Atherosclerotic cardiovascular disease is an inflammatory disease of the arteries, which causes more than 19 million deaths worldwide every year (Naghavi et al., 2003). In atherosclerosis, atherosclerotic plaques develop over decades, ultimately leading to advanced lesions with a lipid-rich, necrotic core separated from the lumen by a fibrous cap. A thick fibrous cap (> 65 ^m) indicates stability of the plaque since it prevents the thrombogenic lipid-rich necrotic core from contacting the blood in the lumen and promoting thrombus formation, which can lead to local or distal arterial occlusion with subsequent ischemia. About 70% of fatal acute myocardial infarctions and/or sudden coronary deaths is caused by rupture of the fibrous cap (Figure 5.1) while in only 2 out of 7 cases the ruptured plaque is stenotic before the acute event (Naghavi et al., 2003).
Thus, the risk of disruption depends on plaque vulnerability rather than on the degree of vascular stenosis.
During the past decade it has become evident that atherosclerosis is a chronic inflammatory disease (Hansson et al., 2002; Hansson, 2005; Tedgui and Mallat et al., 2006). In particular, the macrophage has emerged as the key cellular mediator of inflammation in atherosclerotic lesions, since macrophages participate in all phases of atherogenesis. After subtle endothelial injury, vascular endothelial cells become activated and start to express several types of leukocyte adhesions molecules (including VCAM-1 and E-selectin), which causes monocytes and lymphocytes to adhere to the site of endothelial activation. Once these monocytes and lymphocytes have attached, chemokines (including monocyte chemoattractant protein-1, MCP-1), produced by the underlying intima, stimulate them to migrate into the subendothelial space. Once resident in the arterial intima, monocytes differentiate into macrophages expressing both tolllike receptors and scavenger receptors. These scavenger receptors (including CD36 and SR-BI) internalize a broad range of molecules and particles including bacterial endotoxins, apoptotic cell fragments, and oxidized LDL, ultimately leading to foam cell formation. Toll-like receptors also bind molecules with pathogen-like molecular patterns, but in contrast to scavenger receptors they
can initiate a signal cascade that leads to cell activation. In addition to MCP-1, macrophage colony-stimulating factor (M-CSF) also appears to play an important role in the activation of various macrophage functions implicated in atheroge-nesis. Besides monocytes/macrophages, also T and B cells, natural killer T cells, antigen presenting dendritic cells, and mast cells contribute to plaque inflammation.
Plaque rupture preferentially occurs where the fibrous cap is thin. At these sites, activated immune cells are abundant. Especially, activated macrophages, T cells, and mast cells produce pro-inflammatory cytokines (including IL-1, TNF-a), proteolytic enzymes [e.g., matrix metalloproteinases (MMPs) and cysteine proteases (Cathespins)], coagulation factors, radicals, and vasoactive molecules transforming a stable plaque into a vulnerable plaque that can rupture and thereby induce thrombus formation. Furthermore, postmortem studies showed prominent macrophage accumulation in ruptured lesions, while stable plaques of patients with stable angina definitely contain less macrophages (Falk et al., 1995). Figure 5.2 shows an advanced macrophage-rich atherosclerotic plaque. Given the key role of macrophages in the development of atherosclerosis, imaging of inflammation is expected to be extremely valuable for the evaluation of therapy, e.g. using novel intermediate imaging as endpoint instead of major adverse clinical events as endpoint. Moreover, since an abundance of macrophages is found especially in ruptured lesions, such new imaging techniques might enable identification of patients at risk for future ischemic events, such as stroke. This is of major importance since decision-making in current clinical practice is still mainly based on degree of stenosis, which is a rather poor predictor for future clinical ischemic events.
Was this article helpful?