Anastomotic Intimal Hyperplasia Research Articles

Prevention of Anastomotic Intimal Hyperplasia in Infrainguinal PTFE Bypass Grafts with Distal Arterial Segment Interposition

Anastomotic intimal hyperplasia (AIH) is a common cause of graft failure after femoropopliteal polytetrafluoroethylene (PTFE) bypass. Compliance mismatch between the PTFE graft and the native artery may be a significant factor causing AIH. This study examines whether reduction of compliance mismatch by interposition at the distal anastomosis of a segment of superficial femoral artery after eversion endarterectomy could reduce or eliminate AIH and improve graft patency. Between July 1989 and June 1996, PTFE grafts with a distal arterial segment (AS) were used to revascularize 51 limbs in 45 patients (12 men and 33 women). Twenty-five grafts were above-knee (AK) and 26 below-knee (BK). Disabling claudication was the indication in 32 limbs (AK 20, BK 12) and limb-threatening ischemia in 19 (AK 5, BK 14). Physical examination, measurement of ankle-brachial index, and duplex scanning were used to follow up patients at regular intervals. For those patients who had recurrent symptoms and/or reduction of ankle/brachial index (ABI), arteriography was performed. Follow-up ranged from 1-54 months (mean 20 months) for AK grafts and 1-76 months (mean 19 months) for BK grafts. The overall primary patency rate at 4.5 years was 57.2%. There appears to be no significant difference between AK and BK primary patency survival distributions (64.8% vs 48.5%). The primary patency failure distributions for the two ischemic conditions are statistically significant (69.8% vs 31.9%). The limb salvage rate at 4.5 years was 80%. Of the 51 grafts, the causes of the 19 failures included progression of disease in eight, thromboembolus in three, stenosis of the AS in three, poor runoff in one, AIH at the proximal anastomosis in one, and unknown in three. This pilot study suggests that the femoropopliteal PTFE bypass with distal AS interposition provides improved graft patency and limb salvage rates when compared with those published in the literature for PTFE bypass without the AS. Further evaluation is warranted.

Evaluation of Distal Anastomotic Intimal Hyperplasia: An Experimental Comparison by Arteriography, Duplex Sonography, Angioscopy, and Intravascular Ultrasound

Routine follow-up investigation methods after peripheral arterial bypass surgery, such as arteriography and colour duplex sonography, do not always allow correct analysis of moderate alterations in the vessel wall, e.g. initial stages of distal anastomotic intimal hyperplasia (DAIH). The aim of this study was to evaluate the efficiency of angioscopy and intravascular ultrasound compared to the named routine methods regarding detection of early DAIH. Eight months after bilateral femoropopliteal bypass surgery with venous grafts in 18 sheep, we investigated the distal anastomotic sites using the named methods. The findings were then correlated to histologic specimens. Intravascular ultrasound presented the highest sensitivity followed by angioscopy, with results markedly different from the findings arrived at by conventional methods.

Distal Anastomotic Intimal Hyperplasia: Histocytomorphology, Pathophysiology, Etiology, and Prevention

The ubiquitous relationship of late graft occlusion, particularly the nonautogenous bypasses and distal anastomotic intimal hyperplasia (DAIH), has been extensively investigated. After having established the specific location of DAIH in human autogenous, biologic and prosthetic late graft occlusion, canine models were designed to elucidate the role of compliance mismatch between graft and the host artery and the configuration of the distal end to side versus end to end anastomosis using autogenous artery. DAIH occurred in all end to side anastomosis but not in side matching end to end anastomosis. Compliance mismatched is not the cause of DAIH development, but it enhances the pathogenesis. Further study using pharmacologic agents to modulate the activities of vascular myoblasts was successful in attenuating DAIH development and progression. Since DAIH occurs through a cascade of events initiated by endothelial lifting of the overlapping processes at the gap junction to allow blood borne elements to enter the subendothelial space, then incites myoblast proliferation and matrix synthesis leading to DAIH formation at the heel and toe where oscillatory flow exists. Control of myoblast activity is needed on a permanent basis to prevent DAIH development and progression. Cessation of treatment allows resurgence of DAIH biogenesis. Direct regulation of vascular myoblast activity preclude the need of inhibiting other source of stimuli that increases as our knowledge of the subject grows. Without the participation of myoblast, there will be no DAIH irrespective of the potency and numbers of enzymatic, hormonal, or mechanical inciting factors.

