Atherosclerosis remains the leading cause of death in industrialized societies, and its incidence is projected to increase worldwide in the next two decades.1,2 It also is recognized as a systemic disease affecting the vessel walls of all the major arteries, including the aorta, coronary, carotid, and peripheral arteries, and it leads to a myriad of diseases like stroke, myocardial infarction, peripheral vascular disease, aortic aneurysms, and sudden death.2
Traditionally, clinicians have focused on atherosclerotic lesions that cause flow-limiting stenoses. However, over the past 2 decades, it has been shown that the process of atherosclerosis begins in the blood vessel wall3,4 as an extraluminal phenomenon, and the flow-limiting stenoses constitute a much later stage in the process of atherosclerosis. Also, studies have demonstrated that the benefits of therapy-related decreased clinical events are not proportional to parallel reductions in vessel stenoses. Therefore, the notion of flow-limiting stenoses has been challenged, and studies now focus more on the progressive atherosclerotic vessel wall.
Because of this, the American Heart Association created a detailed classification scheme that was designed to be used as a histological template for images obtained by a variety of invasive and noninvasive techniques in the clinical setting. It has been demonstrated that a vast majority of the thromboembolic events occur due to plaque rupture or erosion, which is characterized by thinning and rupture of the fibrous cap overlying the thrombogenic lipid core. Accurate in vivo tracking of progressive lesions would be extremely useful clinically to determine the status of atherosclerotic disease process.
In an effort to find more clinically pertinent markers of atherosclerosis, a number of alternative imaging strategies have been investigated. Whereas all other methods like angiography, elastography,5 thermography,6 and intravascular ultrasound7,8 either are invasive or characterize late-stage vascular disease, MRI offers a unique, noninvasive opportunity for sensitive detection and characterization of atherosclerotic disease. In this article, we will review the MR techniques used to measure atherosclerosis as well as the development of new contrast agents in the field of MR detection of atherosclerosis.
In order to accurately visualize the atherosclerotic plaque by MRI, many factors need to be taken into consideration. These include obtaining adequate spatial resolution and tissue contrast, avoiding or minimizing artifacts, being highly reproducible to facilitate longitudinal studies, and, at the same time, causing little or no discomfort to the subjects.
A normal artery wall is extremely thin (around 1 mm for the coronaries and thicker for the aorta and carotids), but with progressive arterial remodeling, this thickness can vary from a few millimeters to more than a centimeter. Also, an important consideration is the ability to discern different plaque components, including fibrous cap, lipid core, hemorrhage, and calcification. To achieve that, a spatial resolution in the submillimeter range is necessary.
With the advent of sophisticated receiver coils and improvements in hardware, it is now possible for MRI to achieve an in-plane resolution in the order of 0.25 x 0.25 mm2 in the carotids, 0.8 x 0.8 mm2 in the aorta, and 0.46 x 0.46 mm2 in the coronaries, with a 2 to 5 mm slice thickness, on a 1.5T magnet. The use of phased-array surface coil techniques has proven to be very effective in improving the signal-to-noise ratio (SNR). The widespread availability of 3T magnets likely will help improve the SNR, which can be traded partially for an improved spatial resolution.
MRI of the Artery Wall
|Figure 1. High-resolution MRI of carotid plaque showing a large lipid core (LC) and narrowed lumen. MRI obtained using high-resolution surface coils applied to the neck following administration of a gadolinium-based contrast agent.|
Comparison of T1, T2, and proton density images of atheroma. Studies have shown that T2-weighted (T2W) MRI provides excellent differentiation between the media and adventitia in muscular arteries, while proton-density–weighted (PDW) images are optimal for measurement of average wall thickness.9 Either T1-weighted (T1W) images or gradient echo images may demonstrate areas of calcification.9,10
Atherosclerotic plaques are of heterogeneous composition. In particular, the presence of a large extracellular lipid core (Figure 1), thin fibrous cap, and inflammatory cell infiltrate indicates plaque at risk for rupture.11,12 By use of a combination of inherent MRI contrast generated in T1W, T2W, and PDW images, it has been possible to determine plaque anatomy and composition in experimental animals,13,14 ex vivo specimens,15–17 and human carotid arteries15 and aortas in vivo.18
Contrast agents for imaging atheroma. Despite developments in MRI pulse sequences and use of high-resolution coils, there is overlap of signal intensities within the plaque, especially between lipid core and vessel media. More subtle distinctions within plaque and preatheromatous artery can be detected by the use of paramagnetic and superparamagnetic contrast agents.
