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Ann Thorac Surg 2002;74:1161-1166
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Gene transfer to coronary artery bypass conduits

Cynthia K. Chiu-Pinheiro, MDa, Timothy O’Brien, MD, PhDb, Zvonimir S. Katusic, MD, PhDb, Luis F. Bonilla, MDc, Chad E. Hamner, MDc, Hartzell V. Schaff, MDc*

a Divisions of Endocrinology, Metabolism, Nutrition and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
b Division of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA
c Division of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota, USA

Accepted for publication May 29, 2002.

* Address reprint requests to Dr Schaff, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Gene therapy is a rational approach to prevention of stenosis in saphenous vein grafts used as conduits for coronary artery bypass grafting. To explore this possibility we developed methods for adenoviral-mediated gene transfer to canine saphenous veins.

Methods. During a single procedure, autogenous canine saphenous vein segments were transduced ex vivo and used as coronary artery bypass grafts. The proximal end of each vein was ligated, adenovirus containing the Escherichia coli ß-galactosidase gene (Ad.CMVLacZ) was delivered at titers of 2.5 x 109 or 5 x 109 plaque-forming units (pfu)/mL to the lumen through a distal heparin lock, and the segment was immersed in the viral solution for 1 hour at 37°C. Control segments were exposed to diluent alone in an identical manner. Aortocoronary anastomoses were made using cardiopulmonary bypass. Transgene expression was assessed qualitatively and quantitatively after 3 days.

Results. ß-Galactosidase levels showed a dose-dependent increase: 0.00 ± 0.00 ng/mg total protein for controls; 5.60 ± 2.27 ng/mg total protein for a viral titer of 2.5 x 109 pfu/mL and 11.97 ± 6.14 ng/mg for 5 x 109 pfu/mL. The two dosage groups differed significantly from each other (p = 0.035) and from controls (p = 0.003). X-gal staining demonstrated mostly endothelial and scattered adventitial transgene expression.

Conclusions. Transgene expression after ex vivo gene transfer into saphenous vein grafts in a canine coronary artery bypass model indicates that this method may be useful for delivery of therapeutic genes to prevent or retard vein graft arteriosclerosis.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
The greater saphenous vein is the most common conduit for coronary artery bypass grafting. However, saphenous vein bypass grafts used for coronary revascularization have occlusion rates of 19% at 1 year, 25% at 5 years, and 50% at 12.5 years postoperatively [1]. Arterial grafts have 5-year patency rates of more than 90% [2], but complete revascularization is not always possible with arterial grafts, and the majority of patients undergoing coronary artery procedures receive one or more saphenous vein grafts [3].

Aside from technical failure, luminal thrombosis with or without intimal hyperplasia is the most common mechanism of early occlusion of saphenous vein coronary artery bypass grafts [2, 4]. Vein graft atherosclerosis is the main cause of failure after the first postoperative year. Some investigators believe that early thrombus deposition in saphenous vein grafts is a substrate for later development of atherosclerotic narrowing [5–7]. Several approaches to prevention of thrombus formation in saphenous vein grafts have been explored, including the use of antiplatelet drugs [8–10] and systemic anticoagulation [11]. Systemic therapy with antithrombotic drugs is only partially effective. Its disadvantages are the need for chronic administration and the occurrence of side effects. Our laboratory studies have focused on methods of augmenting production of antithrombotic and antiproliferative molecules from vein grafts by adenoviral-mediated gene transfer to protect grafts from intimal hyperplasia.

Adenoviral vectors have several properties that are advantageous for vascular gene transfer. These vectors can accommodate large cDNA inserts and can be prepared in high-titer stocks. Adenoviruses can also insert and express foreign genes in quiescent cells such as endothelial cells, and their genomes remain separate from the host cell DNA [12]. These vectors have theoretical and practical limitations; for example, duration of gene expression is limited to several weeks [13]. However, transient gene expression may be well suited to vascular therapies requiring expression of a gene product for a short time [14].

