Longitudinal Assessment of Hyperplasia using Magnetic Resonance Imaging without Contrast in a Porcine Arteriovenous Graft Model

Chronic hemodialysis requires a vascular access that provides high flow rates for the extracorporeal recirculation of blood. Although the arteriovenous (AV) fistulas created by the anastomosis of a native artery to a native vein is the preferred access, synthetic polytetrafluoroethylene (PTFE) AV grafts are also widely used in the U.S. Both access types succumb to premature failure due to clotting caused by underlying neointimal hyperplasia formation, although synthetic grafts have a higher rate of failure. The construction or revision of hemodialysis accesses are among the most commonly performed vascular surgery procedures in the U.S (1). Access failure results in significant morbidity in the hemodialysis patient population and currently there is no effective therapy to prevent access failure (2, 3). Synthetic AV grafts could be the preferred access for hemodialysis if the high occurrence of hyperplasia could be prevented, as they generally have larger luminal diameters and shorter waiting times before use than native fistulas. Thus research is ongoing to develop strategies to inhibit hyperplasia and prevent graft failure. Porcine models of AV graft have been developed for the study of the pathogenesis of hyperplasia and treatment modalities. These models recapitulate the pattern of hyperplasia development observed in clinically failed AV grafts, with hyperplasia developing in an accelerated manner (4–7). Thus these models are very useful for studying strategies to prevent AV graft hyperplasia. Analysis of hyperplasia development in the pig model typically involves survival of the animals for 4–8 weeks after graft placement followed by euthanasia and histological analysis of the graft-vessel anastomoses. Hyperplasia occurs most often at the juncture of the graft and vessel but it is also observed within the native vessels, upstream, and downstream of the anastomoses (8). Therefore, histological sampling of multiple sections of the anastomosis and attached vessels is required for a thorough evaluation of hyperplasia development and of treatment effects. Histological analysis provides information regarding the cellular nature of the lesion. Histology from our group and others has shown the lesion consists primarily of cells with smooth muscle cell-like properties, and numerous macrophages and macrophage-derived foreign body cells. The lesion is also a site of conspicuous angiogenesis and deposition of extracellular matrix (4, 5, 9–11). Unfortunately, histological analysis suffers from a number of shortcomings (12). Because of its labor-intensive nature and expense, only a limited number of samples are typically obtained around the graft/vessel anastomosis. Thus, the access region is generally not completely evaluated. Also, the fixation of tissue for histology results in shrinkage and some distortion of vessel structure from the in vivo condition. In addition, artifacts often occur during preparation of thin histology slices due to differences in cutting resistance between the soft vascular tissues and the more resilient sutures and grafts. The graft often becomes detached from the tissue during processing, making the tissue histology difficult to analyze. Another obvious disadvantage to histological analysis is that the animals must be euthanized to obtain the tissue, precluding any further in vivo studies. For these reasons, a technique that readily yields information regarding hyperplasia development throughout the graft and attached vessels in vivo is needed. Development of such a technique could prove useful for evaluating hyperplasia development in patients as well. Some investigators have used intravascular ultrasound or contrast (x-ray) angiography to characterize hyperplasia development in animal models (7, 13–15). Angiography usually requires intravascular catheter placement, and involves exposure of staff to some levels of radiation, as well as the administration of contrast agent to the animal. It also usually provides only two-dimensional images. More importantly, it provides information on the lumen diameter but not the tissues that cause the stenosis. Intravascular ultrasound provides excellent images of the vessel wall with fairly detailed information about the intimal and medial layers but is also invasive, requiring intravenous catheter placement, significant technical skill and expensive non-reusable ultrasound probes. Computed tomography (CT) can provide 3 dimensional images of the lumen but again this technique involves radiation exposure and provides limited information about the hyperplastic tissue. Magnetic resonance imaging (MRI) has previously been used to detect stenoses within AV fistulas and grafts in patients (16–24). These previous investigations used contrast enhanced-MRI to yield luminal images of the vascular tree but no attempts were made to visualize the hyperplastic tissues per se. Recently, MRI has been used to visualize angioplasty-induced coronary lesions in a porcine model and the images were compared to ex vivo MRI and histological specimens from the same animals (25). Good agreement was observed for measurements of vessel wall thickness and area from the MR images and matched histology sections. Here we report the use of MRI to visualize not only the lumen, but also the development of hyperplastic tissue itself in hemodialysis AV grafts in vivo in a porcine model of AV graft failure.