Mechanisms of Restenosis

Question 1

Why were stents developed

Answer 1

Balloon angioplasty is effective in recanalisation
but the restenosis rate is 50%
The development of stents reduced the rate of restenosis.
metal stents- 20-30%
drug eluting stents - 5-10%

Question 2

What are the risk factors for Restenosis

Answer 2

Numonic: Cats, bring, great, love

Clinical: diabetes, history of restenosis
Biological: increased levels of pAI-1
Genetic: polymorphissms of NOS3 gene
Lesions: no. lesions, calcification, tortuous vessel

Question 3

Pathophysiology of Restenosis

Answer 3

The stent insertion procedure may damage the endothelial wall of the vessel, this may trigger the inflammatory response. Macrophages and leukocytes are recruited with release growth factors and cytokines.

The inflammatory response results in platelet activation which activates the coagulation fibrinolysis system. Thrombosis can occur

These growth factors and cytokines cause the migration of smooth muscle cells from the ateriole towards the lumen, resulting in the formation of a neointimal hyperplasia which results in the narrowing of the vessel.
The smooth muscles secrete ECM proteins that strengthen the neointima.

Arteriole remodelling causes the increased thickness of the atery and the loss of elastic fibres and changes in the extracellular matrix deposition

Question 4

What are the different types of stents available

Answer 4

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

Question 5

Paclitaxel mode of action

Answer 5

Paclitaxel: interfere with the normal breakdown of microtubules during cell division.

Question 6

What is the mode of action of Sirolimus

Answer 6

• Inhibitor of the mTOR signalling pathway.
  -Sirolimus binds to FKBP12 to inhibit the mTOR protein.

mTOR signalling pathway functions:
- cell proliferation
-cell cycle progression
-synthesises cell cycle proteins
-Downregulates p27!

p27 functions to inhibit cell cycle progression. Siromilus is an MTOR inhibitor that prevents the downregulation of P27

– this prevents cell cycle progression

rampamyicn analogue: RAPALOGUE of Sirolimus
is Biolimus - which has increased lipophilicity for increased absorption

Question 7

What are the limitations of drug-eluting stents

Answer 7

• Caging of stent effects arterial physiology
• Not all of drug is eluted
  -Long term risk of thrombosis
  -Inflammatory response to coating or polymer
  -The anti-proliferative effect of the drug may effect endothelial cell regeneration

—–This led to the development of Bioabsorbable vascular scaffolds (BSV)

Question 8

Bioabsorbable vascular scaffolds

Answer 8

• Made of Polylactic acid (biodegradable polyester)
• polymer degrades into lactic acid - disolves in 2 years.

Question 9

What are the advantages and disadvantages of bioabsorbable vascular scaffolds

Answer 9

PROS:
-polymer is biocompatible
-100% of the drug is eluted
-complete healing of the endothelium
- return to natural vessel
- reduced restenosis rate

CONs:
May lead to stent thrombosis