Atherosclerotic Plaque Imaging: Aorta and Carotid

Pathobiology of Atherosclerosis

Atherosclerosis is characterized by the gradual accumulation of lipid, inflammatory cells, and connective tissue within the arterial wall. It is a chronic, progressive disease with a very long asymptomatic/subclinical phase. The first abnormality to develop is the fatty streak, caused by the collection of lipid and macrophages in the subendothelial space. Fatty streaks develop primarily in regions of low wall shear stress, which results in endothelial dysfunction and the production of less nitric oxide. The major atherogenic risk factors including smoking, hypertension, and diabetes mellitus also all affect endothelial function, impairing both its barrier function and secretory capacity. Ultimately the blood vessel wall becomes more permeable to blood-derived lipids and inflammatory cells in these regions, encouraging the early stages of atherosclerosis.

Once within the subendothelial space, low-density lipoprotein (LDL) becomes oxidized and attracts monocytes by triggering the release of monocyte chemoattractant protein-1 (MCP-1) from the overlying endothelial cells. Endothelial adhesion molecules, including vascular cell adhesion molecule-1 (VCAM), intercellular adhesion molecule-1, E-selectin, and P-selectin, facilitate the internalization of further monocytes. Once they have escaped the blood pool, monocytes transform into macrophages and bind and internalize oxidative LDL via their scavenger receptors. Eventually, the subendothelial accumulation of modified LDL and macrophage-derived foam cells leads to the formation of the atheromatous lipid core. The thrombogenic components of the lipid core become separated from blood in the lumen by the endothelialized fibrous cap, which consists predominantly of vascular smooth muscle cells (VSMCs) and connective tissue. VSMCs migrate from the arterial media and synthesize the extracellular matrix components of the cap, such as elastin and collagen. The cap also contains variable numbers of inflammatory cells, most importantly macrophages. As the plaque enlarges, the affected artery grows outward (by expansion of the external elastic lamina) so that lumen diameter and therefore blood flow is initially preserved; this is a process known as positive remodeling. As the artery's wall stress increases with outward remodeling, further expansion eventually becomes impossible and the plaque then encroaches into the lumen. Ultimately this may cause angina by compromising blood flow to the myocardium.

Mature plaques may also become calcified, a process that preferentially affects the intima of the artery and is thought to occur as a healing response to inflammation and cell death within the plaque. Although the early stages of microcalcification are associated with high-risk inflamed atheroma, the latter stages of macrocalcification are by contrast associated with burnt-out stable disease. Very advanced plaques with a large necrotic core and associated hypoxia will also often be perforated by new blood vessels under the influence of angiogenic factors, a process called neovascularization , with similarities to that which occurs within growing tumors. However, these small arteries are structurally fragile and have a tendency to spontaneously hemorrhage, which can destabilize the plaque leading to increased plaque inflammation, rupture, and the precipitation of acute myocardial infarction.

Atherosclerotic plaques may remain quiescent for decades. However, when they initiate clot formation in the vessel lumen, they can very quickly become life threatening. This occurs predominantly as a result of fibrous cap rupture, with consequent exposure of the thrombogenic and tissue factor-rich lipid core to circulating blood. Less commonly, there can be erosion of the endothelial cell layer overlying the fibrous cap, which in the context of an advanced thrombogenic response can also lead to intravascular thrombosis. It is estimated that endothelial erosion accounts for ~30% of myocardial infarctions. Regardless of the mechanism, plaque disruption will lead to varying degrees of local platelet activation and thrombus formation, depending on the characteristics of the plaque and the thrombogenicity of the blood. Importantly, however, the majority of these plaque ruptures do not appear to result in overt clinical events but instead remain subclinical and responsible for abrupt plaque growth.

