Controlled delivery of vascular endothelial growth factor promotes neovascularization and maintains limb function in a rabbit model of ischemia.

PURPOSE: Vascular endothelial growth factor (VEGF) modulates new blood vessel development and growth and has been suggested as a potential therapeutic agent that could alleviate debilitating claudication in patients. The objective of this study was to determine whether controlled, local delivery of a low dose of VEGF from an osmotic pump could promote neovascularization, limb perfusion, and functional improvements in the hind limbs of rabbits rendered partially ischemic by surgery. The effects of VEGF were compared with those of the vasodilator nitroglycerin (NTG) and to saline administered similarly. METHODS: Thirty rabbits were randomly assigned to either VEGF (n = 10), NTG (n = 10), or saline (n = 10) treatment groups. Partial ischemia was induced in each left hind limb by surgical ligation of the common and superficial femoral arteries, leaving the internal iliac artery intact. The right limb of each animal served as a nonischemic control. Immediately after vessel ligations, a 28-day osmotic pump was implanted to deliver VEGF (0.22 microg/kg/day), NTG (17.8 microg/kg/day), or saline solution into the common iliac artery just proximal to the ligation site. Comparative vascularity between ischemic and nonischemic limbs within treatment groups and between groups was evaluated by (1) capillary counts from representative fields of hematoxylin and eosin stained muscle tissue taken from hind limbs at day 40; (2) digitized arteriograms of ischemic legs at day 40, which were used to quantify the complexity of vascular branching (fractal dimension index) and the total extent of vascularization (vascular density index); (3) measuring capillary refill times in ischemic limbs; and (4) observations of functional and trophic changes in ischemic limbs. Statistical differences between treatment groups were evaluated by one-way ANOVA. RESULTS: Complexity of vascular branching and vascular density were significantly greater (p < 0.001) in VEGF-treated ischemic limbs compared with NTG- and saline-treated ischemic limbs. By postoperation day 14, all VEGF-treated ischemic limbs had restored capillary refill (p < 0.001), new hair growth, and greatly improved limb function and appearance. Saline-treated limbs exhibited ischemic changes, with poor capillary refill and negligible limb function. Capillary refill in NTG-treated ischemic limbs did not differ significantly from saline-treated limbs. Ischemic VEGF-treated limbs had significantly more capillaries compared with both ischemic and nonischemic limbs in saline-treated animals (p < 0.05). Ischemic NTG-treated limbs also had significantly more capillaries compared with ischemic limbs in saline-treated animals (p < 0.05). Because of high variability, however, capillary counts in VEGF-treated ischemic limbs did not differ significantly from those of contralateral nonischemic limbs, or from capillary counts in either ischemic or nonischemic limbs of NTG-treated rabbits. CONCLUSIONS: Controlled release of microgram quantities of VEGF significantly enhanced neovascularization and vascular perfusion in ischemic limbs compared with controls in this rabbit model of partial ischemia. In addition, VEGF-treated ischemic limbs demonstrated near-normal function and appearance, whereas NTG- and saline-treated ischemic controls remained noticeably impaired. This novel approach of VEGF delivery may prove clinically useful either alone or combined with revascularization procedures.

A rare complication in elective repair of an abdominal aortic aneurysm: multiple transmural colonic infarcts secondary to atheroemboli.

Numerous complications may occur during elective and emergency repair of abdominal aortic aneurysms. The following report will document a rare complication in a patient with chronic renal failure. Multiple atheroemboli were found to produce transmural infarction of the left colon after elective repair of an abdominal aortic aneurysm. The pathologic process and the proposed mechanism of injury are also discussed.

A prospective study on intermittent pneumatic compression in the prevention of deep vein thrombosis in patients undergoing total hip or total knee replacement.

Three hundred and forty-six consecutive patients undergoing total hip or total knee replacement were prospectively studied to evaluate the effectiveness of intermittent pneumatic compression of the legs for the prevention of postoperative deep vein thrombosis. All patients were serially studied using impedance plethysmography and duplex ultrasound with color flow preoperatively and on the fourth and seventh postoperative day. The incidence of postoperative deep vein thrombosis in this series was 4 percent. Each patient with a postoperative duplex ultrasound had positive impedance plethysmography. Of the 14 patients who had postoperative deep vein thrombosis, seven had positive test results on postoperative day four and seven had positive tests on postoperative day seven. No patients were symptomatic. The results suggest that the high incidence of postoperative deep vein thrombosis after extensive orthopedic operation is significantly lowered by the use of intermittent pneumatic compression. Intermittent pneumatic compression, therefore, may be the preferred approach in prophylaxis of postoperative deep vein thrombosis.

