Pathology of coronary artery bypass graft surgery.

Coronary artery bypass graft surgery has been available and widely successful for the symptomatic treatment of ischemic heart disease. Despite its widespread use, there is little information available on the pathological consequences of this procedure on the human heart. In this article, morphological consequences of coronary artery bypass graft surgery is reviewed. Intimal changes occurring within the vein graft itself consist predominately of fibrous initimal proliferation, which in some patients may progress to from an occlusive plaque. Most occlusions, however, occur at the coronary artery bypass graft anastomosis site and the mechanisms of occlusion include compression of the vascular lumen, thrombosis, and dissection of the coronary artery. Most graft failure occurs in the setting of too small a native coronary artery lumen. The myocardium is also at risk for alterations as a result of the bypass operation. Contraction band or reperfusion necrosis is the type of injury most commonly seen, and it appears to occur most often in the distribution of patent grafts. Accelerated atherosclerosis in vein grafts and the myocardial injury associated with revascularization require further detailed morphological studies, but these are important areas for pathological exploration since they bear on important and yet unanswered questions about coronary bypass surgery: can it in the long run perserve myocardium and prolong life?     

A procedure to simulate coronary artery bypass graft surgery

In coronary artery bypass graft (CABG) surgery the involved tissues are overstretched, which may lead to intimal hyperplasia and graft failure. We propose a computational methodology for the simulation of traditional CABG surgery, and analyze the effect of two clinically relevant parameters on the artery and graft responses, i.e., incision length and insertion angle for a given graft diameter. The computational structural analyses are based on actual three-dimensional vessel dimensions of a human coronary artery and a human saphenous vein. The analyses consider the structure of the end-to-side anastomosis, the residual stresses and the typical anisotropic and nonlinear vessel behaviors. The coronary artery is modeled as a three-layer thick-walled tube. The finite element method is employed to predict deformation and stress distribution at various stages of CABG surgery. Small variations of the arterial incision have relatively big effects on the size of the arterial opening, which depends solely on the residual stress state. The incision length has a critical influence on the graft shape and the stress in the graft wall. Stresses at the heel region are higher than those at the toe region. The changes in the mechanical environment are severe along all transitions between the venous tissue and the host artery. Particular stress concentrations occur at the incision ends. The proposed computational methodology may be useful in designing a coronary anastomotic device for reducing surgical trauma. It may improve the quantitative knowledge of vessel diseases and serve as a tool for virtual planning of vascular surgery.     

Bone morphogenic protein-4: A potential novel target for preventing vein graft failure in coronary revascularization

Coronary artery bypass surgery is an effective and durable therapy in both acute coronary syndrome and chronic coronary stenotic disease refractory to pharmacological treatment. Despite rapid development in operation-specific technologies and secondary prevention measures, the benefits of surgical revascularization are largely limited by inadequate patency of one of the most commonly used conduits, namely the autologous saphenous vein. However, apart from antiplatelet and lipid-lowering drugs, no other pharmacologic agent has hitherto proven clinically effective in preventing short- and long-term vein graft failure. Aiming at a large number of known biomolecules, multiple promising strategies failed to translate their beneficial effects observed in animal models into the clinical settings. Bone morphogenic protein-4 (BMP4), originally identified as a mediator in bone formation, has been recently demonstrated to participate in the process of arterial post-injury remodeling. Existing evidence has demonstrated that BMP4 is closely involved in the pathogenesis of thrombus formation, neointimal hyperplasia and superimposed atherosclerosis, all of which significantly contribute to arterial stenotic lesions. Although the post-injury responses inherent to arterial and venous vessel are unique, they share common elements and present with similar physiologic characteristics and clinical sequelae. Therefore, with regard to the multifaceted effects of BMP4 in regulating arterial wall remodeling, we hypothesize that BMP4 may play an important role in mediating the pathological responses of the venous wall to the arterial circulation. If our hypothesis is demonstrated correct, BMP4 inhibition could presumably serve as a novel strategy for preventing vein graft failure in coronary revascularization.     

