Skip to main content
SpringerLink
Log in
Book cover

Advances in Heart Valve Biomechanics pp 153–179Cite as

Calcific Aortic Valve Disease: Pathobiology, Basic Mechanisms, and Clinical Strategies

  • Chapter
  • First Online:

Abstract

Calcific aortic valve disease (CAVD) is a leading cause of cardiovascular morbidity and mortality, and its prevalence is expected to increase in the aging population of the developed world. Currently, no noninvasive therapeutic strategies exist to prevent or treat CAVD. Though the advent of new valve replacement technologies have improved clinical outcomes, these techniques remain suboptimal for the two populations most at risk for valvular complications—pediatric and elderly patients. Recent advances in basic research have shown that CAVD arises through active cellular mechanisms, offering hope that drugs can be developed to target relevant pathways and provide new clinical options for CAVD patients. Translating these benchtop discoveries to clinical realities, however, will require both a holistic understanding of how targetable cellular level processes affect valve tissue function and the ability to identify early CAVD development in patients. This chapter addresses this translation by reviewing the current state of CAVD research and the ongoing efforts to meet the clinical need.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Stewart BF, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health study. J Am Coll Cardiol. 1997;29(3):630–4.

    Article  CAS  PubMed  Google Scholar 

  2. Otto CM, et al. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med. 1999;341(3):142–7.

    Article  CAS  PubMed  Google Scholar 

  3. Ross J Jr, Braunwald E. Aortic stenosis. Circulation. 1968;38(1 Suppl):61–7.

    PubMed  Google Scholar 

  4. Nishimura RA, et al. 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(23):2440–92.

    Article  PubMed  Google Scholar 

  5. Lindman BR, Bonow RO, Otto CM. Current management of calcific aortic stenosis. Circ Res. 2013;113(2):223–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Otto CM. Timing of aortic valve surgery. Heart. 2000;84(2):211–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lloyd-Jones D, et al. Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119(3):e21–181.

    PubMed  Google Scholar 

  8. Rahimtoola SH. Choice of prosthetic heart valve in adults an update. J Am Coll Cardiol. 2010;55(22):2413–26.

    Article  PubMed  Google Scholar 

  9. Pibarot P, Dumesnil JG. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 2009;119(7):1034–48.

    Article  PubMed  Google Scholar 

  10. Sacks MS, Schoen FJ. Collagen fiber disruption occurs independent of calcification in clinically explanted bioprosthetic heart valves. J Biomed Mater Res. 2002;62(3):359–71.

    Article  CAS  PubMed  Google Scholar 

  11. Schoen FJ, Levy RJ. Calcification of tissue heart valve substitutes: progress toward understanding and prevention. Ann Thorac Surg. 2005;79(3):1072–80.

    Article  PubMed  Google Scholar 

  12. Brennan JM, et al. Early anticoagulation of bioprosthetic aortic valves in older patients: results from the Society of Thoracic Surgeons Adult Cardiac Surgery National Database. J Am Coll Cardiol. 2012;60(11):971–7.

    Article  PubMed  Google Scholar 

  13. Leon MB, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363(17):1597–607.

    Article  CAS  PubMed  Google Scholar 

  14. Clavel MA, et al. Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction. Circulation. 2010;122(19):1928–36.

    Article  CAS  PubMed  Google Scholar 

  15. Smith CR, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187–98.

    Article  CAS  PubMed  Google Scholar 

  16. Daneault B, et al. Stroke associated with surgical and transcatheter treatment of aortic stenosis: a comprehensive review. J Am Coll Cardiol. 2011;58(21):2143–50.

    Article  PubMed  Google Scholar 

  17. Rajamannan NM, 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.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Leopold JA. Cellular mechanisms of aortic valve calcification. Circ Cardiovasc Interv. 2012;5(4):605–14.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Misfeld M, Sievers HH. Heart valve macro- and microstructure. Philos Trans R Soc Lond Ser B Biol Sci. 2007;362(1484):1421–36.

