Intimal hyperplasia and hemodynamic factors in arterial bypass and arteriovenous grafts: a review

Stenosis at the graft–vein junction caused by intimal hyperplasia (IH) is the major cause of failure of vascular access grafts used for hemodialysis. There is a strong relationship between hemodynamic factors and formation of IH. The hemodynamic pattern and the location of IH are different in arterial bypass grafts (ABGs) compared with arteriovenous grafts (AVGs). In an ABG, end-to-side anastomosis of the expanded polytetrafluoroethylene graft and artery produces hemodynamic changes around the junction. IH develops at the arterial floor and the toe and heel of the distal anastomosis. Low shear stress and oscillating shear forces at the arterial floor and the heel plus a high wall sheer stress (WSS) gradient at the toe probably promote IH development. Compliance mismatch between the graft and artery causes turbulence that may contribute to IH formation. The blood flow rate in AVGs is 5–10 times greater than that in ABGs. High flow causes turbulence that injures endothelial cells and eventually results in IH. The peak WSS in AVGs is about 6N/m², much higher than that in ABGs. Excessively high WSS may effect IH formation in AVGs. Several venous cuff or patch anastomotic designs have been used in attempts to regulate hemodynamic factors in grafts. In ABGs, these designs appear to help decrease IH formation. In AVGs, however, they generally have not improved patency rates. In a high-flow system such as an AVG, more drastic changes in anastomotic design may be required.     

Preliminary experience with a cuffed ePTFE graft for hemodialysis vascular access

The purpose of this study was to determine graft patency and blood flow rates in recipients of a new cuffed ePTFE graft (Venaflo graft) used for hemodialysis access. A pilot study was conducted with 12 (7 men, 5 women) consecutive patients (age range, 36-76 yr; mean, 65 yr). All patients were recipients of a new cuffed PTFE graft placed for hemodialysis access. Seven were high risk because of a prior history of clotted hemodialysis accesses (1-6; mean, 3.3). Blood flow rates were determined by ultrasound dilution technique at 3 month intervals. One year and 2 year overall graft patency rates were 90.9% and 68.2%, respectively. One graft (high risk, six prior grafts) was lost to thrombosis in the first year; two grafts (one high risk, four prior grafts) were lost to thrombosis in the second year of follow-up. No graft thrombosis resulted from stenosis at the graft-vein anastomosis. Blood flow rates ranged from 550 to 2,110 ml/min (mean, 1,086 ml/min; n = 8) when first measured 3 months after graft placement. Similar flow rates were observed at 12 months (mean, 1,043 ml/min; n = 7) and 24 months (mean, 1,014 ml/min; n = 4) in grafts available for comparison. Dialysis flow rates in excess of 350 ml/min were possible with all patent grafts. A cuffed ePTFE graft provided stable blood flow and satisfactory graft patency during 2 years of follow-up, even in high risk patients with a prior history of vascular access thrombosis.     

A parametric numerical investigation on haemodynamics in distal coronary anastomoses

Anastomotic haemodynamics, which plays an important role in the performance of bypass graft, is known to be profoundly affected by the diameter ratio (Phi) and angle (alpha) between the graft and host artery in the peripheral region. We hypothesize that these geometric factors would play similar roles in distal coronary anastomoses and that they could be improved for clinical applications through parametric studies. Anastomotic models covering a range of Phi (1:1, 1.5:1 and 2:1) and alpha (15 degrees , 30 degrees , 45 degrees and 60 degrees ) were investigated numerically in physiological coronary flow conditions. The transient flow patterns, cycle-averaged wall shear stress (WSS), oscillatory shear index (OSI), spatial and temporal WSS gradients (SWSSG and TWSSG) were compared. Results show a stronger influence of Phi than alpha on haemodynamics in distal coronary artery anastomoses. Substantially higher SWSSG and TSSWG occur on the artery floor when Phi=1:1 compared to larger Phi. High levels of OSI occur in critical regions when Phi=1:1 and 2:1. The largest area of high OSI is found in the anastomotic region when alpha=15 degrees , whereas the highest level of SWSSG appears on the artery floor when alpha=60 degrees . The study suggests the clinical relevance of optimizing geometric parameters of coronary anastomoses to improve their haemodynamic performance. We speculate that for a distal coronary anastomosis with a 20:80 proximal-distal flow division ratio maintained in the host artery, Phi=1.5 and alpha=30-45 degrees would enhance its long-term performance.     

Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives

Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.     

