Differing association of macrophage subsets with atherosclerotic plaque stability.

AIM: While initial research suggests that M2 macrophages are athero-protective, more recently, proatherogenic functions, such as a greater uptake of lipid than M1 macrophages, have been demonstrated, raising the question of their actual association with plaque stability. The present study, therefore, assessed the association between macrophage subset and plaque stability. Furthermore, it examined whether the fibrocyte, that we have previously identified in the plaque, represents a subset of M2 macrophages. METHODS: Twenty human carotid atherosclerotic plaque specimens were examined for the presence of macrophages using immunohistochemistry for pan macrophages (CD68), M1 (CD64, CD86) and M2 (CD163, CD206) subsets. The slides were assessed by digital whole slide scanning/image analysis to quantify the expression of these markers in the plaque. Comparisons in marker distribution and quantity relative to plaque stability were made. Adoption of a fibrocyte phenotype was assessed by double immunofluorescence staining of the markers with procollagen I. RESULTS: M1 and M2 macrophages were present throughout the plaque including the core and cap. While the levels of CD68 (pan macrophage maker) and CD86 negatively correlated with cap thickness, the levels of the M2 marker, CD163, did not and moreover, did not differ between plaques when they were separated into stable and unstable groups. Notably, collagen production was evident in most but not all M2 macrophages. CONCLUSION: Our findings demonstrate that while macrophage levels in general negatively correlate with plaque cap thickness, levels of M2 macrophages do not. This may be in part due to their ability to produce collagen (ie adopt a fibrocyte phenotype) in the plaque.

Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study.

BACKGROUND: Terutroban is a selective prostaglandin endoperoxide (TP) receptor antagonist with antithrombotic, antivasoconstrictive and antiatherosclerotic properties and is currently in development for long-term cardiovascular secondary prevention. OBJECTIVES: TAIPAD is an international, double-blind, randomized controlled study comparing the effects of five dosages of oral terutroban vs. aspirin and placebo on platelet aggregation in peripheral arterial disease (PAD) patients. PATIENTS/METHODS: After 10 day's placebo run-in, included patients (n = 435; ankle-brachial pressure index, 0.7 ± 0.1) were randomly allocated to aspirin 75 mg day(-1), terutroban 1, 2.5, 5, 10 or 30 mg day(-1) or placebo. On day 5, the placebo group was reallocated to one of the terutroban groups for the rest of the study (day 83). Ex vivo platelet aggregation induced by the thromboxane analog U46619 (7 µm) was measured 24 h after dosing, as well as platelet aggregation induced by arachidonic acid (AA), collagen and ADP. RESULTS: Terutroban dose-dependently inhibited U46619-induced platelet aggregation at days 5 and 83. At day 5, the inhibition was significant vs. placebo for all terutroban dosages (P < 0.001). Terutroban (5, 10 and 30 mg day(-1)) was at least as effective as aspirin in inhibiting platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Terutroban was well tolerated, with a safety profile similar to aspirin. CONCLUSIONS: In PAD patients, terutroban dose-dependently inhibited platelet aggregation 24 h after dosing, and was at least as effective as aspirin at 5, 10 and 30 mg day(-1). Terutroban was well tolerated.

Venous thromboembolism following primary total hip arthroplasty.