    Article  Google Scholar 

  20. Thubrikar M, et al. The design of the normal aortic valve. Am J Phys. 1981;241(6):H795–801.

    CAS  Google Scholar 

  21. Yacoub MH, et al. The aortic outflow and root: a tale of dynamism and crosstalk. Ann Thorac Surg. 1999;68(3 Suppl):S37–43.

    Article  CAS  PubMed  Google Scholar 

  22. Anderson RH, et al. The myth of the aortic annulus: the anatomy of the subaortic outflow tract. Ann Thorac Surg. 1991;52(3):640–6.

    Article  CAS  PubMed  Google Scholar 

  23. Anderson RH. Clinical anatomy of the aortic root. Heart. 2000;84(6):670–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Roberts WC. The structure of the aortic valve in clinically isolated aortic stenosis: an autopsy study of 162 patients over 15 years of age. Circulation. 1970;42(1):91–7.

    Article  CAS  PubMed  Google Scholar 

  25. Katayama S, et al. The sinus of Valsalva relieves abnormal stress on aortic valve leaflets by facilitating smooth closure. J Thorac Cardiovasc Surg. 2008;136(6):1528–35, 1535 e1.

    Article  PubMed  Google Scholar 

  26. Balachandran K, Sucosky P, Yoganathan AP. Hemodynamics and mechanobiology of aortic valve inflammation and calcification. Int J Inflam. 2011;2011:263870.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Butcher JT, Mahler GJ, Hockaday LA. Aortic valve disease and treatment: the need for naturally engineered solutions. Adv Drug Deliv Rev. 2011;63(4–5):242–68.

    Article  CAS  PubMed  Google Scholar 

  28. Thubrikar M, Bosher LP, Nolan SP. The mechanism of opening of the aortic valve. J Thorac Cardiovasc Surg. 1979;77(6):863–70.

    CAS  PubMed  Google Scholar 

  29. Aikawa E, et al. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation. 2006;113(10):1344–52.

    Article  PubMed  Google Scholar 

  30. Sacks MS, David Merryman W, Schmidt DE. On the biomechanics of heart valve function. J Biomech. 2009;42(12):1804–24.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schoen FJ. Aortic valve structure-function correlations: role of elastic fibers no longer a stretch of the imagination. J Heart Valve Dis. 1997;6(1):1–6.

    CAS  PubMed  Google Scholar 

  32. Schoen FJ. Evolving concepts of cardiac valve dynamics: the continuum of development, functional structure, pathobiology, and tissue engineering. Circulation. 2008;118(18):1864–80.

    Article  PubMed  Google Scholar 

  33. Stephens EH, Chu CK, Grande-Allen KJ. Valve proteoglycan content and glycosaminoglycan fine structure are unique to microstructure, mechanical load and age: relevance to an age-specific tissue-engineered heart valve. Acta Biomater. 2008;4(5):1148–60.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  PubMed  Google Scholar 

  35. Vesely I, Noseworthy R. Micromechanics of the fibrosa and the ventricularis in aortic valve leaflets. J Biomech. 1992;25(1):101–13.

    Article  CAS  PubMed  Google Scholar 

  36. Merryman WD, et al. The effects of cellular contraction on aortic valve leaflet flexural stiffness. J Biomech. 2006;39(1):88–96.

    Article  PubMed  Google Scholar 

  37. Zhao R, Sider KL, Simmons CA. Measurement of layer-specific mechanical properties in multilayered biomaterials by micropipette aspiration. Acta Biomater. 2011;7(3):1220–7.

    Article  CAS  PubMed  Google Scholar 

  38. Sacks MS, Smith DB, Hiester ED. The aortic valve microstructure: effects of transvalvular pressure. J Biomed Mater Res. 1998;41(1):131–41.

    Article  CAS  PubMed  Google Scholar 

  39. Stella JA, Liao J, Sacks MS. Time-dependent biaxial mechanical behavior of the aortic heart valve leaflet. J Biomech. 2007;40(14):3169–77.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Cimini M, Rogers KA, Boughner DR. Smoothelin-positive cells in human and porcine semilunar valves. Histochem Cell Biol. 2003;120(4):307–17.

