Small-caliber heparin-coated ePTFE grafts reduce platelet deposition and neointimal hyperplasia in a baboon model

PURPOSE: Intimal hyperplasia and graft thrombosis are major causes of graft failure. Heparin prolongs graft patency and inhibits neointimal hyperplasia in animal models. The purpose of this study was to evaluate the effect of a heparin-coated expanded polytetrafluoroethylene (ePTFE) graft on platelet deposition and anastomotic neointimal hyperplasia after aortoiliac bypass grafting in a baboon model. METHODS: Heparin-coated ePTFE grafts (4-mm diameter) were incorporated into exteriorized femoral arteriovenous shunts placed in five baboons. Platelet deposition was analyzed by measuring the accumulation of indium 111-labeled platelets on the grafts, with dynamic scintillation camera imaging. Eight adult male baboons (mean weight, 9.3 kg) underwent bilateral aortoiliac bypass grafting with ePTFE grafts (4-mm internal diameter). In each animal a heparin-coated ePTFE graft was placed in one aortoiliac artery, and an uncoated graft, which served as the control, was placed in the contralateral aortoiliac artery. All grafts were harvested at 4 weeks, and were analyzed quantitatively for neointimal hyperplasia at graft-vessel anastomoses. RESULTS: Early platelet deposition on heparin-coated grafts after 1 to 4 hours of ex vivo circuitry was significantly reduced. All the harvested aortoiliac grafts were patent at 4 weeks. There was a significant reduction in neointimal area at both proximal (0.26 +/- 0.11 mm(2)) and distal (0.29 +/- 0.14 mm(2)) anastomoses in the heparin-coated grafts, compared with proximal (0.56 +/- 0.18 mm(2)) and distal (0.63 +/- 0.21 mm(2)) anastomoses in the untreated control grafts (P <.05). In addition, neointimal cell proliferation assayed with bromodeoxyuridine (BrdU) incorporation was reduced in the graft neointima (3.47% +/- 0.43%) in heparin-coated grafts compared with the graft neointima (6.21% +/- 0.59%) in untreated control grafts (P <.05). CONCLUSIONS: Small-caliber heparin-coated ePTFE grafts significantly reduce platelet deposition and anastomotic neointimal hyperplasia and cell proliferation, without measurable side effects, in baboons. Surface coating with heparin in small-caliber ePTFE grafts is useful for improving prosthetic bypass graft patency. Clinical relevance: An autologous vein graft is the ideal bypass conduit in peripheral arterial reconstruction; however, many patients who undergo bypass grafting do not have adequate or available autologous vein graft. As a result surgeons often must rely on prosthetic grafts as an alternative conduit in arterial bypass procedures. Clinical outcomes with prosthetic grafts in peripheral arterial reconstruction are generally inferior to those with autologous vein bypass grafts, in part because of anastomotic neointimal hyperplasia. This study evaluated the effect of small-caliber heparin-coated expandable polytetrafluoroethylene (ePTFE) grafts in aortoiliac reconstruction in a baboon model. The study found that heparin-coated ePTFE grafts resulted in less intimal hyperplasia and less platelet deposition after implantation, compared with noncoated control ePTFE grafts.     

Locally applied cilostazol suppresses neointimal hyperplasia and medial thickening in a vein graft model.

BACKGROUND: Pathological changes in vein grafts begin immediately after arterial circulation is applied to the grafts. Chemical mediator stimulation and mechanical strain induce neointimal hyperplasia and medial thickening of the vein grafts, resulting in their failure. We investigated the inhibitory effect of locally applied cilostazol, an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, on neointimal hyperplasia and medial thickening of the grafts. METHODS AND RESULTS: We established a distal anastomotic stricture model of femoral vein-abdominal aorta interposition grafting in rats. In this model, neointimal hyperplasia was observed not only at the distal anastomotic sites, but also in the graft body at postoperative day 14 and was markedly progressed at day 28. A strong expression of tenascin-C was found in the media and neointima of the graft body. In the grafts around which cilostazol was administered locally using Pluronic gel, neointimal hyperplasia was significantly suppressed compared with control grafts treated with the gel alone, with the mean neointimal cross-sectional area reduced by 87.1% for the graft body and by 78.9% for the distal anastomotic sites and mean medial cross-sectional area of the graft body reduced by 54.2% at day 28 versus the control. Cilostazol treatment decreased cell proliferation and the number of tenascin-C-producing cells seen by in situ hybridization, but the expression of tenascin-C protein was not suppressed. CONCLUSION: We concluded that a single perivascular application of cilostazol inhibits neointimal hyperplasia and medial thickening of vein grafts in a rat model.     

