Skip to main content
SpringerLink
Log in
Book cover

Surgical Management of Aortic Pathology pp 591–608Cite as

Diagnostic and Therapeutic Targets for Aortic Valve and Ascending Aorta Pathologies: Challenges and Opportunities

  • Chapter
  • First Online:

  • 1663 Accesses

Abstract

This chapter will provide an overview of the rapidly evolving field of diagnostic and therapeutic tools for aortic valve and ascending aortic pathologies, with main emphasis on novel insights into calcific aortic valve disease (CAVD). We will explore the mechanisms associated with the progression of the disease and the challenges and opportunities of targeting early asymptomatic stages. We will then discuss recent insights into the diagnostic tools to evaluate bicuspid aortic valve syndrome, from genetic predisposition to novel microstructural and proteomic approaches. Finally, we will present recent data on ascending aortic disease and highlight some of the established and novel targets, ranging from changes into flow dynamic measurements to circulating and structural biomarkers.

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   189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   249.99
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. Yutzey KE, et al. Calcific aortic valve disease: a consensus summary from the alliance of investigators on calcific aortic valve disease. Arterioscler Thromb Vasc Biol. 2014;34:2387–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Di Eusanio M, et al. Aortic valve replacement: results and predictors of mortality from a contemporary series of 2256 patients. J Thorac Cardiovasc Surg. 2011;141:940–7.

    Article  PubMed  Google Scholar 

  3. Kurtz CE, Otto CM. Aortic stenosis: clinical aspects of diagnosis and management, with 10 illustrative case reports from a 25-year experience. Medicine (Baltimore). 2010;89:349–79.

    Article  Google Scholar 

  4. Iung B, et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease. Eur Heart J. 2003;24:1231–43.

    Article  PubMed  Google Scholar 

  5. Otto CM. Calcific aortic valve disease: new concepts. Semin Thorac Cardiovasc Surg. 2010;22:276–84.

    Article  PubMed  Google Scholar 

  6. Rajamannan NM, Bonow RO, Rahimtoola SH. Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med. 2007;4:254–62.

    Article  CAS  PubMed  Google Scholar 

  7. Rajamannan NM. Calcific aortic stenosis: a disease ready for prime time. Circulation. 2006;114:2007–9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mookadam F, Jalal U, Wilansky S. Aortic valve disease: preventable or inevitable? Futur Cardiol. 2010;6:777–83.

    Article  Google Scholar 

  9. Nishimura RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:e521–643.

    PubMed  Google Scholar 

  10. 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;129:2440–92.

    Article  PubMed  Google Scholar 

  11. Miller JD, Weiss RM, Heistad DD. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ Res. 2011;108:1392–412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Beckmann E, Grau JB, Sainger R, Poggio P, Ferrari G. Insights into the use of biomarkers in calcific aortic valve disease. J Heart Valve Dis. 2010;19:441–52.

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Akerström F, Barderas MG, Rodríguez-Padial L. Aortic stenosis: a general overview of clinical, pathophysiological and therapeutic aspects. Expert Rev Cardiovasc Ther. 2013;11:239–50.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  18. El-Hamamsy I, Chester AH, Yacoub MH. Cellular regulation of the structure and function of aortic valves. J Adv Res. 2010;1:5–12.

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  20. 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;124:1783–91.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hakuno D, Kimura N, Yoshioka M, Fukuda K. Molecular mechanisms underlying the onset of degenerative aortic valve disease. J Mol Med. 2009;87:17–24.

    Article  CAS  PubMed  Google Scholar 

  22. Mathieu P, Boulanger MC. Basic mechanisms of calcific aortic valve disease. Can J Cardiol. 2014;30:982–93.

    Article  PubMed  Google Scholar 

  23. Mathieu P, Boulanger MC, Bouchareb R. Molecular biology of calcific aortic valve disease: towards new pharmacological therapies. Expert Rev Cardiovasc Ther. 2014;12:851–62.

    Article  CAS  PubMed  Google Scholar 

  24. Young EW, Simmons CA. Macro- and microscale fluid flow systems for endothelial cell biology. Lab Chip. 2010;10:143–60.

