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A novel vein graft model: adaptation to differential flow environments

Department of Surgery, University of Florida College of Medicine, and Malcom Randall Department of Veterans Affairs Medical Center, Gainesville, Florida 32610

Submitted 8 August 2003 ; accepted in final form 5 September 2003

	ABSTRACT

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Accelerated intimal hyperplasia in response to altered flow environment is critical to the process of vein bypass graft failure. Lack of a reproducible animal model for dissecting the mechanisms of vein graft (VG) remodeling has limited progress toward solving this clinically significant problem. Combining a cuffed anastomotic technique with other surgical manipulations, we developed a well-defined, more robust method for studying hemodynamic factors in VG arterialization. VG with fistula placement, complete occlusion, or partial distal branch ligation (DBL) was performed in the carotid artery of 56 rabbits. Extensive hemodynamic and physiological analyses were performed to define the hemodynamic forces and histological adaptations of the wall at 1–28 days. Anastomotic time averaged 12 min, with 100% patency of bilateral grafts and unilateral grafts plus no adjunct or delayed fistula. Bilateral VG-DBL resulted in an immediate disparity in wall shear (0.8 ± 0.1 vs. 12.4 ± 1.1 dyn/cm², ligated vs. contralateral graft). Grafts exposed to low shear stress responded primarily through enhanced intimal thickening (231 ± 35 vs. 36 ± 18 µm, low vs. high shear). High-shear-stress grafts adapted through enhanced outward remodeling, with a 24% increase in lumen diameter at 28 days (3.0 ± 0.1 vs. 3.7 ± 0.2 mm, low vs. high shear). We have taken advantage of the cuffed anastomotic technique and combined it with a bilateral VG-DBL model to dissect the impact of hemodynamic forces on VG arterialization. This novel model offers a robust, clinically relevant, statistically powerful small animal model for evaluation of high- and low-shear-regulated VG remodeling.

anastomosis; shear stress; intimal hyperplasia; rabbit model

Several models using vein bypass grafts (12), vein patches (10), fistulas, and their combinations (13) have been used to study the adaptation of vein grafts to the arterial system in multiple animal species (mouse, rat, rabbit, dog, and primate). However, the usefulness of these studies has been limited by factors such as cost and technical complexities in model completion.

Physiological vein graft adaptations, and inherent intimal thickening leading to pathological vein graft stenosis, are intimately linked to the forces imposed by the arterial circulation (13). Blood flow rate, as mediated by surface shearing forces across the endothelium, has been identified as an important regulator of both the biochemical and the morphological changes that occur during early graft remodeling (4). Therefore, the goal of this study was to develop an efficient, reproducible model for the study of vein graft adaptation under conditions of low and high shear.

We describe here in detail our adaptation of a novel anastomotic cuff technique for creation of vein bypass grafts in a small animal model. Various vascular reconstructions (ligations and fistulas) were performed in combination with vein graft placement to evaluate graft performance under altered wall shear conditions. The most reproducible and robust configuration was placement of bilateral interposition vein grafts combined with unilateral partial branch ligation. With discrete regions of high and low wall shear stress, the physiology of early vein graft adaptation in this model was explored in detail.

	METHODS

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This study was performed after approval was secured from the Institutional Animal Care and Use Committee and conforms to the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996).

Male New Zealand White rabbits (3.0–3.5 kg; n = 56) were anesthetized through an intramuscular injection with ketamine hydrochloride (30.0 mg/kg). Anesthesia was maintained with endotracheal intubation and inhaled isoflurane (2.5–3.0%). Heparin (1,000 units) was given intravenously to the animal. The operative procedure was performed with aseptic technique under an operating microscope (magnification x10–60).

Vein graft technique. Vein bypass grafts were constructed with an anastomotic cuff technique (Fig. 1). Polymer cuffs consisting of a 1.0-mm body loop were fashioned from a 4-Fr introducer sheath (Terumo Medical, Elkton, MD). The external jugular veins were harvested (3.0 cm in length) for creation of an interposition graft into the common carotid artery. Jugular vein ends were passed through a cuff, everted, and fixed with 8-0 silk. The carotid artery lumen was then exposed with a 2.0-cm arteriotomy, and the cuffed, reversed vein ends were inserted. A second 8-0 silk was used to secure the artery around the cuff. Finally, 1.0 cm of carotid artery back wall between the cuffs was cut away to permit vein graft extension.

