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Eur J Cardiothorac Surg 2003;24:92-97
© 2003 Elsevier Science NL

Prophylactic gamma radiation of unaffected vein grafts failed to prevent vein graft disease in a chronic hypercholesterolemic porcine model

^a Clinic for Cardiac Surgery, Medical University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany
^b Institute for Anatomy, University of Luebeck, Luebeck, Germany
^c Institute for Pharmacology, University of Luebeck, Luebeck, Germany
^d Institute for Radiation Therapy, University of Luebeck, Luebeck, Germany
^e Clinic for Anesthesiology, University of Luebeck, Luebeck, Germany

Received 23 December 2002; received in revised form 4 March 2003; accepted 17 March 2003.

^* Corresponding author. Tel.: +49-451-2108; fax: +49-451-2051
e-mail: janfelixchristiansen{at}gmx.de

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Limitations of the... 6. Conclusions References

 
Objective: The value of prophylactic brachytherapy on vein graft disease is unknown. Methods and results: Vein bypass grafts in 23 hypercholesterolemic pigs after ex vivo gamma irradiation of the vein grafts (10, 20, and 40 Gy) and 16 control veins were analyzed regarding: (1) expression of platelet-derived growth factor (PDGF-AA and -BB, ELISA); (2) smooth muscle cell (SMC) proliferation/cell death (double-immunohistochemistry Mib-1/TUNEL/SMC -actin); and (3) vessel wall dimensions. Planimetric data on vessel wall dimensions revealed no positive effect of gamma radiation on neointima formation and inner lumen diameter. On the contrary, vein grafts subjected to 40 Gy were significantly more likely to be occluded and to have reduced inner lumen and increased neointima formation. Radiation therapy had no effect on PDGF expression and SMC proliferation/cell death. The mean inner lumen diameter decreased as PDGF-AA expression increased. Conclusions: Prophylactic gamma radiation of unaffected vein grafts failed to prevent vein graft disease in a hypercholesterolemic porcine model. High-dose radiation (40 Gy) resulted in more frequent graft occlusion and vein sclerosis.

Key Words: Bypass • Veins • Atherosclerosis

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Limitations of the... 6. Conclusions References

 
Atherosclerosis frequently develops in saphenous-vein coronary artery bypass grafts, leading to occlusion rates of 30–40% 10–12 years after surgery. The fate of vein graft occlusion depends on many factors: technical faults in harvesting, handling and fashioning the grafts, thrombosis, myointimal hyperplasia, fibrosis, and rapid progression of atherosclerosis. Early neointimal hyperplasia, defined as the accumulation of smooth muscle cells (SMCs) and extracellular matrix, is the major underlying mechanism of vein graft disease. Initially, medial SMCs proliferate and migrate into the intima, with subsequent further proliferation (for review, see Ref. [1]). Neointimal hyperplasia, an important component of the occlusive mass of atherosclerotic plaques in vein graft disease, is mediated by various growth factors. One of the key mediators is platelet-derived growth factor (PDGF). External stenting of vein grafts is associated with a significant reduction of neointimal formation and PDGF expression [2]. Early vein graft disease shares similarities with balloon vascular injury of diseased or normal arteries [1].

Randomized, placebo-controlled clinical trials have shown that adjunct brachytherapy reduces in-stent restenosis after primary coronary interventions [3]. The underlying mechanism of neointimal reduction may be related to reduced SMC proliferation rates, increased cell death rates, or both [4].

Brachytherapy may positively affect the unresolved problem of vein graft disease. More recently, intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts has been shown to be effective [5]. External irradiation of proliferating healthy veins before implantation can be performed quickly and easily, even in the operating room. These considerations prompted us to examine whether acute brachytherapy of fresh vein grafts implanted in the arterial circulation can inhibit development of neointimal hyperplasia, with subsequent improved graft patency. We, therefore, studied how external gamma radiation affected vein grafts in a chronic hypercholesterolemic porcine model with regard to the following key parameters: (1) vessel wall dimensions of the vein graft, (2) SMC proliferation/cell death, and (3) expression of PDGF isoforms.