Application of coacervated alpha-elastin to arterial prostheses for inhibition of anastomotic intimal hyperplasia.

Prevention of anastomotic intimal hyperplasia (AIH) requires inhibition of the migration of smooth muscle cells (SMCs) and promotion of endothelial cell (ECs) growth from the native arterial wall. We investigated the effect of coacervated alpha-elastin on migration of SMCs and ECs in vitro. SMCs and ECs were prepared from porcine aortic media and endothelium. Coacervated alpha-elastin was coated and cross-linked around the perimeter of each 1 cm diameter center of a well in a 12 well plate. SMCs and ECs were placed and cultured within the center of each well. The migration of SMCs and ECs on coacervated alpha-elastin was assayed on the second, third (10 mg/ml), or fourth day (0.1, 1.0, 10.0 mg/ml) of cultivation by measuring the area of migration from the 1 cm diameter center. Coacervated alpha-elastin was then coated and cross-linked on a Dacron graft using 1% glycerol polyglycidyl ether (GPGE) and examined with scanning electron microscopy to determine the feasibility of graft coating. SMC migration was significantly inhibited dose dependently over time (p < 0.005), e.g., 0.1 mg/ml (45.4% +/- 2.7%: % of MES [pH 5] and 1% GPGE without alpha-elastin), 1.0 mg/ml (32.0% +/- 1.4%), 10.0 mg/ml (8.3% +/- 2.9%). EC migration (90.7% +/- 6.2%: p = ns) was not inhibited by 0.1 mg/ml of coacervated alpha-elastin. Cross-linked coacervated alpha-elastin was coated on a dacron graft uniformly. Incorporation of coacervated alpha-elastin into the structure of arterial prostheses offers the possibility of inhibition of SMC hyperplasia without inhibition of EC formation.

Flow waveform effects on end-to-side anastomotic flow patterns

Purpose: Restenosis due to distal anastomotic intimal hyperplasia, a leading cause of arterial bypass graft failure, is thought to be promoted by hemodynamic effects, specifically ‘abnormal’ wall shear stress patterns. The purpose of this study was to quantify the effects of flow waveform on peri-anastomotic flow and wall shear stress patterns. Methods: Blood flow and wall shear stress patterns were numerically computed in a representative three-dimensional anastomosis using femoral, iliac and coronary flow waveforms suitable for humans at rest. Numerical results were validated against experimental data. Results: Peri-anastomotic wall shear stress patterns were influenced by a complex interplay between secondary flow effects and unsteadiness. Peripheral flow waveforms (iliac, femoral) produced large temporal and spatial wall shear stress gradients on the host artery bed. In comparison, the coronary flow waveform produced normalized bed wall shear stress gradients that were a factor of 2–3 less than for the peripheral waveforms, even though average bed wall shear stress magnitudes were similar for the two waveforms. Conclusions: If anastomotic intimal hyperplasia is promoted by large spatial and/or temporal gradients of wall shear stress, as has been proposed, this study predicts that there will be markedly less intimal hyperplasia on the host artery bed of coronary bypass grafts than for peripheral bypass grafts. This information, in conjunction with a comparative histopathologic study of intimal hyperplasia distribution, could help determine specific wall shear stress factors promoting intimal hyperplasia.

Identification of multiple genes with altered expression at the distal anastomosis of healing polytetrafluoroethylene grafts

