Abstract
A model that combines the results of in vivo experiment, 3D image data, and computer simulation has been developed. Twelve identical stents were implanted into six healthy pigs and explanted at a range of different post-recovery periods from 6 h to 28 days. The stented vessel segments were embedded in methacrylate resin for the preparation of transverse histological sections and imaged using ultra-high resolution micro-CT. The resulting CT data was used to reconstruct the 3D geometry of the stents and one case was used to inform a 3D computational fluid dynamic model. Derived hemodynamic parameters such as wall shear stress (WSS), axial WSS, and oscillatory shear index were correlated with the distribution of neointimal hyperplasia, assessed from histomorphometric analyses. The direct comparison of hemodynamic parameters and biological response supports the hypothesis that low and oscillatory WSS lead to a greater neointimal response within the stented region. Moreover, the realistic geometry obtained from micro-CT images, characterized by proximal overexpansion and asymmetric deployment of the stent, leads to a markedly non-uniform distribution of WSS values and correlates with asymmetric neo-intimal growth. This correlation cannot be appreciated from studies of idealized geometries.
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References
Alderson, H., and M. Zamir. Effects of stent stiffness on local haemodynamics with particular reference to wave reflections. J. Biomech. 37(3):339–348, 2004.
Asakura, T., and T. Karino. Flow patterns and spatial distribution of atherosclerotic lesions in human coronary arteries. Circ. Res. 66:1045–1066, 1990.
Chien, S., S. Usami, M. Taylor, J. L. Lundberg, and M. I. Gregersen. Effects of hematocrit and plasma proteins on human blood rheology at low shear rates. J. Appl. Physiol. 21:81–87, 1966.
Gastaldi, D., S. Morlacchi, R. Nichetti, C. Capelli, G. Dubini, L. Petrini, and F. Migliavacca. Modelling of the provisional side-branch stenting approach for the treatment of atherosclerotic coronary bifurcation: effects of stent positioning. Biomech. Model. Mechanobiol. 9(5):551–561, 2010.
Gnasso, A., C. Irace, C. Carallo, M. S. De Franceschi, C. Motti, P. L. Mattioli, and A. Pujia. In vivo association between low wall shear stress and plaque in subjects with asymmetrical carotid atherosclerosis. Stroke 28:993–998, 1997.
Gunn, J., N. Arnold, K. H. Chan, L. Shepherd, D. C. Cumberland, and D. C. Crossman. Coronary artery stretch versus deep injury in the development of in-stent neointima. Heart 88:401–405, 2002.
Huo, Y., J. S. Choy, M. Svendsen, A. K. Sinha, and G. S. Kassab. Effects of vessel compliance on flow pattern in porcine epicardial right coronary arterial tree. J. Biomech. 42:594–602, 2009.
Kastrati, A., J. Mehilli, J. Dirschinger, F. Dotzer, H. Schühlen, F. J. Neumann, M. Fleckenstein, C. Pfafferott, M. Seyfarth, and A. Schömig. Intracoronary stenting and angiographic results. Strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial. J. Am. Coll. Cardiol. 41:1283–1288, 2003.
Kraiss, L. W., R. L. Geary, E. J. Mattsson, S. Vergel, A. Y. Au, and A. W. Clowes. Acute reductions in blood flow and shear stress induce platelet-derived growth factor—a expression in baboon prosthetic grafts. Circ. Res. 79:45–53, 1996.
Ku, D. N. Blood flow in arteries. Annu. Rev. Fluid Mech. 29:399–434, 1997.
LaDisa, J. F. Jr., L. E. Olson, I. Guler, D. A. Hettrick, S. H. Audi, J. R. Kersten, D. C. Warltier, and P. S. Pagel. Stent design properties and deployment ratio influence indexes of wall shear stress: a three-dimensional computational fluid dynamics investigation within a normal artery. J. Appl. Physiol. 97:424–430, 2004.
LaDisa, J. F. Jr., L. E. Olson, I. Guler, D. A. Hettrick, J. R. Kersten, D. C. Warltier, and P. S. Pagel. Circumferential vascular deformation after stent implantation alters wall shear stress evacuate with time-dependent 3D computational fluid dynamics models. J. Appl. Physiol. 98:947–957, 2005.
LaDisa, J. F. Jr., L. E. Olson, D. A. Hettrick, D. C. Warltier, J. R. Kersten, and P. S. Pagel. Axial stent strut angle influences wall shear stress after stent implantation: analysis using 3D computational fluid dynamics models of stent foreshortening. Biomed. Eng. Online 4:59–68, 2005.
