Efficacy of local dipyridamole therapy in a porcine model of arteriovenous graft stenosis

Abstract

Perivascular delivery of antiproliferative drugs has been proposed as an approach to prevent neointimal hyperplasia associated with hemodialysis polytetrafluoroethylene (PTFE) grafts. We examined this approach to deliver dipyridamole in a porcine graft model. PTFE grafts were implanted between the carotid artery and external jugular vein bilaterally in pigs. During the surgery or 1 week post-graft placement, dipyridamole (0.26-52 mg) alone or incorporated in microspheres was mixed with an injectable polymeric gel and applied to the graft-arterial and graft-venous anastomoses on one side, whereas the contralateral control graft received no treatment. Three or four weeks after operation, the grafts and adjacent vessels were explanted en bloc and cross-sections of the anastomoses were examined histologically. The degree of neointimal hyperplasia was quantified by planimetry. In separate experiments, dipyridamole was extracted from the explanted tissues and assayed by spectrofluorometry. The normalized median hyperplasia areas of the treated and control graft-venous anastomoses were 0.45 (25th-75th percentile, 0.30-0.86) and 0.24 (0.21-0.30), respectively (N=7; P=0.08). The median hyperplasia areas of the treated and control graft-arterial anastomoses were 0.12 (0.07-0.39) and 0.11 (0.09-0.13), respectively (N=7; P=0.31). The dipyridamole levels in the vascular walls around the anastomoses were at or above the in vitro inhibitory concentrations for approximately 3 weeks. These results suggest that the local perivascular sustained delivery of dipyridamole, even at high dosages, was ineffective in inhibiting neointimal hyperplasia associated with PTFE grafts in a porcine model.

Use of Aspirin Associates with Longer Primary Patency of Hemodialysis Grafts

“…Consistent with this hypothesis, a recent study in swine showed that direct application of dipyridamole to the periadventitial surface of the graft-vein anastomosis in a concentration that inhibits vascular smooth muscle proliferation in vitro failed to prevent the development of neointimal hyperplasia. 15 Whether the combination of ERDP/ASA is better than aspirin for hemodialysis graft patency remains uncertain. Two large trials in patients with cerebrovascular disease have shown that ERDP/ASA is more effective than aspirin alone for secondary prevention of stroke or vascular death.…”

Establishment of a rat autogenous arteriovenous fistula model following 5/6 nephrectomy

“…This indicates that acute decompensation may gradually transition to residual renal compensation, indicating an improved simulation of chronic renal insufficiency 28 days after surgery. It is currently considered that the important pathological changes of intimal hyperplasia are the increase of vascular smooth muscle cells and extracellular matrix (13,(25)(26)(27)(28). The present study showed that there was intimal hyperplasia of the fistula in the first week after surgery, and the pathological features included smooth muscle cell proliferation, the accumulation of collagen fibers, extensive polypoidal hyperplasia, and evident stenosis in the fourth week after surgery.…”

Pathogensis and Local Drug Delivery for Prevention of Vascular Access Stenosis

“…The addition of polymeric microspheres to the thermosensitive triblock polymer was necessary in order to prolong the drug release, because of the relative hydrophilicity of dipyridamole [26]. There was no significant difference in neointima formation between this intervention and untreated graft [27]. This lack of efficacy may be due to a low potency of dipyridamole to inhibit the proliferation of myofibroblasts and VSMC in vivo, or the suboptimal release profile of the hydrophilic drug.…”