Atherosclerosis - pediagenosis
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Saturday, November 17, 2018


Atherosclerosis is a disease of the larger arteries. It begins in childhood with localized accumulations of lipid within the arterial intima, termed fatty streaks. By middle age some of these develop into atherosclerotic plaques, focal lesions where the arterial wall is grossly abnormal. Plaques may be several centimetres across, and are most common in the aorta, the coronary and internal carotid arteries, and the circle of Willis. An advanced atherosclerotic plaque, illustrated on the right of Figure 37, demonstrates several features.

1. The arterial wall is focally thickened by intimal smooth muscle cell proliferation and the deposition of fibrous connective tissue, forming a hard fibrous cap. This projects into the vascular lumen, restricting the flow of blood, and often causes ischaemia in the tissue region served by the artery.
2.   A soft pool of extracellular lipid and cell debris accumulates beneath the fibrous cap (athera is Greek for ‘gruel’ or ‘porridge’). This weakens the arterial wall, so that the fibrous cap may fissure or tear away. As a result, blood enters the lesions and thrombi (blood clots) are formed. These thrombi, or the material leaking from the ruptured lesion, may be carried to the upstream vascular bed to embolize (plug) smaller vessels. A larger thrombus may totally occlude (block) the artery at the site of the lesion. This causes myocardial infarction or stroke if it occurs in a coronary or cerebral artery, respectively.
3. The endothelium over the lesion is partially or completely lost. This can lead to ongoing formation of thrombi, causing intermittent flow occlusion as in unstable angina.
4.   The medial smooth muscle layer under the lesion degenerates. This weakens the vascular wall, which may distend and eventually rupture (an aneurysm). Aneurysms are especially common in the abdominal aorta.
Atherosclerotic arteries may also demonstrate spasms or reduced vasodilatation. This worsens the restriction of the blood flow and promotes thrombus formation (see Chapters 42 and 44).

Pathogenesis of atherosclerosis
The risk of developing atherosclerosis is in part genetically determined. The incidence of clinical consequences of atherosclerosis such as ischaemic heart disease rises with age, especially after age 40. Atherosclerosis is much more common in men than in women. This difference is probably due to a protective effect of oestrogen, and progressively disappears after menopause. Important risk factors that predispose towards atherosclerosis include smoking, hypertension, diabetes and high serum cholesterol.
The most widely accepted hypothesis for the pathogenesis of atherosclerosis proposes that it is initiated by endothelial injury or dysfunction. Plaques tend to develop in areas of variable haemodynamic shear stress (e.g. where arteries branch or bifurcate). The endothelium is especially vulnerable to damage at such sites, as evidenced by increased endothelial cell turnover and permeability. Endothelial dysfunction promotes the adhesion of monocytes, white blood cells which burrow beneath the endothelial monolayer and become macrophages. Macrophages normally have an important role during inflammation, the body’s response to injury and infection. They do so by acting as scavenger cells to remove dead cells and foreign material, and also by subsequently releasing cytokines and growth factors to promote healing. As described below, however, macrophages in the arterial wall can be abnormally activated, causing a type of slow inflammatory reaction, which eventually results in advanced and clinically dangerous plaques.

Oxidized low-density lipoprotein, macrophages and atherogenesis
Lipoproteins transport cholesterol and other lipids in the bloodstream (see Chapter 36). Elevated levels of one type of lipoprotein, low-density lipoprotein (LDL), are associated with atherosclerosis. Native LDL is not atherogenic. However, oxidative modification of LDL by oxidants derived from macrophages and endothelial and smooth muscle cells can lead to the generation of highly atherogenic oxidized LDL within the vascular wall.
Oxidized LDL is thought to promote atherogenesis through several mechanisms (upper panel of Figure 37). Oxidized LDL is chemotactic for (i.e. attracts) circulating monocytes, and increases the expression of endothelial cell adhesion molecules to which monocytes attach. The monocytes then penetrate the endothelial monolayer, lodge beneath it and mature into macrophages. Cellular uptake of native LDL is normally highly regulated. However, certain cells, including macrophages, are unable to control their uptake of oxidized LDL, which occurs via scavenger receptors. Once within the vascular wall, macrophages therefore accumulate large quantities of oxidized LDL, eventually becoming the cholesterol-laden foam cells forming the fatty streak.
As shown in the lower left of Figure 37, stimulation of macrophages and endothelial cells by oxidized LDL causes these cells to release cytokines. T lymphocytes may also enter the vascular wall and release cytokines. Additional cytokines are released by platelets aggregating on the endothelium at the site at which it has been damaged by oxidized LDL and other toxic substances released by the foam cells. The cytokines act on the vascular smooth muscle cells of the media, causing them to migrate into the intima, to proliferate and to secrete abnormal amounts of collagen and other connective tissue proteins. Over time, the intimal accumulation of smooth muscle cells and connective tissue forms the fibrous cap on the inner arterial wall. Underneath this, ongoing foam cell formation and deterioration forms a layer of extracellular lipid (largely cholesterol and cholesteryl esters) and cellular debris. Still viable foam cells often localize at the edges or shoulders of the lesion. Underneath the lipid, the medial layer of smooth muscle cells is weakened and atrophied.

Clinical consequences of advanced atherosclerosis
Atherosclerotic lesions are of most clinical consequence when they occur in the coronary arteries. Lesions in which the fibrous cap becomes thick tend to cause a significant stenosis, or narrowing of the vascular lumen, which gradually comes to cause cardiac ischaemia, especially when myocardial oxygen demand rises. This leads to stable or exertional angina (see Chapter 39). Advanced plaques often have large areas of endothelial denudation, which serve as sites for thrombus formation. In addition, lipid and foam-cell-rich lesions are particularly unstable and prone to tearing open. This plaque rupture may be favoured by the presence in the lesion of T lymphocytes, as these produce interferon-γ which inhibits matrix formation, and of macrophages, which produce proteases that degrade the connective tissue matrix. Plaque rupture allows blood to enter the lesion, causing thrombi to form on the surface and/or within the lesion, often resulting in an acute coronary syndrome such as unstable angina (see Chapter 42) or myocardial infarction (see Chapter 43). Non-fatal chronic thrombi may gradually be replaced by connective tissue and incorporated into the lesion, a process termed organization. Atherosclerosis of cerebral arteries is the major cause of stroke (cerebral infarction). Atherosclerotic stenosis of the renal arteries causes about two-thirds of cases of renovascular hypertension.

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