John D. Hughes

Recombinant Mitotoxin Basic Fibroblast Growth Factor–Saporin Reduces Venous Anastomotic Intimal Hyperplasia in the Arteriovenous Graft

BACKGROUNDnThe plant cytotoxin saporin (SAP) is a potent ribosome-inactivating protein. When conjugated to basic fibroblast growth factor (FGF2), it selectively kills proliferating cells that have upregulated FGF receptors. In this study, we evaluated the effect of the recombinant chimeric mitotoxin rFGF2-SAP on venous anastomotic intimal hyperplasia, a major cause of failure of arteriovenous (AV) grafts.nnnMETHODS AND RESULTSnRecently designed expanded polytet-rafluoroethylene-based local infusion devices were implanted bilaterally as femoral AV conduits in six dogs. The venous anastomoses were the sites of continuous delivery of rFGF2-SAP (2.7 micrograms.kg-1.d-1) to one side and vehicle (4.6 microL.kg-1.d-1) as control to the contralateral side for 14 days. All animals survived, and all grafts were patent. Liver enzyme levels and histological analyses of liver, kidneys, and brain were normal, indicating the absence of systemic toxicity. Morphometric measurements and measurements of cell proliferation by bromodeoxyuridine index analysis were performed at both arterial and venous anastomoses. There were no significant differences between the treated grafts and the control grafts in intimal hyperplasia and intimal cell proliferation at the arterial anastomoses. In contrast, rFGF2-SAP reduced intimal thickness by 32%, intimal area by 40%, and cell proliferation index by 33% at the treated venous anastomoses compared with the control venous anastomoses (P < .05).nnnCONCLUSIONSnThese data demonstrate that local infusion of rFGF2-SAP significantly reduces venous anastomotic intimal hyperplasia and cell proliferation without systemic toxicity. This study suggests a new strategy for reducing intimal hyperplasia by the selective killing of proliferating smooth muscle cells with a potent chimeric mitotoxin through a novel local infusion device.

Peripheral vascular complications of aortic dissection

BACKGROUNDnThe incidence and management of peripheral vascular complications of aortic dissection is unsettled.nnnPATIENTS AND METHODSnPeripheral vascular complications of spontaneous aortic dissection were examined in a 5-year retrospective review. Patients who had peripheral vascular complications were categorized as group A; those without as group B.nnnRESULTSnThirty-eight major vessels were affected in 18 patients. No patient underwent a peripheral vascular procedure for complications of the carotid, subclavian, celiac, mesenteric, or renal arteries. Three patients underwent femorofemoral bypass for acute iliofemoral occlusion due to dissection. A fourth patient had repair of an iliac aneurysm that developed as a complication of chronic dissection. The mortality rate was 17% for group A, 9% for group B, and 10% overall. Following repair of the aortic dissection, the majority of the peripheral vascular complications resolved.nnnCONCLUSIONSnPeripheral revascularization is infrequently required in aortic dissection following primary dissection repair.

Normothermic Renal Artery Perfusion: A Comparison of Perfusates

Hypothermia and preservative perfusates have been used to decrease ischemic renal injury. This study was performed to identify the preservative function of perfusates independent of the effects of hypothermia. Rats underwent 45 minutes of renal ischemia. Rectal and renal parenchyma temperatures were monitored and maintained within 1° C of normal. Perfusates were University of Wisconsin solution (UW), Euro-Collins solution, normal saline solution, and Ringers lactate solution. A nonperfused ischemic control and a nonischemic control group were also evaluated. Parameters evaluated included serum creatinine and blood urea nitrogen levels, renal ischemic injury grade, renal weight, and gross appearance of the injured kidney. Rats treated with UW solution were found to have a significantly lower creatinine, blood urea nitrogen, and injury grade than the other three perfused groups. The external gross appearance of the UW-treated kidneys was normal, whereas that of the other groups demonstrated moderate to severe injury. Although the mean right/left renal weight difference of the UW-treated group was lower than that of the other three groups, this was not statistically significant. Under normothermic conditions in rats, UW solution affords significant renal protection from ischemia. Euro-Collins, normal saline, and Ringers lactate solutions display no significant protective effect.