    Article  CAS  PubMed  Google Scholar 

  41. Chester AH, et al. Localisation and function of nerves in the aortic root. J Mol Cell Cardiol. 2008;44(6):1045–52.

    Article  CAS  PubMed  Google Scholar 

  42. Marron K, et al. Innervation of human atrioventricular and arterial valves. Circulation. 1996;94(3):368–75.

    Article  CAS  PubMed  Google Scholar 

  43. Liu AC, Joag VR, Gotlieb AI. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am J Pathol. 2007;171(5):1407–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rabkin E, et al. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation. 2001;104(21):2525–32.

    Article  CAS  PubMed  Google Scholar 

  45. Rabkin-Aikawa E, et al. Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves. J Heart Valve Dis. 2004;13(5):841–7.

    PubMed  Google Scholar 

  46. Yperman J, et al. Molecular and functional characterization of ovine cardiac valve-derived interstitial cells in primary isolates and cultures. Tissue Eng. 2004;10(9–10):1368–75.

    Article  CAS  PubMed  Google Scholar 

  47. Taylor PM, et al. The cardiac valve interstitial cell. Int J Biochem Cell Biol. 2003;35(2):113–8.

    Article  CAS  PubMed  Google Scholar 

  48. Walker GA, et al. Valvular myofibroblast activation by transforming growth factor-beta: implications for pathological extracellular matrix remodeling in heart valve disease. Circ Res. 2004;95(3):253–60.

    Article  CAS  PubMed  Google Scholar 

  49. Merryman WD, 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.

    Article  CAS  PubMed  Google Scholar 

  50. Ku CH, et al. Collagen synthesis by mesenchymal stem cells and aortic valve interstitial cells in response to mechanical stretch. Cardiovasc Res. 2006;71(3):548–56.

    Article  CAS  PubMed  Google Scholar 

  51. Schneider PJ, Deck JD. Tissue and cell renewal in the natural aortic valve of rats: an autoradiographic study. Cardiovasc Res. 1981;15(4):181–9.

    Article  CAS  PubMed  Google Scholar 

  52. Schoen FJ. Mechanisms of function and disease of natural and replacement heart valves. Annu Rev Pathol. 2012;7:161–83.

    Article  CAS  PubMed  Google Scholar 

  53. Frater RW, et al. Endothelial covering of biological artificial heart valves. Ann Thorac Surg. 1992;53(3):371–2.

    Article  CAS  PubMed  Google Scholar 

  54. Butcher JT, Simmons CA, Warnock JN. Mechanobiology of the aortic heart valve. J Heart Valve Dis. 2008;17(1):62–73.

    PubMed  Google Scholar 

  55. Butcher JT, et al. Transcriptional profiles of valvular and vascular endothelial cells reveal phenotypic differences: influence of shear stress. Arterioscler Thromb Vasc Biol. 2006;26(1):69–77.

    Article  CAS  PubMed  Google Scholar 

  56. Deck JD. Endothelial cell orientation on aortic valve leaflets. Cardiovasc Res. 1986;20(10):760–7.

    Article  CAS  PubMed  Google Scholar 

  57. Butcher JT, et al. Unique morphology and focal adhesion development of valvular endothelial cells in static and fluid flow environments. Arterioscler Thromb Vasc Biol. 2004;24(8):1429–34.

    Article  CAS  PubMed  Google Scholar 

  58. Kilner PJ, et al. Asymmetric redirection of flow through the heart. Nature. 2000;404(6779):759–61.

    Article  CAS  PubMed  Google Scholar 

  59. Simmons CA, et al. Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circ Res. 2005;96(7):792–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Guerraty MA, et al. Hypercholesterolemia induces side-specific phenotypic changes and peroxisome proliferator-activated receptor-gamma pathway activation in swine aortic valve endothelium. Arterioscler Thromb Vasc Biol. 2010;30(2):225–31.

