The clopidogrel after surgery for coronary artery disease (CASCADE) randomized controlled trial: clopidogrel and aspirin versus aspirin alone after coronary bypass surgery [NCT00228423]

Background

Saphenous vein graft disease remains a major limitation of coronary artery bypass graft surgery. The process of saphenous vein intimal hyperplasia begins just days after surgical revascularization, setting the stage for graft atherosclerotic disease and its sequalae. Clopidogrel improves outcomes in patients with atherosclerotic disease, and is effective at reducing intimal hyperplasia in animal models of thrombosis. Therefore, the goal of this study will be to evaluate the efficacy of clopidogrel and aspirin therapy versus aspirin alone in the prevention of saphenous vein graft intimal hyperplasia following coronary artery bypass surgery.

Methods

Patients undergoing multi-vessel coronary artery bypass grafting and in whom at least two saphenous vein grafts will be used are eligible for the study. Patients will be randomized to receive daily clopidogrel 75 mg or placebo, in addition to daily aspirin 162 mg, for a one year duration starting on the day of surgery (as soon as postoperative bleeding has been excluded). At the end of one year, all patients will undergo coronary angiography and intravascular ultrasound assessment of one saphenous vein graft as selected by randomization. The trial will be powered to test the hypothesis that clopidogrel and aspirin will reduce vein graft intimal hyperplasia by 20% compared to aspirin alone at one year following bypass surgery.

Discussion

This trial is the first prospective human study that will address the question of whether clopidogrel therapy improves outcomes and reduces saphenous vein graft intimal hyperplasia following cardiac surgery. Should the combination of clopidogrel and aspirin reduce the process of vein graft intimal hyperplasia, the results of this study will help redefine modern antiplatelet management of coronary artery bypass patients.     

Statins for the prevention of vein graft stenosis: a role for inhibition of matrix metalloproteinase-9

Saphenous vein (SV) grafts are commonly used to bypass coronary arteries that are diseased due to atherosclerosis. However, the development of intimal hyperplasia in such grafts can lead to patency-threatening stenosis and re-occlusion of the vessel. The proliferation and migration of smooth muscle cells (SMC) play key roles in the development of intimal hyperplasia, and an agent that inhibits both of these processes therefore has therapeutic potential. A prerequisite for SMC proliferation and migration in vivo is degradation of the basement membrane, achieved by secretion of the matrix-degrading gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9. Statins are cholesterol-lowering drugs that also have direct effects on SMC function. Here we report that neointima formation in organ-cultured human SV segments is inhibited by simvastatin, an effect that is associated with reduced MMP-9 activity. Additionally, our work shows that simvastatin not only inhibits proliferation, but importantly also inhibits invasion (migration through a matrix barrier), of cultured human SV SMC. Thus simvastatin treatment appears to inhibit neointima formation as a result of combined inhibition of SMC proliferation and invasion. The potential intracellular mechanisms by which statins affect SMC proliferation and migration, and thus attenuate intimal hyperplasia, are discussed, with particular emphasis on the role of MMP-9.     

Interference of IP-10 Expression Inhibits Vascular Smooth Muscle Cell Proliferation and Intimal Hyperplasia in Carotid Artery: A New Insight in the Prevention of Restenosis