|Figure 2. Intravascular MRI of the common femoral artery (dashed outline). A receiver coil has been placed in the adjacent common femoral vein (thin arrow). The lumen of the artery (L) is narrowed, and lipid-laden plaque (thick arrow) is seen in the wall of the common femoral artery.|
Paramagnetic contrast agents. To obtain good resolution, high signal bandwidth, and low SNR, a T1 shortening contrast agent is required (Figure 2). Gadolinium chelates not only serve this purpose19 but also improve blood-tissue contrast.20 Gadolinium contrast also can be used to detect changes like new vessel formation and inflammatory changes in atherosclerotic plaque.21–23 On T1W MRI, a gadolinium-based contrast agent can enhance differentially areas rich in plaque microvascularization and may distinguish the necrotic core and fibrous cap and thus highlight at-risk plaque (Figure 3).24 Increased vascularity and leakiness of vessels have been observed in the aortic walls by using MS-325 (gadofosveset trisodium), a gadolinium-based contrast agent that binds albumin.
Atherosclerotic plaques have been targeted with antibodies against plaque components, such as proliferating smooth muscle cells,25 fibrin, and fibrinogen,26,27 and extracellular matrix components, such as fibronectin.28 Yu et al29 defined the sensitivity of a fibrin-targeted contrast agent in vitro on human thrombus. The contrast agent was a lipid-encapsulated perfluorocarbon nanoparticle with numerous gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) complexes incorporated into the outer surface. Regardless of size, untreated clots were not detected by T1W MRI, while the targeted contrast agent dramatically improved the detectability of all clots.
|Figure 3. MRI of a human coronary atherosclerotic plaque (arrow) showing marked luminal narrowing (thin arrow). Image obtained with Robson Macedo, MD.|
Winter et al30 used alpha(v)beta3-integrin-targeted nanoparticles in rabbits. These particles provided specific detection of the angiogenesis at clinically relevant field strength (1.5T).
Superparamagnetic contrast agents. Superparamagnetic iron oxide (SPIOs) preparations are a group of highly effective contrast agents for MRI. Use of SPIO MRI contrast agents results in both T1 and T2 relaxation.31 Intravenously administered, SPIOs have long plasma half life and are, hence, blood pool agents. They are eliminated from the blood by phagocytosis by the cells of the mononuclear phagocytic system; thus, they can act as a marker of atherosclerosis-associated inflammatory changes.37 More recent studies now have shown promise that ultrasmall SPIO may allow assessment of atherosclerosis-associated inflammatory changes before luminal narrowing is present.32
Since focal recruitment of monocytes and lymphocytes is one of the earliest detectable cellular responses in the formation of lesions of atherosclerosis, monoclonal antibody-conjugated intra-vascular MR contrast agents against endothelial cell surface proteins, vascular cell adhesion molecule-1, and intercellular adhesion molecule-133–35 can be a possibility in the future.
The development of targeted paramagnetic contrast agents has been pursued for a long time now, but various complexities have contributed to the slow progress in this area, especially inadequate paramagnetic payload. To amplify the signal for MRI, approaches using liposomes have been employed. Coupling paramagnetic complexes to lipid anchors offers the capability of conjugating more gadolinium complexes onto the surface of liposomal particles.36
In the future, clinical investigation of atherosclerosis will not be restricted by the endoluminal approach. MRI has the ability to noninvasively characterize plaque composition and microanatomy and therefore to identify lesions vulnerable to rupture or erosion. This may aid in early intervention in the primary and secondary treatment of vascular disease. The high resolution of MRI and the development of sophisticated contrast agents offer the promise of in vivo molecular imaging of atherosclerosis.
Nishant Gupta, MBBS, is a radiologist and David A. Bluemke, MD, PhD, is clinical director, MRI, and associate professor, radiology, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore.
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