ATHEROSCLEROSIS AND OTHER VASCULAR DIOSORDERS



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.

PAGE 3

You MUST be familiar with this diagram.

PAGE 4

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".

PAGE 5

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.

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