Recent developments and new perspectives on imaging of atherosclerotic plaque: role of anatomical, cellular and molecular MRI Part I and II

Int J Cardiovasc Imaging (2010) 26:433–445 DOI 10.1007/s10554-009-9565-8 REVIEW Recent developments and new perspectives on imaging of atherosclerotic plaque: role of anatomical, cellular and molecular MRI Part I and II Bernard C. M. te Boekhorst • Maarten J. Cramer Gerard Pasterkamp • Cees J. A. van Echteld • Pieter A. F. M. Doevendans • Received: 28 September 2009 / Accepted: 17 December 2009 / Published online: 29 January 2010 Ó Springer Science+Business Media, B.V. 2010 Abstract Atherosclerotic plaque disruption accounts for the major part of cardiovascular mortality and the risk of disruption appears to depend on plaque composition. Carotid plaques in patients, scheduled for endarterectomy, have been successfully characterised with MRI. MRI has the advantage of combining information about morphology and function. Unfortunately, the tortuosity and size of the coronary arteries, and the respiratory and cardiac motion hinder the in vivo characterisation of human coronary plaque. In addition to plaque composition several molecular markers of the different processes involved in atherosclerosis, such as integrins, matrix metalloproteinases and fibrin seem to correlate with risk of plaque rupture and clinical outcome. These molecular markers can be targeted with antibodies coupled to carriers, which are loaded with gadolinium for detection (molecular MRI). Several cellular/molecular MRI studies in animal models and some in human patients have been conducted with varying levels of success. The advent of clinical high field magnets, the development of contrast agent carriers with high relaxivity and the development of relatively new MR contrast techniques are promising in the field of plaque imaging. Future MRI studies will have to focus on the molecular target of the atherosclerotic process, which has the highest prognostic value with regard to acute coronary syndromes and on the most suitable contrast agent to visualize that target. B. C. M. te Boekhorst
M. J. Cramer
G. Pasterkamp
C. J. A. van Echteld
P. A. F. M. Doevendans Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands Keywords Atherosclerosis
Magnetic resonance imaging
Contrast agents
Molecular MRI B. C. M. te Boekhorst Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Present Address: C. J. A. van Echteld Novartis Institutes for BioMedical Research, Basel, Switzerland B. C. M. te Boekhorst (&) Experimental Cardiology, Division Heart and Lungs, E03.511, 3584 CX Utrecht, The Netherlands e-mail: b.c.m.teboekhorst@umcutrecht.nl Part I: Imaging modalities for atherosclerotic plaque staging Atherosclerosis is a systemic disease, which affects particularly the aorta, carotid arteries, iliofemoral arteries and the coronary arteries [1–4]. Mortality from generalized vascular diseases is for 70% caused by myocardial ischemia or infarction, 10–20% by stroke and 10% by ruptured aneurysms or visceral infarctions [1, 2]. Most acute coronary syndromes (ACS) are the result from plaque disruption and 123 434 consequent thrombosis [5]. Many post-mortem examinations have revealed that the risk of plaque rupture (plaque vulnerability) depends mainly on plaque composition [1, 5, 7, 8]. Vulnerable plaques have thin or eroded fibrous caps that overlay large lipid cores and harbour an abundance of inflammatory cells [1, 5]. Coronary angiography is the gold standard technique for lumenography, but it is not apt for detection of vulnerable plaque, since in many cases growing plaque is associated with outward remodeling of the vessel [6]. There is a need for a diagnostic technique, which is suitable for screening patients with coronary artery disease (CAD) for the presence of vulnerable plaques. Table 1 lists an overview of techniques, which provide information about plaque morphology, chemical composition, inflammation or metabolic activity. A variety of techniques is available, which provide information about plaque morphology, such as intravascular