After vascular angioplasty, vascular smooth muscle cell (VSMC) proliferation causes atherosclerosis and intimal hyperplasia leading to restenosis. Interferon-γ-inducible protein (IP)-10 plays a role in atherogenesis, but the mechanism remains unclear. We evaluated the role of IP-10 in intimal hyperplasia and restenosis. IP-10 expression was determined in arterial specimens from 20 arteriosclerotic obliteration patients and 6 healthy individuals. VSMCs were stimulated in vitro with IFN-γ and transfected with IP-10 siRNA. Silencing was verified with RT-PCR/Western blot; cell proliferation rate was detected by methyl-thiazol-tetrazolium. The carotid artery model of atherosclerosis injury was established with IP-10 siRNA. IP-10 expression was detected at 1 and 4 weeks using RT-PCR and immunohistochemistry. Artery morphology was assessed with hematoxylin-and-eosin staining, and intimal hyperplasia was evaluated by electron microscopy. IP-10 was overexpressed in arteriosclerotic obliteration group compared with control group (P < 0.05). IP-10 expression in transfected group was significantly lower than in untransfected group. The intima-to-media ratio of transfected group at 4 weeks was lower than that of untransfected group (P < 0.01). The transfected group exhibited more regular intimal structure and less hyperplasia under electron microscopy. We, therefore, concluded that IP-10 played an important role in intimal hyperplasia as siRNA-mediated IP-10 silencing inhibited aberrant VSMCs hyperplasia and reduced restenosis.     

Coronary atherosclerosis: current therapeutic approaches and future trends

Invasive cardiovascular procedures, such as percutaneous translumenal coronary angioplasty (PTCA) and aorto-coronary bypass surgery (ACBS), that are currently employed in treating the coronary stenosis or occlusion caused by atherosclerosis represent a major therapeutic advance for managing coronary heart disease (CHD). However, the cellular proliferative response and associated intimal hyperplasia that can follow the damage to blood vessels that occurs with these procedures leads to late complications which cannot be effectively controlled by presently available drugs. Hence, a new approach is required for managing these complications, termed "restenosis" (in the case of PTCA) or "stenosis" (in the case of ACBS). Existing drug therapy is reviewed and some new approaches to this problem are provided herein. Further studies of growth factors and other substances that influence the cellular proliferative response that follows injury to the blood vessel wall could lead to the development of effective therapy. Inhibition of intimal hyperplasia and/or acceleration of endothelial cell re-growth provide a basis for such new approaches. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), as well as endothelium-derived relaxing factor(s) (EDRF) and calcitonin gene-related peptide (CGRP) are among the substances discussed. Modification of certain currently available drugs (e.g. Ca(2+)-antagonists) could also be of value in meeting this therapeutic demand.     

ADAMTS-7 promotes vascular smooth muscle cells proliferation <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis>

Vascular smooth muscle cell (VSMC) proliferation and migration are pivotal for the pathogenesis of atherosclerosis and post-angioplasty restenosis. We have recently reported that a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7), a novel metalloproteinase, contributes directly to neointima formation by mediating VSMC migration. However, whether ADAMTS-7 affects VSMC proliferation remains unclear. In this study, we found that luminal adenoviral delivery of ADAMTS-7 aggravated intimal hyperplasia 7 d after injury, paralleled by an increased percentage of PCNA-positive cells in both intima and media. In contrast, perivascular administration of ADAMTS-7 siRNA, but not scrambled siRNA to injured arteries attenuated intimal thickening at day 7, paralleled with reduced intimal VSMC replication, without alteration of VSMC proliferation in the media. In accordance, [³H]-thymidine incorporation assay in primary cultured rat VSMCs revealed an enhanced replication rate (by 61%) upon ADAMTS-7 overexpression and retarded proliferation (by 23%) upon ADAMTS-7 siRNA administration. Our data demonstrates that ADAMTS-7 promotes VSMC proliferation both in vitro and in vivo. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and post-angioplasty restenosis.     

Simulation of flow through a Miller cuff bypass graft

Unnatural temporal and spatial distributions of wall shear stress in the anastomosis of distal bypass grafts have been identified as possible factors in the development of anastomotic intimal hyperplasia in these grafts. Distal bypass graft anastomoses with an autologus vein cuff (a Miller cuff) interposed between the graft and artery have been shown to alleviate the effects of intimal hyperplasia. In this study, pulsatile flow through models of a standard end-to-side anastomosis and a Miller cuff anastomosis are computed and the resulting wall shear stress and pressure distributions analysed. The results are inconclusive, and could be taken to suggest that the unnatural distributions of shear stress that do occur along the anastomosis floor may not be particularly important in the development of intimal hyperplasia. However, it seems more likely that the positive effects of the biological and material properties of the vein cuff, which are not considered in this study, somehow outweigh the negative effects of the shear stress distributions predicted to occur on the floor of the Miller-cuff graft.     