View larger version (22K): [in this window] [in a new window]   Fig. 1. Vein graft bypass with cuff technique. A 3.0-cm section of the external jugular vein was excised. Both proximal and distal ends were fixed to the polymer cuffs with 8-0 silk (steps 1–3). After a longitudinal arteriotomy (2.0 cm), each cuff was inserted into the carotid artery (steps 4 and 5) and fixed to the artery wall with 8-0 silk (steps 6 and 7). Finally, 1.0 cm of carotid artery back wall between the cuffs was cut away to permit vein graft extension (step 8).

Application of cuffed anastomosis to various flow situations. Unilateral vein grafts were constructed to explore the utility of the cuff anastomosis in combination with the study of flow-regulated vein graft remodeling. Vein grafts were placed in isolation (n = 8), with immediate (n = 9) or delayed (n = 6; 4 wk after initial vein grafting) fistula placement, or in conjunction with complete ipsilateral common carotid ligation (n = 3). In animals undergoing fistula placement, the contralateral external jugular vein was harvested for placement as a vein graft and the ipsilateral jugular vein was then anastomosed to the common carotid artery in an end-to-side fashion with 8-0 monofilament suture distal to the vein graft. With the potential for neurological injury secondary to significant alterations in cerebral blood flow, all animals underwent postoperative neurological assessment for evaluation of head tilt, ear droop, and extremity motor weakness. Samples were harvested 4 wk after flow manipulation, and the anastomotic patency was evaluated on the basis of clinical evidence, flow rates recorded at the time of graft harvest, and histological sections.

Bilateral vein graft with branch ligation model. To create differential flow environments within the same animal, bilateral vein grafts with distal branch ligation were created in 30 rabbits. As illustrated in Fig. 2, the internal carotid artery and three of four external carotid branches were completely ligated, with the most inferior branch of the external carotid artery being left unmanipulated (low-flow graft). Animals were euthanized at 1, 3, 7, 14, and 28 days (n = 5 for each time point except 28 days, where n = 10). Animals received bromodeoxyuridine (BrdU) injections (50.0 mg/kg) 24 h before the indicated harvest time points. Graft flow rates were recorded at implantation and harvest with an ultrasonic flowmeter (2.0-mm flow probe; T106, Transonic Systems). High-resolution video images (model DXC-151A, Sony) were obtained at both graft placement and harvest and used to determine external graft dimensions. At the time of harvest, pressure waveforms in the ascending aorta, proximal common carotid artery, and vein graft were recorded with a microtip catheter transducer (1.4-Fr SPR-671, Millar Instruments, Houston, TX) that had been placed into the vessel via a 22-gauge catheter. Five of the 28-day vein grafts underwent in situ perfusion fixation from the ascending aorta with 10% neutral buffered formalin under 50-mmHg pressure. Specimens were equally divided into three segments to evaluate for morphological variation along the graft length, avoiding the tissue immediately adjacent to the foreign body cuffs.

View larger version (30K): [in this window] [in a new window]   Fig. 2. Bilateral vein graft with distal branch ligation model. The most inferior branch of the external carotid served as the only outflow for the low-flow graft on the ligated side.

Morphology and hemodynamics. Morphological analyses were completed with both in vivo external graft diameter (D_V) and cross-sectional measurements (Axiovision version 3.1, Zeiss) on Masson and van Gieson's elastin-stained specimens. Specifically, in vivo lumen diameter (D_L), neointimal thickness (NIT), and wall shear stress () were approximated with the following formulas

where A_V, A_L, and A_I are the cross-sectional areas of the vein graft wall, lumen, and intima, respectively; P_L and P_IEL are the lumen and internal elastic lamina perimeter, respectively; is the flow rate; and µ is the viscosity of blood (0.035 P).