ultrasound (IVUS) [9], optical coherence tomography (OCT) [10] and angioscopy. In addition, Raman spectroscopy (RS) [11] and near-infrared spectroscopy (NIRS) [12] provide information about chemical composition of the plaque. Thermography may provide indirect information about inflammatory activity in the plaque. However, heat was reported to be generated in non-culprit lesions both in patients with stable angina as well as in patients with ACS [13]. All mentioned techniques share a major disadvantage of being invasive. Among the non-invasive techniques are conventional ultrasound (US) [14], electron beam computed tomography (EBCT) or multi detector CT (MDCT) [15], positron emission tomography (PET) and single-photon-emission computed tomography (SPECT) [16] and magnetic resonance imaging (MRI) [1, 17]. Conventional US is only applicable for imaging of vessels close to the skin, because of the low depth resolution [14]. Moreover, only plaque size and, when used in combination with Doppler, arterial stenosis can be assessed [14]. Electron beam CT is suggested to be a good screening tool for risk prediction for CAD, better than traditional Framingham factors, by measuring coronary arterial calcium score. While coronary artery calcification burden appears to correlate with higher chance of significant coronary arterial narrowing, coronary calcification cannot be used to identify sites of stenoses [18] and may reflect a relatively dormant 123 Int J Cardiovasc Imaging (2010) 26:433–445 stage of atherosclerosis instead of current risk of an ACS. Of note, calcified plaque in aortic EBCT is overestimated by the so-called ‘‘blooming’’ effect, when compared to simultaneously performed MRI, especially for smaller plaques [19]. Contrastenhanced MDCT (16 slices) showed a statistically significant difference in attenuation between lipidrich and fibrous plaques [20]. However, the authors stated that in individual cases non-calcified plaque could not be characterized reliably, since the standard deviation of their results was high and the depiction of plaque micro-architecture was poor with MDCT, when compared with MRI [20]. Contrast-enhanced MDCT (64 slices) allowed identification of proximal coronary lesions with reasonable accuracy, but even exact quantification of the degree of occlusion was not possible [21]. Another important disadvantage of MDCT is the involvement of significantly higher radiation exposures as compared to single-slice and EBCT. In PET and SPECT radiolabeled molecules are used to specifically target individual metabolic or enzymatic activities involved in a particular molecular process. For example, SPECT was applied for imaging of apoptosis in an atherosclerotic rabbit model [22]. After rapid blood clearance, intense uptake of Tc-99 m-annexin V in aortic plaque was observed 2 h after injection. Another example of specifically targeting atherosclerotic plaque markers is the use of 125-I-MDA2, which bound to the malondialdehyde epitope on ox-LDL, and showed significantly higher uptake in lipid-rich lesions of atherosclerotic mice and rabbits, when compared to the uptake in healthy arteries [23]. After intravenous administration of the PET-tracer F-18-fluorodeoxyglucose, metabolically active cells may take up this tracer, which has been shown useful for imaging in inflammatory conditions. For example, atherosclerotic plaque inflammation has been imaged with PET/CT and 18F-FDG in carotid, iliac and femoral arteries of patients [24]. This study showed increased uptake of 18F-FDG particularly in the carotid arteries. However, the precise relationship between 18F-FDG, plaque macrophage activity and risk of plaque rupture cannot be determined yet, due to the small number of studied patients and the fact that 18F-FDG is not a macrophage-specific PET ligand. Nevertheless, PET is a very sensitive technique allowing imaging of disease processes in vivo in the Fibrous Inflammation Lipid Molec imag cap core feasible? Sensitivity molec imaga Imaging modality Physical basis Spatial resolution Penetration Catheter (Non)-invasive/ radiation CAG