formation in arteries [7, 8] and vein grafts [9, 10]. In these studies, antisense oligonucleotides against different cell cycle regulatory genes or E2F decoy oligomers were used; however, the neointimal response was assessed no later than 6 weeks after application.

We chose to investigate the effects of antisense oligonucleotides complementary to the mRNA of c-myc because of their consistency in inhibiting the vascular response to injury [7, 11–13]. Recently, we reported the early effects of this treatment on vein graft repair; 3 days after grafting, c-myc antisense-treated veins demonstrated a sequence-specific and dose-dependent reduction of cellular proliferation and macrophage infiltration and a sequence-specific reduction of medial edema [13]. These findings notwithstanding, an important question remaining is whether a single intraoperative exposure of veins to c-myc antisense will result in a sustained reduction of neointima. The results of the present study demonstrated that intraoperative treatment of saphenous veins with c-myc antisense resulted in neointimal reduction 3 months after surgery.

	Material and methods

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Animal preparation
Sixty-two domestic swine (Sus scrofa) weighing between 14 and 47 kg underwent unilateral interposition carotid saphenous vein grafts, as described previously [13]. The animals were equilibrated for 3 days at the housing facility before surgery and pretreated with aspirin. After premedication with ketamine (20 mg/kg) and xylazine (4 mg/kg), the animals were anaesthetized with propofol (10 mg/kg/hour), and ventilated through an endotracheal tube with 100% oxygen. In aseptic conditions, and after administration of intravenous antibiotics (cefazolin, 1 g), the greater saphenous vein was harvested. Branches were secured with 7-0 sutures. No veins were distended. After administration of 5,000 units of heparin, carotid interposition grafting was performed, with the beveled ends of the vein anastomosed to the transected edges of the artery. After hemostasis was achieved and the incision closed, the animals were sent to a farm for a 3-month period. All animals were cared for in compliance with the "Principles of Laboratory Animal Care" formulated by the National Institutes of Health (NIH publication no. 85-23, revised 1985).

Oligomer preparation
Phosphorothioated oligomers complementary to the translation initiation region of the human c-myc gene were provided by Lynx Therapeutics (Hayward, CA). In previous studies, this sequence, 5'-AACGTTGAGGGGCAT-3', has been found to be effective in porcine tissues [11, 12].

Harvested saphenous veins were placed immediately in a room-temperature bath containing saline solution with varying concentrations of c-myc antisense (0, 20, or 200 µmmol/L, n = 21, 21, and 20, respectively). Surgeons unaware of group assignment then performed the procedures. The patency of each anastomosis was confirmed visually, and bath solution was then applied to the perigraft space.

Graft harvesting and tissue processing
Surviving animals were sacrificed after 3 months. Sedation was accomplished as described previously, and the animals were euthanized with an intravenous overdose of Euthasol (Delmarva Laboratory, Midlothian, VA). An extended midline neck incision was made and the operated common carotid artery was exposed at sites proximal and distal to the anastomoses. The artery was cannulated at either end and perfusion-fixed with HistoChoice tissue fixative (Amresco, Inc., Solon, OH) at 80 mm Hg for 1 hour. The vessels were then harvested en bloc, including approximately 5 mm of surrounding perivascular tissue and all adherent scar, cut into 5-mm lengths, and imbedded in paraffin.

Tissues were sectioned and histologic structures visualized with Verhoeff’s stain. All sections were examined, and the three demonstrating the greatest neointimal development were selected for immunohistochemistry. The Vectastain Elite ABC system (Vector Laboratories, Inc., Burlingame, CA) was used as previously described [6]. The primary antibodies we used were a monoclonal mouse DE-R-11 antibody recognizing intermediate filament desmin (1:50; Novocastra laboratory, UK) and a monoclonal mouse 1A4 antibody recognizing -smooth muscle actin (-SM actin, 1:100, Sigma Diagnostics, St. Louis, MO). The slides were incubated with biotinylated secondary horse anti-mouse immunoglobulin G (1:2000; Vector Laboratories) for 1 hour. They were then stained with diaminobenzidine tetrahydrochloride substrate kit (Vector Laboratories), followed by counterstain with Gill’s hematoxylin (Sigma Diagnostics). Positive control staining was performed on ungrafted porcine saphenous veins. Negative controls were prepared with nonimmune serum instead of primary antibody. Adjacent sections were stained with Verhoeff’s stain.