Cell proliferation. Proliferating cells were identified with a BrdU antibody (Zymed Laboratories, South San Francisco, CA) according to the manufacturer's protocol. Density of actively proliferating cells (BrdU-positive cells per unit area) was determined for the neointima.

Statistics. Data are expressed as means ± SE. Statistically meaningful differences were determined with paired t-tests and two-way ANOVA with repeated-measures design (Sigma Stat, version 2.03, Jandel Scientific).

	RESULTS

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The time for graft bypass construction was an average of 12 ± 3 min, with 100% patency of bilateral grafts (Table 1). Postoperative neurological assessment demonstrated a mild ipsilateral ear droop in 5 of 56 rabbits, with no animals showing evidence of extremity weakness or head tilt. Histological examination of the anastomotic cuff region demonstrated no significant narrowing or thrombus formation (Fig. 3). Performance of the cuff anastomosis in combination with a distal fistula demonstrated significant patency variability depending on the timing of fistula placement (Table 1), with all grafts demonstrating anastomotic occlusion or severe narrowing with simultaneous fistula placement but all grafts remaining widely patent when the fistula was placed in a delayed fashion. All grafts with immediate distal carotid ligation developed complete occlusion within 4 wk, with lesions located principally at the distal anastomosis.

View larger version (133K): [in this window] [in a new window]   Fig. 3. Masson staining of longitudinal section of the cuffed anastomotic segment.

Complete ligation of the internal carotid artery and partial ligation of the external carotid artery resulted in an immediate 90% reduction in flow on the ligated (low flow) vein graft side (3.1 ± 0.4 vs. 30.0 ± 2.2 ml/min; Fig. 4A). After a moderate compensatory increase in flow in the contralateral graft (high-flow vein graft), an 15-fold difference in mean flow rates was observed throughout the 28-day perfusion period (P < 0.001, two-way ANOVA). Elevated contralateral flow resulted in graft dilatation (Fig. 4B), observed as a 24% increase in lumen diameter at 28 days (3.0 ± 0.1 vs. 3.7 ± 0.2 mm, low vs. high shear; P = 0.009). There was an immediate 15-fold difference in wall shear stress between low-flow and high-flow grafts (0.8 ± 0.1 vs. 12.4 ± 1.1 dyn/cm²; P < 0.001; Fig. 4C), with normalization of the shear in high-flow grafts secondary to the increase in lumen diameter at the 28-day time point.

View larger version (18K): [in this window] [in a new window]   Fig. 4. Distal branch ligation resulted in a 15-fold difference in flow rate throughout the 28-day perfusion period (P < 0.001; A). By 28 days, the high-flow vein graft adapted a 24% larger lumen size (#P = 0.009; B) and consequently decreased shear stress by 70% (*P = 0.039; C).

Intimal hyperplasia was first noted at day 3 (Figs. 5 and 6A), with enhanced intimal thickening in the low-flow graft (P < 0.001, two-way ANOVA). These differential rates of hyperplasia led to a sevenfold difference in intimal thickness at 28 days (231 ± 35 vs. 36 ± 18 µm for low-flow vs. high-flow graft; P = 0.001). Associated with the accelerated intimal hyperplasia in the low-flow graft was a significant elevation in early cell proliferation (Fig. 6B), as evidenced by the increase in BrdU-positive cell density at 3 days (P = 0.048).

View larger version (38K): [in this window] [in a new window]   Fig. 5. Neointima progression in low-flow (A) and high-flow (B) vein grafts. In the low-flow vein graft, neointima formation started by day 3, with dramatic progression during the first 2 wk. IEL, internal elastic lamina.

View larger version (16K): [in this window] [in a new window]   Fig. 6. Neointimal hyperplasia (A) and cell proliferation (B) over time in low-flow and high-flow vein grafts.