AIM: In the absence of thromboprophylaxis, venographically detected deep vein thrombosis (DVT) occurs in approximately 50% of patients undergoing primary total hip arthroplasty. Despite the existence of national and international guidelines, thromboprophylaxis may be underused. METHODS: A retrospective review was performed of the clinical incidence of venous thromboembolism (VTE) and thromboprophylactic practice patterns over a nine year period. Patient baseline characteristics, VTE risk factors, prophylactic modalities (mechanical and pharmacological), operation duration, type of prosthesis and fixation, mode of anesthesia, hospital length of stay (LOS) were analyzed. The main efficacy outcome was DVT and/or pulmonary embolism (PE). The primary safety outcome was major bleeding. RESULTS: In-hospital incidence of VTE was 2.5% and 3.8% up to three months post hospital discharge. Median time to postoperative VTE development in-hospital and after discharge was 6.5 days (IQR: 5.0 to 8.0 days) and 29.0 days (IQR: 19.5 to 38.0 days) respectively. 66.7% (95% CI: 30.0 to 90.3%) of all readmissions for VTE occurred within one month post-operatively. There were no readmissions for VTE in patients discharged on extended pharmacological prophylaxis. CONCLUSIONS: The use of prophylactic protocols was associated with relatively low VTE rates up to three months with minimal bleeding complications. A more intense in-hospital and extended prophylaxis beyond hospitalization is recommended in this high risk group of patients.

Improved outcomes with endovascular stent grafts for thoracic aorta transections.

OBJECTIVE: To retrospectively assess the outcome of endovascular stent-graft implantation for thoracic aortic transections (ETAT). DESIGN: Retrospective review. METHODS: 16 patients median age 30 years, treated between May 2000 and April 2007. Median injury severity score was 33 (range 29 to 66) in 14 acute patients; 2 patients had thoracic pseudoaneurysms. The Cook-Zenith endograft was used in eight patients, Medtronic-Talent (6) and Gore-Excluder (2). Average procedure time was 90 minutes, blood loss 100 (range 40 to 3000) mls, screening time 10.8 (range 5.9 to 22.6) minutes, and contrast dose was 195 (range 60 to 400) mls. RESULTS: Graft deployment was successful in all cases. There was one death within 30 days. The left subclavian artery was completely covered in one case, and partially in three. Two patients had Type I endoleak, and one delayed Type II endoleak. One patient had iatrogenic right coronary artery dissection. Two patients developed difficult to treat hypertension, and one acute renal failure. CONCLUSION: Endovascular intervention is a safe and effective treatment for aortic transection in multiple trauma patients. ETAT reduces the major morbidity and mortality associated with open repair in multiple trauma patients. The majority of these patients are young and long-term follow up is necessary to assess graft durability.

Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes.

AIM: The stability of an atherosclerotic plaque is a key-determining factor in the clinical outcome of cardiovascular disease. In this respect, smooth muscle (SM) alfa actin positive cells play an important role in maintaining plaque stability through formation of a fibrous cap. Recent evidence suggests that circulating progenitors may be a source of these cells. We hypothesized that they may be fibrocytes bone-marrow derived cells that acquire SM-like characteristics, including the expression of SM alfa actin. METHODS: We examined human carotid endarterectomy specimens for the presence of fibrocytes by immunohistochemistry staining for CD34/procollagen I and leukocyte specific protein-1/procollagen I) and examined fibrocyte differentiation in vitro. RESULTS: Fibrocytes were found in regions of plaque growth/healing. They possessed a SM-like spindle shape, produced collagen, and consistent with being fibrocytes they co-localized with transformation growth factor beta, but not serum amyloid P factors, known to promote and inhibit their formation, respectively. While fibrocytes were detected in regions of new growth in 35/40 specimens, only 1/3 of the specimens expressed the SM cell marker calponin, and smoothelin was absent, in these regions. CONCLUSION: Our results demonstrate that fibrocytes contribute to formation of the fibrous cap. With fibrocytes being a monocyte derived cell, we suggest that monocytes may play a more crucial role in the clinical outcome of atherosclerosis than previously realized as they not only contribute directly to plaque instability (through foam cell formation), but also promote plaque stability by transformation into a fibrocyte.

Effect of leg exercises on popliteal venous blood flow during prolonged immobility of seated subjects: implications for prevention of travel-related deep vein thrombosis.

