In Vivo Atherosclerotic Plaque Characterization Using Magnetic Susceptibility Distinguishes Symptom-Producing Plaques
Subha V. Raman, MD, MS, FACC*,*,
Marshall W. Winner, III, MD*,
Tam Tran, BS*,
Murugesan Velayutham, PhD*,
Orlando P. Simonetti, PhD*,
Peter B. Baker, MD ,
John Olesik, PhD ,
Beth McCarthy, RT*,
Amy K. Ferketich, PhD ,
Jay L. Zweier, MD, FACC*
* Davis Heart and Lung Research Institute and Heart Center, The Ohio State University, Columbus, Ohio
Department of Pathology, The Ohio State University, Columbus, Ohio
School of Earth Sciences, The Ohio State University, Columbus, Ohio
School of Biostatistics, The Ohio State University, Columbus, Ohio.
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Figure 1 LDL Peroxidation Catalyzed by Iron
The Haber-Weiss reaction and Fenton chemistry use iron in generating free radicals that oxidize low-density lipoprotein (LDL). Microhemorrhage into atherosclerotic plaque with macrophage-mediated phagocytosis and degradation of aged red blood cells leads to accumulation of redox-active iron. Oxidized LDL binds the macrophage scavenger-receptor, leading to unregulated uptake, foam cell formation, and accelerated atherogenesis.
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Figure 2 T2*-Weighted Imaging and Intraplaque T2* Measurement
Serial T2*-weighted dark blood images at various echo times (A, echo time [TE] 2.7 ms; B, TE 7.6 ms; C, TE 12.5 ms; D, TE 17.4 ms) obtained at the location of maximum stenosis allow drawing of a region of interest (D) on all the images encompassing the plaque for measurement of mean T2* within the plaque. See the text for T2* imaging scan parameters. (E) T2* is measured in a given plaque by fitting the measured signal intensities at each TE to an exponential decay curve e–TE/T2*. ECA = external carotid artery; ICA = internal carotid artery; J = internal jugular vein; VA = vertebral artery.
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Figure 3 Intraplaque T2* by Symptom Status
(A) Plot of in vivo magnetic resonance-derived T2* values of carotid artery plaque in asymptomatic versus symptomatic patients shows shorter T2* times in symptomatic patients. Mean ± SD is shown. (B) Bland-Altman analysis shows good agreement of carotid T2* measurement between independent observers (r = 0.88).
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Figure 4 EPR Spectroscopy Detection of Iron in Carotid Plaques
Electron paramagnetic resonance (EPR) is a powerful and minimally invasive technique to identify and quantify the presence of paramagnetic ferric iron [Fe(III)] within an explanted carotid specimen. The EPR spectra were recorded on frozen tissue at 77 K. For further experimental details and spectrometer settings, see the Methods section. Representative EPR spectra from control carotid artery (A), asymptomatic patient’s carotid plaque (B), and symptomatic patient’s carotid plaque (C) are shown. Atherosclerotic plaque samples demonstrate the high-spin rhombic iron species peak at a magnetic field of  1,500 Gauss, corresponding to a g value of 4.3. Although no rhombic iron signal was observed in control carotid tissue, a prominent signal was present in asymptomatic patients’ carotid plaques; however, in symptomatic patients’ plaques, the level of this signal was significantly decreased.
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Figure 5 Plaque Histopathology
(Left) Histopathological section with Prussian blue staining at low and high (inset) magnifications demonstrates iron deposits in plaque. (Middle) Staining for glycophorin A shows evidence of red blood cell membrane fragments within plaque. (Right) Staining for Factor VIII demonstrates neovascularization in the plaque neointima.
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Figure 6 Model of Hypothesized Mechanism Underlying Observed Results
Although our work demonstrated similar total iron in symptom-producing versus non–symptom-producing carotid plaques, the former group had less paramagnetic iron by EPR and greater T2*-shortening iron species. This difference suggests a shift from paramagnetic Fe(III) to iron aggregates that have a greater effect on local magnetic susceptibility, measurable using the tissue-specific magnetic resonance imaging relaxation time T2*. Abbreviations as in Figure 4.
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