It has become clear that the cellular and extracellular composition of the plaque is the primary determinant of plaque stability. Lesions with a large lipid core, thin fibrous cap, positive remodeling, angiogenesis, microcalcification, and a preponderance of inflammatory cells compared with VSMCs are at the highest risk of rupture. Inflammatory cells, particularly macrophages, produce metalloproteinase enzymes, which break down matrix proteins, weakening the fibrous cap. In addition, they secrete inflammatory cytokines, in particular interferon γ, which inhibit VSMC proliferation and matrix production. Furthermore, VSMCs in the fibrous cap have a reduced proliferative capacity and a propensity to apoptosis. Consequently, inflammation within the plaques promotes destruction of the fibrous cap, a propensity to plaque rupture, and subsequent thrombosis. However, this is balanced by the action of VSMCs, which nourish and repair the cap, promoting plaque stabilization. This dynamic balance between proinflammatory and healing responses across the vasculature ultimately governs a patient's risk of myocardial infarction or stroke. These processes are independent of the degree of luminal stenosis. Consequently, positively remodeled and angiographically invisible plaques can rupture to precipitate a fatal clinical event, while many large plaques that obstruct flow and cause angina may be stable and not life threatening. There is therefore an urgent need for imaging techniques that can discriminate “stable” from potentially “unstable” lesions in clinical practice. This chapter will investigate the role that cardiovascular magnetic resonance (CMR) imaging might play in this respect, with a focus on its ability to measure the total plaque burden, to investigate high-risk plaque characteristics, and to determine disease activity with advanced molecular techniques.

Imaging Atherosclerosis

CMR can make use of differences in tissue relaxation times (T1 and T2) and proton density, intrinsic material properties that affect the magnitude of the magnetic resonance (MR) signal, to generate soft-tissue contrast, providing detailed information about atherosclerotic plaque composition. This is readily feasible in the large and relatively immobile carotid arteries and thoracic aorta, with intensive research aimed at transferring these techniques into the more challenging coronary vasculature.

The aim of atherosclerotic plaque imaging is ultimately to identify vulnerable patients at high risk of myocardial infarction or stroke before symptoms and complications develop. Similarly, early identification of disease might allow the implementation of pharmacologic treatment to halt or even reverse the process of plaque progression and possibly prevent rupture (e.g., with statin therapy). Recently, rapid advances in CMR hardware, software, and molecular imaging tracers have seen CMR develop into a modality of considerable utility and versatility for imaging large vessel atheroma. In particular, assessments of atherosclerotic plaque burden offer powerful prediction of adverse cardiovascular events, whereas more advanced techniques aimed at evaluating high-risk plaque characteristics and disease activity hold promise in refining this risk prediction even further. Each of these features will be discussed in detail below.

Assessments of Plaque Burden

Simple measures of the atherosclerotic plaque burden in different vascular beds provide powerful prognostic information, presumably because the more plaques a patient has the more likely one will rupture or erode and cause an event. CMR can effectively image atherosclerotic plaque using high-resolution, black-blood, fast-spin echo sequences. Preparatory pulses null signal in the blood pool and perivascular fat, improving contrast between the plaques and vessel lumen, and surrounding tissue, respectively. The atherosclerotic plaque burden can then be quantified using measurements of plaque thickness in two dimensions and plaque volume in three dimensions. In the aorta these measurements demonstrate a close correlation with transesophageal echocardiography and with increasing numbers of cardiovascular risk factors. Similar approaches have been used to measure plaque thickness and the plaque volume in the carotid arteries, providing measures of atherosclerotic burden that compare favorably with histology and predict major adverse cardiovascular outcomes.

Black-blood CMR also allows the early detection of subclinical atherosclerotic disease. Indeed CMR is particularly attractive for this purpose, given the absence of ionizing radiation, and has already proved useful in several large cohort studies. In asymptomatic subjects enrolled in the Framingham Heart Study (FHS), FHS coronary risk score was strongly associated with asymptomatic aortic atherosclerosis detected by CMR. The prevalence and extent of aortic atherosclerosis increased with age. In a substudy of the Multiethnic Study of Atherosclerosis (MESA), CMR aortic wall thickness increased as a function of age, but males and black participants had the greatest wall thickness. In another study of 102 patients undergoing x-ray coronary angiography, aortic atherosclerotic plaques were detected with a higher frequency in active smokers and in those with high levels of LDL-cholesterol, but the volume and area of aortic plaques correlated most strongly with age and the presence of hypertension. Interestingly, only atherosclerotic plaques located in the thoracic aorta were found to be associated with coronary artery disease (CAD). Taken together, these studies confirm the strong correlation between the presence of cardiovascular risk factors and the incidence of aortic atherosclerosis. It should be noted, however, that there are racial and population differences in the response to individual risk factors, which presumably have a genetic basis.

