446
U N I T 5
Circulatory Function
network or plexus of subendocardial vessels. Although
there are no connections between the large coro-
nary arteries, there are anastomotic channels that join
the small arteries. If larger vessels gradually become
occluded, the smaller collateral vessels increase in size
and provide alternative channels for blood flow. One of
the reasons individuals with CAD may not experience
any symptoms until the disease is advanced is due to the
development of collateral channels occurring in concert
with atherosclerotic changes (see Chapter 18).
Physical, metabolic, and neural factors control blood
flow in the coronary arteries. The openings for the coro-
nary arteries originate in the root of the aorta just out-
side the aortic valve. Thus, aortic blood pressure is the
main factor controlling the perfusion pressure in the
coronary arteries; aortic pressure is generated by the
heart itself. Myocardial blood flow, in turn, is largely
regulated by the metabolic activity of the myocardium
and autoregulatory mechanisms that control vessel dila-
tion. In addition to generating the aortic pressure that
propels blood through the coronary vessels, the con-
tracting heart muscle influences its own blood supply
by compressing the intramyocardial and subendocardial
blood vessels during systole.
Coronary blood flow is regulated by oxygen demand
of the cardiac muscle. Under resting conditions, the
heart extracts and utilizes 60% to 80% of oxygen in
the blood flowing through the coronary arteries, as
compared with the 25% to 30% extracted by skeletal
muscle.
4
There is little oxygen reserve in the blood, and
therefore, the coronary arteries vasodilate to meet the
metabolic needs of the myocardium during periods of
increased activity. Metabolic activity is a major deter-
minant of coronary blood flow. Numerous substances
(i.e., metabolites), which include potassium ions, lactic
acid, carbon dioxide, and adenosine, are released from
working myocardial cells and mediate the vasodilation
that accompanies increased cardiac work. Of these sub-
stances, adenosine has the greatest vasodilator effect
and is perhaps the most critical mediator of local blood
flow in coronary circulation.
4
Endothelial cells, which make up the inner lining of
all blood vessels including the coronary arteries, play
an active role in the control of blood flow. These cells
function as a selectively permeable barrier, which allows
for the movement of small and large molecules from
the blood to the tissues and also from the tissues to
the blood. In addition, endothelial cells synthesize and
release substances that affect relaxation or constriction
of the vascular smooth muscle cells in the arterial wall.
Potent vasodilators produced by the endothelium
include nitric oxide (NO), prostacyclin, and endothe-
lium-dependent hyperpolarizing factor (EDHF). The
most important of these is nitric oxide. Most vasodi-
lating stimuli exert their effects through nitric oxide
pathways.
7,8
The endothelium also is the source of endo-
thelium-dependent constricting factors, the best known
of which are the endothelins. Coagulation factors (e.g.,
thrombin), inflammatory mediators (e.g., histamine),
and mechanical factors (e.g., increased shear force
exerted on the vessel wall) and ischemia contribute to
flow-mediated vasodilation, and stimulate the synthesis
and release of nitric oxide.
5
Pathogenesis of Coronary Artery
Disease
The most common cause of CAD is atherosclerosis (dis-
cussed in Chapter 18). Atherosclerosis may affect one
or all three of the major epicardial coronary arteries
and their branches. Clinically significant lesions may be
located anywhere in these vessels, but tend to predomi-
nate in the first several centimeters of the left anterior
descending and left circumflex artery or along the entire
length of the right coronary artery.
6
In some cases the
major secondary branches also are involved.
Coronary heart disease is commonly divided into two
broad disorders: acute coronary syndromes and chronic
ischemic heart disease. The acute coronary syndromes
represent a spectrum ranging from unstable angina to
myocardial infarction that is caused by acute plaque dis-
ruption, whereas chronic ischemic heart disease is caused
by atherosclerosis or vasospasm of the coronary arteries.
Plaque Disruption andThrombus Formation
There are two types of atherosclerotic lesions: (1) the
fixed
or
stable plaque
, which obstructs blood flow, and
(2) the
vulnerable
or
unstable
plaque, which can rup-
ture, activating a cascade of events leading to thrombus
formation.
The fixed or stable plaque is commonly associated
with stable angina, and the unstable plaque is impli-
cated in unstable angina and myocardial infarction
(MI). In most cases the myocardial ischemia underlying
unstable angina and acute MI is precipitated by plaque
disruption, followed by thrombosis. The major deter-
minants of plaque vulnerability to disruption include
the size of its lipid-rich core, lack of stabilizing smooth
muscle cells, presence of inflammation with plaque deg-
radation, and stability and thickness of its fibrous cap
6,9
(Fig. 19-2). Plaques with a thin fibrous cap overlying a
large lipid core are at high risk for rupture.
10
Although plaque disruption may occur spontane-
ously, this event is often triggered by hemodynamic
factors, such as blood flow characteristics and vessel
tension. For example, an elevated risk for plaque dis-
ruption may result from physiologic events including
increased sympathetic activity elicited by rising blood
pressure, heart rate, or cardiac contractility.
6
Plaque
disruption is also associated with diurnal variation,
which commonly occurs within an hour of rising. This
phenomenon suggests that physiologic factors (e.g.,
coronary artery tone and blood pressure) may promote
atherosclerotic plaque disruption and subsequent plate-
let deposition.
6
The elevated sympathetic activity associ-
ated with wakefulness and being active may promote
platelet aggregation and fibrinolytic activity that favor
plaque disruption and thrombosis.
Local thrombosis occurring after plaque disruption
results from a complex interaction among the contents
