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(Circulation. 1996;94:932-938.)
© 1996 American Heart Association, Inc.

Articles

Magnetic Resonance Images Lipid, Fibrous, Calcified, Hemorrhagic, and Thrombotic Components of Human Atherosclerosis In Vivo

Jean-Francois Toussaint, MD, PhD; Glenn M. LaMuraglia, MD, PhD; James F. Southern, MD, PhD; Valentin Fuster, MD, PhD; Howard L. Kantor, MD, PhD

Service de Cardiologie, Hopital Cochin, Paris, Service Hospitalier Frederic Joliot, CEA, Orsay, France (J-F.T.); the Cardiac Unit and NMR Center (J-F.T., H.L.K.), Division of Vascular Surgery (G.M.LaM.), and Pathology Department (J.F.S.), Massachusetts General Hospital, Boston; and the Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (V.F.).

Correspondence to J.F. Toussaint, MD, PhD, Service Hospitalier Frederic Joliot, Groupe de RMN, CEA, 4 Place du General Leclerc, 91401 Orsay, Cedex, France. E-mail toussain@uriens.shfj.cea.fr.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Although MRI can discriminate the lipid core from the collagenous cap of atherosclerotic lesions in vitro with T2 contrast, it has not yet produced detailed in vivo images of these human plaque components.

Methods and Results We imaged seven lesions from six patients who required surgical carotid endarterectomy and calculated T2 in vivo before surgery in various plaque regions. Using the same acquisition parameters, we repeated these measurements in vitro on the resected fragment and compared MR images with histology. T2 values calculated in vivo correlate with in vitro measurements for each plaque component; the in vitro discrimination we demonstrated previously with T2 contrast can therefore be performed similarly in vivo.

Conclusions MRI is the first noninvasive imaging technique that allows the discrimination of lipid cores, fibrous caps, calcifications, normal media, and adventitia in human atheromatous plaques in vivo. This technique also characterizes intraplaque hemorrhage and acute thrombosis. This result may support further investigations that include MRI of plaque progression, stabilization, and rupture in human atherosclerosis.

Key Words: magnetic resonance imaging • lipids • fibrous cap • thrombosis • carotid arteries

	Introduction

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Despite recent trends showing a reduction in the incidence of atherosclerosis, this disease remains the major cause of death in industrialized countries. However, although current technologies for studying the disease in vivo can provide long-term prognostic parameters, they do not help physicians to predict the evolution of a given lesion.¹ Our understanding of disease progression over decades (slow progression) and of the occurrence of acute events (rapid progression)² essentially relies on pathological studies.^{3 4 5} The most common decision-guiding technique used in the clinical field, x-ray angiography, fails to describe the heterogeneity of atheromatous arterial wall. Indeed, no imaging technique has permitted the in vivo discrimination of collagenous cap and atheromatous core, the two main components of atherosclerotic plaques thought to be essential to plaque stability^{6 7} and thrombogenicity.⁸ Their visualization may therefore improve our understanding of plaque susceptibility to rupture⁹ and their role in acute ischemic events¹⁰ or conversely in plaque stabilization.¹¹

MRI allows noninvasive tissue characterization by virtue of its dependence on biophysical and biochemical parameters such as chemical composition and concentration, molecular motion, diffusion, physical state, or water content. Previous investigations^{12 13} have demonstrated that MRI allows in vitro discrimination of wall components in normal and atheromatous arteries, including media, adventitia, perivascular fat, lipid-rich core, collagenous cap, and calcifications at high (9.4-T) and low (1.5-T) field strengths. Although various MR approaches have been used to image the lipid component,^{14 15 16} a robust description based on conventional parameters has been developed that has proved its ability to distinguish in vitro lipid-rich cores and collagenous caps in a single image by T2 contrast with a high contrast-to-noise ratio,¹³ even in early lesions.¹⁷ A recent study showed the usefulness of this technique in describing progression of experimental atherosclerosis and its ability to image in vivo plaque components such as fibrous caps, necrotic cores, and intraplaque hemorrhage resulting from balloon injury to the abdominal aorta in six cholesterol-fed rabbits.¹⁸

We undertook this investigation to compare T2 contrast in vivo and in vitro to apply these previous results to studies of human plaque structure in vivo. Using magnetic resonance at 1.5 T, we studied atherosclerotic lesions from patients requiring carotid endarterectomy and calculated the T2 of various plaque components in vivo before surgery and in vitro after surgery. By comparing both measurements and histology, we specifically tested the ability of MRI to discriminate collagenous caps and lipid cores in vivo.

