Neointimal formation

Todaka T, Yokoyama C, Yanamoto H, Hashimoto N, Nagata I, Tsukahara T, Hara S, Hatae T, Morishita R, Aoki M, Ogihara T, Kaneda Y, Tanabe T (1999) Gene transfer of human prostacyclin synthase prevents neointimal formation after carotid balloon injury in rats. Stroke 30 419-426... 

Yue TL, Vickery-Clark L, Louden CS, Gu JL, Ma XL, Narayanan PK, Li X, Chen J, Storer B, Willette R, Gossett KA, Ohlstein EH (2000) Selective estrogen receptor modulator idoxifene inhibits smooth muscle cell proliferation, enhances reendothelial-ization, and inhibits neointimal formation in vivo after vascular injury. Circulation 102(Suppl 3) III281—288... 

PDGFpR activation in treated animals (rat and rabbit) probably corresponds to a substantial reduction of PDGF-BB protein levels in the lesion, which can explain the reduced SMC migration and neointimal formation in treated animals. Our data are in conjunction with reduction in arterial and blood cytokines, IL-lp, TNFa, NFkB, and MMP-2 activity following injury (52). The systemic inactivation results in reduced expression of local inflammatory mediators leading to reduced activation and proliferation of SMC and decreased neointimal formation. 

The rat carotid artery injured by a balloon catheter has been widely used as a model of angioplasty. The rat model is a proliferation model without foam cells (93). This form of injury causes immediate coagulation and thrombosis cascade in which platelets adhere, spread, and degranulate on the denuded surface of the artery, and approximately 24 hours later SMC begin to proliferate. Liposomal BPs, clodronate, and alendronate were injected to male sabra rats, 15 and 3mg/kg, respectively (52,69,76). Marked neointimal formation and decreased luminal area were observed in control animals. Neointima/media (N/M) ratio was 1.3 0.2, and luminal stenosis was 44 3%. LC and LA suppressed intimal growth when administered intravenously on day -1 and day 6. N/M ratios were reduced by 60% and 69% for LC and LA, respectively. 

Danenberg HD, Fishbein 1, Gao J, et al. Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits. Circulation 2002 106 599-605. 

Danenberg HD, Fishbein I, Epstein H, et al. Systemic depletion of macrophages by liposomal bisphosphonates reduces neointimal formation following balloon-injury in the rat carotid artery. J Cardiovasc Pharmacol 2003 42 671-679. 

Adenoviruses carrying the gene that expresses TIMP-3 has been shown to be able to overexpress TIMP3 within the extracellular matrix. As a result MMP activity was decreased and apoptosis levels in the neointima and medial layer were significantly elevated by TIMP-3 overexpression. Consequently neointimal formation declined by 84% in human veins at 14 days and by 58% in pig vein grafts. 

Aoki M, Morishita R, Hayashi S, et al. Inhibition of neointimal formation after balloon injury by cilostazol, accompanied by improvement of endothelial dysfunction iand induction of hepatocyte growth factor in rat diabetes model. Diabetologia 2001 44 1032-1042. 

Burke SE, Lubbers NL, Chen YW et al. Neointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin. J Cardiovasc Pharmacol 1999 33 829-835. 

Neointimal formation is a multifactorial process, that consists of thrombotic formation, inflammatory response, and smooth muscle cells differentiation, migration, and proliferation... 

Inflammatory response after stent implantation plays an important role in the cascade of neointimal formation. A positive correlation between inflammatory reaction and restenosis has been observed (16). Perivasculitis caused by stent deployment also participates in the neointimal formation (17). Corticosteroids, as an anti-inflammatory agent, have been evaluated. Methylprednisolone (MP)-loaded stents with different doses showed a positive dose-related effect on neointimal hyperplasia (18). Furthermore, MP-coated stents showed decreased macrophages at the stented sites (19). In clinic, dexamethasone-coated stents showed an inhibitive effect on neointimal hyperplasia in selected patients (20), although no beneficial effect was observed in a randomized trial compared to bare stents (21). For other type of drugs with anti-inflammatory characteristics, such as ibuprofen, colchicine, aton/astatin, and probucol, no favorable effects on neointimal hyperplasia were observed (18,22,23). 

Matsumoto Y Shimokawa H, Morishige K, et al. Reduction in neointimal formation with a stent coated with multiple layers of releasable heparin in porcine coronary arteries. J Cardiovasc Pharmacol 2002 39(4)513-522. 