    Article  CAS  PubMed  Google Scholar 

  61. Mohler ER 3rd. Mechanisms of aortic valve calcification. Am J Cardiol. 2004;94(11):1396–402. A6

    Article  PubMed  Google Scholar 

  62. Mohler ER 3rd, et al. Bone formation and inflammation in cardiac valves. Circulation. 2001;103(11):1522–8.

    Article  PubMed  Google Scholar 

  63. Wylie-Sears J, et al. Mitral valve endothelial cells with osteogenic differentiation potential. Arterioscler Thromb Vasc Biol. 2011;31(3):598–607.

    Article  CAS  PubMed  Google Scholar 

  64. Bischoff J, Aikawa E. Progenitor cells confer plasticity to cardiac valve endothelium. J Cardiovasc Transl Res. 2011;4(6):710–9.

    Article  PubMed  Google Scholar 

  65. Hjortnaes J, et al. Valvular interstitial cells suppress calcification of valvular endothelial cells. Atherosclerosis. 2015;242(1):251–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chakraborty S, et al. Shared gene expression profiles in developing heart valves and osteoblast progenitor cells. Physiol Genomics. 2008;35(1):75–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Butcher JT, Nerem RM. Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. Tissue Eng. 2006;12(4):905–15.

    Article  CAS  PubMed  Google Scholar 

  68. Mohler ER 3rd, et al. Identification and characterization of calcifying valve cells from human and canine aortic valves. J Heart Valve Dis. 1999;8(3):254–60.

    PubMed  Google Scholar 

  69. Hutcheson JD, Aikawa E, Merryman WD. Potential drug targets for calcific aortic valve disease. Nat Rev Cardiol. 2014;11(4):218–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hjortnaes J, et al. Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation. Eur Heart J. 2010;31(16):1975–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rajamannan NM, Edwards WD, Spelsberg TC. Hypercholesterolemic aortic-valve disease. N Engl J Med. 2003;349(7):717–8.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Helske S, et al. Aortic valve stenosis: an active atheroinflammatory process. Curr Opin Lipidol. 2007;18(5):483–91.

    Article  CAS  PubMed  Google Scholar 

  73. Mohler ER 3rd. Are atherosclerotic processes involved in aortic-valve calcification? Lancet. 2000;356(9229):524–5.

    Article  PubMed  Google Scholar 

  74. Messier RH Jr, et al. Dual structural and functional phenotypes of the porcine aortic valve interstitial population: characteristics of the leaflet myofibroblast. J Surg Res. 1994;57(1):1–21.

    Article  PubMed  Google Scholar 

  75. Mulholland DL, Gotlieb AI. Cell biology of valvular interstitial cells. Can J Cardiol. 1996;12(3):231–6.

    CAS  PubMed  Google Scholar 

  76. Dilley RJ, McGeachie JK, Prendergast FJ. A review of the proliferative behaviour, morphology and phenotypes of vascular smooth muscle. Atherosclerosis. 1987;63(2–3):99–107.

    Article  CAS  PubMed  Google Scholar 

  77. Orr AW, et al. Complex regulation and function of the inflammatory smooth muscle cell phenotype in atherosclerosis. J Vasc Res. 2010;47(2):168–80.

    Article  PubMed  Google Scholar 

  78. Merryman WD, et al. Differences in tissue-remodeling potential of aortic and pulmonary heart valve interstitial cells. Tissue Eng. 2007;13(9):2281–9.

    Article  PubMed  Google Scholar 

  79. Freeman RV, Crittenden G, Otto C. Acquired aortic stenosis. Expert Rev Cardiovasc Ther. 2004;2(1):107–16.

    Article  PubMed  Google Scholar 

  80. Merryman WD, Schoen FJ. Mechanisms of calcification in aortic valve disease: role of mechanokinetics and mechanodynamics. Curr Cardiol Rep. 2013;15(5):355.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Otto CM, et al. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies. Circulation. 1994;90(2):844–53.

    Article  CAS  PubMed  Google Scholar 

  82. O'Brien KD, et al. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of 'degenerative' valvular aortic stenosis. Arterioscler Thromb Vasc Biol. 1996;16(4):523–32.

