section 20.3
Lipoprotein-Associated Disorders
445
factors, infectious microorganisms (e.g., herpes viruses,
Chlamydia pneumoniae),
or combinations of these fac-
tors. The endothelial response to injury which eventually
leads to atherosclerosis involves platelets, leukocytes, and
a variety of cytokines, e.g., vasoactive molecules, adhe-
sion molecules, and growth factors (Chapter 35). Once
the subendothelial region is exposed, circulating platelets
and monocytes become attached and release factors with
chemotactic and mitogenic properties. Platelet-derived
growth factor (PDGF), for example, binds with high affin-
ity to specific binding sites on the surface of smooth mus-
cle cells. PDGF induces DNA synthesis, thereby initiating
the proliferation of smooth muscle cells. It also increases
binding and degradation of LDL. Monocytes enter the
arterial wall at the site of injury and produce a mitogenic
factor that appears to be as potent as PDGF.
In the pathogenesis of atherothrombosis inflammation
may play a significant role. An acute-phase systemic in-
flammatory marker, C-reactive protein (CRP) is elevated
in patients with acute ischemia or myocardial infarction.
In a prospective study consisting of apparently healthy
men, individuals with high baseline plasma CRP levels
(1.51 vs. 1.31 mg/L) had a higher risk of myocardial in-
farction or ischemic stroke than men in the lower quartile
of CRP values. The use of aspirin, an anti-inflammatory
and antiplatelet drug, reduced the risk of myocardial in-
farction among men in the highest quartile of plasma CRP
levels. These data suggest that the plasma CRP level in
apparently healthy men can predict myocardial infarction
and ischemic stroke, and is an independent marker not
altered by plasma lipid levels, body mass index, smoking,
or blood pressure.
Oxidative modification of LDL (e.g., lipid peroxida-
tion) occurs primarily in the arterial intima and is a pre-
requisite for LDL uptake by macrophages. This uptake by
macrophages is not regulated like LDL uptake by receptor-
mediated endocytosis, and the uptake is done by a scav-
enger receptor. This unregulated uptake leads to accumu-
lation of LDL so that macrophages become foam cells.
The foam cells form yellow patches on the arterial wall
that are called
fatty streaks
(discussed later). Since oxi-
dized LDL is an important and possibly an essential com-
ponent in the pathogenesis of atherosclerosis, the inhibi-
tion of LDL oxidation by variety of antioxidants has been
considered in treating coronary artery disease. There are
two lipophilic antioxidants, a-tocopherol (vitamin E) and
/1-carotene (provitamin A), and the water-soluble antiox-
idant ascorbate (vitamin C). The antioxidants also help
maintain normal endothelial function (e.g., preserving
endothelial-derived nitric oxide production). Epidemio-
logical studies have shown an inverse relationship between
intake of antioxidant vitamins and coronary artery disease.
However, a cause-and-effect association between intake
of antioxidant vitamins and prevention of coronary artery
disease has not yet been determined. Probucol, in addition
to its hypocholesterolemic action (discussed later), also
has antioxidant properties.
Prostaglandins and thromboxanes play major roles in
platelet adhesion and aggregation to damaged intima
(Chapter 18). Normal endothelium synthesizes prosta-
cyclin (PGI
2
), which inhibits platelet aggregation. In
damaged endothelium, platelets
aggregate and form
thromboxanes; thromboxanes and endoperoxide (which
has increased owing to lack of utilization in the synthesis
of PGI
2
) accelerate the platelet aggregation and lead to the
formation of thrombus. Aspirin is an inhibitor of cyclooxy-
genase which initiates the synthesis of prostaglandins and
thromboxanes (Chapter 18). Aspirin therapy is beneficial
in the prevention of heart attacks and strokes by inter-
fering with the function of platelets. However, aspirin
may increase the risk of hemorrhagic stroke. Thus, the ben-
efits and risks of aspirin therapy in patients with known
coronary artery disease or history of stroke have to be
assessed before the initation of aspirin therapy.
Three types of atherosclerotic lesion exist:
1. The fatty streak, which is found at a young age
ubiquitously among the world’s population, consists
of smooth muscle cell aggregates surrounded by
cholesteryl ester deposits; it is a sessile lesion that
does not obstruct and presents no clinical symptoms.
2. The fibrous plaque, which protrudes into the lumen, is
composed chiefly of cholesteryl ester-loaded smooth
muscle cells proliferating in the intimal layer,
surrounded by collagen, elastic fibers, and
proteoglycans; it is enclosed in a fibrous cap.
3. The complicated lesion is associated with occlusive
disease; the contents of the fibrous plaque become
calcified and are altered as a result of hemorrhage,
cell necrosis, and mural thrombosis.
Although only the complicated plaque results in sig-
nificant (>75%) coronary lumenal narrowing, evidence
indicates that complicated lesions originate during the
first two decades of life. Such lesions were found on au-
topsy in more than a third of teenaged military casualties
in Vietnam and Korea. Although the final event that re-
sults in blockage of nutrient flow and myocardial infarc-
tion may be episodic rather than gradual, the degenerative
buildup of material appears to begin in childhood. It is
therefore not surprising that the serum cholesterol level in
children in those countries where coronary disease is rare
is significantly lower than that of “normal” children in the
U.S.A. For example, children between the ages of 10 and
14 years in Mexico have a mean serum cholesterol value