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Limitations of the... 6. Conclusions References

 
2.1. Chronic hypercholesterolemic porcine model
The experimental protocol was approved by the relevant governmental authority (No. 37/g/98). All animals were cared for in compliance with the ‘Guide for the Care and Use of Laboratory Animals’ published by the Institute of Laboratory Animal Resources, National Research Council. Landrace pigs (n=23, weighing 45–70 kg) were fed with a hypercholesterolemic diet. (Ssniff, Spezialdiaeten, Soest, Germany) [6]. A chronic hypercholesterolemic porcine model was used as previously described [2]. Premedication consisted of intramuscular ketamine, xylazine, and atropine. General anesthesia was induced by an intravenous bolus injection of ketamine plus propofol and was later maintained with intravenous propofol and periodically administered ketamine. The animals were intubated and volume-controlled mechanical ventilation was instituted. Once sufficient spontaneous breathing had been restored, the animals were extubated immediately after skin closure and were allowed to recover. All animals received 100 mg aspirin for 4 weeks starting from the day of surgery.

2.2. Surgical procedure
In brief, the right and left cervical vessels were dissected free. The internal jugular veins were resected. The veins were anastomozed end-to-side to the common carotid artery using continuous 8-0 Prolene sutures. Patency of the anastomosis was checked just prior to completion of the anastomosis with a 2.5 mm probe. After completion of the anastomosis, the carotid artery was ligated.

2.3. External irradiation
Vein grafts were harvested and transported in sterile heparinized saline solution. Ex vivo gamma radiation of the vein grafts with 10, 20, and 40 Gy was applied with a 10 MV linear accelerator (Mevatron, Siemens). The animals were sacrificed 3 months after surgery and the following analyses performed.

2.4. Quantitative measurements of vein graft wall dimensions
Grafts and anastomotic areas were removed, pressure fixed, and embedded in paraffin. Transverse (5-µm thick) sections from the vein grafts and the anastomosis were mounted on glass slides and stained with elastic and Masson–Goldner stains. Vessel wall dimensions were measured by computer-aided planimetry (IDMS, Fa. ASS/Haag/Amper, Germany). Luminal, intimal, and medial dimensions were computed using the endothelium and the internal and external elastic laminae as delimiters. Lumen, neointima, and media were expressed as percentages of mean vessel diameter.

2.5. Quantitative assessment of SMC proliferation/cell death
DNA-fragments and proliferative activity of SMC were detected by double-staining techniques (SMC -actin, Sigma) combined with either terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL; TdT, Boehringer Mannheim) or Mib-1 (Dianova), as previously described [7,8]. Mib-1 or TUNEL-staining was labeled using peroxidase-labeled streptavidin and diaminobezidine–H₂O₂ (DAKO). Excessive avidin- and biotin-binding sites in the TUNEL- or Mib-1-stained sections were blocked (Vector Laboratories). Subsequently, SMC-actin was labeled using alkaline phosphatase (APAAP, DAKO) and slides were counterstained with hematoxylin. For negative controls, TdT or the primary antibody was omitted. Porcine lymph nodes served as positive controls.

Intimal and medial TUNEL- and Mib-1-positive SMCs were counted. Cellular density was determined by counting SMC in ten random high-power fields per vessel layer (x400). TUNEL- and proliferation-indices were calculated by combining these data with the measured intimal and medial surfaces and expressed as number of TUNEL- or Mib-1-labeled per 1000 SMCs (two investigators unaware of the experimental protocol).

2.6. PDGF isoforms
Quantification of PDGF-AA and -BB proteins was assessed as described previously [2]. In brief, segments of irradiated veins and control veins were crushed and treated with a lysis solution. The protein concentration of the extracts was determined with a BCA protein assay (Pierce, Rockford, IL). PDGF isoform concentrations were assessed using an enzyme-linked immunosorbent assay (ELISA; standards and antibodies from R&D Systems, Minneapolis, MN). PDGF-AA and -BB concentrations were expressed per microgram of total protein to normalize for differences in size between the samples.

