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Ann Thorac Surg 1998;65:705-711
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Intima–Adventitia Apposition in End-to-Side Arterial Anastomosis: An Experimental Study in the Pig

Department of Cardiology, Utrecht University Hospital, Utrecht, the Netherlands

Accepted for publication September 13, 1997.

Dr Borst, Utrecht University Hospital (Rm G02.523), PO Box 85500, 3508 GA Utrecht, the Netherlands (e-mail: exp.cardio@hli.azu.nl).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

 
Background. To prevent ischemic complications during coronary bypass grafting on the beating heart, a nonocclusive distal anastomosis technique is needed. One recently developed nonocclusive technique requires apposition of the intima of the graft to the adventitia of the recipient artery, in contrast to current surgical practice, which dictates apposition of both intimas.

Methods. To compare the sole effect of intima–adventitia apposition (n = 18) versus traditional intima–intima apposition (n = 18), we investigated radiolabeled platelet deposition and histomorphologic aspects of vascular wall healing quantitatively in a porcine carotid artery bypass graft model. Both groups were evaluated at 2 hours, 2 days, or 4 weeks.

Results. Within the first 2 hours, 3 of 6 pigs with intima–adventitia apposition exhibited cyclic flow reductions as a result of massive mural thrombosis. After intima–adventitia apposition, the number of deposited platelets was significantly higher compared with intima–intima apposition, 147.1 ± 73.0 x 10⁶ and 4.6 ± 1.0 x 10⁶ platelets/cm² (mean ± standard error of the mean), respectively (p = 0.03). At 2 days, the suture line was covered with small mural thrombi, whereas no thrombi were found after intima–intima apposition. At 4 weeks, intimal hyperplasia at heel and toe was not significantly different from that with intima–intima apposition.

Conclusions. Despite thrombotic phenomena in the early phase, intima–adventitia apposition yielded a patent anastomosis with a small intimal hyperplasia response.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

 
There is renewed interest in myocardial revascularization without the use of cardiopulmonary bypass [1][2][3][4]. Coronary artery bypass graft operation on the beating heart requires interruption of native coronary flow to prevent blood flooding the anastomotic area after arteriotomy. Interruption of coronary flow, however, may generate ischemic arrhythmias, jeopardize contractile function, and lead to perioperative myocardial infarction. To reduce occlusive anastomosis time, a large variety of accelerated tissue bonding techniques have been studied including tissue adhesives [5], laser welding [6], and micromechanical coupling [7]. All of these innovative techniques, however, still require occlusion of the recipient vessel.

In neurosurgery, Tulleken and associates [8][9][10][11] have developed an alternative end-to-side anastomosis technique that does not require interruption of flow in the recipient cerebral artery: After the graft has been connected with the exterior of the recipient artery, a laser punch catheter removes the partitioning wall of the latter (see Figure 3 in reference [13]). Tulleken’s technique, however, includes apposition of the intima of the graft to the thrombogenic adventitia [12] of the recipient artery, leaving an adventitial rim inside the lumen [9]. This is in contrast to current surgical practice, which dictates ap-position of both intimas. In a scanning electron microscopic study of the anastomosis site in the rabbit, Tulleken and coworkers [9] observed no early thrombus formation and complete reendothelialization at 6 weeks. Recent experimental work in our laboratory demonstrated the feasibility of this new nonocclusive anastomosis technique in coronary artery bypass graft procedures on the beating heart in the pig [13].

The patency of an anastomosis largely depends on platelet adhesion in the acute phase and intimal hyperplasia in the long term. To compare the sole effect of intima–adventitia apposition versus traditional intima–intima apposition, we investigated the deposition of radiolabeled platelets and histomorphologic aspects of vascular wall healing quantitatively in a porcine carotid artery bypass graft model in which the arteriotomy was made by a mechanical punch rather than a laser punch catheter.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

 
Animals
Thirty-six female Dutch landrace pigs (24 to 37 kg) were used. All pigs were pretreated with acetylsalicylic acid, 80 mg orally each day, for at least 7 days. This was continued after surgery until they were sacrificed. The animals were fed a normal diet and received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1985). All procedures performed in this study were approved by the Animal Experimentation Committee of the Utrecht University.

