J. Golledge

The Symptomatic Carotid Plaque

BACKGROUND The natural histories of equally severe symptomatic and asymptomatic carotid stenoses are very different, which suggests dichotomy in plaque behavior. The vascular biology of the symptomatic carotid plaque is presented in this review. SUMMARY OF REVIEW Histology studies comparing asymptomatic and symptomatic plaques were identified from MEDLINE. Reports in which stenosis severity was not stated or not similar for symptomatic and asymptomatic patients were excluded. In vitro studies and reports from the coronary circulation were reviewed with regard to the vascular biology of the plaque. Histology studies comparing carotid plaques removed from symptomatic and asymptomatic patients reveal characteristic features of unstable plaques: surface ulceration and plaque rupture (48% of symptomatic compared with 31% of asymptomatic, P<0.001), thinning of the fibrous cap, and infiltration of the cap by greater numbers of macrophages and T cells. In vitro studies suggest that macrophages and T cells release cytokines and proteinase, which stimulate breakdown of cap collagen and smooth muscle cell apoptosis and thereby promote plaque rupture. CONCLUSIONS Infiltration of inflammatory cells to the surface of carotid plaques may be a critical step in promoting plaque rupture and resultant embolization or carotid occlusion. Further understanding of cell recruitment and behavior in carotid atherosclerosis may allow better detection of unstable plaques and therapeutic methods of plaque stabilization.

Systematic Comparison of the Early Outcome of Angioplasty and Endarterectomy for Symptomatic Carotid Artery Disease

Background and Purpose —Endoluminal treatment is being increasingly used for carotid artery disease. The aim of this study was to compare the stroke and death risk within 30 days of endovascular treatment or endarterectomy for symptomatic carotid artery disease. Methods —A systematic comparison of the 30-day outcome of angioplasty with or without stenting and endarterectomy for symptomatic carotid artery disease reported in single-center studies, published since 1990, was performed. Results —Thirty-three studies (13 angioplasty and 20 carotid endarterectomy) were included in this analysis. Carotid stents were deployed in 44% of angioplasty patients. Mortality within 30 days of angioplasty was 0.8% compared with 1.2% after endarterectomy (OR 0.68, 95% CI 0.43 to 1.05; P =0.6). The stroke rate was 7.1% for angioplasty and 3.3% for endarterectomy (OR 2.22, CI 1.62 to 3.04; P <0.001), while the risk of fatal or disabling stroke was 3.2% and 1.6%, respectively (OR 2.09, CI 1.3 to 3.33; P <0.01). The risk of stroke or death was 7.8% for angioplasty and 4% for endarterectomy (OR 2.02, CI 1.49 to 2.75; P <0.001), while disabling stroke or death was 3.9% after angioplasty and 2.2% after endarterectomy (OR 1.86, CI 1.22 to 2.84; P <0.01). Conclusions —In the treatment of symptomatic carotid artery disease, the risk of stroke is significantly greater with angioplasty than carotid endarterectomy. At present, carotid angioplasty is not recommended for the majority of patients with symptomatic carotid artery disease.

Quality of life assessment in vascular disease: Towards a consensus

OBJECTIVES To review the assessment of quality of life in vascular disease, with particular reference to the Nottingham Health Profile and Medical Outcomes Study Short Form 36. DESIGN AND METHODS A detailed literature search of relevant publications. Trans-national and trans-cultural convergence and validity of these scales were assessed. RESULTS The Short Form 36 was found to be the most valid and reliable quality of life measure for use in an international vascular setting. CONCLUSION In the absence of a specific dedicated vascular disease quality of life measure, the Medical Outcomes Study Short Form 36 should be used as a quality of life measure in the assessment of vascular disease in an international setting.

