J Korean Med Sci.  2010 May;25(5):716-722. 10.3346/jkms.2010.25.5.716.

Effects of Combined Therapy with Ezetimibe Plus Simvastatin After Drug-Eluting Stent Implantation in a Porcine Coronary Restenosis Model

Affiliations
  • 1Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.
  • 2The Heart Center of Chonnam National University Hospital, Chonnam National University Research Institute of Medical Sciences, Gwangju, Korea. myungho@chollian.net

Abstract

The aim of this study was to examine the anti-proliferative and anti-inflammatory effects of ezetimibe/simvastatin (E/S) after drug-eluting stent (DES) implantation in a porcine coronary restenosis model. Pigs were randomized into two groups in which the coronary arteries (23 pigs) had DES. Stents were deployed with oversizing (stent/artery ratio 1.3:1) in porcine coronary arteries. Fifteen pigs were taken 10/20 mg of E/S and eight pigs were not taken E/S. Histopathologic analysis was assessed at 28 days after stenting. In neointima, most inflammatory cells were lymphohistiocytes. Lymphohistiocyte count was not different between two groups (337+/-227 vs. 443+/-366 cells, P=0.292), but neointima area was significantly smaller (1.00+/-0.49 mm2 vs. 1.69+/-0.98 mm2, P=0.021) and percent area stenosis was significantly lower (23.3+/-10% vs. 39+/-19%, P=0.007) in E/S group compared with control group. There were no significant differences in fibrin score (1.99+/-0.79 vs. 1.81+/-0.88, P=0.49), endothelial score (1.75+/-0.66 vs. 1.80+/-0.59, P=0.79), and the percent of endothelium covered lumen (43+/-21% vs. 45+/-21%, P=0.84) between E/S group and control group. Combined therapy with ezetimibe and simvastatin inhibits neointimal hyperplasia, but does not inhibit inflammatory infiltration and arterial healing after DES implantation in a porcine coronary restenosis model.

Keyword

Stents; Restenosis; Inflammation; Endothelization

MeSH Terms

Animals
Anticholesteremic Agents/administration & dosage
Azetidines/*administration & dosage
Coronary Restenosis/diagnosis/drug therapy/*etiology
*Disease Models, Animal
Drug Combinations
Drug Implants/administration & dosage
Drug-Eluting Stents/*adverse effects
Female
Graft Occlusion, Vascular/diagnosis/*drug therapy/*etiology
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage
Simvastatin/*administration & dosage
Swine
Treatment Outcome
Anticholesteremic Agents
Azetidines
Drug Combinations
Drug Implants
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Simvastatin

Figure

  • Fig. 1 Neointima area was significantly smaller (A) and percent area stenosis was significantly lower (B) in ezetimibe/simvastatin group compared with control group.

  • Fig. 2 Drug-eluting stented porcine coronary arteries (Methyl methacrylate staining: ×25, A, B and ×100, C, D). Neointima area was larger and percent area stenosis was higher in control group compared with ezetimibe/simvastatin group.

  • Fig. 3 Carstair's fibrin stain (×200) for determining delayed arterial healing according to discriminate fibrin score that is not different between ezetimibe/simvastatin (A) and (B) control groups.

  • Fig. 4 There was no significant differences in fibrin score (A), endothelial score (B), and the percent of enthelium covered lumen (C) between ezetimibe/simvastatin group and control group.


