Biological Mechanics of the Heart Valve Interstitial Cell

  • Alex Khang
  • Rachel M. Buchanan
  • Salma Ayoub
  • Bruno V. Rego
  • Chung-Hao Lee
  • Michael S. SacksEmail author


Heart valves are composed of multilayered tissues that contain a population of vascular endothelial cells (VEC) on the blood contacting surfaces and valve interstitial cells (VIC) in the bulk tissue mass that maintain homeostasis and respond to injury. The mechanosensitive nature of VICs facilitates the regulation of growth and remodeling of heart valve leaflets throughout different stages of life. However, pathological phenomenon such as mitral valve regurgitation and calcific aortic valve disease lead to pathological micromechanical environments. Such scenarios highlight the importance of studying the mechanobiology of VICs to better understand their mechanical and biosynthetic behavior. In the present chapter, we review use of novel experimental-computational techniques to link VIC biosynthetic response to changes in in vivo deformation in health and disease. In addition, we discuss the development of tissue-level models that shed light on the biomechanical state of VICs in situ. To conclude, we outline future directions for heart valve mechanobiology including model-driven experiments and highlight the need for high-fidelity, multi-scale models to link the cell-, tissue-, and organ-level events of heart valve growth and remodeling.


Multiscale modeling Heart valve interstitial cell mechanobiology Model-driven experiments 3D hydrogel culture Remodeling Cell mechanics Finite element method Cellular contraction Myofibroblast 



This work was supported by the National Institutes of Health (NIH) Grants R01HL119297. CHL was in part supported by start-up funds from the School of Aerospace and Mechanical Engineering (AME) at the University of Oklahoma, and the American Heart Association Scientist Development Grant Award (16SDG27760143).


  1. 1.
    Merryman WD, Lukoff HD, Long RA, Engelmayr GC Jr, Hopkins RA, Sacks MS. Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast. Cardiovasc Pathol. 2007;16(5):268–76.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Guyton AC. Textbook of medical physiology. 5th ed. Philadelphia: W.B. Saunders Company; 1976.Google Scholar
  3. 3.
    He Z, Ritchie J, Grashow JS, Sacks MS, Yoganathan AP. In vitro dynamic strain behavior of the mitral valve posterior leaflet. J Biomech Eng. 2005;127(3):504–11.PubMedCrossRefGoogle Scholar
  4. 4.
    He Z, Sacks MS, Baijens L, Wanant S, Shah P, Yoganathan AP. Effects of papillary muscle position on in-vitro dynamic strain on the porcine mitral valve. J Heart Valve Dis. 2003;12(4):488–94.PubMedGoogle Scholar
  5. 5.
    Sacks MS, Enomoto Y, Graybill JR, Merryman WD, Zeeshan A, Yoganathan AP, et al. In-vivo dynamic deformation of the mitral valve anterior leaflet. Ann Thorac Surg. 2006;82(4):1369–77.PubMedCrossRefGoogle Scholar
  6. 6.
    Sacks MS, He Z, Baijens L, Wanant S, Shah P, Sugimoto H, et al. Surface strains in the anterior leaflet of the functioning mitral valve. Ann Biomed Eng. 2002;30(10):1281–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Ayoub S, Ferrari G, Gorman RC, Gorman JH, Schoen FJ, Sacks MS. Heart valve biomechanics and underlying mechanobiology. Compr Physiol. 2016;6(4):1743–80.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Sacks MS, Yoganathan AP. Heart valve function: a biomechanical perspective. Philos Trans R Soc Lond Ser B Biol Sci. 2007;362(1484):1369–91.CrossRefGoogle Scholar
  9. 9.
    Buchanan RM, Sacks MS. Interlayer micromechanics of the aortic heart valve leaflet. Biomech Model Mechanobiol. 2014;13(4):813–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Rego BV, Sacks MS. A functionally graded material model for the transmural stress distribution of the aortic valve leaflet. J Biomech. 2017;54:88–95.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Stella JA, Sacks MS. On the biaxial mechanical properties of the layers of the aortic valve leaflet. J Biomech Eng. 2007;129(5):757–66.CrossRefGoogle Scholar
  12. 12.
