Repeated Three-Dimensional Magnetic Resonance Imaging of Atherosclerosis Development in Innominate Arteries of Low-Density Lipoprotein Receptor-Knockout Mice

Abstract

Background-In vivo methods to evaluate the size and composition of atherosclerotic lesions in animal models of atherosclerosis would assist in the testing of antiatherosclerotic drugs. We have developed an MRI method of detecting atherosclerotic plaque in the major vessels at the base of the heart in low-density lipoprotein (LDL) receptor-knockout (LDLR Ϫ/Ϫ ) mice on a high-fat diet. Methods and Results-Three-dimensional fast spin-echo magnetic resonance images were acquired at 7 T by use of cardiac and respiratory triggering, with Ϸ140-m isotropic resolution, over 30 minutes. Comparison of normal and fat-suppressed images from female LDLR Ϫ/Ϫ mice 1 week before and 8 and 12 weeks after the transfer to a high-fat diet allowed visualization and quantification of plaque development in the innominate artery in vivo. Plaque mean cross-sectional area was significantly greater at week 12 in the LDLR Ϫ/Ϫ mice (0.14Ϯ0.086 mm 2 [meanϮSD]) than in wild-type control mice on a normal diet (0.017Ϯ0.031 mm 2 , PϽ0.01). In the LDLR Ϫ/Ϫ mice, but not control mice, increase in plaque burden at week 12 relative to week 1 was also highly significant (Pϭ0.001). Lumen cross section was not significantly different between time points or groups. MRI and histological assessments of plaque size were closely correlated (Rϭ0.8). The lumen of proximal coronary arteries could also be visualized. Conclusions-This

Quantification and 3D Reconstruction of Atherosclerotic Plaque Components in Apolipoprotein E Knockout Mice Using Ex Vivo High-Resolution MRI

“…B, A second reconstructed plane orthogonal to the first has been introduced to highlight the artery structure, which demonstrates the lesion extending in a cranial direction along only 1 side of the artery. 25 Prolonged imaging protocols of the sort described here are not feasible in vivo; therefore, we anticipate that further advances in microscopic plaque characterization will require new contrast agents. 34,35 Gadolinium-conjugated nanoparticles that are targeted to specific molecules have been used to image thrombus 36 and integrins 37 in larger animals.…”

“…Magnetic resonance (MR) has also been shown to discriminate atherosclerotic plaque components in larger animal models including rabbits, [17][18][19] pigs, 20 and nonhuman primates. 21 In apoEϪ/Ϫ mice, MRI accurately quantifies atherosclerosis in the abdominal aorta, 22 aortic arch, 23 aortic root, 24 and brachiocephalic artery 25 in vivo. However, genetic and pharmacological interventions affect not only plaque size but also composition.…”

Serial Studies of Mouse Atherosclerosis by In Vivo Magnetic Resonance Imaging Detect Lesion Regression After Correction of Dyslipidemia

“…The use of the aortic arch as donor tissue is particularly advantageous because (1) lesions form relatively faster and in a predictable manner in this location, 12 and (2) the preservation of the curvature of the implanted aortic arch provides for a clearer landmark for MRI. 11 We 13,14 and others 15,16 have shown that MRI can noninvasively detect atherosclerotic plaques in living mice. To our knowledge, the ability to measure plaque regression and differentiate plaque components in mice has not been demonstrated.…”

In Vivo mouse imaging and spectroscopy in drug discovery

“…Several groups are applying MRI techniques to mouse studies. High-resolution MRI is capable of detecting lipid-rich atherosclerotic plaques in mouse models of atherosclerosis (233)(234)(235)(236)(237). Dynamic contrast-enhanced MRI has been shown to be useful for evaluating atherosclerotic plaque activity in mice (238).…”