Have the results of infrainguinal bypass improved with the widespread utilisation of postoperative surveillance

OBJECTIVES The objectives of this study were to assess the impact of Duplex surveillance on the results of infrainguinal vein grafts. A review has been performed comparing the outcome of vein grafts undergoing Duplex surveillance plus prophylactic treatment of stenoses to that of vein grafts followed clinically. DESIGN, PATIENTS, AND METHODS Only studies providing information on occlusion rates were included. Mortality and limb salvage rates were also analysed but were not available from all studies. RESULTS 2680 surveillance and 3969 non-surveillance vein grafts were analysed. There was no significant difference between the two groups with respect to presence of critical ischaemia (p=0.3) and level of distal anastomosis (p>0.5). Surveillance identified 493 stenoses in 469 (19%) grafts, 397 (16%) grafts were treated by surgery (248; 62%) and angioplasty (149; 38%). Ninety-eight (26%) grafts developed recurrent stenoses. Total number of deaths, total number of occluded grafts and number of occlusions after 30 days were significantly greater for the non-surveillance group (p<0.001; p<0.001; p<0.01). Perioperative occlusion rates were not significantly different (p=0.1). Few surveillance studies reported limb salvage rates (6 of 17). The numbers of amputations were not significantly different between the two groups (p>0.5). CONCLUSIONS The patency of infrainguinal vein grafts would appear to be improved as a result of surveillance. However, no improvement in limb salvage has been demonstrated.

Arterial flow conditions downregulate thrombomodulin on saphenous vein endothelium

BACKGROUND The antithrombogenic properties of venous endothelium may be attenuated when vein is implanted in the arterial circulation. Such changes may facilitate thrombosis, which is the final common pathway for saphenous vein arterial bypass graft occlusion. METHODS AND RESULTS Using human saphenous vein in a validated ex vivo flow circuit, we investigated (1) the possibility that arterial flow conditions (mean pressure, 100 mm Hg, 90 cpm, approximately 200 mL/min) alter the concentration of proteins involved in regulating thrombosis at the vessel wall and (2) the influence of ion channel blockade on such effects. Concentrations of thrombomodulin and tissue factor were quantified by Western blotting (ratio of von Willebrand factor staining) and immunohistochemistry (as a percentage of CD31-staining area). Thrombomodulin concentrations after 90 minutes of venous and arterial flow conditions were quantified by immunostaining (68.9+/-4.8% and 41.0+/-3.0% CD31, respectively; P<0.01) and by Western blotting (1.35+/-0.20 and 0. 15+/-0.03 ratio of von Willebrand factor, respectively; P<0.01). The ability of endothelial cells to generate activated protein C also decreased from 62+/-14 to 19+/-10 ng. min-1. 1000 cells-1 (P=0.01). The significant reduction in thrombomodulin was attenuated if calcium was removed from the perfusate but not by external vein stenting. Inclusion in the vein perfusate of drugs that reduce calcium entry (including Gd3+, to block stretch-activated ion channels, and nifedipine) abolished the reduction in thrombomodulin concentration observed after arterial flow conditions. In freshly excised vein, negligible concentrations of tissue factor were detected on the endothelium and concentrations did not increase after 90 minutes of arterial flow conditions, although the inclusion of nifedipine caused the immunostaining to increase from 3.0+/-0.4% to 8.5+/-0.7% CD31 (P<0.02). CONCLUSIONS In saphenous vein endothelium exposed to arterial flow conditions, there is rapid downregulation of thrombomodulin, sufficient to limit protein C activation, by a calcium-dependent mechanism.

Development of an in vitro model to study the response of saphenous vein endothelium to pulsatile arterial flow and circumferential deformation

