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Can Contrast-Enhanced Cardiac Magnetic Resonance Assess Inflammation of the Coronary Wall?^_*

Debiao Li, PhD^,_*, Zahi A. Fayad, PhD, David A. Bluemke, MD, PhD

Departments of Radiology and Biomedical Engineering, Northwestern University, Chicago, Illinois
Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, New York, New York
Radiology and Imaging Sciences, National Institutes of Health, Clinical Center, Bethesda, Maryland

Key Words: coronary arteries • atherosclerosis • cardiac magnetic resonance • inflammation • contrast-enhanced imaging

Inflammation plays a major role in various stages of atherosclerosis. Endothelial dysfunction and damage to the endothelium is believed to initiate the process of atherosclerosis by stimulating the migration and proliferation of smooth-muscle cells through the inflammatory response. Continued inflammation and accumulation of macrophages, T cells, and smooth-muscle cells and formation of fibrous tissue lead to advanced lesions covered by a protective fibrous cap that overlies a core of lipid and necrotic tissue (6). The destructive enzymes and cytokines produced by the inflammation at the core of the plaque could lead to the breakdown of the fibrous cap of the plaque, which allows flowing blood to be exposed to the thrombogenic lipid core and can precipitate acute blockage of the artery by clot, causing acute events such as myocardial infarction, stroke, or peripheral thrombus embolization (7).

Delayed-enhancement with contrast-enhanced CMR with nonspecific extracellular agents has been demonstrated in several inflammatory vessel wall diseases, such as giant cell arteritis (8) and Takayasu's arteritis (9), myocarditis (10), and atherosclerotic plaques. The CMR markers of plaque in the aorta and carotid arteries, including increased contrast-enhancement, were linked to elevated serum markers of inflammation in humans (11). Contrast-enhancement related to atherosclerotic plaques has been demonstrated in the carotid artery (12,13) and atherosclerotic abdominal aortic aneurysm (3). In the carotid artery, the signal increase was noted to occur most prominently in the fibrous cap rich in plaque neovascularization in histology (12). In the atherosclerotic abdominal aortic aneurysm, selective enhancement was also shown in the fibrous cap with a greater contrast-enhancement in patients with infiltration of inflammatory cells than those without inflammation (3). It is likely that inflammation causes increased water content in the arterial wall and thus increased accumulation of the gadolinium-based contrast agent. In the study by Kerwin et al. (14), strong associations between histologic markers of inflammation (macrophage, neovasculature, and loose matrix) and quantitative indices generated from dynamic contrast-enhanced CMR images in patients scheduled for carotid endarterectomy were observed. The results of this study also elucidate the pathways of plaque enhancement during gadolinium-enhanced CMR of the carotid arteries, including increased entry of contrast agent into the plaque measured by the amount of neovasculature within the plaque, increased delivery of the contrast agent into the extravascular extracellular space, and a combination of increased neovasculature supply and permeability. Macrophages were found to be the dominant mediator of plaque permeability.

Coronary artery plaque imaging presents considerable technical challenges to the CMR system. Coronary artery motion during the respiratory and cardiac cycles requires accurate motion compensation during data acquisition. The small size and tortuous courses of coronary arteries necessitate high-resolution imaging. Despite these challenges, Fayad et al. (15) demonstrated the significantly increased coronary artery wall thickness in patients with 40% stenosis as assessed by X-ray angiography as compared with normal subjects with a 2-dimensional black-blood method. Increased coronary wall thickness has been shown to correlate with increased numbers of risk factors for coronary artery disease (16).

Botnar et al. (17) developed a 3-dimensional spiral acquisition technique for coronary vessel wall imaging, which uses a local inversion method to suppress the luminal blood signal in order to clearly delineate the vessel wall. With this method, Kim et al. (18) detected positive arterial remodeling in patients with nonsignificant coronary artery disease. Recently, selective plaque visualization and differentiation of coronary plaque types were demonstrated in inversion-recovery prepared, contrast-enhanced CMR as confirmed by X-ray angiography and multidetector computed tomography (19,20).