Purpose: Anastomotic intimal hyperplasia remains a significant cause of delayed prosthetic arterial graft failure. Prior studies have identified several genes with altered expression within the hyperplastic region at the downstream polytetrafluoroethylene arterial anastomosis as compared with normal arteries. The purpose of the current study was to determine the sequence of early gene-related events at the distal anastomosis of an in vivo prosthetic arterial graft model. Messenger RNA (mRNA) differential display was used to screen for alterations in gene expression between anastomotic sites and control arterial segments. Methods: Six carotid interposition 6-mm expanded polytetrafluoroethylene grafts were placed in mongrel dogs, with the intervening carotid artery segment serving as the baseline control. Five days after graft implantation, the distal anastomotic artery segments were harvested and total RNA was isolated from both the intervening normal arteries and anastomotic segments. Differential mRNA display was used to identify candidate complementary DNA (cDNA) clones with expression that differed in anastomotic segments as compared with normal intervening arteries. Northern blot analysis confirmed alteration of gene expression. The cDNA clones were sequenced, and gene databases were searched. Novel sequences were used as probes for screening human cDNA libraries. Results: Approximately 7000 mRNA species were screened, and 26 candidate clones were obtained. Northern blot analysis showed altered gene expression in 10 (38%) of the clones, undetectable signals in 13 (50%), and nonregulation in 3 (12%). Seven clones with 92% homology at the nucleotide level to human α 1 (III) procollagen gene and a novel sequence were expressed only at the distal anastomosis. A clone representing apolipoprotein J and a novel sequence had increased expression at the distal anastomosis of 364% ± 236% and 156% ± 47%, respectively (mean percentage, control ± standard deviation). Conclusions: These studies identified genes with expressions that increased or were exclusive to the distal anastomosis of healing prosthetic arterial grafts in an in vivo prosthetic arterial graft model. Type III collagen may contribute significantly to the composition of the extracellular matrix associated with intimal hyperplasia by increasing lesion volume. Apolipoprotein J, through its association with proteases, may modulate some of the matrix changes seen early after grafting. (J Vasc Surg 1998;28:157-66.)

Effect of coacervated alpha-elastin on proliferation of vascular smooth muscle and endothelial cells.

The arterial wall injury associated with arterial graft implantation causes smooth muscle cells (SMCs) in the media to migrate and proliferate in the intima at the graft-artery junction resulting in anastomotic intimal hyperplasia (AIH). An important step in developing a small-diameter prosthesis may be to stimulate endothelialization and thereby inhibit AIH. In this study, we investigated the effect of coacervated and crosslinked alpha-elastin on proliferation of SMCs and endothelial cells (ECs) in vitro. Coacervation is an important step in the conversion of proelastin to make an elastin fiber in vivo. SMCs and ECs were prepared from porcine aortic media and endothelium, respectively. SMCs and ECs (three to five passages, 4 x 10[4] cells/well) were seeded onto 12 well plates, coated and crosslinked with 0 or 10 mg/mL of coacervated alpha-elastin. After the 1st, 2nd, or 3rd day of cultivation, proliferation was assayed by scintillation counting of [3H]-thymidine incorporation. For the 4th day only, 0, 0.1, 1, 10 mg/mL concentration of coacervated alpha-elastin was coated and crosslinked. SMC proliferation (1st, 2nd day: p<0.005; 3rd, 4th day: p<0.0001) was significantly inhibited over time and dose dependently, eg, 0.1 mg/mL (45.7+/-2.3%: % of control p<0.005), 1 mg/mL (5.9+/-0.7%, p<0.0005), 10 mg/mL (2.8+/-0.4%, p<0.0005). EC proliferation was inhibited over time by 10 mg/mL of coacervated alpha-elastin (2nd, 3rd day: p<0.005; 4th day: p<0.0001), but proliferation (132.8+/-9.9%: % of control p=NS) was stimulated by 0.1 mg/mL of coacervated alpha-elastin. These results suggest that coating and crosslinking a coacervated alpha-elastin into the structure of arterial prosthesis may inhibit AIH and stimulate endothelialization.

Compliance mismatch may promote graft–artery intimal hyperplasia by altering suture-line stresses

The role of graft-artery compliance mismatch in the development of distal anastomotic intimal hyperplasia (DAIH) is not yet resolved. Although DAIH develops at all surgically created anastomoses, increased compliance mismatch does not lead to greater hyperplasia formation in end-to-end anastomoses, but in end-to-side anastomoses, it leads to a profound increase in hyperplasia. The current study was undertaken to determine whether suture-induced anastomotic stresses could explain these findings. A large strain finite element analysis of vascular wall mechanics was performed to compare the influence of compliance mismatch on intramural stresses in end-to-end versus end-to-side anastomoses. A novel modelling approach was implemented which includes suture-induced stress concentrations. End-to-end and end-to-side graft-artery simulations were executed using (1) artery (compliance= C=0.44% kPa -1), (2) vein ( C=0.33% kPa -1), and (3) Dacron ( C=0.14% kPa -1) grafts. Residual stresses due to axial tension were included and the anastomoses were statically inflated to 13.3 kPa (100 mmHg). Elevated intramural stresses were found to exist at both the end-to-end and end-to-side graft–artery junctions; however, in the end-to-end anastomosis, the maximum anastomotic stress was not a function of the graft compliance, whereas in the end-to-side anastomosis, the maximum stress was a strong function of graft compliance. For the 45° end-to-side geometry considered in this study, the maximum anastomotic stress concentration obtained using a stiff Dacron graft was more than 40% greater than that obtained using a compliant artery graft. In the end-to-end anastomosis, the Dacron graft led to a less than 5% increase in maximum stress over the artery graft. Therefore, increased compliance mismatch increases stresses and promotes DAIH in end-to-side junctions, but, it has little influence on either stresses or DAIH in end-to-end junctions. Thus, the proliferative influence of increased compliance mismatch on suture-line hyperplasia in end-to-side anastomoses can be explained by the resulting increase in intramural stresses. In addition, since high stresses were found in both geometries, elevated suture-line intramural stresses may be an important proliferative stimulus for intimal hyperplasia formation in all vascular reconstructions.

