Atheroma

PATHOLOGY
A. Definition of Atheroma and Atherosclerosis
The word atheroma is derived from the Greek ‘‘athere’’
meaning porridge or gruel. When a plaque of atheroma
is cut open one sees a gelatinous, porridge-like material
which contains globules of cholesterol fat, neutral fat,
saturated sterols, protein granules, crystals of cholesterol,
fatty acids, calcium, and other cells. The amount of
calcium in the lesion (calcification) is extremely variable.
Fortunately, the porridge-like material does not touch the
blood that flows through the artery, because nature covers
the fatty material with a protective hard layer of cells
called fibrous tissue. The atheromatous material forms a
plaque, an opaque yellowish-white patch of thickening,
that juts into the lumen of the artery. An atheromatous
plaque therefore consists of a central fatty core that has
a variable amount of lipids and calcium covered by a
fibrous cap. Because the cap is hard and the medical word
for hardness is ‘‘sclerosis,’’ the disease is commonly called
atherosclerosis. The fibrous cap, however, may be quite
thin and fragile and prone to fracture and rupture or show
erosion in some individuals. The exposed material is highly
thrombogenic. Figure 2 gives a simplified representation
of an atheromatous plaque and the subsequent rupture
and blood clot that completely obstructs the artery.

B. Arteries Involved
Sites of predilection for atherosclerosis are illustrated in
Fig. 3. Why some arteries are spared and others are severely
involved is of particular concern to the author and appears
to have received small attention from research workers.
Scientific literature shows a paucity of research in this area
versus a great amount of research related to lipoproteins
and inflammation.

1. Aorta
The aorta is virtually always involved in cardiovascular
disease. There must be a reason for this that has not
received sufficient attention. As seen in the aorta, the
process begins with the appearance of yellowish areas in the
intima, which become distinctly raised. These focal areas
increase in extent and thickness and become confluent.
If a well-formed patch is incised, it is seen that a yellow
lipid-rich pulpy material occupies the deeper part of the
intima next to the media separated from the lumen by
connective tissue layers of varying depths. Sometimes this
layer is thick, and the patches show a whitish color
on surface view. ok he focal patches of atheroma are
conspicuously related to the orifice of branches of arteries
that stem from the aorta. Involvement of the aorta is
usually most marked at the lower end before bifurcation
into the iliac arteries.
Microscopic examination shows the lesions start first
and are always more advanced in the deeper part of the
intima, the fibers of which may be saturated with fatty
material. When atheroma of the aorta is advanced, it may
lead to weakening of the media of the artery resulting
in expansion and dilatation of the wall. This is called an
aneurysm.

2. Coronary Arteries
The coronary arteries are commonly involved in cardiovascular
disease (see Figures in the chapter entitled
‘‘Anatomy of the Heart and Circulation’’). This leads to
angina and culminates in fatal or nonfatal heart attacks.
Sudden cardiac death commonly occurs in asymptomatic
individuals. Why the coronary arteries are involved so
often as opposed to arteries in the upper limbs intrigues
this author and will be discussed in Section III. Also, the
coronary arteries are affected by severe atheroma in men
some 10 years before women are affected. Men therefore
between the ages of 40 and 55 commonly suffer heart
attacks. Heart attacks are uncommon in women until after
the age of 60.

3. Carotid Arteries
The carotid arteries and their medium-sized branches as
they enter the brain are commonly involved in atheromatous
disease; this is the cause of stroke. The incidence of
stroke in men and women ages 50–60 are similar however,
and this difference between carotid artery atheroma and
coronary atheroma remains unclear. The normal hormonal
status in women between ages 40 to 50 is believed to
contribute to their cardioprotection.

