Noninvasive In Vivo High-Resolution Magnetic Resonance Imaging of Atherosclerotic Lesions in Genetically Engineered Mice

Abstract

Background-The pathogenesis of atherosclerosis is currently being investigated in genetically engineered small animals.Methods to follow the time course of the developing pathology and/or the responses to therapy in vivo are limited. Methods and Results-To address this problem, we developed a noninvasive MR microscopy technique to study in vivo atherosclerotic lesions (without a priori knowledge of the lesion location or lesion type) in live apolipoprotein E-knockout (apoE-KO) mice. The spatial resolution was 0.0012 to 0.005 mm 3 . The lumen and wall of the abdominal aorta and iliac arteries were identified on all images in apoE-KO (nϭ8) and wild-type (nϭ5) mice on chow diet. Images obtained with MR were compared with corresponding cross-sectional histopathology (nϭ58). MR accurately determined wall area in comparison to histopathology (slopeϭ1.0, rϭ0.86). In addition, atherosclerotic lesions were characterized in terms of lesion shape and type. Lesion type was graded by MR according to morphological appearance/severity and by histopathology according to the AHA classification. There was excellent agreement between MR and histopathology in grading of lesion shape and type (slopeϭ0.97, rϭ0.91 for lesion shape; slopeϭ0.64, rϭ0.90 for lesion type). Conclusions-The combination of high-resolution MR microscopy and genetically engineered animals is a powerful toolto investigate serially and noninvasively the progression and regression of atherosclerotic lesions in an intact animal model and should greatly enhance basic studies of atherosclerotic disease. (Circulation. 1998;98:1541-1547.)Key Words: atherosclerosis Ⅲ magnetic resonance imaging Ⅲ genes G enetically engineered animal models provide enormous potential for the study of the pathogenesis and treatment of numerous human diseases. The mouse is the most widely used animal for genetic studies, and techniques for genetic modification in vivo (transgenic and gene-targeting) are much more advanced in the mouse than any other mammal. 1,2For example, genetically engineered mice are being increasingly used as a model of atherosclerosis. Apolipoprotein E-knockout (apoE-KO) mice produced by gene-targeting technologies 3 spontaneously develop atherosclerotic lesions similar in morphology to those observed in humans.3,4 Most experimental designs are typically limited to in vitro and ex vivo examination. However, it would be advantageous to develop an in vivo technique for serial, noninvasive imaging to monitor progression or regression of the arterial lesions in this and other mouse models. Such a technique would allow the performance of repeated analyses in the same animal, rather than study of multiple experimental groups with larger number of animals killed at different time points. See p 1477MRI is a noninvasive, nondestructive, 3-dimensional imaging technique that differentiates tissue structure on the basis of proton magnetic properties, allowing a wide range of image contrast, ie, proton density-weighted (PDW), T1-, T2-weighted (T1W, T2W), etc.5 Currently, MRI is be...

Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI

“…Precontrast injection MRI of the ApoEϪ/Ϫ mice revealed heterogeneous distribution of aortic wall thickening, which has been correlated with the presence of atherosclerotic plaques, consistent with our previously published findings (6). Baseline MRI of WT mice revealed no areas of aortic wall thickening, as expected.…”

“…Postcontrast MRI was performed at 1-and 24-h postinjection. Slices were precisely anatomically matched to the slices obtained on the preinjection baseline scan (6).…”

“…It is evident that we need better tools to assess atherosclerosis to more accurately predict which patients need the most aggressive management. Targeted molecular imaging using MRI holds the potential to fulfill this role, because it has the intrinsic resolution required to image atherosclerosis (6) and may eventually allow us to accurately assess molecular, cellular, and compositional components of atherosclerotic plaques.…”

Mineral Volume and Morphology in Carotid Plaque Specimens Using High-Resolution MRI and CT

“…11 The potential role of MRI for noninvasive assessment of plaque morphology and lesion burden quantification has been addressed in several investigations ex vivo and in vivo. [12][13][14][15][16][17][18][19][20][21][22][23][24] The appearance of plaque calcification has been described as uniformly dark in signal intensity on all MRI sequences. 18,25,26 However, there are other components of atherosclerotic plaque that may show decreased signal intensity on some or all pulse sequences; for example, solid cholesterol hydrate may be present and plaque lipids may exhibit T2 shortening secondary to liquid crystal behavior, depending on the lipid composition and cholesterol content.…”

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

“…The use of magnetic resonance (MR) to image vessels close to the heart is complicated by respiratory and cardiac motion. For this reason, previous studies have concentrated on vessels well removed from the thoracic cavity and have resorted either to examining very old animals 12 or to inducing lesion development mechanically with a balloon catheter. 13,14 As far as we are aware, this is the first MRI study of atherosclerotic plaque in the thoracic cavity in any animal model and the first to use 3D MRI with cardiac and respiratory triggering in free-breathing rodents.…”