LaDisa, J. F. Jr., L. E. Olson, R. C. Molthen, D. A. Hettrick, P. F. Pratt, M. D. Hardel, J. R. Kersten, D. C. Warltier, and P. S. Pagel. Alterations in wall shear stress predict sites of neointimal hyperplasia after stent implantation in rabbit iliac arteries. Am. J. Physiol. Heart Circ. Physiol. 288:H2465–H2475, 2005.
Malek, A. M., S. L. Alper, and S. Izumo. Hemodynamic shear stress and its role in atherosclerosis. J. Am. Med. Assoc. 282(21):2035–2042, 1999.
Malik, N., J. Gunn, C. M. Holt, L. Shepherd, S. E. Francis, C. M. Newman, D. C. Crossman, and D. C. Cumberland. Intravascular stents: a new technique for tissue processing for histology, immunohistochemistry and transmission electron microscopy. Heart 80:509–516, 1998.
Mejia, J., B. Ruzzeh, R. Mongrain, R. Leask, and O. F. Bertrand. Evaluation of the effects of stent strut profile on shear stress distribution using statistical moments. Biomed. Eng. Online 8:8–17, 2009.
Mondy, J. S., V. Lindner, J. K. Miyashiro, B. C. Berk, R. H. Dean, and R. L. Geary. Platelet-derived growth factor ligand and receptor expression in response to altered blood flow in vivo. Circ. Res. 81:320–327, 1997.
Morton, A. C., D. Crossmann, and J. Gunn. The influence of physical stent parameters upon restenosis. Pathol. Biol. 52:196–205, 2004.
Sanmartín, M., J. Goicolea, C. García, J. García, A. Crespo, J. Rodríguez, and J. M. Goicolead. Influence of shear stress on in-stent restenosis: in vivo study using 3D reconstruction and computational fluid dynamics. Rev. Esp. Cardiol. 59:20–27, 2006.
Seo, T., L. G. Schachter, and A. I. Barakat. Computational study of fluid mechanical disturbance induced by endovascular stents. Ann. Biomed. Eng. 33(4):444–456, 2005.
Takebayashi, H., G. S. Mintz, S. G. Carlier, et al. Nonuniform strut distribution correlates with more neointimal hyperplasia after sirolimus-eluting stent implantation. Circulation 110:3430–3434, 2004.
Topper, J. N., J. Cai, D. Falb, and M. A. Gimbrone. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively upregulated by steady laminar shear stress. Proc. Natl. Acad. Sci. USA 93:10417–10422, 1996.
Uematsu, M., Y. Ohara, J. P. Navas, K. Nishida, T. J. Murphy, R. W. Alexander, R. M. Nerem, and D. G. Harrison. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am. J. Physiol. 269:C1371–C1378, 1995.
Wentzel, J. J., F. J. H. Gijsen, N. Stergiopulos, P. W. Serruys, C. J. Slage, and R. Krams. Shear stress, vascular remodeling and neointimal formation. J. Biomech. 36(5):681–688, 2003.
Wentzel, J. J., R. Krams, J. C. H. Schuurbiers, J. A. Oomen, J. Kloet, W. J. van der Giessen, P. W. Serruys, and C. J. Slager. Relationship between neointimal thickness and shear stress after wallstent implantation in human coronary arteries. Circulation 103:1740–1745, 2001.
Zhang, W., Y. Liu, and G. S. Kassab. Flow-induced shear strain in intima of porcine coronary arteries. J. Appl. Physiol. 103:587–593, 2007.
Acknowledgments
This work has been partially supported by the Italian Institute of Technology (IIT, Genoa, Italy), within the project “Models and methods for local drug delivery from nano/micro structured materials,” and by the European Commission through MeDDiCA Marie Curie Initial Training Network (www.meddica.eu, EU-FP7/2007-2013 under grant agreement PITN-GA-2009-238113).
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Associate Editor Stefan Jockenhoevel oversaw the review of this article.
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Morlacchi, S., Keller, B., Arcangeli, P. et al. Hemodynamics and In-stent Restenosis: Micro-CT Images, Histology, and Computer Simulations. Ann Biomed Eng 39, 2615–2626 (2011). https://doi.org/10.1007/s10439-011-0355-9
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DOI: https://doi.org/10.1007/s10439-011-0355-9