4. Iliac and Leg Arteries
The iliac arteries as they leave the aorta and pelvis are
prone to atherosclerosis as are the femoral arteries in the
thighs and the popliteal arteries behind the knees. Obstruction
in these arteries causes lack of circulation to the calf
muscles. This lack of blood supply causes intermittent pain
in the calf muscle during a brisk walk, and this condition is
referred to as intermittent claudication. The Emperor
Claudius limped because of a painful leg and, the word
claudication is the derived from his name.

5. Other Arteries Rarely Affected
The renal arteries that supply the kidney with blood are
fortunately only occasionally affected by atheroma. Why
the arteries supplying the upper limbs, the liver, and lungs
are spared and the spleen and the entire small and large
intestine are rarely affected is intriguing. Little attention
has been given to this disparity over the last 20 years.
Pulmonary arteries are involved only when there is high
pressure in the pulmonary circulation; thus turbulence
caused by a change in blood pressure is of importance.
Individuals with constant, long-term systolic blood pressure
in the normal range of 115–130 mmHg who show
a change of 20 mmHg to reach borderline hypertensive
l levels of 135–150 mmHg may be at risk for development
of progressive atherosclerosis.

PATHOGENESIS
The precise cause and pathogenesis of atheroma formation
remains unknown.
A. Current Pathogenic Theories
1. The Initial Lesion
The initial lesion is a small focus of injury of the intima
caused by increased turbulence of blood at special arterial
sites such as the orifice of branches — particularly that
of the aorta as mentioned above — bifurcations, and
curvatures that cause characteristic alterations in blood
flow. This small area of injury incites a unique protective,
nonspecific inflammatory response, but nature’s healing
has to contend with further turbulent blood flow and
further injury to the intima.

2. The Accumulation of Lipoprotein Particles
From observations in young adults dying of trauma and in
rabbits fed a diet high in cholesterol and saturated fat, the
accumulation of small lipoprotein particles in the intima
has been noted to be one of the first ultrastructural
alterations. This observation was noted in the 1950s and
still finds space in major cardiology textbooks printed in
2002. The search of a 1958 Muir’s textbook of pathology,
provides similar lines: ‘‘fatty degeneration usually occurs in
the intima. On microscopic examination they are found to
be due chiefly to fatty material in stellate cells of the intima
and macrophages, and to a certain extent in the endothelial
cells. This fatty deposit is cholesterol and glycerol fat. Such
patches have been found in children dying acutely of
trauma. They indicate that fat is prone to accumulate
within the intimal cells but the reason for this is obscure.’’
It appears that much remains to be clarified regarding the
pathogenesis of atheroma formation.

This author attempts to simplify the pathogenesis of
atherosclerosis as follows: atheroma is the result, of hemodynamic
forces that cause patchy arterial injury. This
provokes a healing response which involves a nonspecific
inflammatory reaction with the unfortunate accumulation
of lipid substances from circulating blood. The damaged
area is walled off by nature’s band-aid, a protective fibrous
cap. Smooth muscle cells play a major role in the healing
process.

3. Endothelial Activation and Leukocyte
Recruitment/Inflammatory Response
A nonspecific inflammatory response is central to the
atherosclerotic process from the beginning to its complication
of vessel occlusion which results in cardiovascular
events.

Endothelial injury, or activation, is followed by an
inflammatory process that commences with adherence
of leukocytes to the endothelium and diapedese between
endothelial cell junctions to enter the intima where they
begin to accumulate lipids and transform into foam cells.
Monocytes as well as T lymphocytes tend to accumulate.
The following molecular mediators play a major role in
the development of atheroma:
1. Vascular cell adhesion molecule-1(VCAM-1) facilitates
attraction of leukocytes to the endothelial surface.
Studies indicate that rabbits given a normal diet showed
no expression of VCAM-1 but greatly increased
expression of VCAM-1 and adherent leukocytes when
the rabbits were fed a high-cholesterol diet.
2. Monocyte chemoattractant protein-1 (MCP-1) produced
by the intima and smooth muscle cells from the
medial wall of the artery assist monocyte transfer across
the endothelium.
3. Monocyte activation results in the expression of
scavenger receptors by macrophages and transformation
of macrophages into foam cells. Macrophage-colony
stimulating factor (M-CSF) has a key role in foam
cell formation because it acts as a potent monocyte
activator. Animal studies indicate that M-CSF deficiency
causes decreased atheroma formation in LDLreceptor-
deficient mice.

