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ATHEROSCLEROSIS AND OTHER VASCULAR DISORDERS
STUDY GUIDE
PAT 823
Use this document to further enhance your understanding of Dr. O'Connor's lecture /
handout on atherosclerosis. Note that this does NOT represent additional study material.
It is simply a study guide. Page numbers correspond to the handout.
PAGE 1
Arterial anatomy- The wall of any artery (large or small) consists of 3 layers:
1. The innermost layer (closest to the lumen and directly interfacing with the blood) is
called the intima. It is made up of a layer of endothelial cells, plus the loosely knit
connective tissue located directly below the endothelium (i.e. in the subendothelial
area). Normally, the intima is very thin (IMPORTANT).
2. The “middle” layer is called the media. It consists mostly of smooth muscle cells,
whose claim to fame is that they allow the artery to both constrict and dilate (very
important in blood pressure control). This is normally the thickest of the 3 layers.
3. The outermost layer is the adventitia, which is just a thin lining consisting of
connective tissue and blood vessels. Nothing exciting ever happens here.
Atherosclerosis is a disease of the intima (NB!!) of large and medium sized arteries.
(For some reason, small arteries do not develop atherosclerosis.) What happens is this:
Various substances (see below) invade and accumulate within a focal area of the intima,
just underneath the layer of endothelial cells. The result is a discrete mass, called the
lipid rich fibroatheroma, (or atherosclerotic plaque, or fibromuscular plaque, or just
plain old atheroma). The plaque bulges into the lumen of the artery. This represents an
area of narrowing of the arterial lumen. Although it sounds like no big deal, in fact it is.
The complications of arterial atherosclerosis harm and kill more people in the US than
any other disease.
Plaques have a tendency to form in those areas of turbulent blood flow. Thus, they are
commonly located in places where arteries bifurcate (branch off). Popular locations
include the origins of the coronary arteries (where they come off of the aorta), where the
iliacs branch off of the aorta, etc. The abdominal aorta probably gets hit the hardest
because so many arteries branch off from here.
It takes years for plaques to grow up and mature (this is, after all, a chronic disease). The
appearance of the plaques changes over time. If you cut open a mature plaque (been
around for a while) and looked at it grossly, you would see that it consists of 2 parts: The
center (or core) of the plaque consists of fat (mostly LDL cholesterol-see below). This
fatty core is covered by a layer of “stuff” (see below) called the fibrous cap. The fibrous
cap is covered by the layer of endothelial cells. Remember- all of this is located within
the intima, just below the endothelial cells.
Fatty streaks appear at a very, very young age. They consist of focal areas of lipid-laden
foam cells (see below) that are within the intima of arteries. These are felt to be
precursors to fibromuscular plaques.
It appears likely that, in some cases, early plaques may be able to regress. However, most
plaques will simply progress into bigger, more complicated lesions.
Microscopically, the mature plaque is quite complex. It consists of the following
components:
1. Foam cells- Both macrophages and smooth muscle cells phagocytose some of the
lipids within the core. The cytoplasms of these cells thus appear “foamy” because
they are lipid-laden. Note that the smooth muscle cells get into the intima via
migration from the media (see "anatomy", above).
2. Various connective tissue components- Collagen, etc.
3. Extracellular lipids- These are lipids within the core that have not been
phagocytosed by the foam cells. They’re loose. Most of the lipid within a plaque is
cholesterol, specifically LDL cholesterol. This cholesterol crystallizes.
Microscopically, this appears as needle-like cholesterol clefts.
4. Cellular debris- The foam cells become so full of lipid that they break up and die.
5. Fibrin- Travels from the bloodstream and into the plaque.
6. Neovessels- New, tiny blood vessels (actually capillaries) form within the plaque.
This is a result of angiogenesis (neovascularization). You recall these terms from the
lecture on healing by fibrosis.
Note that all of the components above are found in the core of the plaque.
The fibrous cap that covers the core consists of several elements, including some of the
elements listed above such as fibrin, collagen and even smooth muscle "foam" cells.