OBJECTIVES To develop an in vitro model of human saphenous vein bypass to facilitate study of the early adaptive responses of venous endothelium to arterial flow conditions. DESIGN MATERIAL AND METHODS: Segments of human saphenous vein (with or without external polytetrafluoroethylene (PTFE) stents to limit circumferential and radial deformation) were mounted in a bypass circuit and subjected to pulsatile flow with oxygenated Krebs solution to simulate arterial or venous flow conditions for a period of 90 min. The viability of the vein was assessed by the tissue ATP concentration and vasomotor responses to phenylephrine, sodium nitroprusside and bradykinin (endothelium-dependent). Immunohistochemistry was used to assess both endothelial preservation (CD31) and the expression of proteins involved in leukocyte adhesion: E-selectin, P-selectin and ICAM-1. Freshly excised veins were used as controls. RESULTS The concentration of ATP was 320 +/- 11 nmol/g in freshly excised vein (n = 8) and following exposure to the arterial flow circuit increased to 566 +/- 60 nmol/g (n = 8, paired t-test, p = 0.003) in unstented veins and to 421 +/- 49 nmol/g (n = 8, paired t-test, p = 0.002) in externally stented veins (with PTFE). Both endothelium-dependent and sodium nitroprusside-induced vasodilatation responses were preserved after veins were exposed to the arterial flow circuit, but the sensitivity to phenylephrine was increased: EC50 decreasing from 9 microM, p = 0.008. There was a 5-10% decrease in staining area for CD31 after veins, stented or unstented, were exposed to the arterial flow circuit. However, after exposure to the arterial flow circuit, the staining area ratio for ICAM-1/CD31, which remained unchanged in externally stented veins, increased two-fold in unstented veins, p > 0.01: there were no changes in the staining area ratio P-selectin/CD31 and no staining for E-selectin was observed. CONCLUSION Vasomotor responses and tissue ATP concentration indicate that the viability of saphenous vein can be maintained for up to 90 min in an ex vivo flow circuit and the CD31 staining indicated endothelial preservation. This opens up the possibility of investigating the early changes in saphenous vein endothelium following exposure to arterial pressure, as at bypass surgery. First results suggest that there is rapid upregulation of the leukocyte adhesion molecule ICAM-1, which can be prevented by limiting the circumferential deformation of the vein with an external PTFE stent.

Selection of patients for carotid endarterectomy

OBJECTIVE The aim of this study was the definition of the duplex scan parameters that best select patients for carotid endarterectomy. METHODS This study was set in a regional vascular unit. Duplex scanning and angiography were performed prospectively on 50 patients who were symptomatic (100 carotid bifurcation) to identify the most accurate and sensitive duplex scan criteria to identify an 80% to 99% stenosis according to the European Carotid Symptomatic Trial. With data from the European Carotid Symptomatic Trial, we estimated the effect of three different approaches used to select patients for carotid endarterectomy. The first approach was the selection of patients for carotid surgery on the basis of duplex scanning alone with the most accurate duplex scan criteria (approach I). The second approach was the selection of patients for carotid surgery on the basis of duplex scanning alone with a 100% sensitive duplex scan criteria (approach II). The third approach was the selection of patients for angiography with duplex scanning (100% sensitive criteria) and then the use of angiography to define which patients should undergo surgery (approach III). RESULTS All three approaches appeared to have a similar potential in stroke reduction. However, approach I, which minimized the number of patients who underwent surgery (19% less than approach II) or invasive imaging (65% less than approach III), appeared to be the most appropriate. CONCLUSION These data support the selection of patients for carotid endarterectomy on the basis of duplex scanning alone. The duplex scan criteria should be validated against angiography.

Outcome of selective patching following carotid endarterectomy

OBJECTIVES Routine patch angioplasty has been advocated following carotid endarterectomy but patching can be associated with complications. This study assesses the effect of a selective patching policy based on distal internal carotid diameter on the rate of restenosis and outcome following carotid endarterectomy. DESIGN, MATERIAL AND METHODS A consecutive series of 213 patients underwent carotid endarterectomy performed by one surgeon. Preoperative carotid dimensions were measured intraoperatively using calipers. Following endarterectomy a 5mm Dacron patch was selectively employed if the distal internal carotid was 5mm or less (group 1, 95 patients) or 6mm or less (group 2, 118 patients). Patients underwent colour-coded Duplex scanning at 24 h, 1 week, 3, 6, 9, and 12 months, and yearly following this. RESULTS Overall 27 restenoses (5 residual) of 50% or greater and two occlusions developed. Patching was performed in 47% of group 1 and 61% of group 2 arteries. In group 1 14% of patched compared with 24% of non-patched arteries developed restenosis at 24 months (p=0.4). In group 2 13% of patched compared to 11% of non-patched arteries developed restenosis at 12 months (p>0.5). Stroke rate at 24 months were similar for patched and non-patched patients in groups 1 (p>0.5) and 2 (p=0.4). CONCLUSIONS This study suggests that patch angioplasty of larger carotid arteries may be unnecessary. Randomisation of larger arteries between patch and primary closure would be required to confirm this.