Bone morphogenic protein-4: A potential novel target for preventing vein graft failure in coronary revascularization

Coronary artery bypass surgery is an effective and durable therapy in both acute coronary syndrome and chronic coronary stenotic disease refractory to pharmacological treatment. Despite rapid development in operation-specific technologies and secondary prevention measures, the benefits of surgical revascularization are largely limited by inadequate patency of one of the most commonly used conduits, namely the autologous saphenous vein. However, apart from antiplatelet and lipid-lowering drugs, no other pharmacologic agent has hitherto proven clinically effective in preventing short- and long-term vein graft failure. Aiming at a large number of known biomolecules, multiple promising strategies failed to translate their beneficial effects observed in animal models into the clinical settings. Bone morphogenic protein-4 (BMP4), originally identified as a mediator in bone formation, has been recently demonstrated to participate in the process of arterial post-injury remodeling. Existing evidence has demonstrated that BMP4 is closely involved in the pathogenesis of thrombus formation, neointimal hyperplasia and superimposed atherosclerosis, all of which significantly contribute to arterial stenotic lesions. Although the post-injury responses inherent to arterial and venous vessel are unique, they share common elements and present with similar physiologic characteristics and clinical sequelae. Therefore, with regard to the multifaceted effects of BMP4 in regulating arterial wall remodeling, we hypothesize that BMP4 may play an important role in mediating the pathological responses of the venous wall to the arterial circulation. If our hypothesis is demonstrated correct, BMP4 inhibition could presumably serve as a novel strategy for preventing vein graft failure in coronary revascularization.     

Uterine artery as an arterial conduit for coronary artery bypass graft (CABG) surgery in women: A role for estrogen-receptor alpha (ER-α) in the prevention of post-CABG accelerated atherosclerosis and graft disease

Coronary artery bypass graft (CABG) surgery is the standard of care in the treatment of advanced coronary artery disease (CAD). In order to bypass coronary occlusions, CABG surgery traditionally employs grafts from the left internal thoracic/mammary artery (LITA/IMA), radial artery (RA), and greater saphenous vein (SV). The risk of CABG failure is reported to be higher, or at best similar, for women than for men, and it relates primarily to post-operative accelerated atherosclerosis leading to graft stenosis and recurrent angina, a phenomenon known as “coronary artery bypass graft disease”. In this paper, the authors hypothesize that employing an alternative arterial conduit may help reduce the rate of post-CABG accelerated atherosclerosis in women, and propose that a uterine artery specimen be used instead. Given its greater density of estrogen-receptor alpha (ER-α) relative to other mammalian endothelial cells in the vasculature, uterine arteries may exhibit important anti-atherosclerotic properties. Theoretically, this effect may be amplified with the adjuvant administration of low-dose selective ER-α agonist modulator (SERM) therapy.     

Left main trunk ostial stenosis and aortic incompetence in Takayasu's arteritis.

A 41-year-old woman with recent onset of heart failure and angina due to aortic valve incompetence and critical left coronary ostium stenosis in the setting of Takayasu's arteritis is reported. The patient was successfully surgically treated by aortic valve replacement and coronary artery bypass with saphenous vein graft, showing a cardiac event-free 17 months follow-up. Takayasu's arteritis must be included among the possible causes of coronary artery disease and aortic valve incompetence in young female patients. Although chronic inflammation of the aortic wall may result in late graft occlusion, surgical therapy is effective for short and mid-term clinical improvement.     

Development of an ex vivo model to investigate the effects of altered haemodynamics on human bypass grafts

The insertion of vein grafts into the arterial circulation may contribute to vessel wall thickening and accelerated atherosclerosis, a common feature of late vein graft failure. We aimed to develop a model suitable for investigation of the effects of altered haemodynamics on human saphenous vein following its implantation into the arterial circulation. Segments of human saphenous vein obtained from patients undergoing coronary artery bypass surgery were sutured at each end to PTFE and placed into a flow system. Pressure and flow rates to stimulate the arterial and venous systems were achieved. A theoretical model of the flow chamber was created and computational fluid dynamics software (FLOTRAN, Swanson Analysis Systems) was used to determine the flow profile within the model. In summary, a flow model has been developed to investigate the effect of altered haemodynamics on the molecular and pathological changes that occur in vein grafts incorporated into the arterial circulation.     

Development of an ex vivo model to investigate the effects of altered haemodynamics on human bypass grafts

The insertion of vein grafts into the arterial circulation may contribute to vessel wall thickening and accelerated atherosclerosis, a common feature of late vein graft failure. We aimed to develop a model suitable for investigation of the effects of altered haemodynamics on human saphenous vein following its implantation into the arterial circulation. Segments of human saphenous vein obtained from patients undergoing coronary artery bypass surgery were sutured at each end to PTFE and placed into a flowsystem. Pressure and flowrates to stimulatethe arterial and venous systems were achieved. A theoretical model of the flowchamber was created and computational fluid dynamics software (FLOTRAN, Swanson Analysis Systems) was used to determine the flowprofile within the model. In summary, a flow model has been developed to investigate the effect of altered haemodynamics on the molecular and pathological changes that occur in vein grafts incorpor-ated into the arterial circulation.     