In this issue of iJACC, Ibrahim et al. (21) performed serial contrast-enhanced CMR of coronary arteries in patients with acute myocardial infarction (AMI) at 2 different times after coronary intervention (stenting of the infarct-related artery). At baseline (6 days after intervention), patients demonstrated a significantly increased coronary vessel wall signal, compared with a control group that also received an intravenous administration of 0.2 mmol/kg gadolinium–diethylenetriaminepentaacetic acid. Coronary wall contrast enhancement also significantly correlated with the degree of lumen narrowing by X-ray angiography. At follow-up (3 months after intervention), the coronary vessel signal enhancement decreased significantly as compared with that measured at baseline, which seemed to parallel the decline in systemic inflammatory activity as measured by C-reactive protein. The authors conclude that, due to the short time period between the 2 studies, it is not likely that the significantly decreased coronary wall contrast enhancement observed at the follow-up study is caused by plaque volume regression but rather associated with the regression of systemic inflammation.

The aforementioned findings of contrast enhancement by CMR were not reported with respect to the site of the infarct-related artery but rather to a generalized assessment that included all proximal coronary vessel segments with >25% narrowing. Of note, 1 extracoronary vessel, the descending thoracic aorta, was also included, and it did not show enhancement.

Certain limitations exist with the study. The outcome variable was not strictly "enhancement" of the vessel, because no imaging was performed before gadolinium administration. A surrogate for enhancement was contrast-to-noise ratio (CNR) or simply how bright the artery appeared relative to the adjacent tissue. The authors reported higher CNR level in vessels with higher degrees of atherosclerotic narrowing. This is likely due simply to the greater plaque volume when the vessel is thicker. However, in paired analysis, the vessels showed lower CNR 3 months after infarction. This suggests resolution of "enhancement" over time. Unfortunately, the CMR technique is highly dependent on the choice of the inversion recovery time, introducing an element of uncertainty due to potential blood T1 changes during data acquisition. Further improvement in spatial resolution will reduce partial volume effects, potentially allowing direct visualization of the enhanced vessel wall. In addition, the timing of data acquisition after contrast administration needs to be optimized. Various delay times (30 min to 3 h) have been used for coronary wall imaging (19–21).

The mechanism of coronary wall enhancement is incompletely elucidated for the new observation in this work. The gadolinium-based contrast agent shows little specificity for tissue type or mechanism of enhancement. Various processes have been proposed for enhancing tissues on CMR, including increased distribution volume of water or electrostatic interaction of the contrast agent with various tissue components. Collagen/fibrosis, edema, inflammation, and tumors all show enhancement. The authors showed that C-reactive protein levels were high at the time of the infarction and diminished 3 months later, along with diminishing arterial enhancement. This is interesting but does not suggest a mechanism for selective enhancement of only coronary arteries and not thoracic aorta.

Although the mechanism of coronary enhancement is incompletely understood, the findings of this study suggest potential utility as a marker for disease. It would be of great interest if the observations of this study could be related to coronary inflammation that exists in the absence of an overt arterial infarction. Detection of small plaque components by CMR is likely to be improved after addition of a contrast agent that improves CNR. Certain plaque components of interest including the collagen cap uniquely show enhancement by CMR. With further development, the method used in this study might reveal a noninvasive marker in identifying plaque components, volume, or inflammation versus edema.

In summary, the authors should be congratulated for conducting the first study in humans to demonstrate the feasibility of gadolinium contrast-enhanced CMR for assessing serial changes in the coronary artery wall signal after myocardial infarction. Upon further improvement and validation, it is feasible that this or other related methods could prove useful for going beyond noninvasive coronary luminography to potentially allow identification of patients with active and potentially unstable coronary plaque who might benefit from more aggressive medical treatment or earlier intervention. It might also provide a valuable means for monitoring the effectiveness of novel therapies for coronary atherosclerosis.

	Footnotes

 
^_* Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.

^_* Reprint requests and correspondence: Dr. Debiao Li, Department of Radiology, Northwestern University, Suite 1600, 737 North Michigan Avenue, Chicago, Illinois 60611 (Email: d-li2{at}northwestern.edu).

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