Effects of an Artery/Vascular Graft Compliance Mismatch on Protein Transport: A Numerical Study

Small-diameter vascular graft failure by intimal hyperplasia and thrombosis may result from flow disturbances and disruption of chemical transport in the fluid at the distal anastomosis, because of compliance mismatch between the graft and host artery. In previous studies. lower-than-normal wall shear stress (WSS), particle trapping, and high particle residence times were observed at the distal anastomosis due to a pulsatile tubular expansion effect caused by nonuniform radial deformations. This study was undertaken to examine effects of compliance and radius mismatch on the distribution of a model protein released at the graft-fluid interface. Finite element simulations of end-to-end vascular grafting were performed under pulsatile flow, using fluid-structure coupling to give physiologic wall displacements. Results showed that protein is convected smoothly downstream in a uniform compliant tube. A compliance mismatch disturbed the transport, causing positive and negative gradients in the concentration profile at the distal anastomosis. This was seen when the graft and artery radii were matched at zero pressure and at mean arterial pressure; low WSSs were only observed in the former case. Thus the distal intimal hypertrophy seen in noncompliant grafts may be caused partly by decreased WSS, and partly by concentration gradients of dissolved chemicals affecting chemotaxis of cells.     

管径比对全阻塞动脉旁路移植流场影响的数值研究

目的 研究管径比对全阻塞动脉旁路移植流场的影响,为指导动脉旁路移植手术,减少术后再狭窄提供理论依据。方法 采用数值方法研究5种不同移植管与主血管的管径比对全阻塞情况下动脉旁路移植流场的影响,分析速度、二次流、壁面切应力和壁面切应力梯度等血流动力学参数的分布及其随管径比增大的改变。同时,为表明本文所采用模型的合理性,针对目前常使用的两类模型,比较在管径比1.0情况下全阻塞完整模型（Model A）、全阻塞局部模型（Model B）和75％狭窄完整模型（Model C）之间的血流动力学差异。结果 Model A和Model C的血流动力学特性是完全不同的;移植管顶部截面内的速度分布对下游吻合处的主血管底部壁面切应力的影响是显著的,最大相差达79％。大管径比时,主血管底部的壁面低切应力区较大,但壁面切应力分布均匀,壁面切应力梯度较小。而小管径比时,主血管底部的壁面低切应力区较小,但壁面切应力梯度较大。结论 采用整体模型单独研究全阻塞情况下的管径比对流场的影响是有必要的。管径比对全阻塞动脉旁路移植的流场具有显著影响,采用大管径比进行动脉旁路移植将有助于缓解吻合口处由于再狭窄而产生的阻塞。     

Readily available tissue-engineered vascular grafts

Autologous or synthetic vascular grafts are used routinely for providing access in hemodialysis or for arterial bypass in patients with cardiovascular disease. However, some patients either lack suitable autologous tissue or cannot receive synthetic grafts. Such patients could benefit from a vascular graft produced by tissue engineering. Here, we engineer vascular grafts using human allogeneic or canine smooth muscle cells grown on a tubular polyglycolic acid scaffold. Cellular material was removed with detergents to render the grafts nonimmunogenic. Mechanical properties of the human vascular grafts were similar to native human blood vessels, and the grafts could withstand long-term storage at 4 °C. Human engineered grafts were tested in a baboon model of arteriovenous access for hemodialysis. Canine grafts were tested in a dog model of peripheral and coronary artery bypass. Grafts demonstrated excellent patency and resisted dilatation, calcification, and intimal hyperplasia. Such tissue-engineered vascular grafts may provide a readily available option for patients without suitable autologous tissue or for those who are not candidates for synthetic grafts.     

Computational analyses and design improvements of graft-to-vein anastomoses

For hemodialysis patients, arteriovenous grafts are omnipresent. Unfortunately, a large percentage of such grafts fail within the first year after surgery because of occlusive lesions mainly at the venous anastomotic site. It is textbook knowledge that critical values of certain hemodynamic parameters, such as low (oscillatory) wall shear stresses, large sustained wall shear stress gradients, significant changes in wall shear stress angles, excessive radial pressure gradients, etc., play significant roles in the onset and/or development of vascular diseases. The idea is to geometrically design graft-to-vein configurations such that aggravating flow patterns are reduced, and hence stenotic developments are minimized. Focusing on a new blood rheological model in conjunction with three graft-to-vein anastomotic configurations, that is, a base case, the Bard-IMPRA Venaflo graft, and a new graft-end design, the corresponding transient laminar 3-D hemodynamics are numerically simulated and compared. The design criterion for the best performance of these junction geometries is the most significant reduction in locally disturbed flow as expressed by equally weighted indicator functions for the onset and progression of stenotic developments. As a result of this comparison study, quantitative recommendations for arteriovenous loop graft designs toward increased patency rates are provided. The resulting improved graft design will be scrutinized in clinical trials.     