	Methods

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Patients
We have used MRI to noninvasively image advanced lesions in carotid arteries from six consecutive patients (67±1.9 [mean±SD] years old) referred for endarterectomy. A total of seven lesions were studied (one patient had a severe stenosis of both internal carotid arteries). The decision to proceed with surgery was based on the presence of a severe carotid stenosis identified by ultrasound, which was confirmed by MR angiography or x-ray angiography. Three patients were asymptomatic: one had a recent series of near syncopal episodes, and two had recent transient ischemic attacks. Surgical endarterectomy by double Ender's spatula under systemic heparinization was performed <4 days after in vivo MRI. Informed consent was obtained from each patient before the in vivo MR study. This investigation was approved by the Massachusetts General Hospital Subcommittee on Human Studies.

In Vivo Images
The MR images of the arterial wall characterizing atherosclerosis were obtained from T1w and T2w SE sequences and CSI (with lipid suppression). We acquired in vivo images at 1.5 T on a standard system (Signa, General Electric Corp) with a General Electric–designed neck coil. MR angiography was first performed to determine lesion level and maximal extension. We used a time-of-flight gradient echo sequence (TE, 6 ms; TR, 40 ms; flip angle, 30°). Two-dimensional slices were generated from multiple 3D slabs with maximum-intensity projection. Plaque images were obtained through three successive data sets: (1) a scout of ungated sagittal 3-mm-thick SE slices, centered on the stenosed carotid (TR, 500 ms; TE, 12 ms; FOV, 25 cm; matrix, 256x128; one average); (2) a set of oblique coronal 3-mm-thick slices in the main direction of the stenosed vessel (TR, 1 cardiac cycle; TE, 23 ms; FOV, 16 cm; matrix, 256x192; one average) to align the next set; (3) axial oblique slices in a direction perpendicular to flow. The MR images of the arterial wall characterizing atherosclerosis were performed at the location of greatest stenosis of the common carotid and internal carotid arteries and at three levels on each side of the major stenosis location. T1w image parameters were as follows: TR, 500 ms; TE, 18 ms; FOV, 12 cm; matrix, 256x192; one average. Parameters of the ECG-gated T2w images allowed T2 determination from a double-echo sequence (TE, 20 and 55 ms; TR, 1 cardiac cycle; slice thickness, 5 mm; FOV, 10 cm; matrix, 256x256; two averages, with an in-plane resolution of 390 µm). Regions of interest for T2 calculation were defined from the MR images with a minimum of 10 pixels per analyzed region. A CSI image was also acquired at the level of the main stenosis by adding a lipid suppression pulse, with all other parameters kept equal.

In Vitro Images
After surgery, samples were immediately frozen at -60°C,¹³ except for two thrombosed arteries, which were imaged <2 hours after removal. Great care was taken to determine the effects of freezing and storage conditions. Soila et al¹⁹ demonstrated that relaxation constants of atheromatous plaques sampled during surgery were not altered over 6 days when samples were kept at 4°C in a sterile environment and rewarmed to 37°C before imaging. In a preliminary work, we compared two preservation methods¹³ : arteries were stored at 4°C and compared with arteries stored at -60°C. Both were similarly imaged at 37°C after 20 minutes of rewarming. T2 contrast was identical in both groups, suggesting that low-temperature storage did not alter the respective T2s once the samples were rewarmed for a sufficient time. We applied the same method for this study.

We identified vessel orientation by staining the superior and external sides with black ink, which does not modify the magnetic parameters of arterial wall. Samples were imaged in vitro within 24 hours of surgery after being placed in NMR tubes filled with saline to prevent dehydration; they were rewarmed and imaged at 37°C. Orientation planes and parameters were identical to those used for in vivo axial and longitudinal images (T1w image: TR, 500 ms; TE, 18 ms; T2w image: TE, 20 to 55 ms; TR, set equal to the respective patient cardiac cycle duration; slice thickness, 5 mm; FOV, 10 cm; matrix size, 256x256; two averages).