BACKGROUND: Venous stasis is an important contributing factor in the development of travel-related deep vein thrombosis. This study examined factors affecting popliteal venous blood flow in order to determine the most effective exercise regimen to prevent venous stasis. METHODS: Twenty-one healthy subjects were randomly assigned to various activities over a 9-week period. Subjects remained seated throughout the investigation and 3660 duplex ultrasound examinations were performed by a single examiner using a SonoSite 180 Plus handheld ultrasound. Baseline popliteal vein blood flow velocity, cross-sectional area and volume flow in subjects sitting motionless were assessed in the first 3 weeks.The remaining 6 weeks involved subjects performing airline-recommended activities, foot exercises, foot exercises against moderate resistance and foot exercises against increased resistance in order to determine the most beneficial method for enhancing popliteal venous flow. Sitting with feet not touching the floor and the effect of sleeping were also assessed. RESULTS: The median age of the subjects was 22 years (range: 18-25.5 years), height 171 cm (162.5-180.5 cm) and body mass index 25.3 kg m(-2) (23.2-26.3 kg m(-2)). Blood volume flow in the popliteal vein was reduced by almost 40% with immobility of seated subjects and by almost 2-fold when sitting motionless with feet not touching the floor. Foot exercises against increased resistance positively enhanced volume flow (P < 0.0001). CONCLUSION: Leg exercise regimens enhanced popliteal venous flow during prolonged immobility of seated subjects, reinforcing the importance of regular leg movement to prevent venous stasis during prolonged sitting, such as in long-distance travel.

Venous thromboembolism following primary total knee arthroplasty.

AIM: Total knee arthroplasty is associated with a high postoperative incidence of venous thromboembolism (VTE). Without thromboprophylaxis, as many as 80% of patients may develop deep vein thrombosis (DVT). Evidence suggests that pharmacological prophylaxis may not be offered due to concern of bleeding with anticoagulants. METHODS: We retrospectively reviewed the clinical incidence of VTE and thromboprophylactic practice patterns over a 9-year period. Patient baseline characteristics, diagnosis, VTE risk factors, prophylactic modalities (mechanical and pharmacological), operation duration, type of prosthesis and fixation, mode of anesthesia, hospital length of stay (LOS) and postoperative complications with particular attention to suspected DVT and/or pulmonary embolism (PE) were analysed. RESULTS: Male to female ratio was 1:2.3, median age 71 (interquartile range, IQR: 65-77) years and hospital LOS of 8 (IQR: 7-11) days. The in-hospital VTE incidence was 3.9% (95% confidence interval, CI: 2.2-6.8%) with a possibly underestimated 3-month rate of 5.7% (95% CI: 1.6-18.6%). In-hospital proximal DVT incidence was 0.7% (95% CI: 0.2-2.5%) and 2.9% (95% CI: 0.5-14.5%) at 3 months. Non fatal PE was 0.7% (95% CI: 1.2-5%). DVT rate was higher with cemented prostheses (P=0.008), with a greater rate of bleeding when heparin was commenced preoperatively (P=0.001). CONCLUSIONS: The rate of in-hospital VTE was kept relatively low with the use of prophylactic protocols with all patients receiving prophylaxis. Given our one and a half and four-fold increase in the out of hospital VTE and proximal DVT incidence, consideration should be given to continued prophylaxis beyond hospitalization in this high-risk group of patients.

The role of the fibrocyte in intimal hyperplasia.

BACKGROUND: Experimental animal studies have shown that the intimal hyperplasia (IH) responsible for occlusion after successful revascularization procedures may be partially caused by a bone marrow-derived cell that migrates to the site of vascular injury. Concurrent studies have demonstrated an extensive role in wound healing for the circulating fibrocyte. OBJECTIVES: We aimed to trace the path of the circulating cell that contributes to IH and determine if it is the fibrocyte. METHODS AND RESULTS: We established an in vitro model whereby purified monocytes from six healthy human volunteers were cultured into fibrocytes. These cells were morphometrically similar to the vascular smooth muscle cell (VSMC) found in IH and expressed alpha-smooth muscle actin (alpha-SMA) as well as CD34, CD45 and Collagen I (Col I), markers indicative of the fibrocyte. In an in vivo ovine carotid artery synthetic patch graft model, carboxyfluorescein diacetate, succinimidyl ester (CFSE) labeled circulating leukocytes were observed throughout the graft as well as in the neointima in 18 sheep. These cells were shown to produce collagen and alpha-SMA at 1, 2 and 4 weeks. These cells then underwent immunohistochemical analysis and were found to express a set of markers unique to the fibrocyte (CD34, CD45, Vimentin and alpha-SMA) and also to double stain for CD34 and alpha-SMA. CONCLUSIONS: IH in an ovine carotid artery patch graft model is partially derived from a hematopoietic circulating progenitor cell that acquires mesenchymal features as it matures at the site of injury.

