Mechanisms And Prevention Of Restnosis

Question 1

Milestones in coronary angioplasty

Answer 1

image

Question 2

Restenosis def

Answer 2

Re-occlusion of the vessel - scar tissue formed into and around the site of the stent

Question 3

intervention + restenosis rates (3)

Answer 3

Balloon angioplasty = 50%

Bare-metal stent (BMS) = 20-30%

Drug-eluting stent (DES) =
5-10%

Question 4

Risk factors involved in the development of restenosis - pathphys (6)

Answer 4

• Restenosis is not a random phenomenon!
• 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)

Question 5

Factors involved in the development of restenosis

Answer 5

image

Question 6

Schematic of an integrated cascade of restenosis - steps (6)

Answer 6

image

a) diseased artery pre-stent
b) immediate post-stent
c) leukocyte recruitment
d) leukocyte infiltration
e) neointimal growth
f) restenotic occlusion

Question 7

Types of metal coronary stents (3)

Answer 7

1st gen: stainless steel
2nd gen: cobalt chromium
3rd gen: platinum chromium

• reduced thickness + change in metal overtime to red restenosis

Question 8

Drug-eluting stents benefit

Answer 8

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

Question 9

drug-eluting stents e.g.’s (6)

Answer 9

• CYPHER (sirolimus-eluting coronary stent)
• TAXUS, ION (coated with paclitaxel)
• PROMUS PREMIER (coated with everolimus)
• XIENCE XPEDITION (coated with everolimus)
• ENDEAVOR, RESOLUTE (coated with zotarolimus)

reduced it by 20-25% to 5-10%

Question 10

Mechanisms of anti-proliferative drugs (4)

Answer 10

-prolif drives restenosis scar
-work at cell division level: microtubules - to prevent cc progression

• p27 = cell cycle inhibitor
• mTOR inhibitors prevent
  downreg of p27

Question 11

Paclitaxel (chemo) (3)

Answer 11

 Chemotherapeutic used to treat ovarian, breast, lung, and pancreatic cancers

 Member of taxane family of drugs ( with docetaxel)

 Interferes with the normal
breakdown of microtubules
during cell division

Question 12

mTOR history (5)

Answer 12

Mechanistic target of Rapamycin otherwise known as Mammalian target of Rapamycin (Sirolimus)

found ver 30 years ago
antifungal, immunosuppressive &
anticancer properties

Led to search for its target =mTOR

• reg Protein Synth
  -cell growth
  -metab
• in IGF (PIP3) pathway

Question 13

MoA of rapamycin/sirolimus on mTOR (6)

Answer 13

normally: mTOR
1) in IGF
2) activate PI3K
3) = AKT pathway
4) pro synth + traslation
+ downregs P27

= switching it off = keep P27 high = inhib cell cycle

drug binds to FKBP12 = inhib mTOR activity

Question 14

FDA approved mTOR inhibitors (3)

Answer 14

Rapalogs are all derivatives of Rapamycin

Sirolimus (Rapamycin)
Everolimus (Rapalog)

used in stents

Question 15

Limitations of drug-eluting stents (6)

Answer 15

• Permanent vessel caging affects arterial physiology
• Not all the drug is eluted
• Long term risk of thrombosis (late stent thrombosis)
• Inflammatory response to coating and/or polymer
• Adverse effects of anti-proliferative drugs on endothelial regeneration
• Led to development of bioresorbable vascular scaffolds (BVS) – since 2011 in clinical practice

Question 16

Bioabsorbable stents (3)

Answer 16

made of Polylactic acid
Biodegradable polyester

• BVS are transient vascular scaffolds

= degrades to lactic acid over time = reabsorbed by the vessel in 2yrs

Question 17

Advantages of bioabsorbable stents (8)

Answer 17

• Polymers are biocompatible
• 100% of drug is eluted
• Complete healing of endothelium
• Increased options for retreatment
• Increased options for imaging CT/MRI
• Appeals to concerns over permanent implant
• Return to natural vessel
• But issues with stent thrombosis!

Question 18

Bioresorbable Scaffolds
vs
Metallic Stents in Routine PCI - study (4)

Answer 18

Randomized trial to compare an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent (Xience) in the context of routine clinical practice

The data and safety monitoring board
recommended early reporting of the study
results because of safety concerns

Definite or probable device thrombosis occurred in 31 patients in the scaffold
group as compared with 8 patients in the stent group (2-year cumulative event rates, 3.5% vs. 0.9%; P<0.001)

The bioresorbable scaffold was associated with a higher incidence of device thrombosis than the metallic stent through
2 years of follow-up