Porth's Essentials of Pathophysiology, 4e

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Circulatory Function

U N I T 5

Homocysteine is derived from the metabolism of dietary methionine, an amino acid that is abundant in animal protein. Homocysteine inhibits elements of the anticoagulant cascade and is associated with endothe- lial damage, which is thought to be an important first step in the development of atherosclerosis. 1,6 The nor- mal metabolism of homocysteine requires adequate folate and vitamin B 6 intake, although the jury is still out on whether supplemental folate and vitamin B 6 can reduce the incidence of cardiovascular disease. 1 Homocystinuria, due to rare hereditary errors of metab- olism, results in elevated homocysteine levels and pre- mature cardiovascular disease. 1 Lipoprotein(a) (Lp[a]), which is an altered form of LDL that contains apoB-100 linked to apoA, is consid- ered to be an independent risk factor for the develop- ment of atherosclerosis. 1,2 Lp(a) enhances cholesterol delivery to injured blood vessels, suppresses the genera- tion of plasmin, and promotes smooth muscle prolif- eration. Lipoprotein(a) levels are heritable and are not altered by most cholesterol-lowering drugs. 2

are responsible for the clinically significant manifestations of the disease. 1,2,14 Fatty streaks appear as thin yellow lines running along the major arteries, such as the aorta. The streak consists of smooth muscle cells filled with cholesterol and macrophages (a type of immune system “scavenger” cell that removes harmful substances, such as excess cholesterol particles, from the bloodstream). The first evidence of atherosclerosis, fatty streaks can be found in children 10 to 14 years of age regardless of gender or race. 1,2 They increase in number until about 20 years of age, and then remain static or regress. The fatty streak alone does not cause any symptoms but, over time, can develop into a more advanced form of atherosclerosis called an atheroma or fibrous plaque . The fibrous atheromatous plaque is the basic lesion of clinical atherosclerosis. It is characterized by the accumulation of intracellular and extracellular lipids, proliferation of vascular smooth muscle cells, formation of scar tissue, and calcification. The lesions begin as a gray to pearly white, elevated thickening of the vessel intima with a core of extracellular lipid covered by a fibrous cap of connective tissue and smooth muscle (Fig. 18-7). As the lesions increase in size, they encroach on the lumen of the artery and eventually may occlude the vessel or predispose to thrombus formation, causing a reduction of blood flow. Because blood flow is related to the fourth power of the vessel radius (see Chapter 17),

Pathogenesis and Mechanisms of Development

The lesions associated with atherosclerosis are of three different stages or subtypes: fatty streaks, fibrous athero- matous plaques, and complicated lesions. The latter two

LUMEN

Macrophage

CAP

Smooth muscle cells

Endothelial cell

Lymphocytes

SHOULDER

NECROTIC CORE

Lipid-laden macrophage

ELASTIC MEDIA

FIGURE 18-7. Fibrofatty plaque of atherosclerosis. (A) In this fully developed fibrous plaque, the core contains lipid-filled macrophages and necrotic smooth muscle cell debris.The “fibrous” cap is composed largely of smooth muscle cells, which produce collagen, small amounts of elastin, and glycosaminoglycans. Also shown are infiltrating macrophages and lymphocytes. Note that the endothelium over the surface of the fibrous cap frequently appears intact. (B) The aorta shows discrete raised, tan plaques. Focal plaque ulcerations are also evident. (From Gotlieb AI, Lui A. Blood vessels. In: Rubin R, Strayer DS, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams &Wilkins; 2012:447–448.) A B