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

Posted Dec 31, 2008 Updated Apr 7, 2023
By Christi M. Terry PhD , Seong-Eun Kim PhD , Li Li MD , K. Craig Goodrich MS , J. Rock Hadley PhD , Donald K. Blumenthal PhD , Dennis L. Parker PhD , Alfred K. Cheung MD
13 min read

Rationale and Objectives

Chronic hemodialysis requires a vascular access that provides high blood-flow rates for the extracorporeal recirculation of blood. Synthetic arteriovenous (AV) grafts often fail because of clotting caused by underlying hyperplasia formation. The authors report the use of magnetic resonance (MR) imaging (MRI) without contrast agent to monitor tissue hyperplasia formation as well as luminal area in a porcine model of AV graft stenosis.

Materials and Methods

Expanded reinforced polytetrafluoroethylene grafts were surgically placed between the common carotid artery and the external jugular vein, bilaterally, in pigs. Animals underwent MRI in a 3-T scanner at 3, 4, or 6 weeks after graft placement, followed by euthanasia and the collection of grafts and adjacent tissues for histologic analysis. Two animals underwent sequential scanning at 1, 2, 3, 5, and 7 weeks after graft placement, followed by histologic analysis.

Results

Measurements of hyperplasia obtained from the MR images were compared with, and correlated well with, measurements obtained from the histologic cross-sections ( r = 0.932, P = .02). The MR images provided a more complete view of the venous hyperplasia throughout the graft compared with histology. The MR images could be examined from multiple angles and were unaffected by histologic preparation artifacts.

Conclusion

Unlike histology, MRI provided longitudinal 3-dimensional views of hyperplasia within the AV grafts. This ability of MRI to more completely identify the geometry of hyperplasia and to quantify the tissue volume in vivo could provide benefits over histologic analysis in assessing the pathology of AV graft failure and the efficacy of antihyperplasia interventions.

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 native arteries to native veins are the preferred access, synthetic polytetrafluoroethylene (PTFE) AV grafts are also widely used in the United States. Both access types succumb to premature failure because of clotting caused by underlying neointimal hyperplasia formation, although synthetic grafts have a higher rate of failure. The construction and revision of vascular accesses are among the most commonly performed vascular surgery procedures in the United States ( ). Access failure results in significant morbidity in the hemodialysis population, and currently, there is no effective therapy to prevent access failure ( ). Synthetic AV grafts could be the preferred access for hemodialysis if the high occurrence of hyperplasia could be prevented, because 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 grafts 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 ( ). Thus, these models are very useful for studying strategies to prevent AV graft hyperplasia. The analysis of hyperplasia development in the pig model typically involves survival of the animals for 4 to 8 weeks after graft placement, followed by euthanasia and histologic analysis of the graft-vessel anastomoses. Hyperplasia occurs most often at the juncture of the graft and vessel, but it is also observed within native vessels, upstream and downstream of the anastomosis ( ). Histologic analysis provides two-dimensional (2D) information regarding the size and cellular nature of the hyperplastic lesion. Histologic results from our group and others have shown that lesions consist primarily of cells with smooth muscle cell–like properties and numerous macrophages and macrophage-derived foreign body cells. Lesions are also the site of conspicuous angiogenesis and deposition of the extracellular matrix ( ). Unfortunately, histologic analysis has a number of shortcomings ( ). Because of its labor-intensive nature and expense, only a limited number of samples are typically obtained around a graft-vessel anastomosis. Thus, the access region is generally not completely evaluated, and three-dimensional (3D) information on the lesion area along the length of the vessel is not provided. 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 the preparation of thin histologic slices because of differences in cutting resistance between the soft vascular tissues and the more resilient sutures and grafts. The graft material often becomes detached from the tissue during processing, making the results of tissue histology difficult to analyze. Another obvious disadvantage of histologic analysis is that 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 a graft and attached vessels in vivo is needed. The development of such a technique could prove useful for evaluating hyperplasia development in patients as well.

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Materials and methods

Porcine AV Graft Model

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MRI

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Table 1

Imaging Sequences and Parameters

Sequence Purpose Parameters 3D TSE To obtain black-blood images of vessel wall and suppress flow-related artifacts TE, 11 ms; TR, 665 ms; readout bandwidth, 140 Hz/pixel; ETL, 17; FOV, 192 × 156 mm 2 ; imaging matrix, 384 × 312; voxel dimensions, 0.5 × 0.5 × 0.5 mm 3 3D TOF To obtain 3D white-blood images of graft vascular geometry based on blood flow TE, 4.0 ms; TR, 25.0 ms; readout bandwidth, 190 Hz/pixel; FOV, 130 × 130 or 150 × 150 mm 2 ; imaging matrix, 384 × 312 × 64; voxel dimensions 0.3 × 0.45 × 0.6 mm 3 2D TSE For comparison with 3D TSE images to clarify luminal area TE, 63 ms; TR, 5,000 ms; readout bandwidth, 210 Hz/pixel; ETL, 15; FOV 180 × 180 mm 2 ; imaging matrix, 256 × 256; voxel dimensions, 0.7 × 0.7 × 1.5 mm 3 TSE with double inversion preparation To obtain 2D black-blood images with high in-plane resolution at the anastomoses TE, 13 ms; TR, 700 ms; TI, 500 ms readout bandwidth, 250 Hz/pixel; ETL, 9; FOV, 150 × 150 mm 2 ; imaging matrix, 328 × 328; voxel dimensions 0.48 × 0.48 × 2 mm 3 Axial 2D TOF To obtain white-blood images of longitudinal vessel geometry TE, 5.9 ms; TR, 30 ms; readout bandwidth, 72 Hz/pixel; FOV, 160 × 160 mm 2 ; thickness, 3 mm; imaging matrix, 256 × 256

ETL, echo train length; FOV, field of view; TE, echo time; 3D, 3-dimensional; TI, time inversion; TOF, time-of-flight; TR, repetition time; TSE, turbo spin-echo; 2D, 2-dimensional.

