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CVB by Minnie- 2024 Update > 124 - Atherosclerosis Pathogenesis and Pathology > Flashcards

124 - Atherosclerosis Pathogenesis and Pathology Flashcards

1
Q

What drives atherosclerotic lesions to mature?

A

Macrophages uptake oxidized LDL and become foam cells

  • Foam cells promote migration and proliferation of vascular smooth muscle cells
    • Collagen secretion = lesion grows
    • Lesion outgrows O2 = necrotic center
    • Innate and adaptive immune response = continued inflammation
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2
Q

What effect do matrix metalloproteinases (MMPs) have on atherosclerotic plaques in…

Large arteries?

Small arteries?

A

MMPs from inflammatory cells (macrophages) weaken the fibrous cap of the plaque.

This exposes collagen and necrotic debris to the circulation, leading to rapid blood clotting

  • Large arteries
    • ​Fibrinolytic system ends coagulation before too much damage is caused
  • Small arteries
    • Small clot may block the lumen completely (partial occlusion from plaque, clot does the rest)
    • -> Ischemia
    • -> Infarction
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3
Q

What is the most clinically significant complication of an atherosclerotic plaque?

A

Plaque Rupture

  • Small arteries: Acute, can be fatal
  • Large arteries: May be long-standing. May weaken the media, leading to aneurysm
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4
Q

What is the fatty streak in early atherosclerotic lesions made from?

A

Foam cells

(Macrophages that have ingested oxidized LDL)

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5
Q

Describe the formation of early atherosclerotic lesions

A
  • LDL passively enters the arterial subintima
  • LDL accumulates and becomes oxidized
  • Oxidized LDL = activating stimuli for endothelial cells and antigen presenting cells (ex: macrophages)
  • Inflammatory response
    • Leukocyte recruitment + attachment
      • Especially in areas of tubulent flow
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6
Q

Describe the gross pathology of maturing atherosclerotic lesions

A
  • Firm white plaques
    • May have focal or dystropic calcification (stiff brittle wall)
  • Stenosis of lumen
    • Most sever in small muscular arteries (ex: coronary, cerebral)
  • Eccetric growth
    • Crescent-shaped lumen
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7
Q

What is the role of PDGF in atherosclerosis?

A

Platelet Derived Growth Factor (PDGF)

  • Secreted by macrophages in response to modified LDL molecules and other inflammatory signals durign the development of atherosclerosis
  • Recruits smooth muscle mesenchymal cells
    • They enter the lesion from the media
    • Proliferate
    • Secrete collagen (ECM)
      • Lesion grows into the lumen
    • Accumulate lipid to become foam cells
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8
Q

Where is the most clinically dangerous place to have a weak atherosclerotic plaque?

A

A small artery

It is likely to be complelety occluded by plaque + clot if it ruptures

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9
Q

Describe the structure of a maturing atherosclerotic lesion

A
  • Fibrous cap of collagen and smooth muscle cells
    • Newer part of the lesion
  • Necrotic core of cellular debris
    • Older part of the lesion
    • Source of continued inflammatory stimuli
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10
Q

Describe the histopathology of maturing atherosclerotic lesions

A
  • Fibrous cap + necrotic core
  • Free cholesterol in the core may crystalize
  • Early lesions/edges
    • Many times of immune cells
  • Larger lesions/center
    • Angiogenesis from vasa vasorum to supply nutrients and oxygen
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11
Q

What was the Cantos trial?

What do the results imply?

A

Canakinumab, an anti-inflammatory drug, reduced CV events indepenent of lipid-lowering

This provides evidence that atherosclerosis is an inflammatory disease

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12
Q

Which atherosclerotic lesions are the most clinically significant?

A

The weakest ones

(Not necessarily the largest)

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13
Q

Where does atherosclerosis typically occur?

A

Muscular and elastic arteries

Between the intima and the media

Usually at branch points/areas of turbulent flow

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14
Q

What causes atherosclerotic lesions to weaken?

A

Matrix metalloproteinases (MMPs) from inflammatory cells (macrophages) weaken the fibrous cap of the plaque

  • > exposes collagen and necrotic debris to circulation
  • > Rapid blood clotting
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15
Q

What inflammatory factors are secreted by activated macrophages to contribute to the growth of atherosclerotic lesions?

A
  • Proinflammatory cytokines
  • Platelet-derived growth factor (PDGF)
    • Recruits smooth muscle mesenchymal cells
  • Vascular endothelial growth factor (VEGF)
    • Recruits endothelial mesencymal cells
    • Stimulates angiogenesis
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16
Q

What are the major risk factors for atherosclerosis?