Histology
Arteries were cut every 5 mm at a level corresponding to each imaging plane in the magnet and step-sectioned every 200 µm. Sections were photographed. We stained the two slices adjacent to each section, using Masson's derived trichrome to stain collagenous regions and Sudan black for lipid core identification.¹³

Statistical Analysis
Data are expressed as mean±SD. In vivo measurements were compared by ANOVA with a significance level of 95%. Student's two-tailed paired t test was used to compare in vivo and in vitro T2s. A value of P<.05 was considered significant. Linear regression was used to correlate in vitro and in vivo measurements.

	Results

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T2 was measured in vivo and in vitro in successive wall regions shown by MRI from the lumen to the outer layer. These regions were subsequently characterized by histology as being fibrous cap, lipid core, media, and adventitia. On the seven T2w successive parallel axial MR slices, each patient had at least three short and three long T2 regions in which measurements could be compared with in vitro images and histology, resulting in a total of 18 to 24 T2 measurements for each component. The Table gives the results of these measurements. For each component (lipid core, collagenous cap, normal media, and normal adventitia), T2 calculated in vitro is close to its in vivo value. This is shown in the scatterplot of T2 calculations in Fig 1; similar relations are obtained for medial and adventitial T2s. A significant difference is demonstrated in vivo and in vitro between collagenous cap and lipid core, between normal media and lipid core, and between media and adventitia (see the Table).

View this table: [in this window] [in a new window]   Table 1. T2 Measurements of Lipid Core, Fibrous Cap, Media, and Adventitia as Characterized by Histology From In Vivo and In Vitro Images

View larger version (16K): [in this window] [in a new window]   Figure 1. In vivo and in vitro T2 data obtained from collagenous cap (, solid line; n=19) and lipid core measurements (, dotted line; n=18) with average values and SDs. With linear regression, T2s closely correlate in both fibrous caps (r2=.51, P<.001) and atheromatous cores (r2=.44, P=.002).

The ability of NMR to discriminate fibrous cap from lipid-rich core is illustrated in Fig 2, which characterizes a carotid lesion from a 65-year-old patient. Fig 2A and 2B shows the axial in vivo image of the left common carotid artery 12 mm below the level of maximum stenosis. The three layers of the lesion indicated by the white arrow (two bright layers with long T2 surrounding a layer with short T2) are similarly demonstrated in the in vitro image (Fig 2C). From lumen to adventitia, this result corresponds to a succession of collagenous cap, lipid core (black arrow), and media.¹³ With trichrome and Sudan black staining, histology (Fig 2D and 2E) shows the lipid infiltration in the central layer (arrows), corresponding to the central shortest T2 layer of the MR images. MRI characterizes adventitia in vivo by the black, thin layer surrounding vessels in T2w images; this result agrees with in vitro data showing a similar T2 contrast between media and adventitia.¹³

View larger version (678K): [in this window] [in a new window]   Figure 2. Lesion of the left common carotid artery from an asymptomatic patient. A and B (magnification of box in A), Transaxial in vivo image of the lesion (T2w, SE). From lumen (in black) to adventitia, three successive layers are defined: two long T2 layers (56.4 and 54.2 ms) with high signal intensity surround a short T2 region (32.1 ms; white arrow) with a lower signal. Adventitia is the black short T2 ring around the vessel. C, In vitro axial image with a similar description: two high-intensity layers (with T2=50.7 and 58.9 ms, respectively) surround a low-intensity region (with T2=28.5 ms; black arrow). Corresponding to the short T2 region, Masson's trichrome (D) and Sudan black (E) staining shows an infiltration of extracellular lipids in the atheromatous core (central region; arrowhead) delimited by a collagenous cap (C) on the luminal side (L) and media (M). A longitudinal dissection, which results from histological processing, is seen in the lipid core.

