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Cardio Week 4 > Lecture 40: Atherosclerosis and Restenosis Post-PCI, Moelcular and Cellular Mechanisms > Flashcards

Lecture 40: Atherosclerosis and Restenosis Post-PCI, Moelcular and Cellular Mechanisms Flashcards

1
Q

What is PCI?

A

Percutaneous Coronary Intervention

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2
Q

What is the significance of PCI?

A

Transformational for patients with acute coronary syndromes

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3
Q

What is an acute coronary syndrome? Significance?

A

Unstable angina
Myocardial infarction
Patients who benefit from PCI

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4
Q

What does PCI do for STEMI patients?

A

PCI leads to improved LV function and survival
Decreased mortality from 11 to 7%
Better than conversvative management (2007 Keeley and Hillis)
For UNSTABLE CAD

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5
Q

What is the significance of the COURAGE trial?

A

Showed that there is no advantage of PCI over medical treatment in patients with STABLE angina pectoris
Decreased PCI use by 30% since 2007…that is the significance

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6
Q

What forms the internal elastic lamina? Significance?

A

Made from secretiosn by both tunica intima and media

If internal elastic lamina breaks down, bad things happen

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7
Q

What is the significance of the tunica media?

A

They are the primary determinants of what regulates blood pressure
Smooth muscle cells are the most plastic of all the cells

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8
Q

What is the significance of the tunica adventitia?

A

Does all kinds of things lol

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9
Q

If you see normal lumen, can you assume that you don’t have atherosclerosis?

A

No, lumen could be fine even though there is surrounding atherosclerosis

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10
Q

What initiates restenosis?

A
  1. Endothelial cell denudation
  2. exposure of ECM
  3. platelet activation
  4. release of cytokines
    Restenosis is initiated by the PCI (blowing up the balloon)
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11
Q

What is the pathogenesis of restenosis?

A
  1. SMC activation and proliferation

2. arterial remodeling

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12
Q

What is the histology of restenosis?

A
  1. synthetic SMCs and ECM
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13
Q

What is the clinical course of restenosis?

A

Predictable (within 6 months)

If it doesn’t happen in the first 6 months then it is not going to happen

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14
Q

What causes restenosis following PCI?

A

All about the migratory effects of smooth muscle cells

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15
Q

What accounts for bulk of restenotic lesion?

A

ECM accumulation

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16
Q

What is the significance of SMC with restenosis?

A

SMC proliferation main cause of restenosis
SMCs then reenter the cell cycle, modulate their phenotype from contractile to synthetic and secrete abundant ECM, migrate from media to the intima forming a neointima within seven days of injury

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17
Q

What is the significance of growth factors in restenosis following PCI?

A

Growth factors induce proliferation of SMC proliferation

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18
Q

What are the growth factors that lead to restenosis?

A
  1. PDGF
  2. Basic FGF
  3. Angiotensin II
  4. TGF-beta
    The first three promote SMC proliferation
    The last promotes secretion of ECM
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19
Q

What are the characteristics of PDGF?

A

A growth factor that can lead to restenosis
Induces SMC MIGRATION
-secreed by platelets, endothelial cells, and SMCs

20
Q

What are the characteristics of FGF?

A

Induces SMC proliferation

Secreted by SMC

21
Q

How does angiotensin II contribute to restenosis?

A

Promotes SMC proliferation

Binds to AT1 receptor on SMCs

22
Q

How does TGF-beta contribute to restenosis?

A

Extracellular matrix secretion by SMC

Produced by SMCs, endothelial cells and platelets following PTCA

23
Q

What is the most important growth factor leading to restenosis?

A

TGF-beta

Because it secretes ECM, which is 90% of restenotic area

24
Q

What is the point of stents?

A

They prevent the geometric remodeling of smooth muscle cells that occurs after PCI’s are placed
However smooth muscle cells can migrate through the stent and still occlude the artery

25
Q

Why use rapamycin to treat restenosis?