2.7. Assay of endothelial vasodilatation
Freshly prepared porcine jugular veins were maintained in RPMI 1640 (Biochrom, Berlin) and exposed to 40 Gy radiation. For measurement of isometric contraction force, vessel rings were mounted in an organ bath, and incubated at 37°C in oxygenated, bicarbonate-buffered Krebs–Henseleit solution. With the basal tone set at 10 mN, vessels were precontracted with KCl (20 mmol l^-1). Vasodilatation was induced by cumulatively increasing acetylcholine concentrations (range 0.01–2 µmol l^-1).

2.8. Statistical analysis
Linear regression was used to assess the correlation between radiation dose and the dimensions of each inner lumen, neointima, and media, of PDGF-AA and -BB, of cell death rates, and the association between wall thickness and PDGF isoforms. The results of the immunohistochemical staining were logarithmically transformed before analysis in order to gain more normal distributed data. The Fisher exact test was used to compare the frequencies of vein graft occlusion at the different radiation doses. A P-value of less than 0.05 was regarded as significant. Analyses were carried out using Minitab, release 12, and SAS, version 6.12.

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Limitations of the... 6. Conclusions References

 
3.1. Vein graft vessel wall dimensions
The vessel wall dimensions, graft occlusion rates, and expression of PDGF isoforms are summarized in Table 1.

View larger version (146K): [in this window] [in a new window]   Fig. 1. Stenosed but patent control vein (trichrome staining, x40).

View larger version (132K): [in this window] [in a new window]   Fig. 2. Patent vein graft irradiated with 20 Gy (trichrome staining, x40).

View larger version (144K): [in this window] [in a new window]   Fig. 3. Occluded and thrombosed vein graft irradiated with 40 Gy (trichrome staining, x40).

3.3. SMC proliferation/cell death
Quantitative assessment of SMC proliferation/cell death in the neointima and media are summarized in Table 2.

3.4. Endothelium-dependent vasomotion
Veins subjected to 40 Gy radiation showed a normal contractile response to potassium depolarization and unaltered vasodilatation when provoked by acetylcholine. Thus the endothelium-mediated vasomotor response was unaltered by the radiation therapy.

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Limitations of the... 6. Conclusions References

 
In the present study, acute brachytherapy failed to reduce neointima formation in a hypercholesterolemic porcine model, with expected subsequent larger inner lumen diameter of the implanted vein grafts. Different dosages of acute gamma radiation of unaffected vein grafts had no effect on PDGF isoform expression or SMC proliferation/cell death.

The high rate of saphenous-vein graft stenosis and occlusion limits the success of the most frequently performed surgical procedure in the Western world. Despite advances in medical therapy, e.g. lowering of lipid levels and inhibition of platelet aggregation, vein graft disease remains an unresolved problem. The implantation of arterial grafts seems to offer better long-term results than vein grafting [9]. However, the number of arterial grafts is limited and veins are still frequently used during coronary artery bypass surgery.

In vein grafts, SMC proliferation and migration with subsequent neointima formation and luminal narrowing starts early after implantation in the arterial circulation [10]. Neointimal hyperplasia, whether in the balloon-injured artery or in the vein graft, follows a similar pathogenic mechanism.

Intracoronary brachytherapy appears to be a promising technique for preventing restenosis after stent implantation [11,12]. The porcine model of coronary artery balloon injury with subsequent irradiation has been extensively evaluated [12]. The changes seen in the hypercholesterolemic swine model closely resemble human atherosclerotic changes [1]. This data prompted us to select the chronic hypercholesterolemic porcine model.

How can the negative results of the present study be explained? Selection of the radiation dosage applied in the present study was based on experience collected with various animal models, including pathologic and normal tissue tolerance models, plus human clinical application of brachytherapy [12–14]. The walls of jugular vein are much thinner than those of arterial vessels with advanced atherosclerosis. It is not surprising therefore that high-dose irradiation with 40 Gy resulted in apparent shrinkage and occlusion of these grafts, although a comparable radiation intensity has been successfully applied to coronary arteries [15]. However, in the current investigation even less intense irradiation showed no beneficial effects. In the clinical setting, prolonged chronic irradiation by stent implantation is used. The current investigation subjected veins to a short period of external irradiation only [4,16]. Another explanation for the negative results may be that, although migration and proliferation of SMCs start early after surgery, the inhibitory stimulus of brachytherapy becomes effective only in a later stage of neointimal formation.