What do they all have in common?

A
  • Smoking
  • Hypertension
  • Obesity
  • Aging

All are proinflammatory

17
Q

What is the role of VEGF in atherosclerosis?

A

VEGF = Vascular Endothelial Growth Factor

  • Secreted by activated macrophages (in response to modified LDL molecules and other inflammatory signals)
  • Recruits endothelial cells
  • Stimulates angiogenesis
18
Q

What evidence do we have that atherosclerosis is an inflammatory disease?

A
  • Mice trials
    • Increased inflammation = atherosclerosis
    • Decreased inflammation inhibited atherosclerosis
  • Statins
    • They are anti-inflammatory agents that help to prevent atherosclerosis
  • Risk factors
    • All are pro-inflammatory
  • Cantos trial
    • Canakinumab, an anti-inflammatory drug, reduced CV events indepenent of lipid-lowering
  • Regression of plaques is possible if LDL and inflammation are decreased
19
Q

Describe the histology of an early atherosclerotic lesion

A
  • Fatty streak between intima and media = earliest recognizable sign
  • Accumultaion of foam cells (lipid-filled macrophages)
    • Look like bubbles or bare spaces

At this point, lesions may progress or regress

20
Q

What causes atherosclerotic plaques to regress?

Can they regress completely?

A

Plaques may recress if LDL and inflammation are decreased

If a necrotic core exists, regression will not be complete

  • Difficult to clear the debris in the necrotic core
    • If inflammatory mechanisms are inhibited, infection is likely
21
Q

What is the fibrous cap of an atherosclerotic plaque made from?

A

Collagen

22
Q

Describe the gross pathology of an early atherosclerotic lesion

A

The artery looks mostly normal

(But histopathologic changes are visible: fatty streak, accumulation of foam cells)

23
Q

What recruits smooth muscle mesenchymal cells to growing atherosclerotic lesions?

A

PDGF secreted by activated macrophages

24
Q

What defines “complicated” atherosclerotic plaques?

A

A complicated plaque has one of the follwoing…

  • Dystropic calcification in the necrotic core
  • Hemorrhage that allows blood from the lumen to enter the lesion and clot
  • Plaque rupture that exposes plaque material to the bloodstream
    • Intravascular thrombosis (may be fatal in small arteries, lead to aneurysmal dilation in large arteries)
25
Q

Describe the histopathology of a clinically significant atherosclerotic plaque

A
  • Dystropic calcification (stains blue) in the necrotic core
  • Necrotic core may be large
  • Edges: Activated macrophages secrete MMPs
  • Thrombus + blood clot may be seen if the plaque ruptures
26
Q

What recruits endothelial mesencymal cells to growing atherosclerotic lesions?

What is the effect?

A

VEGF secreted by activated macrophags

Stimulates angiogenesis

27
Q

What is the role of macrophages in the progression of atherosclerosis?

A

Macrophages are recruited to areas with lots of oxidized LDL due to the inflammatory response of the endothelium

They enter the endothelium and ingest the oxidized LDL, thus turning into foam cells

Foam cells form the initial fatty streak and secrete more pro-inflammatory signals to propagate the inflammatory response

  • Proinflammatory cytokines
  • Platelet-derived growth factor (PDGF)
    • Recruits smooth muscle mesenchymal cells
  • Vascular endothelial growth factor (VEGF)
    • Recruits endothelial mesencymal cells
    • Stimulates angiogenesis
28
Q

How are Damage-Associated Molecular Patterns (DAMPs) produced by growing atherosclerotic lesions?

A
  • Apoptotic foam cells cannot be cleared due to metabolic conditions of the plaque
  • Instead, they die via secondary necrosis
  • This creates debris, known as DAMPs
    • DAMPs recruit more inflammatory cells
29
Q

Describe the body’s inflammatory response to oxidized LDL

A
  • Oxidation turns LDL into an inflammatory stimulus
  • Endothelial cells express adhesion molecules, chemokines to attract monocytes
  • Monocytes adhere to the endothelium in areas of turbulent flow
  • Monocytes migrate across the endothelial monolayer
    • Dendritic cells
    • T-cells
    • Macrophages
  • Monocytes ingest oxidized LDL
  • Monocytes become foam cells to form the fatty streak
  • Macrophages produce more inflammaotry signals
    • Cytokines
    • Mesenchymal mitogens
    • ​Positive feedback loop

CVB by Minnie- 2024 Update (43 decks)

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