A

Rapamycin inhibits SMC proliferation

This is the drug that is “eluted” for drug-eluting stents

26
Q

What is being eluted in drug-eluting stents?

A

Drugs that prevent smooth muscle cell proliferation like rapamycin

27
Q

What is the MoA of rapamycin?

A

Aka sirolimus
A macrolide antibiotic that inhibits cytokine and growth factor-mediated cell proliferation
Binds to FKBP-12 receptor and inhibits TOR required for protein synthesis and cell proliferation
Arrests SMCs at the end of G1 phase of cell cycle

28
Q

What is the mechanism of paclitaxel (taxol)?

A

Inhibits mitotic mechanism (so cell doesn’t go back to G1)

Polymerizes tubulin resulting in non-functional microtubules and inhibition of replication at G2/M phase

29
Q

What does DES stand for?

A

Drug eluting stents

30
Q

To what extent is atherosclerosis an inflammatory disease?

A

There is inflammation present but not sure if this is the main etiology (trials being done now to see whats good)

31
Q

What are the stages of progression of atherosclerotic lesions?

A

Type I = isolated macrophage foam cells in artery
Type II = intracellular lipid accumulation
Type III = addition of small extracellular lipid pools
Type IV = addition of core of extracellular lipid (atheroma stage)
Type V = fibrotic layer forms with lipid core (can be calcific and AKA fibroatheroma stage)
Type VI = surface defect, hematoma-hemorrhage, thrombus

32
Q

What are the key steps to the formation of the fatty streak (Type II step)?

A

Characterized by lipid-laden foam cells intracellularly
Responds to injury by endothelial dysfunction, monocyte adhesion emigration, etc.
Foam cell recruitment + formation
Monocyte receptor CCR2 binds MCP-1 in the intima
Foam cells secrete pro-inflammatory cytokines that amplify inflammatory response

33
Q

What are the key characteristics of type IV and V lesions?

A

Atheroma and Fibroatheroma develop primarily in elastic arteries and large/medium sized arterioles (coronaries)

34
Q

What are the components of the atherosclerotic plaques (fibroatheroma)?

A

Formed by
A. SMCs, macrophages, leukocytes
B. collagen, elastic fibers, PGs
C. lipids

35
Q

What is the anatomy of a fibroatheroma?

A
  1. fibrous cap

2. core of macrophages, lipid and debris-apoptosis

36
Q

How do atherosclerotic plaques expand?

A 
Because the vasa vasorum can feed them cells and what not
Leads to
	i. leukocyte infiltration
	ii. cell death and degeneration
	iii. synthesis of ECM
Leads to formation of thrombus
37
Q

If you see a normal lumen, can there still be plaques?

A

Yes the plaques may be underlying

38
Q

What are vulnerable plaques characterized by?

A

Thin fibrous cap and large hypocellular lipid-rich core
Large percentage of lymphocytes and activated macrophages
Abundant cytokine production and MMPs (low pH, hot)

39
Q

What initiates atherosclerosis?

A
  1. genetics
  2. risk factors
  3. LDLox
40
Q

What types of plaques never rupture?

A

Fibrotic plaques

41
Q

What types of plaques rupture?

A

Lipid-rich core with thin cap

42
Q

What is the pathogenesis of atherosclerosis?

A
  1. endothelial cell injury
  2. chronic inflammation
  3. monocyte infiltration/foam cell
  4. slow progression/complex lesion
  5. plaque stabilization/rupture
43
Q

What is the histology of atherosclerosis

A

Lipid rich
Fibrous cap
Prone to rupture

44
Q

What is the clinical course of atherosclerosis?

A
  1. unpredictable

2. small plaques rupture

45
Q

What is the difference between atherosclerosis and restenosis?

A

Restenosis made of SMCs and ECM
Atherosclerosis made of fibrous cap, lipid rich
Restenosis = arterial injury by PCI leading to SMC activation
Atherosclerosis = endothelial cell injury that leads to chronic inflammation and rupture
Clinical course of restenosis is predictable while atherosclerosis is unpredictable

Cardio Week 4 (12 decks)

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