Matrigel-coated stents reduce intimal thickening in a large animal vascular stent model.

BACKGROUND: Restenosis within vascular stents is primarily due to intimal thickening secondary to intimal hyperplasia (IH) which occurs maximally around stent struts. Dedifferentiation of vascular smooth muscle cells (VSMC) with subsequent migration and proliferation is believed to be a key event in IH formation. Matrigel (basement membrane protein) has been shown to inhibit dedifferentiation of VSMC in vitro. Our aim was to test the in vivo effect of Matrigel on IH formation using a novel sheep vascular stent model. METHODS: Twenty vascular stents were implanted in the renal arteries of ten sheep. The left renal artery of each sheep was used to deploy uncoated stent and the right renal artery was used to deploy Matrigel-coated stent. Five sheep were analysed at four weeks and five at eight weeks after stent implantation. The sheep were sacrificed at the end of the study periods and the stented renal artery segments were examined by histology. Luminal, intimal and medial areas were determined using computer-assisted morphometric analysis. RESULTS: All stent sites were widely patent without thrombosis. No luminal stenosis was seen angiographically. IH was quantified from histology cross-sections and expressed as an intima to media (I/M) ratio. The ratio was significantly reduced in the matrigel-coated sites at eight weeks (uncoated 0.49+/-0.23; Matrigel-coated 0.32+/-0.12; p value <0.05). CONCLUSIONS: The sheep renal artery vascular stent model is feasible for the study of stent biology. IH was reduced by Matrigel-coated stents.

Calcium channel antagonist verapamil inhibits neointimal formation and enhances apoptosis in a vascular graft model.

BACKGROUND: The potential of the calcium channel antagonist verapamil to cause apoptosis (programmed cell death) is of considerable importance in arterial injury where the loss of smooth muscle cells may contribute to a reduction in intimal hyperplasia development. The aim of this study was to determine whether verapamil induces vascular cell apoptosis after carotid artery synthetic grafting. METHODS: Thirty-two adult-female Merino sheep received gelatin sealed fusiform shape-Dacron grafts into the left common carotid artery at day 0. After operation animals were randomly allocated to either a control group or one of three treatment groups (groups 2, 3, and 4). Group 1 animals (n = 9) received no treatment. For the treatment groups, intravenous verapamil was given at a rate of 0.5 mg/kg per day in two divided doses. Group 2, 3, and 4 sheep were treated for 1, 2, and 4 weeks, respectively. Animals were sacrificed at 4 weeks. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-fluorescent labelling. Proliferating cells and their phenotype were determined by doublestaining with antiproliferation cellular nuclei antigen and anti-alpha-actin or anti-HAM-56. RESULTS: There were significantly more apoptotic cells in the perigraft adventitia in the 4-week treatment group than in the control group (P <0.05). The average number of proliferating cells at 2 and 4 weeks in the intima were significantly less than in the control (P <0.05). The average numbers of macrophages inside graft matrix in the 2 and 4 weeks treatment groups were significantly less than for the control (P <0.05). The number of proliferating cells inside the graft was significantly lower at 4 weeks compared with control (P <0.05). There was negative correlation between intimal PCNA expression and perigraft apoptotic expression level (P <0.05). CONCLUSION: The antihypertensive agent verapamil inhibits intimal hyperplasia through enhancing adventitial cell apoptosis and inhibiting intimal cell proliferation after vascular grafting.

