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MRI-monitored intra-shunt local agent delivery of motexafin gadolinium: towards improving long-term patency of TIPS.

Wang H, Zhang F, Meng Y, Zhang T, Willis P, Le T, Soriano S, Ray E, Valji K, Zhang G, Yang X - PLoS ONE (2013)

Bottom Line: Shunts were harvested for subsequent histology confirmation.In vitro studies confirmed the capability of SMCs in uptaking MGds in a concentration-dependent fashion, and demonstrated the suppression of cell proliferation by MGds as well.Dynamic MRI displayed MGd/blue penetration into the shunt-vein walls, showing significantly higher CNR of shunt-vein walls on post-delivery images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01), which was confirmed by histology.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

ABSTRACT

Background: Transjugular intrahepatic portosystemic shunt (TIPS) has become an important and effective interventional procedure in treatment of the complications related to portal hypertension. Although the primary patency of TIPS has been greatly improved due to the clinical application of cover stent-grafts, the long-term patency is still suboptimal. This study was to investigate the feasibility of using magnetic resonance imaging (MRI)-monitored intra-shunt local agent delivery of motexafin gadolinium (MGd) into shunt-vein walls of TIPS. This new technique aimed to ultimately inhibit shuntstenosis of TIPS.

Methodology: Human umbilical vein smooth muscle cells (SMCs) were incubated with various concentrations of MGd, and then examed by confocal microscopy and T1-map MRI. In addition, the proliferation of MGd-treated cells was evaluated. For in vivo validation, seventeen pigs underwent TIPS. Before placement of the stent, an MGd/trypan-blue mixture was locally delivered, via a microporous balloon, into eleven shunt-hepatic vein walls under dynamic MRI monitoring, while trypan-blue only was locally delivered into six shunt-hepatic vein walls as serve as controls. T1-weighted MRI of the shunt-vein walls was achieved before- and at different time points after agent injections. Contrast-to-noise ratio (CNR) of the shunt-vein wall at each time-point was measured. Shunts were harvested for subsequent histology confirmation.

Principal findings: In vitro studies confirmed the capability of SMCs in uptaking MGds in a concentration-dependent fashion, and demonstrated the suppression of cell proliferation by MGds as well. Dynamic MRI displayed MGd/blue penetration into the shunt-vein walls, showing significantly higher CNR of shunt-vein walls on post-delivery images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01), which was confirmed by histology.

Conclusion: Results of this study indicate that MRI-monitored intra-shunt local MGd delivery is feasible and MGd functions as a potential therapeutic agent to inhibit the proliferation of SMCs, which may open alternative avenues to improve the long-term patency of TIPS.

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In vivo MRI with subsequent histology confirmations of intra-TIPS delivery of MGd/trypan-blue mixture (a–d) and trypan-blue only (e–h).MRI manifests the TIPS shunts before intra-TIPS local deliveries of MGd/blue mixture (arrow on a) and trypan-blue only (arrow on e), and the MGd distribution around the shunt (arrow on b) as bright signal after intra-TIPS agent delivery of MGd/blue, which is not seen on MRI with intra-TIPS delivery of trypan-blue only (arrow on f). Histological images confirm the successful penetration of trypan-blue (as blue stain on c) and MGd (as red fluorescent spots on d) in the shunt - hepatic vein wall with delivery of MGd/blue, while in the control group with delivery of trypan-blue (g and h), only trypan-blue stain (g) is visualized within the shunt - hepatic vein wall with weak autofluorescence of the intima (arrowhead on h). (Original magnification, ×20). Time-CNR curves of each animal group (i), showing that CNR increases immediately after MGd/blue delivery and remains at a high level within 75 minutes in the MGd/blue-treated group, while in the control group, the CNR does not increase after the trypan blue-only delivery.
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pone-0057419-g006: In vivo MRI with subsequent histology confirmations of intra-TIPS delivery of MGd/trypan-blue mixture (a–d) and trypan-blue only (e–h).MRI manifests the TIPS shunts before intra-TIPS local deliveries of MGd/blue mixture (arrow on a) and trypan-blue only (arrow on e), and the MGd distribution around the shunt (arrow on b) as bright signal after intra-TIPS agent delivery of MGd/blue, which is not seen on MRI with intra-TIPS delivery of trypan-blue only (arrow on f). Histological images confirm the successful penetration of trypan-blue (as blue stain on c) and MGd (as red fluorescent spots on d) in the shunt - hepatic vein wall with delivery of MGd/blue, while in the control group with delivery of trypan-blue (g and h), only trypan-blue stain (g) is visualized within the shunt - hepatic vein wall with weak autofluorescence of the intima (arrowhead on h). (Original magnification, ×20). Time-CNR curves of each animal group (i), showing that CNR increases immediately after MGd/blue delivery and remains at a high level within 75 minutes in the MGd/blue-treated group, while in the control group, the CNR does not increase after the trypan blue-only delivery.