    Article  CAS  PubMed  Google Scholar 

  25. Gould ST, Srigunapalan S, Simmons CA, Anseth KS. Hemodynamic and cellular response feedback in calcific aortic valve disease. Circ Res. 2013;113:186–97.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  27. 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. 2010;159:1335–43.

    Article  Google Scholar 

  28. Holliday CJ, Ankeny RF, Jo H, Nerem RM. Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells. Am J Physiol Heart Circ Physiol. 2011;301:856–67.

    Article  CAS  Google Scholar 

  29. Iyengar AK, Sugimoto H, Smith DB, Sacks MS. Dynamic in vitro quantification of bioprosthetic heart valve leaflet motion using structured light projection. Ann Biomed Eng. 2001;29:963–73.

    Article  PubMed  Google Scholar 

  30. Aggarwal A, et al. Architectural trends in the human normal and bicuspid aortic valve leaflet and its relevance to valve disease. Ann Biomed Eng. 2014;42:986–98.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Capoulade R, et al. Impact of plasma Lp-PLA2 activity on the progression of aortic stenosis: the PROGRESSA study. JACC Cardiovasc Imaging. 2014;8:26–33.

    Article  PubMed  Google Scholar 

  32. Branchetti E, et al. Antioxidant enzymes reduce DNA damage and early activation of valvular interstitial cells in aortic valve sclerosis. Arterioscler Thromb Vasc Biol. 2012;33:66–74.

    Google Scholar 

  33. Butcher JT, Nerem RM. Porcine aortic valve interstitial cells in three-dimensional culture: comparison of phenotype with aortic smooth muscle cells. J Heart Valve Dis. 2004;13:478–85.

    PubMed  Google Scholar 

  34. 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;108:1510–24.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Shavelle DM. Calcific aortic valve disease: imaging studies and therapeutic interventions. J Investig Med. 2007;55:292–8.

    Article  PubMed  Google Scholar 

  37. Gharacholou SM, Karon BL, Shub C, Pellikka PA. Aortic valve sclerosis and clinical outcomes: moving toward a definition. Am J Med. 2011;124:103–10.

    Article  PubMed  Google Scholar 

  38. Le Ven F, et al. Valve tissue characterization by magnetic resonance imaging in calcific aortic valve disease. Can J Cardiol. 2014;30:1676–83.

    Article  PubMed  Google Scholar 

  39. 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 

  40. Owens DS, Otto CM. Is it time for a new paradigm in calcific aortic valve disease? JACC Cardiovasc Imaging. 2009;2:928–30.

    Article  PubMed  Google Scholar 

  41. Rajamannan NM. Mechanisms of aortic valve calcification: the LDL-density-radius theory: a translation from cell signaling to physiology. Am J Physiol Heart Circ Physiol. 2010;298:5–15.

    Article  CAS  Google Scholar 

  42. Poggio P, et al. Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis. Cardiovasc Res. 2013;98:402–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Poggio P, et al. Osteopontin-CD44v6 interaction mediates calcium deposition via phospho-akt in valve interstitial cells from patients with noncalcified aortic valve sclerosis. Arterioscler Thromb Vasc Biol. 2014;34:2086–94.

    Article  CAS  PubMed  Google Scholar 

  44. Grau JB, et al. Analysis of osteopontin levels for the identification of asymptomatic patients with calcific aortic valve disease. Ann Thorac Surg. 2012;93:79–86.

    Article  PubMed  Google Scholar 

  45. Hamilton AM, Boughner DR, Drangova M, Rogers KA. Statin treatment of hypercholesterolemic-induced aortic valve sclerosis. Cardiovasc Pathol. 2011;20:84–92.

    Article  CAS  PubMed  Google Scholar 

  46. Sainger R, et al. Comparison of transesophageal echocardiographic analysis and circulating biomarker expression profile in calcific aortic valve disease. J Heart Valve Dis. 2013;22:156–65.

    PubMed  PubMed Central  Google Scholar 

  47. Shao ES, Lin L, Yao Y, Boström KI. Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood. 2009;114:2197–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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 

  49. Wang W, Vootukuri S, Meyer A, Ahamed J, Coller BS. Association between shear stress and platelet-derived transforming growth factor-β1 release and activation in animal models of aortic valve stenosis. Arterioscler Thromb Vasc Biol. 2014;34:1924–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bernheim AM, Connolly HM, Hobday TJ, Abel MD, Pellikka PA. Carcinoid heart disease. Prog Cardiovasc Dis. 2007;49:439–51.

