410
U N I T 5
Circulatory Function
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
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
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),
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
CAP
Macrophage
Smooth muscle cells
LUMEN
Endothelial cell
Lymphocytes
SHOULDER
NECROTIC
CORE
ELASTIC MEDIA
Lipid-laden
macrophage
B
