Quanti ﬁ cation of Lipid-Rich Core in Carotid Atherosclerosis Using Magnetic Resonance T 2 Mapping Relation to Clinical Presentation

OBJECTIVES The aim of this study was to: 1) provide tissue validation of quantitative T 2 mapping to measure plaque lipid content; and 2) investigate whether this technique could discern differences in plaque characteristics between symptom-related and non – symptom-related carotid plaques. BACKGROUND Noninvasive plaque lipid quanti ﬁ cation is appealing both for strati ﬁ cation in treatment selection and as a possible predictor of future plaque rupture. However, current cardiovascular magnetic resonance (CMR) methods are insensitive, require a coalesced mass of lipid core, and rely on multicontrast acquisition with contrast media and extensive post-processing. METHODS Patients scheduled for carotid endarterectomy were recruited for 3-T carotid CMR before surgery. Lipid area was derived from segmented T 2 maps and compared directly to plaque lipid de ﬁ ned by histology. RESULTS Lipid area (%) on T 2 mapping and histology showed excellent correlation, both by individual slices (R ¼ 0.85, p < 0.001) and plaque average (R ¼ 0.83, p < 0.001). Lipid area (%) on T 2 maps was signi ﬁ cantly higher in symptomatic compared with asymptomatic plaques (31.5 (cid:2) 3.7% vs. 15.8 (cid:2) 3.1%; p ¼ 0.005) despite similar degrees of carotid stenosis and only modest difference in plaque volume (128.0

L ipid accumulation in the subendothelial space, following deposition and retention of apolipoprotein B-containing plasma lipoproteins, is a key process in the initiation and progression of atherosclerosis (1). Studies of ex vivo tissue in coronary (2) and carotid (3)  Although intensive lipid-lowering therapy can reduce total carotid vessel wall area (5), direct evidence of lipid removal has been sparse (6). One particular challenge is that evacuated lipids tend to be replaced by fibrous tissue (7), so that changes in total vessel wall area might be small or indiscernible by conventional imaging. As a new generation of lipid-lowering agents emerges (8,9), tools for robust quantitative assessment of plaque composition may facilitate refinement and stratification for patient selection, and allow better monitoring of treatment response.
Multicontrast cardiovascular magnetic resonance (CMR) is an established technique in plaque characterization (10). However, optimal techniques for quantitative LRNC detection on multicontrast CMR require injection of contrast media (6,11), and rely on tissue contrast relative to the adjacent sternocleidomastoid muscle, which depends on specific system and acquisition parameters. Moreover, multicontrast CMR suffers from blurring artifacts due to fast spin echo acquisitions (12) and needs extensive postprocessing to coregister different contrast-weighted images and correct for image intensity variations (13).
We recently reported a quantitative CMR method to map T 2 relaxation times of plaque components on a voxel-by-voxel basis (14). Compared to multicontrast CMR, this novel approach is more objective, as it requires minimal user interaction in the analysis, and calculates real quantitative information on plaque composition. This raises the important possibility of in vivo plaque lipid quantification, at high resolution, across the entire plaque, and without the use of gadolinium-based contrast. In addition, plaque T 2 mapping addresses the need for an absolute physical parameter that can be standardized among different CMR systems and widely adopted in multicenter studies. Accordingly, here we sought: 1) to validate lipid quantification on carotid T 2 maps using histology gold standard; and 2) to evaluate its potential clinical application in relation to identifying recently unstable plaques.  and rated them from 1 (poor) to 5 (excellent) according to standard procedures (16). Patients with overall quality <3 were excluded from the study. T 2 maps of the carotid arteries were generated voxel by voxel using monoexponential nonlinear fitting (14); lumen and external vessel boundaries were segmented using a validated semiautomated procedure (17). As reported previously, LRNC without IPH had shorter T 2 than normal vessel wall and fibrous tissue, whereas with recent IPH into the core, T 2 was longer than all other plaque components (14). Therefore, to take into account the minority of plaques with recent hemorrhage into the core, segmentation used dual T 2 thresholds, a lower one (T 2L ) indicating the maximum T 2 value associated with lipid alone and a higher one (T 2H ) above which IPH was recorded inside the plaque    Leave-1-out cross-validation was performed on the slice-by-slice dataset of independent lipid area measurements from T 2 maps and histology.

RESULTS
PATIENT CHARACTERISTICS. CMR scan quality $3 was achieved for 26 of 40 plaques, 15 symptomatic and 11 asymptomatic. Patient characteristics are summarized in Table 1. There was no significant difference between genders, major cardiovascular risk factors or medications on admission between groups.
AHA CLASSIFICATION. Figure 1 shows how different plaque components can be identified on T 2 maps. To evaluate how accurately T 2 mapping can determine plaque types, we used the modified AHA plaque classification system and compared this directly against histological classification. Table 2 shows plaque types determined by T 2 map (þ TOF) against histology, which showed good agreement (80.8%) between the 2 methods (Cohen's k ¼ 0.73).   mapping has a good ability to discriminate between symptomatic and asymptomatic plaques in our clinical cohorts. ROC analysis determined the optimal cutoff for LRNC between clinical cohorts to be w25% (sensitivity ¼ 67%, specificity ¼ 91%) ( Figure 5C).

INTRAPLAQUE HEMORRHAGE.
To clarify whether the inclusion of IPH in our calculation with a second T 2 threshold had influenced our results, we examined the prevalence of IPH and its contribution to the total lipid area (%). Sixteen of the total 60 slices contained significant (>5%) IPH. Of these, only 7 had IPH infiltrating >50% of the lipid core. Thus IPH made a relatively minor contribution to the total lipid measurement. Figure 6 shows the copresence of IPH and lipid-filled macrophage foam cells. We then rean-      (32) and has been shown to increase risk of stroke following carotid stenting (32,33). Threedimensional rendering of lipid distribution in relation to local vessel anatomy using quantitative T 2 mapping data may assist interventional procedural planning to minimize such risks ( Figure 2, right panels).
STUDY LIMITATIONS. The main limitation of our method is the sensitivity to motion artifacts, a fact reflected in the scan rejection rate (35%), which is comparable to that of multicontrast CMR (30%) (11).
Strategies for motion correction are currently being actively pursued. Another limitation is the challenge to measure IPH independently, mainly because of the tendency for hemorrhage to be mixed with LRNC.
Moreover, as IPH ages and organizes, not only do its magnetic resonance properties change (16), but also its histological appearance, as organization replaces fibrin with a more collagen-like extracellular matrix structure (34). We therefore analyzed our data using 2