    Article  PubMed  Google Scholar 

  51. Bhattacharyya S, Schapira AH, Mikhailidis DP, Davar J. Drug-induced fibrotic valvular heart disease. Lancet. 2009;374:577–85.

    Article  CAS  PubMed  Google Scholar 

  52. Elangbam CS. Drug-induced valvulopathy: an update. Toxicol Pathol. 2010;38:837–48.

    Article  CAS  PubMed  Google Scholar 

  53. Elangbam CS, et al. 5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats. Exp Toxicol Pathol. 2008;60:253–62.

    Article  PubMed  Google Scholar 

  54. Hajjo R, et al. Development, validation, and use of quantitative structure-activity relationship models of 5-hydroxytryptamine (2B) receptor ligands to identify novel receptor binders and putative valvulopathic compounds among common drugs. J Med Chem. 2010;53:7573–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Huang XP, et al. Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment. Mol Pharmacol. 2009;76:710–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hutcheson JD, Setola V, Roth BL, Merryman WD. Serotonin receptors and heart valve disease—It was meant 2B. Pharmacol Ther. 2011;132:146–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Roth BL. Drugs and valvular heart disease. N Engl J Med. 2007;356:6–9.

    Article  CAS  PubMed  Google Scholar 

  58. Baumann MH, Rothman RB. Neural and cardiac toxicities associated with 3,4-methylenedioxymethamphetamine (MDMA). Int Rev Neurobiol. 2009;88:257–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rothman RB. Anorexogen-related cardiac valvulopathy. Ann Intern Med. 2002;136:779.

    Article  PubMed  Google Scholar 

  60. Rothman RB, Baumann MH. Therapeutic and adverse actions of serotonin transporter substrates. Pharmacol Ther. 2002;95:73–88.

    Article  CAS  PubMed  Google Scholar 

  61. Rothman RB, Baumann MH. Appetite suppressants, cardiac valve disease and combination pharmacotherapy. Am J Ther. 2009;16:354–64.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Rothman RB, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102:2836–41.

    Article  CAS  PubMed  Google Scholar 

  63. Rothman RB, et al. Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin. Am J Cardiol. 2000;85:913–5.

    Article  CAS  PubMed  Google Scholar 

  64. Setola V, Dukat M, Glennon RA, Roth BL. Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor. Mol Pharmacol. 2005;68:20–33.

    CAS  PubMed  Google Scholar 

  65. Setola V, et al. 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol. 2003;63:1223–9.

    Article  CAS  PubMed  Google Scholar 

  66. Setola V, Roth BL. Screening the receptorome reveals molecular targets responsible for drug-induced side effects: focus on ‘fen-phen’. Expert Opin Drug Metab Toxicol. 2005;1:377–87.

    Article  CAS  PubMed  Google Scholar 

  67. Elangbam CS, et al. 5-Hydroxytryptamine (5HT) receptors in the heart valves of cynomolgus monkeys and Sprague-Dawley rats. J Histochem Cytochem. 2005;53:671–7.

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111:3316–26.

    Article  PubMed  Google Scholar 

  70. Parolari A, et al. Do statins improve outcomes and delay the progression of non-rheumatic calcific aortic stenosis? Heart. 2011;97:523–9.

    Article  CAS  PubMed  Google Scholar 

  71. Novo G, Fazio G, Visconti C, Carità P, Maira E, Fattouch K, Novo S. Atherosclerosis, degenerative aortic stenosis and statins. Curr Drug Targets. 2011;12:115–21.

    Article  CAS  PubMed  Google Scholar 

  72. Moura LM, 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 

  73. Cowell SJ, 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 

  74. Benton JA, Kern HB, Leinwand LA, Mariner PD, Anseth KS. Statins block calcific nodule formation of valvular interstitial cells by inhibiting alpha-smooth muscle actin expression. Arterioscler Thromb Vasc Biol. 2009;29:1950–7.

    Article  CAS  PubMed  Google Scholar 

  75. Rossebø AB, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56.

    Article  PubMed  Google Scholar 

  76. Thanassoulis G, 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 

  77. Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol. 2010;55:2789–800.