Morphometric measurements
An observer unaware of group assignment performed morphometric analyses on Verhoeff-stained sections. From each vessel, three blocks demonstrating the greatest neointimal development were selected for analysis. Four quadrants from each section were measured, each representing an area separated from the others by 25% of the total vessel circumference. The selected fields were then digitized using a Sony DXC-750 MD video camera (Sony Corporation, Tokyo, Japan) attached to a Nikon Optiphot-2 microscope (Nikon, Inc., Melville, NY). A computerized image analysis program (Media Cybernetics, Silver Spring, MD) was used for all morphologic measurements. After all fields had been imaged, the total wall thickness, defined as the distance between the external elastic lamina and the lumen, and neointimal thickness, defined as the distance between the lumenal limit of smooth muscle and the lumen, were measured at three locations in each quadrant. We calculated the medial thickness as the difference between the wall thickness and the neointimal thickness. The resulting 12 measurements (three measurements per quadrant, four quadrants per section) were averaged to give a mean value for each section (one of three measured for each graft). The ratio of intima to media was calculated by dividing the intimal thickness from each measurement by the associated medial thickness.

The lumenal area was calculated by digitizing each section with a 35-mm slide scanner and histologic slide adapter (Polaroid, Paramus, NJ). Measurements were performed using a computerized image analysis program (Media Cybernetics). The lumenal index was calculated by dividing the calculated lumenal diameter by the total wall thickness.

Quantification of muscle cell content
We used the three desmin-stained slides representing sections with the greatest neointima from each graft to analyze the smooth muscle content. Selection of four quadrants and digitization of the images was performed as described previously. The area staining positively for desmin was quantified and expressed as a percentage of the wall thickness area, similar to a method described previously [14]. Myofibroblast content in the perivascular space was assessed qualitatively with -SM actin stains.

Data analysis
Numerical data are presented as a mean ± standard error. To detect differences between the groups by morphometric methods and protein quantification, we performed an analysis of variance (ANOVA), evaluating each section as a separate data point. A postANOVA Bonferroni correction was applied, where appropriate. To detect differences in patency and rupture rates, we performed a ² analysis corrected for multiple group comparisons.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Surgical outcomes
The animals (n = 62) were randomized into three groups: 0 µmmol/L (ie, control), 20 µmmol/L, and 200 µmmol/L treatment with c-myc antisense. Two animals died of anesthetic complications, one because of technical error, and one was sacrificed early because of a wound infection. Five of the six deaths of the 0-µmmol/L group, three of the five deaths in the 20-µmmol/L group, and five of the six deaths in the 200-µmol/L group were secondary to vein graft rupture, an average of 5 days after surgery (range, 3 to 10 days). There was no difference in the rupture rate of the vein grafts in the 0-µmmol/L– (24%), 20-µmmol/L– (14%), or 200 µmmol/L– (25%) treated vessels (p = NS, ²).

Of the 45 harvested vessels, 32 (71%) were patent and 14 were occluded. Eighty-six percent of the vessels in the 0-µmmol/L group, 63% of the vessels in the 20-µmmol/L group, and 64% of the vessels in the 200-µmmol/L group were subjected to quantitative analysis. There was no significant difference in occlusion rates among the three groups (p = NS, ²).

Effects of c-myc antisense on graft remodeling
Representative Verhoeff-stained sections, illustrating the effects of c-myc oligomers on vein graft remodeling, are depicted in Figure 1 (control, n = 13; 20-µmmol/L group, n = 10; 200-µmmol/L group, n = 9). The antisense treatment resulted in a 28% reduction in neointimal thickness in the 20-µmmol/L (p < 0.01 versus controls) and a 29% reduction in the 200-µmmol/L group (p < 0.01 versus controls, ANOVA with Bonferroni correction; Fig 2). In addition, there was a significant reduction in the overall wall thickness for the two treated groups (22%, p < 0.005, and 23%, p < 0.01, ANOVA with Bonferroni correction; Fig 3). There was no difference in neointimal or wall thickness between the 20- and 200-µmmol/L–treated groups (p = NS). In addition, medial thickness was comparable among the three groups (Table 1).

View larger version (94K): [in this window] [in a new window]   Fig 1. Verhoeff-stained sections of representative grafts from the control (0 µmmol/L) and c-myc antisense groups (20 µmmol/L and 200 µmmol/L). Arrows indicate border between neointima and media. Magnification; x10, before _% reduction. (n = neointima; m = media).

View larger version (14K): [in this window] [in a new window]   Fig 2. Differences in neointimal thickness (µm) in varying treatment groups, measured in mean µm ± standard error of the mean. Control group, n = 13; 20-µmmol/L group, n = 10; and 200-µmmol/L group, n = 9.

View larger version (15K): [in this window] [in a new window]   Fig 3. Differences in wall thickness (µm) in varying treatment groups, measured in mean µm ± standard error of the mean. Control group, n = 13; 20-µmmol/L group, n = 10; and 200-µmmol/L group, n = 9.