    Rego BV, Wells SM, Lee CH, Sacks MS. Mitral valve leaflet remodelling during pregnancy: insights into cell-mediated recovery of tissue homeostasis. J R Soc Interface. 2016;13(125):20160709.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Lee CH, Carruthers CA, Ayoub S, Gorman RC, Gorman JH 3rd, Sacks MS. Quantification and simulation of layer-specific mitral valve interstitial cells deformation under physiological loading. J Theor Biol. 2015;373:26–39.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Pierlot CM, Lee JM, Amini R, Sacks MS, Wells SM. Pregnancy-induced remodeling of collagen architecture and content in the mitral valve. Ann Biomed Eng. 2014;42(10):2058–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Pierlot CM, Moeller AD, Lee JM, Wells SM. Pregnancy-induced remodeling of heart valves. Am J Physiol Heart Circ Physiol. 2015;309(9):H1565–78.PubMedCrossRefGoogle Scholar
  16. 16.
    Lam NT, Muldoon TJ, Quinn KP, Rajaram N, Balachandran K. Valve interstitial cell contractile strength and metabolic state are dependent on its shape. Integr Biol. 2016;8(10):1079–89.CrossRefGoogle Scholar
  17. 17.
    Tandon I, Razavi A, Ravishankar P, Walker A, Sturdivant NM, Lam NT, et al. Valve interstitial cell shape modulates cell contractility independent of cell phenotype. J Biomech. 2016;49(14):3289–97.PubMedCrossRefGoogle Scholar
  18. 18.
    Ayoub S, Lee C-H, Driesbaugh KH, Anselmo W, Hughes CT, Ferrari G, et al. Regulation of valve interstitial cell homeostasis by mechanical deformation: implications for heart valve disease and surgical repair. J R Soc Interface. 2017;14:20170580.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Lee CH, Zhang W, Feaver K, Gorman RC, Gorman JH 3rd, Sacks MS. On the in vivo function of the mitral heart valve leaflet: insights into tissue-interstitial cell biomechanical coupling. Biomech Model Mechanobiol. 2017;16:1613.PubMedCrossRefGoogle Scholar
  20. 20.
    Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation. 2001;104(21):2525–32.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, et al. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease-2011 update. Circulation. 2011;124(16):1783–91.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Sacks MS, Merryman WD, Schmidt DE. On the biomechanics of heart valve function. J Biomech. 2009;42(12):1804–24.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Carruthers CA, Good B, D’Amore A, Liao J, Amini R, Watkins SC, et al., editors. Alterations in the microstructure of the anterior mitral valve leaflet under physiological stress. In: ASME 2012 summer bioengineering conference. American Society of Mechanical Engineers; 2012.Google Scholar
  24. 24.
    Sakamoto Y, Buchanan RM, Sacks MS. On intrinsic stress fiber contractile forces in semilunar heart valve interstitial cells using a continuum mixture model. J Mech Behav Biomed Mater. 2016;54:244–58.PubMedCrossRefGoogle Scholar
  25. 25.
    Sakamoto Y, Buchanan RM, Sanchez-Adams J, Guilak F, Sacks MS. On the functional role of valve interstitial cell stress fibers: a continuum modeling approach. J Biomech Eng. 2017;139(2):021007.CrossRefGoogle Scholar
  26. 26.
    Buchanan RM. An integrated computational-experimental approach for the in situ estimation of valve interstitial cell biomechanical state. Austin: The University of Texas at Austin; 2016.Google Scholar
  27. 27.
    Merryman WD, Youn I, Lukoff HD, Krueger PM, Guilak F, Hopkins RA, et al. Correlation between heart valve interstitial cell stiffness and transvalvular pressure: implications for collagen biosynthesis. Am J Physiol Heart Circ Physiol. 2006;290(1):H224–31.CrossRefGoogle Scholar
  28. 28.
    Theret DP, Levesque MJ, Sato M, Nerem RM, Wheeler LT. The application of a homogeneous half-space model in the analysis of endothelial cell micropipette measurements. J Biomech Eng. 1988;110(3):190–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Rocnik EF, van der Veer E, Cao H, Hegele RA, Pickering JG. Functional linkage between the endoplasmic reticulum protein Hsp47 and procollagen expression in human vascular smooth muscle cells. J Biol Chem. 2002;277(41):38571–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Merryman WD, Liao J, Parekh A, Candiello JE, Lin H, Sacks MS. Differences in tissue-remodeling potential of aortic and pulmonary heart valve interstitial cells. Tissue Eng. 2007;13(9):2281–9.CrossRefGoogle Scholar
  31. 31.
