Effectiveness of Statin-Eluting Stent on Early Inflammatory Response and Neointimal Thickness in a Porcine Coronary Model

Abstract

irolimus-and paclitaxel-eluting stents are routinely used in coronary revascularization because drugeluting stents (DES) significantly reduce the rates of restenosis and target lesion revascularization compared with bare metal stents (BMS). 1,2 However, available DES have limitations such as stent thrombosis 3 because of local and long-term endothelial dysfunction and inflammation. 4 Late thrombosis, a life-threatening complication, has emerged as a major safety concern. Therefore, a stent-based compound that inhibits smooth muscle cell (SMC) proliferation, but does not suppress endothelial cell proliferation while restoring endothelial function, is the central goal for the development of the next generation of DES. Statins have direct anti-inflammatory properties 5 and restore endothelial function, while exerting potent antiproliferative effects upon SMCs. 6 However, the systemic administration of statins does not reduce the restenosis rate after percutaneous coronary intervention 7 and this absence of a systemic effect might be related to inadequate drug concentrations at the site of stent deployment. DES offer theoretical advantages over systemic pharmacotherapy, such as higher drug concentrations at the injury site and minimal systemic side-effects. The present study evaluated the ability of stent-based cerivastatin delivery to reduce stent-induced inflammatory responses and adverse effects on endothelial function, and to inhibit neointimal hyperplasia. MethodsThe Animal Care and Use Committee of Juntendo University approved this study. Stainless steel balloon-expandable tubular stents (Terumo Japan Co, Tokyo, Japan; 15 mm long) were coated with a thin layer of poly-n-butyl methacrylate and polyethylene vinyl acetate copolymer, then the platform was loaded with 300 g of cerivastatin. In Vitro Drug Release KineticsThe cerivastatin-eluting stents (CES) were placed in vials containing 1 ml of 70% acetonitrile/H2O at 37°C. The cerivastatin content was measured daily using high-performance liquid chromatography (Class VP LC-10, Shimadzu Corp, Kyoto, Japan) at 238 nm for the first 14 days and then after 3 and 4 weeks to determine cerivastatin release. 8 The procedure for the control polymer stent was the same and ultraviolet absorbance values were subtracted from those of the CES. J 2008; 72: 832 -838 (Received October 11, 2007; revised manuscript received December 11, 2007; accepted December 14, 2007 Background Drug-eluting stent (DES) implantation is routine during coronary revascularization because DES significantly reduce rates of restenosis and target lesion revascularization compared with bare metal stent (BMS). However, available DES have limitations, such as late thrombosis because of delayed healing with poorer endothelialization and persistent local inflammation. Statins can inhibit cell proliferation, inflammation, and restore endothelial function. The present study evaluated the ability of stent-based cerivastatin delivery to reduce stentinduced inflammatory responses and adverse effects on endothel...

Comparative Analysis of Plaque Growth after Arterial Stent Implant with Anti-Inflammatory Chemokine and Serine Protease Inhibitors Treatment

“…There was no difference in adverse events when comparing Serp-1 and M-T7 treatments (P = 0.2746 for all adverse events; P = 0.7194 for thrombotic/ hemorrhagic events).This reduction in adverse events may have been due to the anti-inflammatory activity of each protein and is consistent with prior studies demonstrating reduced adverse events with non-specific inhibitors of inflammation such as dexamethasone coated stent implants, statin coated stents or ghrel in peptide treatment [37,38,42,43]. Serp-1 may also have reduced thrombosis and/or hemorrhage through inhibition of fXa and the plasminogen activators (tPA and uPA), respectively.…”

“…Excess bleeding was not seen after treatment with either agent. The fact that there was no significant difference in adverse events and specifically thrombotic and hemorrhagic events would support prior studies form other researchers that have linked excess inflammation in stent implant areas with later stent thrombosis [7][8][9][10][35][36][37][38][39][40][41][42][43]. Specific or selective inflammatory cell responses werenot examined here and remain to be determined.…”

“…Multiple studies report correlations between acute and chronic inflammatory cell invasion and activation with restenosis as well as later stent thrombosis [7][8][9][10]38,39]. Agents targeting inflammatory reactions have been reported in preclinical animal studies and small clinical trials to alter restenosis after stent implant but this work remains investigational [38][39][40][41][42][43].…”

Local sustained delivery of acetylsalicylic acid via hybrid stent with biodegradable nanofibers reduces adhesion of blood cells and promotes reendothelialization of the denuded artery

“…Local acetylsalicylic acid delivery, with a nanofibrous membrane via stent, decreased platelet adhesion during the early stage of incomplete re-endothelialization, and promoted endothelialization for about 4 weeks. The vascular injury scores in this study may be higher than those of previous studies, 41,42 which possibly results from differences in denudation procedures and animal arterial models. The inflammation scores were significantly lower than the scores of previous studies, which raises the possibility that decreased inflammatory response can lead to improved endothelial function at, and adjacent to, the stent site.…”

Pitavastatin-Incorporated Nanoparticle-Eluting Stents Attenuate In-Stent Stenosis without Delayed Endothelial Healing Effects in a Porcine Coronary Artery Model

“…Most of these beneficial effects of statins on neointima formation in animals, however, were observed following daily administration of high doses 8,10) (rosuvastatin 20 mg/kg per day 11) , pitavastatin 40 mg/kg per day 12) , simvastatin 40 mg/kg per day 13) ); this may lead to serious adverse side effects in a clinical setting. Furthermore, it has been reported that the use of polymer-coated stents with atorvastatin or cerivastatin has no consistent effect on neointima formation in a porcine in-stent stenosis model 14,15) . Randomized clinical studies in humans have reported no definite effects of statins within the clinical dose range with respect to indices of restenosis after coronary balloon angioplasty [16][17][18][19] or coronary stenting 20,21) ; therefore, preventing in-stent restenosis via statin-mediated "antihealing" effects requires an efficient local drug delivery system.…”