Carotid artery ligation induced intimal thickening and proliferation is unaffected by ageing

Following interventions to treat atherosclerosis, such as coronary artery bypass graft surgery, restenosis occurs in approximately 40% of patients. Identification of proteins regulating intimal thickening could represent targets to prevent restenosis. Our group previously demonstrated that in a murine model of vascular occlusion, Wnt4 protein expression and β-catenin signalling was upregulated which promoted vascular smooth muscle cell (VSMC) proliferation and intimal thickening. In this study, the effect of age on VSMC proliferation, intimal hyperplasia and Wnt4 expression was investigated. In vitro proliferation of VSMCs isolated from young (2 month) or old (18–20 month) C57BL6/J mice was assessed by immunocytochemistry for EdU incorporation. As previously reported, 400 ng/mL recombinant Wnt4 protein increased proliferation of VSMCs from young mice. However, this response was absent in VSMCs from old mice. As our group previously reported reduced intimal hyperplasia in Wnt4^+/? mice compared to wildtype controls, we hypothesised that impaired Wnt4 signalling with age may result in reduced neointimal formation. To investigate this, carotid artery ligation was performed in young and old mice and neointimal area was assessed 21 days later. Surprisingly, neointimal area and percentage lumen occlusion were not significantly affected by age. Furthermore, neointimal cell density and proliferation were also unchanged. These data suggest that although Wnt4-mediated proliferation was impaired with age in primary VSMCs, carotid artery ligation induced neointimal formation and proliferation were unchanged in old mice. These results imply that Wnt4-mediated proliferation is unaffected by age in vivo, suggesting that therapeutic Wnt4 inhibition could inhibit restenosis in patients of all ages.     

Simulation of Flow through a Miller Cuff Bypass Graft

Unnatural temporal and spatial distributions of wall shear stress in the anastomosis of distal bypass grafts have been identified as possible factors in the development of anastomotic intimal hyperplasia in these grafts. Distal bypass graft anastomoses with an autologus vein cuff (a Miller cuff) interposed between the graft and artery have been shown to alleviate the effects of intimal hyperplasia. In this study, pulsatile flow through models of a standard end-to-side anastomosis and a Miller cuff anastomosis are computed and the resulting wall shear stress and pressure distributions analysed. The results are inconclusive, and could be taken to suggest that the unnatural distributions of shear stress that do occur along the anastomosis floor may not be particularly important in the development of intimal hyperplasia. However, it seems more likely that the positive effects of the biological and material properties of the vein cuff, which are not considered in this study, somehow outweigh the negative effects of the shear stress distributions predicted to occur on the floor of the Miller-cuff graft.     

ADAMTS-7 promotes vascular smooth muscle cells proliferation in vitro and in vivo

Vascular smooth muscle cell(VSMC) proliferation and migration are pivotal for the pathogenesis of atherosclerosis and post-angioplasty restenosis. We have recently reported that a disintegrin and metalloproteinase with thrombospondin motifs-7(ADAMTS-7), a novel metalloproteinase, contributes directly to neointima formation by mediating VSMC migration. However, whether ADAMTS-7 affects VSMC proliferation remains unclear. In this study, we found that luminal adenoviral delivery of ADAMTS-7 aggravated intimal hyperplasia 7 d after injury, paralleled by an increased percentage of PCNA-positive cells in both intima and media. In contrast, perivascular administration of ADAMTS-7 si RNA, but not scrambled si RNA to injured arteries attenuated intimal thickening at day 7, paralleled with reduced intimal VSMC replication, without alteration of VSMC proliferation in the media. In accordance, [3H]-thymidine incorporation assay in primary cultured rat VSMCs revealed an enhanced replication rate(by 61%) upon ADAMTS-7 overexpression and retarded proliferation(by 23%) upon ADAMTS-7 si RNA administration. Our data demonstrates that ADAMTS-7 promotes VSMC proliferation both in vitro and in vivo. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and post-angioplasty restenosis.     

