Pathology of Atherosclerosis

Question 1

What is the leading cause of death in our country?

Answer 1

coronary artery disease

Question 2

What is arteriosclerosis?

Answer 2

“hardening of the arteries” due to thickening of the blood vessel wall.

Question 3

What are the 3 pathologic patterns of arteriosclerosis?

Answer 3

1. atherosclerosis
2. arteriolosclerosis
3. Monckeberg medial calcific sclerosis

Question 4

What is atherosclerosis?

Answer 4

dominant pattern causing intimal fibrofatty plaques that obstructs blood flow. Endothelium is key to the development, because when it becomes damaged due to smoking, hypertension, or any variety of disorders, it can cause atheromas (soft-yellow lesion).

Question 5

What is vascular disease?

Answer 5

diseases that narrow the lumen and injure endothelium, weakening the walls of the vessels.

Question 6

Does vascular disease lead to hypertension and diabetes, and vice versa?

Answer 6

YES. Good thing is hypertension and diabetes are 2 modifiable risk factors.

Question 7

What are some important functions of the endothelium?

Answer 7

maintain a permeable barrier, anti-coagulant, pro-coagulant, modulate blood flow, regulates inflammation, and regulated cell growth.

Question 8

What is Monckeberg’s arteriosclerosis?

Answer 8

calcification of the media of muscular (medium-sized) arteries; nonobstructive (lumen is still preserved). Usually occurs after age 50. May falsely evelvate systolic BP.
Not clinically significant.

Question 9

What is arteriolosclerosis?

Answer 9

narrowing of small arterioles; divided into hylaine and hyperplastic types.

Question 10

**What are the NONMODIFIABLE risk factors for atherosclerosis?

Answer 10

• Age
• Sex (males, or post-menopausal women due to loss of protective estrogen)
• Genetics (familial predisposition)

Question 11

What other some additional atherosclerosis risk factors?

Answer 11

• homocysteine= associated with stroke, CAD, PVD
• lipoprotein A= altered form of LDL associated with CAD and cerebrovascular risk, independent of LDL levels.
• c-reactive protein= acute phase reactant synthesized in the liver and used as a marker for inflammation. It takes endothelial cells from an anti-coagulant state to a pro-coagulant state.

Question 12

What is important to remember about atherosclerosis risk factors?

Answer 12

the more you have, the more likely to have a cardiovascular event :(

Question 13

What causes most cases of hypertension?

Answer 13

idiopathic (we don’t know)

Question 14

What are the 2 types of hypertension?

Answer 14

1. benign hypertension (most)

2. malignant hypertension

Question 15

What is hypertension?

Answer 15

increased blood pressure due to increased blood volume, HR, sodium, and peripheral resistance (angiotensin II or catecholamines)

Question 16

What are some of the ways hypertension can cause vascular pathology?

Answer 16

• hyaline arteriolosclerosis

- hyperplastic arteriolosclerosis

Question 17

What is hyaline arteriolosclerosis?

Answer 17

pink hyaline thickening of the walls of arterioles with narrowing of the lumen. Consistent with benign hypertension.

Question 18

What is hyperplastic arteriolosclerosis

Answer 18

malignant hypertension with onion skinning concentric narrowing of lumen.

Question 19

**What are the MODIFIABLE risk factors for atherosclerosis?

Answer 19

• hypertension
• hypercholesterolemia (LDL increases risk; HDL decreases)
  hypertriglyeridemia (VLDL)
• smoking
• diabetes

Question 20

**What happens to a blood vessel when it begins to undergo atherosclerotic changes?

Answer 20

Damage to endothelium allows lipids to leak into the intima where they are oxidized and then consumed by macrophages via scavenger receptors, resulting in foam cells. Inflammation and healing leads to deposition of extracellular matrix and proliferation of smooth muscle, macrophages, endothelial cells, and collagen deposition.

Question 21

What does V-CAM-1 have to do with the inflammation component of atherosclerosis?

Answer 21

it binds leukocytes, including monocytes and T cells (release proinflammatory molecules and fibrogenic growth factors). The monocytes then transform to macrophages, which engulf lipid and secrete cytokines (IL-1 and TNF), which increase adhesion of leukocytes.

Question 22

Will loss of T cells help to reduce atherosclerosis?

Answer 22

YES

Question 23

What makes up the atheromatous plaques?

Answer 23

cholesterol and cholesterol esters

Question 24

What may antioxidants help to do?

Answer 24

slow the development of plaques due to macrophages oxidizing lipids.

Question 25

How can we slow the rate of progression of plaques?

Answer 25

lower serum cholesterol levels by diet, drugs, and exercise

Question 26

How do oxygen free radicals cause impaired endothelial function in chronic lipidemia?

