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Ann Thorac Surg 1998;65:1273-1278
© 1998 The Society of Thoracic Surgeons

Early Injury to the Media After Saphenous Vein Grafting

^a Division of Cardiovascular Surgery, Jefferson Medical College, Philadelphia, Pennsylvania, USA
^b Division of Cardiology, Jefferson Medical College, Philadelphia, Pennsylvania, USA

Accepted for publication December 11, 1997.

Address reprint requests to Dr Mannion, Jefferson Medical College, 1025 Walnut St, Philadelphia, PA 19107

	Abstract

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Background. Injury to the smooth muscle cells of the media affects the remodeling process of vein grafts. The purpose of this study was to determine whether different techniques of surgical preparation influence the degree of medial smooth muscle injury.

Methods. Carotid–saphenous vein interposition grafting was performed in crossbred pigs (n = 32), using distended (n = 16) or nondistended (n = 16) conduits. After 3 to 90 days, the media was evaluated for the presence of smooth muscle cells (desmin stains), myofibroblast formation (transient -SM actin expression), and apoptosis (TdT-mediated dUTP nick end-labeling [TUNEL]).

Results. Smooth muscle loss was uniformly severe; only 5% ± 5% (p < 0.01) and 14% ± 9% (p < 0.01) of the medial area of distended and nondistended veins were desmin positive in comparison with 80% ± 9% of controls. Apoptosis appeared to contribute to medial smooth muscle loss (5.7% ± 4.3% in vein grafts versus 0.0% ± 0.0% of TUNEL-positive cells in controls; p = 0.05). There was a time dependent increase in medial myofibroblast formation (p < 0.05).

Conclusions. Severe medial smooth muscle loss occurs in vein grafts, even when prepared without distension. Apoptosis contributes to the early disappearance of smooth muscle cells. Adjunctive measures, in addition to ideal surgical techniques, should be developed to prevent medial muscle loss.

	Introduction

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Injury of a saphenous vein during preparation for grafting is one of the primary factors leading to altered late histology within the graft [1]. Even the gentlest surgical technique induces expression of genes that initiate the vascular repair process [2]. Previous studies have documented the important role of endothelial disruption on graft patency [3], and surgical methods have been developed to improve endothelial integrity [1]. Surgical preparation also affects medial viability [4], but it has been difficult to describe quantitatively a relationship between different preparation methods and medial injury.

Medial smooth muscle loss and a wound-healing response may have important implications for the fate of the conduit. Recently, we have demonstrated that surgical dissection activates adventitial fibroblasts [5], which, in turn, migrate through injured media to form neointima [6]. Nonmuscle cells of the media also have the potential to respond to injury by proliferating and migrating. Thus, an injured media can be viewed as a staging ground for activated fibroblasts, which remodel the vein graft. This implies that surgical preparation and disturbances in the media may have considerable influence on the long-term fate of the conduit.

The primary purpose of this study was to quantify the extent and time course of medial smooth muscle cell loss and the vascular healing response in vein grafts receiving different preparation techniques.

	Material and methods

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Animal preparation
Domestic crossbred pigs (n = 32, weight 25 to 35 kg) were premedicated with aspirin (650 mg, oral) one day before the procedure. They were sedated with intramuscular ketamine (20 mg/kg) and xylazine (4 mg/kg), and anesthetized with sodium thiopental (7 to 10 mg/kg). After endotracheal intubation, anesthesia was maintained with inhaled halothane (0.75%).

Using sterile surgical techniques, the long saphenous vein was harvested from both thighs. Side branches were secured with 3-0 silk ties or 7-0 polypropylene sutures. The veins were placed briefly in a bath of sterile saline solution containing heparin (5 U/mL) and papaverine (0.7 mg/mL) at room temperature.

The surgical model was adapted from Angelini and colleagues [3]. A midline neck incision was made, and the carotid arteries were identified and isolated from the surrounding structures. Heparin (150 to 300 U/kg) was given intravenously, proximal and distal control of the artery was obtained, and a 1- to 2-cm section of artery was excised. The reversed saphenous vein was interposed between the beveled edges of the right carotid artery, followed by the left, using a continuous 8-0 polypropylene suture.

The animals were permitted to recover, and were sacrificed at the following time points after operation: early (2 to 4 days, n = 5); intermediate (7 to 14 days, n = 8); and late (30 to 90 days, n = 5). The animals were cared for according to the "Principles of Laboratory Animal Care" formulated by the National Society of Medical Research and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication no. 85-23, revised 1985).

