14 Atherogenesis

Inflammation initiation and fatty streak formation
Until recently, the understanding atherosclerosis has depended on the lipid hypothesis, i.e. that hypercholesterolemia is the major initiating factor in the development of atherosclerotic lesions. The lesions occur principally in large- and medium-sized elastic and muscular arteries with the predilection of regions subject to disturbed flow haemodynamics, such as bifurcations.
The increased level of cholesterol is carried in the blood by either low-density lipoprotein (LDL) or very-low density lipoprotein (VLDL) remnants, and the ’fatty streak’ formation is believed to begin with the diffusion of LDL through the EC junctions into the intima – a process usually appearing within the first decade of life. Lipoproteins are retained in the vessel wall by matrix components, notably proteoglycans, undergoing oxidative modifications by different pathways. Subsequently, the oxLDL can induce the overlying endothelium to express adhesion molecules and increase the secretion of chemotactic factors, which facilitate the homing of monocytes and lymphocytes to the localized and activated endothelial area. Under ordinary homeostatic circumstances, the endothelial monolayer is resistant to prolonged contact with blood leukocytes. However, in the presence of adhesion molecules, blood monocytes adhere to the endothelial layer and penetrate between intact ECs to the intima. The cells differentiate into macrophages (MØs), which internalize oxidized lipoproteins and accumulate them in the cytosol as cholesteryl ester droplets. Due to their foamy appearance under the light microscope, the lipid-laden MØs are also termed foam cells, and the accumulation of these constitutes the hallmark of the early and growing atherosclerotic plaque, designated by some as the ’fatty streak’ or ’fatty xanthoma’.


	Atherogenesis
Inflammation initiation and fatty streak formation Until recently, the understanding atherosclerosis has depended on the lipid hypothesis, i.e. that hypercholesterolemia is the major initiating factor in the development of atherosclerotic lesions. The lesions occur principally in large- and medium-sized elastic and muscular arteries with the predilection of regions subject to disturbed flow haemodynamics, such as bifurcations. The increased level of cholesterol is carried in the blood by either low-density lipoprotein (LDL) or very-low density lipoprotein (VLDL) remnants, and the ’fatty streak’ formation is believed to begin with the diffusion of LDL through the EC junctions into the intima – a process usually appearing within the first decade of life. Lipoproteins are retained in the vessel wall by matrix components, notably proteoglycans, undergoing oxidative modifications by different pathways. Subsequently, the oxLDL can induce the overlying endothelium to express adhesion molecules and increase the secretion of chemotactic factors, which facilitate the homing of monocytes and lymphocytes to the localized and activated endothelial area. Under ordinary homeostatic circumstances, the endothelial monolayer is resistant to prolonged contact with blood leukocytes. However, in the presence of adhesion molecules, blood monocytes adhere to the endothelial layer and penetrate between intact ECs to the intima. The cells differentiate into macrophages (MØs), which internalize oxidized lipoproteins and accumulate them in the cytosol as cholesteryl ester droplets. Due to their foamy appearance under the light microscope, the lipid-laden MØs are also termed foam cells, and the accumulation of these constitutes the hallmark of the early and growing atherosclerotic plaque, designated by some as the ’fatty streak’ or ’fatty xanthoma’.

Figure 2 Atherosclerotic development may be divided into several phases. In childhood and adolescence the lesions become visible as fatty streaks, revealing macrophage (MØ) foam cells under the microscope. These lesion are reversible but may progress to early stages of atherosclerosis. In the third decade, the atherosclerotic lesion, i.e. the atheroma/plaque, appears. It is surrounded by a fibrous cap and depending upon its composition and thickness, the plaque is referred to as stable or unstable. With time, both types are prone to rupture with following thrombus formation. The lesion becomes an advanced complicated lesion. If the thrombus occludes the lumen, ischaemia ensues, with clinical manifestations.