Reference

1. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stent: A meta-analysis of randomized clinical trials. Am J Med. 2006. 119:1056–1061.
2. Farb A, Sangiorgi G, Carter AJ, Walley VM, Edwards WD, Schwartz RS, Virmani R. Pathology of acute and chronic coronary stenting in humans. Circulation. 1999. 99:44–52.
Article
3. Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera K, Skorija K, Weber DK, Gold HK, Virmani R. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation. 2005. 112:270–278.
Article
4. Lim SY, Jeong MH, Hong SJ, Lim DS, Moon JY, Hong YJ, Kim JH, Ahn Y, Kang JC. Inflammation and delayed endothelization with overlapping drug-eluting stents in a porcine model of in-stent restenosis. Circ J. 2008. 72:463–468.
Article
5. Hong YJ, Jeong MH, Lim SY, Lee SR, Kim KH, Sohn IS, Park HW, Kim JH, Kim W, Ahn Y, Cho JG, Park JC, Kang JC. Elevated preprocedural high-sensitivity C-reactive protein levels are associated with neointimal hyperplasia and restenosis development after successful coronary artery stenting. Circ J. 2005. 69:1477–1483.
Article
6. Suzuki T, Kopia G, Hayashi S, Bailey LR, Llanos G, Wilensky R, Klugherz BD, Papandreou G, Narayan P, Leon MB, Yeung AC, Tio F, Tsao PS, Falotico R, Carter AJ. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation. 2001. 104:1188–1193.
Article
7. Heldman AW, Cheng L, Jenkins GM, Heller PF, Kim DW, Ware M Jr, Nater C, Hruban RH, Rezai B, Abella BS, Bunge KE, Kinsella JL, Sollott SJ, Lakatta EG, Brinker JA, Hunter WL, Froehlich JP. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation. 2001. 103:2289–2295.
Article
8. Farb A, Heller PF, Shroff S, Cheng L, Kolodgie FD, Carter AJ, Scott DS, Froehlich J, Virmani R. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. Circulation. 2001. 104:473–479.
Article
9. Ii M, Losordo DW. Statins and the endothelium. Vascul Pharmacol. 2007. 46:1–9.
Article
10. Miyauchi K, Kasai T, Yokayama T, Aihara K, Kurata T, Kajimoto K, Okazaki S, Ishiyama H, Daida H. Effectiveness of statin-eluting stent on early inflammatory response and neointimal thickness in a porcine coronary model. Circ J. 2008. 72:832–838.
Article
11. Aronow HD, Topol EJ, Roe MT, Houghtaling PL, Wolski KE, Lincoff AM, Harrington RA, Califf RM, Ohman EM, Kleiman NS, Keltai M, Wilcox RG, Vahanian A, Armstrong PW, Lauer MS. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet. 2001. 357:1063–1068.
Article
12. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004. 350:1495–1504.
Article
13. Cannon CP, Giugliano RP, Blazing MA, Harrington RA, Peterson JL, Sisk CM, Strony J, Musliner TA, McCabe CH, Veltri E, Braunwald E, Califf RM. IMPROVE-IT Investigators. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J. 2008. 156:826–832.
Article
14. Pearson T, Ballantyne C, Sisk C, Shah A, Veltri E, Maccubbin D. Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels. Am J Cardiol. 2007. 15:1706–1713.
Article
15. Farhan S, Hemetsberger R, Matiasek J, Strehblow C, Pavo N, Khorsand A, Petneházy O, Petrási Z, Kaider A, Glogar D, Huber K, Gyöngyösi M. Implantation of paclitaxel-eluting stent impairs the vascular compliance of arteries in porcine coronary stenting model. Atherosclerosis. 2009. 202:144–151.
Article
16. Schwartz RS, Edelman ER, Carter A, Chronos N, Rogers C, Robinson KA, Waksman R, Weinberger J, Wilensky RL, Jensen DN, Zuckerman BD, Virmani R. Consensus Committee. Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group. Circulation. 2002. 106:1867–1873.
17. Kolodgie FD, John M, Khurana C, Farb A, Wilson PS, Acampado E, Desai N, Soon-Shiong P, Virmani R. Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel. Circulation. 2002. 106:1195–1198.
Article
18. Hong YJ, Jeong MH, Kim W, Lim SY, Lee SH, Hong SN, Lee SH, Kim KH, Yun KH, Kang DG, Lee YS, Park HW, Kim JH, Ahn Y, Cho JG, Park JT, Park CS, Park JC, Kang JC. The effects of abciximab (ReoPro®)-coated stents on extracellular matrix synthesis and apoptosis. Korean Circ J. 2005. 35:290–301.
19. Schwartz RS, Huber KC, Murphy JG, Edwards WD, Camrud AR, Vlietstra RE, Holmes DR. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol. 1992. 19:267–274.
Article
20. Indolfi C, Cioppa A, Stabile E, Di Lorenzo E, Esposito G, Pisani A, Leccia A, Cavuto L, Stingone AM, Chieffo A, Capozzolo C, Chiariello M. Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol. 2000. 35:214–221.
Article
21. Hong YJ, Jeong MH, Kim W, Lim SY, Lee SH, Hong SN, Kim JH, Ahn YK, Cho JG, Park JC, Cho DL, Kim H, Kang JC. Effect of abciximab-coated stent on in-stent intimal hyperplasia in human coronary arteries. Am J Cardiol. 2004. 94:1050–1054.
Article
22. Kim W, Jeong MH, Kim KH, Sohn IS, Hong YJ, Park HW, Kim JH, Ahn YK, Cho JG, Park JC, Cho DL, Kang JC. The clinical results of a platelet glycoprotein IIb/IIIa receptor blocker (abciximab: Reo-Pro)-coated stent in acute myocardial infarction. J Am Coll Cardiol. 2006. 47:933–938.
Article
23. Petronio AS, Amoroso G, Limbruno U, Papini B, De Carlo M, Micheli A, Ciabatti N, Mariani M. Simvastatin does not inhibit intimal hyperplasia and restenosis but promotes plaque regression in normocholesterolemic patients undergoing coronary stenting: a randomized study with intravascular ultrasound. Am Heart J. 2005. 149:520–526.
Article
24. Ong AT, Aoki J, Kutryk MJ, Serruys PW. How to accelerate the endothelialization of stents. Arch Mal Coeur Vaiss. 2005. 98:123–126.
25. van Heek M, Farley C, Compton DS, Hoos LM, Smith-Torhan A, Davis HR. Ezetimibe potently inhibits cholesterol absorption but does not affect acute hepatic or intestinal cholesterol synthesis in rats. Br J Pharmacol. 2003. 138:1459–1464.
Article
26. Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science. 2004. 303:1201–1204.
Article
27. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, Crona JH, Davis HR Jr, Dean DC, Detmers PA, Graziano MP, Hughes M, Macintyre DE, Ogawa A, O'neill KA, Iyer SP, Shevell DE, Smith MM, Tang YS, Makarewicz AM, Ujjainwalla F, Altmann SW, Chapman KT, Thornberry NA. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci USA. 2005. 102:8132–8137.
Article
28. Fujita H, Banno H, Yamanouchi D, Kobayashi M, Yamamoto K, Komori K. Pitavastatin inhibits intimal hyperplasia in rabbit vein graft. J Surg Res. 2008. 148:238–243.
Article
29. van der Harst P, Groenewegen HC, Roks AJ, Buikema H, Zijlstra F, van Gilst WH, de Smet BJ. Rosuvastatin attenuates angiotensin II-induced neointimal formation after stent implantation in the rat. Coron Artery Dis. 2008. 19:47–53.
Article
30. Kiyan J, Kusch A, Tkachuk S, Krämer J, Haller H, Dietz R, Smith G, Dumler I. Rosuvastatin regulates vascular smooth muscle cell phenotypic modulation in vascular remodeling: role for the urokinase receptor. Atherosclerosis. 2007. 195:254–261.
Article
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