SM 126 Atherosclerosis Pathogenesis

Question 1

Where do lesions grow and what is the significance?

Answer 1

Lesions grow and expand at the periphery as more cells are recruited towards older cells that necrose and apoptose at the center

Question 2

What changes make an atherosclerotic plaque “complicated”?

Answer 2

Dystrophic calcifications, fissure formation, and plauque rupture

These changes can cause a mature plaque to rupture

Question 3

Where are atherosclerotic plaque derived thrombi most dangerous?

Answer 3

Small arteries such as those supplying the heart, which are easily totally occluded

Additionally, small arteries are less effectively cleared of clots by the fibrinolytic system

If a person survives a clot, fibrinolysis can clear the clot naturally

Question 4

What is Canakinumab?

Answer 4

mAb against IL-1Beta leads to significant decrease in atherosclerotic cardiovascular disease in the CANTOS trial

Question 5

Why do macrophages become foam cells?

Answer 5

They accumulate oxidized LDL via scavenger receptors faster than they can clear it

Question 6

Describe the pathology of a mature lesion?

Answer 6

Firm what plaques below the endothelium which project into the vascular lumen and cause stenosis

Calcification is present, hardening the walls of the artery

Question 7

How do macrophages clear oxidized LDL?

Answer 7

Oxidized lipid induce transcription factors that stimulate metabolizing enzymes

Eventually overwhelmed by high amounts of LDL

Question 8

Why does Atherosclerosis occur in areas of turbulent flow?

Answer 8

Leukocytes can’t attach in arterial areas due to extremely fast blood flow, so turbulent areas allow for Luekocytes to attach and begin an inflammatory response

Question 9

Why is a mature plaque rupture dangerous?

Answer 9

Rupturing of the fibrous cap exposes blood in the lumen to the material in the plaque, leading to thrombi formation

Thrombi can block arteries, especially small ones, and lead to fatal injury

Question 10

What are the complications of Atherosclerosis?

Answer 10

CAAF = reasons people die

Calcification
Atheroembolism
Aneurysm formation
Fissuring/plaque hemorrhage = heart attack and stroke

Question 11

What are the effects of increased Cholesterol in cells?

Answer 11

Inhibits HMG CoA Reductase to decrease Cholesterol synthesis

Activats ACAT to stimulate Cholesterol Storage

Decreases LDLR expression

Question 12

What is Atherosclerosis?

Answer 12

A lifelong disease characterized by chronic inflammation

Question 13

What are the common late stage manifestations of Athersclerosis?

Answer 13

MGAC

Myocardial Infarction
Cerebral Infarction
Abdominal Aortic Aneurysm
Gangrene of Extremities

Question 14

Why does the fibrous cap of a plaque thin?

Answer 14

Release of MMPs by dying foam cells

Question 15

What are the inflammatory stimuli in chronic inflammation leading to atherosclerosis?

Answer 15

DAMPs from necrotic foam cells and ApoB lipoproteins from high amounts of LDL

Question 16

How are macrophage scavenger receptors effected by the presence of DAMP’s and Oxidized LDL?

Answer 16

They are not effected by the presence of DAMPs and Oxidized LDL; unlike the LDLR, they are not downregulated in the presence of high intracellular ligand, and as a result continually uptake substrate to toxic levels

Question 17

How and where does atherosclerosis cause aneurysms?

Answer 17

Aneurysms = thinning of an arterial wall

Atherosclerosis causes weakening of the media of an artery, leading to thinning of the wall, most commonly in the abdominal aorta

Question 18

What is the relationship between DAMPs and Oxidized LDL?

Answer 18

Both are physically similar and induce a similar pro-inflammatory response, and can be taken up by Macrophage Scavenger receptors

Question 19

How long does it take for LDL to become an inflammatory stimuli?

Answer 19

LDL is converted into oxidized LDL in subintima over the period of decades

Question 20

What are the risk factors for atherosclerosis and why?

Answer 20

DHOC = inflammatory conditions promote atherosclerosis

Diabetes = glycation of proteins activates scavenger receptors on macrophages
Hypertension = activated T cells secrete proinflammatory cytokines
Obesity = more fat
Cigarette smoke = ROS buildup

Question 21

What is “secondary necrosis”?

Answer 21

Macrophages that become foam cells must be cleared by other macrophages, but this rarely happens

Release Damage Associated Molecular Patterns (DAMPs) which recruit more inflammatory cells and the growth of the lesion

Question 22

What is the pathological appearance of an atherosclerotic plaque?

Answer 22

Plaque extends above the vessel and occludes the lumen, with thrombi formation occuring and large stenosis

Question 23

What is a fatty streak?

Answer 23

A fatty streak is the earlier recognized lesion in the progression of Atherosclerosis, and consists of foam cells

May regress or progress into mature lesions, found in young people

Question 24

How are smooth muscle cells recruited to fatty streaks?

Answer 24

Macrophages secrete the pro-inflammatory VEGF, which recruits smooth muscle to the area

Question 25

Why does angiogenesis occur in plaque formation?

Answer 25

Inflammatory cells secrete angiogenic factors to try and restore blood flow, but ultimately the new vessels only make the develop plaque grow even larger and fail to save the tissue

Question 26

What histopathological feature distinguishes a mature lesion?

Answer 26

A fibrous cap derived from collagen produced by smooth muscle cells

Question 27

What effect does infection and autoimmune disease have on atherosclerosis?

Answer 27

They accelerate the progression of atherosclerosis by creating an inflammatory environment

Question 28

How do changes in LDL mediate progression of Atherosclerosis?

Answer 28

LDL invasion of subintima can result in LDL accumulating LDL can be oxidized over time and become pro-inflammatory stimuli for endothelial cells and APC's like Macrophages

Question 29

What type of immune response is involved in atherosclerosis?

Answer 29

Both innate (macrophages) and adaptive (T cells) are involved in Atherosclerosis Knockouts in mice of proteins in both systems lead to reduced Atherosclerotic plaque development

Question 30

What are the 3 layers of arteries?

Answer 30

Innermost to outermost: ``` Intima = innermost layer Media = vascular smooth muscle cells Adventitia = contains vaso venosus which provides nutrients ```

Question 31

What layers of the vessels does Atherosclerosis effect?

Answer 31

Atherosclerosis initially effects subintimal potential space, a single area After it induces a chronic inflammatory response, it affects all 3 layers

Question 32

Why do statins have disproportionate protection against atherosclerosis?

Answer 32

Statins have anti-inflammatory as well as anti-lipid effects Statins are good against atherosclerosis due to anti-inflammatory effect mostly

Question 33

Describe the pathology of a fatty streak?

Answer 33

Small patches of yellow below the endothelium in artery cross sections, mostly normal H&E stains show cells with clear cytoplasm = foam cells

Question 34

How do mature lesions develop?

Answer 34

Develop from fatty streaks as a chronic inflammatory response in a fatty streak continues Buildup of foam cells promotes migration and proliferation of smooth muscle, which secrete collagen and form a fibrous cap Recruitment of cells outgrows metabolic supply, leading to central necrosis which stimulates more inflammation and recruitment of immune cells

Question 35

Where does Atherosclerosis tend to occur?

Answer 35

Atherosclerosis occurs in large muscular and elastic areas at branch points, where non-laminar flow occurs Does not occur in small arterioles or veins

Question 36

Where does Atherosclerosis manifest?

Answer 36

Initially begins when LDL passively enters the arterial subintima, between the intima and the media of the arteries, and binds ECM

Question 37

What are foam cells?

Answer 37

Macrophages that have become oversaturated with oxidized lipids