Klugherz BD, Lianos G, Lieuallen W, et al. Dose-dependent inhibition of neointimal formation using a sirolimus-eluting stent [abstr], Eur HeartJ 2000 2l(suppl) 283. 

Suzuki T Kopia G, Hayashi S, et al. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001 104( 10) I 188-1193. 

I I New G, MosesJW, Roubin GS, etal. Estrogen-eluting, phos-phorylcholine-coated stent implantation is associated with reduced neointimal formation but no delay in vascular repair in a porcine coronary model. Catheter Cardiovasc Interv 2002 57(2) 266-27l. 

Wang L, Salu K, Verbeken E, et al. Stent-mediated methylprednisolone delivery reduces macrophage contents and in-stent neointimal formation. Coron Artery Dis 2005 ... 

Johnson TW, Wu YX, Herdeg C, et al, Stent-based delivery of tissue inhibitor of metalloproteinase-3 adenovirus inhibits neointimal formation in porcine coronary arteries. Arterioscler Thromb Vase Biol 2005 25(4) 754-759. 

Carter AJ, Farb A, Gould KE, Taylor AJ, Virmani R, The degree of neointimal formation after stent placement in atherosclerotic rabbit iliac arteries is dependent on the underlying plaque, Cardiovasc Pathol 1999 8(2) 73-80. 

Simon DI, Dhen Z, Seifert R Edelman ER, Ballantyne CM, Rogers C. Decreased neointimal formation in Mac-I(—/—) mice reveals a role for inflammation in vascular repair after angioplasty. J Clin Invest 2000 l05(3) 293-300. 

Wu CH, PanJS, Chang WC, HungJS, Mao SJ. The molecular mechanism of actinomycin D in preventing neointimal formation in rat carotid arteries after balloon injury. J Biomed Sci 2005 I2(3) 503 512. 

I 5 Hayashi S, Watanabe N, Nakazawa K, et al, Roles of P-selectin in inflammation, neointimal formation, and vascular remodeling in balloon-injured rat carotid arteries, Circulation 2000 102 1710-1717. 

Based on these data, we conducted a study to determine the effects of a l7(3-estradiol-eluting stent on neointimal formation in a high-injury porcine coronary model (29). Our study showed that l7(3-estradiol-eluting PC-coated stents (Abbott/ Biocompatibles) were associated with a 40% reduction in neointimal formation without affecting endothelial regeneration. This approach could have a potential clinical benefit in the prevention and treatment of in-stent restenosis. 

Costa MA, Sabate M, Kay IR et al. Three-dimensional intravascular ultrasonic volumetric quantification of stent recoil and neointimal formation of two new generation tubular stents. Am J Cardiol 2000 85 135-139. 

The last remaining question is if AVI-4126 will find a place in future therapeutic regimens for the prevention of restenosis this answer might be found in the results of phase II clinical studies currently being conducted, such as AVAIL. Our recent data on six-month follow-up on the patients enrolled in the AVAIL study (87) showed that AVI-4126 is effective in reducing neointimal formation, particularly when locally delivered in high dose. We also concluded that local delivery of antisense is safe and feasible, The results indicate that antisense (AVI-4126) can be as effective in prevention of the restenosis as most of the well-known antiproliferative agents do, but in contrast to other chemotherapeutics (paclitaxel, actinomycin D) c-myc antisense inhibits cell cycle in the G-1 phase, which make its effect less toxic and comparable with that of rapamycin. 

Shi Y Fad A, Galleon A, et al. Transcatheter delivery of c-myc antisense oligomers reduced neointimal formation in a porcine model of coronary artery balloon injury. Circulation I 994 90 944-951. 

Kipshidze NN, Iversen B Kim HS, etal. Advanced c-myc anti-sense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model. Catheter Cardiovasc Interv 2004 61 (4) 518-527. 

Kipshidze NN, Porter TR, Dangas G, et al. Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model, Cardiovasc Radiat Med 2003 4(3) 152-159. 

At therapeutic dosimetries in vivo, the main photodynamic mechanism for vascular SMC depletion is apoptosis (10). Re-endothelialization appears to be accelerated after PDT and may contribute to the sustained inhibition of neointimal formation (26,45-47). If so, this would be an important advantage over other restenosis prevention strategies such as brachytherapy or certain drug-eluting stents. 

Suzuki, J., Iwai, M., Nakagami, H., Wu, L., Chen, R., Sugaya, T., Hamada, M., Hiwada, K., and Horiuchi, M. 2002. Role of angiotensin II-regulated apoptosis through distinct ATi and AT2 receptors in neointimal formation. Circulation 106 847-853. 

---