Mentions: Figure 6 summarizes the results of the in vivo dynamic MRI monitoring of local agent deliveries during the TIPS procedure with subsequent histology confirmations. In the animal study group with intra-shunt delivery of MGd/blue mixture, MRI displayed the bright enhancement around the TIPS tract due to MGd/blue penetration into the shunt-vein walls, which was not seen in the control pigs. Histological findings further confirmed the successful penetration of blue-dye (as blue stain) and MGd (as red-fluorescent spots) within the shunt - hepatic vein walls in the animal group with MGd/blue, while in the control group, only blue stain was visualized in the shunt-vein wall with weak auto-fluorescence of the intima. Moreover, compared to the control group, the MGd/blue-delivered animal group demonstrated significantly higher CNR of shunt-vein walls on post-delivery MR images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01). The longitudinal observation demonstrated that the CNR increased immediately and remained continuously at a high level within 75 minutes after the MGd/blue delivery, while in the control group, the CNR did not increase after the blue-only delivery.


MRI-monitored intra-shunt local agent delivery of motexafin gadolinium: towards improving long-term patency of TIPS.

Wang H, Zhang F, Meng Y, Zhang T, Willis P, Le T, Soriano S, Ray E, Valji K, Zhang G, Yang X - PLoS ONE (2013)

In vivo MRI with subsequent histology confirmations of intra-TIPS delivery of MGd/trypan-blue mixture (a–d) and trypan-blue only (e–h).MRI manifests the TIPS shunts before intra-TIPS local deliveries of MGd/blue mixture (arrow on a) and trypan-blue only (arrow on e), and the MGd distribution around the shunt (arrow on b) as bright signal after intra-TIPS agent delivery of MGd/blue, which is not seen on MRI with intra-TIPS delivery of trypan-blue only (arrow on f). Histological images confirm the successful penetration of trypan-blue (as blue stain on c) and MGd (as red fluorescent spots on d) in the shunt - hepatic vein wall with delivery of MGd/blue, while in the control group with delivery of trypan-blue (g and h), only trypan-blue stain (g) is visualized within the shunt - hepatic vein wall with weak autofluorescence of the intima (arrowhead on h). (Original magnification, ×20). Time-CNR curves of each animal group (i), showing that CNR increases immediately after MGd/blue delivery and remains at a high level within 75 minutes in the MGd/blue-treated group, while in the control group, the CNR does not increase after the trypan blue-only delivery.
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Related In: Results  -  Collection

