Skip to main content Accessibility help

Clinical and pathophysiological aspects of bicuspid aortic valve disease

  • Maria Weinkouff Pedersen (a1), Kristian Ambjørn Groth (a2), Kristian Havmand Mortensen (a3), John Brodersen (a4) (a5), Claus Højbjerg Gravholt (a6) (a7) and Niels Holmark Andersen (a1)...


A bicuspid aortic valve is not only a common congenital heart defect but also an enigmatic condition that can cause a large spectrum of diseases, such as aortic valve stenosis and severe heart failure in newborns whereas aortic dissection in adults. On the contrary, a bicuspid aortic valve can also occur with normal function throughout life and never need treatment. Numerous genetic mechanisms are involved in the abnormal cellular functions that may cause abnormal development of the aortic valve during early foetal life. As several chromosomal disorders are also associated with a bicuspid valve, there does not appear to be an apparent common trigger to the abnormal development of the aortic valve. The clinical care of the bicuspid aortic valve patient has been changed by a significant body of evidence that has improved the understanding of the natural history of the disease, including when to best intervene with valve replacement and when to provide prophylactic aortic root surgery. Moreover, as bicuspid valve disease is also part of various syndromes, we can identify high-risk patients in whom a bicuspid valve is much more unfavourable than in the normal population. This review provides an overview of all aspects of the bicuspid aortic valve condition and gives an updated perspective on issues from pathophysiology to clinical care of bicuspid aortic valve disease and associated aortic disease in asymptomatic, symptomatic, and pregnant patients, as well as our viewpoint on population screening.


Corresponding author

Author for correspondence: Dr N. H. Andersen, DMSc, Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark. Tel: +4522558552; Fax: +9748905674; E-mail:


Hide All

Cite this article: Pedersen MW, Groth KA, Mortensen KH, Brodersen J, Gravholt CH, Andersen NH. (2018) Clinical and pathophysiological aspects of bicuspid aortic valve disease. Cardiology in the Young29: 1–10. doi: 10.1017/S1047951118001658