Histological appearances of the long saphenous vein

The long saphenous vein is frequently used as a graft in both coronary artery and femoro-distal bypass surgery. The histological changes which are seen after implantation into the arterial system have been well documented in the past, but little attention has been focused on the histological appearances of the donor long saphenous vein prior to grafting. In this study, samples of the long saphenous vein in excess of that required for bypass have been examined. In none of the veins did the histological appearances conform to the described normal. All showed evidence of intimal fibrosis which contained elastic tissue and enmeshed smooth muscle cells. The longitudinal and circular muscle layers showed evidence of muscle cell hypertrophy with increase in intervening connective tissue. Elsewhere, similar histological changes have been attributed to 'arterialization'. This study shows that many of the changes are present prior to grafting and may be important in graft failure.     

Unsteady simulation of distal blood flow in an end-to-side anastomosed coronary bypass graft with stenosis

In this paper, we report on the unsteady state modeling of blood flow in an end-to-side anastomosed bypass graft, which has a stenosis upstream from the junction. In coronary artery bypass grafting/surgery (CABG), new arteries are created in order to provide blood to the heart using other blood vessels as conduits to bypass the blocked section in the patient's coronary arteries. The failure of coronary artery bypass procedures has been attributed to both intimal hyperplasia (IH) and atherosclerosis. It is believed that these two phenomena are, in turn, related to the local hemodynamic factors. In this work, a three-dimensional computational fluid dynamics analysis is used to simulate the physiological blood flow through a model of a stenosed coronary bypass graft with the realistic assumption of non-Newtonian flow for human blood. For different flow repartitions and at different times of the cycle, both the recirculating areas and wall shear stress (WSS) are studied. Based on the different distribution of flow rates in the bypass graft and the host artery, the flow features are investigated and the influence of non-Newtonian behavior is discussed in terms of separation points, reattachment points, and the wall shear stresses. Various differences are observed based on the assumption of non-Newtonian behavior of blood, which have not been reported before when a simplified Newtonian approach is utilized.     

A novel promising therapy for vein graft restenosis: overexpressed Nogo-B induces vascular smooth muscle cell apoptosis by activation of the JNK/p38 MAPK signaling pathway

Coronary artery bypass grafting using autologous saphenous veins is a standard surgical therapy for coronary artery diseases. However, post-procedure vein graft restenosis impedes its effectiveness and often leads to a high morbidity and mortality, and a reduction in the quality of life. Neointimal hyperplasia is a major cause of vein graft occlusion, and is characterized by an imbalance between vascular smooth muscle cell (VSMC) proliferation and apoptosis. So far, there have been no optimally effective pharmacological or non-pharmacological interventions for the prevention and treatment of vein graft occlusion. Gene therapy has emerged as a potential therapeutic approach, as bypass grafts can be genetically modified ex vivo prior to grafting in the coronary vasculature. Nogo-B, recognized as a vascular protective factor, has been shown to reduce neointimal thickening in graft veins, but its specific mechanism is uncertain. Evidence from diverse sources has documented that overexpressed Nogo-B can induce apoptosis of variant cancer cell lines, suggesting that overexpressed Nogo-B may have a pro-apoptotic role in VSMC. Furthermore, we have found that Nogo-B is associated with the mitogen-activated protein kinase (MAPK) signaling pathway, which plays important roles in cell growth, differentiation, and apoptosis. Recent studies have shown that VSMC apoptosis can be induced by activation of the c-Jun-N-terminal kinase (JNK)/p38 MAPK pathway. Therefore, we propose that overproduction of Nogo-B in the graft vein could result in reduced neointimal hyperplasia, the mechanism of which involves increased VSMC apoptosis induced by activation of the JNK/p38 MAPK pathway. This study will provide a new clue for gene therapy in the treatment of vein graft failure.     

Surgical sealant in the prevention of early vein graft injury in an ex vivo model.

