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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.

^_* Reprint requests and correspondence: Dr. Subha V. Raman, Division of Cardiovascular Medicine, The Ohio State University, 473 West 12th Avenue, Suite 200, Columbus, Ohio 43210. (Email: Raman.1{at}osu.edu).

Objectives: We investigated the role of iron deposition in atherosclerotic plaque instability using a novel approach of in vivo plaque characterization by a noninvasive, noncontrast magnetic resonance-based T2* measurement. This approach was validated using ex vivo plaque analyses to establish that T2* accurately reflects intraplaque iron composition.

Background: Iron catalyzes free radical production, a key step for lipid peroxidation and atherosclerosis development. The parameter T2* measures tissue magnetic susceptibility, which historically has been used to quantify hepatic and myocardial iron. The T2* measurement has not been used for in vivo plaque characterization in patients with atherosclerosis.

Methods: Thirty-nine patients referred for carotid endarterectomy were prospectively enrolled to undergo preoperative carotid magnetic resonance imaging (MRI) and postoperative analysis of the explanted plaque. Clinical history of any symptoms attributable to each carotid lesion was recorded. We could not complete MRI in 4 subjects because of their claustrophobia, and 3 patients scanned before the institution of a neck stabilizer had motion artifact, precluding quantification.

Results: Symptomatic patients had significantly lower plaque T2* values (20.0 ± 1.8 ms) compared with asymptomatic patients (34.4 ± 2.7 ms, p < 0.001). Analytical methods demonstrated similar total iron (138.6 ± 36.5 µg/g vs. 165.8 ± 48.3 µg/g, p = NS) but less low molecular weight Fe(III) (7.3 ± 3.8 µg/g vs. 17.7 ± 4.0 µg/g, p < 0.05) in the explanted plaques of symptomatic versus asymptomatic patients, respectively, which is consistent with a shift in iron from Fe(III) to greater amounts of T2*-shortening forms of iron. Mass spectroscopy also showed significantly lower calcium (37.5 ± 10.8 mg/g vs. 123.6 ± 19.3 mg/g, p < 0.01) and greater copper (3.2 ± 0.5 µg/g vs. 1.7 ± 0.1 µg/g, p < 0.01) in plaques from symptomatic patients.

Conclusions: In vivo measurement of intraplaque T2* using MRI is feasible and distinguishes symptom-producing from non–symptom-producing plaques in patients with carotid artery atherosclerosis. Symptom-producing plaques demonstrated characteristic changes in iron forms by ex vivo analysis, supporting the dynamic presence of iron in the microenvironment of atherosclerotic plaque.

Abbreviations and Acronyms   EPR = electron paramagnetic resonance   ICP-MS = inductively coupled plasma mass spectroscopy   LDL = low-density lipoprotein   MRI = magnetic resonance imaging   PDW = proton density-weighted   TE = echo time   T1W = T1-weighted   T2W = T2-weighted

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