Analysis of intimal proteoglycans in atherosclerosis-prone and atherosclerosis-resistant human arteries by mass spectrometry

The propensity to develop atherosclerosis varies markedly among different sites in the human vasculature. To determine a possible cause for such differences in atherosclerosis susceptibility, a proteomics-based approach was used to assess the extracellular proteoglycan core protein composition of intimal hyperplasia from both the atherosclerosis-prone internal carotid artery and the atherosclerosis-resistant internal thoracic artery. The intimal proteoglycan composition in these preatherosclerotic lesions was found to be more complex than previously appreciated with up to eight distinct core proteins present, including the large extracellular proteoglycans versican and aggrecan, the basement membrane proteoglycan perlecan, the class I small leucine-rich proteoglycans biglycan and decorin, and the class II small leucine-rich proteoglycans lumican, fibromodulin, and prolargin/PRELP (proline arginine-rich end leucine-rich repeat protein). Although most of these proteoglycans seem to be present in similar amounts at the two locations, there was a selective enhanced deposition of lumican in the intima of the atherosclerosis-prone internal carotid artery compared with the intima of the atherosclerosis-resistant internal thoracic artery. The enhanced deposition of lumican in the intima of an atherosclerosis prone artery has important implications for the pathogenesis of atherosclerosis.     

Prevention of late lumen loss after coronary angioplasty by photodynamic therapy: Role of activated neutrophils

Restenosis after coronary angioplasty arises from fibrocellular intimal hyperplasia and possibly failure of the artery to enlarge adequately. Which mechanisms underlie this process is only partly understood. No drugs have been clinically effective in reducing the incidence of restenosis. Since recently, photodynamic therapy (PDT) is being investigated as a possible treatment for intimal hyperplasia. PDT involves the systemic administration of a light-excitable photosensitizer that is takers up rather preferentially by rapidly proliferating cells. During laser irradiation light energy is transferred from the photosensitizer to oxygen generating the highly reactive singlet oxygen. This potent oxidizer can cause severe cellular damage. After PDT of a balloon-injured artery from the rat and rabbit the media remained acellular for several weeks to months, and intimal hyperplasia did not occur. The endothelial lining regenerated by two weeks, but why smooth muscle cells did not repopulated the media is not known.Neutrophils seem to play an important role in the prevention of restenosis after coronary angioplasty, since the activation status of this type of phagocyte is directly related to vessel diameter at late follow-up. Furthermore, it has been observed that neutrophils adhere to the microvascular wall upon PDT in vivo. In vitro findings suggest that the increased neutrophil adherence was not dependent on a decreased release of the anti-adhesive factors NO and prostacyclin by the PDT-treated endothelial cells. Furthermore, PDT did not stimulate the expression of P-selectin by the endothelial cells, one of the adhesion receptors for neutrophils. The endothelial cells only retract upon PDT allowing the adherence of neutrophils by their ₂-integrin adhesion receptors to the subendothelial matrix. On the basis of these findings, we presume that the successful prevention of intimal hyperplasia by PDT partly depends on the presence of the neutrophil at the site of the lesion.     

Inhibition of rat smooth muscle proliferation by radiation after arterial injury: temporal characteristics in vivo and in vitro