Variable flow Doppler for hemodialysis access evaluation: theory and clinical feasibility

Access thrombosis remains an enormous problem for patients on hemodialysis. Current evidence suggests that decreasing access blood flow rate is an important predictor of future access thrombosis and failure. This article describes a method for determining access volume flow and detecting access pathology. The Doppler ultrasound signal downstream from the arterial needle as a function of the variable hemodialysis blood pump flow rate, is used to determine access blood flow. By using this variable flow (VF) Doppler technique compared with duplex volume flow estimates measured in 18 accesses (16 patients with 12 polytetrafluorethylene [PTFE] grafts and 6 autogenous fistulas), the results showed a correlation of 0.83 (p < 0.0001) between these methods. In grafts with lower blood flow rates, aberrant flow patterns were observed, including stagnant or reversed flow during diastole while forward flow was maintained during systole. When reversed diastolic flow was severe, it was accompanied by access recirculation. In conclusion, we report the theory and clinical feasibility of determining access blood flow by using a VF Doppler technique. Measurements are made without the need to determine the access cross sectional area required for duplex volume flow calculations and without the need to reverse the lines required for various indicator dilution techniques. Important information is also obtained about aberrant flow patterns in patients at risk of access failure.     

Cuffed-tunneled femoral catheter for long-term hemodialysis

BACKGROUND: Hemodialysis access is a challenging problem in patients with exhausted dialysis access sites of their upper extremities. Femoral arterio-venous polytetrafluoroethylene (PTFE) graft is often necessary. The safety and efficacy of cuffed tunneled catheters at the femoral site for long-term hemodialysis has not been extensively studied. METHODS: We inserted 14 cuffed-tunneled femoral catheters in 11 hemodialysis patients with exhausted dialysis access sites of their upper extremities. Access survival and risk of infection were compared with the 11 femoral PTFE grafts in 10 patients of our center during the same period. The choice of dialysis access was determined by the individual nephrologist. Access survival was defined as the achievement of a blood flow rate of at least 180 ml/min. RESULTS: The median survival of tunneled femoral catheter and PTFE graft were 166 days and 560 days respectively (log-rank test, p = 0.33). Seven of the 14 tunneled femoral catheter remained in use 3 months after insertion. The incidence of catheter- or graft-related infection was 0.38 and 0.23 episodes per 100 catheter/graft days for tunneled femoral catheters and PTFE graft respectively (p = 0.6). Five tunneled catheters and one PTFE graft had to be removed because of infection. Blood flow rates achieved were comparable between tunneled femoral catheter and PTFE graft. CONCLUSIONS: Our preliminary data suggest that the cuffed tunneled femoral catheter has reasonable access survival and an acceptable risk of infection. It may provide a safe and effective access for long-term hemodialysis patients with exhausted access in their upper extremities, especially high risk patients who are not suitable for femoral PTFE graft creation.     

Endothelial cell seeding of a 4-mm I.D. polyurethane vascular graft

We evaluated the extent (luminal coverage) of the endothelial cell (EC) lining/neointimal development and the thromboresistance of electrostatically EC seeded small diameter ChronoFlex-polyurethane vascular grafts. The evaluation consisted of harvesting autologous, canine jugular vein ECs, electrostatically seeding the polyurethane grafts (4-mm I.D., length = 6 cm) with the harvested ECs, implanting the grafts in a canine femoral artery model for four to six weeks, and excising the grafts for histological and scanning electron microscopy evaluations. Results of the histological evaluation (mid-graft region only) indicated that electrostatic EC seeding led to neointimal development and to minimal to no thrombus formation within the EC seeded grafts. The unseeded control grafts resulted in no neointimal development and substantial thrombus formation on the graft luminal surfaces. Scanning electron microscopy examination demonstrated a mature, confluent endothelium with a "cobblestone" appearance on the EC seeded graft luminal surface after six weeks. We conclude that electrostatic EC seeding enhanced the development of a neointima and reduced the incidence of thrombosis in polyurethane grafts implanted in a canine femoral artery model.     