    Article  CAS  PubMed  Google Scholar 

  83. Yip CY, Simmons CA. The aortic valve microenvironment and its role in calcific aortic valve disease. Cardiovasc Pathol. 2011;20(3):177–82.

    Article  PubMed  Google Scholar 

  84. Mehrabian M, Demer LL, Lusis AJ. Differential accumulation of intimal monocyte-macrophages relative to lipoproteins and lipofuscin corresponds to hemodynamic forces on cardiac valves in mice. Arterioscler Thromb. 1991;11(4):947–57.

    Article  CAS  PubMed  Google Scholar 

  85. Thubrikar MJ, Aouad J, Nolan SP. Patterns of calcific deposits in operatively excised stenotic or purely regurgitant aortic valves and their relation to mechanical stress. Am J Cardiol. 1986;58(3):304–8.

    Article  CAS  PubMed  Google Scholar 

  86. Hinton RB Jr, et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ Res. 2006;98(11):1431–8.

    Article  CAS  PubMed  Google Scholar 

  87. Chen JH, Simmons CA. Cell-matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. Circ Res. 2011;108(12):1510–24.

    Article  CAS  PubMed  Google Scholar 

  88. Tanaka K, et al. Age-associated aortic stenosis in apolipoprotein E-deficient mice. J Am Coll Cardiol. 2005;46(1):134–41.

    Article  CAS  PubMed  Google Scholar 

  89. Rajamannan NM, et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003;107(17):2181–4.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Sabet HY, et al. Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2,715 additional cases. Mayo Clin Proc. 1999;74(1):14–26.

    Article  CAS  PubMed  Google Scholar 

  91. Poggianti E, et al. Aortic valve sclerosis is associated with systemic endothelial dysfunction. J Am Coll Cardiol. 2003;41(1):136–41.

    Article  PubMed  Google Scholar 

  92. Muller AM, et al. Expression of endothelial cell adhesion molecules on heart valves: up-regulation in degeneration as well as acute endocarditis. J Pathol. 2000;191(1):54–60.

    Article  CAS  PubMed  Google Scholar 

  93. Shavelle DM, et al. Soluble intercellular adhesion molecule-1 (sICAM-1) and aortic valve calcification in the multi-ethnic study of atherosclerosis (MESA). J Heart Valve Dis. 2008;17(4):388–95.

    PubMed  Google Scholar 

  94. Aikawa E, et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation. 2009;119(13):1785–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sorescu GP, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Circ Res. 2004;95(8):773–9.

    Article  CAS  PubMed  Google Scholar 

  96. Sucosky P, et al. Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway. Arterioscler Thromb Vasc Biol. 2009;29(2):254–60.

    Article  CAS  PubMed  Google Scholar 

  97. Mirzaie M, et al. Evidence of woven bone formation in heart valve disease. Ann Thorac Cardiovasc Surg. 2003;9(3):163–9.

    PubMed  Google Scholar 

  98. Bosse K, et al. Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. J Mol Cell Cardiol. 2013;60:27–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Richards J, et al. Side-specific endothelial-dependent regulation of aortic valve calcification: interplay of hemodynamics and nitric oxide signaling. Am J Pathol. 2013;182(5):1922–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Riddle JM, Magilligan DJ Jr, Stein PD. Surface topography of stenotic aortic valves by scanning electron microscopy. Circulation. 1980;61(3):496–502.

    Article  CAS  PubMed  Google Scholar 

  101. Armstrong EJ, Bischoff J. Heart valve development: endothelial cell signaling and differentiation. Circ Res. 2004;95(5):459–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Combs MD, Yutzey KE. Heart valve development: regulatory networks in development and disease. Circ Res. 2009;105(5):408–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Person AD, Klewer SE, Runyan RB. Cell biology of cardiac cushion development. Int Rev Cytol. 2005;243:287–335.

    Article  CAS  PubMed  Google Scholar 

  104. Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res. 2002;90(11):1189–96.

