Early identification of aortic valve sclerosis using iron oxide enhanced MRI

Abstract

Purpose: To test the ability of MION-47 enhanced MRI to identify tissue macrophage infiltration in a rabbit model of aortic valve sclerosis (AVS).

Materials and methods: The aortic valves of control and cholesterol-fed New Zealand White rabbits were imaged in vivo pre- and 48 h post-intravenous administration of MION-47 using a 1.5 Tesla (T) MR clinical scanner and a CINE fSPGR sequence. MION-47 aortic valve cusps were imaged ex vivo on a 3.0T whole-body MR system with a custom gradient insert coil and a three-dimensional (3D) FIESTA sequence and compared with aortic valve cusps from control and cholesterol-fed contrast-free rabbits. Histopathological analysis was performed to determine the site of iron oxide uptake.

Results: MION-47 enhanced the visibility of both control and cholesterol-fed rabbit valves in in vivo images. Ex vivo image analysis confirmed the presence of significant signal voids in contrast-administered aortic valves. Signal voids were not observed in contrast-free valve cusps. In MION-47 administered rabbits, histopathological analysis revealed iron staining not only in fibrosal macrophages of cholesterol-fed valves but also in myofibroblasts from control and cholesterol-fed valves.

Conclusion: Although iron oxide labeling of macrophage infiltration in AVS has the potential to detect the disease process early, a macrophage-specific iron compound rather than passive targeting may be required.

Figure 1

a: Retrospectively gated cine fSPGR oblique sagittal images of control and cholesterol-fed rabbit aortic valve right coronary cusps pre- and 48 h post- intravenous administration of 11.2 mg Fe/kg MION-47. b: Average cusp thickness of control and cholesterol-fed rabbit aortic valve cusps pre- and 48 h post-MION-47 administration. Data expressed as mean ±SEM. *P < 0.05.

Figure 2

a: The 3D FIESTA ex vivo MR images of control and cholesterol-fed rabbit aortic valve cusps with and without MION-47. b: Average percent void area of control and cholesterol-fed rabbit aortic valve cusps with and without MION-47. Data expressed as mean ±SEM. **P < 0.01.

Figure 3

a–d: Immunohistochemical analysis of control and cholesterol-fed rabbit aortic valve cusps with and without MION-47. Immunohistochemistry was performed on aortic valve sections using the following antibodies: anti-RAM11 for macrophage infiltration, anti-CD31 for endothelial cells, anti-smooth muscle α-actin for myofibroblasts. Counterstaining was performed with Perl’s Prussian blue to indicate sites of iron uptake. Boxes indicate the site of magnification of lower panels. Arrowheads indicate colocalized staining. Example scale bars for each magnification can be seen in right hand panels.