28.16 Inhibition of anastomotic intimal hyperplasia by a specific collagen type I inhibitor

28.16 Inhibition of anastomotic intimal hyperplasia by a specific collagen type I inhibitor

Anastomotic Intimal Hyperplasia: A Comparison between Conventional and Endovascular Stent Graft Techniques

Endovascular grafts (EVGs) have been proposed as a treatment for a variety of vascular diseases; however, the impact of EVGs on graft healing has not been fully evaluated. The aim of this study is to compare anastomotic intimal hyperplasia (AIH) and endothelialization in EVGs and conventional bypass grafts (CGs). Seven mongrel dogs received an EVG in one iliac artery and a CG in the other iliac artery using a 5 mm × 4 cm polytetrafluoroethylene graft. The EVG was secured to the native vessel wall, with balloon expandable stents at either ends of the graft. CGs were anastomosed using running sutures. Intravascular ultrasound was performed at the time of sacrifice (8 weeks) to determine percentage of stenosis at the distal anastomosis. Specimens were divided longitudinally for light microscopic analysis (thickness of distal AIH) and scanning electron microscopic studies (percentage of endothelial coverage of the graft). Percentage of stenosis at the distal anastomosis was significantly higher in EVGs compared with CGs (28.2 ± 18.2% versus 1.8 ± 2.8%;P< 0.01) due to significantly greater mean intimal thickness in the EVGs (441.1 ± 101.1 μm versus 82.4 ± 41.9 μm;P< 0.01). The total percentage of area covered by endothelial cells was also significantly greater in EVGs compared with CGs (80.5 ± 37.5% versus 30.3 ± 37.1%;P< 0.05). Intraluminal location enhanced endothelialization of the polytetrafluoroethylene graft; however, it also resulted in greater AIH. Further device refinements including stent design may be required to maximize the potential of these endovascular procedures.

Recombinant mitotoxin basic fibroblast growth factor-saporin reduces venous anastomotic intimal hyperplasia in the arteriovenous graft.

The plant cytotoxin saporin (SAP) is a potent ribosome-inactivating protein. When conjugated to basic fibroblast growth factor (FGF2), it selectively kills proliferating cells that have upregulated FGF receptors. In this study, we evaluated the effect of the recombinant chimeric mitotoxin rFGF2-SAP on venous anastomotic intimal hyperplasia, a major cause of failure of arteriovenous (AV) grafts. Recently designed expanded polytet-rafluoroethylene-based local infusion devices were implanted bilaterally as femoral AV conduits in six dogs. The venous anastomoses were the sites of continuous delivery of rFGF2-SAP (2.7 micrograms.kg-1.d-1) to one side and vehicle (4.6 microL.kg-1.d-1) as control to the contralateral side for 14 days. All animals survived, and all grafts were patent. Liver enzyme levels and histological analyses of liver, kidneys, and brain were normal, indicating the absence of systemic toxicity. Morphometric measurements and measurements of cell proliferation by bromodeoxyuridine index analysis were performed at both arterial and venous anastomoses. There were no significant differences between the treated grafts and the control grafts in intimal hyperplasia and intimal cell proliferation at the arterial anastomoses. In contrast, rFGF2-SAP reduced intimal thickness by 32%, intimal area by 40%, and cell proliferation index by 33% at the treated venous anastomoses compared with the control venous anastomoses (P < .05). These data demonstrate that local infusion of rFGF2-SAP significantly reduces venous anastomotic intimal hyperplasia and cell proliferation without systemic toxicity. This study suggests a new strategy for reducing intimal hyperplasia by the selective killing of proliferating smooth muscle cells with a potent chimeric mitotoxin through a novel local infusion device.