Another benefit readily appreciated by pharmaceutical companies and others wishing to study the effects of drugs on plaque progression (and regression) is the low coefficient of variability of CMR plaque volume measurements. This translates directly into the requirement for lower patient numbers for studies investigating the impact of pharmaceutical agents on plaque volume, because any true drug effect will not be swamped by noise within the measuring technique. This was illustrated in two separate studies where high-dose statin regimens were shown to be superior to low-dose regimens in terms of atheroma burden reduction, an effect that could be demonstrated with only 20 patients per group.

Subsequently, in the first double-blind, multicentric, dal-PLAQUE (safety and efficacy of dalcetrapib on atherosclerotic disease using novel noninvasive multimodality imaging) study, 130 patients were randomly assigned to placebo ( N = 66) or 24 months treatment with the cholesterylester transfer protein (CETP) inhibitor dalcetrapib ( N = 64). In patients receiving dalcetrapib, the absolute change from baseline relative to placebo in total vessel area was 4.01 mm ² (90% CI, 7.23 to 0.80; nominal P = .04) over 24 months.

Plaque Characteristics

Plaques at risk of rupture have certain pathological characteristics, including inflammation, positive remodeling, a large necrotic core, angiogenesis, microcalcification, and a thin, fibrous cap. Each represents a potential imaging target, and although not all of these plaques will progress to rupture and even less will cause events, emerging evidence suggests that identification of such plaques may identify patients at increased cardiovascular risk. Again, CMR techniques aimed at resolving these characteristics are best suited to the carotid arteries.

Multicontrast Magnetic Resonance

Multicontrast CMR of the plaque is based on successive high-resolution black-blood fast-spin echo CMR sequences that null signal in the flowing blood and perivascular fat with preparatory pulses. Several sequences with different weightings are generally acquired (e.g., T1 weighted, T2 weighted, and proton density weighted [PDW]). Analysis of the various signal intensities in each of these sequences allows reasonable differentiation of plaque components. In particular, the lipid core, fibrous tissue, plaque hemorrhage, the fibrous cap, and the degree of calcification can all be identified and quantified according to their different relaxation properties on CMR. In Fig. 27.1 an axial section through the thorax reveals a complex aortic plaque. Fig. 27.2 demonstrates a carotid plaque imaged at 3 T, with corresponding T1, T2, and PDW images displayed. A final example of multicontrast CMR showing different plaque components and automatic segmentation of these plaques using a k -means cluster algorithm is shown in Fig. 27.3 .

The lipid rich necrotic core can be identified in the carotid arteries and aorta using multicontrast weightings plus postcontrast T1-weighted imaging, with advances in CMR acquisition protocols allowing acquisition times to be reduced many-fold. The necrotic core usually appears isointense to hyperintense on time-of-flight angiographic and precontrast T1-weighted images and has minimal contrast enhancement compared with the surrounding tissue on postcontrast T1-weighted images. The combination of these images can therefore be used to identify and quantify the lipid necrotic core burden. Yuan et al. demonstrated that multicontrast CMR of human carotid arteries had sensitivity and specificity values of 85% and 92%, respectively, for the identification of a lipid core.

Alterations in the lipid necrotic core burden with therapy have also been demonstrated and may be more sensitive to treatment effects than simple plaque burden measurements. The ORION trial assessed the impact of rosuvastatin on carotid plaque volume and composition in 43 patients treated for 2 years. Although no change in the plaque volume was observed, a reduction in the percentage of lipid necrotic core was demonstrated. A subsequent study by Zhao and colleagues confirmed the effect of lipid-lowering therapy on the lipid content of atherosclerotic plaque after just 1 year of treatment. Importantly, the observed reduction continued in to the second year of therapy and preceded any effects on vessel wall area.