    Article  PubMed  Google Scholar 

  78. Friedman T, Mani A, Elefteriades JA. Bicuspid aortic valve: clinical approach and scientific review of a common clinical entity. Expert Rev Cardiovasc Ther. 2008;6:235–48.

    Article  PubMed  Google Scholar 

  79. Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. Bicuspid aortic valve is heritable. J Am Coll Cardiol. 2004;44:138–43.

    Article  PubMed  Google Scholar 

  80. Hiratzka LF, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease. J Am Coll Cardiol. 2010;5:27–129.

    Article  Google Scholar 

  81. Evangelista A. Bicuspid aortic valve and aortic root disease. Curr Cardiol Rep. 2011;13:234–41.

    Article  PubMed  Google Scholar 

  82. Garg V. Molecular genetics of aortic valve disease. Curr Opin Cardiol. 2006;21:180–4.

    Article  PubMed  Google Scholar 

  83. Aggarwal A, et al. Patient-specific modeling of heart valves: from image to simulation. New York: Springer; 2013. p. 141–9.

    Google Scholar 

  84. Nistri S, Basso C, Marzari C, Mormino P, Thiene G. Frequency of bicuspid aortic valve in young male conscripts by echocardiogram. Am J Cardiol. 2005;96:718–21.

    Article  PubMed  Google Scholar 

  85. Branchetti E, et al. Circulating soluble receptor for advanced glycation end product identifies patients with bicuspid aortic valve and associated aortopathies. Arterioscler Thromb Vasc Biol. 2014;34:2349–57.

    Article  CAS  PubMed  Google Scholar 

  86. Yang SJ, et al. Association between sRAGE, esRAGE levels and vascular inflammation: analysis with 18F-fluorodeoxyglucose positron emission tomography. Atherosclerosis. 2012;220:402–6.

    Article  CAS  PubMed  Google Scholar 

  87. Barlovic DP, Thomas MC, Jandeleit-Dahm K. Cardiovascular disease: what’s all the AGE/RAGE about? Cardiovasc Hematol Disord Drug Targets. 2010;10:7–15.

    Article  CAS  PubMed  Google Scholar 

  88. Barlovic DP, Soro-Paavonen A, Jandeleit-Dahm KA. RAGE biology, atherosclerosis and diabetes. Clin Sci. 2011;121:43–55.

    Article  CAS  PubMed  Google Scholar 

  89. Cecconi M, et al. Aortic dilatation in patients with bicuspid aortic valve. J Cardiovasc Med (Hagerstown). 2006;7:11–20.

    Article  Google Scholar 

  90. Davies RR, et al. Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve. Ann Thorac Surg. 2007;83:1338–44.

    Article  PubMed  Google Scholar 

  91. Michelena HI, et al. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation. 2008;117:2776–84.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Elefteriades JA. Natural history of thoracic aortic aneurysms: indications for surgery, and surgical versus nonsurgical risks. Ann Thorac Surg. 2002;74:S1877–80.

    Article  PubMed  Google Scholar 

  93. Inamoto S, et al. TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. Cardiovasc Res. 2010;88:520–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Nathan DP, et al. Increased ascending aortic wall stress in patients with bicuspid aortic valves. Ann Thorac Surg. 2011;92:1384–9.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Cordes KR, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460:705–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Hope MD, et al. Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns. Radiology. 2010;255:53–6.

    Article  PubMed  Google Scholar 

  97. Bauer M, Siniawski H, Pasic M, Schaumann B, Hetzer R. Different hemodynamic stress of the ascending aorta wall in patients with bicuspid and tricuspid aortic valve. J Card Surg. 2006;21:218–20.

    Article  PubMed  Google Scholar 

  98. Tadros TM, Klein MD, Shapira OM. Ascending aortic dilatation associated with bicuspid aortic valve: pathophysiology, molecular biology, and clinical implications. Circulation. 2009;119:880–90.

    Article  PubMed  Google Scholar 

  99. Torell D, et al. MicroRNA-133 controls vascular smooth muscle cell phenotypic switch in vitro and vascular remodeling in vivo. Circ Res. 2011;109:880–93.