Material and structural characterization of human saphenous vein.

Saphenous vein patch rupture after carotid endarterectomy is an infrequent but devastating complication. This study was undertaken to evaluate the material and structural properties of fresh human saphenous veins to understand the causes of this complication. Segments of saphenous veins were obtained from 22 patients from vein harvested during coronary artery bypass surgery. Ninety-three specimens, oriented in both circumferential (n = 45) and longitudinal (n = 48) directions, were prepared from the available vein segments for testing. Specimens were mounted on specially designed grips and then subjected to uniaxial tension testing. For each specimen the following material and structural parameters were determined: vessel diameter, tensile stiffness, failure and ultimate forces, and tensile modulus, failure stress, and strain. The physical properties of specimens evaluated in longitudinal orientations and thus limit the inherent strength of the vein. The physical properties of circumferentially tested vein specimens were negatively correlated to age, female gender, diabetes, and hypertension. The data obtained in this investigation suggest that age, hypertension, as well as diabetes and gender may adversely influence the circumferential tensile strength of human saphenous veins used as patch grafts.

The effects of heparin upon atherogenesis in the Watanabe heritable hyperlipidemic rabbit.

Heparin is routinely added to vascular cell cultures to inhibit smooth muscle cell proliferation. The in vivo effects of heparin upon atherogenesis have remained controversial, however. In this experiment 13 four-month-old, heritably hyperlipidemic, Watanabe rabbits were randomly assigned to three treatment groups: 1500 U heparin, 500 U heparin, or saline. An injection protocol was followed for nine months. The rabbits were bled monthly from their marginal ear veins and plasma from these bleeds was analyzed for cholesterol and triglyceride content. At sacrifice each rabbit's aorta was sampled at 10 specific locations from the arch to the iliac bifurcation. The reduction in the area of the aorta by atherosclerotic plaque at each site was calculated using a video imaging system. Heparin injections significantly reduced mean plasma levels of cholesterol and triglycerides compared to pretreatment levels and saline injected controls. However, the magnitude of the reduction was not dose-related. The aortic luminal area occupied by atherosclerotic plaque in rabbits injected with 1500 U of heparin was significantly less (p less than .05) than in rabbits injected with saline or 500 U of heparin. Plaques from heparin-treated animals contained more fatty deposits and foam cells compared to the plaques from saline-treated rabbits which were more fibromuscular in organization. We conclude that heparin modulates the occurrence and composition of atherosclerotic plaques in this animal model of naturally occurring atherogenesis.

A canine model of intimal hyperplasia (IH) in autogenous vein grafting: a preliminary report.

High failure rates (10-40% at 1 year and 2-6% per year thereafter) of autologous vein grafts in peripheral bypass surgery due to progressive intimal hyperplasia (IH) have prompted researchers to search for an animal model that develops IH in a relatively short period of time. This study summarizes our experiences in promoting IH in a canine model. Eight to ten centimeters of both jugular veins were exposed in 40 adult mongrel conditioned dogs. After division into 4-5-cm lengths, the segment of jugular vein most proximal was ballooned at 800-900 mm Hg with a modified 8F Fogarty catheter to induce intimal and medial layer injury. The distal segment was left nonballooned. Segments of these autologous vein grafts, 1.5 cm in length, both ballooned and nonballooned, were then anastomosed, end to end, into the carotid and femoral circulations. Six weeks postoperatively the grafts were perfusion-fixed, harvested, and histologically processed, and the amount of the lumen in midgraft sections occupied by IH was determined by image analysis. In all dogs, the degree of IH was significantly greater in the balloon catheterized vs noncatheterized graft segments. IH was more severe in the femoral than in the carotid arteries. The grafts that developed the most severe intimal hyperplasia were femoral grafts that had been balloon catheterized. We conclude that these protocols are effective in inducing IH in a canine model in short postoperative times.

Analysis of benefit of anticoagulation after placement of Kimray-Greenfield filter.