Operation and Study Protocol
The animals were anesthetized and monitored hemodynamically as described before [14]. In each animal, the left and right common carotid arteries were carefully exposed through a midline pretracheal incision. The outer diameter of the carotid arteries measured about 4.5 mm. Before occlusion, all pigs were heparinized intravenously with a single bolus of 150 IU/kg to obtain an activated clotting time (ACT; Hemotec, Inc., Englewood, CO) of twice the control value. The ACT was determined at 0, 5, 60, 90, and 120 minutes after injection. The heparin was not counteracted at the end of the procedure. The right carotid artery was then excised for a length of about 10 cm. Because of its elasticity, the artery shortened to approximately 60% of its original length. Under the operating microscope (Opmi-6, Zeiss, Oberkochen, Germany), the right carotid artery was prepared for use as a graft to bypass the left carotid artery. Both ends of the graft were cut at an angle of 45 degrees. Loose periadventitial tissue was sharply removed at both anastomosis sites of the recipient artery. Two single bulldog clamps were then placed proximally and distally across the left carotid artery. Two standardized elliptic arteriotomies were created with the use of a vascular punch (Deknatel Snowden Pencer, Lübeck, Germany), described in more detail below. All arteries were connected end-to-side with a running polypropylene 8-0 suture (Ethicon, Somerville, NJ). After restoration of blood flow and adequate removal of air, the left carotid artery was ligated in between both anastomoses with polypropylene 4-0.

The pigs were divided into two groups consisting of 18 pigs each. In the control group, both the proximal and distal arteriotomies were created by a 4.0-mm sized punch (MDP-40), which resulted in an elliptic opening (length, 5.5 mm) that allowed meticulous intima-to-intima apposition using conventional suturing (I-I). In the study group, the distal arteriotomy was created by a 2.8-mm punch (MDP-28), which resulted in an opening (length, 4.5 mm) that allowed approximation of the intima of the graft to the adventitia of the recipient artery (I-A), leaving an adventitial rim of about 0.5 mm inside the anastomotic orifice exposed to blood (Fig 1) [9]. The proximal anastomosis in the study group was conventionally sutured. Both groups were evaluated at 2 hours (n = 6 in each group), 2 days (n = 6 in each group), or 4 weeks (n = 6 in each group) after operation.

View larger version (35K): [in this window] [in a new window]   Schematic drawing of the suturing technique. The suture needle is guided through the outer layers of the recipient artery and brought out at a distance of about 0.5 mm from the arteriotomy (A). The needle is guided through the graft from the inside out, close to the intimal cut edge (B). This results in intima–adventitia contact leaving an adventitial rim of about 0.5 mm inside the anastomotic orifice.

Quantification of Early Platelet Deposition (2 Hours)
In 12 animals (I-I, n = 6; I-A, n = 6), autologous platelets of the pigs were labeled with ¹¹¹In-oxinate according to a modified method of Søfteland and colleagues [15] (Appendix 1).

After completion of the bypass procedure, approximately 20 MBq of indium-111–labeled platelets was injected in an ear vein after complete hemostasis at the anastomoses was ensured (6.0 ± 0.8 minutes after restoration of blood flow). The radiolabeled platelets were allowed to circulate for 2 hours. Before sacrifice with an overdose of barbiturate, the pigs were fully heparinized (400 IU/kg).