    Article  CAS  Google Scholar 

  100. Parmacek MS. Myocardin-related transcription factor-A: mending a broken heart. Circ Res. 2010;107:168–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Corte Della A, et al. Spatiotemporal patterns of smooth muscle cell changes in ascending aortic dilatation with bicuspid and tricuspid aortic valve stenosis: focus on cell-matrix signaling. J Thorac Cardiovasc Surg. 2008;135:8–18.

    Article  CAS  Google Scholar 

  102. Xin M, et al. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev. 2009;23:2166–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nataatmadja M, et al. Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm. Circulation. 2003;108:S329–34.

    Article  Google Scholar 

  104. Nathan DP, et al. Pathogenesis of acute aortic dissection: a finite element stress analysis. Ann Thorac Surg. 2011;91:458–63.

    Article  PubMed  Google Scholar 

  105. Branchetti E, et al. Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm. Cardiovasc Res. 2013;100:316–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Rangrez AY, Massy ZA, Metzinger-Le Meuth V, Metzinger L. miR-143 and miR-145: molecular keys to switch the phenotype of vascular smooth muscle cells. Circ Cardiovasc Genet. 2011;4:197–205.

    Article  CAS  PubMed  Google Scholar 

  107. LeMaire SA, et al. Matrix metalloproteinases in ascending aortic aneurysms: bicuspid versus trileaflet aortic valves. J Surg Res. 2005;123:40–8.

    Article  CAS  PubMed  Google Scholar 

  108. Kang H, Hata A. MicroRNA regulation of smooth muscle gene expression and phenotype. Curr Opin Hematol. 2012;19:224–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Cotrufo M, et al. Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results. J Thorac Cardiovasc Surg. 2005;130:504–11.

    Article  CAS  PubMed  Google Scholar 

  110. Davis-Dusenbery BN, et al. Down-regulation of Kruppel-like factor-4 (KLF4) by MicroRNA-143/145 Is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor- and bone morphogenetic protein. J Biol Chem. 2011;286:28097–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Fedak PW, et al. Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation. J Thorac Cardiovasc Surg. 2003;126:797–806.

    Article  PubMed  Google Scholar 

  112. Parish LM, et al. Aortic size in acute type A dissection: implications for preventive ascending aortic replacement. Eur J Cardiothorac Surg. 2009;35:941–6.

    Article  PubMed  Google Scholar 

  113. Das D, et al. S100A12 expression in thoracic aortic aneurysm is associated with increased risk of dissection and perioperative complications. J Am Coll Cardiol. 2012;60:775–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lewin MB, Otto CM. The bicuspid aortic valve: adverse outcomes from infancy to old age. Circulation. 2005;111:832–4.

    Article  PubMed  Google Scholar 

  115. Jondeau G, Boileau C. Genetics of thoracic aortic aneurysms. Curr Atheroscler Rep. 2012;14:219–26.

    Article  CAS  PubMed  Google Scholar 

  116. Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature. 2011;473:308–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. LeMaire SA, et al. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat Genet. 2011;43:996–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Holmes KW, et al. GenTAC registry report: gender differences among individuals with genetically triggered thoracic aortic aneurysm and dissection. Am J Med Genet. 2013;161A:779–86.

    Article  PubMed  Google Scholar 

  119. Hagan PG, et al. The international registry of acute aortic dissection (IRAD): new insights into an old disease. JAMA. 2000;283:897–903.

    Article  CAS  PubMed  Google Scholar 

  120. Albornoz G, et al. Familial Thoracic aortic aneurysms and dissections—incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg. 2006;82:1400–5.

    Article  PubMed  Google Scholar 

  121. Achneck H. Ascending thoracic aneurysms are associated with decreased systemic atherosclerosis. Chest. 2005;128:1580–6.

    Article  PubMed  Google Scholar 

  122. Cohn LH, et al. Reduced mortality and morbidity for ascending aortic aneurysm resection regardless of cause. Ann Thorac Surg. 1996;62:463–8.

    Article  CAS  PubMed  Google Scholar 

  123. Trimarchi S, et al. Contemporary results of surgery in acute type A aortic dissection: the international registry of acute aortic dissection experience. J Thorac Cardiovasc Surg. 2005;129:112–22.