To investigate potential alterations in the hemodynamic environment induced by the cuff anastomosis, the pressure profile along the length of the arterial reconstruction was interrogated (Fig. 7). Our results demonstrate a near-equivalent pressure profile in the low-flow and high-flow grafts without significant pressure drop across the cuffed anastomosis. Pooled data from five 28-day vein grafts demonstrated no difference in the pressure drop between the ascending aorta and graft for the low-flow and high-flow grafts (3.8 ± 1.2 vs. 3.5 ± 1.3 mmHg for low-flow vs. high-flow graft; P > 0.05).

View larger version (24K): [in this window] [in a new window]   Fig. 7. Dynamic pressure measurements from a representative animal demonstrating little change in mean and maximum pressure across the cuffed anastomosis.

Also of potential concern is the effect of the rigid cuff on graft compliance near the anastomosis and its impact on intimal thickening and graft remodeling. Excluding the 2.0-mm segment of graft adjacent to the cuff, serial sections from the proximal, middle, and distal portions of perfusion-fixed vein grafts showed no consistent variation in the extent of intimal thickening, with overall intimal thickness ranging from 80 to 165 µm (mean 109 ± 11 µm) for the low-flow grafts and from 6 to 46 µm (mean 21 ± 5 µm) for the high-flow grafts. Similarly, no difference in lumen diameter across the length of perfusion-fixed vein grafts was observed (data not shown).

	DISCUSSION

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Model development. Although many investigators have used rabbit carotid interposition vein grafts to study graft adaptation and intimal hyperplasia (2, 4, 5, 13, 17, 18), our initial experience with the standard techniques for this model, using hand-sewn anastomoses, was variable. Mastering the microsurgical techniques required for a hand-sewn model presented a steep learning curve with inconsistent initial results. Whether the variability in our initial experience was related to prolonged conduit ischemia, increased conduit manipulation, or other factors was unclear. As our experience with the hand-sewn techniques increased and we began to develop complex vascular reconstructions focused on isolating the impact of hemodynamics on graft remodeling, it became apparent that these standard techniques were prohibitively time consuming and could not be fashioned into a reproducible, efficient surgical model. To meet these goals, we adapted a cuff anastomotic technique previously used in a rodent lung transplantation model (11). Use of these techniques, as described here, provided a technically less demanding and more reproducible method for vein graft placement. Significant improvements in the length of operation were also introduced with this model, with the time for bypass construction averaging 12 min for the experiments in this report. This improved efficiency proved instrumental in our ability to increase the complexity of the surgical models while providing reproducible hemodynamic environments with the power of paired internal controls.

This model system has direct application to understanding the array of early biochemical responses that occur during vein graft arterialization. Recent gene therapy research suggests that it is these early changes, during initial vein graft adaptation, which set the milieu for later development of pathological intimal hyperplasia and critical graft stenoses (1, 2, 9). One notable limitation of the current model configuration is an inability to duplicate the complex biomechanics that characterize the proximal and distal anastomoses. The compliance mismatch induced by the rigid cuff (15) and the use of an end-to-end configuration (8) precludes detailed study of healing and remodeling within the perianastomotic graft.

In this study we have applied the cuff anastomotic technique to multiple arterial reconstructions in the rabbit neck with variable clinical outcomes. Of particular note, vein graft placement in combination with immediate flow augmentation via a distal arteriovenous fistula resulted in a high failure rate, secondary to extensive hyperplasia within the distal vein cuff. In contrast, placement of a cuffed anastomosis without flow augmentation with a fistula or with delayed fistula placement demonstrated excellent patency. Also investigated was the effect of complete distal carotid ligation after interposition vein grafting. Although the murine carotid ligation model has become an important tool in the study of shear-regulated arterial remodeling (7), carotid ligation in our vein graft model led to graft occlusion within 4 wk after implantation. Although not a focus of the current project, insight into the failure mechanisms in those model configurations that progress to early occlusion has significant clinical implications. In particular, detailed understanding of graft adaptation under extremely low shear (e.g., complete carotid ligation) or extremely high shear (e.g., immediate fistula placement) offers an important area for additional investigation.

