Full Mimicking of Coronary Hemodynamics for Ex-Vivo Stimulation of Human Saphenous Veins


After coronary artery bypass grafting, structural modifications of the saphenous vein wall lead to lumen narrowing in response to the altered hemodynamic conditions. Here we present the design of a novel ex vivo culture system conceived for mimicking central coronary artery hemodynamics, and we report the results of biomechanical stimulation experiments using human saphenous vein samples. The novel pulsatile system used an aortic-like pressure for forcing a time-dependent coronary-like resistance to obtain the corresponding coronary-like flow rate. The obtained pulsatile pressures and flow rates (diastolic/systolic: 80/120 mmHg and 200/100 mL/min, respectively) showed a reliable mimicking of the complex coronary hemodynamic environment. Saphenous vein segments from patients undergoing coronary artery bypass grafting (n = 12) were subjected to stimulation in our bioreactor with coronary pulsatile pressure/flow patterns or with venous-like perfusion. After 7-day stimulation, SVs were fixed and stained for morphometric evaluation and immunofluorescence. Results were compared with untreated segments of the same veins. Morphometric and immunofluorescence analysis revealed that 7 days of pulsatile stimulation: (i) did not affect integrity of the vessel wall and lumen perimeter, (ii) significantly decreased both intima and media thickness, (iii) led to partial endothelial denudation, and (iv) induced apoptosis in the vessel wall. These data are consistent with the early vessel remodeling events involved in venous bypass adaptation to arterial flow/pressure patterns. The pulsatile system proved to be a suitable device to identify ex vivo mechanical cues leading to graft adaptation.

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  1. 1.

    Anwar, M. A., J. Shalhoub, C. S. Lim, M. S. Gohel, and A. H. Davies. The effect of pressure-induced mechanical stretch on vascular wall differential gene expression. J. Vasc. Res. 49:463–478, 2012.

  2. 2.

    Berne, R. M., B. M. Koeppen, and B. A. Stanton. Berne & Levy Physiology (6th ed.). Philadelphia: Mosby/Elsevier, p. xii, 2010.

  3. 3.

    Borin, T. F., A. A. Miyakawa, L. Cardoso, L. de Figueiredo Borges, G. A. Goncalves, and J. E. Krieger. Apoptosis, cell proliferation and modulation of cyclin-dependent kinase inhibitor p21(cip1) in vascular remodelling during vein arterialization in the rat. Int. J. Exp. Pathol. 90:328–337, 2009.

  4. 4.

    Cattaruzza, M., C. Dimigen, H. Ehrenreich, and M. Hecker. Stretch-induced endothelin B receptor-mediated apoptosis in vascular smooth muscle cells. FASEB J. 14:991–998, 2000.

  5. 5.

    Çengel, Y. A., and J. M. Cimbala. Fluid Mechanics: Fundamentals and Applications. McGraw-Hill Series in Mechanical Engineering. Boston: McGraw-HillHigher Education, 2006.

  6. 6.

    de Vries, M. R., K. H. Simons, J. W. Jukema, J. Braun, and P. H. Quax. Vein graft failure: from pathophysiology to clinical outcomes. Nat. Rev. Cardiol. 13:451–470, 2016.

  7. 7.

    Garcia, D., P. G. Camici, L. G. Durand, K. Rajappan, E. Gaillard, O. E. Rimoldi, and P. Pibarot. Impairment of coronary flow reserve in aortic stenosis. J. Appl. Physiol. 106:113–121, 2009.

  8. 8.

    Gray, S. P., E. Di Marco, K. Kennedy, P. Chew, J. Okabe, A. El-Osta, A. C. Calkin, E. A. Biessen, R. M. Touyz, M. E. Cooper, H. H. Schmidt, and K. A. Jandeleit-Dahm. Reactive oxygen species can provide atheroprotection via NOX4-dependent inhibition of inflammation and vascular remodeling. Arterioscler. Thromb. Vasc. Biol. 36:295–307, 2016.

  9. 9.

    Gusic, R. J., R. Myung, M. Petko, J. W. Gaynor, and K. J. Gooch. Shear stress and pressure modulate saphenous vein remodeling ex vivo. J. Biomech. 38:1760–1769, 2005.

  10. 10.

    Guyton, A. C., and J. E. Hall. Textbook of Medical Physiology (2d ed.). Philadelphia: W.B. Saunders Co., p. 1181, 1961.

  11. 11.

    Harskamp, R. E., M. A. Beijk, P. Damman, J. G. Tijssen, R. D. Lopes, and R. J. de Winter. Prehospitalization antiplatelet therapy and outcomes after saphenous vein graft intervention. Am. J. Cardiol. 111:153–158, 2013.

  12. 12.

    Harskamp, R. E., J. B. Williams, R. C. Hill, R. J. de Winter, J. H. Alexander, and R. D. Lopes. Saphenous vein graft failure and clinical outcomes: toward a surrogate end point in patients following coronary artery bypass surgery? Am. Heart J. 165:639–643, 2013.

  13. 13.

