The development of an in vitro flow model of human saphenous vein graft intimal hyperplasia.

OBJECTIVE: Although the role of blood flow has been investigated in animal models of intimal hyperplasia, there have been no detailed studies in intact human vein owing to the difficulties in designing a suitable laboratory model. The aim of this study was to develop a flow model of human vein graft intimal hyperplasia. METHODS: Organ cultures of human saphenous vein were exposed to laminar flow by culturing in a closed circulatory system under predetermined conditions of venous and arterial shear stress for 14 days. Following fixation and processing, paraffin sections were immunostained and neointimal thicknesses measured. RESULTS: It was found that arterial flow completely inhibited neointima formation, but venous flow only partly suppressed the response when compared with vein cultured under static conditions. These results are in agreement with previous in vivo studies in a primate graft model, where increased shear stress inhibited intimal proliferation. CONCLUSION: The endothelial cell is believed to be the key mediator of haemodynamic effects which influence smooth muscle cell proliferation, and the flow rig developed in this study offers the potential to study inter-cellular interactions within the intact vessel. Furthermore, this method provides the facility to study the effects of different flow conditions on segments of vein from the same patient. This model has scope for further development and sophistication which may ultimately lead to increasing our understanding of the aetiology of vein graft stenoses, and hence formulation of preventative strategies.

Effect of heparin on thrombin inhibition in the microcirculation.

Disappearance of thrombin enzymatic activity was measured during recirculation through the microvasculature in a rat Langendorff heart preparation. This resulted in a 50% loss of thrombin from the recirculating solution. No increased loss of thrombin could be demonstrated if a mixture of antithrombin III and thrombin was recirculated, compared to thrombin alone. If, however, a heparin/thrombin mixture was recirculated, a 90% loss of thrombin could be demonstrated. Pretreating the microvasculature with large amounts of heparin resulted in recovery of antithrombin III in the recirculated heparin solution. At a subsequent recirculation with a heparin/thrombin mixture the loss of thrombin was decreased to the control level, as seen when recirculation with thrombin alone was performed. It is concluded that disappearance of thrombin enzymatic activity from a solution when recirculated through the microcirculation can be considerably increased if recirculated together with heparin, which probably reacts with endogenous antithrombin III on the vessel wall. The disappearance of thrombin in the absence of heparin was, however, unaffected by antithrombin III. The latter finding is compatible with the hypothesis that, in the microcirculation, antithrombin III/glycosaminoglycans play only a minor role for inhibition of thrombin coagulant activity and that thrombin binds mainly to thrombomodulin.

Thrombin inactivation and the effects of antithrombin and heparin in a recirculating Langendorff preparation.

A recirculating Langendorff preparation was developed in order to study the effects of antithrombin III (AT) and heparin on thrombin inactivation in the capillary bed. Using this technique, rat hearts were shown to inhibit approximately 50% of the recirculated thrombin, while surface-bound thrombin displayed no enzymatic activity towards recirculated fibrinogen. By displacing thrombin bound to the endothelial surface with Polybrene, thrombin enzymatic activity was found to be equally active against a synthetic chromogenic substrate (S-2238) and fibrinogen. This indicates that thrombin bound to the capillary endothelial surface is not coagulantly active, but, when displaced from the endothelium, its coagulant activity is retained. Hearts pretreated with AT or heparin had no effect on thrombin inhibition or surface-bound thrombin, although there was an uptake of both substances to the heart. These findings are in contrast with the results obtained from large vessel preparations, where pretreatment with AT increased thrombin inhibition and also demonstrated lower levels of surface-bound thrombin, and where heparin eluted endogenous AT from the endothelium. It is concluded that AT plays a more important role in the inhibition of thrombin on large vessels than in the microcapillary system where thrombomodulin is the major inactivator of thrombin.

Coagulant and noncoagulant thrombin enzymatic activity on the endothelium.

