Noninvasive Assessment of Atherosclerotic Plaque Progression in ApoE −/− Mice Using Susceptibility Gradient Mapping

Abstract

Background— Macrophages have been identified as a major contributor to plaque development and destabilization in atherosclerosis. The aim of this study was to noninvasively assess uptake of citrate coated very small iron oxide particles at different stages of plaque development in the brachiocephalic artery of apoE −/− mice. Susceptibility gradient mapping (SGM) was applied to generate positive contrast images and to quantify iron oxide uptake. Methods and Results— ApoE −/− mice were fed a high-fat diet for 4, 8, or 12 weeks; 300 μmol Fe/kg was injected 24 and 48 hours before final MRI. Increasing very small iron oxide particle uptake was observed over the course of atherosclerotic plaque development. Simultaneous administration of pravastatin led to a significant decrease in very small iron oxide particle uptake, assessed by mass spectroscopy and histology. SGM-MRI allowed the generation of positive contrast images, and magnitudes (mT/m) of contrast enhancement in SG parameter maps significantly correlated with the absolute iron oxide content ( R 2 =0.70, P <0.05) and the macrophage density ( R 2 =0.71, P <0.05). Conclusions— This study shows an increase in iron oxide uptake (measured by in vivo SGM-MRI, histology, and mass spectroscopy) with the progression of plaque development in an apoE −/− mouse model of accelerated atherosclerosis. Positive contrast provided by SGM-MRI allowed for a clear visualization of intraplaque iron oxide depositions, and magnitudes (mT/m) of contrast enhancement in SG parameter maps allowed for the quantification of intraplaque iron oxide particles.