Pathogenesis of an atherosclerotic lesion

The initial lesion in the pathway to an atherosclerotic plaque is thought to be intimal disruption. The cause of the intimal damage may be physiological, for example shear stress at vessel bifurcations. Damage is probably exacerbated by other factors such as hypertension, smoking and dyslipidaemia.

Ideally the intimal damage is resolved however a chronic inflammatory response may be initiated, particulary in the patient with elevated cholesterol.

The early lesion, or fatty streak, is characterised by macrophages and vascular smooth muscle cells which are full of oxidised LDL cholesterol. They appear as foam cells within the vascular wall. The intiating event in the formation of the fatty streak is the passage of increased levels of LDL levels across the endothelium of an artery into its wall. This is likely to occur at a site of intimal damage (as described above). The damaged endothelium attracts monocytes from the blood circulation who cross the endotheliumto enter the subintimal space, where they also take LDL and assume the morphology of macrophages.

The formation of atheroma from fatty streaks depends on the differentiation and proliferation of smooth-muscle cells into fibroblasts, the elaboration of collagen and repetition of the whole process. This process, which is clearly part of an inappropriately activated tissue repair process, leads to the development of the atheromatous plaque, the mature atheromatous lesion.

With time the plaque develops a central necrotic core containing oxidised cholesterol. The collagen elaborated by fibroblasts comes to overlie the macrophage foam cells, which undergo either aptosis or necrosis. The shoulder of the atheromatous lesion - this is where the fibrous cap joins the arterial wall - is a site of continued active formation of foam cells as the atheromatous lesion progresses across the inner surface of the artery. The atheromatous plaque is weak at the shoulder of the lesion and it is this part of the cap that usually ruptures. If plaques are cholesterol-rich then they are especially liable to rupture their overlying fibrous cap. Plaques with tough fibrous caps are relatively low risk.

The cholesterol lake may be discharged from the plaque following rupture of a fibrous cap. If this occurs then either:

• there is formation of a mainly atheromatous lesion if the healing occurs uneventfully, or,
• formation of thrombosis at the site of the ruptured cap - if there is extension of this thrombosis then this may result in unstable angina, myocardial infarction or sudden cardiac death

With respect to coronary atheroma, factors which determine the pathological consequences of the atheroma include:

• factors that promote rupture of plaques e.g. high circulating concentration of LDL cholesterol which contribute to cholesterol-rich plaques
• factors increasing likelihood of thrombosis e.g. cirgarette smoking, diabetes - associated with increased levels of circulating fibrinogen
• myocardial factors e.g. extent of damage of myocardium which occurs when occlusion occurs or the tendency of the ischaemic myocardium to dysrhythmia
• traditionally, the development of coronary artery disease (CAD) was described as a gradual growth of plaques within the intima of the vessel. The outer boundaries of the intima, the media and the external elastic membrane (EEM), were thought to be fixed in size. In this model plaque growth would always lead to luminal narrowing and the number and severity of angiographic stenoses would reflect the extent of coronary disease. However, histologic studies demonstrated that certain plaques do not reduce luminal size, presumably because of expansion of the media and EEM during atheroma development. This phenomenon of "arterial remodeling" was confirmed in necropsy specimens of human coronary arteries. More recently, the development of contemporary imaging technology, particularly intravascular ultrasound, has allowed the study of arterial remodeling in vivo. These new imaging modalities have confirmed that plaque progression and regression are not closely related to luminal size (1)

Reference:

1. J Am Coll Cardiol 2001 Aug;38(2):297-30