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Mechanisms of drug-eluting stent restenosis

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Abstract

Drug-eluting stents (DES) were developed to overcome in-stent restenosis (ISR), which has long been considered the main complication limiting the long-term efficacy of coronary stenting. New-generation DES which composed of advanced stent design with and without specific biocompatible polymer contributes a reduction of the incidence of ISR to rate ranging from 5 to 10%. The precise reasons of DES restenosis are still controversial and not fully understood. Angiographic and coronary images at the index procedure, systemic status of patients, medications, and intracoronary imaging at ISR site are all considered to find the possible mechanisms of DES restenosis. Multiple biological, genetic, mechanical, and technical factors might intricately contribute to DES restenosis. Biological and genetic factors of ISR are not able to be sufficiently modified by the current medical approaches. Tailored treatments avoiding mechanical and technical factors of ISR are required to reduce DES restenosis. Elucidation of DES restenosis leads to further improvement in the current DES system and finds the optimal approach to treat DES restenosis. The possible mechanisms of DES restenosis are discussed in this review.

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References

  1. Serruys PW, Kutryk MJ, Ong AT. Coronary-artery stents. N Engl J Med. 2006;354:483–95.

    CAS  PubMed  Google Scholar 

  2. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:1773–80.

    CAS  PubMed  Google Scholar 

  3. Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman PE, et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med. 2010;363:136–46.

    CAS  PubMed  Google Scholar 

  4. Aoki J, Kozuma K, Awata M, Nanasato M, Shiode N, Tanabe K, et al. Three-year clinical outcomes of everolimus-eluting stents from the post-marketing surveillance study of cobalt-chromium everolimus-eluting stent (XIENCE V/PROMUS) in Japan. Circ J. 2016;80:906–12.

    PubMed  Google Scholar 

  5. Kozuma K, Kimura T, Kadota K, Suwa S, Kimura K, Iwabuchi M, et al. Angiographic findings of everolimus-eluting as compared to sirolimus-eluting stents: angiographic sub-study from the Randomized Evaluation of Sirolimus-eluting versus Everolimus-eluting stent Trial (RESET). Cardiovasc Interv Ther. 2013;28:344–51.

    CAS  PubMed  Google Scholar 

  6. Moussa ID, Mohananey D, Saucedo J, Stone GW, Yeh RW, Kennedy KF, et al. Trends and outcomes of restenosis after coronary stent implantation in the United States. J Am Coll Cardiol. 2020;76:1521–31.

    PubMed  Google Scholar 

  7. Hamon M, Bauters C, McFadden EP, Wernert N, Lablanche JM, Dupuis B, et al. Restenosis after coronary angioplasty. Eur Heart J. 1995;16(Suppl I):33–48.

    PubMed  Google Scholar 

  8. Jukema JW, Verschuren JJ, Ahmed TA, Quax PH. Restenosis after PCI. Part 1: pathophysiology and risk factors. Nat Rev Cardiol. 2011;9:53–62.

    PubMed  Google Scholar 

  9. Mehran AJ, Dangas GD. In-stent restenosis. ACC Cathsap. 2008;3:752–69.

    Google Scholar 

  10. Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol. 2010;56:1897–907.

    PubMed  Google Scholar 

  11. Huang S, Houghton PJ. Mechanisms of resistance to rapamycins. Drug Resist Updat. 2001;4:378–91.

    CAS  PubMed  Google Scholar 

  12. Costa MA, Simon DI. Molecular basis of restenosis and drug-eluting stents. Circulation. 2005;111:2257–73.

    PubMed  Google Scholar 

  13. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB. Mechanisms of taxol resistance related to microtubules. Oncogene. 2003;22:7280–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Yusuf RZ, Duan Z, Lamendola DE, Penson RT, Seiden MV. Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets. 2003;3:1–19.

    CAS  PubMed  Google Scholar 

  15. Niccoli G, Montone RA, Ferrante G, Crea F. The evolving role of inflammatory biomarkers in risk assessment after stent implantation. J Am Coll Cardiol. 2010;56:1783–93.

    PubMed  Google Scholar 

  16. Walter DH, Fichtlscherer S, Sellwig M, Auch-Schwelk W, Schachinger V, Zeiher AM. Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation. J Am Coll Cardiol. 2001;37:839–46.

    CAS  PubMed  Google Scholar 

  17. Ferrante G, Niccoli G, Biasucci LM, Liuzzo G, Burzotta F, Galiuto L, et al. Association between C-reactive protein and angiographic restenosis after bare metal stents: an updated and comprehensive meta-analysis of 2747 patients. Cardiovasc Revasc Med. 2008;9:156–65.