Vein cuff interposition prevents juxta-anastomotic neointimal hyperplasia.

This study sought to minimize juxta-anastomotic neointimal hyperplasia (JNIH) following the use of polytetrafluorethylene (PTFE) conduits. PTFE anastomoses to canine carotid arteries (noncuff grafts) were compared with grafts with vein cuffs interposed proximally and distally between the graft and native artery. This technique has been suggested clinically for below-knee PTFE femoropopliteal reconstruction. Twelve dogs received aspirin for 1 week before operation, which was continued after each animal received bilateral cuff and noncuff 4-mm PTFE grafts. At sacrifice, after 3-12 weeks, graft patency was assessed and luminal diameters measured with ophthalmic calipers at three sites along the anastomoses and 1 mm proximal or distal to graft toe (A' diameter). Specimens were perfusion fixed at arterial pressure for gross and histologic study; selected arteries were additionally fixed with 4% buffered glutaraldehyde, stored at 4 C, and examined immunochemically using antimyosin antibody immunopurified for smooth muscle. Overall patency of noncuff grafts in 11 long-term surviving dogs was 4 of 11; patency of the cuff grafts was 7 of 11. Regardless of graft thrombosis, antibody positive cellular proliferation occurred mainly at noncuffed PTFE anastomoses. Luminal encroachment was predominantly due to subintimal proliferation of cells highly reactive to smooth muscle derived antibody. JNIH was most prominent 1 mm distal to the graft toe (A' distal diameter). Average A' for noncuff grafts was 1.82 mm +/- 0.97 SEM; average A' diameter for cuff grafts was 3.41 mm +/- 0.74 SEM (p less than 0.001). Vein cuff inhibition of proliferation of smooth muscle or cells derived from smooth muscle possibly relates to wider distribution of kinetic energy (less compliance mismatch) or to interposition of venous endothelium.     

Inferior vena cava bypass: experimental evaluation of externally supported grafts and initial clinical application

Inferior vena caval obstruction is an unusual but important clinical problem for which adequate treatment previously has not been available. Recently, a polytetrafluoroethylene (PTFE) graft with external rigid spiral supports was developed that appeared particularly applicable to the venous system. In 18 dogs a 15 cm length of Impraflex was placed from the proximal right common iliac vein to the inferior vena cava (IVC) at the level of the renal veins after IVC and right iliac vein interruption. End-to-end and end-to-side iliac vein anastomoses were alternated, with and without distal femoral arteriovenous (AV) fistulas (AVFs). At 2 months, with a distal AV fistula, 11 of 12 (92%) grafts were patent, angiograms demonstrated no evidence of intraluminal clot, and there was no hind limb edema. Following AVF ligation 2 months after graft insertion, 10 grafts remained patent, but five developed some intraluminal thrombus and one of them progressed to complete occlusion. Four months after fistula ligation (6 months after graft insertion) 9 of 12 grafts (75%) remained patent. All six grafts without distal AVF were occluded within 1 week. This procedure was performed on one severely symptomatic patient who had IVC occlusion, and currently the patient shows marked improvement. Thus IVC bypass is possible when an externally supported PTFE prosthesis is complemented by a temporary AVF.     

Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts.

