28 - Atherosclerosis

Question 1

What are the clinical consequences of atherosclerosis?

Answer 1

MI: myocardial infarction

CI: cerebral infarction

Question 2

Just for review, describe the layers of a normal vascular wall

Answer 2

Normal vascular wall

• Tunica intima with endothelium sitting on basal lamina
• Sub endothelial compartment (connective tissue):
  
  • Harboring smooth muscle cells
  • As smooth muscle cells (from tunica media) start to invade subendothelial compartment this triggers a negative series of events
• Internal elastic lamina: fenestrated (allow smooth muscle cells to gain entry into subendothelial compartment)
• Tunica media
• External elastic lamina: fenestrated
• Tunica adventitia

Question 3

Is diffuse intimal thickening a pathological finding or a normal consequence of aging? How does intimal thickening occur?

Answer 3

A normal consequence of aging

• The tunica intima will thicken
  
  • This can also occur in response to injury
• The thickening occurs as smooth muscle cells gain entry into the subendothelial compartment
• There are two methods of entry:
  
  • Muscle from the tunica media can migrate through fenestrations and become proliferative
  • Proposed new mode of entry: smooth muscle precursor cells in blood that in response to injury will squeeze between the damage and contribute to smooth muscle cell population

Question 4

Define atherosclerosis

Answer 4

Atherosclerosis

• Atherosclerosis is a form of arteriosclerosis (hardening of arteries) that is characterized by fibrofatty lesions (aka atheromas) in the tunica intima
• The lesions protrude into the vascular lumen thereby producing obstruction and they weaken the tunica media
• Obstruction of the vascular lumen leads to ischemia and/or infarction and a weakened media may lead to the development of an aneurysm
  
  • Specifically: abdominal aorta aneurysm (AAA)

Question 5

What are fibrofatty lesions? What is the other name for these lesions?

Answer 5

Fibrofatty lesions (AKA atheromas)

• Smooth muscle cells have gained entry into subendothelial compartments
• Here the muscle cells damage the endothelium
• LDLs will gain access to the subendothelial compartment this way
• LDLs will become oxidizes, phagocytosed by macrophages and smooth muscle cells and foam cells will result
• Above the lision (toward the endothelium) you will see a deposition and elaboration of ECM components (collagen fibers) and a fibrous cap will then form over the lesion

Question 6

What are early changes that occur in atherosclerosis and affect the tunica intima?

Answer 6

Fatty streaks

• These are fat deposits that have not progressed to the point of atheromas, but they are precursors to atheromas
• You will only see a minor degree of fatty deposition
• If you stain a sample with Sudan Red, the fatty streaks in the subendothelial compartmetn will show up red
• Note that this commonly occurs at points of bifurcation - this is an area where there is a lot of turbulence in the blood flow and injury occurs readily

Question 7

What are the clincal effects of progressive atherosclerosis?

Answer 7

Progressive damage

• Plaques
• Lesions
  
  • Lesions will occur within the wall of the blood vessel, the aorta, for example
  • The lesion will start to become calcified
  • This calcification is nonreversible
  • The “Western diet” contributes to the development of these lesions

Question 8

Outline the findings of a large clinical study regarding the development of atherosclerotic lesions

Answer 8

Atherosclerotic lesions

• In various age groups, strips of the abdominal aorta were taken and the posterior wall was analyzed
• The study was looking for the prevalence of fatty streaks and raised lesions
• It was found that fatty streaks are present, even at a young age, and as you get older, things get progressively worse
• Raised lesions were not found in the youngest group, but they begin to present in the age group of 20-24 years old
• It was noted that diet contributes greatly to the development of fatty streaks and raised lesions in the abdominal aorta

Question 9

Give the epidemeological figures for IHD - ischemic heart disease

Answer 9

Epidemeology of IHD (ischemic heart disease)

• Around 500,000 Americans die each year from IHD
• The death rate from IHD and strokes has been on the decline from 1963 to 2000
  
  • 50% deacrease in death rate from IHD
  • 70% decrease in death rate from strokes
• Decreases are due to surveillance and early intervention, also better treatments available, however, this is still a significant problem

Question 10

What are the non-modifiable risk factors for atherosclerosis?

Answer 10

Non-modifiable risk factors

• Increasing age
  
  • Between 40-60 years there is 5x increase in cardiovascular adverse events
• Family history
• Male gender
  
  • After menopause men and women have about the same degree of risk
• Genetic abnormalities
  
  • Example: familial hyperlipidemia

Question 11

What are the modifiable risks of atherosclerosis?

Answer 11

Modifiable

• Hyperlipidemia
  
  • Diet
• Cigarette smoking
• C-reactie protein
  
  • An inflammatory marker
• Hypertension
• Diabetes mellitus

Question 12

What are the guidelines for cholesterol levels? (total, LDL, HDL, triglycerides)

Answer 12

1. Total cholesterol < 200 mg/dl
2. LDL < 130 mg/dl or less depending on additional risk factors
3. HDL > 45 mg/dl
4. Triglycerides < 150 mg/dl

This is an important conversation to have with your patients - encourage healthy diets/behaviors

Question 13

How do atherosclerotic risk factors contribute to the probability of an adverse event? Does this apply to both men and women?

Answer 13

Increasing number of risk factors increases the probability of an adverse event for both men and women

Question 14

What is the C-reactive protein? How does this contribute to relative risk?

Answer 14

The C-reactive protein…

• Causes endothelial cells to become prethrobotic
• This increases the adhesiveness of WBCs
• The result is an inflammation of the walls of the vasculature

Risk factor

• The C-reactie proetin is NOT a huge risk factor alone, but when added with other risk factors, there is an increase in the probability of an adverse event

Question 15

What are some types of chronic endothelial “injury”?