    PubMed  Google Scholar 

  18. Dibra A, Mehilli J, Braun S, Hadamitzky M, Baum H, Dirschinger J, et al. Inflammatory response after intervention assessed by serial C-reactive protein measurements correlates with restenosis in patients treated with coronary stenting. Am Heart J. 2005;150:344–50.

    CAS  PubMed  Google Scholar 

  19. Park DW, Lee CW, Yun SC, Kim YH, Hong MK, Kim JJ, et al. Prognostic impact of preprocedural C reactive protein levels on 6-month angiographic and 1-year clinical outcomes after drug-eluting stent implantation. Heart. 2007;93:1087–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Park DW, Yun SC, Lee JY, Kim WJ, Kang SJ, Lee SW, et al. C-reactive protein and the risk of stent thrombosis and cardiovascular events after drug-eluting stent implantation. Circulation. 2009;120:1987–95.

    CAS  PubMed  Google Scholar 

  21. Katsaros KM, Kastl SP, Zorn G, Maurer G, Wojta J, Huber K, et al. Increased restenosis rate after implantation of drug-eluting stents in patients with elevated serum activity of matrix metalloproteinase-2 and -9. JACC Cardiovasc Interv. 2010;3:90–7.

    PubMed  Google Scholar 

  22. Katsaros KM, Speidl WS, Kastl SP, Zorn G, Huber K, Maurer G, et al. Plasminogen activator inhibitor-1 predicts coronary in-stent restenosis of drug-eluting stents. J Thromb Haemost. 2008;6:508–13.

    CAS  PubMed  Google Scholar 

  23. Speidl WS, Katsaros KM, Kastl SP, Zorn G, Huber K, Maurer G, et al. Coronary late lumen loss of drug eluting stents is associated with increased serum levels of the complement components C3a and C5a. Atherosclerosis. 2010;208:285–9.

    CAS  PubMed  Google Scholar 

  24. Farooq V, Gogas BD, Serruys PW. Restenosis: delineating the numerous causes of drug-eluting stent restenosis. Circ Cardiovasc Interv. 2011;4:195–205.

    PubMed  Google Scholar 

  25. Koster R, Vieluf D, Kiehn M, Sommerauer M, Kahler J, Baldus S, et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet. 2000;356:1895–7.

    CAS  PubMed  Google Scholar 

  26. Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, et al. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol. 2006;47:175–81.

    PubMed  Google Scholar 

  27. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation. 2004;109:701–5.

    PubMed  Google Scholar 

  28. Otsuka F, Vorpahl M, Nakano M, Foerst J, Newell JB, Sakakura K, et al. Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans. Circulation. 2014;129:211–23.

    CAS  PubMed  Google Scholar 

  29. Kadakia MB, Epps KC, Julien ME, Ogbara J, Giri J, Kolansky DM, et al. Early aneurysm formation after everolimus-eluting stent implantation. Circ Cardiovasc Interv. 2014;7:266–7.

    PubMed  Google Scholar 

  30. Nakano M, Vorpahl M, Otsuka F, Taniwaki M, Yazdani SK, Finn AV, et al. Ex vivo assessment of vascular response to coronary stents by optical frequency domain imaging. JACC Cardiovasc Imaging. 2012;5:71–82.

    PubMed  Google Scholar 

  31. Glover C, Ma X, Chen YX, Miller H, Veinot J, Labinaz M, et al. Human in-stent restenosis tissue obtained by means of coronary atherectomy consists of an abundant proteoglycan matrix with a paucity of cell proliferation. Am Heart J. 2002;144:702–9.

    PubMed  Google Scholar 

  32. Park SJ, Kang SJ, Virmani R, Nakano M, Ueda Y. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol. 2012;59:2051–7.

    PubMed  Google Scholar 

  33. Otsuka F, Byrne RA, Yahagi K, Mori H, Ladich E, Fowler DR, et al. Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment. Eur Heart J. 2015;36:2147–59.

    PubMed  Google Scholar 

  34. Shlofmitz E, Iantorno M, Waksman R. Restenosis of drug-eluting stents: a new classification system based on disease mechanism to guide treatment and state-of-the-art review. Circ Cardiovasc Interv. 2019;12:e007023.

    CAS  PubMed  Google Scholar 

  35. Nakamura N, Torii S, Tsuchiya H, Nakano A, Oikawa Y, Yajima J, et al. Formation of calcified nodule as a cause of early in-stent restenosis in patients undergoing dialysis. J Am Heart Assoc. 2020;9:e016595.

