ATHEROSCLEROSIS

Definition

Arteriosclerosis literally means “hardening of the arteries”; it is a generic term reflecting arterial wall thickening and loss of elasticity; from the Greek αρτηρία, meaning arteary, and σκληρωτικός, meaning sclerotic (Hardened). Three distinct types are recognized, each with different clinical and pathologic consequences:
Arteriolosclerosis
Thickening of the wall in small arteries and arterioles which carry important nutrients and blood to the body’s organs, causes a reduction in lumen size. Often related to systemic hypertension and diabetes mellitus
Atherosclerosis
is the narrowing of arteries from a build up of plaque, made up of cholesterol, fatty substances, cellular waste products, calcium and fibrin, inside the arteries. This affects large and medium-sized arteries; however, its positioning varies person to person
Monckeberg's arteriosclerosis or medial calcific sclerosis
Seen mostly in the elderly, Characterized by calcification of the tunica media (middle layer of the walls of arteries) but without thickening of the intima or narrowing of the vessel lumen

Pathophysiology

1. Atherosclerosis begins with injury to the endothelial cells that line artery walls. Inflamed endothelial cells cannot make normal amounts of antithrombic and vasodilating cytokines. Injury increases permeability to lipids and LDL, allowing their accumulation in the intima
2. Inflamed endothelial cells express adhesion molecules that bind macrophages and other inflammation immune cells (platelet). Macrophages adhere to the injured endothelium and release numerous inflammatory cytokines (Tumor necrosis factor-alpha [TNF-α], interferons, interleukins, and C-reactive protein)
3. Toxic oxygen radicals generated by the inflammatory process cause oxidation of LDL that has accumulated in the vessel intima. Hyperlipidemia, diabetes, smoking, and hypertension contribute to LDL oxidation and its accumulation in the vessel wall. Local oxidation of LDL is chemotactic for macrophages
4 Oxidized LDL causes additional adhesion molecule expression with the recruitment of monocytes that differentiate into macrophages; activate complement, and stimulate chemokine secretion. All of these factors cause adhesion and entry of mononuclear leukocytes, particularly monocytes and T lymphocytes
5. These macrophages penetrate into the intima where they engulf oxidized LDL. These lipid-laden macrophages are now called foam cells, and when they accumulate in significant amounts, they form a lesion called a fatty streak. Macrophage uptake of oxidized LDL also leads to presentation of its fragments to antigen-specific T cells. This induces an autoimmune reaction
6. Platelets adhere to activated endothelial cells or areas of denuded matrix and become activated. Activated platelets, activated endothelial cells and macrophages release platelet-derived growth factor (PDGF) stimulating smooth muscle cell migration from the media to the intima. Additional cytokines and growth factors produced by activated macrophages and platelets promote additional monocyte and smooth muscle infiltration
7. Smooth muscle cells in the region of endothelial injury proliferate, produce collagen, and migrate over the fatty streak, forming a fibrous plaque. The fibrous plaque may calcify, protrude into the vessel lumen, and obstruct blood flow to distal tissues (especially during exercise). Lipid may also be released from dying foam cells, contributing to extracellular free lipid pools
8. Advanced plaques: advanced atherosclerotic plaque consists of a lipid rich ‘core’ and a fibrous ‘cap’.The core of the lesion (which can become necrotic) consists of free lipid, macrophages, smooth muscle cells and cellular debris. The fibrous cap is composed primarily of collagen and lies over the core, beneath the endothelium
8.1 A stable advanced atherosclerotic plaque, is likely to remain asymptomatic for years. Initially, as the plaque expands it causes remodelling of the media allowing the vessel to increase its diameter, accommodating the plaque without compromising the vessel lumen. This is the principle
of Glagovian remodelling (Glagov phenomenon)

(The Glagov Phenomenon)

In the absence of this remodelling the plaque will grow, protruding into the lumen and progressively decreasing lumen size. It may only become apparent when the luminal diameter is not sufficient to
allow adequate organ perfusion
The stability of the plaque is dependent on the strength and thickness of the fibrous cap, which relies on the balance between inflammation and repair. If this balance is disturbed and inflammation predominates, the cap may become thinner, less stable and may rupture. Atherosclerotic plaques also predispose to aneurysm formation

8.2 Many plaques, however, are “unstable,” meaning they are prone to rupture even before they affect blood flow significantly and are clinically silent until they rupture
8.3 Plaque rupture occurs because of the inflammatory activation of proteinases, such as the matrix metalloproteinases and the cathepsins, and can be accelerated by bleeding within the lesion (plaque hemorrhage)
8.4 Once rupture occurs, exposure of underlying tissue results in platelet adhesion, initiation of the clotting cascade, and rapid thrombus formation. The thrombus may suddenly occlude the affected vessel, resulting in ischemia