    Article  PubMed  Google Scholar 

  124. Fann JI, et al. Surgical management of aortic dissection during a 30-year period. Circulation. 1995;92:I113–21.

    Article  Google Scholar 

  125. Stevens LM, et al. Surgical management and long-term outcomes for acute ascending aortic dissection. J Thorac Cardiovasc Surg. 2009;138:1349–57.

    Article  PubMed  Google Scholar 

  126. Liberman M, et al. Oxidant generation predominates around calcifying foci and enhances progression of aortic valve calcification. Arterioscler Thromb Vasc Biol. 2008;28:463–70.

    Article  CAS  PubMed  Google Scholar 

  127. Gaudino M, et al. Aortic expansion rate in patients with dilated post-stenotic ascending aorta submitted only to aortic valve replacement. J Am Coll Cardiol. 2011;58:581–4.

    Article  PubMed  Google Scholar 

  128. LeMaire SA, Russell L. Epidemiology of thoracic aortic dissection. Nat Rev Cardiol. 2010;8:103–13.

    Article  PubMed  Google Scholar 

  129. Rajamannan NM. Bicuspid aortic valve disease: the role of oxidative stress in Lrp5 bone formation. Cardiovasc Pathol. 2011;20:168–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Phillippi JA, et al. Basal and oxidative stress-induced expression of metallothionein is decreased in ascending aortic aneurysms of bicuspid aortic valve patients. Circulation. 2009;119:2498–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Phillippi JA, Eskay MA, Kubala AA, Pitt BR, Gleason TG. Altered oxidative stress responses and increased type I collagen expression in bicuspid aortic valve patients. Ann Thorac Surg. 2010;90:1893–8.

    Article  PubMed  Google Scholar 

  132. Mueller GC, et al. Retrospective analysis of the effect of angiotensin II receptor blocker versus β-blocker on aortic root growth in paediatric patients with Marfan syndrome. Heart. 2014;100:214–8.

    Article  PubMed  Google Scholar 

  133. Phomakay V, et al. β-Blockers and angiotensin converting enzyme inhibitors: comparison of effects on aortic growth in pediatric patients with Marfan syndrome. J Pediatr. 2014;165:951–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Brooke BS, et al. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med. 2008;358:2787–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Heinemann M, Laas J, Jurmann M, Karck M, Borst HG. Surgery extended into the aortic arch in acute type A dissection. Indications, techniques, and results. Circulation. 1991;84:III25–30.

    CAS  PubMed  Google Scholar 

  136. Parolari A, et al. Biological features of thoracic aortic diseases. Where are we now, where are we heading to: established and emerging biomarkers and molecular pathways. Eur J Cardiothorac Surg. 2013;44:9–32.

    Article  PubMed  Google Scholar 

  137. Ikonomidis JS, et al. Aortic dilatation with bicuspid aortic valves: cusp fusion correlates to matrix metalloproteinases and inhibitors. Ann Thorac Surg. 2012;93:457–63.

    Article  PubMed  Google Scholar 

  138. Theruvath TP, Jones JA, Ikonomidis JS. Matrix metalloproteinases and descending aortic aneurysms: parity, disparity, and switch. J Card Surg. 2012;27:81–90.

    Article  PubMed  Google Scholar 

  139. Ikonomidis JS, et al. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome. Circulation. 2006;114:I365–70.

    Article  PubMed  CAS  Google Scholar 

  140. Ikonomidis JS, et al. Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg. 2013;145:1326–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ikonomidis JS, et al. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with bicuspid or tricuspid aortic valves. J Thorac Cardiovasc Surg. 2007;133:1028–36.

    Article  CAS  PubMed  Google Scholar 

  142. Ejiri J, et al. Oxidative stress in the pathogenesis of thoracic aortic aneurysm: protective role of statin and angiotensin II type 1 receptor blocker. Cardiovasc Res. 2003;59:988–96.

    Article  CAS  PubMed  Google Scholar 

  143. Laiho M, Saksela O, Andreasen PA, Keski-Oja J. Enhanced production and extracellular deposition of the endothelial-type plasminogen activator inhibitor in cultured human lung fibroblasts by transforming growth factor-beta. J Cell Biol. 1986;103:2403–10.

