Skip to main content
SpringerLink
Log in

Effects of endothelium, stent design and deployment on the nitric oxide transport in stented artery: a potential role in stent restenosis and thrombosis

  • Original Article
  • Published:
Medical & Biological Engineering & Computing Aims and scope Submit manuscript

Abstract

Extrinsic factors such as stent design, deployment and damage to endothelium are associated with stent restenosis and thrombosis. We hypothesize that these extrinsic factors can affect nitric oxide (NO) concentration and disturb its distribution in the stented artery, hence contributing to stent restenosis and thrombosis. We numerically investigated the effects of different endothelium coverage and high-risk factors including thicker strut, stent malapposition and overlapping on the NO distribution in the stented artery. The decrease in the endothelium coverage would greatly reduce the NO concentration, and the location of the coverage relative to the strut significantly affected its distribution. Strut protrusion and thicker strut would induce flow disruption, which not only decreases NO concentration but also greatly changes NO distribution, leading to very low NO concentration near the strut, especially the distal region. Likewise, strut malapposition and overlap would both diminish the NO concentration. However, the distribution of NO for relatively large malapposition was much evener than that for small malapposition. Moreover, proper deployment of the overlapping strut would result in relatively high and uniform NO concentration. In conclusion, less endothelium coverage, thicker struts and improper stent deployment may decrease NO concentration and lead to relatively low NO concentration near the strut.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Andrews AM, Jaron D, Buerk DG, Kirby PL, Barbee KA (2010) Direct, real-time measurement of shear stress-induced nitric oxide produced from endothelial cells in vitro. Nitric Oxide 23:335–342

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Balakrishnan B, Tzafriri AR, Seifert P, Groothuis A, Rogers C, Edelman ER (2005) Strut position, blood flow, and drug deposition: implications for single and overlapping drug-eluting stents. Circulation 111:2958–2965

    Article  PubMed  Google Scholar 

  3. Balligand JL, Feron O, Dessy C (2009) eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev 89:481–534

    Article  CAS  PubMed  Google Scholar 

  4. Boo YC, Jo H (2003) Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases. Am J Physiol Cell Physiol 285:C499–C508

    Article  CAS  PubMed  Google Scholar 

  5. Cho YI, Kensey KR (1991) Effects of the non-Newtonian viscosity of blood on flows in a diseased arterial vessel. Part 1: steady flows. Biorheology 28:241–262

    CAS  PubMed  Google Scholar 

  6. Cook S, Wenaweser P, Togni M, Billinger M, Morger C, Seiler C, Vogel R, Hess O, Meier B, Windecker S (2007) Incomplete stent apposition and very late stent thrombosis after drug-eluting stent implantation. Circulation 115:2426–2434

    Article  CAS  PubMed  Google Scholar 

  7. Csonka C, Páli T, Bencsik P, Görbe A, Ferdinandy P, Csont T (2014) Measurement of nitric oxide in biological samples. Br J Pharmacol. doi:10.1111/bph.12832

    PubMed Central  Google Scholar 

  8. Denny WJ, Walsh MT (2014) Numerical modelling of mass transport in an arterial wall with anisotropic transport properties. J Biomech 47:168–177

    Article  PubMed  Google Scholar 

  9. Dodge JT Jr, Brown BG, Bolson EL, Dodge HT (1992) Lumen diameter of normal human coronary arteries. Influence of age, sex, anatomic variation, and left ventricular hypertrophy or dilation. Circulation 86:232–246

    Article  PubMed  Google Scholar 

  10. Douglas G, Van Kampen E, Hale AB, McNeill E, Patel J, Crabtree MJ, Ali Z, Hoerr RA, Alp NJ, Channon KM (2013) Endothelial cell repopulation after stenting determines in-stent neointima formation: effects of bare-metal vs. drug-eluting stents and genetic endothelial cell modification. Eur Heart J 34:3378–3388

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Ellis SG, Savage M, Fischman D, Baim DS, Leon M, Goldberg S, Hirshfeld JW, Cleman MW, Teirstein PS, Walker C et al (1992) Restenosis after placement of Palmaz-Schatz stents in native coronary arteries. Initial results of a multicenter experience. Circulation 86:1836–1844

    Article  CAS  PubMed  Google Scholar 

  12. Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera K, Skorija K, Weber DK, Gold HK, Virmani R (2005) Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 112:270–278