Numerical study of wall mechanics and fluid dynamics in end-to-side anastomoses and correlation to intimal hyperplasia

In order to analyse the wall mechanics and the flow dynamics in compliant vascular distal end-to-side anastomoses, computer simulation has been performed. In a model study the effect of compliance mismatch on the wall displacements and on the intramural stresses as well as the influence of wall distensibility on the flow patterns are demonstrated applying two distensible models with different graft elasticity. In addition, the flow in a rigid model simulating a vein graft without adaption of the venous lumen has been investigated. The geometries for these models were obtained from a concurrent experimental study, where the formation of distal anastomotic intimal hyperplasia (DAIH) was studied in untreated and externally stiffened autologous venous grafts in sheep. In the flow study the time-dependent, three-dimensional Navier-Stokes equations describing the motion of an incompressible Newtonian fluid are applied. The vessel wall is modelled using a geometrically non-linear shell structure. In an iteratively coupled approach the transient shell equations and the governing fluid equations are solved numerically using the finite element method. In both compliant models maximum displacement and areas of steep stress gradients are observed in the junction region along the graft-artery intersection. The comparison of the normal deformations and the distribution and magnitude of intramural stress shows quantitative differences. The graft elasticity acts as a regulating factor for the deformability and the stress concentration in the junction area: In the model with high graft-elasticity maximum normal deformation at the side wall is 17%. This is twice as large as in the stiff graft model and maximum principle stress at the inner surface differs by one order of magnitude. The numerical results concerning the flow patterns indicate strongly skewed axial velocity profiles downstream of the junction, large secondary motion, flow separation and recirculation on the artery floor opposite the junction and at the inner wall downstream of the toe. In these regions a correlation between the time-averaged fluid wall shear stress and intimal thickening found in the animal experiment can be observed, whereas the pronounced formation of DAIH at the suture line seems to be mainly dependent on wall mechanical factors such as intramural stress and strain.

Evaluation of anastomotic hyperplasia progression using the cyclin specific antibody MIB-1

Delayed failure of prosthetic arterial grafts is primarily due to the development of anastomotic intimal hyperplasia. This report follows the proliferation of smooth muscle cells that ensues after prosthetic arterial grafting, using the cyclin-specific antibody MIB-1. Six-mm expandable polytetrafluoroethylene (ePTFE) grafts were placed end-to-end in the carotid arteries of mongrel dogs. Animals were randomly assigned to sacrifice intervals of 2, 7, 14, and 30 days. Serial coronal sections were cut and immunohistocytochemistry performed using the MIB-1 antibody. The control carotid artery had no definable proliferation. Two days after grafting, there was brisk proliferation in the upper one third of the arterial media. By 7 days, proliferation and migration of smooth muscle cells was seen above the internal elastic lamina, in which 50% of the cells were MIB-1 positive. Fourteen days after graft placement, proliferation continued in the neointima; however, the proliferation index was diminished compared with previous time intervals. At 30 days, despite a dramatic increase in lesional increase, there was a marked decrease in the overall proliferation of cells. Following placement of a prosthetic arterial graft, there is initial brisk proliferation of cells in the arterial media, with migration, ongoing proliferation, and resultant development of a localized cellular neointima. Over a 30-day period, the percentage of cells proliferating subsides in contrast to the progressive increase in the size of the neointima. Immunohistocytochemistry with the MIB-1 antibody is a useful tool in defining the cellular kinetics after prosthetic arterial grafting.

Ultrastructural features of progressive intimal hyperplasia at the distal end-to-side anastomosis of vein grafts

The features of intimal hyperplasia at the distal end-to-side anastomosis of artertally implanted autovein bypass grafts in dogs were examined using light and transmission electron microscopy. The bypass grafting was done under conditions of reduced blood flow with an abnormal flow wave and high peripheral resistance. Anastomotic intimal hyperplasia was evident 14 to 31 days after implantation, then gradually increased, particularly at the toe portion of the anastomosis. From 6 to 12 months after implantation, the intimal hyperplasia was excessively increased and severe luminal stenosis had developed. The hyperplastic neointima consisted of two layers; a laminated superficial layer and a randomly arranged deeper layer. The superficial layer had three to four layers of smooth muscle cells, while the deeper layer was mostly fibrocollagenous tissues. Thus, the intimal hyperplasia at the distal end-to-side anastomosis of the arterially implanted autovein graft developed as a result of infiltration of fibroblast-like cells, presumably tissue-synthesizing mesenchymal cells. The neointima at the distal anastomosis, under conditions of reduced blood flow with high peripheral resistance, remained in an active phase of intimal hyperplasia even 12 months after bypass grafting.