EVT endovascular graft for abdominal aortic aneurysm.

BACKGROUND: A variety of prostheses are now available for the endovascular treatment of abdominal aortic aneurysm (AAA). Significant advantages of the EVT device are its unibody design, secure hook attachment system and graft fabric approximating that used in conventional surgery. METHODS: Implantation of the EVT device was attempted in 60 patients who were studied prospectively with an analysis of subsequent problems encountered. RESULTS: Conversion to open repair was required in four cases (6.7%). There were nine tube grafts inserted, 13 aorto-unilateral iliac with crossover grafts and 34 aorto-bi-iliac grafts. There was one death (mortality 1.7%). Endoleaks were identified in eight patients (14%), none of which were proximal; three sealed spontaneously, two were treated with coil embolization, two are being observed and one patient had an iliac attachment converted to an open anastomosis. Access vessel problems were seen in 21 patients (35%); two-thirds were corrected at the time of initial surgery. Seven patients (12%) had primary graft limb problems identified and treated before leaving the operating room. Nine patients (16%) developed secondary graft limb problems, which were diagnosed and treated after the initial surgery. Endovascular treatment was used in eight and was successful in six with surgical revision required in two. On review of these cases to assess if the problem could have been predicted at the time of initial surgery, it was felt that more aggressive treatment of intraoperatively diagnosed graft limb stenoses, even though considered mild, may have prevented 50% of subsequent secondary graft limb occlusions. CONCLUSION: Although the EVT device has significant advantages in the endovascular management of aortic aneurysm, potential graft limb problems need to be actively identified with the majority able to be successfully managed by supplementary endovascular techniques.

Colonisation of prosthetic grafts by immunocompetent cells in a sheep model.

The present study examined the distribution of immunocompetent cells in synthetic vascular grafts in an experimental sheep model. Sixty-two adult Merino sheep underwent synthetic patch closure of a longitudinal arteriotomy in the left common carotid artery. The synthetic patch materials used were gelatin sealed Dacron (n=10), fluoropassivated Dacron (n=10), Fluoropassiv (n=12), polyurethane (n=10), expanded polytetrafluoroethylene (n=10) and carbon-lined expanded polytetrafluoroethylene (n=10). The sheep were sacrificed after four weeks when the prosthetic patches were harvested and fixed in 10% neutral buffered formalin. Transverse sections were taken along the graft and paraffin embedded. Serial sections were stained with cell type specific antibodies to identify T-lymphocytes (CD3(+)), dendritic cells (S-100(+)), endothelial cells (von Willebrand factor(+)) and smooth muscle cells (smooth muscle alpha-actin(+)). All six graft types contained CD3(+) and S-100(+) cells in the neointima, within the synthetic matrix and in the perigraft layer. Three different tissue responses to synthetic materials were observed and the grafts were classified accordingly into three groups: (1) gelatin sealed Dacron, fluoropassivated Dacron and Fluoropassiv; (2) expanded polytetrafluoroethylene and carbon-lined expanded polytetrafluoroethylene; (3) polyurethane. The three synthetic materials in Group 1 showed almost identical reactions with least accumulation of immunocompetent cells within the synthetic material but greater accumulation of immuno-inflammatory infiltrates in the perigraft vascular tissue. In this group, new vessels penetrated into the synthetic material and there was prominent formation of foreign body (giant) cells. Group 2 showed greater accumulation of immunocompetent cells within the synthetic material itself but only sparse immuno-inflammatory infiltrates in the perigraft tissue. Group 3 showed a high degree of inflammatory response within both the synthetic material and the perigraft vascular tissue. These observations demonstrate that immunocompetent cells colonise the synthetic matrix of grafts and accumulate in the perigraft tissue, but inflammatory responses vary in different graft types.

Development of intimal hyperplasia in six different vascular prostheses.

