Pathology of Atherosclerosis

Question 1

What are the nonmodifiable risk factors for atherosclerosis?

Answer 1

Increasing age
Male gender (estrogen is protective)
Genetic predisposition

Question 2

What are the major modifiable risk factors for atherosclerosis?

Answer 2

Hyperlipidemia, smoking, hypertension, diabetes

Question 3

What are the four biochemical labs which, when elevated, are associated with atherosclerosis?

Answer 3

1. C-reactive protein (inflammation
2. Homocysteine
3. Lipoprotein (a)
4. Plasminogen activator inhibitor (PAI) -> released by endothelial cells in prothrombotic states

Question 4

What is the pathogenesis of atherosclerosis?

Answer 4

1. Arterial endothelial injury
2. Increased vascular permeability, endothelial activation, adhesion of platelets, monocytes, lymphocytes
3. Influx of cholesterol, monocytes, and T lymphocytes into intma
4. Release of chemotaxic agents via endothelium, platelets, macrophages
5. Oxidation of accumulated LDL
6. Migration of smooth muscles from media to intima
7. Intimal SMC prolferation and production of ECM
8. Organization of thrombotic material, mediated by growth factors from endothelium, platelets, and MACs
9. Enlargement and progression of plaque

Question 5

What hemodynamic stresses predispose to endothelial injury?

Answer 5

Turbulent blood flow -> occurs preferentially at brain points, allowing endothelial exposure to injurious products and formed blood elements which damage endothelium

Question 6

What are chemical and physical agents which can damage the endothelium?

Answer 6

1. Extra cholesterol particles
2. Toxins from cigarette smoke
3. Hyperglycemia (why diabetes predisposes)
4. Chronic inflammation -> direct infection is associated
5. Homocysteine levels (perpetuated by low B9/B12 levels)

Question 7

How do activated endothelial cells contribute to the atherosclerotic process?

Answer 7

Increased vascular permeability lets more cells / particles in, increased expression of leukocyte adhesion molecules (i.e. ICAM / VCAM), platelet adherence increased, production of growth factors

Question 8

How do macrophages amplify the atherosclerosis response?

Answer 8

Increase IL-1/TNF levels to increase leukocyte adhesion, give chemotactic cytokines, and oxidize LDL via oxygen-free radicals. They also secrete growth factors.

Question 9

What are intracellular / extracellular cholesterol inclusions called in atherosclerosis?

Answer 9

Intracellular - foam cells -> inside SMCs and macrophages (via scavenger receptor)

Extracellular - cholesterol clefts, in the fatty, necrotic core

Question 10

How do platelets contribute to pathogenesis of atherosclerosis?

Answer 10

Adhere to activated endothelium producing growth factors (SMC proliferation) and form thrombus / organization of atherosclerotic plaques

Question 11

How do vascular smooth muscle cells contribute to pathogenesis of atherosclerosis?

Answer 11

Synthesize growth factors, migrate into intima and proliferate, deposit ECM, and ingest oxidized LDL to become foam cells

Question 12

What is the gross and microscopic appearance of a fatty streak? Is it atherosclerosis?

Answer 12

Gross - narrow, flat, yellow, linear streak

Microscopic - Small aggregation of lipid-filled macrophages (foam cells) in the intima

Not considered an atheromatous plaque (need to be an atheroma) -> may be the precursor

Question 13

What is an atheroma? How does it appear grossly?

Answer 13

Uncomplicated fibrofatty plaque (within the intima)

Grossly - raised, yellow-white lesion protruding into blood vessel

Question 14

What are the three components of the atheroma?

Answer 14

1. Fibrous cap - immediately under endothelium, predominantly ECM made of collagen and scattered smooth muscle cells
2. Lipid core - underneath the cap, a mixture of clefts, foam cells, plasma proteins, and necrotic cell debris
3. Mononuclear inflammatory cells (T cells and macrophages) with proliferating capillaries - appear around the periphery and surrounding the lipid core

Question 15

Why does calcification occur as a plaque complication?

Answer 15

There is increased cell permeability with necrosis

-> allows calcium influx and dystrophic calcification

Question 16

Give two causes for hemorrhage of an atherosclerotic plaque?

Answer 16

1. Rupture of intrinsic capillaries -> may remain contained within the atheroma
2. Rupture of fibrous plaque, with bleeding into media

Question 17

What forces make ulceration or rupture of an atheroma likely?

Answer 17

1. Mechanical forces -> i.e. calcification, high blood pressure, tubulent blood flow
2. Proteolytic enzymes -> plaque instability + enzymes released by macrophages

Question 18

What are the potential complications of ulceration or rupture? What is most common?

Answer 18

1. **Superimposed thrombosis - most common

2. Embolization of atheroma

Question 19

What is the most common complication of atherosclerosis in small to medium sized arteries? Give an example.

Answer 19

Vascular occlusion

• > usually intimal atheromas which decrease arterial blood flow and lead to organ ischemia and necrosis
• > Example: occlusion of coronary artery in stable angina. Can lead to MI.

Question 20

What complication of atherosclerosis is commonly seen in large, elastic arteries? Where specially, and why?

Answer 20

Aneurysmal dilatation

• > specifically in abdominal aorta, where the vasa vasorum is more sparse
• > caused by SMCs leaving media to intima, and progressive hypoxia to remaining due to growing plaque
• > media becomes week and blood vessel dilates

Question 21

If a plaque embolization doesn’t cause an acute infarct, what is it liable to cause?

Answer 21

Embolus becomes lodged in a blood vessel, and will heal with a scar (organization). This scar will occlude the lumen, and will show fibroblasts / collagen deposition
-> can progressively narrow the lumen with repeated incidents and cause ischemic change in that organ.