At the time of sacrifice, the animals were sedated in the fashion described above. The neck incision was opened and the distal aspect of the carotid was divided to ensure patency of the vessel. The animals were sacrificed with an overdose of Beuthanasia (Burns-Biotec). The carotid artery, interposition vein graft, and surrounding tissue were then harvested en bloc. Control specimens were obtained by sampling sections of saphenous veins immediately after initial isolation.

Vessel preparation
The vessels were rinsed in phosphate-buffered saline and placed in HistoChoice tissue fixative (Amresco, OH), sectioned into 3-mm segments, processed (Tissue-Tek VIP processor, Miles Inc, IN), embedded in paraffin, and cut in 5-µm thick sections. The sections were then placed on Vectabond (Vector Laboratories) coated slides for staining.

Immunohistochemistry
The Vectastain Elite ABC system (Vector Laboratories) was used for immunohistochemistry. Sections were deparaffinized, incubated with 0.6% hydrogen peroxide in methanol for 30 minutes, and blocked with 5% horse serum. After washing in phosphate-buffered saline, the sections were incubated with primary antibodies for 1 hour at room temperature or overnight at 4°C in a moisture chamber. The following primary antibodies were used: monoclonal mouse 1A4 antibody recognizing -smooth muscle actin (-SM actin, 1:100, Sigma Diagnostics, St. Louis, MO), and monoclonal mouse DE-R-11 antibody recognizing intermediate filament desmin (1:50, Novocastra). Afterward, slides were washed and incubated with biotinylated secondary horse antimouse antibodies (1:2000, Vector Laboratories) for 1 hour. They were visualized with DAB substrate (Vector Laboratories) followed by a counterstain with Gill’s hematoxylin (Sigma Diagnostics). Negative controls were carried out using nonimmune serum instead of primary antibody.

DNA nick-end labeling of tissue sections
Identification of apoptotic figures was accomplished using terminal deoxynucleotidyl transferase DNA fragmentation identification as per the kit manufacturer’s specifications (Oncogene Research Products, Cambridge, MA). Paraffin-embedded tissue sections from vein grafts were treated with 0.3% H₂O₂ in methanol to quench endogenous peroxidase activity, then incubated for 30 minutes in equilibration buffer (1 mol/L sodium cacodylate, 0.15 mol/L Tris, 1.5 mg/mL bovine serum albumin, and 3.75 mmol/L CoCl₂). The DNA fragments within the nuclei of the apoptotic cells were labeled by incubating the slides in a solution containing a 1:20 ratio of terminal deoxynucleotidyl transferase and a mixture of labeled and unlabeled deoxynucleotides. The slides were incubated with stop solution (0.5 mol/L EDTA) and blocking buffer (4% bovine serum albumin), followed by incubation with peroxidase streptavidin conjugate. The slides were stained with diaminobenzidine tetrahydrochloride substrate kit (Sigma Diagnostics), then counterstained with Gill’s hematoxylin (Sigma Diagnostics).

Medial apoptotic cell calculations were performed under 40x magnification in grafts harvested after 2 to 4 days (Optiphot 2, Nikon Instrument Corp). Eight microscopic fields were selected at random, and the percentage of apoptotic cells in the media was determined by dividing the number of positively stained cells by the total number of medial cells.

Quantification of expression of smooth muscle proteins
A representative section was chosen from each vessel. From the section, four quadrants were selected at random for analysis. The media of the vessel wall in sections stained for smooth muscle proteins was identified by comparison of adjacent sections with Verhoeff’s stain. The slides were magnified 20x and analyzed for desmin and -SM actin staining with the Image-Pro Plus image analysis program (Media Cybernetics, Silver Spring, MD). The quantity of desmin and -SM actin was expressed as a percent of the medial area in the quadrant.

Statistical methods
All results are expressed as mean ± standard deviation. Analysis of variance and Student’s t tests were used for data analysis as appropriate. A probability value of less than 0.05 was considered statistically significant.

	Results

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A total of 52 vessels were harvested from 26 animals. Thirteen of 30 (43%) distended vessels were patent versus 18 of 22 (82%) nondistended vessels (p < 0.05). Of the 31 patent vessels, 26 were suitable for histologic analysis.