    Article  CAS  PubMed  Google Scholar 

  105. Paranya G, et al. Aortic valve endothelial cells undergo transforming growth factor-beta-mediated and non-transforming growth factor-beta-mediated transdifferentiation in vitro. Am J Pathol. 2001;159(4):1335–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Balachandran K, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Piera-Velazquez S, Li Z, Jimenez SA. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am J Pathol. 2011;179(3):1074–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kovacic JC, et al. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. Circulation. 2012;125(14):1795–808.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Dal-Bianco JP, et al. Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation. Circulation. 2009;120(4):334–42.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Chaput M, et al. Mitral leaflet adaptation to ventricular remodeling: prospective changes in a model of ischemic mitral regurgitation. Circulation. 2009;120(11 Suppl):S99–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Aikawa E, et al. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation. 2007;115(3):377–86.

    Article  CAS  PubMed  Google Scholar 

  112. Deb A, et al. Bone marrow-derived myofibroblasts are present in adult human heart valves. J Heart Valve Dis. 2005;14(5):674–8.

    PubMed  Google Scholar 

  113. Visconti RP, et al. An in vivo analysis of hematopoietic stem cell potential: hematopoietic origin of cardiac valve interstitial cells. Circ Res. 2006;98(5):690–6.

    Article  CAS  PubMed  Google Scholar 

  114. Hajdu Z, et al. Recruitment of bone marrow-derived valve interstitial cells is a normal homeostatic process. J Mol Cell Cardiol. 2011;51(6):955–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chen JH, et al. Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. Am J Pathol. 2009;174(3):1109–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Helske S, et al. Possible role for mast cell-derived cathepsin G in the adverse remodelling of stenotic aortic valves. Eur Heart J. 2006;27(12):1495–504.

    Article  CAS  PubMed  Google Scholar 

  117. Leskela HV, et al. Calcification and cellularity in human aortic heart valve tissue determine the differentiation of bone-marrow-derived cells. J Mol Cell Cardiol. 2006;41(4):642–9.

    Article  PubMed  CAS  Google Scholar 

  118. Gossl M, et al. Role of circulating osteogenic progenitor cells in calcific aortic stenosis. J Am Coll Cardiol. 2012;60(19):1945–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Egan KP, et al. Role for circulating osteogenic precursor cells in aortic valvular disease. Arterioscler Thromb Vasc Biol. 2011;31(12):2965–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nomura A, et al. CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification. Biochem Biophys Res Commun. 2013;440(4):780–5.

    Article  CAS  PubMed  Google Scholar 

  121. Aikawa E, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation. 2007;116(24):2841–50.

    Article  CAS  PubMed  Google Scholar 

  122. Aikawa E, Otto CM. Look more closely at the valve: imaging calcific aortic valve disease. Circulation. 2012;125(1):9–11.

    Article  PubMed  Google Scholar 

  123. Towler DA. Molecular and cellular aspects of calcific aortic valve disease. Circ Res. 2013;113(2):198–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Grinnell F, Ho CH. Transforming growth factor beta stimulates fibroblast-collagen matrix contraction by different mechanisms in mechanically loaded and unloaded matrices. Exp Cell Res. 2002;273(2):248–55.

    Article  CAS  PubMed  Google Scholar 

  125. Merryman WD, et al. Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast. Cardiovasc Pathol. 2007;16(5):268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Fisher CI, Chen J, Merryman WD. Calcific nodule morphogenesis by heart valve interstitial cells is strain dependent. Biomech Model Mechanobiol. 2013;12(1):5–17.

    Article  PubMed  Google Scholar 

  127. Chen JH, et al. Beta-catenin mediates mechanically regulated, transforming growth factor-beta1-induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol. 2011;31(3):590–7.

    Article  CAS  PubMed  Google Scholar 

  128. Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19(1):128–39.

    Article  CAS  PubMed  Google Scholar 

  129. Hutcheson JD, et al. 5-HT(2B) antagonism arrests non-canonical TGF-beta1-induced valvular myofibroblast differentiation. J Mol Cell Cardiol. 2012;53(5):707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hutcheson JD, et al. Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts. Arterioscler Thromb Vasc Biol. 2013;33(1):114–20.