    Costa KD, Yin FC. Analysis of indentation: implications for measuring mechanical properties with atomic force microscopy. J Biomech Eng. 1999;121(5):462–71.PubMedCrossRefGoogle Scholar
  32. 32.
    Mathur AB, Collinsworth AM, Reichert WM, Kraus WE, Truskey GA. Endothelial, cardiac muscle and skeletal muscle exhibit different viscous and elastic properties as determined by atomic force microscopy. J Biomech. 2001;34(12):1545–53.PubMedCrossRefGoogle Scholar
  33. 33.
    Sato M, Theret DP, Wheeler LT, Ohshima N, Nerem RM. Application of the micropipette technique to the measurement of cultured porcine aortic endothelial cell viscoelastic properties. J Biomech Eng. 1990;112(3):263–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Guilak F, Ting-Beall HP, Baer AE, Trickey WR, Erickson GR, Setton LA. Viscoelastic properties of intervertebral disc cells. Identification of two biomechanically distinct cell populations. Spine. 1999;24(23):2475–83.PubMedCrossRefGoogle Scholar
  35. 35.
    Na S, Sun Z, Meininger GA, Humphrey JD. On atomic force microscopy and the constitutive behavior of living cells. Biomech Model Mechanobiol. 2004;3(2):75–84.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Frisch-Fay R. Flexible bars. Washington, DC: Butterworths; 1962. 220 p.Google Scholar
  37. 37.
    Merryman WD, Huang HY, Schoen FJ, Sacks MS. The effects of cellular contraction on aortic valve leaflet flexural stiffness. J Biomech. 2006;39(1):88–96.CrossRefGoogle Scholar
  38. 38.
    Mirnajafi A, Raymer J, Scott MJ, Sacks MS. The effects of collagen fiber orientation on the flexural properties of pericardial heterograft biomaterials. Biomaterials. 2005;26(7):795–804.PubMedCrossRefGoogle Scholar
  39. 39.
    Mirnajafi A, Raymer JM, McClure LR, Sacks MS. The flexural rigidity of the aortic valve leaflet in the commissural region. J Biomech. 2006;39(16):2966–73.PubMedCrossRefGoogle Scholar
  40. 40.
    Billiar KL, Sacks MS. Biaxial mechanical properties of the native and glutaraldehyde-treated aortic valve cusp: Part II—A structural constitutive model. J Biomech Eng. 2000;122(4):327–35.PubMedCrossRefGoogle Scholar
  41. 41.
    Billiar KL, Sacks MS. Biaxial mechanical properties of the natural and glutaraldehyde treated aortic valve cusp—Part I: Experimental results. J Biomech Eng. 2000;122(1):23–30.PubMedCrossRefGoogle Scholar
  42. 42.
    Mohri H, Reichenback D, Merendino K. Biology of homologous and heterologous aortic valves. In: Ionescu M, Ross D, Wooler G, editors. Biological tissue in heart valve replacement. London: Butterworths; 1972. p. 137.Google Scholar
  43. 43.
    Vesely I, Boughner D. Analysis of the bending behaviour of porcine xenograft leaflets and of natural aortic valve material: bending stiffness, neutral axis and shear measurements. J Biomech. 1989;22(6/7):655–71.PubMedCrossRefGoogle Scholar
  44. 44.
    Song T, Vesely I, Boughner D. Effects of dynamic fixation on shear behavior of porcine xenograft valves. Biomaterials. 1990;11:191–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Lu SCH, Pister KS. Decomposition of deformation and representation of the free energy function for isotropic thermoelastic solids. Int J Solids Struct. 1975;11(7–8):927–34.CrossRefGoogle Scholar
  46. 46.
    Benton JA, Fairbanks BD, Anseth KS. Characterization of valvular interstitial cell function in three dimensional matrix metalloproteinase degradable PEG hydrogels. Biomaterials. 2009;30(34):6593–603.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Byrant SJ, Anseth KS. Photopolymerization of hydrogel scaffolds. In: Ma PX, Elisseeff J, editors. Scaffolding in tissue engineering. New York: CRC Press; 2005. p. 71–90.CrossRefGoogle Scholar
  48. 48.