Although several studies have suggested that inhibition of arterial narrowing by radiation after angioplasty is dependent on both time and dose, little is known regarding the temporal aspects of this effect and the mechanisms by which radiation affects the response of smooth muscle cells to injury. To determine the time course of inhibition of intimal hyperplasia by radiation, 135 rats were given single-fraction external gamma irradiation (1-10 Gy) to one carotid artery at intervals from 5 days before to 5 days after bilateral carotid artery balloon catheter injury, and intimal cross-sectional area was determined from histological sections at 20 days after injury. There was a prominent time- and dose-dependent inhibition of intimal hyperplasia by radiation when it was administered before or after balloon injury, with the greatest effect noted within 24 h before or after injury. To investigate the effect of radiation on smooth muscle cell growth (by cell counting) and proliferation, cell cycle kinetics (by BrdU incorporation), and cell killing (by clonogenic assay), smooth muscle cell cultures derived from rat aortic explants were seeded in equine plasma to induce quiescence, and radiation (2.5-10 Gy) was administered at various intervals before or after synchronous growth stimulation by 10% whole blood serum. A similar time and dose dependence was noted in growth kinetics, BrdU incorporation and cell killing for smooth muscle cells irradiated in vitro; in each case, the effect was most prominent for radiation administered in temporal proximity to stimulation with whole blood serum. By Western blot analysis, cultured smooth muscle cells showed a rapid time-dependent increase in Cdkn1a (formerly known as p21) protein expression, followed by a delayed increase in Tp53 (formerly known as p53) expression after irradiation. Activation of intracellular caspases, manifest by proteolytic poly(ADP-ribose) polymerase (PARP) cleavage, was not detected in smooth muscle cell cultures after irradiation. These observations suggest that radiation limits intimal hyperplasia in vivo by a transient, reversible process. Although apparent cytotoxic injury occurs in vitro, apoptosis of smooth muscle cells is not apparent. Both inhibition of proliferation of smooth muscle cells and cell cycle delay may contribute to inhibition of intimal hyperplasia in vivo by radiation.     

Combination of Periaortic Elastase Incubation and Cholesterol-Rich Diet: A Novel Model of Atherosclerosis in Rabbit Abdominal Aorta

Atherosclerosis, the leading cause of most cardiovascular disease, is a progressive multifaceted inflammatory disease characterized by extracellular matrix degradation and extensive remodeling of artery wall. However, its mechanism has not been completely understood, and animal models are useful to study its pathogenetic process. An analysis of literature on the nature of atherosclerosis indicates that focal accumulation of smooth muscle cells (SMCs) into the intima by plasma factors is fundamental to the entire process of plaque growth. In our previous study, vascular SMCs proliferation was obvious in elastase-induced aorta by day 15, which led to intimal hyperplasia and regression of rabbit aneurysm. Model induced by combination of balloon injury and an atherogenic diet in rabbits is the conventional, but most largely used experimental model of atherosclerosis. Since proliferation and accumulation of intimal SMCs are found in elastase-induced aorta, and hypercholesterolemia is usually induced by cholesterol-rich diets in rabbits, a novel atherosclerosis model may be induced by combination periaortic elastase incubation and cholesterol-rich diet.     

Numerical study of hemodynamics and wall mechanics in distal end-to-side anastomoses of bypass grafts.

The development and progress of distal anastomotic intimal hyperplasia seems to be promoted by altered flow conditions and intramural stress distributions at the region of the artery-graft junction of vascular bypass configurations. From clinical observations, it is known that intimal hyperplasia preferentially occurs at outflow anastomoses of prosthetic bypass grafts. In order to gain a deeper insight into post-operative disease processes, and subsequently, to contribute to the development of improved vascular reconstructions with respect to long term patency rates, detailed studies are required. In context with in vivo experiments, this study was designed to analyze the flow dynamics and wall mechanics in anatomically correct bypass configurations related to two different surgical techniques and resulting geometries (conventional geometry and Miller-cuff). The influence of geometric conditions and of different compliance of synthetic graft, the host artery and the interposed venous cuff on the hemodynamic behavior and on the wall stresses are investigated. The flow studies apply the time-dependent, three-dimensional Navier-Stokes equations describing the motion of an incompressible Newtonian fluid. The vessel walls are described by a geometrically non-linear shell structure. In an iterative coupling procedure, the two problems are solved by means of the finite element method. The numerical results demonstrate non-physiological flow patterns in the anastomotic region. Strongly skewed axial velocity profiles and high secondary velocities occur downstream the artery-graft junction. On the artery floor opposite the junction, flow separation and zones of recirculation are found. The wall mechanical studies show that increased compliance mismatch leads to increased intramural stresses, and thus, may have a proliferative influence on suture line hyperplasia, as it is observed in the in vivo study.     