    Article  CAS  PubMed  Google Scholar 

  13. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, Gold HK, Virmani R (2007) Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 115:2435–2441

    Article  PubMed  Google Scholar 

  14. Garg S, Serruys PW (2010) Coronary stents: current status. J Am Coll Cardiol 56:S1–S42

    Article  CAS  PubMed  Google Scholar 

  15. Gradus-Pizlo I, Bigelow B, Mahomed Y, Sawada SG, Rieger K, Feigenbaum H (2003) Left anterior descending coronary artery wall thickness measured by high-frequency transthoracic and epicardial echocardiography includes adventitia. Am J Cardiol 91:27–32

    Article  PubMed  Google Scholar 

  16. Hassan AKM, Bergheanu SC, Stijnen T, van der Hoeven BL, Snoep JD, Plevier JWM, Schalij MJ, Jukema JW (2010) Late stent malapposition risk is higher after drug-eluting stent compared with bare-metal stent implantation and associates with late stent thrombosis. Eur Heart J 31:1172–1180

    Article  CAS  PubMed  Google Scholar 

  17. Iliceto S, Marangelli V, Memmola C, Rizzon P (1991) Transesophageal Doppler echocardiography evaluation of coronary blood flow velocity in baseline conditions and during dipyridamole-induced coronary vasodilation. Circulation 83:61–69

    Article  CAS  PubMed  Google Scholar 

  18. Indolfi C, Torella D, Coppola C, Curcio A, Rodriguez F, Bilancio A, Leccia A, Arcucci O, Falco M, Leosco D, Chiariello M (2002) Physical training increases eNOS vascular expression and activity and reduces restenosis after balloon angioplasty or arterial stenting in rats. Circ Res 91:1190–1197

    Article  CAS  PubMed  Google Scholar 

  19. Iqbal J, Gunn J, Serruys PW (2013) Coronary stents: historical development, current status and future directions. Br Med Bull 106:193–211

    Article  CAS  PubMed  Google Scholar 

  20. Jaffe R, Strauss BH (2007) Late and very late thrombosis of drug-eluting stents: evolving concepts and perspectives. J Am Coll Cardiol 50:119–127

    Article  CAS  PubMed  Google Scholar 

  21. Jiang S, Cheng R, Wang X, Xue T, Liu Y, Nel A, Huang Y, Duan X (2013) Real-time electrical detection of nitric oxide in biological systems with sub-nanomolar sensitivity. Nat Commun 4:2225

    PubMed  Google Scholar 

  22. Joner M, Nakazawa G, Finn AV, Quee SC, Coleman L, Acampado E, Wilson PS, Skorija K, Cheng Q, Xu X, Gold HK, Kolodgie FD, Virmani R (2008) Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol 52:333–342

    Article  CAS  PubMed  Google Scholar 

  23. Jukema JW, Verschuren JJ, Ahmed TA, Quax PH (2012) Restenosis after PCI. Part 1: pathophysiology and risk factors. Nat Rev Cardiol. 9:53–62

    Article  CAS  Google Scholar 

  24. Kastrati A, Mehilli J, Dirschinger J, Dotzer F, Schuhlen H, Neumann FJ, Fleckenstein M, Pfafferott C, Seyfarth M, Schomig A (2001) Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO) trial. Circulation 103:2816–2821

    Article  CAS  PubMed  Google Scholar 

  25. Kipshidze N, Dangas G, Tsapenko M, Moses J, Leon MB, Kutryk M, Serruys P (2004) Role of the endothelium in modulating neointimal formation: vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions. J Am Coll Cardiol 44:733–739

    CAS  PubMed  Google Scholar 

  26. Kolachalama VB, Levine EG, Edelman ER (2009) Luminal flow amplifies stent-based drug deposition in arterial bifurcations. PLoS ONE 4:e8105

    Article  PubMed Central  PubMed  Google Scholar 

  27. Kolachalama VB, Tzafriri AR, Arifin DY, Edelman ER (2009) Luminal flow patterns dictate arterial drug deposition in stent-based delivery. J Control Release 133:24–30

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Kolandaivelu K, Swaminathan R, Gibson WJ, Kolachalama VB, Nguyen-Ehrenreich KL, Giddings VL, Coleman L, Wong GK, Edelman ER (2011) Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 123:1400–1409