To preserve anastomotic geometry and to prevent elastic retraction after transsecting the bypassed carotid artery, the artery was perfused with agarose 2% (SeaPlaque, FMC BioProducts, Rockland, ME) at 80 mm Hg and secured in situ by a metal brace. To ascertain that no platelet thrombi would be flushed away, we determined the viscosity of both porcine blood (3 mPa · s) and the agarose 2% solution at 38°C (18 mPa · s) by means of a Couette-flow viscometer. With these data, we determined the maximal flow rate of the agarose solution (30 to 40 mL/min) at which the shear force at the vascular wall would equal physiologic shear force by the flowing blood: The artery was passively flushed by means of a pressurized jar containing agarose 2% at 38°C. The flow ranged between 5 and 10 mL/min. Therefore, it is unlikely that platelet thrombi have been swept away by the described procedure in any significant amount.

After excision, all radioactively contaminated loose periadventitial tissue was removed, and the artery was submerged overnight in formalin 4%. The artery was divided into four segments; proximal and distal anastomosis, graft, and reference. The most proximal part of the left carotid artery was used as reference.

The number of platelets deposited in each segment per square centimeter inner surface area was calculated according to a protocol modified from Dewanjee and associates [16] (Appendix 2).

Angiography
In the remaining 24 pigs, the bypassed left carotid artery was visualized by angiography (C-arm BV27; Philips, Eindhoven, the Netherlands) at 2 days or 4 weeks after the operation. After animal sacrifice, the artery was fixed and divided into segments as described above.

Histologic Analysis
Standard procedures for histologic processing were followed. Sections were stained with hematoxylin and eosin, and elastin van Gieson. Light microscopy was used to identify deendothelialization and reendothelialization, medial necrosis (smooth muscle cell nucleolysis), and intimal hyperplasia.

Three adjacent midline longitudinal sections at 200-µm intervals of each distal anastomosis were recorded on videotape and analyzed with a digital video analyzer. The area enclosed by the endothelium and internal elastic lamina adjacent to the suture line in donor and recipient vessel was defined as intimal hyperplasia. Mean values of intimal hyperplasia (mm²) at toe or heel were calculated for each distal anastomosis.

Statistical Analysis
Data are presented as mean ± standard error of the mean (SEM) or as median and range. The Student’s t test (two-tailed) or the Wilcoxon test was used to compare data. A p value less than 0.05 was regarded as statistically significant.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

 
Surgical Procedure
All 72 anastomoses were performed by one investigator (R.H.H.). The median time required to perform the conventionally sutured anastomosis was 15 minutes (range, 8 to 34 minutes). It did not differ from the distal anastomosis with intima–adventitia apposition (16 minutes; range, 13 to 36 minutes). Intima–intima and intima–adventitia apposition required 20.6 ± 0.3 and 20.3 ± 0.3 bites, respectively. All conventionally sutured anastomoses showed initial oozing of blood from the suture line for several minutes, whereas intima–adventitia apposition resulted in complete hemostasis within 30 seconds. The activated clotting time at 0, 5, 60, 90, and 120 minutes after administration of heparin was 81 ± 2, 150 ± 6, 117 ± 4, 102 ± 3, and 89 ± 3 seconds, respectively. No difference was noted between the groups. All pigs tolerated the clamping of both carotid arteries for 61 ± 3 minutes, and no signs of nerologic deficit were noted after the operation.

Flow Measurements
Blood flow measurements in the carotid artery are listed in Table 1. At sacrifice, 2 days or 4 weeks after operation, mean flow through the graft was not significantly different from initial blood flow in the carotid artery.

View larger version (6K): [in this window] [in a new window]   Representative recording from a pig with cyclic flow reductions. A progressive decline in blood flow (calibration, 100 to 200 mL/min) occurred in spite of a constant mean arterial pressure (calibration, 40 to 80 mm Hg). It was followed by a spontaneous and abrupt return to near control level.

View larger version (15K): [in this window] [in a new window]   Segmental comparison of early platelet deposition per square centimeter inner surface area, after intima–intima apposition (I-I, open circles, n = 6) and intima–adventitia apposition (I-A, closed circles, n = 6) on a logarithmic scale. Individual observations and their mean value are represented. The absolute number of platelets deposited on the distal anastomosis segments after intima–intima and intima–adventitia apposition was 4.6 ± 1.0 and 147.1 ± 73.0 x 106 platelets/cm2, respectively (p = 0.03). (*Proximal anastomosis [Ap, n = 5] versus reference, each p 0.001; Graft versus reference, each p 0.003; Distal anastomosis [Ad] versus reference, each p = 0.001; Student’s t tests [two-tailed] after logarithmic transformation.)

