JOURNAL OF MAGNETIC RESONANCE IMAGING 41:1190–1202 (2015)

Review Article

Coronary Artery Wall Imaging Jennifer Keegan, PhD* Like X-Ray contrast angiography, MR coronary angiograms show the vessel lumens rather than the vessels themselves. Consequently, outward remodeling of the vessel wall, which occurs in subclinical coronary disease before luminal narrowing, cannot be seen. The current gold standard for assessing the coronary vessel wall is intravascular ultrasound, and more recently, optical coherence tomography, both of which are invasive and use ionizing radiation. A noninvasive, low-risk technique for assessing the vessel wall would be beneficial to cardiologists interested in the early detection of preclinical disease and for the safe monitoring of the progression or regression of disease in longitudinal studies. In this review article, the current state of the art in MR coronary vessel wall imaging is discussed, together with validation studies and recent developments. Key Words: coronary vessel wall; magnetic resonance; review J. Magn. Reson. Imaging 2015;41:1190–1202. C 2014 Wiley Periodicals, Inc. V

LIKE COMPUTED TOMOGRAPHY (CT) angiography and invasive X-ray contrast coronary angiography, magnetic resonance coronary angiography (MRCA) shows the vessel lumens. A recent multicenter study has shown that whole heart MRCA is able to detect significant coronary artery disease (CAD) with a high sensitivity (88%) and moderate specificity (72%) (1). This result was achieved at 1.5 Tesla (T) using a three-dimensional (3D) balanced steady state free precession imaging sequence with radial k-space sampling. Signal from surrounding epicardial fat was eliminated and imaging was performed in a patient specific acquisition window to minimize the effects of cardiac motion. T2-preparation was implemented to reduce the signal from myocardium and respiratory motion was reduced by using diaphragmatic navigator gating. The study reported a high negative predictive value (88%) suggesting that MRCA can effectively be

Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, London. *Address reprint requests to: J.K., Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP. E-mail: [email protected] Received June 9, 2014; Accepted August 6, 2014. DOI 10.1002/jmri.24766 View this article online at wileyonlinelibrary.com. C 2014 Wiley Periodicals, Inc. V

used to rule out significant disease in patients with a low pretest probability of disease (2). Atherosclerosis, however, is a disease of the vessel wall that starts with endothelial dysfunction and with outward remodeling of the vessel wall, and does not result in a reduction in vessel lumen diameter until the disease is relatively advanced (3). Landmark X-ray coronary angiography studies have shown that in the majority of cases, the lesion responsible for myocardial infarction—the culprit lesion—reduces the lumen diameter by 70%) to 2.5% (for plaque burden 60– 70%) and to 0% (for plaque burden < 40%). Imaging the vessel wall then, rather than the lumen, is important as it enables the study of clinically important disease before it becomes angiographically significant. The gold standard for assessing the coronary vessel wall is intravascular ultrasound (IVUS) (9). For assessing the thin fibrous cap, which is an important feature of vulnerable and culprit plaques, optical coherence tomography (OCT) is the technique of choice (10). The latter has superb spatial resolution (15 mm) although tissue penetration is poor and it requires the removal of red blood cells from the field of view (using a saline injection for example) before imaging. Both techniques are invasive and require placement of probes in the vessel of interest under Xray fluoroscopy. A noninvasive alternative which has been used with some success in selected patient groups is CT angiography (11), although this is limited by the presence of coronary calcification and by radiation dose which precludes its use for monitoring disease progression or regression. A noninvasive

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Figure 1. Timing of components of a typical coronary vessel wall imaging sequence. Following a gating delay, a black blood preparation is output and imaging is performed after a delay which ensures that blood flowing into the imaging slice is nulled. The imaging is usually performed with a turbo spin echo (TSE), gradient echo (GRE) or balanced steady state free precession sequence and the k-space coverage may be Cartesian, radial or spiral. Fat suppression is required for the vessel to be seen with good contrast. For free-breathing studies, a diaphragmatic navigator (and a navigator restore pulse) is typically used. The black blood preparation may be replaced by an inversion recovery preparation for both contrast enhanced and noncontrast enhanced T1 weighted studies. A chest wall saturation band may be additionally implemented to reduce residual respiratory motion artifact.