OBJECTIVE: Rapamycin is an immunosuppressive agent with marked antiproliferative properties and is effective in reducing in stent restenosis and vein graft neointimal hyperplasia. Apoptosis is one mechanism counterbalancing cellular proliferation. We therefore investigated the role of apoptosis in rapamycin treated vein grafts in a mouse model. METHODS: C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a cuff technique. In the treatment group 200 microg of rapamycin were applied locally in pluronic gel. The control group did not receive local treatment. Vein grafts were harvested at 4 weeks postoperatively and underwent morphometric analysis as well as immunohistochemical analysis for apoptosis (TUNEL). RESULTS: In grafted veins without treatment (controls) neointimal thickness was 50 (12-58) microm at 4 weeks postoperatively. In 200 microg rapamycin treated grafts the neointimal thickness was 17 (5-55) microm. Rapamycin treated vein grafts showed a significantly increased rate of apoptosis in the adventitia as compared with controls (P=0.032). In the neointima the apoptosis rate was lower in both groups with no significant difference between rapamycin treated grafts and controls. CONCLUSION: We conclude that treatment of experimental vein grafts with rapamycin is associated with an increased apoptosis rate in the vascular wall and a trend towards reduction of neointimal hyperplasia. These results suggest that apoptosis may be a beneficial antiproliferative component for the treatment of vein graft disease.     

Compliance in anastomoses with and without vein cuff interposition.

OBJECTIVE: to compare anastomotic compliance in end-to-side anastomoses with and without vein cuff interposition. Materials polytetrafluoroethylene graft to bovine carotid artery without (standard) and with vein interposition (Linton-patch and Miller-cuff). METHODS: zonewise compliance measurement of end-to-side anastomoses in an in-vitro circulation system. The zone most distal to the suture-line served as reference compliance. RESULTS: directly distal to the suture-line the compliance of the Linton-patch (5.6+/-1.6%/100 mmHg) and Miller-cuff anastomosis (5.2+/-1.1%/100 mmHg) more closely approached reference compliance (standard: 5.0+/-1.2, Linton-patch: 4.5+/-1.5, Miller-cuff: 4.9+/-1.0%/100 mmHg) than that of the standard anastomosis (7.9+/-3.0%/100 mmHg). The maximal compliance values of the Linton-patch (9.5+/-2.3%/100 mmHg) and Miller-cuff anastomoses (9.8+/-2.7%/100 mmHg) were significantly higher than that of the standard end-to-side anastomosis (7.9+/-3.0%/100 mmHg). However, maximal compliance was shifted from the zone directly distal to the suture line in the standard end-to-side anastomosis, to the vein cuff interposition in the Linton-patch and Miller-cuff anastomoses. CONCLUSION: the shift in maximal compliance to the wider portion of the anastomosis in the Miller-cuff and Linton-patch anastomoses may obviate reocclusion.     

Locally applied cilostazol suppresses neointimal hyperplasia by inhibiting tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts

OBJECTIVE: Accumulation of smooth muscle cells and extracellular matrix in the intima of artery bypass grafts induces neointimal hyperplasia, resulting in graft failure. We investigated the inhibitory effect of locally applied cilostazol, an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, on neointimal hyperplasia and the role of tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts.Methods and results We established a distal anastomotic stricture model of free artery graft stenosis using rat abdominal aorta. In this model, neointimal hyperplasia was observed not only in the distal anastomotic site but also in the graft body at postoperative day 14 and was markedly progressed at day 28. Strong expression of tenascin-C was found in the media and neointima of the graft body. When cilostazol was locally administered around the graft using Pluronic gel, neointimal hyperplasia of the graft was significantly suppressed in comparison with gel-treated control graft. The mean neointima/media area ratio was reduced by 86.6% for the graft body and by 75.8% for the distal anastomotic site versus the control. Cilostazol treatment decreased cell proliferation and tenascin-C expression in the neointima. In an in vitro experiment using cultured smooth muscle cells isolated from rat aorta, cilostazol completely suppressed the tenascin-C mRNA expression induced by platelet-derived growth factor-BB. CONCLUSION: A single topical administration of cilostazol may suppress neointimal hyperplasia by inhibiting cell proliferation and tenascin-C synthesis in free artery grafts, presenting the potential for clinical use in vascular surgery.     