Previous studies have shown the feasibility of adenoviral-mediated gene transfer in interposition vein grafts in the peripheral circulation. This approach has been used successfully for transfer of soluble vascular cell adhesion molecule into porcine carotid interposition jugular vein grafts [15]. Huynh and colleagues [16] have shown that perioperative adenoviral-mediated ß-adrenergic receptor kinase-1 (ßARK-1) transduction of rabbit carotid interposition jugular vein grafts markedly attenuates development of intimal hyperplasia. We have performed genetic modification of human coronary artery bypass grafts ex vivo with adenovirus containing the Escherichia coli ß-galactosidase (LacZ) and bovine nitric oxide synthase genes and have demonstrated increased gene product production [17–20].

Although adenoviral gene transfer has been shown to be possible in interposition vein grafts, we believe that these results cannot be extrapolated to coronary artery bypass grafts, which are exposed to different hemodynamic forces [21] and have special time constraints regarding vein harvest and transduction. The present study evaluates the use of an adenoviral vector to introduce the LacZ reporter gene into canine saphenous vein coronary artery bypass grafts.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Animals
Five male, adult mongrel purpose-bred dogs were used for the surgical procedure. An additional 3 dogs served as controls. The Institutional Animal Care and Use Committee of the Mayo Foundation reviewed and approved the care of all animals in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1996). Handling of recombinant adenovirus was approved by the Biosafety Committee of the Mayo Foundation in accordance with the "Guidelines for Research Involving Recombinant DNA Molecules" published by the National Institutes of Health (National Institutes of Health publication 59FR34496, amended 1995).

General anesthesia was induced in each dog with thiopental (5 mg/kg) and maintained by halothane inhalation and pancuronium infusion. A cuffed endotracheal tube was placed, and animals were mechanically ventilated.

Operative procedures
The greater saphenous vein was harvested from each hindlimb, distally cannulated, and proximally ligated. Excised graft segments were infused with 500 µL of phosphate-buffered saline with albumin containing recombinant adenovirus encoding E. coli ß-galactosidase [18] (Ad.CMVLacZ) at titers of 2.5 x 109 plaque-forming units (pfu)/mL or 5.0 x 109 pfu/mL to a distension pressure of approximately 75 mm Hg, submerged in the viral solution, and incubated at 37°C for 1 hour [16, 22–24]. The hindlimb wounds were closed in layers.

After standard sterile preparation, the heart was exposed through a left thoractomy, and heparin (300 U/kg) was administered. Cardiopulmonary bypass was established with a venous cannula inserted through the right atrial appendage, and arterial flow was provided through the right femoral artery. Cardiopulmonary bypass was maintained at normothermia for the duration of the operative procedure. Heart motion was controlled by induced fibrillation [25], and distal vein graft-to-coronary anastomoses were facilitated by local snaring of the coronary artery proximal and distal to the anastomotic site. Before implantation, the reversed saphenous vein grafts were rinsed with normal saline; end-to-side anastomoses were made to the left anterior descending artery and the circumflex coronary artery with a continuous 7-0 Prolene (Ethicon, Somerville, NJ) suture. The distal location of the treated grafts was alternated in successive animals. After completion of the distal anastomoses, the heart was defibrillated and proximal aortocoronary anastomoses were made with an aortic partial occlusion clamp and a continuous Prolene suture. The aortic clamp was then released, and the left anterior descending and circumflex coronary arteries were ligated proximally to the anastomoses. Cardiopulmonary bypass was discontinued, the cannulas were removed, and the thoracic and femoral wounds were closed in layers. Each dog was euthanized 3 days after bypass grafting, at which time the conduits were harvested.

Saphenous veins were harvested from the hindlimbs of the 3 control dogs. These control vessel segments were incubated in phosphate-buffered saline with albumin alone for 1 hour at 37°C, incubated in organ culture for 3 days, and then analyzed.

Gene expression
Five-millimeter vessel segments were mounted on silicone-coated dissection plates or placed in cryoform embedding medium (International Equipment, Needham, MA), sectioned to 5-µm thickness, and fixed in paraformaldehyde for 30 minutes. Histochemical staining for ß-galactosidase expression was then performed by exposure to 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside (X-gal, GIBCO BRL, Grand Island, NY) reagent at 37°C for 4 hours.