OBJECTIVES: to compare six vascular prostheses for the development of intimal hyperplasia (IH) in a sheep model. MATERIAL AND METHODS: prostheses tested were gelatin sealed Dacron (GSD), fluoropassivated Dacron (FPD), FluroIpassiv TM (FD), expanded polytetrafluoroethylene (ePTFE), carbon-lined expanded polytetrafluoroethylene (CL-ePTFE) and vascular access graft (VAG). Sixty-two adult female Merino sheep (35-45 kg) were used. Elliptical graft patches were implanted into the left common carotid artery using one of the six graft types: GSD (n=10), FPD (n=10), FD (n=12) VAG (n=10), ePTFE (n=10), or CL-ePTFE (n=10). Four weeks later grafts were removed for histopathological assessment and measurement of the degree of IH obtained on a computerised image analysis system. RESULTS: IH indices were significantly less for FPD (0.191+/-0.095, p<0.05), FD (0.199+/-0. 081, p<0.05), ePTFE (0.213+/-0.078, p<0.05) and CL-ePTFE (0.161+/-0. 066,p<0.01), compared to the GSD group (0.287+/-0.077). The VAG group (0.257+/-0.091) showed no difference compared to GSD. There was no significant difference between the FPD, FD, ePTFE and CL-ePTFE grafts. CONCLUSION: this study indicates that less IH occurred in the two-ePTFE grafts and two fluoropolymer coated Dacron grafts than in gelatin sealed Dacron or polyurethane grafts.

Does in situ replacement of a staphylococcal infected vascular graft with a rifampicin impregnated gelatin sealed Dacron graft reduce the incidence of subsequent infection?

BACKGROUND: The aim of this study was to treat methicillin-resistant Staphylococcus aureus (MRSA) or S. epidermidis prosthetic vascular graft infections by in situ replacement with a rifampicin bonded Gelsoft graft. METHODS: Interposition grafts were placed in the carotid artery of 56 sheep and the graft surface directly inoculated with 10(8) colony forming units of MRSA or S. epidermidis. At three weeks, grafts were harvested and sheep allocated to three groups. In the MRSA group, sheep received grafts soaked in 1.2 mg/ml (12), 10 mg/ml (10) and no rifampicin (7). For S. epidermidis, sheep received grafts soaked in 1.2 mg/ml (10), 10 mg/ml (9) and no rifampicin (8). There were two deaths, in the MRSA study group. Remaining sheep were euthanased and grafts harvested three weeks following regrafting. Swabs were taken to assess bacterial growth in the perigraft tissues, and external and internal graft surfaces. A 3-5 mm segment of graft was incubated in broth medium. RESULTS: For MRSA, no statistical difference between the groups was reached for any of the measured parameters. For S. epidermidis, a significant reduction was reached for total infected specimens in the 10 mg/ml group compared to both control (p<0.001) and 1.2 mg/ml (p<0.005) groups. Graft re-infection was also less likely to occur with S. epidermidis than MRSA. CONCLUSIONS: Replacement of S. epidermidis infected vascular grafts with 10 mg/ml rifampicin soaked Gelsoft graft is effective in reducing subsequent S. epidermidis infection. This conclusion cannot be extended to MRSA infected vascular grafts.

Duplicated popliteal and superficial femoral veins: incidence and potential significance.