BACKGROUND: The amelioration of the adaptation process (arterialisation) of the vein graft wall to the arterial circulation in coronary artery bypass surgery by using extravascular support is clearly established in animal models and in in vitro and ex vivo set-ups. This support consists of some form of external graft-supporting modality like a prosthetic graft of stent. The clinical application of perivenous support, however, is hampered due to the fact that no easy applicable external support is available. Considering that application in the form of a spray is the most convenient modality, we evaluated whether polyethylene glycol is capable of providing adequate perivenous support. Polyethylene glycol is a synthetic, biodegradable product, used in cardiac surgery as a sealant, and is commercially available in the form of a spray. METHODS: Segments of human saphenous vein graft obtained during coronary artery bypass graft (CABG) procedures were placed in an ex vivo model, a side loop of the extracorporeal perfusion circuit, and perfused with autologous blood, making the circumstances identical to the implanted saphenous vein grafts concerning pressure, temperature, level of complement and leukocyte activation and blood pressure. Alternately around every other study vein graft segment polyethylene glycol was applied. Unsupported grafts served as control. After 1 min of solidification, perfusion was started with a pressure of about 60 mmHg (nonpulsatile flow). Perfusion was maintained for 60 min, after which the grafts were collected for light microscopy and electron microscopy. RESULTS: Light microscopy and electron microscopy showed remarkable attenuation of endothelial cell loss and less injury of smooth muscle cells of the circular and longitudinal layer of the media in the supported group compared to the nonsupported vein graft segments. CONCLUSION: Polyethylene glycol is able to provide adequate external vein graft support, preventing overdistension, in an ex vivo model. This provides a basis for clinical application. Further investigation is warranted to evaluate long-term effects.     

CT血管造影分析体外循环与非体外循环冠状动脉旁路移植后的桥血管通畅率

背景：近年来,非体外循环冠状动脉旁路移植后桥血管通畅率是否与传统的体外循环冠状动脉旁路移植相同存在争议。 目的：探讨体外循环与非体外循环冠状动脉旁路移植后桥血管时间通畅率的差异性。 方法：选取同一操作者行体外循环冠状动脉旁路移植患者100例,按其临床特征及桥血管病变危险因素匹配抽取非体外循环冠状动脉旁路移植患者137例。采用64排多螺旋CT血管造影分析冠脉搭桥后1个月,1年,2年,3年,4年的桥血管通畅情况。 结果与结论：共对641条桥血管进行评价,两组中左侧乳内动脉桥血管时间通畅率均高于大隐静脉桥,两组左侧乳内动脉桥和大隐静脉桥血管时间通畅率比较差异均无显著性意义。说明非体外循环与体外循环冠状动脉旁路移植后患者桥血管时间通畅率相似,对于某些适当的患者来说,非体外循环冠状动脉旁路移植不失为一个良好的选择。     

The role of depression and anxiety symptoms in hospital readmissions after cardiac surgery

The objective of this study was to determine the association between depression, anxiety and general stress symptoms with hospital readmissions after coronary artery bypass graft surgery. Two hundred and twenty six coronary artery bypass graft patients completed baseline self-report measures of depression, anxiety and stress and 222 patients completed these measures after surgery on the hospital ward. The hospital readmission outcomes at six months were analyzed using multivariable proportional hazard models. When analyzed as continuous variables in multivariable analyses, preoperative anxiety and postoperative depression predicted readmissions independent of medical covariates. In multivariable analyses with dichotomized anxiety, depression and stress, more than two-fold increase in readmission risk was attributable to preoperative anxiety and postoperative depression, independent of covariates. These results lend further support to previous research that has shown the symptoms of depression and anxiety are associated with morbidity following coronary artery bypass graft surgery. The findings highlight the need to develop suitable interventions for anxiety and depression among coronary artery bypass graft surgery patients.     

Estimation of wall shear stress in bypass grafts with computational fluid dynamics method

Coronary artery bypass graft (CABG) operation for coronary artery disease with different types of grafts has a large clinical application world wide. Immediately after this operation patients are usually relieved of their chest pain and have improved cardiac function. However, after a while, these bypass grafts may fail due to for example, neointimal hyperplasia or thrombosis. One of the causes for this bypass graft failure is assumed to be the blood flow with low wall shear stress. The aim of this research is to estimate the wall shear stress in a graft and thus to locate areas were wall shear stress is low. This was done with the help of a blood flow computer model. Post-operative biplane angiograms of the graft were recorded, and from these the three-dimensional geometry of the graft was reconstructed and imported into the computational fluid dynamics (CFD) program FLUENT. The stationary diastolic flow through the grafts was calculated, and the wall shear stress distribution was estimated. This procedure was carried out for one native vessel and two different types of bypass grafts. One bypass graft was a saphenous vein and the other one was a varicose saphenous vein encased in a fine, flexible metal mesh. The mesh was attached to give the graft a defined diameter. The computational results show that each graft has distinct areas of low wall shear stress. The graft with the metal mesh has an area of low wall shear stress (< 1 Pa, stationary flow), which is four times smaller than the respective areas in the other graft and in the native vessel. This is thought to be caused by the smaller and more uniform diameter of the metal mesh-reinforced graft.     