Histology
The grossly mounted, X-gal-stained vessel segments were fixed in formalin and embedded in paraffin. Standard glass slides were prepared by sectioning the samples in transverse orientation. These sections were counterstained with eosin.

Gene product quantification
Vessel segments were homogenized in 100 mmol/L potassium phosphate, 0.2% Triton-X (Sigma, St. Louis, MO), 200 mmol/L phenylmethylsulfonyl fluoride, and 0.1% leupeptin buffer with a Polytron homogenizer (Kinematica, Lucerne, Switzerland). Homogenates were centrifuged at 8,000 g for 10 minutes at 4°C. The supernatants were collected. After bicinchoninic acid protein assay (Pierce, Rockford, IL) for total protein, the supernatants were assayed for ß-galactosidase activity with a ß-galactosidase enzyme-linked immunosorbent assay kit (5 Prime->3 Prime, Boulder, CO). Enzymatic activity was measured in duplicate with a Spectromax Plus microplate reader and a System 3 Scanning Spectrofluorometer (Molecular Devices, Sunnyvale, CA). The results were subtracted from background activity, compared to a standard curve generated by a ß-galactosidase standard, and normalized to total protein.

Statistical analysis
The results for each group are expressed as the mean ± standard error of the mean. Analysis of variance was performed to evaluate overall differences among the three groups. If a significant overall difference existed, the Fisher protected least significant difference test was used for post hoc pair comparisons (StatView). P values of less than 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
ß-galactosidase expression and histology
Endogenous ß-galactosidase expression was not detected in control canine saphenous vein segments. In saphenous vein grafts transduced with Ad.CMVLacZ, staining for ß-galactosidase showed localized transgene expression in the endothelium, with scattered expression in the adventitia (Fig 1). Qualitatively less staining was visible in the segments exposed to 2.5 x 109 pfu/mL of adenovirus than in those exposed to 5 x 109 pfu/mL (Fig 2).



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  		Fig 1. Saphenous vein grafts harvested 3 days after gene transfer of Ad.CMVLacZ. (A) Adventitial and (B) endothelial transgene expression at 2.5 x 109 pfu/mL. Dose-dependent increase in (C) adventitial and (D) endothelial expression at 5 x 109 pfu/mL. Expression appeared to be greater on the luminal surface. (X-gal stain; magnification, x10.)

 


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  		Fig 2. Microscopic evaluation of saphenous vein graft with eosin counterstaining. (A) No staining for ß-galactosidase in a control specimen. In contrast, histologic staining demonstrates dose-dependent localization of ß-galactosidase to luminal endothelial cells 3 days after Ad.CMVLacZ transduction at (B) 2.5 x 109 pfu/mL and at (C) 5 x 109 pfu/mL. (Magnification, x40.)

 
ß-galactosidase quantification
Levels of ß-galactosidase in control vein segments and transduced grafts are shown in Figure 3. One-way analysis of variance showed a significant overall difference in LacZ gene expression of F = 8.144 (p = 0.008). Post hoc comparisons revealed that production of ß-galactosidase was significantly greater in grafts incubated in 5 x 109 pfu/mL of Ad.CMVLacZ (11.97 ± 6.14 µg/mg total protein) than in grafts incubated in 2.5 x 109 pfu/mL (5.60 ± 2.27 µg/mg total protein) (n = 5) (p = 0.035). ß-Galactosidase levels were also significantly greater in the transduced grafts than in the control vessels (0.00 ± 0.00 µg/mg total protein) (n = 3) (p = 0.003).