Intima–Adventitia Apposition
The occurrence of postoperative cyclic flow reductions (n = 3) corresponded with increased numbers of adhered platelets both in the distal anastomosis and in other arterial segments. However, platelet deposition in the proximal anastomosis and graft segments was approximately 8 and 3 to 4 times higher than the corresponding reference, respectively.

Angiography
All anastomoses were found fully patent at sacrifice after 2 days or 4 weeks. After intima–adventitia apposition, the protruding rim could always be identified in the lumen.

Histology
The vascular punch resulted in a sharply edged arteriotomy. After conventional suturing, the medial layer of the recipient vessel was often exposed to the bloodstream. In none of the anastomoses was the adventitia inadvertently exposed to blood. After intima–adventitia apposition, the adventitial rim extended 0.4 to 0.6 mm into the lumen. Fig 4 schematically summarizes anastomotic healing.

View larger version (26K): [in this window] [in a new window]   Schematic synopsis of anastomotic healing.

View larger version (99K): [in this window] [in a new window]   Longitudinal section of the heel of an anastomosis with intima–adventitia apposition, 2 hours after operation. Closed arrow indicates boundary between adventitia and platelet-thrombus. Open arrow indicates intraorifice thrombus adherent to recipient artery wall. (Elastin van Gieson stain; bar = 100 µm.)

Medial Necrosis
At 2 days, there was no necrosis in the media of graft and reference segment. At the anastomosis site, intima–intima apposition resulted in a full thickness necrosis of the media of both the graft and recipient artery caught in the suture loop. With intramural stitches, the inner half of the media remained unaffected after approximation of intima and adventitia. No medial necrosis was noted in the rim inside the lumen.

Intimal Hyperplasia
At 4 weeks, the graft segment showed a thin intimal layer about 10 µm thick. After intima–intima apposition, intimal hyperplasia was predominantly present at the heel (Table 2). Intimal hyperplasia at the toe was only a few cell layers thick. After intima–adventitia apposition, intimal hyperplasia varied widely. Either minimal neointima covered the exposed adventitial layer of the rim at both toe and heel (Fig 6) or the anastomosis recess was completely filled out with neointima. Minimal intimal hyperplasia was seen at the exposed media at the edge of the arteriotomy.

View larger version (124K): [in this window] [in a new window]   Longitudinal section of the heel of an anastomosis with intima–adventitia apposition, 4 weeks after operation. Closed arrow indicates boundary between adventitia and neointima. (Elastin van Gieson stain; bar = 100 µm.)

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

Intima–Adventitia Apposition
In search of a nonocclusive end-to-side arterial anastomosis technique applicable to coronary artery bypass graft procedures on the beating heart, we extended the experimental evaluation of the nonocclusive anastomosis technique described by Tulleken and associates [8][9][10][11]. In both experimental and clinical studies [8][9][10][11], Tulleken and colleagues reported patency rates up to 90%. Qualitative assessment by scanning electron microscopy of the adventitial rim in the rabbit showed no early thrombus formation and complete reendothelialization at 6 weeks [8][9][10]. Those studies, however, did not present quantitative data on initial platelet deposition and vascular wall healing after intima–adventitia apposition compared with intima–intima apposition.

The technique described by Tulleken and coworkers [8][9][10][11] requires a laser punch catheter to create the anastomotic orifice (see Fig 3C in reference [13]). In porcine coronary arteries, the laser punch catheter failed in about 30% of cases to remove the punched-out arterial wall disk properly [13]. This increased the incidence of primary anastomotic closure. In atherosclerotic human coronary arteries, a mechanical device may eventually be required to perform the arteriotomy effectively and at low cost. In the present study, we mechanically performed the arteriotomy by means of a vascular punch. The intima of the graft was apposed to the adventitia of the recipient artery using a modified anastomosis technique, deliberately leaving a rim of about 0.5 mm inside the lumen.

