Pathophysiology of Aortic Valve Stenosis



The calcific aortic valve stenosis is one of the most common heart valve diseases in the western countries and its prevalence is growing with the aging of population. The second cause of aortic valve stenosis in the developed countries comes from rheumatic disease. The third cause of aortic valve stenosis in terms of prevalence comes from congenital anatomic variations, unicuspid or bicuspid valves. Several mechanisms are involved in the process of progressive calcification. Inflammation, risk factors for atherosclerosis, oxygen free radicals, and calcium metabolism alteration cause a progressive sclerosis and calcification of the valve leading to a leaflet movement reduction and pressure gradient increase across the valve. With progressive reduction of leaflets movement, there is a continuum spectrum of augmented pressure overload of the left ventricle with the consequent development of myocardial hypertrophy. The mechanisms of valve degeneration and ventricle response are elucidated in this chapter.


Aortic valve Stenosis Inflammation Left ventricle hypertrophy Calcification CAVD 



Conflict of interest disclosure: no disclosure


  1. 1.
    Iung B. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on valvular heart disease. Eur Heart J [Internet]. 2003;24(13):1231–43.
  2. 2.
    Lindroos M, Kupari M, Heikkilä J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 1993;21(5):1220–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, et al. Clinical factors associated with calcific aortic valve disease. J Am Coll Cardiol. 1997;29(3):630–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med [Internet]. 1999;341(3):142–7.
  5. 5.
    Cimini M, Boughner DR, Ronald JA, Aldington L, Rogers KA. Development of aortic valve sclerosis in a rabbit model of atherosclerosis: an immunohistochemical and histological study. J Heart Valve Dis. 2005;14(3):365–75.PubMedGoogle Scholar
  6. 6.
    Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O’Brien KD. Characterization of the early lesion of “degenerative” valvular aortic stenosis: histological and immunohistochemical studies. Circulation. 1994;90(2):844–53.PubMedCrossRefGoogle Scholar
  7. 7.
    Wallby L, Janerot-Sjöberg B, Steffensen T, Broqvist M. T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves. Heart [Internet]. 2002;88(4):348–51.
  8. 8.
    Olsson M, Rosenqvist M, Nilsson J. Expression of HLA-DR antigen and smooth muscle cell differentiation markers by valvular fibroblasts in degenerative aortic stenosis. J Am Coll Cardiol. 1994;24(7):1664–71.PubMedCrossRefGoogle Scholar
  9. 9.
    Kaden JJ, Dempfle CE, Grobholz R, Tran HT, Kilic R, Sarikoc A, et al. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis [Internet]. 2003;170(2):205–11.
  10. 10.
    Jian B, Narula N, Li QY, Mohler ER, Levy RJ. Progression of aortic valve stenosis: TGF-β1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg. 2003;75(2):457–65.PubMedCrossRefGoogle Scholar
  11. 11.
    Helske S, Lindstedt KA, Laine M, Mäyränpää M, Werkkala K, Lommi J, et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol. 2004;44(9):1859–66.PubMedCrossRefGoogle Scholar
  12. 12.
    Ghaisas NK, Foley JB, O’Briain DS, Crean P, Kelleher D, Walsh M. Adhesion molecules in nonrheumatic aortic valve disease: endothelial expression, serum levels and effects of valve replacement. J Am Coll Cardiol [Internet]. 2000;36(7):2257–62.
  13. 13.
    Weinberg EJ, Kaazempur Mofrad MR. A multiscale computational comparison of the bicuspid and tricuspid aortic valves in relation to calcific aortic stenosis. J Biomech. 2008;41(16):3482–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Robicsek F, Thubrikar MJ, Fokin AA. Cause of degenerative disease of the trileaflet aortic valve: review of subject and presentation of a new theory. Ann Thorac Surg. 2002;73:1346–54.Google Scholar
  15. 15.
    Stritzke J, Linsel-Nitschke P, Markus MRP, Mayer B, Lieb W, Luchner A, et al. Association between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal population-based KORA/MONICA survey. Eur Heart J. 2009;30(16):2044–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol [Internet]. 1997;29(3):630–4.
  17. 17.
    Olsen MH, Wachtell K, Bella JN, Gerdts E, Palmieri V, Nieminen MS, et al. Aortic valve sclerosis relates to cardiovascular events in patients with hypertension (a LIFE substudy). Am J Cardiol. 2005;95(1):132–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Miller JD, Chu Y, Brooks RM, Richenbacher WE, Peña-Silva R, Heistad DD. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Cosmi JE, Kort S, Tunick PA, Rosenzweig BP, Freedberg RS, Katz ES, et al. The risk of the development of aortic stenosis in patients with “benign” aortic valve thickening. Arch Intern Med [Internet]. 2002;162(20):2345.