Desmin stains within the media
Control samples demonstrated a thick muscular media, in which 80% ± 9% of the medial area stained positively for desmin (Fig 1). At 2 to 4 days after grafting, there was a significant loss of medial desmin content. Early distended vessels suffered a greater early loss of medial desmin (5% ± 4% versus 14% ± 10%; p < 0.02) than nondistended vessels. However, in comparison with controls, the early desmin loss in the nondistended vessels was also considerable (p < 0.01). A typical desmin stain in distended and nondistended vessels at 2 to 4 days after grafting is seen in Figure 2.

View larger version (123K): [in this window] [in a new window]   Fig 1. Photomicrographs depicting cross-sections of a control saphenous vein with Verhoeff (A) and desmin stains (B). Note the thick muscular media (m) with extensive positive staining for smooth muscle proteins. (Original magnification, x20.)

View larger version (164K): [in this window] [in a new window]   Fig 2. Photomicrograph demonstrating wide variability in medial desmin preservation in nondistended vessels at early (A, B), middle (C, D), and late (E, F) time points. Examples of vessels with poorly preserved (A, C, E) and well-preserved (B, D, F) media are shown. (Original magnification, x20.) (m = muscular media.)

By 1 to 3 months after operation, there was no further change in medial desmin area (p = not significant, analysis of variance for medial desmin area over time). Thus, the desmin loss occurred early and was not progressive.

A prominent aspect of the loss of desmin was its focality. Some veins were well preserved, whereas others suffered significantly more damage. Likewise, the same focal nature of the medial smooth muscle loss was evident within different quadrants of the same sections and within different sections of the same vein. This focality of smooth muscle cell loss was evident in both the nondistended and the distended vessels, and is depicted in Figure 3.

View larger version (15K): [in this window] [in a new window]   Fig 3. Plot demonstrating the percent of medial area staining positive for desmin in nondistended (A) and distended (B) grafts over time. Each point represents one of four randomly selected quadrants of the wall of each analyzed vessel. Note the large variability of desmin expression in both the distended and nondistended vessels.

-SM actin stains within the media

At later time points, there is a quantitative difference in the medial area stained by the two proteins. The early desmin loss was sustained, but the early -SM actin loss was followed by a significant reappearance over time (p < 0.05) (Table 1). After grafting, the increase within the media of -SM actin with a stable desmin content is consistent with myofibroblast formation resulting from medial injury.

View this table: [in this window] [in a new window]   Table 1. -Actin Expression in Media of Vein Graftsa

Apoptosis
In ungrafted control saphenous veins, there was no evidence of apoptosis within the media either by nick- end labeling or by morphologic criteria (0 ± 0, n = 3). Two to 4 days after grafting, a significant increase in apoptotic figures was observed, as identified with nick-end labeling (5.7% ± 4.3%; p = 0.05 by Student’s t test). These findings were supported by additional morphologic criteria of cell shrinkage and nuclear condensation. The type of cells undergoing apoptosis were not identified with cell-specific markers; however, cells with the appearance of smooth muscle origin did appear to be undergoing apoptosis (Fig 4).

View larger version (117K): [in this window] [in a new window]   Fig 4. Photomicrograph demonstrating an ungrafted saphenous vein (A) and a saphenous vein graft harvested after 3 days (B) stained with TUNEL technique. The nuclei of apoptotic cells are brown. Note the marked cell shrinkage (s) and chromatin condensation (c). (Original magnification, x40.) (m = muscular media.)

After the initial injury, the population of medial smooth muscle cells was stable. In fact, 1 month after grafting, the media of experimental vein grafts seen here had similarities to the media of human vein grafts removed after years in the circulation [7]. The same general appearance of remnants of smooth muscle cells amidst fibrous tissue seen at 30 to 90 days is evident up to 10 years after operation. This comparison suggests that medial smooth muscle loss and subsequent wound healing in the perioperative period is the major determinant in the long-term histologic appearance of the media.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study demonstrates a rapid loss of smooth muscle cells within the media of vein grafts, even when prepared with standard intraoperative techniques. Medial smooth muscle loss is focal but quantitatively significant, occurs early after grafting, and is not progressive. Cell death through apoptosis contributes to smooth muscle attrition. As a consequence of medial disruption, there is a vigorous wound healing response, with replacement of injured medial smooth muscle cells with myofibroblasts and their extracellular products. These observations suggest that more sophisticated methods of medial protection must be developed to prevent unfavorable vein graft remodeling.