    Article  CAS  PubMed  Google Scholar 

  131. Durbin AD, Gotlieb AI. Advances towards understanding heart valve response to injury. Cardiovasc Pathol. 2002;11(2):69–77.

    Article  PubMed  Google Scholar 

  132. Balachandran K, et al. Elevated cyclic stretch induces aortic valve calcification in a bone morphogenic protein-dependent manner. Am J Pathol. 2010;177(1):49–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. O'Brien KD, et al. Osteopontin is expressed in human aortic valvular lesions. Circulation. 1995;92(8):2163–8.

    Article  CAS  PubMed  Google Scholar 

  134. Mathieu P, et al. Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity. J Heart Valve Dis. 2005;14(3):353–7.

    PubMed  Google Scholar 

  135. Kaden JJ, et al. Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. J Heart Valve Dis. 2004;13(4):560–6.

    PubMed  Google Scholar 

  136. Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res. 2006;99(10):1044–59.

    Article  CAS  PubMed  Google Scholar 

  137. Miller JD, et al. Evidence for active regulation of pro-osteogenic signaling in advanced aortic valve disease. Arterioscler Thromb Vasc Biol. 2010;30(12):2482–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Alexopoulos A, et al. Bone regulatory factors NFATc1 and Osterix in human calcific aortic valves. Int J Cardiol. 2010;139(2):142–9.

    Article  PubMed  Google Scholar 

  139. Yang X, et al. Pro-osteogenic phenotype of human aortic valve interstitial cells is associated with higher levels of toll-like receptors 2 and 4 and enhanced expression of bone morphogenetic protein 2. J Am Coll Cardiol. 2009;53(6):491–500.

    Article  CAS  PubMed  Google Scholar 

  140. Miller JD, et al. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol. 2008;52(10):843–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Bostrom KI, Rajamannan NM, Towler DA. The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ Res. 2011;109(5):564–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Caira FC, et al. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol. 2006;47(8):1707–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Alfieri CM, et al. Wnt signaling in heart valve development and osteogenic gene induction. Dev Biol. 2010;338(2):127–35.

    Article  CAS  PubMed  Google Scholar 

  144. Xu S, Gotlieb AI. Wnt3a/beta-catenin increases proliferation in heart valve interstitial cells. Cardiovasc Pathol. 2013;22(2):156–66.

    Article  CAS  PubMed  Google Scholar 

  145. Rajamannan NM. The role of Lrp5/6 in cardiac valve disease: experimental hypercholesterolemia in the ApoE−/−/Lrp5−/− mice. J Cell Biochem. 2011;112(10):2987–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Shiotani A, et al. Regulation of osteoclast differentiation and function by receptor activator of NFkB ligand and osteoprotegerin. Anat Rec. 2002;268(2):137–46.

    Article  CAS  PubMed  Google Scholar 

  147. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292(4):490–5.

    Article  CAS  PubMed  Google Scholar 

  148. Steinmetz M, et al. Differential profile of the OPG/RANKL/RANK-system in degenerative aortic native and bioprosthetic valves. J Heart Valve Dis. 2008;17(2):187–93.

    PubMed  Google Scholar 

  149. Kaden JJ, et al. Influence of receptor activator of nuclear factor kappa B on human aortic valve myofibroblasts. Exp Mol Pathol. 2005;78(1):36–40.

    Article  CAS  PubMed  Google Scholar 

  150. Kaden JJ, et al. Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. Int J Mol Med. 2005;16(5):869–72.

    CAS  PubMed  Google Scholar 

  151. Bucay N, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12(9):1260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Weiss RM, et al. Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice. PLoS One. 2013;8(6):e65201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hilton MJ, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008;14(3):306–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Nigam V, Srivastava D. Notch1 represses osteogenic pathways in aortic valve cells. J Mol Cell Cardiol. 2009;47(6):828–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nus M, et al. Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL. Arterioscler Thromb Vasc Biol. 2011;31(7):1580–8.