Ultrastructural Features of Progressive Intimal Hyperplasia at the Distal End-to-Side Anastomosis of Vein Grafts

The features of intimal hyperplasia at the distal end-to-side anastomosis of arterially implanted autovein bypass grafts in dogs were examined using light and transmission electron microscopy. The bypass grafting was done under conditions of reduced blood flow with an abnormal flow wave and high peripheral resistance. Anastomotic intimal hyperplasia was evident 14 to 31 days after implantation, then gradually increased, particularly at the toe portion of the anastomosis. From 6 to 12 months after implantation, the intimal hyperplasia was excessively increased and severe luminal stenosis had developed. The hyperplastic neointima consisted of two layers; a laminated superficial layer and a randomly arranged deeper layer. The superficial layer had three to four layers of smooth muscle cells, while the deeper layer was mostly fibrocollagenous tissues. Thus, the intimal hyperplasia at the distal end-to-side anastomosis of the arterially implanted autovein graft developed as a result of infiltration of fibroblast-like cells, presumably tissue-synthesizing mesenchymal cells. The neointima at the distal anastomosis, under conditions of reduced blood flow with high peripheral resistance, remained in an active phase of intimal hyperplasia even 12 months after bypass grafting. Copyright © 1996 The International Society for Cardiovascular Surgery.

An immunohistochemical analysis of implanted woven Dacron and expanded polytetrafluoroethylene grafts in humans.

An immunohistochemical analysis was performed to clarify the healing process in implanted vascular grafts in human. Eight woven Dacron grafts and 6 expanded polytetrafluoroethylene grafts were obtained following redo surgery, limb amputation, and autopsy. The implantation periods ranged from 5 days to 148 months. The antibodies used for the analysis were specific to alpha-actin (smooth muscle cells), macrophages, von Willebrand factor (endothelial cells), fibrin, elastin, collagen types 1-5, CD3 (T cells), and CD20 (B cells). At 5 and 24 days after implantation, thrombi containing red blood cells and fibrin covered the anastomotic lines and some of the luminal surfaces of the grafts. Macrophages were scattered throughout the thrombi. At 11-148 months after implantation, either a single layer of endothelial cells or a thin layer of fibrin covered the anastomotic segments of the grafts, and smooth muscle cells and collagen fiber were seen forming anastomotic intimal hyperplasia (AIH). The AIH in the grafts at 94 and 148 months after implantation was almost the same thickness and length a that in the grafts at 11-36 months after implantation Apart from the anastomotic segments, a connective tissue matrix containing collagen fibers covered the luminal surfaces, and some thrombi were noted. Most of the collagen present was type 3, in addition to some type 1, 4, and 5 collagen. No type 2 collagen was noted. Some elastin was also detected in the AIH but not in the midportion of the grafts. Some macrophages and T cells were noted in the perigraft tissues.

Anastomotic intimal hyperplasia in prosthetic arteriovenous fistulas for hemodialysis is associated with initial high flow velocity and not with mismatch in elastic properties.

Stenotic intimal thickening at the venous end of prosthetic arteriovenous (AV) fistulas for hemodialysis has been associated with perianastomotic mismatch in elastic properties, and low shear rates. In a prospective way, the role of these factors on the occurrence of intimal hyperplasia in prosthetic AV fistulas in hemodialysis patients was investigated. In 24 hemodialysis patients, the elastic properties were assessed in the distal graft segment and the outflow vein postoperatively with the use of Vessel Wall Doppler Tracking (VWDT), a noninvasive ultrasound technique. In addition, normalized peak systolic velocity (nPSV) was calculated from diameter (VWDT) and peak systolic velocity. The initial mismatch around the venous anastomoses and local nPSV were correlated with the occurrence of stenoses during follow-up (2 yr). The detection of a stenosis was performed with both Duplex ultrasound and angiography. In four cases, a stenosis developed in the venous anastomosis; in eight cases, a stenosis developed in the venous outflow segment; and in four cases, stenoses developed at both sites. A better initial match in elastic properties around the venous anastomosis was observed in the fistulas developing a stenosis at this site as compared with the nonstenotic fistulas (P < 0.05). The initial local nPSV values at the site of the later stenosis were higher in the fistulas developing a stenosis as compared with the nonstenotic fistulas (P < 0.05). It was concluded that the occurrence of stenoses in prosthetic AV fistulas for hemodialysis in or adjacent to the venous anastomoses is associated with a high initial flow velocity but not with a mismatch in elastic properties.