In this study, the persistent rim that is inherent in Tulleken’s technique [9] resulted in a diameter reduction of about 20% without an impediment to mean carotid blood flow. The same rim in a smaller vessel will result in a greater percentage of stenosis. When applied to the coronary circulation, however, the reactive hyperemia response was not reduced [13]. Decreasing the anastomotic angle, and hence increasing the surface area, will slightly reduce the significance of the persistent rim.

Cyclic Flow Reductions
In 1976, Folts and associates [17] described the occurrence of cyclic flow reductions in mechanically stenosed dog coronary arteries. A fixed stenosis of 60% to 80% with endothelial and medial damage resulted in cyclic flow reductions occurring about eight times per hour [18]. We have observed similar blood flow patterns, although, in contrast to Folts’ model, 28 to 36 minutes passed until cyclic flow reductions started. This may be attributed to the initial buildup of a relatively large thrombus necessary to attain a critical stenosis first. Prolonged observation of blood flow may therefore be indicated in all alternative anastomosis studies to detect abnormal flow patterns, which may be a sign of serious thrombotic phenomena.

Repetitive thrombus formation and spontaneous dislodgment result in microemboli downstream. Although none of the present animals showed evidence of cerebral ischemic attacks, coronary cyclic flow reductions have been found to correlate with myocardial infarction [19].

In this study, thrombotic phenomena in the early phase did not correlate with early carotid graft occlusion. The increasing pressure gradient across the growing fragile platelet-thrombus may have been sufficient to displace the thrombus distally in all animals. Both experimental and clinical studies, however, suggest that coronary cyclic flow reductions eventually progress to persistent thrombotic occlusion [19][20]. Various agents that interfere with platelet-mediated thrombus formation have been shown to abolish cyclic flow reductions and may play a crucial role in the development of a nonocclusive anastomosis technique with a mechanically performed arteriotomy in cardiac surgical practice.

We pretreated all animals with acetylsalicylic acid to reduce the platelet aggregatory response to a foreign surface. Although not apparent histologically, the amount of exposed collagen of the adventitia (type I, a potent stimulus to platelet adhesion) may have differed between experiments. This may have prompted vigorous platelet aggregation in some animals, despite the use of aspirin.

Mural Thrombosis and Intimal Hyperplasia
The present study in the pig supports the previous findings by Tulleken and associates [8][9][10] for long-term observation. All anastomoses were fully patent and the protruding adventitial rim was completely covered by regenerated endothelium. In addition, our study shows that the presence of reactive thrombogenic adventitia [12] at the suture line does not provoke excessive intimal proliferation. Surprisingly, intimal hyperplasia only filled out the anastomotic recess above the rim, resulting in a more funnel-shaped configuration, and did not proceed toward the lumen of the recipient artery. Hence, the anastomotic orifice was not additionally narrowed by formation of neointima. In the atherosclerotic human coronary artery, however, the arterial wall may be thickened at the anastomotic site. Exposed plaque in the persistent rim may promote mural thrombosis and subsequent neointima formation.

In contrast to earlier observations in the rabbit by Tulleken and colleagues [8][9][10], we observed massive platelet-mediated thrombosis at the adventitial rim and subsequent cyclic flow reductions in 3 of 6 pigs with intima–adventitia apposition studied for initial platelet deposition. It is also conceivable that in some of our subacute and chronic experiments cyclic flow reductions have occurred. This may have caused the observed variation from animal to animal with respect to suture line intimal hyperplasia (see Table 2) [21]. Whether the noted discrepancy in findings for the acute phase is caused by interspecies differences or thermal tissue damage [22] by the laser punch catheter is unclear.