The present study examines the role of antithrombin III (ATIII) and heparin in the inactivation of thrombin on rabbit aortae in vitro. Thrombin on the endothelium was functionally assayed with a synthetic chromogenic substrate (thrombins) or with fibrinogen (thrombinf), measured as the liberation of fibrinopeptide A. After incubation with thrombin, residual amounts were found on the endothelium. Surface-bound thrombinf constituted approximately one-half of surface-bound thrombins. Displacement of thrombin activity from the thrombin loaded endothelial surface was achieved with Polybrene. The thrombin could be quantitatively recovered in the Polybrene solution and equal amounts of thrombins and thrombinf were found. Incubation of endothelial segments with ATIII resulted in only a minimal uptake of ATIII on the surface but in a significantly increased capacity to inactivate thrombin, whereas incubation of the segments with heparin alone had the opposite effect. The effect of ATIII could be inhibited by prior incubation with Polybrene or by a subsequent incubation with heparin. It is concluded that the vessel wall content of ATIII is one determinant for the capacity to inhibit thrombin and that ATIII is bound to glycosaminoglycans on the vessel wall since it could be displaced by heparin.

Ligation of the superior mesenteric vein: a cautionary tale.

Acute interruption of flow in the superior mesenteric vein can, in most instances, be tolerated. In the event of compromised venous collateral circulation, however, continuity of the main venous flow must be restored.

Low molecular mass heparin instead of unfractionated heparin during infrainguinal bypass surgery.

OBJECTIVES: To test whether low molecular mass heparin (LMMH) is comparable to unfractionated heparin (UFH) as an anticoagulant during infrainguinal bypass surgery and to investigate laboratory evidence of hypercoagulation in patients undergoing infrainguinal bypass surgery. MATERIALS AND METHODS: Eighteen patients were randomised to receive either UFH or LMMH (70 anti-Xa units/kg b.w.). Soluble fibrin, measured as fibrin monomers (FM) and fibrinopeptide A (FPA), were measured in blood from the femoral vein before, during and after release of the occluding clamps during surgery. In addition, fibrinogen prothrombin complex, thrombin-antithrombin complex, platelets and antithrombin were measured before surgery. Heparin levels (Anti Xa) were measured during surgery. RESULTS: Increased levels of fibrinogen, FPA, thrombin antithrombin complex and FM were recorded prior to surgery. During surgery no further increase was noted. The anti Xa levels were slightly higher in patients with LMMH than in patients receiving UFH. Levels of FM were significantly lower in patients receiving LMMH. No difference in FPA was noted. A positive correlation between fibrinogen and FPA and FM respectively was recorded. Four patients, two in each group, were reoperated for graft occlusion. One patient in the UFH group required reoperation because of bleeding. CONCLUSIONS: LMMH is comparable to UFH as an anticoagulant during infrainguinal bypass surgery. Variables reflecting hypercoagulability are elevated in this group of patients and are positively correlated to the fibrinogen level. High fibrinogen levels could thus be a risk for perioperative thrombosis.

"Nonspecific" erosions and ulcers of the colonic mucosa.

A total of 26 cases of "nonspecific" erosions and ulcers of the colonic mucosa are reported. The most common causes were previous abdominal irradiation or ischemic disease due to arteriosclerosis. The lesions were localized to all segments of the colon. Of the 26 cases, five (19.2%) had erosions (ie, not penetrating beyond the muscularis mucosae) and the remaining 21, ulcers (ie, penetrating beyond the muscularis mucosae). In seven of the 26 cases (26.9%) more than one ulcer was found in the same specimen. Erosions may heal completely by epithelial regeneration (ie, restitutio ad integrum) while ulcers usually heal by replacing scarring tissue. Thus, the two lesions may not be clinically synonymous. The relatively high proportion of erosions among nonspecific ulcerations of the colonic mucosa has not been previously pointed out in the literature.

Peroperative anticoagulation with antithrombin or heparin in infrainguinal bypass surgery.

