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

  • Giovanni Ferrari
  • Juan B. GrauEmail author


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.


Aortic valve Aortic valve replacement Bioprosthetic aortic valve Aortic valve stenosis Aortic valve sclerosis Thoracic aortic aneurysm Biomarkers 


  1. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Otto CM. Calcific aortic valve disease: new concepts. Semin Thorac Cardiovasc Surg. 2010;22:276–84.PubMedCrossRefGoogle Scholar
  6. 6.
    Rajamannan NM, Bonow RO, Rahimtoola SH. Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med. 2007;4:254–62.PubMedCrossRefGoogle Scholar
  7. 7.
    Rajamannan NM. Calcific aortic stenosis: a disease ready for prime time. Circulation. 2006;114:2007–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Mookadam F, Jalal U, Wilansky S. Aortic valve disease: preventable or inevitable? Futur Cardiol. 2010;6:777–83.CrossRefGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 11.
    Miller JD, Weiss RM, Heistad DD. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ Res. 2011;108:1392–412.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hutcheson JD, Aikawa E, Merryman WD. Potential drug targets for calcific aortic valve disease. Nat Rev Cardiol. 2014;11:218–31.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 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.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Towler DA. Molecular and cellular aspects of calcific aortic valve disease. Circ Res. 2013;113:198–208.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 16.
    Sacks MS, Smith DB, Hiester ED. The aortic valve microstructure: effects of transvalvular pressure. J Biomed Mater Res. 1998;41:131–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Merryman WD, et al. Differences in tissue-remodeling potential of aortic and pulmonary heart valve interstitial cells. Tissue Eng. 2007;13:2281–9.PubMedCrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 19.
    Yip CY, Simmons CA. The aortic valve microenvironment and its role in calcific aortic valve disease. Cardiovasc Pathol. 2011;20:177–82.PubMedCrossRefGoogle Scholar
  20. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Mathieu P, Boulanger MC. Basic mechanisms of calcific aortic valve disease. Can J Cardiol. 2014;30:982–93.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 24.
    Young EW, Simmons CA. Macro- and microscale fluid flow systems for endothelial cell biology. Lab Chip. 2010;10:143–60.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 26.
    Bischoff J, Aikawa E. Progenitor cells confer plasticity to cardiac valve endothelium. J Cardiovasc Transl Res. 2011;4:710–9.PubMedCrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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. 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.PubMedGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 36.
    Shavelle DM. Calcific aortic valve disease: imaging studies and therapeutic interventions. J Investig Med. 2007;55:292–8.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 40.
    Owens DS, Otto CM. Is it time for a new paradigm in calcific aortic valve disease? JACC Cardiovasc Imaging. 2009;2:928–30.PubMedCrossRefGoogle Scholar
  41. 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.CrossRefGoogle Scholar
  42. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 45.
    Hamilton AM, Boughner DR, Drangova M, Rogers KA. Statin treatment of hypercholesterolemic-induced aortic valve sclerosis. Cardiovasc Pathol. 2011;20:84–92.PubMedCrossRefGoogle Scholar
  46. 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.PubMedPubMedCentralGoogle Scholar
  47. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Weiss RM, Ohashi M, Miller JD, Young SG, Heistad DD. Calcific aortic valve stenosis in old hypercholesterolemic mice. Circulation. 2006;114:2065–9.PubMedCrossRefGoogle Scholar
  49. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Bernheim AM, Connolly HM, Hobday TJ, Abel MD, Pellikka PA. Carcinoid heart disease. Prog Cardiovasc Dis. 2007;49:439–51.PubMedCrossRefGoogle Scholar
  51. 51.
    Bhattacharyya S, Schapira AH, Mikhailidis DP, Davar J. Drug-induced fibrotic valvular heart disease. Lancet. 2009;374:577–85.PubMedCrossRefGoogle Scholar
  52. 52.
    Elangbam CS. Drug-induced valvulopathy: an update. Toxicol Pathol. 2010;38:837–48.PubMedCrossRefGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Roth BL. Drugs and valvular heart disease. N Engl J Med. 2007;356:6–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Baumann MH, Rothman RB. Neural and cardiac toxicities associated with 3,4-methylenedioxymethamphetamine (MDMA). Int Rev Neurobiol. 2009;88:257–96.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Rothman RB. Anorexogen-related cardiac valvulopathy. Ann Intern Med. 2002;136:779.PubMedCrossRefGoogle Scholar
  60. 60.
    Rothman RB, Baumann MH. Therapeutic and adverse actions of serotonin transporter substrates. Pharmacol Ther. 2002;95:73–88.PubMedCrossRefGoogle Scholar
  61. 61.
    Rothman RB, Baumann MH. Appetite suppressants, cardiac valve disease and combination pharmacotherapy. Am J Ther. 2009;16:354–64.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 63.