Vulnerable atherosclerotic plaques (very top of page 2)- REALLY, REALLY
IMPORTANT. These represent lipid rich fibroatheromas whose fibrous caps are
particularly thin. Several things can occur because of these thin caps, none of them good,
since they lead to several (dreaded) clinical complications (back to page 1!):
1. Erosion (also known as ulceration)- Bad. Essentially, the plaque has eroded through
the overlying layer of endothelial cells. The plaque now has a rough surface, and this
surface is now exposed to the bloodstream. This is a setup for platelets and fibrin
(from the bloodstream) to attach themselves to the surface of the plaque. This is the
dreaded phenomenon known as mural thrombosis. This overlying thrombus may be
large enough to cause total and sudden occlusion of the arterial lumen. Also, a piece
of the thrombus may break off and travel downstream (thromboembolization) where
it may then lodge (and suddenly occlude) a narrower portion of the artery. All this is
the set-up for ischemic infarcts of the heart (MI), brain (stroke), etc. This
phenomenon of atherothrombosis is a main cause of myocardial infarct.
2. Plaque rupture- Bad. Here, the thin fibrous cap has disintegrated. All of the contents
of the plaque (lipids, calcium, etc.) will be released into the bloodstream. This
atheromatous embolus may then suddenly occlude the artery further downstream
[may cause infarct (MI, etc.)]. The ruptured plaque may also allow a thrombus to
form within the plaque ("in situ"). This can cause rapid expansion in the size of the
plaque, with sudden occlusion of the artery as the result.
3. Hemorrhage into plaque- Bad. A crack in the thin cap will lead to bleeding from the
bloodstream and into the plaque (happens quickly). Alternatively, the neovessels that
are already present within the plaque may bleed. All of this blood within the plaque
leads to sudden expansion of the size of the plaque. This may result in sudden
occlusion of the arterial lumen, leading to, you guessed it, infarct.
4. Calcification- Over time, tremendous amounts of calcium accumulate within a
plaque. Initially, this causes the diseased area of artery to be brittle (e.g. you can
crush the artery with your hands). In extreme stages, the artery becomes as hard as a
pipe (i.e. “hardening of the arteries”).
5. Degeneration of the media- If the plaque becomes large enough, it will compress
against the adjacent media (middle layer of artery, remember?). This will cause that
area of media to become thin (pressure atrophy). Thus, this portion of the arterial wall
will be weakened. Result: the wall will balloon outward. This is an aneurysm, and
this is a really bad complication of atherosclerosis. These aneurysms tend to burst
and, if the artery is big enough (e.g. abdominal aorta), you’ll suffer serious
consequences (e.g. exsanguination).
PAGE 2
All of the events noted above can lead to a variety of clinical complications, the nature of
which depend on the anatomic location of the plaque (see diagram on page 3):
1. Lower (abdominal) aorta and iliac arteries- Typically, these arteries are loaded
with plaques. Thus, pressure atrophy of the media leads to aneurysms (very
common). The aneurysm may involve one focal area of the wall (saccular), or may
involve the entire wall circumferentially (fusiform). An abdominal aortic aneurysm
can burst. Certain death. Recall that the renal arteries and mesenteric (intestinal)
arteries originate off of the abdominal aorta. If plaques occur at the origins of these
arteries (where they come off of the aorta), this will lead to narrowing of their
lumens, with a decrease in blood flow (and thus ischemia) to these organs. Ischemia
of the kidneys can cause hypertension, and ischemia to the intestines can cause
bleeding and other things.
2. Coronary arteries- Specifically, the larger coronaries. (These cruise over the outside
surface, i.e. the epicardium, of the heart.) If a coronary plaque produces a 75% (or
greater) stenosis of the lumen, then that portion of the heart muscle supplied by the
coronary will become chronically ischemic (not enough blood/oxygen to the area).
Little by little, more and more heart muscle cells will die off and will be replaced by
scar tissue. If someone has bad atherosclerosis of all the major coronaries, he will
ultimately lose so many heart muscle cells that he will go into congestive heart
failure. Also, a vulnerable coronary plaque may suddenly develop complications, e.g.
ulceration (same thing as erosion), hemorrhage, superimposed thrombus, etc.), and
these can lead to sudden occlusion and myocardial infarct.