Patients suffering from atherosclerosis may have a hypercoagulable state which is further aggravated by surgery. Thrombin, a central enzyme in the coagulation process, cleaves fibrinogen to fibrin. Therefore, inhibition of thrombin is an important anticoagulant mechanism. This is accomplished by heparin in concert with antithrombin III (AT), but vessel wall glycosaminoglycans may act as substitutes for heparin and catalyse thrombin inhibition. The present study examines whether administration of AT or heparin is effective as an anticoagulant during infrainguinal bypass surgery. Preoperatively and during surgery the patients had elevated levels of fibrinogen, fibrinopeptide A (FPA) and thrombin-antithrombin (T-AT) complexes. There were higher levels of FPA in the venous outflow from the ischemic leg than in the arterial inflow. Taken together these measurements indicate ongoing coagulation in the operated leg. Administration of heparin decreased FPA levels and prevented intraoperative graft thrombosis, whereas in patients receiving AT, T-AT levels increased but FPA levels were unchanged. In the latter group, intraoperative graft thrombosis occurred in a high proportion. Based on additional case histories in these patients with hypercoagulability, it is suggested that fibrinogen is a risk factor for thromboembolic complications and that a combination of low dose of heparin and AT might be an effective regimen to prevent intraoperative thrombosis with a low risk of haemorrhage.

Inhibition of thrombin on subendothelium. Studies on rabbit aorta, ex vivo.

The endothelium plays an active role in inhibiting and promoting the activation of coagulation. Loss of the endothelial lining results in a thrombogenic state. The inactivation of thrombin on rabbit aorta after a superficial and deep injury to the vessel wall was studied. The thrombin enzymatic activity on the subendothelium could be modulated and decreased activity was found on both types of injured vessel segments when exposed to antithrombin III (AT). An increased activity by exposing the superficially injured vessels. Most probably, heparin elutes AT from the surface of the superficially injured vessels, but on the deeply injured surface no AT is present and, consequently, heparin has no effect in this respect. These results speak in favour of treatment with AT instead of heparin in cases of arterial injury.

Use of colour duplex imaging to diagnose and guide angioplasty of lower limb arterial lesions.

BACKGROUND: The purpose of this study was to investigate whether colour duplex imaging alone could safely and effectively be used to diagnose lower limb arterial lesions and guide subsequent percutaneous transluminal angioplasty (PTA). METHODS: Patients with discrete lower limb arterial lesions, preferably stenoses, which could be visualized clearly by colour duplex imaging were selected for duplex-guided PTA. Duplex-guided PTA was performed in an operating theatre using conventional balloon catheters. RESULTS: Duplex imaging was used to diagnose and guide PTA of 55 arterial lesions in 50 legs of 45 patients. There were 53 stenoses and two occlusions. The median (range) ankle : brachial pressure index was 0. 86 (0.52-1.10) before dilatation and 1.00 (0.83-1.40) immediately after dilatation (P = 0.0001). There were no complications during or after any of the procedures and 46 of the 47 symptomatic legs were markedly improved at a median follow-up of 23 days. Radiographic imaging was not required for any of the procedures. CONCLUSION: It is possible to diagnose and angioplasty lower limb arterial lesions using colour duplex imaging alone.

The surgical management of acute limb ischaemia due to native vessel occlusion.

OBJECTIVES: Data from the STILE study have indicated that for patients with subacute limb ischaemia due to native vessel occlusion, surgery is both more effective, and durable than thrombolysis. The purpose of this study was to evaluate the outcome of an aggressive surgical approach in patients presenting with acute limb-threatening ischaemia. DESIGN: Details of patients presenting with salvageable acute limb ischaemia due to native artery occlusion over a 6-year period in a University hospital vascular unit setting were obtained from the vascular audit and the outcome of the surgical management of these patients was analysed. RESULTS: One hundred and seventy-four consecutive patients underwent surgery for acute native vessel limb ischaemia (76% lower, 24% upper limb). Fogarty thrombectomy or embolectomy was initially performed in 153 (89%) patients. Of these, 37 (24%) immediately underwent a further procedure: 28 (18%) had on-table thrombolysis and 14 (9%) underwent vascular reconstruction. Twenty-six patients (15%) underwent further limb salvage surgery within 30 days. Life table analysis demonstrated a limb salvage rate of 88% and 76% at 30 days and 2 years, respectively. Patient survival was 75% and 48% at the same time intervals. CONCLUSIONS: These results demonstrate that a role for aggressive surgical intervention still exists, resulting in high limb salvage rates.