Answer 26

deactivate NO, which is a major endothelial relaxing factor.

Question 27

Can smooth muscle cells syntesize ECM?

Answer 27

YES and stable the plaques :(

Question 28

What does the prominent connective tissue of the intima do?

Answer 28

forms a fibrous cap around the atheroma (which can be good) unless it is disrupted, it can form a pro-thrombotic state, which can lead to fatal MI.

Question 29

**How does atherosclerosis progress in the pre-clinical phase?

Answer 29

Begins as FATTY STREAKS (flat yellow lesions of the intima consisting of lipid-laden macrophages); present in most teenagers. This will then progress to a FIBROFATTY plaque, that will advance to an ATHEROMATOUS plaque (often eccentric). This is the pre-clinical phase.

Question 30

**How does atherosclerosis progress in the clinical phase?

Answer 30

In the elderly, you can then see weakening of the vessel wall leading to an aneurysm that can rupture, or progress to occlusion of the already narrowed lumen via thrombus, and finally clinical stenosis.

Question 31

Where do plaques commonly develop?

Answer 31

abdominal or thoracic aorta, coronary arteries, carotid arteries, and circle of willis

Question 32

** What are the 3 major components to atherosclerotic plaques?

Answer 32

1. smooth muscles cells, T cells, and macrophages 2. ECM (proteoglycans, collagen and elastic fibers) 3. intracellular and extracellular lipid

Question 33

What are complicated plaques?

Answer 33

more advanced plaques that have calcification, ulceration, thrombosis, and hemorrhage

Question 34

Can smooth muscle cells also engulf lipids?

Answer 34

YES

Question 35

What are the 2 different ways diabetes can present?

Answer 35

1. MACROvascular disease= large arteries leading to atherosclerosis, hyaline arteriolosclerosis, increased myocardial infarcts, strokes, and gangrene. 2. MICROvascular disease= retina (retinopathy), kidney (nephropathy), and peripheral nerves (neuropathy).

Question 36

**What are the 3 metabolic pathways that account for diabetic pathology?

Answer 36

1. formation of advanced glycation end products (AGEs) 2. activation of protein kinase C 3. disturbance in polyol pathways

Question 37

How are AGEs formed?

Answer 37

from reaction between intracellular glucose derived dicarbonyl precursors with amino group of intracellular and extracellular proteins forming cross-links of collagen I molecules (decreasing elasticity) and collagen IV of the basement membrane (increasing fluid filtration; leakiness). So an increased glucose level will stimulate this interaction.

Question 38

Are AGE cross-linked proteins resistant to proteolytic degradation?

Answer 38

YES :(

Question 39

What do the matrix components, modified by AGEs, trap?

Answer 39

nonglycated or interstitial materal such as LDL, contributing to atherosclerosis. This is why diabetics really need to control their LDL levels, because they are more prone to the adverse effects of LDL.

Question 40

How may albumin lead to basement membrane thickening, in diabetics?

Answer 40

by binding to glycated basement membrane. Seen in microangiopathy.

Question 41

What will AGEs do to circulating plasma proteins?

Answer 41

modify them causing them to bind to AGE receptors of macrophages, endothelial cells and mesangial cells (kidney), resulting in generation of proinflammatory cytokines and growth factors. *Remember in diabetics due to high glucose levels.

Question 42

**How does activation of protein kinase C (PKC) lead to diabetic pathology?

Answer 42

- intracellular hyperglycemia causes synthesis of diacylglycerol and activation of PKC= VEGF production leading to neovascularization in diabetic retinopathy. - More importantly, PKC activates vasoconstrictor endothelin 1 (constricting the lumen) and decreases activity of eNOS (reducing vasodilation) :( - produces transforming GF beta= more ECM deposition causing basement membrane thickening. - produces plasminogen activator INHIBITOR-1= procoagulant by decreased fibrinolysis - produces proinflammatory cytokines

Question 43

**Summary: So why is diabetes such a problem?

Answer 43

its hitting the blood vessels from all different sides: prothrombotic, vasoconstriction, and damage to endothelial cells making you more prone to damage of LDLs.

Question 44

**How does intracellular hyperglycemia (polyol pathway) lead to diabetic pathology?

Answer 44

- increases cell response to oxidative injury. - increased glucose leads to more conversion to fructose (which requires NADPH as a cofactor). Because NADPH is being taken away from its other role in the production of glutathione (important antioxidant) we have more ROS! :(

Question 45

What is the morphology of diabetes?

Answer 45

change in pancreas is not too dramatic, but will see amyloid replacements of islets in DM2. These occur around blood vessels and between cells!

Question 46

What is the most common cause of death in DM?

Answer 46

MI