Noninvasive In vivo high-resolution magnetic resonance imaging of atherosclerotic lesions in genetically engineered mice.

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 mm3. The lumen and wall of the abdominal aorta and iliac arteries were identified on all images in apoE-KO (n=8) and wild-type (n=5) mice on chow diet. Images obtained with MR were compared with corresponding cross-sectional histopathology (n=58). MR accurately determined wall area in comparison to histopathology (slope=1.0, r=0.86). 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 (slope=0.97, r=0.91 for lesion shape; slope=0. 64, r=0.90 for lesion type). CONCLUSIONS The combination of high-resolution MR microscopy and genetically engineered animals is a powerful tool to 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.

[1]  E. Rubin,et al.  Atherogenesis Insights from the study of transgenic and gene-targeted mice. , 1993, Trends in cardiovascular medicine.

[2]  D C Levin,et al.  Significance of the Angiographic Morphology of Localized Coronary Stenoses: Histopathologic Correlations , 1982, Circulation.

[3]  S. Rose,et al.  High resolution high field rodent cardiac imaging with flow enhancement suppression. , 1994, Magnetic resonance imaging.

[4]  G. Cofer,et al.  High‐Field MR microscopy using fast spin‐echoes , 1993, Magnetic resonance in medicine.

[5]  V. Fuster,et al.  Water diffusion properties of human atherosclerosis and thrombosis measured by pulse field gradient nuclear magnetic resonance. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[6]  S M Schwartz,et al.  Peripheral vascular stenosis in apolipoprotein E-deficient mice. Potential roles of lipid deposition, medial atrophy, and adventitial inflammation. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[7]  A. Lusis.  The mouse model for atherosclerosis. , 1993, Trends in cardiovascular medicine.

[8]  C. Zarins,et al.  Compensatory enlargement of human atherosclerotic coronary arteries. , 1987, The New England journal of medicine.

[9]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[10]  Chun Yuan,et al.  Serial magnetic resonance imaging of experimental atherosclerosis detects lesion fine structure, progression and complications in vivo , 1995, Nature Medicine.

[11]  L W Hedlund,et al.  Histology by magnetic resonance microscopy. , 1993, Magnetic resonance quarterly.

[12]  M. McConnell,et al.  Comparison of respiratory suppression methods and navigator locations for MR coronary angiography. , 1997, AJR. American journal of roentgenology.

[13]  W. Hull,et al.  In Vivo 1H‐NMR microimaging with respiratory triggering for monitoring adoptive immunotherapy of metastatic mouse lymphoma , 1997, Magnetic resonance in medicine.

[14]  W D Wagner,et al.  A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[15]  V. Fuster,et al.  T2-weighted contrast for NMR characterization of human atherosclerosis. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[16]  E. McFarland,et al.  Three-dimensional NMR microscopy: improving SNR with temperature and microcoils. , 1992, Magnetic resonance imaging.

[17]  G. Johnson,et al.  Magnetic resonance microscopy of mouse embryos. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  V. Fuster,et al.  Magnetic resonance images lipid, fibrous, calcified, hemorrhagic, and thrombotic components of human atherosclerosis in vivo. , 1996, Circulation.

[19]  R. Balaban,et al.  Magnetization transfer contrast (MTC) and tissue water proton relaxation in vivo , 1989, Magnetic resonance in medicine.

[20]  M. Vannier,et al.  A High-Temperature Superconducting Receiver for Nuclear Magnetic Resonance Microscopy , 1993 .

[21]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[22]  N. Maeda,et al.  Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[23]  E. Haacke,et al.  Contrast‐enhanced magnetic resonance angiography of carotid arterial wall in pigs , 1997, Journal of magnetic resonance imaging : JMRI.

[24]  N. Maeda,et al.  Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. , 1992, Science.

[25]  R. Nagel,et al.  High expression of human beta S- and alpha-globins in transgenic mice: erythrocyte abnormalities, organ damage, and the effect of hypoxia. , 1992, Proceedings of the National Academy of Sciences of the United States of America.