Assessment of coronary artery bypass graft patency by multislice computed tomography

The recently developed multislice computed tomography (MSCT) is capable of rapid imaging of cardiac structures, including coronary arteries, during a single breath-hold. We evaluated coronary artery bypass graft (CABG) patency by comparing MSCT results to those of contrast angiography. MSCT and contrast angiography were performed in 39 patients (10 women, 29 men and mean age 60.0 +/- 7.8 years) with a total of 115 bypass grafts including 36 left internal mammary arteries, 4 right internal mammary arteries, 19 radial arteries, 2 gastroepiploic arteries and 54 vein grafts. Patients were investigated for an average of 14 +/- 27 months (range 1 - 108 months) after CABG surgery. Contrast angiography showed a patency rate of 87.0% (100/115). Ninety-nine of these 100 patent grafts by contrast angiography and 14 of the remaining 15 occluded grafts were correctly classified by MSCT (93.3% sensitivity and 99.0% specificity for bypass graft occlusion). The positive and negative predictive values for bypass graft occlusion were 93.3% and 99%, respectively, with an overall diagnostic accuracy of 98.3% (97.2% for left internal mammary artery, 100% for radial artery, 98.1% for vein graft and 100% for other grafts). In conclusion, MSCT is a useful and accurate diagnostic tool for the evaluation of bypass graft patency.     

Mechanisms of vessel injury during percutaneous transluminal angioplasty of saphenous vein bypass grafts and coronary arteries

Three patients were studied in whom percutaneous transluminal angioplasty (PTA) was attempted in stenotic saphenous vein bypass grafts. In two cases, large splits were present in the thick fibrotic intima of the vein grafts, accompanied by rupture of atherosclerotic plaques or hemorrhage into atherosclerotic plaques. Both cases required emergency coronary artery bypass surgery. In the third case, a vein graft failed to dilate after multiple attempts. Only small splits were present in that fibrotic intima. Two other patients were studied in whom coronary artery PTA was attempted. In both cases, laceration of a nonatherosclerotic segment of the artery occurred. Combined with our previous report, these observations indicate that PTA results in lacerations of atherosclerotic plaques, fibrotic intima, and otherwise normal vessel walls and that laceration is the mechanism of both successful dilation and serious complications.     

组织型纤溶酶原激活剂在移植血管桥再狭窄动物血管的差异表达

目的研究组织型纤溶酶原激活剂（t—PA／PLAT）在移植血管桥再狭窄动物血管的差异表达。方法通过兔双侧颈动脉进行动脉桥和静脉桥的移植,形成双侧移植血管桥再狭窄动物模型。应用免疫组化检测t-PA在动物模型动脉桥、静脉桥的表达并进行比较。结果血管桥移植前,t-PA在实验动物颈动脉和颈静脉的表达差异无统计学意义（P〉0．05）;血管桥移植后,t-PA在动脉桥的表达明显高于静脉桥（P〈0．05）,于16周时达到高峰[（32．34±4．74）％比（16．74±3．14）％],以后随时间延长而出现表达减少（P〈0．05）。结论t-PA在术后早期对血管桥具有保护作用,其表达的高低与术后血管桥再狭窄关系密切。     

Vein graft disease in a knockout mouse model of hyperhomocysteinaemia

A major reason for vein graft failure after coronary artery bypass grafting is neointimal hyperplasia and thrombosis. Elevated serum levels of homocysteine (Hcy) are associated with higher incidence of cardiovascular disease, but homocysteine levels also tend to increase during the first weeks or months after cardiac surgery. To investigate this further, C57BL/6J mice (WT) and cystathionine‐beta‐synthase heterozygous knockout mice (CBS+/?), a mouse model for hyperhomocysteinaemia, underwent interposition of the vena cava of donor mice into the carotid artery of recipient mice. Two experimental groups were examined: 20 mice of each group underwent bypass surgery (group 1: WT donor and WT recipient; group 2: CBS+/? donor and CBS+/? recipient). After 4 weeks, the veins were harvested, dehydrated, paraffin‐embedded, stained and analysed by histomorphology and immunohistochemistry. Additionally, serum Hcy levels in CBS knockout animals and in WT animals before and after bypass surgery were measured. At 4 weeks postoperatively, group 2 mice showed a higher percentage of thrombosis compared to controls, a threefold increase in neointima formation, higher general vascularization, a lower percentage of elastic fibres with shortage and fragmentation in the neointima, a lower percentage of acid mucopolysaccharides in the neointima and a more intense fibrosis in the neointima and media. In conclusion, hyperhomocysteinaemic cystathionine‐beta‐synthase knockout mice can play an important role in the study of mechanisms of vein graft failure. But further in vitro and in vivo studies are necessary to answer the question whether or not homocysteine itself or a related metabolic factor is the key aetiologic agent for accelerated vein graft disease.