The Kimray-Greenfield venal caval filter is widely accepted as a means of preventing pulmonary embolism when medical anticoagulation has failed or complications have developed. When indicated, anticoagulants are usually resumed after placement of the filter. A retrospective study was performed comparing the thromboembolic and postphlebitic complications in patients who continued to receive anticoagulants after placement of the filter versus those who did not. Sixty-eight Kimray-Greenfield filters were placed in 68 patients (43 men and 25 women) during a four year period. After placement of the filter, 26 patients received anticoagulants and 42 did not. Three of those receiving anticoagulants and six of those who did not had significant swelling of the leg; two of those receiving anticoagulants and two of those who did not had a recurrent deep venous thrombosis. There were no instances of recurrent pulmonary embolism. There were no significant differences in the results of these two groups of patients. These results are consistent with those reported in the literature in that no correlation has been found between the use of anticoagulants after placement of the filter and recurrent thromboembolism or stasis sequelae. In view of the complications associated with medical anticoagulation, we recommend its discontinuation in all patients after placement of the Kimray-Greenfield filter.

Angioscope-assisted occlusion of venous tributaries with prolamine in in situ femoropopliteal bypass: preliminary results of canine experiments.

Ten mongrel dogs underwent left lower extremity in situ femoropopliteal bypass with femoral vein. A 20 to 25 cm myocutaneous bridge was left between femoral and popliteal anastomoses. A 2.8 mm angioscope was introduced intraluminally to visualize venous tributaries (VT). A balloon occlusion catheter was placed alongside the angioscope and directed in each VT. Prolamine was injected into each VT to effect occlusion. Seven dogs were followed up for 1 week and three dogs for 1 month. A total of 34 VT (range one to five per dog) were available for attempted occlusion. Twenty-nine of 84 (85%) VT were able to be occluded based on comparison of pre-VT and post-VT occlusion angiograms. Poor visualization of VT or VT too small to admit the 5F catheter were reasons for failure. We conclude that (1) in the canine model studied angioscope-assisted occlusion of femoropopliteal during bypass is technically feasible, (2) this technical detail makes unnecessary medial thigh dissection for exposure of the vein graft, and (3) during short-term observation prolamine appeared to be a suitable occluding substance.

Experimental pharmacologic cerebroprotection.

In the first part of this experiment, the effects of pharmacotherapy on the neurologic consequences of transient global ischemia were examined in Wistar rats. The control and four experimental groups each contained six rats. In comparison to the control group receiving normal saline (NS) solution, in which no rats survived, all rats given naloxone (Nx) (23 mg/kg), superoxide dismutase (SOD) (10,000 U/kg), or allopurinol (APL) (35 mg/kg), 15 minutes before interruption of cerebral blood flow, survived the 20-minute period of global ischemia (p less than 0.01, p less than 0.01, p less than 0.01, respectively). No rat receiving deferoxamine (DEF) (20 mg/kg) survived the same ischemic period. In the second part of the experiment, the arachidonic acid (AA) content of brain samples was determined by gas chromatography and was used as an indicator of cerebral ischemia. Two control and four experimental groups consisted of six rats each. An ischemia control group received NS, whereas experimental groups were given Nx, SOD, APL, or DEF with the same previous dosage schedule. The animals were decapitated 15 minutes after drug infusion and cerebral ischemia was simulated by incubation of the heads in a 37 degrees C water bath for 60 minutes. AA content of ischemic brain treated with NS was markedly elevated (60.0 +/- 24.1 micrograms/gm of brain tissue), whereas in comparison the AA content of brain treated with Nx (5.1 +/- 3.0 micrograms/gm of brain tissue, p less than 0.05), SOD (3.5 +/- 2.7 micrograms/gm of brain tissue, p less than 0.05), or APL (2.9 +/- 1.5 micrograms/gm of brain tissue, p less than 0.05) all demonstrated much lower levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Retroperitoneal approach to the abdominal aorta: revisited.

Experience with retroperitoneal approach to the abdominal aorta for aortic reconstruction in 30 cases is reported. The authors' interest in this exposure stemmed from observations made at the time of scoliosis surgery. The technique was modified and used in poor risk patients and resulted in a significant decrease in operative morbidity and hospitalization. A literature review revealed that several modifications have been described dating back as far as 1836. The authors emphasize technical features and advantages and disadvantages of this approach.

Team approach in the management of diabetic foot infections.

Foot infections are common in the diabetic patient. They result from a interplay of neuropathy, ischemia, and metabolic alterations. The team approach in the management of diabetic foot infections can provide the most optimal and probably the most cost-effective care. The cornerstone of treatment is early recognition and prompt intervention. After diagnostic cultures are obtained, infections should be treated with appropriate antibiotics. Bony deformities should be corrected. The vascular status of the patient should be evaluated, and if necessary, treatment should be directed at improving blood flow to the affected foot.