Transgraft Infusion of Heparin to Prevent Early Thrombosis of Expanded PTFE Grafts in Canine Femoral Veins

Recently we designed an expanded polytetrafluoroethylene (ePTFE)-based local infusion device that delivers therapeutic agents directly through the graft wall in the region adjacent to the upstream anastomosis, thereby achieving a high drug concentration downstream along the graft-blood interface. In this study we evaluated the effects of infusing heparin by this method on graft patency and neointimal hyperplasia in a canine model of femoral vein replacement. Five dogs underwent bilateral femoral vein replacement with the device. In each case one graft was infused with continuous heparin (48 U/kg/day) while the contralateral control graft received phosphate-buffered saline solution for 14 days. All heparin-treated grafts were patent and all control grafts were thrombosed at 14 days. There was no significant difference in systemic activated partial thromboplastin time among samples taken preoperatively, at 48 hours, and at 14 days of implantation (p > 0.5). There was no significant difference in neointimal hyperplasia between the upstream and downstream anastomoses in heparin-treated grafts. These data demonstrate that the transgraft infusion of heparin preserved venous ePTFE graft patency without measurable systemic anticoagulation. Thus this approach may represent an attractive strategy for maintaining patency of synthetic venous grafts.

Reduced Blood Flow Accelerates Intimal Hyperplasia in Endarterectomized Canine Arteries

The purpose of this study was to evaluate a technique that accelerates intimal hyperplasia by reduction of blood flow. Bilateral endarterectomies were performed in both femoral and carotid arteries in six dogs. One week later, all animals underwent banding of an artery distal to the injured region to reduce the blood flow by 50%. The contralateral injured arteries served as controls. At 11 weeks, the specimens were harvested and analyzed. Five of 12 (42%) of the flow-restricted arteries and nine of 12 (75%) of the non-flow-restricted arteries were patent at 11 weeks (P<0.05). Marked stenotic intimal hyperplastic lesions developed in the flow-restricted arteries (69% stenosis) as compared with the non-flow-restricted arteries (37% stenosis). Mean(s.d.) intimal thickness, intimal areas, and intimal/medial area ratio were 0.52(0.19) mm, 3.17(1.11) mm2, and 1.12(0.33)%, respectively, in the flow-restricted arteries. Their counterparts in the non-flow-restricted arteries were 0.21(0.09) mm, 1.70(1.09) mm2, and 0.58(0.14)%, respectively (P<0.05). Extracellular matrix comprised 48% of total intimal volumes in the flow-restricted arteries. Cell proliferation and occluded arteries were also characterized. These data demonstrate that reduction of blood flow significantly accelerated intimal hyperplasia and occlusion rates in endarterectomized arteries. Advanced intimal hyperplastic lesions (>50% stenosis) possess a high extracellular matrix content. This new animal model is a reliable generator of advanced stenotic lesions in a relatively short time period and can be used to study biologic mechanisms of stenosis and evaluate therapeutic interventions.

The thrombosed arteriovenous graft: An endovascular model for vascular surgeons

Arteriovenous dialysis grafts are the most commonly implanted prosthetic grafts. Thrombectomy with selective graft revision is traditional therapy for occlusions, but patency is minimally prolonged. Stenoses are determined by tactile feedback from an embolectomy catheter and lack of prograde and retrograde bleeding. An objective method for studying the graft and inflow and outflow tracts that permits appropriate endoluminal or surgical correction is described. This approach is appealing because: (i) the current approach is inadequate; (ii) it offers an objective, quantitative method to determine frequency and severity of critical stenoses within the failed access graft; (iii) remote and perigraft stenoses can be treated at the same setting; and (iv) it promotes the development of endovascular skills by surgeons in a high-volume, low-risk setting.