    PubMed  PubMed Central  Google Scholar 

  36. Jia H, Abtahian F, Aguirre AD, Lee S, Chia S, Lowe H, et al. In vivo diagnosis of plaque erosion and calcified nodule in patients with acute coronary syndrome by intravascular optical coherence tomography. J Am Coll Cardiol. 2013;62:1748–58.

    PubMed  Google Scholar 

  37. Higuma T, Soeda T, Abe N, Yamada M, Yokoyama H, Shibutani S, et al. A combined optical coherence tomography and intravascular ultrasound study on plaque rupture, plaque erosion, and calcified nodule in patients with st-segment elevation myocardial infarction: incidence, morphologic characteristics, and outcomes after percutaneous coronary intervention. JACC Cardiovasc Interv. 2015;8:1166–76.

    PubMed  Google Scholar 

  38. Monraats PS, Pires NM, Agema WR, Zwinderman AH, Schepers A, de Maat MP, et al. Genetic inflammatory factors predict restenosis after percutaneous coronary interventions. Circulation. 2005;112:2417–25.

    PubMed  Google Scholar 

  39. Monraats PS, Pires NM, Schepers A, Agema WR, Boesten LS, de Vries MR, et al. Tumor necrosis factor-alpha plays an important role in restenosis development. FASEB J. 2005;19:1998–2004.

    CAS  PubMed  Google Scholar 

  40. Pons D, Monraats PS, de Maat MP, Pires NM, Quax PH, van Vlijmen BJ, et al. The influence of established genetic variation in the haemostatic system on clinical restenosis after percutaneous coronary interventions. Thromb Haemost. 2007;98:1323–8.

    CAS  PubMed  Google Scholar 

  41. Kastrati A, Schomig A, Seyfarth M, Koch W, Elezi S, Bottiger C, et al. PlA polymorphism of platelet glycoprotein IIIa and risk of restenosis after coronary stent placement. Circulation. 1999;99:1005–10.

    CAS  PubMed  Google Scholar 

  42. Rudez G, Pons D, Leebeek F, Monraats P, Schrevel M, Zwinderman A, et al. Platelet receptor P2RY12 haplotypes predict restenosis after percutaneous coronary interventions. Hum Mutat. 2008;29:375–80.

    CAS  PubMed  Google Scholar 

  43. Fujii K, Mintz GS, Kobayashi Y, Carlier SG, Takebayashi H, Yasuda T, et al. Contribution of stent underexpansion to recurrence after sirolimus-eluting stent implantation for in-stent restenosis. Circulation. 2004;109:1085–8.

    PubMed  Google Scholar 

  44. Koskinas KC, Chatzizisis YS, Antoniadis AP, Giannoglou GD. Role of endothelial shear stress in stent restenosis and thrombosis: pathophysiologic mechanisms and implications for clinical translation. J Am Coll Cardiol. 2012;59:1337–49.

    PubMed  Google Scholar 

  45. Jenei C, Balogh E, Szabo GT, Dezsi CA, Koszegi Z. Wall shear stress in the development of in-stent restenosis revisited. A critical review of clinical data on shear stress after intracoronary stent implantation. Cardiol J. 2016;23:365–73.

    PubMed  Google Scholar 

  46. Raber L, Mintz GS, Koskinas KC, Johnson TW, Holm NR, Onuma Y, et al. Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J. 2018;39:3281–300.

    PubMed  Google Scholar 

  47. Omar A, Pendyala LK, Ormiston JA, Waksman R. Review: stent fracture in the drug-eluting stent era. Cardiovasc Revasc Med. 2016;17:404–11.

    PubMed  Google Scholar 

  48. Aoki J, Nakazawa G, Tanabe K, Hoye A, Yamamoto H, Nakayama TO, et al. Incidence and clinical impact of coronary stent fracture after sirolimus-eluting stent implantation. Catheter Cardiovasc Interv. 2007;69:380–6.

    PubMed  Google Scholar 

  49. Nakazawa G, Finn AV, Vorpahl M, Ladich E, Kutys R, Balazs I, et al. Incidence and predictors of drug-eluting stent fracture in human coronary artery a pathologic analysis. J Am Coll Cardiol. 2009;54:1924–31.

    PubMed  Google Scholar 

  50. Kuramitsu S, Iwabuchi M, Haraguchi T, Domei T, Nagae A, Hyodo M, et al. Incidence and clinical impact of stent fracture after everolimus-eluting stent implantation. Circ Cardiovasc Interv. 2012;5:663–71.