3. Femoral, popliteal arteries- These supply blood to the lower extremities. Thus, bad
atherosclerosis can lead to chronic ischemia of the muscles of the legs. This decrease
in the blood supply can make it painful to walk or run (intermittent claudication).
Also, thrombosis of a plaque with total occlusion can lead to necrosis of a toe or the
foot.
4. Vertebral, basilar, and internal carotid arteries- These big arteries originate off
the aortic arch, and they supply blood to the brain. Bad plaques can cause chronic
ischemia to the brain (can cause TIA’s). But worse, these plaques can become eroded
and thrombi can form on top of them. This thrombosis can cause total occlusion of
blood flow to part of the brain. Also, these thrombi can embolize and travel to an
artery within the brain. Result: sudden and total occlusion of that artery, with death to
a portion of the brain tissue, i.e. stroke.
5. Circle of Willis- This is a circular artery located at the base of the brain. It receives
blood from several other arteries. Thus it provides anastomosis of blood flow within
the brain. Of all of the brain’s arteries, this is the one that gets most heavily involved
with atherosclerosis. You see it all the time at autopsy.
6. Other vessels- 1. Saphenous veins that are used in CABG procedures will, over time,
develop atherosclerosis. 2. Pulmonary arteries usually do not develop atherosclerosis
because the blood within them is under very low pressure. However, someone with
pulmonary hypertension (for whatever reason) can develop atherosclerosis. This
presumably is a consequence of this higher blood pressure.
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You MUST be familiar with this diagram.
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ACUTE AORTIC DISSECTION See diagram.
Here’s how it works: Blood within the ascending aorta (typically near the aortic valve)
enters the wall of the aorta (it does so via a knick, or tear, of the intima). The blood
dissects its way within the aortic wall. (Specifically, the blood travels through, and splits,
the media layer.) In essence, the dissecting blood creates a new lumen within the wall of
the aorta. Ultimately, the blood will exit the wall via another, more distal intimal tear,
and reenter the aortic lumen. This happens mostly in older, hypertensive men. Clinically,
aortic dissection results in sudden onset of excruciating chest pain.
Several very serious complications will happen:
1. The bulging aortic wall will compress against, and deform, the aortic valve (see
diagram!). This leads to aortic insufficiency in that the valve is unable to close all the
way. Blood will be “falling back” into the left ventricle during diastole.
2. The wall of the aorta may rupture. This will allow the dissecting blood present within
the wall to empty out into the pericardial cavity (i.e. the space between the heart and
the pericardial sac). Blood within the pericardial space is called hemopericardium.
The rapidly expanding blood cannot escape the pericardial space and thus it will
compress the heart. This situation is referred to as pericardial tamponade, and it is an
emergency. Essentially, the compressed heart cannot contract and expand (it cannot
beat!). Thus the heart cannot receive blood from the systemic veins (i.e. no venous
return to the right atrium). And the left ventricle cannot pump blood out (cardiac
output and blood pressure falls). This acute heart failure results in death.
N.B. Acute aortic dissection has nothing to do with atherosclerosis. This is one of the
"other vascular disorders".
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COARCTATION OF THE AORTA See diagram.
This is a congenital disease (although symptoms can occur as an adult). The person is
born with a severe narrowing of a portion of the aorta. The area of constriction is
located in the thoracic aorta, just distal to the aortic arch. Look at diagram closely! Not
much blood is able to get past the narrowed area. Result: the upper portion of the body
(head, neck, arms) gets too much blood. The lower part of the body gets too little. If you
took a blood pressure in one of the arms (“proximal” BP), it would be hypertensive. If
you took the pressure in a leg (“distal” BP), it would be hypotensive. Also, the distal
pulses (feet, ankle, etc.) would barely be palpable. This condition is usually accompanied
by cardiac abnormalities, with bicuspid aortic valve being the most common one. If the
coarctation is untreated, CHF can be the result. (The left ventricle has to work real hard to
pump blood past the obstruction. It will ultimately fail.). Surgical correction is the cure.
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VASCULITIS- is well covered in pages 515-523 of Robbins. Please note that in the past,
Dr. O'Connor has asked exam questions from the table on the last page of the handout.