Endothelial cell seeding improves 4 mm PTFE vascular graft performance in antiplatelet medicated dogs.

The ideal prosthetic vascular graft for the replacement or bypass of small vessels has not yet been developed. Many studies have documented the success of endothelial cell seeding in small-diameter Dacron grafts, but few have reported the application of this protocol to small-diameter PTFE grafts, and none have reported seeding small-diameter PTFE grafts in antiplatelet medicated dogs. The present study was undertaken to assess the efficacy of endothelial cell seeding of small-diameter (4 mm ID) PTFE (Gore-Tex) carotid artery interposition grafts in the antiplatelet medicated dog. Twenty-five male mongrel dogs were included in this study. In each dog one carotid artery was replaced with an endothelial cell seeded PTFE graft; the contralateral artery was replaced with a nonseeded graft. The in vivo progress of graft performance was evaluated from 1 to 4 weeks postoperatively. The endothelial cell seeded grafts achieved significantly higher patencies and mean thrombus-free surfaces than nonseeded grafts. Midgraft endothelium was identified only on the seeded grafts at 3 and 4 weeks, with a maximal luminal coverage of 10-12%. The measurements of prostacyclin (PGI2) production indicated that the antiplatelet agent therapy did inhibit endothelial cell cyclooxygenase. The presence of outer capsule vasa vasora, anastomotic pannus ingrowth, transinterstitial cellular ingrowth, and thin inner capsules characterized the endothelial cell seeded grafts in contrast to the nonseeded grafts. We conclude that enhancement of graft performance is achieved by combining both an antiplatelet regimen and endothelial cell seeding in small-diameter PTFE vascular grafts.

Management of intra-abdominal aneurysms associated with periarteritis nodosa.

Periarteritis nodosa is a disease of small and medium-sized arteries, frequently associated with multiple visceral artery aneurysms. Infrequently, these aneurysms rupture, usually with fatal results. A case of spontaneous rupture of a middle colic artery aneurysm in a patient with periarteritis nodosa is reported, and similar cases in the literature are reviewed. Treatment of a ruptured visceral artery aneurysm requires ligation or resection of the aneurysm without delay. Residual aneurysms are treated with cyclophosphamide and/or prednisone in an attempt to induce regression of the aneurysms. An arteriogram performed after 3 to 4 months of medical therapy determines the need for further surgical intervention.

Abdominal aortic aneurysm and the pseudorupture syndrome.

A consistently high mortality for ruptured abdominal aortic aneurysm has given rise to an aggressive approach in the management of these patients. However, there is a group of patients who present with signs and symptoms suggesting a ruptured abdominal aortic aneurysm but instead have other life threatening conditions. These patients and their management are presented herein.

Prostaglandin biochemistry of seeded endothelial cells on Dacron prostheses.

The beneficial effect of seeding endothelial cells on synthetic vascular conduits has been well established. The biochemical production and interaction of the prostaglandins, prostacyclin (PGI2) and thromboxane (TxA2), were studied on Dacron vascular grafts that were seeded with autogenous venous endothelial cells. Seventy-three seeded and nonseeded grafts were implanted into the carotid arteries of dogs. Animals were medicated with either cyclooxygenase inhibitors (aspirin and dipyridamole, or ibuprofen, or U-53,059), or dipyridamole alone, or a thromboxane synthase inhibitor, U-63557A. All animals were killed at 5 weeks and analyzed for patency, thrombus-free surface (TFS), and PGI2 and TxA2 production from mid-graft punch biopsies. PGI2 and TxA2 identifications were made by radioimmunoassay determination of 6-keto PGF1 alpha and TxB2, respectively. Results of the study demonstrated in nonmedicated animals a slightly increased patency rate in seeded vs. nonseeded grafts (50% vs. 40%) and a more significant difference in TFS (49% vs. 24%). The addition of cyclooxygenase inhibitors or TxA2 synthase inhibitors significantly improved both patency (90% vs. 47%) and TFS (87% vs. 9%) in seeded vs. nonseeded grafts. PGI2 production was decreased in seeded grafts with the use of cyclooxygenase inhibitors in all cases. It is concluded that seeded endothelial cells on Dacron velour grafts can synthesize PGI2; these PGI2 levels are far less than PGI2 levels produced by endothelial cells from the adjacent carotid artery; and TxA2 synthase inhibitors best improve thromboresistance of seeded grafts without significant reduction in PGI2 production.

