mechanisms and prevention of restenosis Flashcards
what is the restenosis rate of balloon angioplasty, bare-metal stent (BMS) and drug-eluting stent (DES)?
(TREATMENT OF ACS)
Balloon angioplasty- 50%
Bare-metal stent (BMS)- 20-30%
Drug-eluting stent (DES)- 5-10%
what are the risk factors involved in the development of restenosis?
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) when cardiologist is doing the procedure
what are the factors involved in the development of restenosis?
barotrauma: endothelial denudation and subintimal hemorrhage
(not possible to put stent in place without some abrasion to the endothelial cell layer)
this can lead to an inflammatory response: VSMC proliferation and migration, extracellular matrix formation and neointimal hyperplasia= restenosis
PROCEDURE-RELATED RISK FACTORS
LESION RELATED RISK FACTORS
describe the mechanisms of restenosis
Normal artery–> narrowing of the lumen (significant stenosis)–> opening of vessel after stent insertion–> restenosis (narrowing of vessel again and proliferation of cellular components of the vessel)
once you have stent in place, in certain circumstances an inflammatory response is generated IN THE ENDOTHELIAL CELL LINING: activation of thrombosis, if subendothelial collagen is exposed and tissue factor released= likelihood of activation of coagulation system
Also have vascular smooth muscle cells start proliferating into intima (can be affected by inflammation [inflammatory mediators like TNF as well as other factors like smoking]
give a summary of an integrated cascade of restenosis
A) diseased artery pre-stent- atherosclerotic plaque
B) Immediate post-stent: endothelial denudation and exposure of subendothelial collagen leads to fibrin deposition and platelet activation.
c+d) Leukocyte recruitment and infiltration: this is an inflammatory response and causes the release of various cytokines (e.g. interleukins)
e) neointimal growth: various cytokines (e.g. interleukins) which can cause SMCs to migrate and reocclude the lumen.
e) restenotic lesion: Becomes more ECM rich over time but will depend on whether have to re-stent patient or other way to repair vessel
describe the different types of metal coronary stents
1st gen:
• CYPHER
• TAXUS, ION
2nd gen:
• XIENCE XPEDITION
• ENDEAVOR, RESOLUTE
3rd gen:
• PROMUS PREMIER
what is better than bare-metal stents?
Drug-eluting stents cause a significant reduction in restenosis rates as compared with bare-metal stents
- CYPHER (sirolimus-eluting coronary stent)
- TAXUS, ION (coated with paclitaxel)
- XIENCE XPEDITION (coated with everolimus)
- ENDEAVOR, RESOLUTE (coated with zotarolimus)
• PROMUS PREMIER (coated with everolimus)
what are the 2 families of compounds used to coat/elute the stents?
siroliumus or compounds ending with mus (everolimus, zoto, ever)= variation of same drug; rapamycin and mTOR inhibtiros
The taxels like paclitaxel
essentially, they are drugs taken from oncology field–>cancer drugs’ primary function is to try prevent cell proliferation therefore…we also want to inhibit cell cycle and cell proliferation…antiproliferative used for drug eluting stent!
how does paclitaxel work?
Paclitaxel works on cell division/ metaphase stage of the cell cycle
- 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
how do mTOR inhibitors work?
inhibit cell cycle by preventing the downregulation of p27 (Cell cycle inhibitor) = prevent the cell from dividing.
controls a lot of protein synthesis through protein translation–> can inhibit new protein formation
what is mTOR (mechanistic target of rapamycin otherwise known as mammalian target of rapamycin)
- Serine/Threonine kinase
- Phosphoinositide 3-kinase-related kinase (PIKK)
- Other family members include ATM, ATR and DNA-PKs
- Primarily functions in cell growth to regulate protein synthesis
Rapamycin (=Sirolimus) –> antifungal, immunosuppressive & anticancer properties Led to search for its target
describe the mTOR signalling pathway
- mTOR kinase domain itself but also the particular accessory proteins that bind to it depends on whether it is called mTORC 1 or mTORC 2
- sit in cytoplasm of cell= receive signals (e.g. growth factor signals or insulin) that go through classic cell signalling pathways (PIP3 kinase- AKT signalling is upstream and activates mTOR) via receptor tyrosine kinase binding
- As mTOR is a kinase, it phosphorylates substrates and activates them e.g. 4E-BP1
- mTORC 2 can activation other kinases involved in cell proliferation too
- TARGET OF DRUG DISCOVERY–> drugs that will bind to the TOR complexes
- First generation: rapalogs
- 2nd generation mTOR inhibitors= bind to the kinase domain of mTOR
rapamycin (1st generation mTOR inhibitor) binds to cytosolic protein, FKBP12= together they inhibit Torc1.
Essentially, that is how the first generation drugs work!
describe the mechanism of action of rapamycin (sirolimus)
sirolimus coming into cell= binds to FKBP12= together they inhibit TOR= prevent processes like:
- synthesis of cell cycle proteins
- p27 down-regulation
- cell-cycle activation
- cell proliferation
what does the chemical structure of sirolimus show?
showing the binding sites of FKBP, mTOR and radical group that is replaced in other rapamycin analogs (e.g. everolimus, ABT-578) to change the property
name some FDA approved mTOR inhibitors
sirolimus (rapamycin):
trade name= rapamune
inhibits mTORC1
everolimus(Rapalog):
trade name= afinitor (novartis)
inhibits mTORC1
temsirolimus (Rapalog):
trade name= wyeth
inhibits mTORC1
Rapalogs are all derivatives of Rapamycin
- Everolimus and sirolimus used in drug eluting stents
- A lot are used for oncology and to prevent kidney transplantation rejection too.