BACKGROUND: Duplication of the popliteal and superficial femoral veins (PV, SFV) is a normal variant previously reported in up to 25% of limbs. Little clinical significance, however, has been attributed to this apparently common anomaly. The present study was designed to determine the incidence of duplications in individuals presenting for venous incompetence studies, and whether their presence could, in theory, act as a predisposing factor to deep venous thrombosis (DVT) formation. METHODS: Duplex ultrasound examinations were performed in which venous duplications were actively searched for and recorded. The diameters of both limbs of any duplicated system and the single vessel immediately distal to it were recorded. Using these measurements, the changes in total cross-sectional area (CSA) associated with these anomalies were calculated. In addition, with the knowledge that the volume flow rate must remain constant, the velocity changes associated with such systems were calculated. RESULTS: A total of 248 limbs from 177 patients was scanned. Duplications were found in 39 (15.7%) of these limbs. Of these, 30 limbs (77%) involved only the SFV, seven (18%) involved both the SFV and PV, and two (5%) involved only the PV. Short-segment SFV duplications were used to calculate the percentage change in total CSA and therefore blood flow velocities. Of the 13 (33%) suitable for such calculations, and calculating for each individual duplicated system, a mean increase in the vessel's total CSA of 42%, which corresponded to a theoretical decrease in blood flow velocity of 36%, was found. CONCLUSION: The present study confirms the significantly high incidence of duplications of the PV and SFV and raises the possibility of the potential for DVT formation secondary to changes in flow velocities.

Verapamil reduces intimal hyperplasia in a sheep carotid artery patch graft model.

BACKGROUND: The current study investigated the effect of verapamil on the development of intimal hyperplasia (IH) using a sheep model. METHODS: A gelatin-sealed Dacron patch graft was implanted into the left common carotid artery in 40 adult Merino sheep. Sheep were then randomly allocated to four groups. Group 1 were controls given no treatment (n = 10). Groups 2-4 were treated with intravenous verapamil 0.5 mg/kg per day in two divided doses for different lengths of time. Group 2 (n = 10) received treatment for 1 week; group 3 (n = 10) received treatment for 2 weeks and group 4 (n = 10) received treatment for 4 weeks. All sheep were killed at 4 weeks and the grafted segments of artery were harvested for IH assessment by an image analysis system. RESULTS: The IH index from the three groups treated with verapamil was significantly less than that of the control (group 1,0.287+/-0.077: group 2,0.205+/-0.064, P<0.05; group 3, 0.193+/-0.059, P<0.01; group 4,0.171+/-0.046, P<0.01). CONCLUSION: The present study suggests that verapamil inhibits the development of IH even when treatment is given for only 1 week.

Progression of macrovascular disease after transplantation.

INTRODUCTION: Cardiovascular and cerebrovascular disease are major causes of morbidity and mortality after kidney transplantation. The aim of this longitudinal study was to examine the natural history of carotid plaque and to determine risk factors for the progression of vascular disease in uremic, type 1 diabetic patients who received a combined kidney and pancreas transplant. METHODS: Carotid artery (n=765) and lower limb vascular duplex scanning (n=656) were prospectively undertaken in 82 recipients before transplantation, at 6 months, and then at annual intervals for up to 10 years. Plaque in the internal carotid artery (ICA), external carotid artery, and common carotid artery was classified by type, location, extent, and degree of functional obstruction, and evaluated using multivariate analysis. RESULTS: Carotid plaque was present in 22.5% of patients at initial scanning, but increased to 56.6% by 7-10 years after transplantation, especially in the ICA and common carotid artery. Both the severity and extent of plaque increased, and plaque became more complex and heterogeneous with time after transplantation (P<0.001). Carotid plaque was associated with older age, current cigarette smoking, hyperphosphatemia, hypoalbuminemia, duration of pretransplantation dialysis, and presence of lower limb plaque (P<0.05-0.001). The severity of carotid plaque increased in older, hypertensive recipients and was associated with metabolic acidosis and hyperphosphatemia (all P<0.05). Severity of ICA disease correlated with disease in the contralateral ICA (r=0.57, P<0.001) and femoral arteries (r=0.42, P<0.001). Paradoxically, each carotid artery progressed independently of the other. ICA disease severity progressed when heterogenous, calcified, or new plaque was present on scanning, and with reduced renal transplant function (P<0.01-0.001). The mean ICA blood flow remained stable with time but was progressively impaired by hypertension, fasting hyperglycemia, and a lower prednisolone dose (P<0.05). Cerebrovascular events occurred in only four patients and were unrelated to carotid disease, implying relative plaque stability. CONCLUSION: Extensive carotid vascular wall abnormalities increased significantly despite kidney and pancreas transplantation. Initiation of plaque was associated with systemic factors, whereas progression of established plaque was largely influenced by local factors within the arterial wall.