Connective tissue changes in a mouse model of vein graft disease

AIM: The extracellular matrix plays an important physiological role in the architecture of the vascular wall. In arterialized vein grafts severe early changes, such as thrombosis and neointimal hyperplasia occur. Paclitaxel is in clinical use as antiproliferative coating of coronary stents. We aimed to investigate the early connective tissue changes in arterialized vein grafts and the influence of perivascular paclitaxel treatment in an in vivo model. METHODS: C57 black mice underwent interposition of the vena cava into the carotid artery. Neointimal hyperplasia, thrombosis, acid mucopolysaccharides (Alcian), collagen fibers (trichrome Masson), elastic fibers, and apoptosis rate (TUNEL) were quantified in paclitaxel treated veins and controls. RESULTS: In both, controls and paclitaxel treated vein grafts acid mucopolysaccharides and elastic fibers were found predominantly in the neointima, whereas collagen fibers were found mainly in the media and adventitia. At 4 weeks postoperatively the neointimal thickness in controls was 52 (13-130) microm, whereas in 0.6 mg/mL l paclitaxel treated veins it was 103 (43-318) microm (P=0.094). At 8 weeks postoperatively paclitaxel treated veins showed a significantly increased neointimal thickness of 136 (87-199) microm compared with 79 (62-146) microm in controls (P=0.032). There was no difference in apoptosis rate between the two groups (P=NS). Even with the lowest concentration of 0.008 mg/mL paclitaxel veins showed a neointimal thickness of 67 (46-205) microm at 4 weeks postoperatively (P=NS vs controls). CONCLUSION: Early vein graft disease is characterised by an accumulation of acid mucopolysaccharides and elastic fibers in the thickened neointima. Paclitaxel treatment increases the neointimal hyperplasia in mouse vein grafts in vivo.     

The direct effect of graft compliance mismatch per se on development of host arterial intimal hyperplasia at the anastomotic interface

To study thedirect andsole effect of compliance mismatch on anastomotic intimal hyperplasia of the host arterial wall and to minimize possible confounding factors, dogs with a low thrombotic potential were selected as experimental subjects. Externally supported 6 cm × 5 mm Dacron grafts with a compliance value of approximately 1/300 of the host artery were implanted into the carotid arteries with end-to-end anastomoses on one side and end-to-side anastomoses on the other. The control graft was an autogenous carotid artery segment 4 cm in length transplanted into the femoral artery. Eight cases (24 grafts) were studied for 1 year and three (nine grafts) for 6 months. All were patent throughout the study period except for two noncompliant grafts with end-to-end anastomoses; thrombosis was the documented cause of occlusion. For the patent grafts, follow-up arteriograms showed no progressive narrowing of noncompliant anastomoses. Whether compliant or noncompliant, light microscopy studies showed slight intimal thickening within 1 to 2 mm of the anastomotic line, possibly the result of the normal healing response to stitch and surgical trauma. Quantitatively, 22 measurements representing longitudinal and circumferential thickness of the neointima were taken at each of the 40 patent noncompliant and 22 patent compliant control anastomoses. There was no statistically significant difference in anastomotic neointimal thickness in compliant and noncompliant grafts or for the different implantation periods. These data suggest that graft/host artery compliance mismatch does not cause arterial intimal hyperplasia at the anastomotic interface.Presented at the Seventh Annual Meeting of the Western Vascular Society, Maui, Hawaii, January 11–15, 1992.     

Pro-UK基因抑制静脉移植物细胞增生的实验研究

目的：探讨Ｐｒｏ－ｕｋ基因对静脉桥移植物细胞增生的影响。方法：３００￣３５０ｇ Ｗｉｓｔａｒ大鼠４２只,取下双鼠颈静脉,两端阻断后,用含Ａｄｖ５－ＣＭＶ／Ｐｒｏ－ＵＫ质粒（治疗组,２１只）的溶液扩张静脉,使溶液在静脉 腔内滞留３０分钟降温末然后置于同一大鼠的颈总动脉。术后２８天,取静脉移植物行尿激酶原活性测定,观察Ｐｒｏ－ＵＫ表达（２６５ｉｕ／ｇｔｉｓｓｕｅ）,对照组未测到Ｐｒｏ－ＵＫ活性。虽然两     