Three-phase CFD analytical modeling of blood flow

The behavior of blood cells in disturbed flow regions of arteries has significant relevance for understanding atherogenesis. However, their distribution with red blood cells (RBCs) and leukocytes is not so well studied and understood. Our three-phase computational fluid dynamics approach including plasma, RBCs, and leukocytes was used to numerically simulate the local hemodynamics in such a flow regime. This model has tracked the wall shear stress (WSS), phase distributions, and flow patterns for each phase in a concentrated suspension shear flow of blood. Unlike other computational approaches, this approach does not require dispersion coefficients as an input. The non-Newtonian viscosity model was applied to a wide physiological range of hematocrits, including low shear rates. The migration and segregation of blood cells in disturbed flow regions were computed, and the results compared favorably with available experimental data. The predicted higher leukocyte concentration was correlated with relatively low WSS near the stenosis having a high WSS. This behavior was attributed to flow-dependent interactions of the leukocytes with RBCs in pulsatile flow. This three-phase hemodynamic analysis may have application to vulnerable plaque formation in arteries with in vivo complex flow conditions.     

Compliance, elastic modulus, and burst pressure of small-intestine submucosa (SIS), small-diameter vascular grafts.

Small-intestine submucosa (SIS) is cell-free collagen, 100 mu thick, derived from the small intestine. It has been used as a vascular graft and has the highly desirable property of remodeling itself to become host tissue. To date there has been limited reporting on its preimplantation mechanical properties as a vascular graft. In this study, compliance, elastic modulus, and burst pressure have been measured on 5- and 8-mm SIS grafts. The compliance (percent of diameter increase for a pressure rise from 80 to 120 mmHg) was 4.6% av (range 2.9 to 8.6%) for the 5-mm grafts. For the 8-mm graft, the increase in diameter for the same pressure rise was 8.7% av (range 7.2 to 9.5%). The modulus of elasticity (E) increased exponentially with increasing pressure according to E = E(o)e(alphaP), where Eo is the zero-pressure modulus and alpha is the exponent that describes the rate of increase in E with pressure; the units for E, Eo, and P are g/cm2. The mean value for Eo was 4106 (g/cm2 range 1348-5601). The mean value for alpha was 0.0059 (range 0.0028-0.0125). At 100 mmHg, the mean value for E was 8.91 x 10(3) g/cm2 (range 1.02-8.80 x 10(3)). The mean burst pressure for 5.5-mm grafts was 3517 mm Hg (range 2069-4654). In terms of preimplant compliance, the small-diameter SIS graft is about (1/2) as compliant as the dog carotid artery, about four times more compliant than a typical vein graft, and more than an order of magnitude more compliant than synthetic vascular grafts.     

Creation and use of a composite polyurethane-expanded polytetrafluoroethylene graft for hemodialysis access

The Thoratec (Vectra) polyurethane vascular access graft (TPVA) is among the most recent additions to the list of materials used to construct prosthetic grafts for vascular access during hemodialysis. We give the TPVA very high marks, and recognize the utility of such a graft for use in hemodialysis. However, the strong elasticity of this graft can lead to unexpected complications after suturing. We devised a new surgical method using a TPVA-ePTFE (expanded polytetrafluoroethylene) composite graft, substituting the anastomosis section of the TPVA with a portion of ePTFE graft material, and have been able to overcome most of the TPVA's potential problems. We herein describe the technique.     

Rapid endothelialization of PhotoFix natural biomaterial vascular grafts

To date, no off-the-shelf graft has performed better than the autologous vessel in applications requiring small-bore (< 6-mm diameter) vascular grafts. Much research has been devoted to seeding endothelial cells on synthetic grafts to improve their long-term clinical performance. One key challenge is the ability to retain the endothelium on the graft lumen for extended times. The goal of this research was to develop a process to seed endothelial cells inside a vascular graft and to quickly condition the cells so as to minimize their damage or removal under physiological flow. In addition, the use of PhotoFix(R) natural biomaterial grafts as an improved substrate for human umbilical vein endothelial cells has been evaluated. A motorized system that provides uniform cell seeding of a small-diameter graft (4-mm inner diameter, 10-cm length) by automated radial rotation has been developed. The same system is subsequently adapted for gradual increases in flow rates to strengthen the endothelium, which ultimately was exposed to a final flow rate of 300 ml/min. This process is accomplished without graft transfer, decreasing risks of contamination and physical damage. Cell coverage and cell morphology were evaluated with the use of fluorescence microscopy and scanning-electron microscopy to determine the effectiveness of the flow conditioning process. It was found that endothelial cells exhibit roughly 20-50% improved adhesion to PhotoFix vessels compared to fibrin-treated polytetrafluoroethylene (PTFE) synthetic grafts. Flow conditioning for 6 h enhanced in vitro cell retention by 24% and 40% on PhotoFix and PTFE grafts, respectively.     