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Histologic Analysis

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Correlation of Surface Areas Collected From MRI and Histology

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Results

Histology of AV Graft Hyperplasia

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Figure 1, Histologic sections from the porcine model of arteriovenous graft stenosis. (a) A tissue section taken 4 weeks after graft placement and stained with elastic van Gieson stain, as described in the text. The elastic lamina is stained dark black , and hyperplasia is stained lighter purple . (b) A tissue section taken 6 weeks after graft placement and then stained with hematoxylin and eosin. The graft has partially pulled away from the slide in the areas indicated by the asterisks .

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Comparison of In Vivo MR Image and Corresponding Ex Vivo Histologic Section

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Figure 2, Longitudinal vessel geometry. (a) Magnetic resonance (MR) image of the carotid artery (CA) and jugular vein (JV) obtained 1 week before graft placement. (b) MR image of the CA and JV of the same animal 2 weeks after graft placement.

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Figure 3, Serial magnetic resonance (MR) images and corresponding histologic sections along an arteriovenous graft taken 6 weeks after graft placement. The axial MR image (a 3-dimensional volume collected by 3-dimensional turbo spin-echo MR imaging [MRI]) of the left venous anastomosis in a pig (a) underwent 2-dimensional multiplanar reconstruction to yield (b) and (c) . (b) A view orthogonal to the vertical dotted line dissecting the anastomosis in (a) . (c) A view orthogonal to the horizontal dotted line dissecting (b) . The view in (b) provides orientation of the angle and the location at which the image in (c) was collected, allowing accurate registration of the MR image with the histologic image in (e) . (d) The enlarged image of the venous anastomosis collected in (c) , with the closed arrow pointing to the hyperplastic tissue lining the graft. The line drawing represents the graft image in (b) and the location from which the MR image in (d) and histologic section in (e) were obtained. (f,h) Respective MR images obtained from the sequential middle and heel sections of the same venous anastomosis presented in (a) . (g,i) Corresponding histologic sections (stained with hematoxylin and eosin). The open arrows in (h) and (i) indicate an adjacent blood vessel. Closed arrows in this figure indicate hyperplastic tissue.

Figure 4, Examples from additional animals comparing magnetic resonance (MR) images with histologic sections. In vivo MR images (a–d) obtained without contrast injection and the corresponding postmortem histologic sections (e–h) were obtained within the same day. The image pairs in (a,e) and (b,f) are from two different animals; those in (c,g) and (d,h) are from the same animal but different sections of the right venous anastomosis. Asterisks indicate a clot formed postmortem.

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Comparison of 2D Black-Blood TSE Images and 3D Black-Blood TSE Images

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Figure 5, Comparison of 3-dimensional black-blood turbo spin-echo (TSE) sequence (a) and 2-dimensional black-blood TSE sequence (b) for visualizing hyperplasia within the arteriovenous graft. Images were taken from the venous anastomosis of the same animal at the same location 2 weeks after graft placement. No contrast was injected for these images. The 2-dimensional black-blood TSE sequence yields higher in-plane resolution.

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Serial MRI of AV Graft Hyperplasia Development

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Figure 6, Magnetic resonance (MR) imaging of hyperplasia development in one animal over time. (a,b) Cross-sectional MR images obtained in the absence of contrast injection at the venous anastomoses of the right and left arteriovenous grafts in the same animal at the same location and angle over a period of 1 to 7 weeks. Images in frames without black borders (1 and 3 weeks) were obtained with 3-dimensional black-blood turbo spin-echo (TSE) sequences; images in frames with black borders (2, 5, and 7 weeks) were obtained with 2-dimensional black-blood TSE sequences. The two bottom histologic sections correspond to the respective MR images (7 weeks) at the time of euthanasia. (c,d) Coronal vessel geometry collected at 2 and 5 weeks after graft placement by MR imaging with gadolinium contrast injection. Graft, jugular vein (JV), and carotid artery (CA) are indicated. Black-blood images in (a) and (b) were collected before contrast injection. The two graphs at the bottom of the figure illustrate the changes in luminal area and hyperplasia area for the right (e) and left (f) sides.

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Figure 7, Magnetic resonance image collected with 3-dimensional turbo spin-echo sequence showing a longitudinal cross-sectional view of an arteriovenous graft at 7 weeks after placement. The external plastic spiral reinforcements of the polytetrafluoroethylene graft were detected by the absence of signal.

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Quantification of Hyperplasia Surface Areas by MRI and Histology

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Table 2

Area of Hyperplasia Determined by Histology and Magnetic Resonance (MR) Imaging

Hyperplasia Area (mm 2 ) Section Histology MR Imaging 1 8.4 8.4 2 14.2 16.5 3 15.6 18.8 4 10.6 16.1 5 5.4 7.3

Arteriovenous grafts were explanted and fixed with formalin directly after MR image acquisition. Hyperplasia surface areas were obtained from MR images using OsiriX software (OsiriX Foundation, Geneva, Switzerland) and from histologic sections using ImageJ (National Institutes of Health, Bethesda, MD). The areas obtained from histologic sections and from MR images were significantly correlated ( r = 0.932, P = .02). Five different anastomoses from three animals were used.

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Discussion

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Acknowledgments

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Academic Radiology, Volume 16, Issue 1
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