Evaluation of platelet deposition and neointimal hyperplasia of heparin-coated small-caliber ePTFE grafts in a canine femoral artery bypass model

INTRODUCTION: Bypass graft failure due to acute thrombosis and intimal hyperplasia remains a major challenge in small-diameter vascular prosthetic graft reconstruction. Heparin has been shown to prevent thrombus formation and inhibit intimal antithrombotic in animal studies. In this study, we evaluated the effect of small-caliber heparin-coated expanded polytetrafluoroethylene (ePTFE) grafts on platelet deposition and intimal hyperplasia in a canine model of femoral artery bypass grafting. METHODS: Nine adult greyhound dogs underwent placement of bilateral femorofemoral artery bypass grafts with ePTFE grafts (4 mm diameter and 7 cm long). In each animal, a heparin-coated ePTFE graft was placed on one side while a noncoated graft was placed on the contralateral side which served as the control. Platelet deposition was measured by autologous (111)indium-labeling and scintillation camera imaging analysis in 24 h. The graft patency was assessed at 4 weeks following the bypass. The effect of intimal hyperplasia was assessed with histological and morphometric analysis. RESULTS: Platelet deposition on the heparin-coated grafts at 24 h was significantly reduced by 72% as compared to controls (P = 0.001). The patency rate was 44% in control grafts and 89% in heparin-coated grafts. There was a significant reduction of graft intimal hyperplasia at both proximal (0.38 +/- 0.21 mm(2)) and distal (0.19 +/- 0.06 mm(2)) anastomoses in the heparin-coated grafts as compared with proximal (1.01 +/- 0.28 mm(2)) and distal (0.42 +/- 0.01 mm(2)) anastomoses in the untreated control grafts, respectively (P < 0.05). Heparin coating significantly reduced graft neointimal hyperplasia at patent graft anastomoses by 55-72% as compared to controls. CONCLUSIONS: These data demonstrate that heparin coating of ePTFE significantly reduced early platelet deposition and inhibited anastomotic neointimal hyperplasia. Moreover, small-caliber heparin-coated ePTFE graft significantly increased graft patency in a canine femoral artery bypass model. This may represent a promising treatment strategy for improving the clinical performance of small-caliber prosthetic vascular grafts.     

Intimal hyperplasia and neointima: An ultrastructural analysis of thrombosed grafts in humans

The distal anastomoses of thrombosed saphenous vein (11), bovine (4), Dacron (7), and polytetrafluoroethylene (PTFE) (27) grafts removed en bloc during reoperation or amputation were studied with light microscopy, scanning electron microscopy, and transmission electron microscopy. Analysis of the ultrastructures of the distal anastomostic regions was done to characterize morphogenesis of intimal hyperplasia and neointimal proliferation. Complete reendothelialization occurred in all vein grafts. In bovine heterografts, there were isolated areas of endothelia. Thrombosed PTFE grafts were lined with gelatinous, proteinaceous material with no consistent organized cellular pattern. In contrast, laminated fibrous tissue produced by fibroblasts lined the Dacron grafts. Intimal hyperplasia was found in 6 of 11 vein grafts and in all prosthetic grafts examined. Regardless of the type of graft used, intimal hyperplasia was found predominantly at the heel of the graft and on the floor of the artery. Beneath the endothelia, collagenous ground substance and myofibroblasts mixed with smooth muscle cells were seen, characterized by pyknotic nuclei, reduced cytoplasm/nuclei ratio, and loss of cytoplasmic organelles. Endothelialization occurred exclusively in vein grafts. Prosthetic grafts lacked endothelia, with the neointima consisting of fibroblasts and fibrous matrix. In intimal hyperplasia, two forms of smooth muscle cell pathomorphogenesis were recognized. Formation of myofibroblasts induced medial fibroplasia, whereas degeneration of muscle cells progressed to medial necrosis. Smooth muscle cells seem to play a role not previously recognized in the pathogenesis of graft failure.     