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Kuchan MJ, Frangos JA (1994) Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells. Am J Physiol 266:C628–C636

    CAS  PubMed  Google Scholar 

  30. Lancaster JR Jr (1994) Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci USA 91:8137–8141

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Liu X, Srinivasan P, Collard E, Grajdeanu P, Zweier JL, Friedman A (2008) Nitric oxide diffusion rate is reduced in the aortic wall. Biophys J 94:1880–1889

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Liu X, Fan Y, Deng X, Zhan F (2011) Effect of non-Newtonian and pulsatile blood flow on mass transport in the human aorta. J Biomech 44:1123–1131

    Article  PubMed  Google Scholar 

  33. Liu X, Fan Y, Xu XY, Deng X (2012) Nitric oxide transport in an axisymmetric stenosis. J R Soc Interface 9:2468–2478

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Napoli C, Aldini G, Wallace JL, de Nigris F, Maffei R, Abete P, Bonaduce D, Condorelli G, Rengo F, Sica V, D’Armiento FP, Mignogna C, de Rosa G, Condorelli M, Lerman LO, Ignarro LJ (2002) Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis. Proc Natl Acad Sci USA 99:1689–1694

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Sica V, Ignarro LJ (2006) Nitric oxide and atherosclerosis: an update. Nitric Oxide-Biol Ch 15:265–279

    Article  CAS  Google Scholar 

  36. Napoli C, Paolisso G, Casamassimi A, Al-Omran M, Barbieri M, Sommese L, Infante T, Ignarro LJ (2013) Effects of nitric oxide on cell proliferation: novel insights. J Am Coll Cardiol 62:89–95

    Article  CAS  PubMed  Google Scholar 

  37. Neishi Y, Mochizuki S, Miyasaka T, Kawamoto T, Kume T, Sukmawan R, Tsukiji M, Ogasawara Y, Kajiya F, Akasaka T, Yoshida K, Goto M (2005) Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration. Proc Natl Acad Sci USA 102:11456–11461

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. O’Brien CC, Kolachalama VB, Barber TJ, Simmons A, Edelman ER (2013) Impact of flow pulsatility on arterial drug distribution in stent-based therapy. J Control Release 168:115–124

    Article  PubMed Central  PubMed  Google Scholar 

  39. Otsuka F, Finn AV, Yazdani SK, Nakano M, Kolodgie FD, Virmani R (2012) The importance of the endothelium in atherothrombosis and coronary stenting. Nat Rev Cardiol 9:439–453

    Article  CAS  PubMed  Google Scholar 

  40. Ozaki Y, Okumura M, Ismail TF, Naruse H, Hattori K, Kan S, Ishikawa M, Kawai T, Takagi Y, Ishii J, Prati F, Serruys PW (2010) The fate of incomplete stent apposition with drug-eluting stents: an optical coherence tomography-based natural history study. Eur Heart J 31:1470–1476

    Article  PubMed  Google Scholar 

  41. Pache J, Kastrati A, Mehilli J, Schuhlen H, Dotzer F, Hausleiter J, Fleckenstein M, Neumann FJ, Sattelberger U, Schmitt C, Muller M, Dirschinger J, Schomig A (2003) Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial. J Am Coll Cardiol 41:1283–1288

    Article  PubMed  Google Scholar 

  42. Plata AM, Sherwin SJ, Krams R (2010) Endothelial nitric oxide production and transport in flow chambers: the importance of convection. Ann Biomed Eng 38:2805–2816

    Article  CAS  PubMed  Google Scholar 

  43. Raber L, Juni P, Loffel L, Wandel S, Cook S, Wenaweser P, Togni M, Vogel R, Seiler C, Eberli F, Luscher T, Meier B, Windecker S (2010) Impact of stent overlap on angiographic and long-term clinical outcome in patients undergoing drug-eluting stent implantation. J Am Coll Cardiol 55:1178–1188

    Article  PubMed  Google Scholar 

  44. Rogers C, Parikh S, Seifert P, Edelman ER (1996) Endogenous cell seeding. Remnant endothelium after stenting enhances vascular repair. Circulation 94:2909–2914

    Article  CAS  PubMed  Google Scholar 

  45. Savill NJ, Weller R, Sherratt JA (2002) Mathematical modelling of nitric oxide regulation of rete peg formation in psoriasis. J Theor Biol 214:1–16