2型糖尿病患者肝损伤标志物与下肢动脉病变的相关性分析

目的：探讨2型糖尿病患者肝损伤标志物水平与其下肢动脉病变的相关性,为2型糖尿病并发症的防治提供参考依据。方法：选取我院收治的2型糖尿病患者946例,根据下肢动脉内膜中层厚度分为以下3组,即无动脉硬化组（276例）、单纯性动脉硬化组（598例）和动脉硬化伴管腔狭窄或闭塞组（72例）。分析和比较三组之间肝损伤标志物谷丙转氨酶（ALT）、谷草转氨酶（AST）、γ-谷氨酰转肽酶（GGT）水平的差异,及其与2型糖尿病患者下肢动脉硬化程度的相关性。结果：随着动脉硬化程度的加重,2型糖尿病患者的ALT水平逐渐升高,三组之间两两比较差异均有统计学意义（P〈0．05）。动脉硬化伴管腔狭窄或闭塞组AST水平显著高于非动脉硬化组和单纯性下肢动脉硬化组,而动脉硬化组和非动脉硬化组之间AsT水平比较无显著差异（P〉0．05）。三组之间γ-谷氨酰转肽酶水平比较无显著性差异（P〉0．05）。Spearman等级相关分析显示ALT与糖尿病下肢动脉硬化的相关系数为0．30484。结论：2型糖尿病患者ALT水平与其下肢动脉硬化程度显著相关。     

2 型糖尿病患者肝损伤标志物与下肢动脉病变的相关性分析

目的：探讨2 型糖尿病患者肝损伤标志物水平与其下肢动脉病变的相关性,为2 型糖尿病并发症的防治提供参考依据。方 法：选取我院收治的2 型糖尿病患者946 例,根据下肢动脉内膜中层厚度分为以下3 组,即无动脉硬化组(276 例)、单纯性动脉硬 化组(598 例)和动脉硬化伴管腔狭窄或闭塞组(72 例)。分析和比较三组之间肝损伤标志物谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ-谷氨酰转肽酶(GGT)水平的差异,及其与2型糖尿病患者下肢动脉硬化程度的相关性。结果：随着动脉硬化程度的加重,2 型糖尿病患者的ALT 水平逐渐升高,三组之间两两比较差异均有统计学意义(P<0.05)。动脉硬化伴管腔狭窄或闭塞组AST 水平显著高于非动脉硬化组和单纯性下肢动脉硬化组,而动脉硬化组和非动脉硬化组之间AST 水平比较无显著差异(P>0.05)。三组之间γ-谷氨酰转肽酶水平比较无显著性差异(P>0.05)。Spearman 等级相关分析显示ALT 与糖尿病下肢动脉硬化的相关系数为0.30484。结论：2型糖尿病患者ALT 水平与其下肢动脉硬化程度显著相关。     

Telomeric restriction analysis of vascular smooth muscle cells following balloon angioplasty in rabbits

Intimal hyperplasia due to smooth muscle cell proliferation and migration has been reported to be responsible for the pathogenesis of atherosclerosis and restenosis, manifested following balloon angioplasty. In this study, we employed the balloon angioplasty model to study telomere length regulation in proliferating vascular smooth muscle cells. Our results showed that balloon angioplasty in iliac arteries resulted in intimal hyperplasia due to proliferation of the smooth muscle cells and small size telomeric restrictional fragments were evident in injured arteries.     