    Rothman RB, et al. Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin. Am J Cardiol. 2000;85:913–5.PubMedCrossRefGoogle Scholar
  64. 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.PubMedGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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.PubMedCrossRefGoogle Scholar
  68. 68.
    Rajamannan NM. Calcific aortic stenosis: lessons learned from experimental and clinical studies. Arterioscler Thromb Vasc Biol. 2009;29:162–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111:3316–26.PubMedCrossRefGoogle Scholar
  70. 70.
    Parolari A, et al. Do statins improve outcomes and delay the progression of non-rheumatic calcific aortic stenosis? Heart. 2011;97:523–9.PubMedCrossRefGoogle Scholar
  71. 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.PubMedCrossRefGoogle Scholar
  72. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedCrossRefGoogle Scholar
  75. 75.
    Rossebø AB, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56.PubMedCrossRefGoogle Scholar
  76. 76.
    Thanassoulis G, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368:503–12.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol. 2010;55:2789–800.PubMedCrossRefGoogle Scholar
  78. 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.PubMedCrossRefGoogle Scholar
  79. 79.
    Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. Bicuspid aortic valve is heritable. J Am Coll Cardiol. 2004;44:138–43.PubMedCrossRefGoogle Scholar
  80. 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.CrossRefGoogle Scholar
  81. 81.
    Evangelista A. Bicuspid aortic valve and aortic root disease. Curr Cardiol Rep. 2011;13:234–41.PubMedCrossRefGoogle Scholar
  82. 82.
    Garg V. Molecular genetics of aortic valve disease. Curr Opin Cardiol. 2006;21:180–4.PubMedCrossRefGoogle Scholar
  83. 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. 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.PubMedCrossRefGoogle Scholar
  85. 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.PubMedCrossRefGoogle Scholar
  86. 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.PubMedCrossRefGoogle Scholar
  87. 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.PubMedCrossRefGoogle Scholar
  88. 88.
    Barlovic DP, Soro-Paavonen A, Jandeleit-Dahm KA. RAGE biology, atherosclerosis and diabetes. Clin Sci. 2011;121:43–55.PubMedCrossRefGoogle Scholar
  89. 89.
    Cecconi M, et al. Aortic dilatation in patients with bicuspid aortic valve. J Cardiovasc Med (Hagerstown). 2006;7:11–20.CrossRefGoogle Scholar
  90. 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.PubMedCrossRefGoogle Scholar
  91. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Elefteriades JA. Natural history of thoracic aortic aneurysms: indications for surgery, and surgical versus nonsurgical risks. Ann Thorac Surg. 2002;74:S1877–80.PubMedCrossRefGoogle Scholar
  93. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Nathan DP, et al. Increased ascending aortic wall stress in patients with bicuspid aortic valves. Ann Thorac Surg. 2011;92:1384–9.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Cordes KR, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460:705–10.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Hope MD, et al. Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns. Radiology. 2010;255:53–6.PubMedCrossRefGoogle Scholar
  97. 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.PubMedCrossRefGoogle Scholar
  98. 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.PubMedCrossRefGoogle Scholar
  99. 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.CrossRefGoogle Scholar
  100. 100.
    Parmacek MS. Myocardin-related transcription factor-A: mending a broken heart. Circ Res. 2010;107:168–70.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 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.CrossRefGoogle Scholar
  102. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 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.CrossRefGoogle Scholar
  104. 104.
    Nathan DP, et al. Pathogenesis of acute aortic dissection: a finite element stress analysis. Ann Thorac Surg. 2011;91:458–63.PubMedCrossRefGoogle Scholar
  105. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 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.PubMedCrossRefGoogle Scholar
  107. 107.
    LeMaire SA, et al. Matrix metalloproteinases in ascending aortic aneurysms: bicuspid versus trileaflet aortic valves. J Surg Res. 2005;123:40–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Kang H, Hata A. MicroRNA regulation of smooth muscle gene expression and phenotype. Curr Opin Hematol. 2012;19:224–31.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 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.PubMedCrossRefGoogle Scholar
  110. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 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.PubMedCrossRefGoogle Scholar
  112. 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.PubMedCrossRefGoogle Scholar
  113. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Lewin MB, Otto CM. The bicuspid aortic valve: adverse outcomes from infancy to old age. Circulation. 2005;111:832–4.PubMedCrossRefGoogle Scholar
  115. 115.
    Jondeau G, Boileau C. Genetics of thoracic aortic aneurysms. Curr Atheroscler Rep. 2012;14:219–26.PubMedCrossRefGoogle Scholar