    Article  CAS  PubMed  Google Scholar 

  46. Shankaran H, Alexandridis P, Neelamegham S (2003) Aspects of hydrodynamic shear regulating shear-induced platelet activation and self-association of von Willebrand factor in suspension. Blood 101:2637–2645

    Article  CAS  PubMed  Google Scholar 

  47. Sun N, Wood NB, Hughes AD, Thom SA, Xu XY (2006) Fluid-wall modelling of mass transfer in an axisymmetric stenosis: effects of shear-dependent transport properties. Ann Biomed Eng 34:1119–1128

    Article  PubMed  Google Scholar 

  48. Tahir H, Hoekstra AG, Lorenz E, Lawford PV, Hose DR, Gunn J, Evans DJ (2011) Multi-scale simulations of the dynamics of in-stent restenosis: impact of stent deployment and design. Interface Focus 1:365–373

    Article  PubMed Central  PubMed  Google Scholar 

  49. Tahir H, Bona-Casas C, Hoekstra AG (2013) Modelling the effect of a functional endothelium on the development of in-stent restenosis. PLoS ONE 8:e66138

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Tahir H, Bona-Casas C, Narracott AJ, Iqbal J, Gunn J, Lawford P, Hoekstra AG (2014) Endothelial repair process and its relevance to longitudinal neointimal tissue patterns: comparing histology with in silico modelling. J R Soc Interface 11:20140022

    Article  PubMed  Google Scholar 

  51. Taite LJ, West JL (2011) Sustained delivery of nitric oxide from poly(ethylene glycol) hydrogels enhances endothelialization in a rat carotid balloon injury model. Cardiovascr Eng Technol 2:113–123

    Article  Google Scholar 

  52. Tanigawa J, Barlis P, Dimopoulos K, Dalby M, Moore P, Di Mario C (2009) The influence of strut thickness and cell design on immediate apposition of drug-eluting stents assessed by optical coherence tomography. Int J Cardiol 134:180–188

    Article  PubMed  Google Scholar 

  53. Togni M, Windecker S, Cocchia R, Wenaweser P, Cook S, Billinger M, Meier B, Hess OM (2005) Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction. J Am Coll Cardiol 46:231–236

    Article  CAS  PubMed  Google Scholar 

  54. Togni M, Raber L, Cocchia R, Wenaweser P, Cook S, Windecker S, Meier B, Hess OM (2007) Local vascular dysfunction after coronary paclitaxel-eluting stent implantation. Int J Cardiol 120:212–220

    Article  PubMed  Google Scholar 

  55. Vaughn MW, Kuo L, Liao JC (1998) Estimation of nitric oxide production and reaction rates in tissue by use of a mathematical model. Am J Physiol 274:H2163–H2176

    CAS  PubMed  Google Scholar 

  56. Zahedmanesh H, Lally C (2009) Determination of the influence of stent strut thickness using the finite element method: implications for vascular injury and in-stent restenosis. Med Biol Eng Comput 47:385–393

    Article  PubMed  Google Scholar 

  57. Zahedmanesh H, Van Oosterwyck H, Lally C (2014) A multi-scale mechanobiological model of in-stent restenosis: deciphering the role of matrix metalloproteinase and extracellular matrix changes. Comput Methods Biomech Biomed Eng 17:813–828

    Article  Google Scholar 

Download references

Acknowledgments

This work is supported by Grants-in-Aid from the National Natural Science Research Foundation of China (No. 11332003, 31200703, 11421202, 11202016, 11228205), Specialized Research Fund for the Doctoral Program of Higher Education (20121102120038) and the 111 Project (B13003).

Author information

Authors and Affiliations

  1. Key Laboratory for Biomechanics and Mechanobiology of the Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China

    Xiao Liu, Yubo Fan & Xiaoyan Deng

  2. The 306 Hospital of PLA, Beijing, China

    Min Wang

  3. Radiologic Department, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Nan Zhang & Zhanming Fan

Authors
  1. Xiao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhanming Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yubo Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoyan Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yubo Fan or Xiaoyan Deng.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Wang, M., Zhang, N. et al. Effects of endothelium, stent design and deployment on the nitric oxide transport in stented artery: a potential role in stent restenosis and thrombosis. Med Biol Eng Comput 53, 427–439 (2015). https://doi.org/10.1007/s11517-015-1250-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11517-015-1250-6

Keywords

Search

Navigation