Survival in patients with abdominal aortic aneurysms. Comparison between operative and nonoperative management.

This study evaluates the risk benefit relationship in the surgical treatment of abdominal aortic aneurysm (AAA). Two hundred and thirteen patients with AAA diagnosed by CT were selectively managed depending upon the size of the aneurysm, and were followed with a mean follow-up time of 5 years and 4 months. Aneurysms greater than 5 cm were generally operated on if no serious contraindication existed. Aneurysms less than 5 cm were followed by repeated examinations and operated on if an increase in size occurred. Some small aneurysms were operated on for other reasons. Elective surgical management of 134 patients resulted in a thirty day mortality of 7.5%. Later, seven additional patients died from causes related to the surgery. Survival of electively operated patients by life table analysis was 68% at 5 years. A significantly higher mortality was noted among those who had evidence of coronary heart disease at the time of operation. Forty-two patients with AAA less than 5 cm at the initial examination were not operated on and three ruptured, but all had grown to a size greater than 5 cm at the time of rupture. Patients with AAA less than 5 cm that were not operated on had a slightly but not significantly higher mortality than those who were operated on electively. This difference was mainly attributable to deaths from cardiac causes and not to ruptures. Patients with aneurysms greater than 5 cm who were not operated on had a significantly higher mortality than those that were, only 14% in the former group survived.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of adjacent segment disease on the accuracy of colour duplex scanning for the diagnosis of lower limb arterial disease.

OBJECTIVE: To assess the effect of multisegment disease upon the accuracy of lower limb colour Duplex scanning. DESIGN: Prospective, semi-blind study. SETTING: Vascular Laboratory and Radiology Department, University Hospital. METHODS: A total of 148 limbs (1106 individual arterial segments) were examined from the distal aorta to the origins of the tibial arteries by colour-coded Duplex and arteriography. Individual segments were graded as 0-49%, 50-99% diameter reduced or occluded on the basis of peak systolic velocity ratios < 2.0, > or = 2.0 or an absent Doppler signal, and compared with similarly graded segments from blinded angiographic studies. The agreement (Kappa analysis) between Duplex and arteriography in segments adjacent to at least one proximal or distal > or = 50% diameter reducing lesion was then compared to the agreement between segments free of adjacent disease. RESULTS: For isolated areas of disease, the kappa value (95% confidence interval) of agreement between Duplex ultrasonography and arteriography was 0.63 (0.53-0.73) and in the presence of neighbouring disease the value was 0.78 (0.73-0.83). CONCLUSION: We conclude therefore that providing appropriate criteria are used, Duplex assessment of lower limb arterial disease is not adversely affected by adjacent disease.

A prospective comparison of lower limb colour-coded Duplex scanning with arteriography.

OBJECTIVE: To compare the diagnostic value of colour Duplex scanning with arteriography for the detection of arterial disease of the aortoiliac arteries, femoropopliteal arteries and the origins of the tibial vessels. DESIGN: Prospective, semi-blind study. SETTING: Vascular laboratory and radiology department, University Hospital. METHODS: A total of 1658 arterial segments in 148 limbs were studied both by colour Duplex scanning and digital subtraction arteriography. Individual arterial segments were classified on the basis of peak systolic velocity ratios < 2.0, > or = 2.0 or an absent Doppler signal, as 0-49%, 50-99% diameter reduced, or occluded. The same arterial segments were similarly classified on the basis of arteriography and the two modalities were compared using a Kappa (k) analysis. RESULTS: The overall agreement between arteriography and colour-coded Duplex was kappa = 0.74 (95% CI, 0.70-0.78), this indicates substantial agreement. Kappa values (95% CI) from the aortoiliac, femoropopliteal and the origins of the infrapopliteal arteries were kappa = 0.59 (0.49-0.73; moderate agreement), kappa = 0.80 (0.76-0.84; substantial agreement) and kappa = 0.48 (0.35-0.61; moderate agreement) respectively. CONCLUSIONS: We conclude that there is substantial agreement between colour-coded Duplex and arteriography of the lower limbs, and that the ability of colour-coded Duplex to plan and guide lower limb vascular interventions requires investigation.

