Early animal model evaluation of an implantable contrast agent to enhance magnetic resonance imaging of arterial bypass vein grafts

Abstract

Background Non-invasive monitoring of autologous vein graft (VG) bypass grafts is largely limited to detecting late luminal narrowing. Although magnetic resonance imaging (MRI) delineates vein graft intima, media, and adventitia, which may detect early failure, the scan time required to achieve sufficient resolution is at present impractical. Purpose To study VG visualization enhancement in vivo and delineate whether a covalently attached MRI contrast agent would enable quicker longitudinal imaging of the VG wall. Material and Methods Sixteen 12-week-old male C57BL/6J mice underwent carotid interposition vein grafting. The inferior vena cava of nine donor mice was treated with a gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based contrast agent, with control VGs labeled with a vehicle. T1-weighted (T1W) MRI was performed serially at postoperative weeks 1, 4, 12, and 20. A portion of animals was sacrificed for histopathology following each imaging time point. Results MRI signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significantly higher for treated VGs in the first three time points (1.73 × higher SNR, P = 0.0006, and 5.83 × higher CNR at the first time point, P = 0.0006). However, MRI signal enhancement decreased consistently in the study period, to 1.29 × higher SNR and 2.64 × higher CNR, by the final time point. There were no apparent differences in graft morphometric analyses in Masson's trichrome-stained sections. Conclusion A MRI contrast agent that binds covalently to the VG wall provides significant increase in T1W MRI signal with no observed adverse effects in a mouse model. Further optimization of the contrast agent to enhance its durability is required.

Keywords: Magnetic resonance imaging; contrast media; gadolinium; image enhancement; peripheral vascular diseases; signal-to-noise ratio; vascular grafting.

Figure 1.

In vivo T1W MRI of a failed 8-month-old human VG at a spatial resolution of 0.19 mm3 (2 mm slice thickness, 0.31 mm in-plane resolution) in 10 min scan time at 1.5 Tesla. MRI cross-sections (B-H) and curved multi-planar reformation (I) are in excellent agreement with corresponding Masson trichrome histology obtained after excision (J-P), for both intimal hyperplasia (all images) and wall remodeling (negative B-D & G-H; positive E-F). Conventional angiography (A) shows only lumen stenoses (arrows).

Figure 2.

In vivo 7 Tesla FLASH MRI of mouse interposition carotid vein graft at 4 weeks post-implantation. ROIs for MR signal measurements (air for noise, vein graft wall for signal-to-noise ratio and tissue surrounding vein graft for contrast-to-noise ratio) are shown in the right-hand panel.

Figure 3.

Representative Masson’s trichrome stained microscopic images of vein grafts in controls and treated mice. The specimens were collected and analyzed at 1, 4, 12, and 20 weeks postoperatively. The microscopic graphs were taken at 600 μm to the proximal cuff edges of the vein grafts. Scale bars = 100 μm.

Figure 4.

Vein graft morphometric analysis at 1, 4, 12, and 20 weeks post the isograft carotid interposition vein grafts implantation; calculated Ideal luminal area in controls and treated mice (A), with each bar representing an average of at least 3 locations (200 μm, 400 μm, and 600 μm) of vein grafts harvested at that time point (n=1~2). Ratio of the intimal / (medial + adventitial) area in controls and treated vein grafts. Neointima development and (medial + adventitial) thickening were observed in both control and MRI contrast agent-treated vein grafts, with no apparent gross or microscopic differences observed between the two groups.

Figure 5.

Longitudinal MRI of one control and one treated mouse included in study; in the control animal the vein graft (arrow) exhibits similar MRI signal at all 4 imaging time points (top row). The VG in the animal that received a Gd-DTPA labeled VG (arrow) shows increased signal and delineation from surrounding tissues at all time points (bottom row), although at 4 weeks enhancement is segmental (strongest at 12–3 and 4–6 o’clock) and further reduced at 20 weeks.

Figure 6.. Average (+/− ____) longitudinal CNR data from all 15 animals successfully imaged in the study (7 control, 8 labeled VG).

Control VGs maintained a stable CNR throughout the study period. The CNR of labeled VGs was higher than that of control VGs at all time points but decreased throughout the study period, as indicated by linear regression analyses.