    Article  CAS  PubMed  Google Scholar 

  156. Garg V, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270–4.

    Article  CAS  PubMed  Google Scholar 

  157. Acharya A, et al. Inhibitory role of Notch1 in calcific aortic valve disease. PLoS One. 2011;6(11):e27743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Helske S, et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol. 2004;44(9):1859–66.

    Article  CAS  PubMed  Google Scholar 

  159. Helske S, et al. Increased expression of profibrotic neutral endopeptidase and bradykinin type 1 receptors in stenotic aortic valves. Eur Heart J. 2007;28(15):1894–903.

    Article  CAS  PubMed  Google Scholar 

  160. Arishiro K, et al. Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits. J Am Coll Cardiol. 2007;49(13):1482–9.

    Article  CAS  PubMed  Google Scholar 

  161. Capoulade R, et al. Impact of hypertension and renin-angiotensin system inhibitors in aortic stenosis. Eur J Clin Investig. 2013;43(12):1262–72.

    Article  CAS  Google Scholar 

  162. Rosenhek R, et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation. 2004;110(10):1291–5.

    Article  CAS  PubMed  Google Scholar 

  163. Schoen FJ, Levy RJ. SnapShot: calcification of bioprosthetic heart valves. Biomaterials. 2009;30(26):4445–6.

    Article  PubMed  CAS  Google Scholar 

  164. Sacks MS. Biomechanics of engineered heart valve tissues. Conf Proc IEEE Eng Med Biol Soc. 2006;1:853–4.

    Article  Google Scholar 

  165. Zweng I, et al. Transcatheter versus surgical aortic valve replacement in high-risk patients: a propensity-score matched analysis. Heart Lung Circ. 2016;25:661.

    Article  PubMed  Google Scholar 

  166. Phan K, et al. Transcatheter valve-in-valve implantation versus reoperative conventional aortic valve replacement: a systematic review. J Thorac Dis. 2016;8(1):E83–93.

    PubMed  PubMed Central  Google Scholar 

  167. Bach DS. Prevalence and characteristics of unoperated patients with severe aortic stenosis. J Heart Valve Dis. 2011;20(3):284–91.

    PubMed  Google Scholar 

  168. Czarny MJ, Resar JR. Diagnosis and management of valvular aortic stenosis. Clin Med Insights Cardiol. 2014;8(Suppl 1):15–24.

    PubMed  PubMed Central  Google Scholar 

  169. Guerraty MA, et al. Relation of aortic valve calcium to chronic kidney disease (from the Chronic Renal Insufficiency Cohort Study). Am J Cardiol. 2015;115(9):1281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Rattazzi M, et al. Aortic valve calcification in chronic kidney disease. Nephrol Dial Transplant. 2013;28(12):2968–76.

    Article  CAS  PubMed  Google Scholar 

  171. Thanassoulis G, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368(6):503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Rogers MA, Aikawa E. A not-so-little role for lipoprotein(a) in the development of calcific aortic valve disease. Circulation. 2015;132(8):621–3.

    Article  PubMed  PubMed Central  Google Scholar 

  173. New SE, Aikawa E. Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circ Res. 2011;108(11):1381–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Dweck MR, et al. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation. 2012;125(1):76–86.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Payal Vyas, Joshua D. Hutcheson & Elena Aikawa

Authors
  1. Payal Vyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua D. Hutcheson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elena Aikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elena Aikawa .

Editor information

Editors and Affiliations

  1. The Oden Institute and the Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA

    Michael S. Sacks

  2. The Department of Bioengineering, The University of Texas at Arlington, Arlington, TX, USA

    Jun Liao

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Vyas, P., Hutcheson, J.D., Aikawa, E. (2018). Calcific Aortic Valve Disease: Pathobiology, Basic Mechanisms, and Clinical Strategies. In: Sacks, M., Liao, J. (eds) Advances in Heart Valve Biomechanics. Springer, Cham. https://doi.org/10.1007/978-3-030-01993-8_7

Download citation

Publish with us

Policies and ethics

Search

Navigation