    Balachandran K, Alford PW, Wylie-Sears J, Goss JA, Grosberg A, Bischoff J, et al. Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve. Proc Natl Acad Sci U S A. 2011;108(50):19943–8.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Balachandran K, Hussain S, Yap CH, Padala M, Chester AH, Yoganathan AP. Elevated cyclic stretch and serotonin result in altered aortic valve remodeling via a mechanosensitive 5-HT(2A) receptor-dependent pathway. Cardiovasc Pathol. 2012;21(3):206–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Balachandran K, Konduri S, Sucosky P, Jo H, Yoganathan A. An ex vivo study of the biological properties of porcine aortic valves in response to circumferential cyclic stretch. Ann Biomed Eng. 2006;34(11):1655–65.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Balachandran K, Sucosky P, Jo H, Yoganathan AP. Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease. Am J Physiol Heart Circ Physiol. 2009;296(3):H756–64.CrossRefGoogle Scholar
  52. 52.
    Sacks MS, Smith DB, Hiester ED. A small angle light scattering device for planar connective tissue microstructural analysis. Ann Biomed Eng. 1997;25(4):678–89.PubMedCrossRefGoogle Scholar
  53. 53.
    Amini R, Eckert CE, Koomalsingh K, McGarvey J, Minakawa M, Gorman JH, et al. On the in vivo deformation of the mitral valve anterior leaflet: effects of annular geometry and referential configuration. Ann Biomed Eng. 2012;40(7):1455–67.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Carruthers CA, Alfieri CM, Joyce EM, Watkins SC, Yutzey KE, Sacks MS. Gene expression and collagen Fiber micromechanical interactions of the semilunar heart valve interstitial cell. Cell Mol Bioeng. 2012;5(3):254–65.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Lee CH, Rabbah JP, Yoganathan AP, Gorman RC, Gorman JH 3rd, Sacks MS. On the effects of leaflet microstructure and constitutive model on the closing behavior of the mitral valve. Biomech Model Mechanobiol. 2015;14(6):1281–302.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Khalighi AH, Drach A, Bloodworth CH, Pierce EL, Yoganathan AP, Gorman RC, et al. Mitral valve chordae tendineae: topological and geometrical characterization. Ann Biomed Eng. 2017;45(2):378–93.PubMedCrossRefGoogle Scholar
  57. 57.
    Khalighi AH, Drach A, Gorman RC, Gorman JH 3rd, Sacks MS. Multi-resolution geometric modeling of the mitral heart valve leaflets. Biomech Model Mechanobiol. 2018;17(2):351–66.PubMedCrossRefGoogle Scholar
  58. 58.
    Drach A, Khalighi AH, Sacks MS. A comprehensive pipeline for multi-resolution modeling of the mitral valve: validation, computational efficiency, and predictive capability. Int J Numer Methods Biomed Eng. 2018;34(2)CrossRefGoogle Scholar
  59. 59.
    Sacks MS, Khalighi A, Rego B, Ayoub S, Drach A. On the need for multi-scale geometric modelling of the mitral heart valve. Healthc Technol Lett. 2017;4(5):150.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Alex Khang
    • 1
  • Rachel M. Buchanan
    • 1
  • Salma Ayoub
    • 1
  • Bruno V. Rego
    • 2
  • Chung-Hao Lee
    • 3
  • Michael S. Sacks
    • 4
    Email author
  1. 1.James T. Willerson Center for Cardiovascular Modeling and Simulation, The Oden Institute and the Department of Biomedical EngineeringThe University of Texas at AustinAustinUSA
  2. 2.James T. Willerson Center for Cardiovascular Modeling and Simulation, Institute for Computational Engineering and Sciences, Department of Biomedical EngineeringThe University of Texas at AustinAustinUSA
  3. 3.School of Aerospace and Mechanical EngineeringThe University of OklahomaNormanUSA
  4. 4.The Oden Institute and the Department of Biomedical EngineeringThe University of Texas at AustinAustinUSA

Personalised recommendations