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

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Flashcards in Lecture 40: Atherosclerosis and Restenosis Post-PCI, Moelcular and Cellular Mechanisms Deck (45):

What is PCI?

Percutaneous Coronary Intervention


What is the significance of PCI?

Transformational for patients with acute coronary syndromes


What is an acute coronary syndrome? Significance?

Unstable angina
Myocardial infarction
Patients who benefit from PCI


What does PCI do for STEMI patients?

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


What is the significance of the COURAGE trial?

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


What forms the internal elastic lamina? Significance?

Made from secretiosn by both tunica intima and media
If internal elastic lamina breaks down, bad things happen


What is the significance of the tunica media?

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


What is the significance of the tunica adventitia?

Does all kinds of things lol


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

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


What initiates restenosis?

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)


What is the pathogenesis of restenosis?

1. SMC activation and proliferation
2. arterial remodeling


What is the histology of restenosis?

1. synthetic SMCs and ECM


What is the clinical course of restenosis?

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


What causes restenosis following PCI?

All about the migratory effects of smooth muscle cells


What accounts for bulk of restenotic lesion?

ECM accumulation


What is the significance of SMC with restenosis?

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


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

Growth factors induce proliferation of SMC proliferation


What are the growth factors that lead to restenosis?

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


What are the characteristics of PDGF?

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


What are the characteristics of FGF?

Induces SMC proliferation
Secreted by SMC


How does angiotensin II contribute to restenosis?

Promotes SMC proliferation
Binds to AT1 receptor on SMCs


How does TGF-beta contribute to restenosis?

Extracellular matrix secretion by SMC
Produced by SMCs, endothelial cells and platelets following PTCA


What is the most important growth factor leading to restenosis?

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


What is the point of stents?

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


Why use rapamycin to treat restenosis?

Rapamycin inhibits SMC proliferation
This is the drug that is “eluted” for drug-eluting stents


What is being eluted in drug-eluting stents?

Drugs that prevent smooth muscle cell proliferation like rapamycin


What is the MoA of rapamycin?

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


What is the mechanism of paclitaxel (taxol)?

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


What does DES stand for?

Drug eluting stents


To what extent is atherosclerosis an inflammatory disease?

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


What are the stages of progression of atherosclerotic lesions?

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


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

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


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

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


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

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


What is the anatomy of a fibroatheroma?

1. fibrous cap
2. core of macrophages, lipid and debris-apoptosis


How do atherosclerotic plaques expand?

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


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

Yes the plaques may be underlying


What are vulnerable plaques characterized by?

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


What initiates atherosclerosis?

1. genetics
2. risk factors
3. LDLox


What types of plaques never rupture?

Fibrotic plaques


What types of plaques rupture?

Lipid-rich core with thin cap


What is the pathogenesis of atherosclerosis?

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


What is the histology of atherosclerosis

Lipid rich
Fibrous cap
Prone to rupture


What is the clinical course of atherosclerosis?

1. unpredictable
2. small plaques rupture


What is the difference between atherosclerosis and restenosis?

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