Seminal work by Yuan and colleagues established multi-contrast vessel wall MRI as a noninvasive technique for in vivo characterization of carotid plaque components 1-3, enabling longitudinal assessment of plaque pathophysiology and its relationship to clinical outcomes. Subsequent studies have shown that high-risk plaque features such as intraplaque hemorrhage (IPH), large lipid-rich necrotic core, and fibrous cap disruption provide information beyond luminal stenosis in predicting cerebrovascular events 4. In this issue of JMRI, the authors revisit an often-overlooked limitation within this framework by investigating whether hypointense regions on conventional multi-contrast MRI truly represent calcification, or whether they may instead reflect iron-related components, including isolated hemosiderin deposition, using quantitative susceptibility mapping (QSM) with histopathologic validation 5. Within the conventional multi-contrast MRI paradigm, calcification has long been defined as a component that appears hypointense across almost all sequences, including T1-weighted (native and contrast-enhanced), T2-weighted, proton density, and time-of-flight imaging 1, 4. However, iron-containing products of prior hemorrhage, particularly in chronic stages, may exhibit similar hypointense appearances across contrasts. This signal intensity overlap has important biological implications. Calcification has traditionally been regarded as a stabilizing feature 6; however, its association with plaque vulnerability is heterogeneous, as certain patterns such as superficial or fibrous cap–associated calcifications may increase local stress and contribute to rupture risk, whereas more dense or nodular calcifications may confer mechanical stability 7, 8. In contrast, IPH is consistently linked to plaque progression and increased ischemic risk 6, while the specific role of isolated hemosiderin deposition remains less well defined. Although both plaque components appear hypointense, their underlying mechanisms are fundamentally different. The calcification showing hypointense is primarily due to its low mobile proton density and extremely short T2/T2*, resulting in minimal signal generation. By contrast, hypointensity from prior hemorrhage arises from susceptibility effects: as hemorrhage evolves, iron is sequestered as hemosiderin, a paramagnetic compound that induces local magnetic field inhomogeneities and signal dephasing. Because of these fundamentally different magnetic properties, QSM offers a mechanism to distinguish them based on tissue magnetic susceptibility. Previous studies have demonstrated the feasibility of QSM for identifying hemorrhagic components and differentiating them from calcification in vivo 9, although these investigations have largely focused on IPH as a composite entity and have not specifically addressed isolated hemosiderin, also without direct histopathologic validation. Against this background, this study presents an ex vivo evaluation of QSM for differentiating calcification and hemosiderin in carotid plaques. Using formalin-fixed endarterectomy specimens embedded in agarose, the authors demonstrated that these components exhibit both hypointensity signal characteristics on conventional multi-contrast MRI with no significant difference (p = 0.12 for T1-weighted, p = 0.096 for T2-weighted, and p = 0.67 for FLASH imaging). However, QSM provides clear separation based on relative susceptibility values without overlap (hemosiderin 506.8 ± 320.5 vs. calcification −440.5 ± 296.3 ppb). These findings suggest that conventional signal intensity alone is insufficient for reliable discrimination for such, while QSM enables differentiation grounded in underlying magnetic properties. Importantly, these findings point toward a broader opportunity for more pathophysiologically meaningful plaque characterization. Quantitative MRI techniques such as T1, T2, and T2* mapping have been explored to improve reproducibility and component specificity 10. When combined with QSM, they may provide a more comprehensive framework for detailed, accurate, and robust plaque characterization, potentially complementing and refining, or even replacing the conventional multi-contrast MRI. In particular, the ability to identify isolated hemosiderin deposition, an underexplored component, may enable more detailed investigation of its relationship to ischemic risk and plaque evolution. In addition, the work also helps to understand better the role of calcification in plaque vulnerability by more accurate calcification identification. At the same time, several considerations should temper interpretation of these results. The study is performed under ex vivo conditions using formalin-fixed specimens, which allow high-resolution imaging and precise histologic correlation but do not fully reflect the constraints of in vivo imaging. QSM is inherently sensitive to motion, as it relies on phase information that can be disrupted by pulsatile flow and patient movement, potentially leading to artifacts and errors in susceptibility estimation. Combined with a lower signal-to-noise ratio and spatial resolution in clinical settings, these factors may reduce the robustness of susceptibility-based discrimination, particularly for small or spatially limited components such as isolated hemosiderin deposition. In addition, formalin fixation may alter the relaxation properties of tissue components, including calcification and hemosiderin, potentially affecting their signal characteristics and susceptibility measurements. As such, validation in fresh specimens and also in vivo validation may provide a more physiologically representative assessment of these contrasts and further strengthen the translational relevance of the findings. Optimizations on the sequence, reconstruction, or processing procedure, such as the use of cardiac gating or motion correction strategies, may be required to support reliable clinical implementation. From a practical perspective, the analysis in this study relies on histopathology-guided ROI delineation, which is appropriate for mechanistic validation but differs from clinical practice, where such ground truth is unavailable. Whether calcification and hemosiderin can be independently identified on imaging alone remains to be established. Future work should therefore focus on evaluating the diagnostic performance of QSM in realistic clinical scenarios, for example, by assessing whether radiologists can prospectively delineate plaque components using QSM, either alone or in combination with multi-contrast MRI. Similarly, optimization of QSM techniques dedicated to carotid vessel wall imaging will be important considerations for translation. In conclusion, this study highlights the potential of QSM to resolve a fundamental ambiguity in carotid plaque MRI by distinguishing calcification from iron-related components at the substrate level. While further validation is required, it represents an important step toward more specific and biologically grounded characterization of atherosclerotic disease.
Ning et al. (Thu,) studied this question.