Importance of cell type and medial remodeling
There is no single immunohistochemical marker that absolutely distinguishes smooth muscle cells from myofibroblasts [8]. However, in a series of studies on vascular repair, we have demonstrated that adventitial myofibroblasts transiently acquire -SM actin, and only infrequently express desmin [6, 9, 10]. Consequently, in this study, we evaluated the maintenance of medial smooth muscle cells with desmin stains. We have purposely chosen not to use -SM actin as a distinguishing marker for smooth muscle cells, as myofibroblasts prominently exhibit this protein [6, 8, 10].

Although the medial smooth muscle cell has generally been accepted as the most reactive cell after vein grafting, the proliferating cells seen within the media of the injured vessel have many characteristics of fibroblasts [11]. In support of this concept, we have recently observed that fibroblasts can proliferate and migrate toward the lumen and contribute to neointimal formation in both the arterial [9, 10] and vein graft repair processes [6]. The active role of fibroblasts in vascular remodeling is also supported by our recent observation that the extracellular matrix production of the injured adventitia, populated with myofibroblasts, parallels the formation of neointima [12]. These studies lend credence to the idea that the -SM actin-positive, desmin-negative cells, which in vein grafts also proliferate in the media, are myofibroblasts rather than dedifferentiated medial smooth muscle cells. Because an intact media appears to limit unfavorable graft remodeling [13], protecting the smooth muscle cells of the media may be an important therapeutic goal.

Causes of smooth muscle cell loss
The most likely cause of smooth muscle loss and the subsequent vascular repair response is medial injury induced by vein grafting. Surgical trauma can directly injure muscle cells or induce an inflammatory response [14, 15], which can contribute to cell necrosis. Preprogrammed cell death, or apoptosis, has been noted after arterial injury and after vein grafting [7, 16]. We observed a prominent rate of apoptosis in vein grafts, which is apparent early after grafting. Inflammatory cells, smooth muscle cells, and fibroblasts can all undergo apoptosis. All three cell types are within the vein graft media. These findings raise the possibility that apoptosis may be an important mechanism for smooth muscle attrition.

Careful surgical technique minimizes but does not eliminate medial smooth muscle loss
In a classic experiment on vein graft morphology, Brody and colleagues [17] suggested that medial damage was inevitable, as it was secondary to interruption of vasa vasorum. However, this view is contradicted partially by the observations that optimal methods of surgical preparation can minimize damage to the media. Ramos and coworkers [18] noted that distended veins had more medial disruption than nondistended veins acutely, and that distention with saline rather than blood was even more deleterious. Angelini and colleagues [19] assessed acute medial damage by analysis of ATP, and noted a significant reduction of ATP with vein distension. In addition, performance of the proximal anastomosis first, which presumably helps by preventing the drying of the vein and adds the protection of blood, also improved the media [4, 20]. Sottiurai and associates [21] suggested that storage of the vein in blood rather than Ringer’s lactate decreased early medial injury and late fibrosis. Quist and LoGerfo [22] noted improved medial integrity with the use of papaverine infiltration and storage with Dulbecco’s modified Eagle’s solution with added protein, heparin, and papaverine.

The above observations suggest that, although medial damage is not a certainty, it is difficult to prevent. It appears unlikely that surgical techniques alone can be improved to the point that there is complete prevention of medial damage. Recently, we have demonstrated that the media of saphenous vein grafts appears to be amenable to pharmacologic interventions. Intraoperative incubation of saphenous veins with c-myc antisense decreased cell proliferation at 3 days and also improved medial histology [15]. It remains to be determined whether adjunctive therapies can affect favorably the long-term fate of vein graft conduits.

In conclusion, the media of saphenous vein grafts undergoes extensive remodeling after grafting. Both mechanically injured and optimally prepared veins have a highly variable histology; some veins demonstrate excellent preservation of the media, whereas others exhibit extensive smooth muscle attrition. It appears that late histologic changes in the media are secondary to early smooth muscle cell loss and an activation of a vascular healing response. Apoptosis may contribute to early medial smooth muscle loss. Vein graft longevity might be improved if the medial smooth muscle cell loss can be prevented and the subsequent vascular repair modified.

	Acknowledgments

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This study was supported by National Institutes of Health grant HL-44150.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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