X-rays ±300 lm No limit ? Invasive, radiation - - - No Not applicable IVUS Reflection of HF sound 250–500 lm Poor ? Invasive - - - Yes ? OCT Reflection of light 1–10 lm 1–2 mm ? Invasive ? ? ? Yes ? PAT AS Reflection of light Visible light 15–45 lm Unknown 3 mm Very poor ? ? Invasive Invasive ? - ? - ? ± Yes No ? Not applicable Thermo Temperature 0.5 mm Unknown ? Invasive - ? - No Not applicable RS Energy exchange between light and molecules Not applicable 1.0– 1.5 mm ? Invasive - ? ? Yes ‘‘Molecular fingerprint’’ US Reflection of HF sound [400 lm - Non-invasive - - - Yes ? CT X-rays 400–600 lm No limit Very poor - Non-invasive, radiation - - - Yes ? Optical fluorescence techniques Visible light/NIR 2–5 mm ? Non-invasive - ? - Yes Not well characterized, likely 10-9– 10-12 mol/L SPECT Low energy c- rays Several mms No limit - Non-invasive, radiation - ? - Yes 10-10–10-11 mol/L PET High energy c- rays Several mms No limit - Non-invasive, radiation - ? - Yes 10-11–10-12 mol/L MRI Radiowaves 150–200 lm No limit - Non-invasive ? ? ? Yes 10-3–10-5 mol/L \1 cm Int J Cardiovasc Imaging (2010) 26:433–445 Table 1 Comparison of Imaging Modalities for Identification of Atherosclerosis in Humans CAG coronary angiography, IVUS intravascular ultrasound, OCT optical coherence tomography, PAT photo-acoustic tomography, AS Angioscopy, Thermo thermography, RS Raman spectroscopy, US conventional ultrasound, CT computed tomography, NIR near infra-red, MRI magnetic resonance imaging Molec Imag molecular imaging HF high-frequency a Sensitivity of Molec Imag: the ability to detect a molecular probe, relative to the background, measured in moles/L 435 123 436 nanomolar/picomolar range [25]. However, PET and SPECT lack definition of anatomic structure and have limited spatial resolution, so they are unable to precisely localize the site of increased tracer uptake. Combination of imaging modalities, which can define anatomic structure, like CT and MRI, avoids this problem, yet is more expensive. MRI has the ability to localize plaque and detect its constituents. As PET does, MRI also offers the possibility to image specific molecular targets with contrast enhancing targeted probes [17, 25]. In the scope of universal clinical applicability, MRI is the most versatile technique. MRI does not involve ionising radiation, is safe and non-invasive, apt as a screening tool, which can be repeated several times and provides high-resolution images of the plaque [26]. Disadvantages of MRI are relatively long acquisition times and poor suitability for patients, who are claustrophobic. Sequences which have been most successfully used for coronary MRI differ from those used in current clinical practice for cardiac MRI. Motion artifacts caused by respiration and cardiac contractions pose an upper limit to the timewindow of MRI signal acquisition during the cardiac cycle. However, development of high-field magnet systems and more efficient pulse sequence programs may lessen these problems in the near future. Part II: MRI of atherosclerotic plaque: up to date Ex-vivo MRI: recent developments Nearly two decades ago a water suppression technique was applied in order to highlight plaque lipids [27]. However, limited resolution hindered differentiation between peri-adventitial fat and plaque lipids. Another study compared in vivo fat suppression images with water suppression images, both obtained with chemical shift imaging [28]. Plaque was more clearly delineated in the in vivo images using fat suppression than in the images using water suppression, which may be due to the limited resolution of the Spin Echo (SE) image. Water suppression images were only useful for localising mobile lipid-containing areas, like peri-adventitial fat [28]. More recently the lipid-water ratio in perivascular fat was reported to be 1.7, whereas the lipid-water ratio in the 123 Int J Cardiovasc Imaging (2010) 26:433–445 atheromatous core was 0.11 [29], which explains the clearer delineation of plaque using fat suppression when compared to water suppression [28]. Further, the discriminative role of T2 