In the present study, the right carotid artery was excised for use as a graft to bypass the ligated left carotid artery, which initially increased blood flow in the latter significantly. At the end of the surgical procedure, however, the primary increase in flow was attenuated, which may in part be attributed to the well-developed collateral cerebral circulation in the pig. Hence, all anastomoses were subjected to normal blood flow with respect to vessel size, ie, a normal shear rate. It remains to be established, however, whether the current results hold if smaller sized vessels are used or if graft flow is reduced.

Conclusions
Despite thrombotic phenomena in the first hours, intima–adventitia apposition in the porcine carotid artery yielded a patent anastomosis with a small intimal hyperplasia response that was comparable to conventional intima–intima apposition. The initial thrombotic phenomena, however, may imply an increased risk of early occlusion of a mammary artery to coronary artery anastomosis if initial graft flow is reduced by, for example, spasm of the mammary artery.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

 
We acknowledge the technical assistance or advice of Yvonne J. M. van der Helm, Oswald A. M. Kessels, Jolanda van der Zande, BSc, Henny IJzerman, Fred D. van het Schip, PhD, and Hans W. G. Vosmeer and colleagues from the Utrecht University Central Animal Facilities. Comments by Rob van Dalen, MSc, Geert J. Streekstra, MSc, PhD, Erik W. L. Jansen, MD, Jaap J. Bredée, MD, PhD, Cornelis A. F. Tulleken, MD, PhD, Paul M. N. Werker, MD, PhD, and Moshe Kon, MD, PhD, are appreciated.

	Appendix 1

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

 
Radioactive Labeling of Platelets
After induction of anesthesia, blood was withdrawn from the arterial line into a 5-mL EDTA tube to determine platelet count (424,000 ± 20,000 platelets/mL) and into a 50-mL siliconized glass vial filled with 12 mL of acid citrate dextrose-saline solution (pH 4.47) for platelet labeling. Platelet-rich plasma was obtained by centrifugation of the 50-mL vial at 200 g for 15 minutes at room temperature. The platelet-rich plasma supernatant was then transferred into a 50-mL plastic conical centrifuge tube, acidified with 0.8 mL acid citrate dextrose-saline solution per 10 mL platelet-rich plasma and centrifuged at 1,000 g for 15 minutes to obtain a platelet pellet. The platelet-poor plasma supernatant was removed and saved in a plastic tube. Next, approximately 30 MBq of ¹¹¹In-oxinate was added to the platelet pellet suspended in 1 mL of phosphate-buffered saline solution. After incubation at 37°C for 20 minutes, the labeled cell suspension was washed with 37 mL of platelet-poor plasma followed by centrifugation for 15 minutes at 640 g to remove unbound ¹¹¹In. Next, labeled platelets were resuspended in platelet-poor plasma and transferred to a 5-mL syringe to reinject into the pig. Radioactivity-bound-to-platelets was divided by total-radioactivity-added to determine efficiency of labeling (75.4% ± 1.8%).

	Appendix 2

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

 
Quantification of Platelets
Before sacrifice, blood was withdrawn from the arterial line and centrifuged for 15 minutes at 1,000 g to obtain platelet-poor plasma. The radioactivity in counts per minute (cpm) in whole blood and platelet-poor plasma was used to determine the fraction of free ¹¹¹Indium, 2.8% ± 1.5%. With that, radioactivity bound to platelets was calculated:

Next, the platelet count was used to determine the number of platelets per ¹¹¹In-cpm (3,141 ± 441, range, 1,355 to 5,920).

The internal diameter of each vessel segment was measured by means of an ocular grid. The calculated circumference wasmultiplied by the measured length to determine the inner surface area. With the data then known—the area (cm²) of each segment, radioactivity (cpm) in each, and number of platelets per cpm—the total number of platelets (labeled plus unlabeled) deposited on each square centimeter of inner surface of the blood vessel was calculated:

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments Appendix 1 Appendix 2 References

 

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