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  		Fig 3. ß-Galactosidase (B-gal) protein levels in canine saphenous vein coronary artery bypass grafts transduced with the lacZ gene. Saphenous vein grafts were exposed to phosphate-buffered saline with albumin (PBSA) as a control or to Ad.CMVLacZ at 2.5 x 109 pfu/mL or 5 x 109 pfu/mL and were measured for ß-galactosidase protein 3 days postoperatively. *Significantly different from each other and from phosphate-buffered saline with albumin controls (p < 0.05).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Other investigators have proposed genetic manipulation strategies to intervene in the mechanisms of vein graft atherosclerosis in interposition vein graft models. Bai and colleagues [24] demonstrated the feasibility of transduction of rabbit carotid interposition external jugular vein grafts by using the hemagglutinating virus of Japan-liposome method. Their studies showed that staining of the reporter gene product was still present in medial and adventitial tissue after 14 days. Other researchers have suggested therapies to inhibit the development of vein graft intimal hyperplasia and subsequent vein graft failure. Davies and colleagues [26] found that intimal hyperplasia was decreased by 37% with gene transfer of the G{gamma}ß inhibitor ßARK-1 using plasmid DNA as compared with controls 28 days after carotid interposition external jugular vein grafts in rabbits. Mann and colleagues [23] altered gene expression using antisense oligodeoxynucleotide blockage of the expression of proliferating cell nuclear antigen and cell division cycle 2 kinase by the hemagglutinating virus of Japan-liposome transduction technique to rabbit carotid interposition jugular vein grafts. This redirected vein graft biology away from neointimal hyperplasia and toward medial hypertrophy and increased the resemblance of the conduits to normal arteries. These arterialized grafts also proved resistant to accelerated vein graft atherosclerosis. More recently, the same group observed that gene therapy with a decoy oligonucleotide that binds and inactivates the cell cycle transcription factor E2F attenuated vein graft failure in human infrainguinal arterial bypass vein grafts [27]. At 12 months, fewer graft occlusions, revisions, and critical stenoses were seen in the E2F decoy-treated group than in untreated controls.

The importance of our study lies in demonstration of the feasibility of ex vivo gene transfer to saphenous vein grafts with an adenoviral vector in a canine coronary artery bypass model within the time constraints of an operative procedure. Our data on localization and dose dependence of transgene expression were consistent with data previously reported for other vein graft models. The distribution of transgene expression at 3 days in our study supports data reported by Kupfer and associates [28], which indicated mostly endothelial and subintimal expression in a nearly identical gene transfer technique for rabbit carotid interposition jugular vein grafts. The discrepancy between these findings and those of Chen and colleagues [15], who showed staining of both the luminal surface and the adventitia, might be explained by the lack of intraluminal pressure designed in that group’s gene transduction technique for porcine carotid interposition jugular vein grafts [16].

We found excellent transgene expression, although our grafts were incubated in solutions with viral titers that were twofold less than those used by Chen and colleagues [15]. Use of lower doses of adenoviral vector may avoid some of the inflammatory response that can be associated with this method of gene transfer. Channon and colleagues [29] suggested that in vivo adenoviral gene transfer with viral titers greater than 4 x 109 pfu/mL increases the acute inflammatory response without increasing transgene expression in normal rabbit carotid arteries. Schulick and associates [30] additionally found that acute adenovirus-associated tissue toxicity is significantly increased after infusion of a viral titer of 1 x 1011 into injured rat carotid arteries. In contrast to these studies, our grafts did not demonstrate any inflammatory infiltrate, even at higher viral titers. This phenomenon may be explained by interspecies differences in inflammatory reactivity to the adenovirus, which supports the need for additional investigation with these techniques in larger animal models before human application. However, we also acknowledge that the absence of inflammation at the time point studied does not completely negate the possibility of adenoviral-mediated inflammation occurring at later time points.

In conclusion, adenoviral-mediated gene transfer appears to be a promising strategy for delivery of potentially therapeutic genes to coronary artery bypass saphenous vein grafts. These experiments document the ability of adenoviral transduction to augment transgene production in coronary artery bypass grafts. The short duration of adenoviral vector gene expression, limited to several weeks [13], is a clinically relevant time frame for the prevention of early thrombosis and may prevent subsequent vein graft failure.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank William J. Anding, Marilyn R. Oeltjen, Sharon A. Stephan, Rebecca M. Wilson, and Tyra A. Witt for their technical assistance. This study was supported by a gift from Mr. and Mrs. Tomas Furth, the Mayo Molecular Medicine Research Award, and research grant HL58080 (TOB) from the National Institutes of Health.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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