Subintimal angioplasty of infrapopliteal occlusions in critically ischaemic limbs.

OBJECTIVE: To review the outcome of subintimal angioplasty of infrapopliteal artery occlusions in critically ischaemic limbs. DESIGN: Retrospective review. MATERIALS: Twenty-eight consecutive limbs with critical ischaemia that had undergone subintimal angioplasty of infrapopliteal occlusions. RESULTS: There were 32 infrapopliteal artery occlusions in 28 critically ischaemic limbs in 27 patients. The median (range) patient age was 81 (48-88) years. Seventeen limbs (61%) were ulcerated, seven (25%) were gangrenous and four (14%) had rest pain only. Twenty-five (89%) procedures were to a single calf vessel, and three (11%) procedures were to multiple calf vessels. The median (range) length of the occlusions was 7 (2-30) cm. The initial technical success rate was 27/32 (84%). There were three minor complications--one groin haematoma, one vessel perforation and one distal embolus. There were no limbs lost as a result of the procedure itself and the 30-day mortality was zero. The 12-month actuarial haemodynamic and symptomatic patencies (including initial failures) were 53% and 56%, respectively. The 12-month limb salvage rate was 85% and patient survival was 81%. CONCLUSION: We conclude that subintimal angioplasty in patients with infrapopliteal artery occlusions and critical ischaemia is safe, effective, and offers a low-risk alternative to distal reconstructive surgery.

Results of surgery and angioplasty for the treatment of chronic severe lower limb ischaemia.

OBJECTIVE: To aims of this study was to assess and compare the efficacy of PTA and surgery in the treatment of severe lower limb ischaemia. DESIGN: Prospective 12-month study of 180 consecutive patients with severe chronic lower limb ischaemia. METHODS: PTA was used as first line therapy whenever possible and appropriate. Surgical revascularisation, primary amputation and conservative therapy were used in eh remaining patients. Patient survival and limb salvage were derived using life table analysis. RESULTS: Revascularisation was attempted in 135 (75%) patients, with PTA in 82 (46%), surgery in 19 (27%) and a combination of both in four (2%). Overall 12-month survival and limb salvage was 75% and 71%, respectively. Surgery and PTA had significantly higher survival rates (91% and 78%) than primary amputation or conservative therapy (57% and 52%) (p < 0.0001 log rank test). Revascularisation with either surgery or PTA achieved the same limb salvage rate of 76%. CONCLUSION: A large proportion of patients with severe chronic lower limb ischaemia can be managed by PTA. THis management strategy produces a clinically effective outcome at 1-year.

Colour-coded duplex imaging and dependent Doppler ultrasonography in the assessment of cruropedal vessels.

BACKGROUND: It has been suggested that ultrasonography could replace diagnostic arteriography in the assessment of patients who present with leg ischaemia. This study investigated a group of consecutive patients who had femorodistal bypass and who were assessed before operation with colour-coded duplex and dependent Doppler insonation alone. METHODS: Thirty-seven consecutive patients with critical lower limb ischaemia underwent surgical exploration with a view to femorodistal bypass. Results of preoperative colour-coded duplex and dependent Doppler insonation were compared with intraoperative arteriograms and surgical findings. RESULTS: There was very good agreement between colour-coded duplex imaging and dependent Doppler insonation with intraoperative angiography and surgical findings in the prediction of the optimal run-off vessel (kappa = 1.0) and the site of the distal anastomosis (kappa = 0.85; 95 per cent confidence interval 0.71-1.0). There was also very good agreement between dependent Doppler insonation and intraoperative arteriography (kappa = 1.0) in predicting pedal arch patency and the predominant feeding vessel. CONCLUSION: Assessment of leg arteries before femorodistal bypass can be performed accurately with non-invasive colour-coded duplex imaging and dependent Doppler insonation alone, thus obviating the need for preoperative arteriography.