Answer 15

Chronic endothelial injury

• Hyperlipidemia
• Hypertension
• Smoking
• Homocysteine
• Hemodynamic factors
• Toxins
• Viruses
• Immune reactions

Note that you NEED some type of injurious event to cause endothelial cell dysfunction

Question 16

What is endothelial dysfunction?

Answer 16

An endothelial layer that does not do its job or function properly

• Could have an increased permeability that causes problems
• Could be adhesive to leukocytes and cause problems that way

What happens when monocytes are able to adhere to the endothelial layer and emigrate upward?

• Platelets become more adherent to the endothelium
• Monocytes sueeze into the subendothelial compartment
• LDLs accumulate in the subendothelial compartment

Question 17

What happens when smooth muscle fibers are recruited to the tunica intima?

Answer 17

Macrophage activation

• The smooth muscle will first change its phenotype from contractile in nature to proliferative/synthetic
• Smooth muscle precursors cells will also emigrate from the blood into the subendothelial compartment
• Macrophages are taking up oxidized LDLs
  
  • Macrophages engulf the oxidized LDLs and assume a foamy appearance
  • This foamy appearance can also include smooth muscle cells, but note that macrophages are predominant in fomy cell types

Question 18

Describe the process of forming a fatty fibroatheroma

Answer 18

Fatty fibroatheroma

• Smooth muscle cells proliferate and become synthetic
• Fibrous cap of collagen is formed
• Lipid debris is deposited at the center of the fibroatheroma
• The entire structure is considered a fatty fibroatheroma

Question 19

Now let’s summarize the key events in atherosclerosis…

Answer 19

Summary of key events

1. Endothelial cells will become dysfunction in response to injury
2. These dysfunctional endothelial cells express adhesion molecules to allow attachment of leukocytes
3. The leukocytes will attach to the endothelium and squeeze through the endotherlium
4. At this point, the leukocytes become macrophages
5. They engulf oxidized LDL (key event for prevention)
   
   • Key for prevention because if you can inhibit oxidation, you can decelerate the entire process
6. Foam cells formed upon LDLs being oxidized
7. Smooth muscle cells will migration through the fenestrations
8. Smooth muscle cells will undergo proliferation once they are in the subendothelial compartment
9. The overall result is a cholesterol efflux into lumen of blood

Question 20

What is the role of NO (nitric oxide) in the process of leukocyte adhesion to the endothelium?

Answer 20

Role of NO

• The role of NO is to prevent the adhesion of leukocytes to the endothelium
• This will reduce the adhesion of platelets, which, as you may recall, contain growth factors that will cause proliferation of the ECM components

What is the result of a damaged endothelium?

• A decrease in NO
• This also increases the adhesion of leukocytes and platelts, causing further damage and advancing the atherosclerosis

Question 21

What is the “widow maker”?

Answer 21

The “widow maker”

• The most frequent stenotic segment of the arterial coronary tree is the left anterior descending (LAD)

Question 22

What is the order of critical stenosis of the coronary arteries (1, 2 and 3)

Answer 22

1. Left anterior descending
   
   • LAD
   • “widow maker”
2. Right coronary artery
3. Circumflex

Question 23

Describe the characteristics of an atherosclerotic lesion in the coronary arteries

Answer 23

Two examples

1. Decreased diameter of the lumen of the coronary artery
   
   • Lesions are present
   • You can see a lipid necrotic core
   • This case would probably not cause angina
2. Remarkable thickening of the tunica intima
   
   • A thrombus can form in the center
   • The lumen will be slit-like
   • Blood flow will be tremendously reduced
   • This case would contribute to angina and possibly event sudden cardiac death

Question 24

What is the wavefront phenomenon of necrosis?

Answer 24

Wavefront phenomenon of necrosis

• When coronary arteries become occluded there will be areas of the heart that do not receive blood flow
• Necrosis will occur in the inner layer of the myocardium first
  
  • The necrosis will then proceed to the outer myocardium

Question 25

Why is the inner layer of the myocardium affected by necrosis first?

Answer 25

Necrosis

• The inner layer of the myocardium is responsible for the pumping action of the heart
• It has a greater metabolic activity and therefore a higher demand for oxygen
• This results in the damage being most severe in this layer, and the first layer to be affected

Question 26

What is the result of a myocardial infarction or ischemia?

Answer 26

Result of MI or ischemia

• Arrythmias
• Acute rupture of cardiac wall of the IV septum
  
  • This occurs due to weakening of the wall
  • The result is a “blow out”
• Rupture of papillary muscles
  
  • This will cause a prolapse of the affected cusp
• Ventriclar aneurysm
  
  • This will result in destruction of the ventricular wall

Question 27

What is a cerebral infarction?

Answer 27

Cerebral infarction

• A blockage of a portion of the cerebral vasculature
• This causes insufficient blood flow to the brain
• Microscopic changes
  
  • These changes will occur 12-24 hours post-infarct
  • There will be early, acute changes that you can recognize
  • Eosinophilia (acidophilia) of neurons - the neurons will appear to be red
• Neutrophils will invade the area to “clean up” the damage
• Macrophages will then come in
• The macrophages cause proliferation of glial cells, leading to gliosis
  
  • Gliosis is the scar tissue that forms within the CNS approximately 10 days post-infarct

Question 28

You need to know the order/timing of events post-cerebral infarct, so let’s review…

Answer 28

1. Eosinophilia (12-24 hours post-infarct)
2. Neutrophils
3. Macrophages
4. Glial cells (10 days post-infarct)