Compliance mismatch and formation of distal anastomotic intimal hyperplasia in externally stiffened and lumen-adapted venous grafts

Compliance and formation of distal anastomotic intimal hyperplasia (DAIH) were investigated in externally stiffened venous grafts of varying calibers. 36 femoropopliteal reconstructions were performed in 18 sheep. The autologous venous grafts were inserted into tubes made of Dacron mesh to achieve compliance-mismatch and lumen adaptation. Compliance was measured by echotracked ultrasonography and profiles of DAIH were generated from histologic sections harvested after 8.3 months. The external mesh tube significantly lowered the local compliance of graft and host artery. DAIH appeared extensively in those groups where mesh tube constricted venous grafts met untreated host arteries (p = 0.002). No differences in compliance and DAIH formation were observed when grafts with large and adapted diameters were compared. For prevention of DAIH the distal venous graft diameter is not important, while the local compliance of an autologous vein is a predictive factor for DAIH formation and thus long-term patency.

Pharmacologic Intervention to Prevent Graft Failure

Lower extremity vascular grafts, either vein or synthetic, fail for diverse reasons. Technical defects or poor surgical judgment doom a graft beyond any benefit pharmacotherapy can offer. Graft failure due to spontaneous thrombosis particularly affects prosthetic conduits, and use of antiplatelet agents (dextran, ASA) or anticoagulants (heparin, warfarin) is probably useful in this setting. An effective way to inhibit vein graft or anastomotic intimal hyperplasia remains elusive. Perhaps the most permanent and longstanding influence on lower extremity graft survival can be made through risk factor intervention aimed at arresting the progression of atherosclerosis. Aggressive treatment of hyperlipidemia, hypertension, smoking, and other known risk factors should be routinely and aggressively pursued in patients with lower extremity grafts, either autogenous or prosthetic. Lower extremity graft patency is optimally ensured by technically adept insertion of a proper autologous conduit in a well-selected patient. Pharmacotherapy may have a significant adjunctive role in the maintenance of graft patency, especially in high-risk settings such as limb salvage with associated poor outflow, a marginal vein graft, or the obligatory use of prosthetic material.

Isolation of genes differentially expressed at the downstream anastomosis of prosthetic arterial grafts with use of mRNA differential displaydisplay*Winner of the 1994 Resident Prize Research Award.

Downstream anastomotic intimal hyperplasia in prosthetic arterial grafts remains a major cause of delayed graft failure. The new method of messenger RNA (mRNA) differential display was used to screen numerous genes to gain insight into the molecular mechanisms of intimal hyperplasia. Fifty-centimeter-long 8 mm expanded polytetrafluoroethylene grafts were placed in four mongrel dogs from the carotid artery to the distal abdominal aorta. At 3 months the distal anastomoses and adjacent normal aortas were harvested; a portion was taken for histologic examination, and total RNA was isolated from the remainder. Differential mRNA display was used to identify candidate cDNA clones whose expression differed in anastomotic intimal hyperplasia as compared with adjacent unaffected aorta. The clones were sequenced, and national gene databases were searched. Northern blot analysis confirmed alteration of gene expression. Approximately 5000 mRNA species were screened, and 11 candidate clones were obtained. DNA sequence revealed homology of five clones to known gene sequences. Homologous genes included an interferon-gamma-induced human gene, (IGUP I-5111), alpha-1 protease inhibitor gene, human retinoblastoma susceptibility gene, and human creatine kinase gene (two clones). Northern blot analysis revealed altered gene expression in 4 of 11, nonregulation in 1 of 11, and undetectable signals in 6 of 11. Expression of the clone representing IGUP I-5111 in the segment of intimal hyperplasia was found to be decreased over threefold to only 31% +/- 16.4% SE of the level seen in normal aorta. The technique of mRNA differential display has identified differences in gene expression in an in vivo model of anastomotic intimal hyperplasia. Expression of RNA with homology to an interferon-gamma-induced human gene was consistently decreased within the hyperplastic region at the downstream polytetrafluoroethylene arterial anastomosis.