Pathologic Intimal Hyperplasia as a Response to Vascular Injury and Reconstruction

Background Ebolectomy catheter induced intimal thickening (accumulation of smooth muscle cells [SMCs] and extracellular matrix) Balloon angioplasty – 30% coronary arteries develop marked restenosis after 6 months – fibrous with many SMCs

Background Carotid endarterectomy – intimal hyperplasia >50% stenosis in 10-20%, symptomatic in 1% Vascular grafts, reversed or in situ, autologous or synthetic

Background

The Problem Neointimal Hyperplasia Acute s/p PTCA, Elastic van Giesen stain 30 days s/p PTCA, Elastic van Giesen stain Schwartz et.al. Rev Cardiovasc Med. 2002;3:S4

The Problem Neointimal Hyperplasia Schwartz et.al. Rev Cardiovasc Med. 2002;3:S4 In-stent restenosis is almost exclusively the result of neointimal formation.

Pathophysiology Neointimal Hyperplasia Platelets accumulate on denuded region Endothelial cells proliferate SMCs also proliferate and migrate into intima, causingd intimal thickening

Pathophysiology Neointimal Hyperplasia New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima

Pathophysiology Neointimal Hyperplasia Conde et.al. Cath & Cardiovasc Int. 2003;60:236 New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima

Pathophysiology Neointimal Hyperplasia Conde et.al. Cath & Cardiovasc Int. 2003;60:236 New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima

Pathophysiology Neointimal Hyperplasia Conde et.al. Cath & Cardiovasc Int. 2003;60:236 New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima

Pathophysiology Neointimal Hyperplasia New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima

Pathophysiology Neointimal Hyperplasia Factors from platelets, leukocytes, smooth muscle cells, and extracellular matrix interact and regulate the process of intimal hyperplasia, making each step a potential therapeutic target New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima

Pathophysiology Neointimal Hyperplasia New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima

Treatment Vascular reconstruction Principal way to salvage failing grafts Based on assumption that renewed or continued intimal thickening is unlikely With regular follow-up, stenoses in vein grafts may be discovered prior to graft thrombosis If these lesions are reconstructed in time, long-term outcome is generally good

Treatment Neointimal Hyperplasia ASA, plavix, IIb/IIIa inhibitors New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima

Treatment Neointimal Hyperplasia New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima Heparin HELVETICA- In 1141 patients randomized to hirudin, heparin, or placebo, there was no difference in restenosis at 6 months. Coumadin BAAS- In 530 patients randomized to ASA or ASA/Coumadin, composite clinical endpoint was lower in ASA/Coumadin arm at 1 yr. However, Coumadin did not affect restenosis.

Pathophysiology Neointimal Hyperplasia New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima Oxidative stress promotes the expression of endothelial adhesion molecules (e.g. VCAM) that increase monocyte adhesion and transmigration. Probucol is an antioxidant drug.

Treatment Neointimal Hyperplasia New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima START trial: Brachytherapy Patients with in-stent stenosis randomized to radiation showed reduction of restenosis from 45% to 29% at 8 months compare to control. Intracoronary radiation reduces neointimal proliferation after PTCA, likely by inhibiting SMC proliferation and by inducing apoptosis.

Treatment Neointimal Hyperplasia New matrix synthesized Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops endothelial layer Leukocytes demarginate from bloodstream, migrate into subendothelial mural thrombus Smooth muscle cells proliferate and migrate into intima MCAM is an Ig superfamily adhesion molecule expressed on endothelial cells and circulating endothelial precursors. It mediates cell adhesion and intracellular signal transduction.

Treatment Neointimal Hyperplasia MCAM deficiency abrogated neointimal hyperplasia in the carotid ligation model in mice. ? ? ? Wild-type MCAM-/-

Treatment Restenosis and Drug-Eluting Stents A. Rapamycin (Sirolimus): -A macrolide produced by Streptomyces hygroscopicus -Found in soil from Easter Island in Inhibits migration and proliferation of vascular smooth muscle cells -Anti-inflammatory properties

Treatment Restenosis and Drug-Eluting Stents A. Rapamycin: Rapamycin inhibits neointimal hyperplasia in porcine coronary restenosis model at 30 days. Gallo et.al. Circulation. 1999;99:2164

Treatment Restenosis and Drug-Eluting Stents B. Paclitaxel -An anti-neoplastic drug derived from Pacific yew tree. -Inhibits migration and proliferation by enhancing microtubule assembly.

Treatment Restenosis and Drug-Eluting Stents B. Paclitaxel TAXUS I -61 patients with de novo or restenotic lesions -Randomzed to TAXUS stent or bare metal Grube et.al. Circulation. 2003;107:38

Conclusion Intimal hyperplasia Intimal hyperplasia is a complex response to injury. Vascular reconstruction is effective in salvage of vein grafts if performed in time Antiplatelet agents are effective if given at or withing a short time of surgery Development of effective therapy requires an understanding of the underlying pathophysiology.