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Osteocardiology pp 21–38Cite as

Osteocardiology: Calcific Aortic Valve Disease

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Abstract

Calcific aortic valve disease is the most common cause of valvular heart disease, globally. The risk factors for CAVD are similar to that of coronary atherosclerosis. The presence of these risk factors initiate the early stages of aortic valve sclerosis which over time, calcifies and causes severe stenosis. MESA and the CHS databases have defined the prevalence of severe stenosis and the association of calcification burden in the valves. Ongoing discoveries in the field of CAVD such as Lp(a) as risk factor for progression will become increasingly important as to date there are no positive randomized clinical trials to treat this disease. However, targeting novel lipoproteins may unlock the key to treat CAVD.

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References

  1. Rajamannan NM, Evans FJ, Aikawa E, 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;124:1783–91.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Nishimura RA, Otto CM, Bonow RO, 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. J Am Coll Cardiol. 2014;63:2438–88.

    Article  PubMed  Google Scholar 

  3. Rajamannan NM, Nealis TB, Subramaniam M, et al. Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation. Circulation. 2005;111:3296–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rajamannan NM, Subramaniam M, Rickard D, et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003;107:2181–4.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mohler ER 3rd, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation. 2001;103:1522–8.

    Article  PubMed  Google Scholar 

  6. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol. 1997;29:630–4.

    Article  CAS  PubMed  Google Scholar 

  7. Figueiredo CP, Rajamannan NM, Lopes JB, et al. Serum phosphate and hip bone mineral density as additional factors for high vascular calcification scores in a community-dwelling: the Sao Paulo Ageing & Health Study (SPAH). Bone. 2013;52:354–9.

    Article  CAS  PubMed  Google Scholar 

  8. Cowell SJ, Newby DE, Prescott RJ, et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005;352:2389–97.

    Article  CAS  PubMed  Google Scholar 

  9. 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. 1999;341:142–7.

    Article  CAS  PubMed  Google Scholar 

  10. Owens DS, Katz R, Takasu J, Kronmal R, Budoff MJ, O’Brien KD. Incidence and progression of aortic valve calcium in the Multi-ethnic Study of Atherosclerosis (MESA). Am J Cardiol. 2010;105:701–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Owens DS, Budoff MJ, Katz R, et al. Aortic valve calcium independently predicts coronary and cardiovascular events in a primary prevention population. JACC Cardiovasc Imaging. 2012;5:619–25.

    Article  PubMed  PubMed Central  Google Scholar 

  12. O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis. Arterioscler Thromb Vasc Biol. 1996;16:523–32.

    Article  PubMed  Google Scholar 

  13. 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;90:844–53.

    Article  CAS  PubMed  Google Scholar 

  14. Rajamannan NM. Calcific aortic stenosis: lessons learned from experimental and clinical studies. Arterioscler Thromb Vasc Biol. 2009;29:162–8.

    Article  CAS  PubMed  Google Scholar 

  15. Rajamannan NM. Oxidative-mechanical stress signals stem cell niche mediated Lrp5 osteogenesis in eNOS(−/−) null mice. J Cell Biochem. 2012;113:1623–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Mohler ER 3rd, Adam LP, McClelland P, Graham L, Hathaway DR. Detection of osteopontin in calcified human aortic valves. Arterioscler Thromb Vasc Biol. 1997;17:547–52.

    Article  PubMed  Google Scholar 

  17. Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368:503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thanassoulis G. Lipoprotein(a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis. J Lipid Res. 2015. https://doi.org/10.1194/jlr.R051870.

  19. Smith JG, Luk K, Schulz CA, et al. Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis. JAMA. 2014;312:1764–71.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cao J, Steffen BT, Budoff M, et al. Lipoprotein(a) levels are associated with subclinical calcific aortic valve disease in White and Black individuals: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2016;36:1003–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bild DE, Detrano R, Peterson D, et al. Ethnic differences in coronary calcification: the multi-ethnic study of atherosclerosis (MESA). Circulation. 2005;111:1313–20.

    Article  PubMed  Google Scholar 

  22. Huang CC, Lloyd-Jones DM, Guo X, et al. Gene expression variation between African Americans and whites is associated with coronary artery calcification: the multiethnic study of atherosclerosis. Physiol Genomics. 2011;43:836–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Elmariah S, Delaney JA, O’Brien KD, et al. Bisphosphonate use and prevalence of valvular and vascular calcification in women MESA (the multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2010;56:1752–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nasir K, Katz R, Al-Mallah M, et al. Relationship of aortic valve calcification with coronary artery calcium severity: the multi-ethnic study of atherosclerosis (MESA). J Cardiovasc Comput Tomogr. 2010;4:41–6.

