Stenting:επαναστένωση ISR (intra stent restenosis) Μετεκπαιδευτικό Πρόγραμμα στην Αγγειοχειρουργική - Ενδαγγειακή Χειρουργική Κ. Α. Φίλης Αν. Καθηγητής ΕΚΠΑ

ISR can be defined clinically or angiographically. Definitions ISR can be defined clinically or angiographically. Clinically, it is defined as the presentation of recurrent ischaemia Angiographically, ISR is the presence of >50% diameter stenosis in the stented segment. 50%-70% : moderate 70%-99% : severe Teirstein PS, N Engl J Med, 1997

Cellular response to injury Platelet adherence and degranulation (10-30min) Subenthothelial collagen exposure Platelets adherence (αΙΙb βIΙa, Von Villebrand, Fibronectin) ADP, thromboxane A2, Platelets recruitment (αΙΙb βΙΙIa) Platelets degranulation (PDGF) Leukocyte, monocytes, macrophages SMC proliferation and migration (1day – 3months) Endothelial cell regrowth

Diffuse in stent restenosis

Initial role of stents : optional to support the dissected ballooned plaque from further dissection-rupture to prevent arterial recoil by their radial force

PTA result PTA result

Το δίλημμα Αγγειοπλαστική με μπαλόνι Αγγειοπλαστική με ενδοπρόθεση Constrictive remodeling (αναδιαμόρφωση σύσπασης) Elastic recoil (ελαστική επαναφορά) Αγγειοπλαστική με ενδοπρόθεση Αυξημένη μυο-ενδοθηλιακή υπερπλασία

Intimal hyperplasia

Various ISR rates @ 1 year according to locations

Time course of ISR

Factors influencing ISR Cardiovascular risk factors Endogenous risk factors Exogenous factors

Cardiovascular factors Smoking Diabetes Hyperlipidemia

Effect of smoking in ISR Cardiovascular factors

Effect of diabetes in ISR Cardiovascular factors P=0.89 (NIDM) P=0.04 (IDM)

Genomic Blood flow Plaque

Genomic Endogenous factors

Blood flow Endogenous factors

Plaque Endogenous factors

Endogenous factors

Endogenous factors

Endogenous factors

Endogenous factors

Exogenous factors Stent

Stent Ευλυγισία Πάχος Ευκολία καθοδήγησης Ακτινική δύναμη Exogenous factors Ευλυγισία Πάχος Ευκολία καθοδήγησης Ακτινική δύναμη Ικρίωμα/Σκαλωσιά Βιοσυμβατότητα Μηχανική αντοχή Αντίσταση στη ρήξη

Stent asymetry Exogenous factors

Self expanding V balloon expanded Exogenous factors

Cell design Exogenous factors

Strut Thickness Exogenous factors

Stent fracture Exogenous factors

Restenosis-Thrombosis Pharmacologic prevention ASA & Heparin ASA & Ticlopidin

Restenosis-Thrombosis Pharmacologic prevention

Gold standard : Clopidogrel + aspirin

Σημασία των αντιαιμοπεταλιακών Αναστολή αιμοπεταλιακής δραστικότητας με σκοπό την πρόληψη της οξείας θρόμβωσης της αγγειοπλαστικής Ανεπαρκή για την επαναστένωση

Prevention of ISR Medicines Drug eluting stents Brachytherapy, Cryoplasty Genes

Medicines ISR on coronary PTA/stent Reo pro PDGF I antiallergic

Induction of vascular atrophy as a novel approach to treating restenosis. A review Seung-Kee Min MDa, Richard D. Kenagy PhDb and Alexander W. Clowes MDb, , Journal of Vascular Surgery Volume 47, Issue 3, March 2008, Pages 662-670 After vascular reconstruction, luminal narrowing is in part caused by intimal thickening, the consequence of endothelial injury and inflammation, smooth muscle cell hyperplasia, and extracellular matrix accumulation. It may be possible to induce these lesions to shrink. This novel approach to the treatment of restenosis is supported by animal experiments and a few clinical observations demonstrating vascular atrophy in response to drugs such as Gleevec (EDGF I). A potential limitation to this approach might be the formation of aneurysms.

But fewer reinterventions to keep the artery patent Drug eluting stents sirolimus (rapamycin) paclitaxel inhibit smooth muscle cells and endothelial cells They inhibit ISR They are more thrombogenic Clinical practice : no benefit in survival, no benefit in MACE, But fewer reinterventions to keep the artery patent

Drug eluting stents in peripheral arteries SMART (SIROLIMUS) CORDIS ENDOVASCULAR ZILVER (PACLITAXEL) COOK

Drug eluting balloons in peripheral arteries THUNDER trial (Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries), 2008 Femoral Paclitaxel (FemPac) trial, 2008 ILLUMENATE trial, 2013, euroPCR DANCE trial, 2013, MEET (subenthothelial dexamethazone injections)

Drug eluting balloons plus nitinol bare stent in peripheral arteries

Stent-grafts in peripheral arteries VIASTAR study, 2013 Heparin-bonded stent-graft V metal stent For type D lesions

Biodegradable Stents

Brachytherapy

Gene therapy Genetically engineered cells secreting a thrombolytic enzyme (tPA) which are topically applied (on the stent). Major problem : cells are moving away by the blood flow.

STRATEGIES TO INHIBIT ISR Conclusions ISR is a stable endothelial reaction to injury STRATEGIES TO INHIBIT ISR systematic topical Medicines DES, Drug eluting balloons Brachytherapy, Cryoplasty Photodynamic therapy Genes