Figure 1 give a simplified portrait of how
the hidden key, turbulence of blood, initiates endothelial
injury and dysfunction. This calls forth activated macrophages
to the scene of injury followed by accumulation
of oxidized LDL cholesterol and a nonspecific inflammatory
response occurs. This response is similar to that
observed following allergic reactions, autoimmune processes,
and trauma, but with the unique features imposed
by the silky, smooth endothelial lining of arteries that has
a protective, strong media (see Fig. 2). The media contains
smooth muscle cells which migrate into the injured area
to assist in healing the minute wound. Much research
has been done on the smooth muscle cell and its important
contribution to the atherosclerotic process. The
contribution of the smooth muscle cells, however,
commences after the injury has been inflicted. Figure 1
illustrates further details.

It has been noted that increased turbulence of blood
at specific arterial sites causes rolling and adherence of
monocytes and T cells. This is believed to be the result of
the upregulation of adhesion molecules on both the
endothelium and on leukocytes.
4. Intracellular Lipid Accumulation and Foam
Cell Formation
Monocytes once trapped in the arterial intima imbibe
lipid substances. This lipid-laden macrophage is called
a foam cell. These macrophages are stimulated to divide
under the influence of a co-mitogen, M-CSF, and
interleukin-3.
5. The Smooth Muscle Cell Migration and Proliferation
Tough smooth muscle cells migrate from the media
into the intima probably to strengthen the injured area.
The chemoattractants for smooth muscle cells appear to
be platelet-derived growth factor secreted by activated
macrophages. The smooth muscle cells also divide vigorously,
but some cell death occurs.
6. LDL Cholesterol Involvement
LDL activates foam cells and causes injury to these cells
within the intimal lesion. It appears that LDL cholesterol
is chemotactic for other monocytes. This enhances the
inflammatory response by stimulating the replication of
monocyte-derived macrophages and the attraction of new
monocytes into the early atheromatous lesion. This activity
further stimulates migration and proliferation of smooth
muscle cells into the intimal area of injury. The tough
smooth muscle cells, along with other cellular and noncellular
components, assume a protective role in an
endeavor to form a fibroproliferative barrier that thickens
the arterial wall at the site of injury. This is nature’s way
of healing, but occasionally the healing process is incomplete,
which results in a thin, fragile protective cap prone
to erosion and rupture.
7. Infection
There is unconvincing evidence that certain infectious
organisms including Chlamydia pneumoniae, cytomegalovirus,
Helicobacter pylori, and others may be involved in
the inflammatory process and evolution of plaque rupture.
Increased antibody titers to these organisms have been
used as predictors of further cardiac events in patients
following a heart attack. Examination of atheromatous
lesions has occasionally identified C. pneumoniae. Clinical
trials using antibiotics have thus far not been beneficial,
but this organism may contribute to destabilization of
atheromatous plaques and may play a role in initiating
plaque rupture. Clarification of this is necessary.
A recent study by Agmon et al. indicated that C. pneumoniae
IgG antibody titers are not associated with the
presence or severity of aortic atherosclerosis in the general
population. This observation does not support a role
for infection by this organism in the initiation or progression
of atherosclerosis.

The levels of circulating markers of inflammation such
as C-reactive protein, a marker of nonspecific inflammatory
processes, are higher in patients with unstable coronary
artery disease than in those with stable coronary
disease. Persistent elevation of C-reactive protein in
patients with unstable angina strongly predicts further
serious cardiac events. The precise mechanisms by which
early plaque formation initiates an inflammatory response
in the absence of infection by microorganisms remains
unclear. (see the chapter C-Reactive Protein.)