    Hashmi, S. F., B. Krishnamoorthy, W. R. Critchley, P. Walker, P. W. Bishop, R. V. Venkateswaran, J. E. Fildes, and N. Yonan. Histological and immunohistochemical evaluation of human saphenous vein harvested by endoscopic and open conventional methods. Interact. CardioVasc. Thorac. Surg. 20:178–185, 2015.

  14. 14.

    Iwasaki, K., K. Kojima, S. Kodama, A. C. Paz, M. Chambers, M. Umezu, and C. A. Vacanti. Bioengineered three-layered robust and elastic artery using hemodynamically-equivalent pulsatile bioreactor. Circulation 118:S52–S57, 2008.

  15. 15.

    Kajiya, F., S. Matsuoka, Y. Ogasawara, O. Hiramatsu, S. Kanazawa, Y. Wada, S. Tadaoka, K. Tsujioka, T. Fujiwara, and M. Zamir. Velocity profiles and phasic flow patterns in the non-stenotic human left anterior descending coronary artery during cardiac surgery. Cardiovasc. Res. 27:845–850, 1993.

  16. 16.

    Kim, F. Y., G. Marhefka, N. J. Ruggiero, S. Adams, and D. J. Whellan. Saphenous vein graft disease: review of pathophysiology, prevention, and treatment. Cardiol Rev. 21:101–109, 2013.

  17. 17.

    Liu, S. Q., Y. Y. Ruan, D. Tang, Y. C. Li, J. Goldman, and L. Zhong. A possible role of initial cell death due to mechanical stretch in the regulation of subsequent cell proliferation in experimental vein grafts. Biomech. Model. Mechanobiol. 1:17–27, 2002.

  18. 18.

    Longchamp, A., F. Alonso, C. Dubuis, F. Allagnat, X. Berard, P. Meda, F. Saucy, J. M. Corpataux, D. Sebastien, and J. A. Haefliger. The use of external mesh reinforcement to reduce intimal hyperplasia and preserve the structure of human saphenous veins. Biomaterials 35:2588–2599, 2014.

  19. 19.

    Loudon, C., and A. Tordesillas. The use of the dimensionless Womersley number to characterize the unsteady nature of internal flow. J. Theor. Biol. 191:63–78, 1998.

  20. 20.

    Malek, A. M., S. L. Alper, and S. Izumo. Hemodynamic shear stress and its role in atherosclerosis. JAMA 282:2035–2042, 1999.

  21. 21.

    Mandel, E. R., C. Uchida, E. Nwadozi, A. Makki, and T. L. Haas. tissue inhibitor of metalloproteinase 1 influences vascular adaptations to chronic alterations in blood flow. J Cell Physiol 2016. doi:10.1002/jcp.25491.

  22. 22.

    Meissner, M. H., G. Moneta, K. Burnand, P. Gloviczki, J. M. Lohr, F. Lurie, M. A. Mattos, R. B. McLafferty, G. Mozes, R. B. Rutherford, F. Padberg, and D. S. Sumner. The hemodynamics and diagnosis of venous disease. J. Vasc. Surg. 46(Suppl S):4S–24S, 2007.

  23. 23.

    Milnor, W. R. Hemodynamics. Baltimore: Williams & Wilkins, p. xiii, 1982.

  24. 24.

    Mitra, A. K., D. M. Gangahar, and D. K. Agrawal. Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia. Immunol. Cell Biol. 84:115–124, 2006.

  25. 25.

    Miyakawa, A. A., L. A. O. Dallan, S. Lacchini, T. F. Borin, and J. E. Krieger. Human saphenous vein organ culture under controlled hemodynamic conditions. Clinics. 63:683–688, 2008.

  26. 26.

    Muto, A., L. Model, K. Ziegler, S. D. D. Eghbalieh, and A. Dardik. Mechanisms of vein graft adaptation to the arterial circulation. Circ. J. 74:1501–1512, 2010.

  27. 27.

    Narita, Y., K. Hata, H. Kagami, A. Usui, M. Ueda, and Y. Ueda. Novel pulse duplicating bioreactor system for tissue-engineered vascular construct. Tissue Eng. 10:1224–1233, 2004.

  28. 28.

    Newby, A. C., and A. B. Zaltsman. Molecular mechanisms in intimal hyperplasia. J. Pathol. 190:300–309, 2000.

  29. 29.

    Ochsner, Jr, A., R. Colp, Jr, and G. E. Burch. Normal blood pressure in the superficial venous system of man at rest in the supine position. Circulation 3:674–680, 1951.

  30. 30.

    Owens, C. D. Adaptive changes in autogenous vein grafts for arterial reconstruction: clinical implications. J. Vasc. Surg. 51:736–746, 2010.

  31. 31.

    Parang, P., and R. Arora. Coronary vein graft disease: pathogenesis and prevention. Can. J. Cardiol. 25:57–62, 2009.

  32. 32.

    Piola, M., F. Prandi, N. Bono, M. Soncini, E. Penza, M. Agrifoglio, G. Polvani, M. Pesce, and G. B. Fiore. A compact and automated ex vivo vessel culture system for the pulsatile pressure conditioning of human saphenous veins. J. Tissue Eng. Regen. Med. 10:E204–E215, 2016.