Fig 3 shows the lesion of a 66-year-old asymptomatic patient with severe stenosis involving the proximal right internal carotid artery. As expected from previous investigations,²⁰ the in vivo morphological measurements (9.4-mm length, 4.4-mm thickening in the outer wall, 3.1-mm thickening in the inner wall; Fig 3B) are similar to the in vitro measurements in Fig 3C (T1w, SE; 9.1-mm length, 4.5-mm outer wall, 2.1-mm inner wall) and to the histological evaluation. A calcification, shown as a signal void,^{13 21} is demonstrated in the lower part of the wall (white arrow, Fig 3B and 3C). On the axial sections (Fig 3D and 3E), two different regions appear. The double arrow shows a region with low T2 (29.4 ms). A more homogeneous layer with a T2 of 49.1 ms is present on the luminal side (arrowhead). The in vitro image (Fig 3F) demonstrates a similar pattern with two regions: a heterogeneous region with short T2 (31.3 ms) and calcifications, and the opposite side (C in Fig 3F), which is more homogeneous with higher intensity and longer T2 (52.7 ms). This distribution is consistent with a lipid-rich and calcified region encompassing the right side (double arrow) and a fibrous region on the left side (C in Fig 3F) of the artery.¹³ The microscopic appearance of this plaque (Fig 3G) demonstrates the presence of a white dense collagenous region (C in Fig 3G) over an atheromatous lipid core (A in Fig 3G) with calcified components. With lipid suppression, the CSI image of the same slice as in Fig 3D yields a contrast-to-noise ratio only slightly reduced in the lipid core (6.7 versus 7.5; 12% reduction) compared with nonfrequency selective images, whereas the contrast-to-noise ratio was reduced by 80% (5.7 versus 29.1) in subcutaneous fat. For the six patients, the reduction of contrast-to-noise ratio by CSI was 11.5±6.5% in the atheromatous core and 82.4±4.9% in subcutaneous fat.

View larger version (221K): [in this window] [in a new window]   Figure 3. Lesion of the right common carotid artery with severe stenosis involving the proximal internal carotid artery. A and B (magnified box in A), In vivo coronal section parallel to the main arterial axis (T1w, SE) allows measurement of plaque size and morphological parameters and reveals a calcification in the lower outer part of the wall (arrow). C, In vitro coronal section (T1w, SE) shows the same shape and calcification (arrow). D and E (magnified box in D), Perpendicular in vivo axial images showing a heterogeneous region (double arrow) with signal voids identified from the T1w (image not shown) surrounded by regions of low intensity (T2=29.4 ms). The region indicated by the arrowhead is more homogeneous with a higher signal (T2=49.1 ms). F, The in vitro image shows a similar pattern with two regions; the arrowhead indicates a region with low-intensity components (T2=31.3 ms) and calcifications. A higher signal intensity (C) is visible (T2=52.7 ms) around the lumen (L). G, Dissection microscopy discriminates the atherosclerotic core (A) with calcified components from the dense overlying fibrous cap (C); the plaque and the artery have been opened during surgery, explaining the large tear dissecting the cap.

Two patients had complex lesions with intraplaque hemorrhage. Fig 4 shows the MR angiography and MRI of the suboccluded left internal carotid artery of a 68-year-old asymptomatic patient. On the axial images, the plaque shows a striated pattern in its central part in vivo and in vitro (Fig 4F and 4G): on the luminal side is a long T2 layer (45.3 ms), whereas the black double arrow indicates a low-intensity layer with a T2 of 22.8 ms, shorter than mean lipid core value. Histology depicts an intraplaque hemorrhage corresponding to the deep short T2 layer. For the two hemorrhagic lesions, T2 in the central zone was 21.5±1.7 ms.