    CAS  PubMed  Google Scholar 

  51. Saia F, Lemos PA, Arampatzis CA, Hoye A, McFadden E, Sianos G, et al. Clinical and angiographic outcomes after overdilatation of undersized sirolimus-eluting stents with largely oversized balloons: an observational study. Catheter Cardiovasc Interv. 2004;61:455–60.

    PubMed  Google Scholar 

  52. Iakovou I, Stankovic G, Montorfano M, Airoldi F, Chieffo A, Sangiorgi GM, et al. Is overdilatation of 3.0 mm sirolimus-eluting stent associated with a higher restenosis rate? Catheter Cardiovasc Interv. 2005;64:129–33.

    PubMed  Google Scholar 

  53. Balakrishnan B, Tzafriri AR, Seifert P, Groothuis A, Rogers C, Edelman ER. Strut position, blood flow, and drug deposition: implications for single and overlapping drug-eluting stents. Circulation. 2005;111:2958–65.

    PubMed  Google Scholar 

  54. Hwang CW, Levin AD, Jonas M, Li PH, Edelman ER. Thrombosis modulates arterial drug distribution for drug-eluting stents. Circulation. 2005;111:1619–26.

    CAS  PubMed  Google Scholar 

  55. Takebayashi H, Mintz GS, Carlier SG, Kobayashi Y, Fujii K, Yasuda T, et al. Nonuniform strut distribution correlates with more neointimal hyperplasia after sirolimus-eluting stent implantation. Circulation. 2004;110:3430–4.

    CAS  PubMed  Google Scholar 

  56. Wiemer M, Butz T, Schmidt W, Schmitz KP, Horstkotte D, Langer C. Scanning electron microscopic analysis of different drug eluting stents after failed implantation: from nearly undamaged to major damaged polymers. Catheter Cardiovasc Interv. 2010;75:905–11.

    PubMed  Google Scholar 

  57. Kitahara H, Kobayashi Y, Yamaguchi M, Fujimoto Y, Nameki M, Nakayama T, et al. Damage to polymer of undelivered sirolimus-eluting stents. J Invasive Cardiol. 2008;20:130–3.

    PubMed  Google Scholar 

  58. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315–23.

    CAS  PubMed  Google Scholar 

  59. Costa MA, Angiolillo DJ, Tannenbaum M, Driesman M, Chu A, Patterson J, et al. Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (final results of the multicenter prospective STLLR trial). Am J Cardiol. 2008;101:1704–11.

    CAS  PubMed  Google Scholar 

  60. Morino Y, Tamiya S, Masuda N, Kawamura Y, Nagaoka M, Matsukage T, et al. Intravascular ultrasound criteria for determination of optimal longitudinal positioning of sirolimus-eluting stents. Circ J. 2010;74:1609–16.

    PubMed  Google Scholar 

  61. Kang SJ, Cho YR, Park GM, Ahn JM, Kim WJ, Lee JY, et al. Intravascular ultrasound predictors for edge restenosis after newer generation drug-eluting stent implantation. Am J Cardiol. 2013;111:1408–14.

    CAS  PubMed  Google Scholar 

  62. Ino Y, Kubo T, Matsuo Y, Yamaguchi T, Shiono Y, Shimamura K, et al. Optical coherence tomography predictors for edge restenosis after everolimus-eluting stent implantation. Circ Cardiovasc Interv. 2016;9:1.

    Google Scholar 

  63. Kereiakes DJ, Wang H, Popma JJ, Kuntz RE, Donohoe DJ, Schofer J, et al. Periprocedural and late consequences of overlapping Cypher sirolimus-eluting stents: pooled analysis of five clinical trials. J Am Coll Cardiol. 2006;48:21–31.

    CAS  PubMed  Google Scholar 

  64. Raber L, Juni P, Loffel L, Wandel S, Cook S, Wenaweser P, et al. Impact of stent overlap on angiographic and long-term clinical outcome in patients undergoing drug-eluting stent implantation. J Am Coll Cardiol. 2010;55:1178–88.

    PubMed  Google Scholar 

  65. O’Sullivan CJ, Stefanini GG, Raber L, Heg D, Taniwaki M, Kalesan B, et al. Impact of stent overlap on long-term clinical outcomes in patients treated with newer-generation drug-eluting stents. EuroIntervention. 2014;9:1076–84.

    PubMed  Google Scholar 

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Aoki, J., Tanabe, K. Mechanisms of drug-eluting stent restenosis. Cardiovasc Interv and Ther 36, 23–29 (2021). https://doi.org/10.1007/s12928-020-00734-7

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