先天性心脏病相关性肺动脉高压血流动力学特异性研究

目的先天性心脏病相关性肺动脉高压(pulmonary arterial hypertension related to congenital heart disease,PAH-CHD)是肺动脉血流动力学异常所致的一种疾病。研究肺循环血流动力学特异性,有助于了解PAH-CHD发生发展的生物力学因素。方法对5例PAH-CHD患儿和5例无PAH(Non-PAH)的先天性心脏病患儿通过临床及影像资料收集,重建三维血管模型,利用计算流体动力学模拟肺动脉血液流动,对比分析肺动脉血流动力学相关速度流线、壁面剪切力(wall shear stress,WSS)及单位体表面积平均能量损失(·E)差异。结果血流动力学相关指标显示,PAH-CHD患儿左右肺动脉分支处流速和WSS明显升高,主肺动脉处WSS明显降低,·E呈显著增加趋势且与肺动脉直径及入口流量呈明显正相关。结论 PAH-CHD患儿较Non-PAH患儿肺动脉分支处流速和WSS明显升高,主肺动脉WSS降低,·E增加,表明这些血流动力学因素与PAH-CHD密切相关,是临床评估PAH-CHD的潜在血流动力学指标。     

A new vascular prosthesis coated with polyamino-acid urethane copolymer (PAU) to enhance endothelialization

Clinically available synthetic ePTFE vascular grafts frequently fail when used for small-diameter arterial substitution. The lower long-term patency of ePTFE grafts is due mainly to thrombogenicity and poor healing. We developed a new small-diameter (1.5-mm) ePTFE vascular prosthesis coated with polyamino-acid urethane copolymer (PAU) to enhance endothelialization. Coating with PAU made the hydrophobic ePTFE vascular graft hydrophilic. Scanning electron microscopy (SEM) observation showed that PAU was homogeneously coated on the ePTFE graft while maintaining the graft's porous structure. Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectra showed PAU was present on graft inner surfaces. Noncoated and PAU-coated ePTFE vascular grafts were implanted into the rat abdominal aorta and evaluated within 1 week and at 8 weeks after implantation. We evaluated the extent of neoendothelialization by SEM, light microscopy, and immunohistochemical staining. Noncoated grafts showed partial endothelialization at proximal and distal areas of grafts but none at midsection. One-percent PAU-coated grafts showed incomplete neoendothelialization, but endothelial cells were observed in the midsection of grafts. Three-percent PAU-coated ePTFE grafts showed complete endothelialization with typical endothelial cell layers under SEM and histologic observation. Immunohistochemical staining also showed that an endothelial cell lining positively reacted with anti-von Willebrand factor (endothelial cell marker) antibody. We conclude that PAU-coated ePTFE vascular grafts enhance endothelialization.     

自发性高血压大鼠颈总动脉的平均壁面切应力和周向应力

目的确定自发性高血压大鼠(SHR)颈总动脉的平均壁面切应力(WSS)和周向应力(CS),并与同龄正常血压大鼠(WKY)相对比,观察SHR和WKY大鼠颈总动脉平均WSS和CS的特征。方法选取12周龄SHR作为动物模型,同龄WKY为对照组;通过在体测定颈总动脉的平均血流量与平均血压,离体测量颈总动脉的无载荷状态形态学数据,以及在体轴向伸长比条件下颈总动脉段的压力(p)-容积(V)关系,确定颈总动脉平均WSS和CS;同时比较SHR和WKY颈总动脉的平均血压和血流量、无载荷和载荷状态几何尺寸以及平均WSS和CS的特征。结果与正常血压的WKY组相比,SHR组颈总动脉血压明显增高、流量明显降低;无载荷和载荷状态下SHR组动脉的内外半径均增大,载荷状态下SHR组动脉壁厚减小;SHR颈总动脉平均WSS明显降低,而CS明显增高。结论高血压和低流量引起了SHR颈总动脉重建;低WSS和高CS是SHR颈总动脉血液动力学参数的重要特征;WSS和CS的协同作用可能是反映动脉重建的敏感指标之一。