Small-diameter vascular prostheses: two designs of PTFE and endothelial cell-seeded and nonseeded Dacron.

Despite numerous advances in biomaterials design and utilization, the perfect artificial small-vessel substitute has yet to be developed. Dacron and expanded polytetrafluoroethylene (PTFE) are two materials potentially appropriate for use as small-vessel prostheses. We report the patencies of endothelial cell-seeded and nonseeded 4 mm I.D. Dacron grafts and two designs of nonseeded 4 mm I.D. PTFE (Gore-Tex and Impra) in the carotid position in dogs. All graft lengths exceeded the calculated maximum critical length for the material being tested. Dacron grafts, both endothelial cell-seeded and nonseeded, achieved higher patencies than both designs of PTFE. Endothelial cell-seeded Dacron grafts achieved the highest patencies. Endothelium was present to a significant extent only on endothelial cell-seeded Dacron grafts. There was little pannus ingrowth or midgraft pseudointima on nonseeded Dacron or on patent PTFE grafts although thrombus-free surface areas of patent PTFE grafts were high. These comparative data support the utility of endothelial cell seeding in achieving high patencies of small-diameter vascular grafts.

Blunt trauma to the axillary artery.

Blunt trauma to the axillary artery is an unusual injury. Patients with these injuries may not present with "classic" signs of arterial insufficiency; therefore a high index of suspicion is necessary to avoid delay in treatment. This article presents three patients with unusual injuries to the axillary artery and discusses their management.

Persistent sciatic artery: two case reports with emphasis on embryologic development.

Prior to development of the femoral arterial system, the sciatic artery serves as the principal blood supply to the lower extremity in the embryo. There have been only 32 reported cases in the world literature of a persistent sciatic artery in the adult. Two additional cases are presented in this report with a review of the embryologic development of the arterial system in the lower extremity. Diagnosis and treatment of associated problems involving the sciatic artery are discussed.

Arterial occlusive disease: a function of vessel bifurcation angle.

A clinical observation that patients with aortoiliac occlusive disease have a high aortic bifurcation serves as the stimulus for this study. A review of 100 consecutive abdominal aortograms revealed that patients with occlusive disease had an average bifurcation angle of 38 degrees and those with normal studies or aneurysmal disease had an average angle of 52 degrees. A flow visualization system was constructed to study shear stress using eight Pyrex models with varying bifurcation angles (20 to 90 degrees). The perfusate consisted of a 35% sucrose solution with anion-exchange beads to serve as flow particles. The bifurcations were photographed at three different flow rates. The length of each tracer particle was measured to determine its velocity. Velocity profile curves were constructed and shear stress calculated by the formula shear stress = mu x dv/dr, where mu is viscosity, v is velocity, and r is radius. Results of the study suggest that more acute angles cause a greater shear stress on the inner wall of the bifurcation and decreased shear stress on the outer wall. Two theories of atheroma predilection, high shear stress and low shear stress, are applied to patients with high acute aortic bifurcations.

Operation for ruptured abdominal aortic aneurysms: a community-wide experience.

From 1975 through 1979, 29 members of The Cleveland Vascular Society operated on 1049 patients with abdominal aortic aneurysms; of these, 152 ruptured aneurysms. The postoperative mortality rate was 38% (58 of 152). In 27% (41 of 152) of the patients, a diagnosis was made prior to rupture, and the average interval from diagnosis rupture was 16 months. A history of diabetes, hypertension, or a single myocardial infarction (MI) prior to rupture was not associated with an increased mortality rate. Patients with a history of more than one MI prior to rupture had a 75% (six of eight) mortality rate. The average time from onset of symptoms to examination was 2 days 10 hours. When the initial diagnosis was correct, or an intra-abdominal disease was at least suspected, the mortality rate was 35% (47 of 135). When the initial diagnosis was incorrect and a cardiopulmonary or cerebral cause was suspected, the mortality rate was 75% (13 of 17). When the diagnosis was incorrect, the interval from diagnosis to surgery was 2 1/2 days. With only intramural bleeding or a small hematoma in the area of rupture, the mortality rate was 17% (4 of 24); when the hematoma was more extensive, the mortality rate was 43% (55 of 128). This study encompassed a large number of operations performed in a metropolitan area during a relatively short period of time, during which there had been few changes in operative technique or supportive measures. It demonstrated that the most critical factors influencing survival were correct initial diagnosis, the extent of the hematoma, and the history of more than one preoperative MI.