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pone-0057419-g006: In vivo MRI with subsequent histology confirmations of intra-TIPS delivery of MGd/trypan-blue mixture (a–d) and trypan-blue only (e–h).MRI manifests the TIPS shunts before intra-TIPS local deliveries of MGd/blue mixture (arrow on a) and trypan-blue only (arrow on e), and the MGd distribution around the shunt (arrow on b) as bright signal after intra-TIPS agent delivery of MGd/blue, which is not seen on MRI with intra-TIPS delivery of trypan-blue only (arrow on f). Histological images confirm the successful penetration of trypan-blue (as blue stain on c) and MGd (as red fluorescent spots on d) in the shunt - hepatic vein wall with delivery of MGd/blue, while in the control group with delivery of trypan-blue (g and h), only trypan-blue stain (g) is visualized within the shunt - hepatic vein wall with weak autofluorescence of the intima (arrowhead on h). (Original magnification, ×20). Time-CNR curves of each animal group (i), showing that CNR increases immediately after MGd/blue delivery and remains at a high level within 75 minutes in the MGd/blue-treated group, while in the control group, the CNR does not increase after the trypan blue-only delivery.
Mentions: Figure 6 summarizes the results of the in vivo dynamic MRI monitoring of local agent deliveries during the TIPS procedure with subsequent histology confirmations. In the animal study group with intra-shunt delivery of MGd/blue mixture, MRI displayed the bright enhancement around the TIPS tract due to MGd/blue penetration into the shunt-vein walls, which was not seen in the control pigs. Histological findings further confirmed the successful penetration of blue-dye (as blue stain) and MGd (as red-fluorescent spots) within the shunt - hepatic vein walls in the animal group with MGd/blue, while in the control group, only blue stain was visualized in the shunt-vein wall with weak auto-fluorescence of the intima. Moreover, compared to the control group, the MGd/blue-delivered animal group demonstrated significantly higher CNR of shunt-vein walls on post-delivery MR images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01). The longitudinal observation demonstrated that the CNR increased immediately and remained continuously at a high level within 75 minutes after the MGd/blue delivery, while in the control group, the CNR did not increase after the blue-only delivery.

Bottom Line: Shunts were harvested for subsequent histology confirmation.In vitro studies confirmed the capability of SMCs in uptaking MGds in a concentration-dependent fashion, and demonstrated the suppression of cell proliferation by MGds as well.Dynamic MRI displayed MGd/blue penetration into the shunt-vein walls, showing significantly higher CNR of shunt-vein walls on post-delivery images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01), which was confirmed by histology.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

ABSTRACT

Background: Transjugular intrahepatic portosystemic shunt (TIPS) has become an important and effective interventional procedure in treatment of the complications related to portal hypertension. Although the primary patency of TIPS has been greatly improved due to the clinical application of cover stent-grafts, the long-term patency is still suboptimal. This study was to investigate the feasibility of using magnetic resonance imaging (MRI)-monitored intra-shunt local agent delivery of motexafin gadolinium (MGd) into shunt-vein walls of TIPS. This new technique aimed to ultimately inhibit shuntstenosis of TIPS.

Methodology: Human umbilical vein smooth muscle cells (SMCs) were incubated with various concentrations of MGd, and then examed by confocal microscopy and T1-map MRI. In addition, the proliferation of MGd-treated cells was evaluated. For in vivo validation, seventeen pigs underwent TIPS. Before placement of the stent, an MGd/trypan-blue mixture was locally delivered, via a microporous balloon, into eleven shunt-hepatic vein walls under dynamic MRI monitoring, while trypan-blue only was locally delivered into six shunt-hepatic vein walls as serve as controls. T1-weighted MRI of the shunt-vein walls was achieved before- and at different time points after agent injections. Contrast-to-noise ratio (CNR) of the shunt-vein wall at each time-point was measured. Shunts were harvested for subsequent histology confirmation.

Principal findings: In vitro studies confirmed the capability of SMCs in uptaking MGds in a concentration-dependent fashion, and demonstrated the suppression of cell proliferation by MGds as well. Dynamic MRI displayed MGd/blue penetration into the shunt-vein walls, showing significantly higher CNR of shunt-vein walls on post-delivery images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01), which was confirmed by histology.

Conclusion: Results of this study indicate that MRI-monitored intra-shunt local MGd delivery is feasible and MGd functions as a potential therapeutic agent to inhibit the proliferation of SMCs, which may open alternative avenues to improve the long-term patency of TIPS.

Show MeSH
Related in: MedlinePlus