    Article  PubMed  Google Scholar 

  25. Ix JH, Shlipak MG, Katz R, et al. Kidney function and aortic valve and mitral annular calcification in the multi-ethnic study of atherosclerosis (MESA). Am J Kidney Dis. 2007;50:412–20.

    Article  CAS  PubMed  Google Scholar 

  26. Tintut Y, Alfonso Z, Saini T, et al. Multilineage potential of cells from the artery wall. Circulation. 2003;108:2505–10.

    Article  PubMed  Google Scholar 

  27. Rajamannan NM. Embryonic cell origin defines functional role of Lrp5. Atherosclerosis. 2014;236:196–7.

    Article  CAS  PubMed  Google Scholar 

  28. Moura LM, Ramos SF, Zamorano JL, et al. Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J Am Coll Cardiol. 2007;49:554–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J, Investigators A. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010;121:306–14.

    Article  CAS  PubMed  Google Scholar 

  30. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56.

    Article  PubMed  Google Scholar 

  31. Capoulade R, Chan KL, Yeang C, et al. Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis. J Am Coll Cardiol. 2015;66:1236–46.

    Article  CAS  PubMed  Google Scholar 

  32. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437:270–4.

    Article  CAS  PubMed  Google Scholar 

  33. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation. 2005;111:920–5.

    Article  PubMed  Google Scholar 

  34. Lee TC, Zhao YD, Courtman DW, Stewart DJ. Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase. Circulation. 2000;101:2345–8.

    Article  CAS  PubMed  Google Scholar 

  35. Lazaros G, Toutouzas K, Drakopoulou M, Boudoulas H, Stefanadis C, Rajamannan N. Aortic sclerosis and mitral annulus calcification: a window to vascular atherosclerosis? Expert Rev Cardiovasc Ther. 2013;11:863–77.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Aikawa E, Whittaker P, Farber M, et al. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation. 2006;113:1344–52.

    Article  PubMed  Google Scholar 

  39. Davies PF, Passerini AG, Simmons CA. Aortic valve: turning over a new leaf(let) in endothelial phenotypic heterogeneity. Arterioscler Thromb Vasc Biol. 2004;24:1331–3.

    Article  CAS  PubMed  Google Scholar 

  40. Simmons CA, Grant GR, Manduchi E, Davies PF. Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circ Res. 2005;96:792–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xing Y, Warnock JN, He Z, Hilbert SL, Yoganathan AP. Cyclic pressure affects the biological properties of porcine aortic valve leaflets in a magnitude and frequency dependent manner. Ann Biomed Eng. 2004;32:1461–70.

    Article  PubMed  Google Scholar 

  42. 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. 2009;296:H756–64.

    CAS  Google Scholar 

  43. Demer LL. Cholesterol in vascular and valvular calcification. Circulation. 2001;104:1881–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Olsson M, Thyberg J, Nilsson J. Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. Arterioscler Thromb Vasc Biol. 1999;19:1218–22.

    Article  CAS  PubMed  Google Scholar 

  45. Goldstein JL, Brown MS. Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci U S A. 1973;70:2804–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sprecher DL, Schaefer EJ, Kent KM, et al. Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients. Am J Cardiol. 1984;54:20–30.

    Article  CAS  PubMed  Google Scholar 

  47. Kawaguchi A, Miyatake K, Yutani C, et al. Characteristic cardiovascular manifestation in homozygous and heterozygous familial hypercholesterolemia. Am Heart J. 1999;137:410–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  49. O’Brien KD, Shavelle DM, Caulfield MT, et al. Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma. Circulation. 2002;106:2224–30.

    Article  PubMed  Google Scholar 

  50. Shavelle DM, Takasu J, Budoff MJ, Mao S, Zhao XQ, O’Brien KD. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet. 2002;359:1125–6.

    Article  CAS  PubMed  Google Scholar 

  51. Rajamannan NM, Subramaniam M, Stock SR, et al. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart. 2005;91:806–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fukai T, Galis ZS, Meng XP, Parthasarathy S, Harrison DG. Vascular expression of extracellular superoxide dismutase in atherosclerosis. J Clin Invest. 1998;101:2101–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Miller JD, Chu Y, Brooks RM, Richenbacher WE, Pena-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;52:843–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Weiss RM, Ohashi M, Miller JD, Young SG, Heistad DD. Calcific aortic valve stenosis in old hypercholesterolemic mice. Circulation. 2006;114:2065–9.

    Article  PubMed  Google Scholar 

  55. Chen JH, Yip CY, Sone ED, Simmons CA. Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. Am J Pathol. 2009;174:1109–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tanaka K, Sata M, Fukuda D, et al. Age-associated aortic stenosis in apolipoprotein E-deficient mice. J Am Coll Cardiol. 2005;46:134–41.