Impact of shear stress on vein graft remodeling. The initial work evaluating the importance of hemodynamic forces on rabbit vein graft remodeling was completed by Zwolak et al. (17). Examining the early changes in wall thickness and graft diameter under normal flow conditions, they identified normalization of the luminal radius-to-wall thickness ratio, a surrogate marker for circumferential wall tension, as an important component of graft adaptation. To further explore the impact of physical forces on myointimal thickening, Schwartz et al. (13) used various surgical reconstructions, including both arteriovenous fistulas and partial outflow obstructions, to independently manipulate shear stress and wall tension. Although relationships with both shear stress and wall tension were observed, an increase in wall tension most closely correlated with an increase in myointimal thickening, suggesting this to be the dominant mediator of the remodeling process.

The work of Galt et al. (4) focused on the effect of wall shear in the rabbit vein graft model, and the current model draws significantly on this experimental design. After bilateral placement of carotid interposition vein grafts, flow through the grafts was modulated with complete, unilateral distal ligation of the external carotid artery. In contrast to our work, the internal carotid artery was left widely patent. Their result was a reduced flow on the ligated side, without a compensatory increase in contralateral flow, leading to a 40% reduction in flow and a 50% reduction in wall shear. The impact on graft wall morphology was a 60% increase in intimal thickness (at 4 wk) under low-flow conditions, without significant change in lumen diameter.

To produce a more robust model with well-defined but disparate regions of high and low flow, we adapted the branch ligation techniques of Meyerson et al. (10) into the current experimental design. Through unilateral internal carotid ligation, in combination with extensive ligation of the external carotid system, a significant reduction in flow ipsilateral to the ligation combined with a marked elevation in compensatory contralateral flow was achieved. The result was a 15-fold difference in mean flow rate and wall shear stress throughout much of the 28-day perfusion period examined in this study. The impact on graft remodeling was a sevenfold difference in intimal thickening and a modest increase in lumen diameter. Despite the marked reduction in ipsilateral flow, all grafts remained patent throughout the 1- to 28-day perfusion period. Of note, no neurological ischemic events were noted as a result of this extensive unilateral ligation.

Unique to our model is the use of a rigid cuff for creation of the proximal and distal anastomoses. To validate this new technique, several potential sources of artifact were explored. With microtipped pressure catheters, grafts were interrogated along the length of the arterial reconstruction, with particular emphasis on evaluating the pressure gradient across the cuffed anastomosis. Although mild variations in the pressure wave-forms were observed secondary to impedance differences, kinetic energy loss across the cuffed anastomosis, most notably on the high-flow side, was not significant enough to impact mean pressure (Fig. 7). Also of potential concern was the impact of the rigid cuff on perianastomotic compliance and the secondary influence on the uniformity of remodeling along the graft length. Histological sections collected in the graft midportion and 2.0 mm from the proximal and distal cuffs demonstrated no significant differences in intimal thickening or graft diameter. Further evaluation at these sites with digital imaging of the graft in vivo demonstrated no significant difference in wall motion or dynamic wall compliance (unpublished observation).

In summary, we have taken advantage of a simplified technique for the creation of small-caliber vascular anastomoses and combined it with a bilateral vein graft-distal branch ligation model to dissect the impact of flow on vein graft arterialization. With the marked differences in intimal thickness, this model offers a robust, clinically relevant, economically viable, and statistically powerful small animal model for the evaluation of high- and low-shear-regulated vein graft remodeling.

	ACKNOWLEDGMENTS

 
GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grant 1K08 [PDB] -HL-04070-01A1, the Lifeline Foundation, the William J. von Liebig Foundation, the Association for Academic Surgery, the Whitaker Foundation, and the Howard Hughes Medical Research Foundation.

	FOOTNOTES

 

Address for reprint requests and other correspondence: S. A. Berceli, PO Box 100286, Gainesville, FL 32610-0286 (E-mail: bercesa{at}mail.surgery.ufl.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

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This Article Abstract Full Text (PDF) All Versions of this Article: 286/1/H240    most recent 00760.2003v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Jiang, Z. Articles by Berceli, S. A. Search for Related Content PubMed PubMed Citation Articles by Jiang, Z. Articles by Berceli, S. A.