C h a p t e r 1 8
Disorders of Blood Flow and Blood Pressure
411
(
text continues on page 414
)
the reduction in blood flow becomes increasingly greater
as the disease progresses.
Complicated atherosclerotic lesions
develop when
the fibrous plaque breaks open, producing hemorrhage,
ulceration, and scar tissue deposits. Thrombosis is the
most important complication of atherosclerosis. It is
caused by slowing and turbulence of blood flow in the
region of the plaque and ulceration of the plaque.
Although the risk factors associated with atheroscle-
rosis have been identified through epidemiologic studies,
many unanswered questions remain regarding the mech-
anisms that contribute to the development of athero-
sclerotic lesions. The vascular endothelial layer, which
consists of a single layer of cells with cell-to-cell attach-
ments, normally serves as a selective barrier that protects
the subendothelial layers by interacting with blood cells
and other blood components. One hypothesis of plaque
formation suggests that injury to the endothelial vessel
layer is the initiating factor.
1,2
A number of factors are
regarded as possible injurious agents, including prod-
ucts associated with smoking, immune mechanisms, and
mechanical stress such as that associated with hyperten-
sion. The fact that atherosclerotic lesions tend to form
where vessels branch or where there is turbulent flow
suggests that hemodynamic factors may also play a role.
Hyperlipidemia, particularly elevated LDL, is also
believed to play an active role in the pathogenesis of the
atherosclerotic lesion. Interactions between the endo-
thelial layer of the vessel wall and white blood cells,
particularly the monocytes (blood macrophages), nor-
mally occur throughout life; these interactions increase
when blood cholesterol levels are elevated. One of
the earliest responses to elevated cholesterol levels is
the attachment of monocytes to the endothelium. The
monocytes have been observed to move through the
cell-to-cell attachments of the endothelial layer into the
subendothelial spaces, where they are transformed into
macrophages.
Activated macrophages release free radicals that oxi-
dize LDL, which in turn is toxic to the endothelium,
causing endothelial cell loss and exposure of the sub-
endothelial tissue to blood components. This leads to
platelet adhesion and aggregation and fibrin deposition.
Platelets and activated macrophages release various fac-
tors that are thought to modulate the proliferation of
smooth muscle cells and the deposition of extracellular
matrix in the lesions.
1,2,14
Activated macrophages also
ingest the oxidized LDL to become foam cells, which
are present in all stages of atherosclerotic plaque forma-
tion. Some of these cells die in place, releasing their fat
and cholesterol-laden membranes into the intercellular
space. This attracts more macrophages. Lipids released
from necrotic foam cells accumulate to form unstable
plaques (also known as vulneral plaque). Unstable
plaques typically are characterized histologically by
a large central lipid core, an inflammatory infiltrate,
and a thin fibrous cap. These vulnerable plaques are at
risk of rupture, often at the shoulder of the plaque (see
Fig. 18-7A) where the fibrous cap is thinnest and the
mechanical stresses highest.
2,14
Clinical Manifestations
Atherosclerosis usually doesn’t cause signs and symp-
toms until it severely narrows or totally blocks an
artery. Many people don’t know they have the disease
until they have a medical emergency, such as a heart
attack or stroke. Signs and symptoms will depend on
the vessels involved and the extent of vessel obstruction.
Atherosclerotic lesions produce their effects through
narrowing of the vessel and production of ischemia;
sudden vessel obstruction due to plaque hemorrhage or
rupture; thrombosis and formation of emboli resulting
from damage to the vessel endothelium; and aneurysm
formation due to weakening of the vessel wall.
1,2
In
larger vessels, such as the aorta, the important compli-
cations are those of thrombus formation and weakening
of the vessel wall. In medium-sized arteries, such as the
coronary and cerebral arteries, ischemia and infarction
due to vessel occlusion are more common. Although
atherosclerosis can affect any organ or tissue, the arter-
ies supplying the heart, brain, kidneys, lower extremi-
ties, and small intestine are most frequently involved
(see Fig. 18-6).
Vasculitis
The vasculitides are a group of vascular disorders that
cause inflammatory injury and necrosis of the blood ves-
sel wall.
1,2,15,16
Vessels of any type in virtually any organ
can be affected, resulting in a broad spectrum of signs
and symptoms. Because they may affect veins and capil-
laries, the terms
vasculitis, angiitis,
and
arteritis
often
are used interchangeably. Besides the finding referable to
the specific tissue or organ involved, the clinical manifes-
tations typically include constitutional signs and symp-
toms such as fever, myalgia, arthralgia, and malaise.
The two most common pathogenic mechanisms of
vasculitis are direct invasion of the vascular wall by an
infectious agent and immune-mediated inflammation.
1
The most common mechanisms that initiate nonin-
fectious vasculitis are pathological immune responses
that result in endothelial activation, with subsequent
vessel obstruction, and ischemia of the dependent tis-
sue. In almost all forms of vasculitis, the triggering
event initiating and driving the inflammatory process
is unknown.
2,16
A number of persons with vasculitis have circulating
antibodies called
antineutrophil cytoplasmic antibodies
(ANCAs) that react with antigens in the cytoplasm of
neutrophils.
1
Although the precise pathologic mecha-
nism is unknown, these antibodies may serve to initi-
ate an inflammatory state that continually recruits and
stimulates neutrophils to release reactive oxygen species
and proteolytic enzymes.
1
Serum ANCA titers, which
can correlate with disease activity, may serve as a use-
ful quantitative diagnostic marker for ANCA-associated
vasculitides.
The vasculitides are commonly classified based
on etiology, pathologic findings, and prognosis. One
