We investigated iron's role in atherosclerosis and plaque instability with a novel approach to in vivo atherosclerotic plaque characterization using noninvasive, noncontrast magnetic resonance-based T2* measurement. We validated this approach using ex vivo plaque analyses to establish that T2* reflects intraplaque iron composition.
Iron catalyzes free radical production, a key step for lipid peroxidation and atherosclerosis development. The parameter T2* measures tissue magnetic susceptibility, historically has been used to quantify hepatic and myocardial iron. To date, T2* measurement has not been previously developed for in vivo plaque characterization in patients with atherosclerosis.
Thirty-nine patients referred for carotid endarterectomy were prospectively enrolled to undergo preoperative carotid MRI and postoperative analysis of the explanted plaque. Clinical history of any symptoms attributable to each carotid lesion was recorded.
MRI could not be completed in 4 subjects due to claustrophobia, and three patients scanned prior to the use of a neck stabilizer had motion artifact precluding quantification. In the remaining subjects, symptomatic compared to asymptomatic patients had significantly lower plaque T2* values (20.0±1.8 vs. 34.4±2.7 ms, respectively, p<0.001). Analytical methods demonstrated similar total iron (138.6±36.5 vs. 165.8±48.3 mg/kg, p=NS) but less low-molecular weight Fe(III) (7.3±3.8 vs. 17.7±4.0 nmol/mg, p<0.05) in the explanted plaques of symptomatic versus asymptomatic patients, respectively, consistent with a shift in iron from Fe(III) to higher amounts of T2*-shortening forms of iron. Mass spectroscopy also showed significantly lower calcium (37.5±10.8 vs. 123.6±19.3 g/kg, p<0.01) and higher copper (3.2±0.5 vs. 1.7±0.1 mg/kg, p<0.01) in plaques from symptomatic patients.
In vivo measurement of intraplaque T2* using MRI is feasible and reproducible, 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.