Ultrasound imaging for risk assessment in atherosclerosis

Abstract

Atherosclerosis and its consequences like acute myocardial infarction or stroke are highly prevalent in western countries, and the incidence of atherosclerosis is rapidly rising in developing countries. Atherosclerosis is a disease that progresses silently over several decades before it results in the aforementioned clinical consequences. Therefore, there is a clinical need for imaging methods to detect the early stages of atherosclerosis and to better risk stratify patients. In this review, we will discuss how ultrasound imaging can contribute to the detection and risk stratification of atherosclerosis by (a) detecting advanced and early plaques; (b) evaluating the biomechanical consequences of atherosclerosis in the vessel wall;

Figure 1

Pathogenesis of atherosclerosis. (a) In the first stage, low density lipoprotein-cholesterol (LDL) is deposited in the endothelium and undergoes oxidative modification, resulting in oxidized LDL (oxLDL). OxLDL stimulates endothelial cells to express adhesion molecules (vascular cell adhesion molecule-1 (VCAM-1), P-Selectin) and various chemokines (e.g., Monocyte Chemoattractant Protein-1 (MCP-1), Interleukin 8 (IL-8)). This leads to a recruitment of monocytes, which transmigrate into the intima and differentiate to pro-atherogenic macrophages; (b) Macrophages harvest residual oxLDL via their scavenger receptors and add to the endothelial activation and, subsequently, leukocyte recruitment with the secretion of Tumor Necrosis Factor α (TNF-α) and IL-6; (c) The increasing plaque volume promotes neovascularization. Proliferating smooth muscle cells (SMCs) stabilize the nascent fibrous plaque. With deposition of fibrin and activated platelets on the dysfunctional endothelium that expresses tissue factor (TF) and von Willebrand factor (vWF), a pro-thrombotic milieu is formed; (d) Foam cells can undergo apoptosis and release cell-debris and lipids, which will result in the formation of a necrotic core. In addition, proteases secreted from foam cells can destabilize the plaque. This can lead to plaque rupture, in which case extracellular matrix molecules (e.g., collagens, elastin, TF, vWF) catalyze thrombotic events.

Figure 2

B-mode imaging of the carotid artery. These images illustrate (a) a normal carotid artery; and (b) a large atherosclerotic plaque protruding into the lumen of the carotid artery. Reproduced from [25], with permission.

Figure 3

Contrast-enhanced ultrasound (CEUS) imaging of plaque neovascularization in a carotid plaque. (a) Carotid artery with intraplaque neovascularization on CEUS. The arrows denote microbubbles within neovessels in a plaque at the origin of the internal carotid artery; (b) Corresponding B-mode ultrasound image. Reproduced from [71] with permission.

Figure 4

Algorithm for ultrasound molecular imaging. After a bolus injection of targeted microbubbles, a percentage of the total number of microbubbles injected will adhere to the molecule of interest. Freely circulating microbubbles will be cleared in the liver over several minutes. The signal intensity before destruction at the site of interest will be the summation of adhering and free floating microbubbles. The signal intensity after destruction and a short period of reperfusion is generated only by the remaining circulating free microbubbles. Digital subtraction of pre- and post-destruction images can then be used to obtain signal from adhered microbubbles only. Adapted from [76].

Figure 5

Determinants of targeted micobubble retention. The determinants of targeted microbubble retention within a vessel is dependent on various factors, including the targeted molecules and the contrast agent itself as well as hemodynamic properties. Adapted from [78].

Figure 6

Molecular imaging of the effect of statin treatment on VCAM-1 expression in a mouse model of atherosclerosis. The images show (a) high signal in a non-treated animal after injection of VCAM-1 targeted microbubbles; (b) low signal in the same mouse after injection of microbubbles bearing a control antibody, whereas in a mouse treated with statins; both VCAM-1 targeted (c) and control microbubbles (d) show low signal. The color scale for the contrast enhanced ultrasound (CEU) images is shown at the bottom of each frame; (e,f) illustrate the outline of the ascending aorta on B-mode ultrasound images, which was used as a region of interest for acoustic intensity measurements. Reproduced from [96] with permission.