Characterization of the Inhibition of Vein Graft Intimal Hyperplasia by a Biodegradable Vascular Stent

Characterization of biodegradable stent vein graft thickening. Polydioxanone vascular sutures (PDSs) were used in a biodegradable arteriovenous bypass model. Twenty-four rabbits underwent carotid interposition bypass via ipsilateral jugular vein. One half received the stent (PDS group) and the remaining half a simple vein graft (controls). Group subsets received external stent removal or sham-control exploration at 4 and 12 weeks. At 4 and 12 weeks, the PDS group had significantly less medial and intimal thickening than the control group (P < 0.05), and there were fewer proliferating smooth muscle cells and extra cellular matrix formation than the control group at every interval. At 12 weeks, partial stent degradation occurred without deleterious effects. Furthermore proliferating cell nuclear antigen (PCNA), angiotensin type 1 receptor (AT1R), and transforming growth factor beta 1 (TGF-β1) levels were significantly lower than the control group. The external stent inhibited medial and intimal hyperplasia, an effect that remains after the material has completely degraded. This PDS stent is feasible option for vein grafts.     

Computational model of blood flow in the aorto-coronary bypass graft

Background

Coronary artery bypass grafting surgery is an effective treatment modality for patients with severe coronary artery disease. The conduits used during the surgery include both the arterial and venous conduits. Long- term graft patency rate for the internal mammary arterial graft is superior, but the same is not true for the saphenous vein grafts. At 10 years, more than 50% of the vein grafts would have occluded and many of them are diseased. Why do the saphenous vein grafts fail the test of time? Many causes have been proposed for saphenous graft failure. Some are non-modifiable and the rest are modifiable. Non-modifiable causes include different histological structure of the vein compared to artery, size disparity between coronary artery and saphenous vein. However, researches are more interested in the modifiable causes, such as graft flow dynamics and wall shear stress distribution at the anastomotic sites. Formation of intimal hyperplasia at the anastomotic junction has been implicated as the root cause of long- term graft failure.Many researchers have analyzed the complex flow patterns in the distal sapheno-coronary anastomotic region, using various simulated model in an attempt to explain the site of preferential intimal hyperplasia based on the flow disturbances and differential wall stress distribution. In this paper, the geometrical bypass models (aorto-left coronary bypass graft model and aorto-right coronary bypass graft model) are based on real-life situations. In our models, the dimensions of the aorta, saphenous vein and the coronary artery simulate the actual dimensions at surgery. Both the proximal and distal anastomoses are considered at the same time, and we also take into the consideration the cross-sectional shape change of the venous conduit from circular to elliptical. Contrary to previous works, we have carried out computational fluid dynamics (CFD) study in the entire aorta-graft-perfused artery domain. The results reported here focus on (i) the complex flow patterns both at the proximal and distal anastomotic sites, and (ii) the wall shear stress distribution, which is an important factor that contributes to graft patency.

Methods

The three-dimensional coronary bypass models of the aorto-right coronary bypass and the aorto-left coronary bypass systems are constructed using computational fluid-dynamics software (Fluent 6.0.1). To have a better understanding of the flow dynamics at specific time instants of the cardiac cycle, quasi-steady flow simulations are performed, using a finite-volume approach. The data input to the models are the physiological measurements of flow-rates at (i) the aortic entrance, (ii) the ascending aorta, (iii) the left coronary artery, and (iv) the right coronary artery.

Results

The flow field and the wall shear stress are calculated throughout the cycle, but reported in this paper at two different instants of the cardiac cycle, one at the onset of ejection and the other during mid-diastole for both the right and left aorto-coronary bypass graft models. Plots of velocity-vector and the wall shear stress distributions are displayed in the aorto-graft-coronary arterial flow-field domain. We have shown (i) how the blocked coronary artery is being perfused in systole and diastole, (ii) the flow patterns at the two anastomotic junctions, proximal and distal anastomotic sites, and (iii) the shear stress distributions and their associations with arterial disease.

Conclusion

The computed results have revealed that (i) maximum perfusion of the occluded artery occurs during mid-diastole, and (ii) the maximum wall shear-stress variation is observed around the distal anastomotic region. These results can enable the clinicians to have a better understanding of vein graft disease, and hopefully we can offer a solution to alleviate or delay the occurrence of vein graft disease.