  33. 33.

    Piola, M., F. Prandi, G. B. Fiore, M. Agrifoglio, G. Polvani, M. Pesce, and M. Soncini. Human saphenous vein response to trans-wall oxygen gradients in a novel ex vivo conditioning platform. Ann. Biomed. Eng. 44:1449–1461, 2016.

  34. 34.

    Piola, M., M. Soncini, M. Cantini, N. Sadr, G. Ferrario, and G. B. Fiore. Design and functional testing of a multichamber perfusion platform for three-dimensional scaffolds. Sci. World J. 2013:123974, 2013.

  35. 35.

    Piola, M., M. Soncini, F. Prandi, G. Polvani, G. B. Fiore, and M. Pesce. Tools and procedures for ex vivo vein arterialization, preconditioning and tissue engineering: a step forward to translation to combat the consequences of vascular graft remodeling. Recent Pat. Cardiovasc. Drug Discov. 7:186–195, 2012.

  36. 36.

    Prandi, F., M. Piola, M. Soncini, C. Colussi, Y. D’Alessandra, E. Penza, M. Agrifoglio, M. C. Vinci, G. Polvani, C. Gaetano, G. B. Fiore, and M. Pesce. Adventitial vessel growth and progenitor cells activation in an ex vivo culture system mimicking human saphenous vein wall strain after coronary artery bypass grafting. PLoS ONE 10:e0117409, 2015.

  37. 37.

    Punchard, M. A., C. Stenson-Cox, E. D. O’Cearbhaill, E. Lyons, S. Gundy, L. Murphy, A. Pandit, P. E. McHugh, and V. Barron. Endothelial cell response to biomechanical forces under simulated vascular loading conditions. J. Biomech. 40:3146–3154, 2007.

  38. 38.

    Ruiter, M. S., J. M. van Golde, N. C. Schaper, C. D. Stehouwer, and M. S. Huijberts. Diabetes impairs arteriogenesis in the peripheral circulation: review of molecular mechanisms. Clin Sci (Lond). 119:225–238, 2010.

  39. 39.

    Stick, C., U. Hiedl, and E. Witzleb. Venous pressure in the saphenous vein near the ankle during changes in posture and exercise at different ambient temperatures. Eur. J. Appl. Physiol. Occup. Physiol. 66:434–438, 1993.

  40. 40.

    Tsui, J. C., and M. R. Dashwood. Recent strategies to reduce vein graft occlusion: a need to limit the effect of vascular damage. Eur. J. Vasc. Endovasc. Surg. 23:202–208, 2002.

  41. 41.

    Vanhoutte, P. M., Y. Zhao, A. Xu, and S. W. Leung. Thirty years of saying no: sources, fate, actions, and misfortunes of the endothelium-derived vasodilator mediator. Circ. Res. 119:375–396, 2016.

  42. 42.

    Vismara, R., M. Soncini, G. Talò, L. Dainese, A. Guarino, A. Redaelli, and G. B. Fiore. A bioreactor with compliance monitoring for heart valve grafts. Ann. Biomed. Eng. 38:100–108, 2009.

  43. 43.

    Voisard, R., E. Ramiz, R. Baur, I. Gastrock-Balitsch, H. Siebeneich, O. Frank, V. Hombach, A. Hannekum, and B. Schumacher. Pulsed perfusion in a venous human organ culture model with a Windkessel function (pulsed perfusion venous HOC-model). Med. Sci. Monit. 16:523–529, 2010.

  44. 44.

    Westerband, A., D. Crouse, L. C. Richter, M. L. Aguirre, C. C. Wixon, D. C. James, J. L. Mills, G. C. Hunter, and R. L. Heimark. Vein adaptation to arterialization in an experimental model. J. Vasc. Surg. 33:561–569, 2001.

  45. 45.

    Zacharias, A., T. A. Schwann, C. J. Riordan, S. J. Durham, A. S. Shah, and R. H. Habib. Late results of conventional versus all-arterial revascularization based on internal thoracic and radial artery grafting. Ann. Thorac. Surg. 87:19e1–26e2, 2009.

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This work was supported by the Italian Ministry of Health research Project RF-2011-02346867. The authors would like to thank Dr. Emilio Savoldelli for his support during the preliminary design of the CPD circuit and Dr. Francesco Sturla for his support with MATLAB.


The authors declare no conflict of interest to disclose.

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Correspondence to Marco Piola.

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Marco Piola and Matthijs Ruiter contributed equally to this work.

Associate Editor Michael Gower oversaw the review of this article.

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Piola, M., Ruiter, M., Vismara, R. et al. Full Mimicking of Coronary Hemodynamics for Ex-Vivo Stimulation of Human Saphenous Veins. Ann Biomed Eng 45, 884–897 (2017).

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  • Coronary flow rate
  • Pulsatile pressure
  • Saphenous vein graft disease
  • Ex vivo platform
  • Wall remodeling