Efficacy of local dipyridamole therapy in a porcine model of arteriovenous graft stenosis

Perivascular delivery of antiproliferative drugs has been proposed as an approach to prevent neointimal hyperplasia associated with hemodialysis polytetrafluoroethylene (PTFE) grafts. We examined this approach to deliver dipyridamole in a porcine graft model. PTFE grafts were implanted between the carotid artery and external jugular vein bilaterally in pigs. During the surgery or 1 week post-graft placement, dipyridamole (0.26-52 mg) alone or incorporated in microspheres was mixed with an injectable polymeric gel and applied to the graft-arterial and graft-venous anastomoses on one side, whereas the contralateral control graft received no treatment. Three or four weeks after operation, the grafts and adjacent vessels were explanted en bloc and cross-sections of the anastomoses were examined histologically. The degree of neointimal hyperplasia was quantified by planimetry. In separate experiments, dipyridamole was extracted from the explanted tissues and assayed by spectrofluorometry. The normalized median hyperplasia areas of the treated and control graft-venous anastomoses were 0.45 (25th-75th percentile, 0.30-0.86) and 0.24 (0.21-0.30), respectively (N=7; P=0.08). The median hyperplasia areas of the treated and control graft-arterial anastomoses were 0.12 (0.07-0.39) and 0.11 (0.09-0.13), respectively (N=7; P=0.31). The dipyridamole levels in the vascular walls around the anastomoses were at or above the in vitro inhibitory concentrations for approximately 3 weeks. These results suggest that the local perivascular sustained delivery of dipyridamole, even at high dosages, was ineffective in inhibiting neointimal hyperplasia associated with PTFE grafts in a porcine model.     

Local infusion of heparin reduces anastomotic neointimal hyperplasia in aortoiliac expanded polytetrafluoroethylene bypass grafts in baboons

PURPOSE: Recently, we designed and characterized a novel expanded polytetrafluoroethylene (ePTFE)-based local drug delivery approach that selectively concentrates infused pharmacologic agents specifically within those blood layers adjacent to the graft wall and at downstream anastomotic sites. In this study, we locally administrated standard heparin therapy and evaluated its effects on neointimal hyperplasia formation in a baboon model of aortoiliac bypass graft placement. METHODS: Six adult male baboons underwent bilateral aortoiliac bypass grafting with ringed ePTFE (4 mm internal diameter x 5 cm length). In each animal, the distal anastomosis of one graft was continuously infused with heparin (50 U/h) and the distal anastomosis of the contralateral graft was infused with saline solution at the same rate (2.5 microL/h), with osmotic pumps implanted for 4 weeks. Platelet counts and activated partial thromboplastin time measurements were performed weekly. The specimens were harvested at 4 weeks and were subjected to morphometric analysis. Cell proliferation was assessed with bromodeoxyuridine immunostaining. RESULTS: All the harvested grafts were patent except for one control graft. There were no significant differences in platelet counts or activated partial thromboplastin time measurements taken before and during heparin infusion. As expected, there were no significant differences in graft neointimal hyperplasia and cell proliferation at the proximal anastomoses between the heparin-infused and control grafts. In contrast, at the treated distal anastomoses, heparin infusion significantly reduced the graft neointimal area by 65% and the cell proliferation index by 47% as compared with the untreated control distal anastomoses. CONCLUSION: These results show that local infusion of heparin significantly reduces distal anastomotic neointimal hyperplasia and cell proliferation without measurable systemic anticoagulation or other side effects. Thus, this approach may represent an attractive strategy for prolonging ePTFE bypass graft patency.     