Hide All
1. Fernandes, S, Khairy, P, Graham, DA, et al. Bicuspid aortic valve and associated aortic dilation in the young. Heart 2012; 98: 10141019.
2. Michelena, HI, Desjardins, VA, Avierinos, J-F, et al. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation 2008; 117: 27762784.
3. Koenraadt, WMC, Bartelings, MM, Bökenkamp, R, et al. Coronary anatomy in children with bicuspid aortic valves and associated congenital heart disease. Heart 2018; 104: 385393.
4. Phillips, HM, Mahendran, P, Singh, E, Anderson, RH, Chaudhry, B, Henderson, DJ. Neural crest cells are required for correct positioning of the developing outflow cushions and pattern the arterial valve leaflets. Cardiovasc Res 2013; 99: 452460.
5. Garg, V, Muth, AN, Ransom, JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005; 437: 270274.
6. Freeze, SL, Landis, BJ, Ware, SM, Helm, BM. Bicuspid aortic valve: a review with recommendations for genetic counseling. J Genet Couns 2016; 25: 11711178.
7. Giusti, B, Sticchi, E, De Cario, R, Magi, A, Nistri, S, Pepe, G. Genetic bases of bicuspid aortic valve: the contribution of traditional and high-throughput sequencing approaches on research and diagnosis. Front Physiol 2017; 8: 612.
8. Lin, C-J, Lin, C-Y, Chen, C-H, Zhou, B, Chang, C-P. Partitioning the heart: mechanisms of cardiac septation and valve development. Development 2012; 139: 32773299.
9. Kerneis, C, Pasi, N, Arangalage, D, et al. Ascending aorta dilatation rates in patients with tricuspid and bicuspid aortic stenosis: the COFRASA/GENERAC study. Eur Heart J Cardiovasc Imaging, July 2017 [Epub ahead of print].
10. Itagaki, S, Chikwe, JP, Chiang, YP, Egorova, NN, Adams, DH. Long-term risk for aortic complications after aortic valve replacement in patients with bicuspid aortic valve versus Marfan syndrome. J Am Coll Cardiol 2015; 65: 23632369.
11. McKellar, SH, Michelena, HI, Li, Z, Schaff, H V., Sundt, TM 3rd. Long-term risk of aortic events following aortic valve replacement in patients with bicuspid aortic valves. Am J Cardiol 2010; 106: 16261633.
12. Brodersen, J, Schwartz, LM, Heneghan, C, O’Sullivan, JW, Aronson, JK, Woloshin, S. Overdiagnosis: what it is and what it isn’t. Evid Based Med 2018; 23: 13.
13. Hoffman, JIE, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 18901900.
14. Tutar, E, Ekici, F, Atalay, S, Nacar, N. The prevalence of bicuspid aortic valve in newborns by echocardiographic screening. Am Heart J 2005; 150: 513515.
15. Mortensen, KHKH, Andersen, NHNH, Gravholt, CHCH. Cardiovascular phenotype in Turner syndrome—integrating cardiology, genetics, and endocrinology. Endocr Rev 2012; 33: 677714.
16. Niaz, T, Poterucha, JT, Olson, TM, et al. Characteristic morphologies of the bicuspid aortic valve in patients with genetic syndromes. J Am Soc Echocardiogr 2018 Feb; 31: 194200.
17. Pierpont, ME, Basson, CT, Benson, DWJ, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115: 30153038.
18. Nistri, S, Porciani, MC, Attanasio, M, Abbate, R, Gensini, GF, Pepe, G. Association of Marfan syndrome and bicuspid aortic valve: frequency and outcome. Int J Cardiol 2012; 155: 324325.
19. Van Hemelrijk, C, Renard, M, Loeys, B. The Loeys-Dietz syndrome: an update for the clinician. Curr Opin Cardiol 2010; 25: 546551.
20. Yassine, NM, Shahram, JT, Body, SC. Pathogenic mechanisms of bicuspid aortic valve aortopathy. Front Physiol 2017; 8: 687.
21. Martin, PS, Kloesel, B, Norris, RA, Lindsay, M, Milan, D, Body, SC. Embryonic development of the bicuspid aortic valve. J Cardiovasc Dev Dis 2015; 2: 248272.
22. Fernandez, B, Duran, AC, Fernandez-Gallego, T, et al. Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities. J Am Coll Cardiol 2009; 54: 23122318.
23. McKellar, SH, Tester, DJ, Yagubyan, M, Majumdar, R, Ackerman, MJ, Sundt, TM 3rd. Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J Thorac Cardiovasc Surg 2007; 134: 290296.
24. Li, W, Li, Q, Jiao, Y, et al. Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. J Clin Invest 2014; 124: 755767.
25. Jiao, J, Xiong, W, Wang, L, et al. The aortopathy of bicuspid aortic valve disease has distinctive patterns and usually involves the transverse aortic arch. J Thorac Cardiovasc Surg 2008; 10: 516517.
26. Laforest, B, Nemer, M. Genetic insights into bicuspid aortic valve formation. Cardiol Res Pract 2012; 1: 180297.
27. Papagiannis, J. Sudden death due to aortic pathology. Cardiol Young 2017; 27: S36S42.
28. Tukiainen, T, Villani, A-C, Yen, A, et al. Landscape of X chromosome inactivation across human tissues. Nature 2017; 550: 244248.
29. Schaefer, BM, Lewin, MB, Stout, KK, et al. The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape. Heart 2008; 94: 16341638.
30. Sievers, H-H, Schmidtke, C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007; 133: 12261233.
31. Della Corte, A, Body, SC, Booher, AM, et al. Surgical treatment of bicuspid aortic valve disease: knowledge gaps and research perspectives. J Thorac Cardiovasc Surg 2014; 147: 17491757.
32. Kong, WKF, Regeer, M V, Poh, KK, et al. Inter-ethnic differences in valve morphology, valvular dysfunction, and aortopathy between Asian and European patients with bicuspid aortic valve. Eur Heart J 2018; 14: 13081313.
33. Mortensen, KHKH, Hjerrild, BEBE, Stochholm, K, et al. Dilation of the ascending aorta in Turner syndrome – a prospective cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 2011; 13: 24.
34. Verma, S, Siu, SC. Aortic dilatation in patients with bicuspid aortic valve. N Engl J Med 2014; 370: 19201929.
35. Mahadevia, R, Barker, AJ, Schnell, S, et al. Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy. Circulation 2014; 129: 673682.