technique which does not require the use of ionizing radiation would allow serial investigation of disease and response to drug therapy and potentially allow the use of surrogate endpoints in drug studies which would aid faster and more efficacious drug development. In this review article, MRI of the coronary vessel wall is investigated. The technical difficulties and the imaging sequences used are discussed together with the results of current studies. The use of conventional contrast agents is also discussed and novel technical developments are reported.

MR CORONARY VESSEL WALL IMAGING There has been considerable progress over the last two decades in MR imaging of carotid and aortic wall morphology and composition (12,13). Imaging the coronary vessel wall however is more difficult as the vessels are smaller, more tortuous and considerably more mobile. Sequence and Technique Development Autopsy studies in subjects who did not die of CAD have shown that the coronary vessel wall is typically 0.4–0.8 mm thick (14) so a high spatial resolution technique is required. The tortuous pathways of the vessels are such that orienting the image plane so that the vessel runs either in-plane or through-plane is difficult and imaging is further complicated by the fact that the vessels move with both the cardiac and respiratory cycles. In addition, to see the vessel wall clearly, signal from surrounding epicardial fat and from blood in the vessel lumen must be eliminated. The thinness of the vessel walls means that coronary vessel wall imaging requires higher spatial

resolution than MRCA and more stringent motion control. Eliminating the signal from epicardial fat is required by both techniques, as is imaging in a subject-specific window and the application of methods to reduce respiratory motion. However, while MRCA uses T2-preparation, for coronary vessel wall imaging, blood suppression techniques are essential. These generally rely on the inflow of saturated blood between magnetization preparation and imaging which precludes whole heart imaging. The sequence components for coronary vessel wall imaging are outlined in Figure 1. Following a gating delay, a black blood preparation is output and imaging is performed after a delay which ensures that the longitudinal magnetization of blood flowing into the imaging slice is passing through the null point. The imaging is usually performed with a 2D or targeted 3D turbo spin echo (TSE), gradient echo (GRE), or balanced steady state free precession sequence and the k-space coverage may be Cartesian, radial, or spiral. Fat suppression is required for the vessel to be seen with good contrast. For free-breathing studies, a diaphragmatic navigator (and a navigator restore pulse) is typically used and a chest wall saturation band may be additionally implemented to reduce residual respiratory motion artifact. The black blood preparation may be replaced by an inversion recovery preparation for both contrast enhanced and non contrast enhanced T1 weighted studies. Unlike MRCA, coronary vessel wall imaging is generally performed with alternate R-wave gating to allow sufficient longitudinal magnetization recovery between black blood preparation or inversion preparation pulses. Alternate Rwave gating increases signal-to-noise ratio (SNR) and reduces sequence sensitivity to heart rate variations. The first MR coronary vessel wall images (15) were acquired with a breathhold 2D black-blood prepared

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Figure 2. A: X-ray angiogram from 76-year-old male patient shows high-grade stenosis in proximal left anterior descending artery (arrows). B: In vivo cross-sectional black-blood MR images of left anterior descending artery lumen shows obstructed lumen (elliptical shape). C: The wall image shows a large eccentric plaque with heterogeneous signal intensity (maximum thickness 5.73 mm). (LV ¼ left ventricle, RV ¼ right ventricle, RVOT ¼ right ventricular outflow tract.) Reproduced with permission from Fayad et al (15).