Suppression of intimal hyperplasia with low molecular weight heparin in a sheep model.

BACKGROUND: Both unfractionated heparin (UH) and low molecular weight heparin (LMWH) in therapeutic anticoagulant doses have been shown to inhibit the development of intimal hyperplasia (IH) but with an increased risk of haemorrhage. In this study we investigated the effect of a "low dose" and "high dose" of UH and LMWH on the inhibition of IH together with their effect on plasma anti-Xa activity (AXa) and activated partial thromboplastin time (APTT) using a carotid artery sheep model. METHODS: A gelatin sealed Dacron patch graft was implanted into the common carotid artery of sheep which were randomly allocated to a control group (Group 1, n=10) or to one of four treatment groups receiving either low-dose LMWH enoxaparin 1 mg/kg/day (group 2, n=11), high-dose LMWH enoxaparin 2 mg/kg/day (Group 3, n=13), low-dose UH 125 u/kg/day (Group 4, n=10) or high-dose UH 250 u/kg/day (Group 5, n=10). The LMWH was administered subcutaneously once daily for four weeks and the UH in two divided doses per day for four weeks. During the treatment period, AXa and APTT were assayed from blood collected prior to and at 1 and 2 h after heparin administration on day 3, 7, 14, 21 and 28. On day 28, all animals were sacrificed and grafts were collected for analysis after taking blood samples prior to, then at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h following the last injection. Measurements of intimal thickness were obtained under light microscopy from eight transverse sections of each grafted artery using an eyepiece graticule. RESULTS: IH measurements (Mean+/-SD) were: Group 1 (controls) 288+/-86 microm, Group 2 (low-dose LMWH) 222+/-50 mm (p<0.05 compared to Group 1), Group 3 (high-dose LMWH) 203+/-78 microm (p<0.01), Group 4 (low-dose UH) 275+/-61 microm, and Group 5 (high-dose UH) 206+/-71 microm (p<0.01). There was no significant difference between Groups 2, 3 and 5. Groups 2, 3 and 5 demonstrated significant AXa during the 28 days period of which Groups 2 and 5 showed a significant increase in AXa levels with time. In the 24 h study after the last dose of treatment both Groups 2 and 3 showed longer AXa than group 5 (12-24 h vs 8 h). When compared to the control group, significant elevation of APTT was demonstrated in Groups 3 and 5. Group 5 had significantly longer APTT than Group 3. In the 24 h study, APTT reflected the changes of AXa in all groups. CONCLUSIONS: In this study the LMWH enoxaparin was effective in reducing the formation of IH both at a standard anticoagulant therapeutic dose of 2 mg/kg/day and also at a lower dose of 1 mg/kg/day.

A prospective randomized multicentre comparison of expanded polytetrafluoroethylene and gelatin-sealed knitted Dacron grafts for femoropopliteal bypass.

PURPOSE: To compare graft patency between expanded polytetrafluoroethylene (PTFE) and gelatin-sealed knitted Dacron for femoropopliteal bypass. METHODS: A prospective, multicentre trial was performed in 108 patients randomized to receive either a PTFE or Dacron prosthetic graft. Distal anastomosis was above knee in 75 and below knee in 33 patients. RESULTS: Primary patency at 1, 2 and 3 years was 72, 52 and 52% for PTFE, and 70, 56 and 47% for Dacron (P = 0.87). Secondary patency at 1, 2 and 3 years was 74, 54 and 54% for PTFE and 78, 70 and 53% for Dacron (P = 0.39). The most significant predictors of early graft failure were poor vessel run-off (P = 0.04) and critical limb ischaemia (P = 0.04). CONCLUSION: There was no difference in graft patency between PTFE and Dacron for femoropopliteal bypass.