  116. 116.
    Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature. 2011;473:308–16.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 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.PubMedCrossRefGoogle Scholar
  119. 119.
    Hagan PG, et al. The international registry of acute aortic dissection (IRAD): new insights into an old disease. JAMA. 2000;283:897–903.PubMedCrossRefGoogle Scholar
  120. 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.PubMedCrossRefGoogle Scholar
  121. 121.
    Achneck H. Ascending thoracic aneurysms are associated with decreased systemic atherosclerosis. Chest. 2005;128:1580–6.PubMedCrossRefGoogle Scholar
  122. 122.
    Cohn LH, et al. Reduced mortality and morbidity for ascending aortic aneurysm resection regardless of cause. Ann Thorac Surg. 1996;62:463–8.PubMedCrossRefGoogle Scholar
  123. 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.PubMedCrossRefGoogle Scholar
  124. 124.
    Fann JI, et al. Surgical management of aortic dissection during a 30-year period. Circulation. 1995;92:I113–21.CrossRefGoogle Scholar
  125. 125.
    Stevens LM, et al. Surgical management and long-term outcomes for acute ascending aortic dissection. J Thorac Cardiovasc Surg. 2009;138:1349–57.PubMedCrossRefGoogle Scholar
  126. 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.PubMedCrossRefGoogle Scholar
  127. 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.PubMedCrossRefGoogle Scholar
  128. 128.
    LeMaire SA, Russell L. Epidemiology of thoracic aortic dissection. Nat Rev Cardiol. 2010;8:103–13.PubMedCrossRefGoogle Scholar
  129. 129.
    Rajamannan NM. Bicuspid aortic valve disease: the role of oxidative stress in Lrp5 bone formation. Cardiovasc Pathol. 2011;20:168–76.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 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.PubMedCrossRefGoogle Scholar
  132. 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.PubMedCrossRefGoogle Scholar
  133. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Brooke BS, et al. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med. 2008;358:2787–95.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 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.PubMedGoogle Scholar
  136. 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.PubMedCrossRefGoogle Scholar
  137. 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.PubMedCrossRefGoogle Scholar
  138. 138.
    Theruvath TP, Jones JA, Ikonomidis JS. Matrix metalloproteinases and descending aortic aneurysms: parity, disparity, and switch. J Card Surg. 2012;27:81–90.PubMedCrossRefGoogle Scholar
  139. 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.PubMedCrossRefGoogle Scholar
  140. 140.
    Ikonomidis JS, et al. Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg. 2013;145:1326–33.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 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.PubMedCrossRefGoogle Scholar
  142. 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.PubMedCrossRefGoogle Scholar
  143. 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.PubMedCrossRefGoogle Scholar
  144. 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.PubMedCrossRefGoogle Scholar
  145. 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.PubMedCrossRefGoogle Scholar
  146. 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.PubMedCrossRefGoogle Scholar
  147. 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.PubMedCrossRefGoogle Scholar
  148. 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.PubMedCrossRefGoogle Scholar
  149. 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.PubMedCrossRefGoogle Scholar
  150. 150.
    Ihara A, et al. Relationship between hemostatic markers and platelet indices in patients with aortic aneurysm. Pathophysiol Haemost Thromb. 2006;35:451–6.PubMedCrossRefGoogle Scholar
  151. 151.
    del Porto F, et al. Inflammation and immune response in acute aortic dissection. Ann Med. 2010;42:622–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Wang Y, et al. Gene expression signature in peripheral blood detects thoracic aortic aneurysm. PLoS One. 2007;2:e1050.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 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.CrossRefGoogle Scholar
  154. 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.CrossRefGoogle Scholar
  155. 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.PubMedCrossRefGoogle Scholar
  156. 156.
    Maegdefessel L, et al. Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J Clin Invest. 2012;122:497–506.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Boon RA, et al. MicroRNA-29 in aortic dilation: implications for aneurysm formation. Circ Res. 2011;109:1115–9.PubMedCrossRefGoogle Scholar
  158. 158.
    Barker AJ, Markl M. The role of hemodynamics in bicuspid aortic valve disease. Eur J Cardiothorac Surg. 2011;39:805–6.PubMedCrossRefGoogle Scholar
  159. 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.PubMedCrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of SurgeryColumbia University Vagelos College of Physicians and SurgeonsNew YorkUSA
  2. 2.Cardiac Surgery, University of Ottawa Heart InstituteOttawaCanada

Personalised recommendations