TSE sequence (Fig. 2) and showed that patients with >40% diameter-reducing stenoses have localized wall thicknesses which are significantly greater than those in healthy subjects. Using a breathhold acquisition, the SNR and spatial resolution are limited by the need to complete the acquisition in a comfortable

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breathhold period. Alternatively, a navigator-gated free-breathing approach has been developed which allows multiple averages to be acquired to increase SNR and shows similarly increased wall thickness in patients with CAD (16). Removing the constraints on acquisition duration by using navigator gating not only allows more flexible setting of the acquisition parameters, but also allows the acquisition of a 3D volume which has the advantage of thinner slices and reduced partial volume effects (Fig. 3). This was first achieved using a blackblood prepared spiral imaging technique (17), which is more efficient than Cartesian imaging, and additionally enabled the acquisition of in-plane images showing the length of the coronary of interest in a single acquisition. The acquisition of 2 spiral interleaves in each cardiac cycle with alternate R-wave gating was achieved in a short subject-specific diastolic window of 60 ms and allowed the acquisition of 10 crosssectional images (0.7 mm  0.7 mm) of 2 mm thickness (after zero-filling) or 20 in-plane images (0.8 mm  0.8 mm) of 1 mm thickness (after zero-filling) in 6–9 min and 14–18 min, respectively. Black-blood preparation (18) was performed using a localized selective re-inversion which excited a carefully positioned column of material and achieved good blood signal suppression for the thicker 3D slab acquisitions regardless of image plane orientation. 3D coronary vessel wall imaging has also been performed using a navigator-gated black-blood prepared radial technique (19) which resulted in fewer motion artifacts and improved SNR and CNR compared with Cartesian imaging. This technique has also been used to show increased wall thickness in patients with angiographically proven CAD compared with asymptomatic subjects (20).

Figure 3. a–f: A 3D dataset of a cross-sectional right coronary artery wall scan. In all slices, the wall of the RCA is well defined with good contrast between wall, blood, and epicardial fat. The reconstructed slice thickness (zero-filled) was 2 mm with an in-plane spatial resolution of 0.7  0.7 mm. (RCA ¼ right coronary artery, RV ¼ right ventricle). Reproduced with permission from Botnar et al (17).

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0.06 mm 6 0.12 mm (ICC ¼ 0.70) and 0.01 6 0.10 mm (ICC ¼ 0.87) respectively (23). Validation of MR Coronary Vessel Wall Thickness Measurements

Figure 4. a–c: 3D black-blood right coronary artery vessel wall images acquired  1 month apart demonstrating excellent visual reproducibility (a,b) and Bland-Altman plot of the difference in wall thickness measurements in two studies against the mean (c). Reproduced with permission from Desai et al (21).

Reproducibility of MR Coronary Vessel Wall Thickness Measurements Example in-plane images acquired in two separate scanning sessions with a navigator-gated local re-inversion black-blood prepared 3D spiral acquisition are shown in Figure 4 together with a BlandAltman analysis of inter-study reproducibility of wall thickness measurements (21). Images (acquired spatial resolution 0.8  0.8  2 mm3, acquisition window 59 ms) showed excellent visual reproducibility and a high intraclass correlation coefficient (ICC ¼ 0.86) suggesting that this technique may be suited to longitudinal studies of coronary atherosclerosis. The interstudy reproducibility (mean 6 standard deviation of the signed differences) of wall thickness measurements made from breathhold black-blood prepared 2D cross-sectional TSE images (acquired spatial resolution 0.7  0.6  3 mm3) in healthy volunteers is 0.02 mm 6 0.20 mm (22). Similarly, the healthy subject inter-study reproducibility of navigator-gated black-blood prepared 2D TSE imaging is 0.06 mm 6 0.14 mm (ICC ¼ 0.72) while in the same group, the interstudy reproducibilities of navigatorgated 2D black-blood prepared spiral data (acquired spatial resolution 0.7  0.7  6 mm3, acquisition window 43 ms) and navigator-gated black-blood prepared 3D spiral data (acquired spatial resolution 0.7  0.7  3 mm3, acquisition window 35 ms) are