weighting (T2w) with respect to identification of plaque constituents became evident [30]. A 10 years ago, the value of a combination of various MRI weightings already was recognized for characterization of carotid artery plaque [31]. Multi-contrast weighted MRI, including T1w, partially T2w, fully T2w and diffusion weighted (Dw) images, allowed full ex vivo classification of carotid atherosclerotic plaque components [31]. The authors suggested that Dw imaging would be necessary for identification of thrombus [31]. Water diffusion was reported to vary with the ageing process of thrombus, consistent with the degree of crosslinking of the fibrin strands occurring in the acute phase and the later phase of thrombus organisation [32]. Water in recent (1 week old) thrombus, but also atheromatous core diffuses more isotropically due to absence or destruction of confining structures [32]. Therefore, acute and late thrombus both had higher water diffusion coefficients, whereas atheromatous core and recent thrombus had lower diffusion coefficients. Water molecules bound to macromolecules such as collagen, fibronectin and elastin can be differentiated from free water molecules by their sensitivity to an off-resonance saturation pulse, a technique called magnetisation transfer. Magnetisation transfer has been shown to decrease signal from the fibrous cap in contrast to regions of lipid in human carotid endarterectomy specimens [33]. However, another study failed to show a difference in sensitivity of lipid region and fibrous cap of ex vivo plaques from apoE knockout mouse aortic roots to magnetisation transfer pulses [34]. Successful discrimination between thick fibrous and thin fibrous caps, based on the difference in water diffusion, was achieved with an intravascular selfcontained MRI probe and fast SE (FSE) with an extremely short inter-echo time (12 ls) [35]. Table 2 lists MRI parameters and appearance of atherosclerotic plaque components of some ex-vivo studies. In contrast to ex vivo MRI, for in vivo MR studies many problems need to be solved. Laminar/pulsating flow and motion related to cardiac contraction and respiration produce artefacts, which need to be minimized. Author Species Source of material Shinnar [31] Human Field Resolution: in plane 9 slice strength thickness MR technique 9.4 T 48.3 9 48.3 lm 9 0.5 mm Carotid endarterectomy TR (ms) TE (ms) Appearance of plaque components LC Calc SMC/FT Thr Haem SE PDW 2,000 13 Hyper Dark Hyper Hyper NA SE T1w 300/700 13 Hyper Dark Hyper Hyper NA SE T2w 2,000 30/50 Dark Dark Hyper Variable NA SE Dw 2,000 30 Dark Dark Dark Light NA 547 9 273 lm 9 10 mm Total proton SE image 1,000 28 No differentiation between plaque components Toussaint [29] Human 9.4 T Carotid, coronary, iliac artery and aorta 156 9 156 lm 9 0.6 mm SE T1w SE T2w 700 2,000 3 50 Iso Hypo Dark Dark Iso Hyper NA NA NA NA Itskovich [65] Human 39 9 39 9 39 lm 3D FSE PDw 2,000 9 Hypo Dark Hyper Iso NA Booth [27] Rabbit 2T Aorta WS SE image 9.4 T Coronary artery Worthley [66] Mini-swine coronary artery/aorta 1.5 T Itskovich [58] Mouse 9.4 T Schneider [34] Mouse aortic root 11.7 T Only lipids visible, both adventitial and plaque lipids 3D FSE T1w 500 9 Hypo Dark Iso Iso NA 3D FSE T2w 2,000 25 Hypo Dark Iso Hypo NA 156 9 156/234 9 234 lm 9 FSE PDw 2/3 mm FSE T1w 2,300 19/16 Iso Dark Hyper NA Iso 600 13/14 Iso Dark Hyper NA High FSE T2w SE PDw 2,300 2,000 55/80 9 Hypo Hypo Dark NA Hyper Hyper NA NA Low NA 50 9 50 lm Aortic root Int J Cardiovasc Imaging (2010) 26:433–445 Table 2 Ex-vivo MRI studies on atherosclerotic plaques: species, MRI parameters and appearance of plaque components SE T1w 500 9 Hyper NA Hyper NA NA SE T2w 2000 30 Hypo NA Hyper NA NA 47 9 47 9 63 lm 3D multi-SE and FS 200 7/14/21/28 Hypo NA Hyper NA NA 47 9 47 9 125 lm MT 480 18 Hypo NA Hyper NA NA 47 9 47 9 252 lm WS 100 6.1 Dark NA Iso NA NA TR repetition time, TE echo time, LC lipid core, Calc Calcification, SMC/FT smooth muscle cells/fibrous tissue, Thr Thrombus, Haem Haemorrhage, (F)SE (fast) spin echo, PDw proton density weighting, intensity on MR images: hyper [ iso [ hypo [ dark, NA not available or not assessed, WS water suppression, FS fat suppression, IR inversion recovery, MT magnetisation transfer, Dw diffusion weighting, for other abbreviations, see Table 1 437 123 438 Int J Cardiovasc Imaging (2010) 26:433–445 Intravascular in vivo MRI Whole body in vivo MRI Intravascular in vivo MRI yields enhanced image quality and permits high-resolution MR images by virtue of the proximity of the MR detector coil to the arterial wall (Fig. 1). Catheters nowadays are typically 5 F in outer diameter and a close match between coil and arterial diameter is required to prevent motion of the coil, caused by pulsating flow. Loss of signal received from regions outside the loop (Fig. 1) may lead to severe image degradation [36]. However, a close match is difficult to achieve in atherosclerotic vessels with various degrees of obstruction. In addition, image quality is reduced significantly as the intravascular coil moves off axis from the external magnet field, a significant limitation for imaging tortuous coronary arteries [37]. Nevertheless, intravascular MRI was successfully applied for characterisation of human iliac artery plaque ex-vivo and in vivo [38, 39]. In comparative in vivo studies, IVUS images were inferior to MR images with regard to reliable identification of plaque constituents, due to acoustic shadowing in the presence of calcifications. However, an intravascular coil could cause plaque disruption and for this reason the invasive approach is not apt for screening. Owing to its superficial position and the absence of respiratory motion, the constituents of atherosclerotic plaque in human carotid artery have been characterized successfully in vivo with MRI [4, 40–45]. Figure 2 shows an example of successful in vivo multi-contrast weighted MRI for detection of intraplaque hemorrhage. Table 3 lists technical details of some studies conducted with respect to in vivo MRI of human atherosclerotic plaque. The readily available histo-pathological data for comparison of MRI images after carotid endarterectomy have made in vivo MRI studies of carotid artery plaque attractive. Lipid core has traditionally been visualized with T2 weighted spin echo techniques [30]. More recently, T1 weighted fast spin echo and time-of-flight (TOF) imaging have gained interest, because these sequences may lead to better visualization and bright depiction of lipid core [43, 46, 47]. Multi-contrast weighted MRI at 3T showed nice depiction of large lipid cores and an association was reported between large lipid core and thin or ruptured fibrous cap [48], which is another marker of plaque vulnerability. Time-of-flight images were used to investigate the state of the fibrous cap [49]. Not only thick fibrous caps were distinguished from intact thin caps, but Fig. 1 Printed with permission from Larose et al. [39]. Comparison of IVMRI and surface MRI. T1w surface MRI (a) and IVMRI (b) of a common iliac artery in a subject with an atheromatous plaque illustrates better image quality with IVMRI compared with surface MRI. Both images were produced by use of identical parameters (TR, 500 ms; TE, 13 ms; band width, 16 kHz; field of view, 9 cm; matrix, 256 9 256; no phase wrap) and in-plane resolution of 316 lm, but the relative SNR is superior for IVMRI. However, in case of a circumferential plaque the position of the catheter coil determines the local signal intensity of a plaque component, so homogeneity of the image SNR is impaired 123 Int J Cardiovasc Imaging (2010) 26:433–445 439 Fig. 2 Printed with permission from Cai et al. [44]. Example of type VI lesion just distal to carotid bifurcation (acute and subacute hemorrhages were detected by histology). On multicontrast-weighted MR images, acute and subacute hemorrhage had high SI on both TOF and T1WI images, isoSI to slightly high SI on PDWI and T2WI images (arrow). * indicates lumen. Original magnification9 10 also intact caps could be distinguished from ruptured ones with support of T1w, proton density (PDw) and T2w images [49]. Intra-plaque hemorrhage (IPH) has also been accepted as a marker of plaque vulnerability and is caused by rupture of fragile neovasculature not supported with firm connective tissue [50]. A followup MRI study in humans showed that hemorrhage into the carotid atherosclerotic plaque accelerated plaque progression in an 18 month period [50]. Erythrocyte membranes contain more free cholesterol than any other cell in the body and macrophages surrounding the bleeding are activated and ingest more oxidized LDL [50]. Classification of stages of IPH in carotid arteries of patients scheduled for carotid endarterectomy was performed using multi-contrast weighted MRI [45]. The classification showed moderate agreement with the classification into fresh, recent and old categories according to histopathological criteria after carotid endarterectomy. Another study reported successful discrimination between IPH and luminal thrombus in human carotid artery lesions with four different MR weightings [51]. The ability of a non-invasive imaging technique to discriminate fresh from old luminal thrombus has obvious clinical relevance. Definitely, recent thrombosis has prognostic implications with regard to future acute coronary events [7]. Carotid thrombi were induced in swine by arterial injury and could be differentiated in recent and old thrombi by assessment of signal intensity on T2w at 1.5 T [52]. In recent years, various mouse models have been developed in order to study the role of specific genes in cardiovascular pathophysiology. Several transgenic and knockout models to study vascular biology and atherosclerosis have been reported: e.g. apolipoprotein E deficient [53], apoE3-Leiden [54], lowdensity lipoprotein receptor deficient [26], and apoE/ eNOS double knockout mice [55]. Successful MRI of aortic plaque in mice at high field may close the gap between successful in vivo MRI of human carotid plaque and thus far unsuccessful coronary plaque MRI at low field, because of similarity of size of human coronary artery and mouse aorta and the advent of clinical high field magnets. Wild-type mouse aortic wall thickness has 123 440 123 Table 3 In vivo MRI studies on atherosclerotic plaques: MRI parameters and appearance of plaque components FA TE (ms) Appearance plaque components Technique Field strength Resolution: in plane 9 slice thickness TR (ms) Rabbit/ Abdominal human aorta/ carotid artery 1.5 T 500 9 500 lm 9 4 mm 700 ms 90 12 No differentiation between plaque components 90 14 No differentiation between plaque components 90 14 Only peri-adventitial lipid visible Toussaint [30] Human Carotid artery 1.5 T SE T2w 390 9 390 lm 9 5 mm 1 RR 90 20/55 Hypo Cai [43] Human Carotid artery 1.5 T DIR FSE PDw 500 9 500 lm 9 1/2 mm 3 RR 90 20 IsoDark Hyper NA hyper (Sub)acute: isohyper DIR FSE T1w 800 90 9.3 Iso (Sub)acute: hyper DIR FSE T2w 3 RR 90 40 IsoDark Iso hyper NA (Sub)acute: isohyper 3D TOF 23 25 3.8 Iso Dark Hypo NA (Sub)acute: hyper NA Author Vinitski [28] Species Cappendijk Human [40] Imaged vessel Carotid artery SE T1w CSI FS CSI WS 1.5 T FSE PDw Dark Hyper NA Hypo 90 20 Hypo Dark Iso 570 90 14 Iso Dark Hyper NA Hyper 390 9 490 lm 9 3 mm 2 RR 90 30/50 Hypo Dark Hyper NA Iso 10.3 15 4.0 Hypo Dark Iso Hyper Fresh hem. Recent hem. Old hem. 3–4 RR 90 20 Hypo/iso Hyper Hypo FSE T1w 800 90 9.3 Hyper Hyper Hypo FSE T2w 3–4 RR 90 40 Hypo/iso Hyper Hypo 3D TOF 23 25 3.5 Hyper Hyper Hypo 1.5 T FSE PDw 625 9 625 lm 9 2 mm NA Iso FA flip angle of excitation pulse, DIR double inversion recovery, EPI echo planar imaging, RR R-peak (ECG) to R-peak interval. For explanation of other abbreviations, see Table 2 Int J Cardiovasc Imaging (2010) 26:433–445 Carotid artery Dark Hyper Fresh: hyper organising: hypo Haem. 2 RR 3D EPI T1w with IR Human Calc SMC/ Thr FT 390 9 390 lm 9 2.5 mm DIR FSE T1w FSE T2w Chu [45] LC Author Mouse strain Target of imaging Fayad [54] ApoE-/- Field strength MRI technique TR (ms) TE (ms) Resolution 9.4 T SE PDw 2,000 13 97 9 97 9 500 lm/48 9 48 9 500 lm SE T1w 1,000 13 97 9 97 9 500 lm/48 9 48 9 500 lm Hist.: 0.300 ± 0.035 SE T2w 2,000 30 97 9 97 9 500/48 9 48 9 500 lm r = 0.86 SE PDw 2,000 9 109 9 109 9 500 lm Abdominal aorta, iliac artery Choudhury [57] ApoE-/-, apoE-/-/ apoA-Ia 9.4 T Correlation between MR and histology Maximal wall thickness ± SD, lm Wall area, mm2 NA MRI: 0.384 ± 0.046 NA Int J Cardiovasc Imaging (2010) 26:433–445 Table 4 Mouse MRI studies on atherosclerotic vessel wall: MRI parameters and correlation with histology MRI: 0.334b Hist.: 0.126b Abdominal aorta r = 0.85 Itskovich [56] ApoE-/-(/apoA-I) 9.4 T SE PDw 2,000 9 MRI: 589 ± 164 MRI: 2.09 ± 1.04 SE T1w 500 9 Hist.: 486 ± 155 Hist.: 1.74 ± 0.92 SE T2w SE T1w 2,000 1,000 30 10 49 9 98 9 300 lm r [ 0.90 MRI: 238 ± 100 r [ 0.90 MRI: 1.19 ± 0.19 3D FLASH 4.6 1.5 100 9 100 9 39 lm Hist.: ? Hist.: 0.96 ± ? 3D FSE ± FS 800 13 140 9 187 9 187 lm NA Aortic root Wiesmann [55] ApoE-/- 7T Thoracic aorta 156/78 9 156/78 9 300 lm r = 0.97 Hockings [26] LDLR-/-c 7T Innominate artery MRI: 0.14 ± 0.086 Hist.: 0.308 ± 0.081 r = 0.8 a Human apolipoprotein A-I, Choudhury et al. [60]: total study group has a wide range of severity of atherosclerosis b Median value c Low-density lipoprotein receptor-deficient mice For explanation of abbreviations, see Table 2 441 123 442 been reported to measure *50 lm at the abdominal level [56] and *70 lm at the thoracic level [57]. MRI measurements of abdominal aortic wall thickness of ApoE deficient mice revealed doubled wall thickness when compared to wild-type mice [56]. At the thoracic and aortic root level the effect of the gene defect on the aortic wall thickness was even more conspicuous than at the abdominal level [57, 58]. Aortic wall area/thickness measurements in atherosclerotic mouse models and correlation coefficients between MRI and histopathology obtained from various mouse MR studies are listed in Table 4. MRI showed that increased wall area of the abdominal aorta of apoE deficient mice was completely compensated by outward remodeling, resulting in a constant lumen, as could be verified with histopathology [59]. Aortic wall thickness was larger as assessed by MRI than when assessed by histopathology, which probably is caused by shrinkage through dehydration by the alcohol. Imaging of the thoracic aorta in the mouse requires a nontrivial effort, because of small size and cardiac and respiratory motions. The heart in an awake mouse beats 600/min [60, 61]. In vivo assessment of plaque composition with MRI in the murine aorta has not been achieved thus far. Nevertheless, wall thickness/ area and plaque area in the murine aortic root and brachiocephalic artery have been measured with MRI and compared with histopathology [26, 58]. A 3-dimensional MR technique was used, which offers the advantage to reconstruct an image in any chosen orientation after the measurements have taken place [26]. A very high correlation between MRI measurements and histopathology measurements of aortic wall area was demonstrated [57]. Probably, the smaller difference between MRI and histopathology measurements of wall area in the latter study when compared to Choudhury et al. [59] can be explained by the smaller pixel dimensions of the images. In vivo imaging of human coronary arteries requires cardiac and respiratory gating. Prospective gating increases measurement time, however retrospective gating and breath-hold techniques increase time efficiency tremendously. For use as a clinical screening tool, which scans the whole coronary artery tree, a sophisticated tracking strategy is required, to compensate for the motion and tortuosity of the coronary arteries [62]. Wall thickness and remodelling of coronary arteries have been studied in vivo 123 Int J Cardiovasc Imaging (2010) 26:433–445 with MRI [63, 64]. Until now it has not been possible to identify different plaque constituents in the coronary arteries in vivo because of earlier mentioned problems. Several research groups are involved in the solution of technical problems, while others are involved in contrast-enhanced MRI, which allows lower SNR because of increased contrast between targets of interest and their background. 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