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Cardio and Resp diseases > Mechanism and prevention of restenosis > Flashcards

Mechanism and prevention of restenosis Flashcards

1
Q

What are the surgical interventions for acute coronary syndromes?

A
  • Balloon angioplasty

* Stent

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2
Q

What is restenosis?

A

re-occlusion of vessel through scar tissue that forms around the site of stent

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3
Q

Rates of restenosis for:

  • Balloon angioplasty
  • Bare-metal stent (BMS)
  • Drug eluting stent (DES)
A
  • Balloon angioplasty: 50%
  • Bare-metal stent (BMS): 20-30%
  • Drug eluting stent (DES): 5-10%
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4
Q

Risk factors involved in the development of restenosis?

A
  • Clinical (diabetes, history of restenosis)
  • Biological (increased PAI-1)
  • Genetic (NOS3 polymorphisms)
  • Lesion-related risk factors (number and length of lesions, calcification, tortuous vessel)
  • Procedural (balloon angioplasty, BMS)
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5
Q

How do the risks eventually lead to restenosis?

A
  • The patient specific risk factors lead to inflammation
  • Inflammation drives VSMC proliferation and migration into the lumen of vessel
  • inflammatory response caused by risk factors can increase platelet activation
  • extracellular matrix deposition and neointimal hyperplasia happens leading to restenosis
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6
Q

How can stents cause restenosis?

A

after stent gets introduced there’s opening of vessel but re-occlusion and narrowing can happen, scar tissue starts to infiltrate into lumen

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7
Q

How can smoking play a role in causing restenosis?

A
  • Smoking can induce reactive oxidation species
  • oxidised products induce neointima proliferation, proliferation of VSMC and extracellular matrix deposition
  • Causes stiffening and thickening of vessels
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8
Q

How do matrix metalloproteinases lead to restenosis?

A

Matrix metalloproteinases can lead to ECM deposition

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9
Q

What are the steps of restenosis after a stent gets put in?

A
  1. Endothelial erosion and platelet/fibrinogen deposition right after the stent is put in
  2. Cytokine release and leukocyte recruitment
  3. Smooth muscle cell proliferation and migration, and leukocyte infiltration
  4. Macro recruitment of smooth muscle cells and they continue to proliferate - neointimal growth
  5. A restenotic lesion forms - flow of blood is reduced, vessel can become fully occluded
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10
Q

What are the triggers for restenosis?

A

EC denudation and EC dysfunction are the triggers for restenosis – trauma activates coagulation (cause fibrin formation)

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11
Q

What are some important mediators secreted post stent?

A
  • Cytokines ie IL-6 and 8
  • leukocyte recruitment
  • monocyte chemo attractive protein – recruits more immune cells
  • various different growth factors also released
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12
Q

What happens to the smooth muscle cell phenotype?

A

Smooth muscle cells switch to proliferative phenotype

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13
Q

What are the different types of metal coronary stents?

A

1st generation:

  • Made of stainless steel
  • Cypher and Taxus

2nd generation:

  • Made of cobalt chromium
  • Xience and Endeavor

3rd generation:

  • Made of Platinum Chromium
  • Promus

Stents got thinner with each generation – prevents restenosis

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14
Q

What do drug-eluting stents do?

A

Drug-eluting stents cause a significant reduction in restenosis rates as compared with bare-metal stents

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15
Q

What drugs are stents usually coated with?

A
  • sirolimus
  • paclitaxel
  • everolimus
  • zotarolimus
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16
Q

What is paclitaxel?

A
  • Chemotherapeutic used to treat ovarian, breast, lung, and pancreatic cancers
  • Member of taxane family of drugs ( with docetaxel)
17
Q

How does paclitaxel work?

A

Interferes with the normal breakdown of microtubules during cell division - works on microtubules to prevent cell division

18
Q

How does sirolimus work?

A

cell cycle inhibition
• Act on p27, prevents it from being downregulated – it’s a cell cycle inhibitor
• Inhibits protein translation – no new proteins, cell cycle progression halted

19
Q

What is a target of rapamycin?

A

mTOR - Mechanistic target of Rapamycin otherwise known as Mammalian target of Rapamycin

20
Q

What is mTOR?

A
  • mTOR is an important kinase within the cells
  • regulates protein synthesis and other responses that drive cell growth and proliferation
  • has multiple binding partners
21
Q

What is the mTOR signalling pathway?

A
  • mTOR in the IGF (insulin like growth factor) signalling pathway – pathway leads to AKT activation
  • mTOR phosphorylates downstream mediators to increase cell growth and proliferation
22
Q

What is sirolimus a derivative of?

A

Sirolimus is a derivative of rapamycin – they both inhibit mTOR

23
Q

What is the mechanism of action of rapamycin/sirolimus on mTOR?

A
  • upstream mediators like growth factors and insulin activate PI3K which activates AKT and that activates TOR
  • Protein synthesis and protein translation induced – TOR plays a role in driving cell cycle
  • TOR downregulates p27
  • TOR activates cell proliferation
  • Sirolimus binds to FKBP12 – they both bind to mTOR to inhibit it and its functions
  • FKBP12 is a cytosolic protein, poorly defined functions, aka immunophilins
24
Q

What are rapalogs?

A

Rapalogs are all derivatives of Rapamycin

25
Q

What are FDA approved mTOR inhibitors?

A
  • Sirolimus (rapamycin)

- Everolimus (rapalog)

26
Q

What is biolimus?

A
  • Biolimus is a new mTOR inhibitor

- Superior lipophilicity for increased absorption

27
Q

What are the limitations of drug-eluting stents?

A
  • Permanent vessel caging affects arterial physiology
  • Not all the drug is eluted
  • Long term risk of thrombosis (late stent thrombosis)
  • There could be an inflammatory response to coating and/or polymer
  • Adverse effects of anti-proliferative drugs on endothelial regeneration – EC cell repair/regeneration may be affected
28
Q

What are bioresorbable vascular scaffolds (BVS)?

A

BVS are transient vascular scaffolds – will be reabsorbed by the vessel

29
Q

What are bioabsorbable stents?

A
  • Made of Polylactic acid - Biodegradable polyester

* It will degrade to lactic acid overtime, stent will be reabsorbed by vessel in 2 years

30
Q

Advantages of bioabsorbable stents?

A
  • Polymers are biocompatible
  • 100% of drug is eluted
  • Complete healing of endothelium
  • Increased options for retreatment
  • Increased options for imaging CT/MRI – cant do CT/MRI with metal stents
  • Appeals to concerns over permanent implant
  • Return to natural vessel
31
Q

What do clinical trials show about bioabsorbable stents?

A

Clinical trial showed that bioabsorbable stends had higher incidence of thrombosis than metal stents

Cardio and Resp diseases (29 decks)

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