The protective effect of vein cuffed anastomoses is not mechanical in origin

Purpose: Intimal hyperplasia (IH) is a proliferative process of vascular smooth muscle cells that occurs after an arterial injury, particularly at outflow anastomoses of prosthetic bypass grafts. IH causes stenosis that leads ultimately to graft flow reduction and thrombosis. We have demonstrated previously that vein cuff interposition between an expanded polytetrafluoroethylene (e-PTFE) graft and artery at distal anastomoses diminished IH formation in the arterial outflow as compared with noncuffed anastomoses. Improved long-term patency rates associated with the placement of an interposition vein cuff at the distal anastomosis of e-PTFE grafts to infrageniculate arteries have also been demonstrated clinically. This study examined the mechanical factors that may contribute to the protective effect of cuffed anastomoses. These factors include the expansibility of the vein cuff as compared with e-PTFE, as well as the angle of the cuffed anastomosis.Methods: Compatible animals were selected by use of platelet aggregation studies. Nine dogs, group A, received a 4 mm e-PTFE graft plus a 1 cm long interposition vein cuff at the distal anastomosis in the left carotid artery. The same procedure was done on the right side, and in addition the vein cuff was encircled by an e-PTFE jacket incorporated into the anastomosis to prevent the expansion of the vein cuff with arterial pulsation. To study the effect of distal anastomotic angle and geometry on the formation of IH, five dogs, group B, received a 4 mm e-PTFE graft in both sides. On the left, the distal anastomosis was performed between the graft and the artery at an acute angle as it is commonly done when a bypass graft is placed. On the right side a 1 cm long, 6 mm diameter e-PTFE segment was interposed between the artery and the graft at a perpendicular angle. This geometry mimicked the right angle of a vein cuff - to-artery anastomosis. After 10 weeks the grafts were harvested, and the thickness of IH was measured with an ocular micrometer under light microscopy.Results: In group A, one dog had bilateral graft thrombosis (12%), and these grafts were discarded. In the remaining eight dogs there was no statistically significant difference in the thickness of IH between the right (jacketed group) and the left side (nonjacketed/control group), showing that vein cuff expansibility did not play a role in protecting against the formation of IH. In group B, bilateral graft thrombosis occurred in four of five dogs (80%), suggesting that the perpendicular anastomotic angle was not protective.Conclusion: These results suggested that the protective effect of the vein cuff is not mechanical in origin. (J VASC SURG 1995;21:558-66.)     

Optimal graft diameter: effect of wall shear stress on vascular healing

Arterial walls tend to adapt to maintain a specific wall shear stress. The formation of neointimal hyperplasia and endothelial cell healing of polytetrafluoroethylene grafts may also be governed by wall shear stress, which suggests that an optimal graft diameter may exist. To test this, 40 polytetrafluoroethylene grafts with internal diameters of 3, 6, and 8 mm were inserted end to end in the femoral and carotid arteries of 10 mongrel dogs. Total flow and diameter were measured, and grafts were stained with Evans blue dye, fixed by pressure perfusion, and analyzed by computer for anastomotic neointimal thickening, graft pseudointimal thickening, and degree of endothelial coverage. Mean calculated shear stress was 41 dyne/cm2 for the 3 mm grafts, 7 dyne/cm2 for the 6 mm grafts, and 3 dyne/cm2 for the 8 mm grafts. Fifteen weeks later the patency rate was 0 of 10 for the 3 mm grafts, 16 of 20 for the 6 mm grafts, and 7 of 10 for the 8 mm grafts. The mean graft shear stress was calculated to be 10 dyne/cm2 for the 6 mm grafts and 4 dyne/cm2 for the 8 mm grafts. Pseudointima lining the graft was composed of disorganized protein and cell remnants. The rough surface contained no overlying endothelium. Anastomotic neointima contained a layer of well-organized smooth muscle cells covered by a single layer of polygonal-shaped endothelial cells. A transition zone of thrombus, which is sandwiched by a wedge of smooth muscle cells near the graft surface and covered by endothelial cells, is described. Mean thickness of pseudointima of the patent 8 mm grafts was 150 microns thicker than that of the 6 mm grafts. Anastomotic neointimal thickness was 110 microns thicker in the 8 mm grafts compared with the 6 mm grafts. Among the 6 mm grafts, the carotid grafts had an average initial shear stress of 10 dyne/cm2, whereas the femoral grafts averaged a lower 5 dyne/cm2 and yielded pseudointima and neointima that were 40 microns thicker. The percent graft surface area covered with neointima did not differ among the grafts of differing diameter either proximally or distally. Lower shear stresses produced greater amounts of pseudointimal thickening within polytetrafluoroethylene grafts and neointimal thickening at their anastomoses. Conversely, the high shear stress from small-diameter grafts was associated with poor graft patency. These results suggest that an optimal graft diameter may help to prevent neointimal hyperplasia and graft thrombosis.     