There are currently only two studies in the literature which have made a direct comparison between MR wall thickness measurements with invasively obtained IVUS measurements. In the first of these, He et al (24) showed that matched MR and IVUS slices showed good correlation for outer vessel area, luminal cross sectional area and plaque burden (wall area as a percentage of outer vessel area) at sites containing plaque (Fig. 5). This study was performed with navigator-gated black-blood prepared 2D cross-sectional TSE imaging with an acquired spatial resolution of 1  1  5 mm3 and an acquisition window of 79 ms. In the second study, Gerretsen et al performed in-plane imaging of the right coronary artery vessel wall in 17 patients with chest pain with both IVUS and a navigator-gated black-blood prepared 3D radial sequence (25). The acquired spatial resolution was 0.8  0.8  3 mm3 and the typical MR acquisition duration was 19.2 mins. An example study is shown in Figure 6. In matched segments of arteries, MRI identified 29% as normal (compared with 33% with IVUS) and 71% as diseased (compared with 67% with IVUS), resulting in a sensitivity of 94% and a specificity of 76%. However, a direct comparison between MR and IVUS measures of wall thickness resulted in a low correlation coefficient (0.41), most likely due to partial volume averaging or possibly, due to imperfect respiratory motion compensation over the very long acquisition durations, and the authors conclude that in-plane vessel wall imaging is not recommended for absolute vessel wall thickness measurements. Imaging Subclinical Disease Outward Remodeling of the Vessel Wall The first demonstration of outward remodeling of the coronary vessel wall in patients with nonsignificant CAD was made using in-plane imaging with the 3D spiral technique (Fig. 7a) (26). In this study, 6 patients with angiographically nonsignificant CAD were compared with 6 healthy volunteers and showed thickened vessel walls, despite vessel lumen diameters being the same (Figs. 7b and c). Regression of outward remodelling of the vessel wall in 22 patients with acute coronary syndromes following 6 months of medical therapy has been demonstrated using serial breathhold black-blood prepared crosssectional 2D TSE imaging (27). Outward remodeling of the vessel wall has also been investigated in 179 subjects in the MESA (Multi-Ethnic Study of Atherosclerosis) (28) and in 223 subjects in the ADVANCE study (atherosclerotic disease, vascular function, and genetic epidemiology) study (29). For the MESA study, cross-sectional images were acquired using a navigator-gated black-blood prepared 2D TSE

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Figure 5. a: Contiguous cross-sectional MR coronary vessel wall images in a patient with an eccentric coronary plaque (arrow) (top), corresponding IVUS images (middle and bottom). b: Scatter plot of MRI measured plaque burden against IVUS plaque burden at sites containing plaque. Reproduced with permission from Wiley (24).

sequence (acquired spatial resolution 0.8  0.8  5 mm3, acquisition window 70–100 ms). For the ADVANCE study, cross-sectional images of the proximal RCA were acquired using a 20 cardiac cycle breathhold black-blood prepared 2D spiral sequence (acquired spatial resolution 0.7  0.7  5 mm3, acquisition window 34 ms). In the ADVANCE study, suppression of signal from surrounding epicardial fat was achieved with a spectral-spatial excitation for water selective imaging while in the MESA study, it was achieved with an asymmetric adiabatic spectral inversion recovery pulse. Both studies showed results consistent with outward remodeling of the vessel wall by plotting the lumen and outer vessel areas against wall thickness and showing that while the lumen area showed little increase, the rate of increase of the outer vessel area was much greater (Fig. 8).

Subclinical disease has also been demonstrated in 63 patients with type 1 diabetes and nephropathy compared with 73 patients with type 1 diabetes and normoalbuminaria. In this study, using navigatorgated 3D black-blood prepared spiral imaging, the mean and maximal wall thicknesses were significantly increased in the patients with nephropathy (30). In asymptomatic older subjects in the ADVANCE study, increased wall area and wall thickness are associated with type II diabetes and with a positive coronary artery calcium score (29), while looking specifically at those younger asymptomatic subjects in the MESA study who had a zero coronary calcium score, the mean and maximum vessel wall thicknesses were shown to be related to the number of risk factors for coronary artery disease. A recent study in a small cohort of healthy volunteers using black-blood prepared 3D spiral imaging

Figure 6. Left: A 61-year-old female patient with stable angina. A,B: X-ray angiography (a) and coronary MRA (b) demonstrate high grade stenosis in the proximal RCA. C: Corresponding MR vessel wall image demonstrates several areas with vessel wall thickening and high signal intensity. D–H: Distal RCA (E), diseased area (F), and proximal RCA (G) are crosssectional IVUS images and refer to the corresponding areas as shown on the stretched multiplanar reformation (MPR) of the vessel wall (D) and the longitudinal IVUS reformat (H). Panel F is the area of maximum stenosis. Right: plot of mean wall thickness by MR against mean wall thickness by IVUS. Reproduced with permission from Gerretsen et al (25).

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Coronary Plaque Imaging The goal of MR imaging of the coronary vessel wall is to detect atherosclerotic plaque and ultimately, to differentiate plaque components so that “vulnerable” or “high-risk” plaques may be identified. These plaques tend to have a large lipid core and a thin fibrous cap which is typically highly inflamed and prone to rupture, leading to acute coronary syndromes (3,32). MR coronary plaque imaging has been performed with both noncontrast and contrast techniques. Noncontrast Imaging Methemoglobin which is present in acute thrombus and intraplaque hemorrhage has a short T1 and may be visualised using a T1-weighted black-blood technique, as first demonstrated by Maintz et al (33). This noncontrast approach has been used to image intracoronary thrombus in patients with acute myocardial infarction who were scanned within 72 h of symptom onset, the coronary thrombus being detected with a specificity of 88% and a sensitivity of 91% (34). A study of patients with angina pectoris which used OCT as the gold standard also showed that high intensity plaques (HIPs) on noncontrast enhanced T1weighted imaging were associated with intracoronary thrombus (35). A comprehensive study comparing HIPs with the results of IVUS and multislice CT has shown that they are typically associated with features of vulnerable plaques such as ultrasound attenuation, positive remodeling, low CT density and a high incidence of slow-flow phenomena following percutaneous coronary intervention (36). A recent prospective study on 568 patients with suspected or known CAD has shown that HIPs are a strong independent predictor of future coronary events (Table 1) (37). An example is shown in Figure 9 alongside a bar chart showing the event rate for all coronary events in this study in a median follow up period of 55 months as a function of plaque-myocardium ratio of signal intensities.

Figure 7. a: X-ray angiogram (left) in a patient with minor luminal irregularities (white arrows). The corresponding 3D coronary vessel wall image (right) shows an irregularly thickened wall (>2 mm, dotted arrows) indicative of an increased atherosclerotic plaque burden. b,c: Average vessel wall thickness (b) and luminal diameter (c) in patients versus healthy subjects. Reproduced with permission from Kim et al (26).

and a highly efficient image based method of respiratory motion compensation has also shown increasing coronary wall thickness with age (31). This is possibly a precursor of atherosclerosis or it may be part of the normal aging process, or these may be one and the same thing, but the rate of increase in wall thickness observed (0.09 mm per decade) is similar to that observed in autopsy studies.

Figure 8. Coronary wall thickness compared with both vessel area (solid squares, solid line) and lumen area (open circles, dashed line) by linear regression, showing significant positive correlation for vessel area but no significant change in lumen area, consistent with positive remodeling. Reproduced from Terashima et al (29).

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Table 1 Best Predictive Model Selected by Stepwise Cox Regression Analysis of Risk Factors for All Coronary Events* Multivariate Analysis Variable

Hazard Ratio

p Value

95% CI

Age Male HbA1c Proven CAD PMR 1.4

1.04 2.61 1.04 3.56 3.96

0.023 0.071 0.018 85 beats per min being excluded from the study. As discussed previously, spiral k-space coverage is more time-efficient than Cartesian imaging and allows imaging with a short acquisition window without greatly prolonging acquisition duration. Alternatively, Lin et al (51) have exploited the greater time efficiency of balanced steady state free precession (bSSFP) imaging compared with TSE imaging and shown that in healthy subjects with fast heart rates (> 80 beats per min), the image quality of bSSFP is superior. In a comparative study, the acquisition of a fixed number of k-space lines per cardiac cycle resulted in an acquisition window of 57 ms for the bSSFP sequence (compared with 93 ms for the TSE sequence) which fitted more easily into the subject-specific coronary rest period at fast heart rates. A further bSSFP feasibility study was carried out in heart transplant patients who have a rapid

heart rate due to de-enervation, or subnormal reenervation of the donor heart (52). The stability of the breathing pattern affects image quality with minimal diaphragm drift and high navigator efficiency resulting in high image quality (48). The effects of respiratory motion and spatial resolution have been investigated through numerical simulations of the Bloch equations and phantom acquisitions (53). These showed that vessel wall thickness and area were increasingly over-estimated as spatial resolution decreased, while vessel wall lumen area was increasingly underestimated. A resolution of four pixels across the vessel wall resulted in a wall area overestimation of 20%. In addition to cardiac motion, respiratory motion, spatial resolution and patient characteristics, image quality is also affected by the quality of black-blood suppression which is generally achieved using a double inversion black-blood preparation. This relies on imaging at the null time of inverted blood flowing into the imaging slice, which is both heart rate and T1 specific, and also relies on adequate blood flow between magnetization preparation and imaging. Using this technique, the signal from slow flowing blood may therefore be inadequately suppressed and result in an apparently larger wall thickness and plaque burden.

Recent Developments Multiphase Acquisitions All coronary vessel wall imaging techniques discussed so far acquire data at a single time-point in the cardiac cycle with the exact timing of the data acquisition being determined on a subject-specific basis so as to minimize cardiac motion within the acquisition window. This stringent requirement is mitigated in a recently developed multiphase technique which acquires four or five images at different times after the dark blood preparation and which enables the user to select the optimal image for analysis (54).

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Figure 11. TRAPD signed-magnitude cine phases of four different subjects show subject variability encountered in this study. White circles ¼ images with good to excellent image quality, filled circles ¼ images with thinnest vessel wall. Cases 1 and 2 are healthy subjects in whom all images had good or excellent image quality. Cases 3 and 4 are subjects with CAD risk factors and short cardiac cycles in whom it was impossible to acquire a 5th cine frame. Case 3 also shows a situation in which only the first two frames had good or excellent quality. The label besides each case shows average, minimum and maximum heart rate (HR) in beats per min during the examination, age in years, Framingham risk factor (RF), and body mass index (BMI). Reproduced with permission from Abd-Elmoniem et al (54).

Example data using this are shown in Figure 11. While acquiring images at different times after the black-blood preparation would affect the quality of conventional black-blood suppression, with this technique, the constraint of imaging when blood is passing though the null point is relaxed by using phasesensitive dual inversion recovery which results in good blood signal suppression over a range of inversion times (55). Using this multiphase Time-Resolved Acquisition of Phase-sensitive Dual-inversion recovery (TRAPD) technique, the authors reported that the success rate for acquiring at least one image of good or excellent quality increased from 76% to 95% compared with the conventional single phase approach. The difference in vessel wall thicknesses between healthy volunteers and patients with CAD was also statistically significant using TRAPD and greater than that obtained using a conventional single-phase technique. 3T Imaging While 3T imaging should theoretically result in a doubling of SNR, this is complicated by increased T1 values which may adversely affect black-blood suppression. The first coronary vessel wall images at 3T (56) were acquired with a navigator-gated blackblood prepared 2D fast gradient echo sequence in healthy volunteers and demonstrated an approximate SNR increase of 50% over 1.5T images. Breathhold and navigator gated black-blood prepared TSE images

have also been acquired (57) although consistently good image quality was challenged by ECG gating, fat suppression and specific-absorption rate issues. ECG gating at 3T has since been improved by using a vector-ECG and more advanced R-wave detection algorithms, and fat suppression has been improved by using adiabatic pulses which are less sensitive to field inhomogeneities. A 2D spiral technique with phase-sensitive dual inversion recovery has been used to image both healthy subjects and asymptomatic patients with known variable degrees of CAD at 3T (58). Imaging was successful in 88% of healthy subjects and in 76% of patients and showed arterial wall thickening and positive arterial remodeling in patients compared with healthy subjects. Figure 12 shows an example of the excellent image quality that is possible with navigator gated 3D spiral images at 3T (59). However, in a direct comparison with 1.5T imaging in healthy subjects, the image quality of cross-sectional images was not improved and there was less artifact at 1.5T. For in-plane imaging, although excellent images could sometimes be achieved, image quality was reduced compared with 1.5T. Improvements in shimming and reducing the duration of the spiral readout could potentially improve the robustness of the technique. Alternatively, radial imaging is less sensitive to off-resonance than spiral imaging and has shown promising results at 3T (60,61). In the radial approaches implemented to date, the cylindrical localized reinversion pulse of the black-blood suppression preparation has been replaced by an obliquely

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Figure 12. 3D cross-sectional images taken at 3T. The six slices were acquired with an in-plane spatial resolution of 0.5  0.5 mm2 and a slice thickness of 3 mm. Reproduced with permission from Peel et al (59).

oriented re-inversion slab (62) which is less dependent on high field homogeneity. Improved Respiratory Efficiency While 3D imaging is preferable to 2D imaging, poor navigator efficiency can result in very long and variable acquisition durations which impact on image quality (48). Recently a method has been developed which allows imaging with almost 100% navigator efficiency so that 3D datasets can be acquired in an efficient and predictable duration (23,63). In this technique, very low resolution 3D images of the fat surrounding the vessel are acquired in each cardiac cycle during free-breathing and beat-to-beat cross-correlation of these low resolution fat images is used to determine the respiratory motion (3D translation) of the vessel which is then corrected for retrospectively (Fig. 13). The reproducibility of this technique has been favorably compared with navigator-gated imaging and it has demonstrated increasing vessel wall thickness with age in a healthy

population (31). While other techniques with near 100% efficiency have been developed more recently, these have not as yet been applied to imaging the coronary vessel wall where the requirements of respiratory motion control are most stringent. Self-navigation techniques which rely on monitoring the blood pool for example (64) will require further development before use with the majority of coronary wall imaging techniques as the blood signal is suppressed using blackblood preparation. In addition, many of the self navigation techniques in use detect and correct superior–inferior translational respiratory motion only which is not likely to be adequate for coronary wall imaging studies. Flow-independent Blood Suppression The black-blood preparation used for coronary vessel wall studies relies on inflow of fresh blood into the imaging slice between selective re-inversion and imaging. The efficacy of this flow-sensitive approach will be compromised if blood flow is slow. An alternative,

Figure 13. Left a–f: A single spatially fixed slice from 3D low resolution fat excitation datasets acquired over six cardiac cycles during free-breathing. The excursion of the diaphragm (in mms) from the end-expiratory image (a) is noted in each. The ROI for cross-correlation (encompassing the fat around the artery) was defined on the end expiratory image (a) and superimposed on the remaining images (b–f). Right: A slice from a 3D acquisition acquired without motion correction (100% efficiency) together with the same slice after retrospective beat-to-beat motion correction. Reproduced with permission from Keegan et al (63).

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Figure 14. a,b: Reformatted images of a whole heart acquisition without (a) and with (b) T2 preparation. c: The aortic, left coronary artery (LCA), and right coronary artery (RCA) vessel wall in a weighted subtraction of the two data sets is shown. Reproduced with permission Andia et al (65).

flow-independent approach has recently been introduced in which the vessel wall images are obtained following weighted subtraction of two interleaved 3D datasets, one acquired with T2-preparation and one without (65), example data being shown in Figure 14. While this technique has the obvious drawback of requiring two datasets (and, therefore, has a long imaging time), the imaging protocol is easy to set up and there is no need for careful positioning of a localized selective re-inversion pulse and no need to determine a black-blood inversion time. A motion-sensitized driven equilibrium preparation is another alternative to conventional black-blood preparation that has been proposed recently (66).

Targeted Contrast-Enhanced Imaging: Molecular Imaging MR imaging of specific biological processes in the atherosclerotic pathway with highly targeted contrast agents is a potentially powerful technique which may improve early detection of disease, guide therapy and monitor the response to treatment. These gadoliniumor iron-based agents bind selectively to specific proteins, or they may accumulate in certain cell types or pathological tissue. Their development is highly complex and for more information on this and on preclinical and early clinical studies, the reader is directed to several excellent recent review articles (67,68). Only a

Figure 15. A–G: Comparison of coronary MRA (A), delayed-enhancement MRI (B), and positron-emission CT–like fusion of A and B (C) of stented and control coronary vessel segments and corresponding histology (D–G). Strong enhancement can be observed at the stent location (dotted white arrow), whereas little to no enhancement is visible in the normal noninjured left anterior descending artery segment (B,C). Elastic von Gieson stain of noninjured coronary vessel segment (D,E) shows intact internal elastic lamina (IEL) and circular arranged elastin fibers (black) in the media. Elastic von Gieson of stented vessel segment (F,G) demonstrates disruption of IEL and neointima formation with diffuse elastin deposition (black dots). E and G, Magnifications of D and F. A indicates adventitia; M, media; L, lumen; and N, neointima. Reproduced with permission from von Bary et al (72).

Coronary Artery Wall Imaging

few agents have been investigated in the coronary circulation in large animal models to date. A gadolinium-based fibrin binding contrast agent (EP2104R) has been shown to accumulate in coronary thrombus and in in-stent thrombosis following intracoronary delivery in swine (69). The potential of this agent to allow selective visualization of coronary (69) and pulmonary (69,70) thrombi was further verified by Vymazal et al and a phase II clinical trial of the agent concluded that it allows detection of thrombi which are not readily visible in precontrast scanning and that it improves the visibility of those that are (71). An elastin-binding small molecular weight contrast agent with rapid blood clearance has also been used in pigs to demonstrate coronary vessel wall remodeling following injury, as shown in Figure 15, with the enhanced region agreeing well with the area of remodeling obtained in histological studies (72). SUMMARY MR is a powerful technique which potentially allows the noninvasive investigation of the coronary vessel lumen, the coronary vessel wall, plaque morphology and composition. Progress over the last two decades has been rapid and continued development of efficient respiratory and cardiac motion corrections techniques will improve the robustness of the techniques and allow acquisitions within acceptable scan times. ACKNOWLEDGMENT This project was supported by the NIHR Cardiovascular Biomedical Research Unit of the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. This report is independent research by the National Institute for Health Research Biomedical Research Unit Funding Scheme. The views expressed in this publication are those of the author and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. REFERENCES 1. Kato S, Kitagawa K, Ishida N, et al. Assessment of coronary artery disease using magnetic resonance coronary angiography: a national multicenter trial. J Am Coll Cardiol 2010;56:983–991. 2. Nagel E. Magnetic resonance coronary angiography: the condemned live longer. J Am Coll Cardiol 2010;56:992–994. 3. Glagov S, Weisenberg E, Zarins C, Stankunavicius R, Kolettis G. Compensatory enlargement of human atherosclerotic coronary arteries. N Eng J Med 1987;316:1371–1375. 4. Ambrose JA, Tannenbaum MA, Alexopoulous D, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12:56–62. 5. Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78:1157–1166. 6. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316:1371–1375. 7. Stone G, Narula J. The myth of the mild vulnerable plaques. JACC Cardiovasc Imaging 2013;6:1124–1126. 8. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural history study of coronary atherosclerosis. N Eng J Med 2011;364: 226–235.

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