    Article  CAS  PubMed  Google Scholar 

  144. Laiho M, Saksela O, Keski-Oja J. Transforming growth factor beta alters plasminogen activator activity in human skin fibroblasts. Exp Cell Res. 1986;164:399–407.

    Article  CAS  PubMed  Google Scholar 

  145. Sakakura K, et al. Peak C-reactive protein level predicts long-term outcomes in type B acute aortic dissection. Hypertension. 2010;55:422–9.

    Article  CAS  PubMed  Google Scholar 

  146. Wen D, Du X, Dong JZ, Zhou XL, Ma CS. Value of D-dimer and C reactive protein in predicting inhospital death in acute aortic dissection. Heart. 2013;99:1192–7.

    Article  CAS  PubMed  Google Scholar 

  147. Eggebrecht H, et al. Value of plasma fibrin D-dimers for detection of acute aortic dissection. J Am Coll Cardiol. 2004;44:804–9.

    Article  CAS  PubMed  Google Scholar 

  148. Makita S, et al. Behavior of C-reactive protein levels in medically treated aortic dissection and intramural hematoma. Am J Cardiol. 2000;86:242–4.

    Article  CAS  PubMed  Google Scholar 

  149. Wen D, et al. Plasma concentrations of interleukin-6, C-reactive protein, tumor necrosis factor-α and matrix metalloproteinase-9 in aortic dissection. Clin Chim Acta. 2012;413:198–202.

    Article  CAS  PubMed  Google Scholar 

  150. Ihara A, et al. Relationship between hemostatic markers and platelet indices in patients with aortic aneurysm. Pathophysiol Haemost Thromb. 2006;35:451–6.

    Article  PubMed  Google Scholar 

  151. del Porto F, et al. Inflammation and immune response in acute aortic dissection. Ann Med. 2010;42:622–9.

    Article  PubMed  CAS  Google Scholar 

  152. Wang Y, et al. Gene expression signature in peripheral blood detects thoracic aortic aneurysm. PLoS One. 2007;2:e1050.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Quintavall M, Elia L, Condorelli G, Courtneidge SA. MicroRNA control of podosome formation in vascular smooth muscle cells in vivo and in vitro. J Cell Biol. 2010;189:13–22.

    Article  CAS  Google Scholar 

  154. Jones JA, et al. Selective microRNA suppression in human thoracic aneurysms: relationship of miR-29a to aortic size and proteolytic induction. Circu Cardiovasc Genet. 2011;4:605–13.

    Article  CAS  Google Scholar 

  155. Pei H, et al. Overexpression of microRNA-145 promotes ascending aortic aneurysm media remodeling through TGF. Eur J Vasc Endovasc Surg. 2015;49:52–6.

    Article  CAS  PubMed  Google Scholar 

  156. Maegdefessel L, et al. Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J Clin Invest. 2012;122:497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Boon RA, et al. MicroRNA-29 in aortic dilation: implications for aneurysm formation. Circ Res. 2011;109:1115–9.

    Article  CAS  PubMed  Google Scholar 

  158. Barker AJ, Markl M. The role of hemodynamics in bicuspid aortic valve disease. Eur J Cardiothorac Surg. 2011;39:805–6.

    Article  PubMed  Google Scholar 

  159. Viscardi F, et al. Comparative finite element model analysis of ascending aortic flow in bicuspid and tricuspid aortic valve. Artif Organs. 2010;34:1114–20.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

    Giovanni Ferrari

  2. Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, ON, Canada

    Juan B. Grau

Authors
  1. Giovanni Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan B. Grau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan B. Grau .

Editor information

Editors and Affiliations

  1. Fmr Royal Brompton Hospital, London, UK

    Olaf H. Stanger

  2. Royal Brompton Hospital, London, UK

    John R. Pepper

  3. Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

    Lars G. Svensson

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer-Verlag GmbH Austria, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ferrari, G., Grau, J.B. (2019). Diagnostic and Therapeutic Targets for Aortic Valve and Ascending Aorta Pathologies: Challenges and Opportunities. In: Stanger, O., Pepper, J., Svensson, L. (eds) Surgical Management of Aortic Pathology. Springer, Vienna. https://doi.org/10.1007/978-3-7091-4874-7_41

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-4874-7_41

  • Published:

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-4872-3

  • Online ISBN: 978-3-7091-4874-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation