Atherosclerosis is a systemic disease that can silently affect the entire vascular system and often manifests clinically as stroke, myocardial infarction or sudden cardiac death. Despite advances in diagnosis and treatment, the sequelae of atherosclerosis remain the leading cause of death in adult Americans. Traditionally the gold standard for the diagnosis and assessment of atherosclerosis severity has been X-ray angiography which visualizes the reduction in arterial luminal diameter. However, it is now well-known that significant atherosclerotic plaque may be present within the arterial wall long before the lumen is compromised.1 In addition, plaque vulnerability, as determined by plaque composition, may be a better predictor of clinical risk than the severity of arterial stenosis.2 Angiographic modalities, which are blind to the vessel wall, cannot adequately delineate plaque composition and routinely underestimate atherosclerotic burden. Diagnostic techniques capable of imaging the arterial wall and characterizing atherosclerotic plaque provide a more accurate assessment of plaque burden, vulnerability, and possibly patient risk. Thus there is substantial interest in imaging modalities which can look beyond the arterial lumen into the vessel wall, such as high resolution magnetic resonance imaging (MRI).
Magnetic Resonance Imaging of Atherosclerosis
MRI has emerged as a leading non-invasive imaging modality of atherosclerotic disease due to its ability to assess the arterial lumen, plaque burden and plaque components in an accurate and non-invasive manner. MRI has been utilized in the research setting to evaluate atherosclerosis in human carotid, aortic, peripheral and coronary arteries. Several in vitro and in vivo studies have validated the ability of MRI to differentiate the major components of atherosclerotic plaque. In addition, MRI can accurately and reproducibly measure arterial wall dimensions. This has lead to its use as the imaging efficacy end-point in therapeutic trials of plaque regression.
Carotid Atherosclerosis
The carotid artery is an excellent target for MRI of atherosclerosis because of its superficial location, minimal motion, and available tissue pathology from carotid endarterectomy specimens. A substantial amount of work by Yuan and colleagues has validated the ability of MRI to detect and characterize carotid plaque.
They have shown that in vivo MRI can identify the components of a high risk or ‘vulnerable’ plaque such as the lipid rich necrotic core, intraplaque hemorrhage,3 as well as the thickness4 and integrity5 of the fibrous cap. In addition they have demonstrated that a ruptured fibrous cap seen on MRI correlates with a recent history of a transient ischemic attack or stroke.6 Takaya and colleagues have recently shown that patients with asymptomatic moderate carotid stenosis and high risk plaque features had an increased risk of having a subsequent cerebral vascular event.7 It has also been demonstrated that in patients admitted with stroke symptoms, the presence of ruptured hemorrhagic carotid plaque (American Heart Association [AHA] type 6 plaque) strongly correlated with a discharge diagnosis of cerebral ischemic event.8 Thus, a patient could be potentially risk-stratified based on the recognition of high-risk plaque morphology.
Aortic Atherosclerosis
Several investigators have demonstrated the ability to quantify and determine plaque composition in the aorta. Aortic plaque composition and size when visualized with MRI shows a high correlation with transesophageal echocardiography (TEE).9 MRI can measure aortic luminal area as well as plaque area with excellent reproducibility.10 The author’s group has verified the ability of MRI to differentiate fibrous cap, lipid core, and thrombus components of plaque within abdominal aortic aneurysms (AAA) in patients prior to AAA repair (see Figure 1).11
Peripheral Artery Atherosclerosis
Although the peripheral arteries are ideal for vessel wall imaging due to their superficial location, long length, straight course, and lack of motion, they have not been extensively investigated. MRI has been used successfully to define the extent of atherosclerotic plaque and characterize the changes that occur with arterial remodeling following angioplasty of the popliteal artery.12 The feasibility and reproducibility of MRI to assess plaque volume in the superficial femoral artery has been demonstrated13 (see Figure 2). Based on the reproducibility of MRI, sample sizes for clinical trials of atherosclerosis regression could be reduced substantially. These two studies highlight the tremendous potential MRI has to survey the effects of treatment, whether it is invasive or medical, on the progression or regression of atherosclerosis.
Coronary Atherosclerosis
An ultimate goal of MRI is to accurately and rapidly image the coronary artery lumen and vessel wall, and thus provide a more detailed non-invasive alternative to X-ray or computed tomography (CT) angiography. However, the coronary arteries have proven difficult to image due to respiratory and cardiac motion, small size, and tortuosity. Initial attempts aimed at imaging solely the coronary lumen with MRI have met with modest success. In a recent meta-analysis, coronary MR angiography (CMRA) was able to detect nearly 75% of significant proximal stenoses with a specificity of 86% compared with conventional X-ray angiography. Only 80% of the coronary segments were able to be evaluated.14 Thus, at present, CMRA has limited clinical use in diagnosing coronary artery disease (CAD) due to the inability to evaluate distal coronary segments and the high rate of unevaluable segments. Furthermore, it has the same shortcomings as conventional angiographic techniques discussed previously. Investigators have successfully imaged the coronary wall in humans with MRI. Black blood imaging techniques have been used to demonstrate increased coronary wall thickness in patients with CAD (see Figure 3).15 Using three-dimensional (3-D) free-breathing MRI and semi-automated analysis software, coronary vessel wall thickness has been measured with excellent reproducibility.16 Contrast-enhanced coronary plaque imaging is feasible and may aid in differentiating coronary plaque composition.17 However, despite these encouraging studies, it is not yet possible to adequately determine plaque composition, mainly due to limited in-plane spatial resolution of current techniques.
Magnetic Resonance Imaging and Monitoring Atherosclerotic Therapy
Enthusiasm for MRI as the imaging efficacy end-point in therapeutic trials of plaque regression is on the rise due to its ability to image the vessel wall reliably, reproducibly, and in a non-invasive manner. Furthermore, because MRI can measure atherosclerotic plaque with excellent reproducibility, the sample sizes needed to adequately power clinical studies could be dramatically reduced. Excitement over using MRI for this purpose has already spawned several small clinical studies in which MRI has demonstrated significant carotid and aortic plaque regression after treatment with lipid-lowering therapy. Most notably, Corti et al.18,19 used MRI to detect carotid and aortic plaque in 21 asymptomatic hypercholesterolemic patients.
These patients were then placed on lipid-lowering therapy and followed with serial MRI. They found a significant reduction in total vessel area (TVA), a surrogate of atherosclerotic plaque burden, but not luminal area (LA), at one year in both the carotid and aortic plaques. Interestingly, at two years they found a further reduction in TVA and a small but significant increase in LA in both carotid and aortic lesions.
Future Directions
Atherosclerotic plaque imaging with MRI is in a phase of rapid development. Newer pulse sequences are being developed to allow broader coverage in less time.20 Higher field strength magnets, such as 3.0T21 and 7.0T, along with advances in receiver coils, will improve signal/noise ratio (SNR). Undoubtedly, these technological advances will be utilized in vessel wall imaging, especially in the coronary artery where increased spatial resolution and broader coverage is greatly needed. In addition to the developments in MRI hardware and software, the recent developments in contrast agents have improved contrast/noise ratio and thus allow for improved plaque differentiation. Further experience with ultra-small superparamagnetic particles of iron oxide (USPIO)22 in combination with compounds targeting cell adhesion molecules23 will enable visualization of inflamed plaques that are considered vulnerable or at high risk of rupture. Already, USPIOs that are ingested by macrophages have been used to identify macrophage activity, hence inflammation, in in vivo human carotid plaque.24 In addition, there has been excitement over the development of contrast agents that specifically target plaque components such as the lipid core25 or intraplaque thrombus.26 Finally, in the development phase are newer targeted contrast agents aimed at specific cell surface receptors or proteins, which will allow for earlier, more sensitive detection of atherosclerosis. Intravascular MRI (IVMRI) may have a future role in imaging human atherosclerosis. This technique, while invasive, overcomes important limitations of conventional MRI such as SNR and spatial resolution by placing the imaging coil in close proximity to the vessel wall. Plaque imaging has been validated against histopathology in a variety of vascular territories of animals and humans27 with excellent spatial resolution.
Summary
Insights into the pathogenesis of atherosclerosis and technological improvements have moved MRI to the forefront of atherosclerotic imaging. It is developing into an important technique for vessel wall imaging and plaque characterization in the carotid and peripheral arteries as well as in the aorta. While the current spatial resolution hinders the ability of MRI to evaluate the vessel wall of coronary arteries, newer technology is already beginning to overcome this limitation. Clinically, MRI has created a unique opportunity to non-invasively monitor plaque modification over time. This provides an unprecedented platform for efficacy trials of current and novel drugs used in atherosclerosis as well as in interventional therapy. By diagnosing atherosclerosis earlier and by identifying high-risk vulnerable plaque, MRI of atherosclerosis may potentially provide better risk stratification than current angiographic techniques. Ultimately, MRI might be a key modality in the identification of the vulnerable patient in whom focal or systemic intervention could be started to prevent cardiovascular events.