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Noninvasive Detection of Macrophage-Rich Atherosclerotic Plaque in Hyperlipidemic Rabbits Using "Positive Contrast" Magnetic Resonance Imaging

Grigorios Korosoglou, MD^_*,,_*, Robert G. Weiss, MD^,, Dorota A. Kedziorek, MD, Piotr Walczak, MD, Wesley D. Gilson, PhD, Michael Schär, PhD^,, David E. Sosnovik, MD^||, Dara L. Kraitchman, VMD, PhD, Raymond C. Boston, PhD^¶, Jeff W.M. Bulte, PhD, Ralph Weissleder, MD, PhD^|| and Matthias Stuber, PhD

^_* Department of Cardiology, University of Heidelberg, Heidelberg, Germany
Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Department of Medicine, Cardiology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Philips Medical Systems, Cleveland, Ohio
^|| Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
^¶ School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania.

Manuscript received October 31, 2007; revised manuscript received February 12, 2008, accepted March 19, 2008.

^_* Reprint request and correspondence: Dr. Grigorios Korosoglou, University of Heidelberg, Department of Cardiology, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. (Email: grigorios_korosoglou{at}med.uni-heidelberg.de).

Objectives: This study was designed to identify macrophage-rich atherosclerotic plaque noninvasively by imaging the tissue uptake of long-circulating superparamagnetic nanoparticles with a positive contrast off-resonance imaging sequence (inversion recovery with ON-resonant water suppression [IRON]).

Background: The sudden rupture of macrophage-rich atherosclerotic plaques can trigger the formation of an occlusive thrombus in coronary vessels, resulting in acute myocardial infarction. Therefore, a noninvasive technique that can identify macrophage-rich plaques and thereby assist with risk stratification of patients with atherosclerosis would be of great potential clinical utility.

Methods: Experiments were conducted on a clinical 3-T magnetic resonance imaging (MRI) scanner in 7 heritable hyperlipidemic and 4 control rabbits. Monocrystalline iron-oxide nanoparticles (MION)-47 were administrated intravenously (2 doses of 250 µmol Fe/kg), and animals underwent serial IRON-MRI before injection of the nanoparticles and serially after 1, 3, and 6 days.

Results: After administration of MION-47, a striking signal enhancement was found in areas of plaque only in hyperlipidemic rabbits. The magnitude of enhancement on magnetic resonance images had a high correlation with the number of macrophages determined by histology (p < 0.001) and allowed for the detection of macrophage-rich plaque with high accuracy (area under the curve: 0.92, SE: 0.04, 95% confidence interval: 0.84 to 0.96, p < 0.001). No significant signal enhancement was measured in remote areas without plaque by histology and in control rabbits without atherosclerosis.

Conclusions: Using IRON-MRI in conjunction with superparamagnetic nanoparticles is a promising approach for the noninvasive evaluation of macrophage-rich, vulnerable plaques.

Key Words: atherosclerosis vulnerable plaque superparamagnetic nanoparticles molecular imaging inversion recovery with ON-resonant water suppression (IRON) positive contrast magnetic resonance imaging

Abbreviations and Acronyms   CNR = contrast-to-noise ratio   FA = flip angle   IRON = inversion recovery with ON-resonant water suppression   MION = monocrystalline iron-oxide nanoparticle   MRA = magnetic resonance angiography   MRI = magnetic resonance imaging   NER = normalized enhancement ratio   ROI = regions of interest   SNR = signal-to-noise ratio   TE = echo time   TR = repetition time

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