View larger version (17K): [in this window] [in a new window]   Fig 4. Differences in intimal index (lumenal diameter/wall thickness), measured as mean ± standard error of the mean. Control group, n = 13; 20-µmmol/L group, n = 10; and 200-µmmol/L group, n = 9.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We have shown previously that ex vivo treatment of saphenous vein grafts with phosphorothioated c-myc antisense oligonucleotides significantly reduces cell proliferation, inflammatory cell infiltration, and medial edema at 3 days after grafting [13]. In this study, we present evidence that this treatment has sustained biologic effects that are apparent 3 months after surgery. Intraoperative treatment with c-myc antisense reduced neointimal and wall thickness and increased lumenal index. In contrast, c-myc antisense treatment did not suppress perivascular myofibroblast formation.

The principal finding of our study, that a single application of c-myc antisense exerts long-term biologic effects in arterialized saphenous vein grafts, is consistent with previous observations showing that intramural delivery of oligonucleotides produced sustained reduction in neointimal formation after coronary arterial injury [12]. Hence, sustained biologic effects occur, despite the possibility that c-myc antisense delivered as a single dose is likely metabolized within vascular tissue in a matter of days. There are several possible explanations for the observed long-term effectiveness of c-myc antisense oligonucleotides. The late reduction of neointima may be secondary to the inhibition of cells that proliferate early after vascular injury and are destined to migrate to the neointima [7]. In addition, prevention of cell activation within the graft may be accompanied by reduced synthetic function [12], which might reduce extracellular matrix production and therefore decrease the size of the neointima.

The decrease in neointimal formation may affect the longevity of saphenous vein grafts in several ways. First, the inhibition of neointima may reduce early attrition of venous grafts observed within the first several months after surgery [15]. Our findings are particularly noteworthy because saphenous vein grafts have been reported to lack the compensatory dilation more prevalent with chronic arterial remodeling [16, 17]. The inability of stiff arterialized venous conduits to enlarge their dimensions in response to neointimal formation points to the necessity of developing effective means to inhibit endoluminal events and preserve lumenal patency. Although a single ex vivo treatment with c-myc antisense reduced neointimal formation, no adverse effect on perigraft healing was observed, as evidenced by perivascular myofibroblast formation. Second, the reduction in neointimal formation may have an impact on later events, such as graft degenerative disease. Neointima has been considered a so-called soil for atherosclerosis because of its ability to retain atherogenic lipoproteins [3, 18]. It remains to be determined whether the observed quantitative changes in the remodeling of vein graft walls after treatment with c-myc antisense are accompanied by the changes in specific matrix components involved in the interactions with low-density lipoprotein and lipoprotein(a) that begin to accumulate early after vein grafting [18].

Several genes have crucial roles in the initiation and maintenance of cell cycle progression [19], including the protooncogenes c-fos, c-myc, and c-myb, which are upregulated after various forms of vascular injury. In particular, c-myc appears to be crucial for vascular cell replication, because most extracellular growth factors lead to its upregulation [20]. After vascular injury, c-myc reaches peak expression within the first few hours [21], making it a suitable target for the inhibitory effect of antisense oligonucleotides that are designed to hybridize with the target mRNA. Although the mechanism of action of antisense oligomers is likely more complex, also including nonantisense effects [22–24], there is an increasing number of reports on the efficacy of these compounds [8, 11, 12].

Treatment of vein grafts with c-myc antisense is attractive for several reasons. Because c-myc antisense can be applied ex vivo, possible systemic side effects are minimized; high concentrations can be delivered to the vein graft wall, and their use would not prolong surgery. We have elected to use naked DNA, because ex vivo vein exposure to oligomers for 30 minutes results in a rapid, uniform cellular uptake of c-myc antisense [13]. It is important to emphasize that the delivery of genetic material to vascular cells can be accomplished with several other techniques [9]. Further studies will be required to determine whether additional benefits can be derived from the use of various carrier systems.

It is unlikely that arterial grafts will entirely eliminate the saphenous vein as a bypass conduit, because most surgical patients demonstrate multivessel disease and require multiple grafts. All arterial operations are technically demanding and associated with an increased rate of certain complications [25]. Because saphenous vein grafting continues to have an important role in surgical revascularization, prevention of vein graft conduit disease remains a therapeutic challenge.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study was supported in part by grants from the NIH (HL 60672 and 55410) and Lynx Therapeutics, Hayward, California.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) 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 Add to Personal Folders Download to citation manager Author home page(s): John D. Mannion Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mannion, J. D. Articles by Zalewski, A. Search for Related Content PubMed PubMed Citation Articles by Mannion, J. D. Articles by Zalewski, A.