View larger version (426K): [in this window] [in a new window]   Figure 4. Subocclusion of the left internal carotid artery of an asymptomatic patient. A, Time-of-flight MR angiography demonstrates the site of subocclusion (arrow). B, In vivo coronal section (T1w, SE). C, In vivo magnified area (from box in B) shows an upper calcification (arrow). D, In vitro coronal section shows the calcification and better defines the lesion borders by eliminating the slow flow effects seen upstream of the lesion in the in vivo image. E, In vivo T2w axial section shows a striated pattern, with a superficial long T2 layer (45.3 ms) and a deeper short T2 layer (22.8 ms). F, In vivo magnified area (from box in E) shows the region with lower T2 (black double arrow). G, Same pattern from the in vitro T2w axial section, with a central short T2 layer (white double arrow) under a long T2 superficial region (arrowhead). H, Trichrome staining showing the intraplaque hemorrhage (arrow) corresponding to the deep short T2 layer under the fibrous cap (C) on the luminal side (L).

Two patients had large luminal thromboses. Fig 5 shows the subocclusive thrombus of the left common carotid artery of a 70-year-old patient. The patient was referred after recent transient ischemic attacks with a very severe stenosis on the early Doppler study, and alternating patency and occlusion was visible on successive ultrasound and x-ray angiography studies. Fig 5A shows a bright area at the site of occlusion. In this area, a long T2 region surrounds a superficial shorter T2 layer. The perioperative histological analysis revealed a fresh thrombus of the left bifurcation, upstream of a severe stenosis of the proximal internal carotid artery. Fig 5B shows the T2w in vitro image of this thrombus. Two layers are clearly distinguished: a shorter T2 region in the luminal superficial zone and a longer T2 region in the deeper layer. Histology shows the bilayer pattern with intact red cells in the most recent dark-red superficial layer (arrow) and elements of thrombus organization in the deep, older region.

View larger version (341K): [in this window] [in a new window]   Figure 5. Subocclusive thrombus of the left common carotid artery of a patient who suffered two recent transient ischemic attacks. A, In vivo axial section (T2w, SE). A high-intensity signal is shown in the center of this vessel. A component with lower signal intensity is present at the luminal side (arrow). B, T2w in vitro image of this thrombus showing two regions, with the shortest T2 (30.1 ms) in the superficial layer. C, Histology. The luminal layer (arrowhead) shows a large concentration of red cells, whereas the deeper layer shows membrane ghosts, fragments of erythrocytes, and fibrous elements corresponding to a process of thrombus organization (). L indicates the lumen.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this investigation, we discriminated atherosclerotic plaque components in vivo using ¹H-NMR imaging in a clinical imager with routinely available pulse sequences. Our data from seven carotid lesions demonstrate that the water resonance in lipid core has a short T2 in vivo, as has been shown in vitro.¹³ In the same study, we had also demonstrated that the major contributor to the MR signal in the atheromatous core is water and not lipid, with a ratio of 10/1. In vivo spectroscopic measurements have not yet confirmed the same property; however, the similitude of the lipid core T2s in vivo and in vitro shown here and the 6.5-times-poorer signal from atheromatous core lipids compared with subcutaneous fat (water CSI with lipid suppression) strongly suggest that the content of liquid lipids in the atheromatous core is as small in vivo as in vitro.¹³ The relative content of these lipids such as cholesteryl esters decreases further with stenosis severity,²² as solid cholesterol cleft content increases. Therefore, sequences with water as the principal signal source for atherosclerosis imaging benefit from a larger signal-to-noise ratio than techniques based on direct lipid analysis. Furthermore, such water proton sequences allow the simultaneous description of other major components such as fibrous cap, media, and adventitia.

With increasing acquisition speed, other methods that directly visualize atheromatous lipids (by use of diffusion-weighted sequences¹⁵ or long T2 suppression¹⁶ ) may help to define lipid-rich regions. Determination of the diffusion coefficient, which is decreased in atheromatous core,²³ may also enhance atherosclerosis characterization. However, these techniques have yet to be tested in vivo.

The T2 measurements we performed in this study substantially differ from our previous data, which showed larger values.¹³ However, these earlier results were obtained under different conditions: we used a long spectroscopic Hahn SE sequence with echo times ranging from 10 µs to 1000 ms, whereas in the present study we used two images with TEs of 20 and 55 ms. In a multiexponential relaxation system, the much longer echo times used in the Hahn SE sequence increase the relative contribution of the longest T2 species of each component and therefore lengthen the resulting relaxation constant.