B. Hydrodynamic Forces/Pulsatile Blood Flow
Mechanical forces on the walls of arteries consist of three
types:
(1) the tangential fictional force from the flow of blood
across the endothelial surface, (2) the transmural pressure
(the direct effect of pressure), and (3) wall stress as a result
of pressure-induced wall deformation and subsequent
cyclic strain. Increased blood pressure appears to promote
atherogenesis through biomechanical effects of pulsatile
blood flow, or cyclic strain, which has been observed
to affect endothelial cell gene expression and function.
Okada et al. have shown that changes in shear stress
regulate endothelial production of several factors including
vasodilators such as nitric oxide (NO) and prostacyclin and
vasoconstrictors such as endothelin-1. They also showed
that increased cyclic stretch augments production of IL-8
and MCP-1 in a dose-dependent fashion.

Linear shear stress forces appear to be atheroprotective
and associated with reduced production of reactive oxygen
species (ROS). Oxidative stress results from the production
of ROS, superoxide anion, and hydrogen peroxide.
These are molecules that cause oxidative damage and
trigger intracellular signaling cascades. The muscular wall
of arteries is a rich source of ROS; the constituents of
atheromatous plaques produce and use ROS. Hypercholesterolemia
induced in rabbits causes an increase in
ROS in rabbit aortas. Treatment with the antioxidant
polyethyleneglycol superoxide appears to reverse impaired
endothelial-dependent relaxation observed in rabbit aortic
tissue. Dietary lowering of cholesterol reduces ROS
production in rabbits.

Low shear stress and disturbed flow are associated
with increased production of ROS and redox sensitive
upregulation of chemoattractant adhesion molecules
(VCAM-1). Cyclic strain increases s1CAM-1 expression
by human endothelial cells in a time- and strain-dependent
manner resulting in increased monocyte adhesion.
In vitro studies with animal models of hypertension
have shown increased production of ROS in arterial
tissues. Increased cyclic biomechanical strains modify
macrophage function by increasing expression of scavenger
receptors that participate in the deposit of lipid in the
arterial wall.

C. Arteries of Predilection
As described in Section II, several arteries are spared atheromatous
lesions.
1. Veins
Atheroma does not occur in veins because the thin-walled
veins do not contain an appreciable media, and they are
not exposed to the same hemodynamic stress and turbulence
of blood that occurs in arteries.
2. Pulmonary Arteries
Atheroma is virtually never seen in the pulmonary arteries
and pulmonary veins. These arteries are large and mediumsized.
The pulmonary artery receives blood that is ejected
from the right ventricle and circulates the blood to the
lungs. It is similar to blood being ejected from the left
ventricle into the aorta. The only difference is that the left
ventricle pumps blood more vigorously and at higher
pressures and velocity therefore submitting arteries to
turbulent flow. Thus, the tendency for atheroma to be
most marked in the lower part of the aorta is probably due
to the increased hydrostatic pressure in that position. The
right ventricle ejects blood into the pulmonary artery at a
low pressure (25 mmHg vs. greater than 120 mmHg in the
aorta). The resistance to flow of blood through the lungs is
low, thus the right ventricle ejects blood at a much lower
velocity than the left ventricle. Atheroma in the pulmonary
arteries is virtually absent except in the presence of severe
pulmonary hypertension. This author was intrigued by this
finding more than 25 years ago. The finding seems
to support the hypothesis that turbulent flow may initiate
the lesions of atheroma in arteries at points in which
maximum turbulence occur.

Vulnerable areas are present in the aorta which have
to withstand the force of cardiac ejection velocity.
Branches of the aorta, particularly the carotid, iliac, and
femoral-popliteal arteries are vulnerable. More important,
the coronary arteries have a unique flow pattern as they are
empty during cardiac systole and fill only during diastole.
This spurt-flow phenomenon may perhaps explain their
predilection to hemodynamic injury.