Animal investigations with intracoronary radiotherapy have shown profound inhibition of neointimal proliferation at 2–4 weeks after balloon or stent injury [17,18]. The long-term effects of intracoronary irradiation, however, are not well known. Kaluza et al. [19] observed that the inhibition by intracoronary beta-radiotherapy was not sustained in a long-term (6 months) porcine model of restenosis. This lack of effect on neointimal formation was accompanied by subacute and late thrombosis. In the present study, the animals were sacrificed after 3 months. It is possible that our negative findings are related to the unsustained application of acute gamma radiation. Carter et al. [20] studied the differential effects of various doses of continuous irradiation on neointima formation and stenosis in coronary arteries in a chronic hypercholesterolemic porcine model. These authors observed a dose-dependent increase in neointimal formation and in the incidence of in-stent stenosis with increasing stent radiation activity. Furthermore, continuous low-dose irradiation promotes atheromatous neointimal formation [20].

Negative results following endovascular irradiation of coronary arteries in a chronic porcine model were also reported by Schulz et al. [21]. The applied low-dose beta-irradiation (3–18 Gy) resulted in increased neointima formation. In the present study, a wide range of radiation intensity (10, 20, and 40 Gy) was applied. It seems unreasonable to expect different results using other radiation intensities in this experimental setting. However, longer application of radiation may lead to positive findings.

PDGF is a dimeric polypeptide (existing as PDGF-AA, -AB, and -BB isoforms) produced by endothelial cells, SMC, fibroblasts, and macrophages. It exerts chemotactic and mitogenic activity on SMCs. Reports support the role of PDGF in mediating arterial intimal hyperplasia after angioplasty and in the formation of atherosclerotic lesions [22]. Both PDGF expression and neointimal formation are reduced after external stenting of vein grafts [2]. Noiseux et al. [23] demonstrated that luminal delivery of antisense PDGF to injured rat carotids reduced intimal hyperplasia. In our study, radiation therapy had no effect on PDGF isoform expression. The underlying mechanism may be the same as for the negative finding regarding neointimal formation. In the present study, mean inner lumen decreased as PDGF-AA expression increased, a finding that supports the suspected role of PDGF in vessel wall development.

Experimental studies have demonstrated an impairment of endothelial function in the short term after intracoronary irradiation [24]. High-dose external irradiation (40 Gy) of the vein grafts did not affect endothelium-dependent vasomotion. Thus endothelial dysfunction does not appear to be responsible for the lack of neointima formation or graft occlusion.

Radiation therapy had no effect on SMC proliferation or cell death in the implanted vein grafts compared to control veins.

	5. Limitations of the study

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Limitations of the... 6. Conclusions References

 
Waksman [25] characterized the risk of late thrombosis following successfully applied brachytherapy as ‘sitting on a time bomb’. Competent antiplatelet therapy is now part of the clinical scenario following intracoronary irradiation. Due to obvious bleeding problems with patients on GP IIb/IIIa blockade during cardiac surgery, animals in the present study were treated immediately after surgery with aspirin for a duration of 4 weeks. This regimen may have contributed to the vein graft occlusion and unaltered neointima formation of the irradiated veins.

	6. Conclusions

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Limitations of the... 6. Conclusions References

 
External acute gamma radiation of proliferating vein grafts did not reduce vessel wall dimensions or prevent a decrease in inner lumen diameter in our chronic hypercholesterolemic porcine model. Whether a longer irradiation period, e.g. by external vein graft stenting with irradiating stents, and more effective antiplatelet therapy can reduce vein graft disease remains to be elucidated.

	Acknowledgments

 
This study was supported by grant F/05/01 from the Deutsche Stiftung für Herzforschung. There exists no conflict of interest by the authors. The authors acknowledge the expert statistical analyses performed by Dr D.R. Robinson, Centre for Statistics and Stochastic Modelling, School of Mathematics Sciences, University of Sussex, UK.

	References

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