Peptide inhibition of neointimal hyperplasia in vein grafts.

Angiopeptin, a novel synthetic octapeptide, was evaluated as a new approach toward the inhibition of neointimal hyperplasia in vein grafts. Male New Zealand white rabbits (n = 22) underwent carotid artery interposition bypass grafting with autologous reversed jugular vein. Nine rabbits were in the treatment group, and 13 were in the control group. The treatment group received angiopeptin 20 micrograms/kg/day by subcutaneous injection beginning 1 day before operation and continuing for 3 weeks until they were killed. At death the vein grafts were fixed in situ with 10% buffered formalyn at 80 mm Hg perfusion pressure. Histologic sections through each vein graft were analyzed by computerized morphometric analysis for area of neointimal hyperplasia (mm2). Neointimal hyperplasia in the control animals was 0.080 + 0.017 mm2 (mean + SEM), whereas neointimal hyperplasia in the group treated with angiopeptin was 0.022 + 0.006 mm2 (mean + SEM) (p = 0.02). This is the first time that peptide inhibition of neointimal hyperplasia has been demonstrated in vein grafts and may have significant implications for future use in vascular surgery.     

Technique for the Coronary Snake Graft Operation

The use of one end-to-side anastomosis with side-to-side technique for all additional vein-coronary anastomoses has given continually good results and has been used in 227 of 411 patients undergoing vein graft operations, including all multiple graftings done since April, 1972. The operative mortality was 4.6%.Arteriography by the end of the third postoperative month has been obtained in 98.4% of the 377 eligible patients. It showed that 98% of the 304 side-to-side anastomoses were patent, with 289 (95%) having unrestricted communication with the aorta. The proximal segment was widely patent in 193 (97%) of the 200 patients with snake grafts having postoperative arteriography. The distal end-to-side anastomosis was patent in 176 (88%) of these 200 patients. The average was 2.3 unrestricted grafts per patient. These results are better than the patency rates of 89 and 87% obtained previously with single and Y-grafts, respectively.Technical details have been worked out for construction of suture lines, choosing the correct length for segments, obtaining a reliable proximal segment, routing grafts to multiple coronary branches, and removing air from the grafts.     

Long-term effects of extraluminal dilatation with a rigid circle on arteriovenous anastomotic line in venous grafts transposed into arterial defects

Postanastomotic narrowing resulting from subintimal hyperplasia is a well-known phenomenon. In the current study the authors compared a metallic circle and conventional suture technique in anastomoses performed in two ends of external jugular vein grafts interposed in carotid arteries of rabbits. They recorded the patency rates, fluid flow rates, and histological effects of the circle on the anastomotic line and compared them with conventional suture anastomoses. In 16 rabbits (experimental group) a standard suture was used in both ends of the jugular vein graft transposed to the carotid arteries on one side. On the other side, circle anastomoses were performed on both ends of the vein graft. In an additional 8 rabbits (control group), the anterior jugular veins and carotid arteries were dissected on both sides and left. During postoperative week 12, in 8 rabbits of the experimental group, the flow rates of carotid arteries were measured in vitro, and intraluminal silicone casts were prepared. In the remaining 8 experimental rabbits, carotid angiographies were performed and anastomotic segments were harvested for histological examination. Flow rates were also measured in the control group, and artery and vein segments were harvested. The patency rates of the vein grafts with metallic circle anastomoses were 100%, whereas conventional suture patency was 75% at week 12. Flow rates were significantly higher in the metallic circle-anastomosed vein grafts (74 ml per minute vs. 123 ml per minute, mean values; p < 0.05). Histological examination revealed reduced intimal thickness in the metallic circle anastomoses compared with conventional suture anastomoses. Dilatation of the arteriovenous end-to-end anastomotic line by a rigid circle prevents anastomotic narrowing in the long term.