3. Arteries of the Upper Limbs
The arteries of the upper limbs include the subclavian
and brachial arteries and medium-sized arteries similar to
the ones in the legs or the carotid arteries of the head.
Atheroma is not usually seen in these arteries. The reason
why these arteries are not involved may hold the key to
the puzzle of atheroma formation. The kidney arteries
circulate the entire blood volume to be filtered by the
kidney. Atheromatous lesions in these arteries were relatively
rare compared to the involvement of the coronary
and carotid arteries.

4. Aorta and Iliac Vessels
These vessels withstand the entire hemodynamic force
transmitted directly by ejection of blood into the aorta
from the powerful heart muscle. The velocity and turbulence
is excessive at branching points including the
bifurcation of the aorta and iliac arteries and in individuals
who have high circulating LDL cholesterol lesions are
expected to be more aggressive.

5. Coronary Arteries
The coronary arteries are commonly involved and this is
not surprising. These are unique arteries. They are
different from the arteries in the rest of the body. It is
important to stress that these arteries collapse during the
systolic contraction of the heart. They fill intermittently
during diastole when the heart is relaxed. This intermittent
flow to cardiac muscles that work harder and longer than
any muscles in the body probably cause hemodynamic
injury to the coronary arterial wall.
Agents that reduce turbulence and velocity of flow,
particularly the beta-blocking drugs, may prove beneficial
in clinical trials when used in conjunction with statins to
reduce LDL cholesterol levels to less than 80 mg/dl in
younger individuals at risk. It is of interest that in the
management of patients with ruptured aortic aneurysms
or dissecting aneurysms a beta-blocking drug is given
immediately to quell the ejection velocity of blood that
further tears the ruptured artery.

6. Angiogenesis in Plaques
During the past decade therapeutic angiogenesis has come
into vogue. The use of angiogenic peptides is believed to
produce therapeutic angiogenesis in the heart to improve
blood supply and oxygen to muscles deprived of blood.
Unfortunately, this may not be such a good therapeutic
strategy.
It appears that old and important information has been
lost amongst recent researchers. In some cases of
myocardial infarction and sudden death, sudden occlusion
of the artery occurs because of hemorrhage into the plaque
followed by rupture of the plaque and subsequent
thrombosis. The initiating event in these cases is not the
usual cause of a heart attack — Unfortunately, because
micro vessels within the plaque are friable and prone to
burst, attempts to augment myocardial blood flow by
enhancing new vessel growth by transfer of angiogenic
proteins or their genes might have deleterious effects on
lesion growth. They may initiate hemorrhage and plaque
rupture, a disaster that researchers are trying desperately to
prevent. See the section below, Vulnerable Atheromatous
Plaques.