Rapid Changes in the Coagulant Proteins on Saphenous Vein Endothelium in Response to Arterial Flow

Healthy endothelium provides a nonthrombogenic surface. In this study the authors investigated the effect of arterial flow on the saphenous vein endothelial expression of proteins controlling thrombosis. Human saphenous vein segments, freshly excised from patients, were placed in a validated in vitro circuit with flow conditions shown to simulate arterial or venous circulations. In separate experiments, placement of an external polytetrafluoroethylene (PTFE) stent was used to differentiate the effects of pulsatile wall deformation and shear stress, while addition of drugs to the vein perfusate allowed study of the role of ion channels in transducing the response of the vein to arterial flow. Endothelial concentrations of thrombomodulin, nitric oxide synthase, tissue factor, and tissue plasminogen activator were assessed by quantitative immunohisto chemistry and Western blotting of endothelial cell lysates, in paired vein samples, in comparison to control proteins. Arterial flow conditions caused a rapid and significant reduction in the endothelial concentration of thrombomodulin: The immunostaining area decreased from 80.1 ± 7.0 to 48.3 ±5.0 and 32.9 ±3.0% at 45 and 90 minutes respectively, p = 0.01. These findings were confirmed by Western blotting. The reduction in thrombomodulin concentration was unaffected by eliminating vein wall deformation by placement of an external PTFE stent or by including the K+ channel blocker tetraethylammonium (TEA) in the vein perfusate. In contrast, thrombomodulin concentrations remained high when blockers of stretch-activated cation and calcium channels were included in the vein perfusate. The endothelial concentration of nitric oxide synthase increased after 90 minutes of arterial flow and this change was abolished when TEA was included in the vein perfusate. Arterial flow induced rapid changes in saphenous vein antithrombotic proteins. Different cation channels mediated the flow-induced changes in thrombomodulin and nitric oxide synthase.

Dilatation of saphenous vein grafts by nitric oxide

OBJECTIVES To investigate firstly whether flow-dependent vasodilation is maintained in vein grafts, and secondly whether nitric oxide donors dilate vein grafts to improve the flow through graft stenoses. DESIGN, MATERIALS AND METHODS The vasodilatation of mature patent vein grafts, in response to reactive hyperaemia and glyceryl trinitrate (GTN), was assessed by the change in external diameter using duplex ultrasonography. The severity (ratio of proximal systolic velocity, V1, to peak systolic velocity at the stenosis, V2, of vein graft stenoses was determined by duplex ultrasonography before and after 24 h of local application of GTN patches. RESULTS In post-occlusion hyperaemia the diameter of patent distal vein grafts (n = 7) increased to a maximum of 112 +/- 1.9% of resting diameter after 2 min, p = 0.026. The diameter increased further to 117 +/- 2.5% of the resting value 5 min after oral GTN (n = 5), p = 0.007. The velocity ratio, V2/V1, through graft stenoses (n = 6) decreased by 20 +/- 5% after application of GTN patches, principally as a result of reduction in V2, mean difference 0.8, p = 0.15. The changes in response to GTN were more evident for proximal than distal vein graft stenoses. CONCLUSION Flow-induced vasodilatation responses, which have been attributed to the endothelial release of nitric oxide, are maintained in patent vein grafts: the grafts dilate even further in response to GTN. The application of GTN patches close to a vein graft stenoses appears to reduce the velocity ratio through vein graft stenoses. GTN patches might be used to reduce the risk of graft occlusion when there is a delay between the detection and the treatment of haemodynamically significant graft stenoses.