We have used T1w images to identify calcifications. Calcified regions appear as low-intensity zones in all NMR sequences owing to low water content.^{21 24} The contrast-to-noise ratio for calcified regions compared with other components is higher in T1w than T2w images (see Fig 6 in Reference 13). Imaging calcification simultaneously with other components such as caps and cores, as demonstrated here, remains critical to a better understanding of their role in plaque aging,²⁵ stabilization,⁷ or arterial dysfunction.²⁶

Intraplaque Hemorrhage and Thrombosis
We have been able to identify intraplaque hemorrhage using methods similar to those reported in animal models.¹⁸ This result is also consistent with data from human myocardium²⁷ and experimental brain hemorrhage,²⁸ which demonstrated that the signal loss on T2w images is due to magnetic susceptibility of hemosiderin and ferritin, two iron-storing proteins present in macrophages. Such proteins and other degradation metabolites of hemoglobin in scavenger macrophages²⁹ may be involved in a similar way in human plaque hemorrhage¹⁸ and are responsible for the imaging susceptibility-induced pattern shown in Fig 4.

The two different components inside the thrombus shown in Fig 5 are consistent with in vivo data obtained in aortic thrombi.³⁰ The shorter T2 region of the luminal side corresponds to the most recent layer as shown by histology (Fig 5D); this layer has the largest content of intact red blood cells³¹ filled with iron-rich products from deoxyhemoglobin breakdown. These metabolites produce a large magnetic susceptibility effect and decrease T2.³² During later thrombus organization, they are degraded, internalized by macrophages,³¹ and replaced with fibrosis,³⁰ a process that diminishes the intensity of the susceptibility effect, as seen in the deeper layer with a longer T2.

Perspectives
MRI provides a unique method of discriminating the main components of human plaques in the carotid artery. Chemical shift imaging, along with diffusion, and dynamic studies³⁰ are likely to help further characterization of atherothrombosis in vivo. Technical improvements are aimed at obtaining high resolution, high signal-to-noise ratios, small FOVs, motion compensation, and 3D reconstruction of plaque structure in clinically available NMR systems.²¹ These may be provided by localized gradient coils,³³ specialized receiver coils,³⁴ high magnetic field strength, and improved in vivo NMR microscopy.³⁵

The capability to discriminate atheromatous components allows large-scale clinical studies of plaque progression, regression, and stabilization and their effect on clinical events. This could also improve our understanding of the slow evolution of atherosclerosis in the early decades of life and may provide a basis for screening young patients. Longitudinal studies of vascular interventional therapies may also benefit from these results.³⁶ The combination of MR angiography for luminal morphometry, 3D velocity mapping for the analysis of peristenotic blood flow streamlines,³⁷ and local vortices,³⁸ time-of-flight echo-planar MRI for the determination of flow reserve in terminal arteries,³⁹ perfusion measurement based on T1 changes,⁴⁰ and tissue characterization sequences may provide a complete description of the atherosclerotic process and its dynamic consequences. Finally, identification of intraplaque hemorrhage and acute thrombosis allows study of the cascade of events leading from plaque rupture to arterial thrombosis, acute ischemia, and infarction,⁴¹ which may provide newer methods for the prediction and prevention of these life-threatening events.

	Selected Abbreviations and Acronyms

 

3D = three-dimensional CSI = chemical shift imaging FOV = field of view SE = spin echo T1 = MR longitudinal relaxation constant T1w = T1 weighted T2 = MR transverse relaxation constant T2w T2 weighted TE = echo time TR = repetition time

	Acknowledgments

 
We gratefully acknowledge the support of the Harold M. English Fund from the Harvard Medical School, La Bourse Accelli de la Societe Francaise de Cardiologie, and Le Fonds d'Etudes et de Recherche du Corps Medical des Hopitaux de Paris. We thank Drs Erling Falk and Anne Leroy-Willig for very helpful discussions. We are grateful for the photographic assistance of Michele Forrestall and Steve Conley. We thank Tom Brady and the staff and members of the MGH-NMR Center for the use of the NMR systems and for beneficial discussions.

Received December 28, 1995; revision received February 26, 1996; accepted February 27, 1996.

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