    Article  CAS  PubMed  Google Scholar 

  57. Paranya G, Vineberg S, Dvorin E, 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;159:1335–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Antonini-Canterin F, Hirsu M, Popescu BA, et al. Stage-related effect of statin treatment on the progression of aortic valve sclerosis and stenosis. Am J Cardiol. 2008;102:738–42.

    Article  CAS  PubMed  Google Scholar 

  59. Sciaudone M, Gazzerro E, Priest L, Delany AM, Canalis E. Notch 1 impairs osteoblastic cell differentiation. Endocrinology. 2003;144:5631–9.

    Article  CAS  PubMed  Google Scholar 

  60. Deregowski V, Gazzerro E, Priest L, Rydziel S, Canalis E. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling. J Biol Chem. 2006;281:6203–10.

    Article  CAS  PubMed  Google Scholar 

  61. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation. 2005;112:I229–34.

    PubMed  PubMed Central  Google Scholar 

  62. Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005;115:1210–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rajamannan NM, Helgeson SC, Johnson CM. Anionic growth factor activity from cardiac valve endothelial cells: partial purification and characterization. Clin Res 1988:309A.

    Google Scholar 

  64. Johnson CM, Hanson MN, Helgeson SC. Porcine cardiac valvular subendothelial cells in culture: cell isolation and growth characteristics. J Mol Cell Cardiol. 1987;19:1185–93.

    Article  CAS  PubMed  Google Scholar 

  65. Mohler ER 3rd, Chawla MK, Chang AW, et al. Identification and characterization of calcifying valve cells from human and canine aortic valves. J Heart Valve Dis. 1999;8:254–60.

    PubMed  Google Scholar 

  66. Osman L, Yacoub MH, Latif N, Amrani M, Chester AH. Role of human valve interstitial cells in valve calcification and their response to atorvastatin. Circulation. 2006;114:I547–52.

    Article  PubMed  Google Scholar 

  67. Johnson CM, Helgeson SC. Glycoproteins synthesized by cultured cardiac valve endothelial cells: unique absence of fibronectin production. Biochem Biophys Res Commun. 1988;153:46–50.

    Article  CAS  PubMed  Google Scholar 

  68. Wada T, McKee MD, Steitz S, Giachelli CM. Calcification of vascular smooth muscle cell cultures: inhibition by osteopontin. Circ Res. 1999;84:166–78.

    Article  CAS  PubMed  Google Scholar 

  69. Kirton JP, Crofts NJ, George SJ, Brennan K, Canfield AE. Wnt/beta-catenin signaling stimulates chondrogenic and inhibits adipogenic differentiation of pericytes: potential relevance to vascular disease? Circ Res. 2007;101:581–9.

    Article  CAS  PubMed  Google Scholar 

  70. Hurlstone AF, Haramis AP, Wienholds E, et al. The Wnt/beta-catenin pathway regulates cardiac valve formation. Nature. 2003;425:633–7.

    Article  CAS  PubMed  Google Scholar 

  71. Caira FC, Stock SR, Gleason TG, 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;47:1707–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Paruchuri S, Yang JH, Aikawa E, et al. Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-A and transforming growth factor-beta2. Circ Res. 2006;99:861–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rajamannan NM. Atorvastatin attenuates bone loss and aortic valve atheroma in LDLR mice. Cardiology. 2015;132:11–5.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Makkena B, Salti H, Subramaniam M, et al. Atorvastatin decreases cellular proliferation and bone matrix expression in the hypercholesterolemic mitral valve. J Am Coll Cardiol. 2005;45:631–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rajamannan NM, Subramaniam M, Springett M, et al. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation. 2002;105:2260–5.

    Article  Google Scholar 

  77. Rajamannan NM. Mechanisms of aortic valve calcification: the LDL-density-radius theory: a translation from cell signaling to physiology. Am J Physiol. 2010;298:H5–15.

    CAS  Google Scholar 

  78. Aikawa E, Nahrendorf M, Sosnovik D, et al. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation. 2007;115:377–86.

    Article  CAS  PubMed  Google Scholar 

  79. Miller JD, Weiss RM, Serrano KM, et al. Lowering plasma cholesterol levels halts progression of aortic valve disease in mice. Circulation. 2009;119:2693–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Newby DE, Cowell SJ, Boon NA. Emerging medical treatments for aortic stenosis: statins, angiotensin converting enzyme inhibitors, or both? Heart. 2006;92:729–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rajamannan NM, Moura L. The lipid hypothesis in calcific aortic valve disease: the role of the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2016;36:774–6.

    Article  CAS  PubMed  Google Scholar 

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  1. Most Sacred Heart of Jesus Cardiology and Valvular Institute, Sheboygan, Wisconsin, USA

    Nalini M. Rajamannan

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Rajamannan, N.M. (2018). Osteocardiology: Calcific Aortic Valve Disease. In: Osteocardiology. Springer, Cham. https://doi.org/10.1007/978-3-319-64994-8_3

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