D. Other Risk Factors
1. Diabetes
The importance of diabetes as the cause of accelerated
and progressive atherosclerosis is described in the chapter
Diabetes and Cardiovascular Disease. The role of hypertension,
elevated LDL cholesterol, and low levels of HDL
cholesterol are discussed above. These factors in diabetic
patients cause aggressive atheromatous obstruction of
arteries at many sites in the body.
2. Cigarette Smoking
Antioxidant stress and other deleterious effects caused by
cigarette smoking are believed to play a role in cardiovascular
disease, but the exact mechanisms have not been
clarified yet.
3. Familial Predisposition
Undefined genetic factors play a major role in the predisposition
for the development of atheromatous coronary
artery disease and its complication of myocardial infarction
and sudden cardiac death. A family history of sudden
coronary death before age 50 places the individual at
high risk.
4. Stressful Lifestyle
A stressful lifestyle in individuals with other risk factors
increases the likelihood of atheromatous coronary disease
(see the chapter Stress and Heart Disease).
5. Age
Age is an overwhelming factor in cardiovascular disease.
It is well known that atheroma formation is more prevalent
in the elderly. Realistically the disease starts from
approximately age 25 and increases gradually culminating
in most populations between the age of 40 and 50. It takes
10–15 years for lesions to grow sufficiently to obstruct
vessels, except when an asymptomatic plaque that is
causing less than 60% occlusion of an artery accelerates
and ruptures for reasons that are presently obscure and
associated thrombosis occludes the artery. This commonly
occurs in diabetics and in patients with high LDL
cholesterol levels. In many patients the disease advances
slowly between the age of 50 and 70 without causing
symptoms. In women often after age 75 cardiovascular
disease culminates in obstruction of an artery, myocardial
infarction, or death. Men, unfortunately, are weaker and
die earlier.
6. Homocysteine
There has been much talk in the past decade about
the influence of elevated plasma homocysteine, atheroma
formation and risk for cardiac events. The evidence linking
elevated homocysteine levels and atherosclerosis is indeed
weak. In a randomized clinical trial the administration of
pyridoxine and folic acid caused a reduction of homocysteine
levels, but resulted in a greater number of occlusions
to intracoronary stents. In the Vitamin Intervention
for Stroke Prevention (VISP) randomized controlled trial
reduction of total homocysteine after nondisabling cerebral
infarction had no effect on vascular outcomes during the
2 years of follow up.

VULNERABLE ATHEROMATOUS PLAQUES
A. Rupture of the Plaque
Uneven thinning and fracture or fissuring of the plaque’s
fibrous cap leads to rupture. The porridge-like substances
exposed to the flowing blood are highly thrombogenic
and trigger thrombosis that blocks the lumen of the artery.
This is the main underlying cause of a myocardial infarct
(see Fig. 2). Fracture of the fibrous cap occurs often at
the shoulders of a lipid-rich plaque where macrophages
enter. The processes and mechanisms that underlie thinning
fracture and rupture of plaques are unclear, and they
are presently a subject of extensive research.
The provision of durable collagenous tissue processed
by smooth muscle cells is important in maintaining the
existence of the plaque’s fibrous cap. Collagen provides
most of the biomechanical resistance to disruption of
the fibrous cap. Substances found in degranulating
platelets appear to increase smooth muscle cell collagen
synthesis that may reinforce the strength and viability of
the fibrous cap. Additionally, in some lesions there is a
marked decrease in the presence of smooth muscle cells
or increased smooth muscle cell death within the plaque
occurs, and this reduces collagen production. It is possible
that the new capillaries and vessels within the plaque
may be important for the survival of smooth muscle cells.
Thus, angiogenesis may be hazardous.
Platelets play an important role in initiating clotting
in arteries and arterioles. They form an initial plug or
clot and are followed by the deposit of a fibrin mesh that
forms a firm clot. Platelets are trapped by the material
exposed by the fractured plaque and the first phase of
thrombosis is initiated. Aspirin or platelet glycoprotein
IIa/IIIb receptor blockers are used to prevent this deleterious
platelet aggregation. Platelets are intriguing blood
particles that require much research in order to uncover
their therapeutic potential.

B. Superficial Erosion of the Endothelial Lining
Covering the Plaque
Evidence of superficial erosion of the intimal lining has
been observed in approximately 25% of patients who have
sustained a myocardial infarction and died within a few
hours. Endothelial cell desquamation through activation of
basement membrane degrading metalloproteinases appears
to be involved, but the mechanisms are unclear.

C. Hemorrhage into the Plaque
New capillaries and small vessels grow into the plaque
and provide a useful function in that they may provide
nutrient material for smooth muscle cells that form
collagen necessary to strengthen the fibrous cap. These
new vessels are, however, fragile and may burst causing
a minute hemorrhage within the plaque. The pressure
within the plaque may cause disruption of the fibrous cap,
and thrombosis completes the occlusion of the artery.

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