  21. 21.
    Mohler ER, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation. 2001;103(11):1522–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111:3316–26.Google Scholar
  23. 23.
    Clavel M-A, Pibarot P, Messika-Zeitoun D, Capoulade R, Malouf J, Aggarval S, et al. Impact of aortic valve calcification, as measured by MDCT, on survival in patients with aortic stenosis results of an international registry study. J Am Coll Cardiol. 2014;64:1202–13.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest. 1975;56(1):56–64.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med [Internet]. 1990;322(22):1561–6.
  26. 26.
    Salcedo EE, Korzick DH, Currie PJ, Stewart WJ, Lever HM, Goormastic M. Determinants of left ventricular hypertrophy in patients with aortic stenosis. Cleve Clin J Med. 1989;56(6):590–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Kupari M, Turto H, Lommi J. Left ventricular hypertrophy in aortic valve stenosis: preventive or promotive of systolic dysfunction and heart failure? Eur Heart J. 2005;26(17):1790–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Gunther S, Grossman W. Determinants of ventricular function in pressure-overload hypertrophy in man. Circulation. 1979;59(4):679–88.PubMedCrossRefGoogle Scholar
  29. 29.
    Dweck MR, Joshi S, Murigu T, Gulati A, Alpendurada F, Jabbour A, et al. Left ventricular remodeling and hypertrophy in patients with aortic stenosis: insights from cardiovascular magnetic resonance. J Cardiovasc Magn Reson [Internet]. 2012;14(1):50.
  30. 30.
    Orlowska-Baranowska E, Placha G, Gaciong Z, Baranowski R, Zakrzewski D, Michalek P, et al. Influence of ACE I/D genotypes on left ventricular hypertrophy in aortic stenosis: gender-related differences. J Heart Valve Dis [Internet]. 2004;13(4):574–81.
  31. 31.
    Rieck AE, Cramariuc D, Staal EM, Rossebø AB, Wachtell K, Gerdts E. Impact of hypertension on left ventricular structure in patients with asymptomatic aortic valve stenosis (a SEAS substudy). J Hypertens. 2010;28(2):377–83.PubMedCrossRefGoogle Scholar
  32. 32.
    Briand M, Dumesnil JG, Kadem L, Tongue AG, Rieu R, Garcia D, et al. Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment. J Am Coll Cardiol. 2005;46(2):291–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Hachicha Z, Dumesnil JG, Pibarot P. Usefulness of the valvuloarterial impedance to predict adverse outcome in asymptomatic aortic stenosis. J Am Coll Cardiol. 2009;54(11):1003–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Cioffi G, Faggiano P, Vizzardi E, Tarantini L, Cramariuc D, Gerdts E, et al. Prognostic effect of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis. Heart. 2011;97(4):301–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Bishopric NH, Andreka P, Slepak T, Webster KA. Molecular mechanisms of apoptosis in the cardiac myocyte. Curr Opin Pharmacol. 2001;1(2):141–50.PubMedCrossRefGoogle Scholar
  36. 36.
    Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, et al. Stretch-induced programmed myocyte cell death. J Clin Invest. 1995;96(5):2247–59.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Pierzchalski P, Reiss K, Cheng W, Cirielli C, Kajstura J, Nitahara JA, et al. p53 induces myocyte apoptosis via the activation of the renin-angiotensin system. Exp Cell Res. 1997;234(1):57–65.PubMedCrossRefGoogle Scholar
  38. 38.
    Camici PG, Olivotto I, Rimoldi OE. The coronary circulation and blood flow in left ventricular hypertrophy. J Mol Cell Cardiol. 2012;52:857–64.PubMedCrossRefGoogle Scholar
  39. 39.
    Anderson KR, Sutton MGSJ, Lie JT. Histopathological types of cardiac fibrosis in myocardial disease. J Pathol. 1979;128(2):79–85.PubMedCrossRefGoogle Scholar
  40. 40.
    Krayenbuehl HP, Hess OM, Monrad ES, Schneider J, Mall G, Turina M. Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement. Circulation. 1989;79(4):744–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Investig. 2007;117:568–75.PubMedCrossRefGoogle Scholar
  42. 42.
    Bishop JE, Lindahl G. Regulation of cardiovascular collagen synthesis by mechanical load. Cardiovasc Res. 1999;42(1):27–44.PubMedCrossRefGoogle Scholar
  43. 43.
    Treibel TA, López B, González A, Menacho K, Schofield RS, Ravassa S, et al. Reappraising myocardial fibrosis in severe aortic stenosis: an invasive and non-invasive study in 133 patients. Eur Heart J [Internet]. 2017.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institute of Cardiac Surgery, Department of Neurosciences, Imaging and Clinical SciencesUniversity “G. D’Annunzio” Chieti & PescaraChietiItaly
  2. 2.Department of Cardiac SurgeryOspedale “S. S. Annunziata”ChietiItaly
  3. 3.Department of Cardiac SurgeryOspedale “S. S. Annunziata”ChietiItaly

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