36. Mahle, WT, Sutherland, JL, Frias, PA. Outcome of isolated bicuspid aortic valve in childhood. J Pediatr 2010; 157: 445449.
37. Groth, KA, Stochholm, K, Hove, H, et al. Aortic events in a nationwide Marfan syndrome cohort. Clin Res Cardiol 2017; 106: 105112.
38. Ramsbottom, SA, Sharma, V, Rhee, HJ, et al. Vangl2-regulated polarisation of second heart field-derived cells is required for outflow tract lengthening during cardiac development. PLoS Genet 2014; 10: e1004871.
39. Abdulkareem, N, Smelt, J, Jahangiri, M. Bicuspid aortic valve aortopathy: genetics, pathophysiology and medical therapy. Interact Cardiovasc Thorac Surg 2013; 17: 554559.
40. Meierhofer, C, Schneider, EP, Lyko, C, et al. Wall shear stress and flow patterns in the ascending aorta in patients with bicuspid aortic valves differ significantly from tricuspid aortic valves: a prospective study. Eur Heart J Cardiovasc Imaging 2013; 14: 797804.
41. Vergara, C, Viscardi, F, Antiga, L, Luciani, GB. Influence of bicuspid valve geometry on ascending aortic fluid dynamics: a parametric study. Artif Organs 2012; 36: 368378.
42. Viscardi, F, Vergara, C, Antiga, L, et al. Comparative finite element model analysis of ascending aortic flow in bicuspid and tricuspid aortic valve. Artif Organs 2010; 34: 11141120.
43. Bissell, MM, Hess, AT, Biasiolli, L, et al. Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type. Circ Cardiovasc Imaging 2013; 6: 499507.
44. Thanassoulis, G, Yip, JWL, Filion, K, et al. Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves. Nat Clin Pract Cardiovasc Med 2008; 5: 821828.
45. Novaro, GM, Tiong, IY, Pearce, GL, Grimm, RA, Smedira, N, Griffin, BP. Features and predictors of ascending aortic dilatation in association with a congenital bicuspid aortic valve. Am J Cardiol 2003; 92: 99101.
46. Page, M, Mongeon, F-P, Stevens, L-M, Souliere, V, Khairy, P, El-Hamamsy, I. Aortic dilation rates in patients with bicuspid aortic valve: correlations with cusp fusion phenotype. J Heart Valve Dis 2014; 23: 450457.
47. Avadhani, SA, Martin-Doyle, W, Shaikh, AY, Pape, LA. Predictors of ascending aortic dilation in bicuspid aortic valve disease: a five-year prospective study. Am J Med 2015; 128: 647652.
48. Detaint, D, Michelena, HI, Nkomo, VT, Vahanian, A, Jondeau, G, Sarano, ME. Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy. Heart 2014; 100: 126134.
49. de Simone, G, Roman, MJ, De Marco, M, et al. Hemodynamic correlates of abnormal aortic root dimension in an adult population: the strong heart study. J Am Heart Assoc 2015; 4: e002309.
50. Quenot, J-P, Boichot, C, Petit, A, et al. Usefulness of MRI in the follow-up of patients with repaired aortic coarctation and bicuspid aortic valve. Int J Cardiol 2005; 103: 312316.
51. Etz, CD, von Aspern, K, Hoyer, A, et al. Acute type A aortic dissection: characteristics and outcomes comparing patients with bicuspid versus tricuspid aortic valve. Eur J Cardiothorac Surg 2015; 48: 142150.
52. Groth, KA, Stochholm, K, Hove, H, et al. Aortic events in a nationwide Marfan syndrome cohort. Clin Res Cardiol 2017; 106: 105112.
53. Weinsaft, JW, Devereux, RB, Preiss, LR, et al. Aortic dissection in patients with genetically mediated aneurysms: incidence and predictors in the GenTAC registry. J Am Coll Cardiol 2016; 67: 27442754.
54. Della Corte, A, Bancone, C, Buonocore, M, et al. Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve. JACC Cardiovasc Imaging 2013; 6: 13011310.
55. Erbel, R, Aboyans, V, Boileau, C, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European. Eur Heart J 2014; 35: 28732926.
56. Groth, KAKA, Hove, H, Kyhl, K, et al. Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet J Rare Dis 2015; 10: 153.
57. Stochholm, K, Juul, S, Juel, K, Naeraa, RW, Gravholt, CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006; 91: 38973902.
58. Hiratzka, LF, Creager, MA, Isselbacher, EM, et al. Surgery for aortic dilatation in patients with bicuspid aortic valves: a statement of clarification from the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 67: 724731.
59. Eleid, MF, Forde, I, Edwards, WD, et al. Type A aortic dissection in patients with bicuspid aortic valves: clinical and pathological comparison with tricuspid aortic valves. Heart 2013; 99: 16681674.
60. Wojnarski, CM, Svensson, LG, Roselli, EE, et al. Aortic dissection in patients with bicuspid aortic valve-associated aneurysms. Ann Thorac Surg 2015; 100: 16641666.
61. Gravholt, CH, Andersen, NH, Conway, GS, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017; 177: G1G70.
62. Hochstrasser, L, Ruchat, P, Sekarski, N, Hurni, M, von Segesser, LK. Long-term outcome of congenital aortic valve stenosis: predictors of reintervention. Cardiol Young 2015; 25: 893902.
63. Spaziani, G, Ballo, P, Favilli, S, et al. Clinical outcome, valve dysfunction, and progressive aortic dilation in a pediatric population with isolated bicuspid aortic valve. Pediatr Cardiol 2014; 35: 803809.
64. Tzemos, N, Therrien, J, Yip, J, et al. Outcomes in adults with bicuspid aortic valves. JAMA 2008; 300: 13171325.
65. Kong, WKF, Delgado, V, Poh, KK, et al. Prognostic implications of raphe in bicuspid aortic valve anatomy. JAMA Cardiol 2017; 2: 285292.
66. Borger, MA, Preston, M, Ivanov, J, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004; 128: 677683.
67. Hagl, C, Strauch, JT, Spielvogel, D, et al. Is the Bentall procedure for ascending aorta or aortic valve replacement the best approach for long-term event-free survival? Ann Thorac Surg 2003; 76: 698703.
68. Naito, S, Petersen, J, Reichenspurner, H, Girdauskas, E. The impact of coronary anomalies on the outcome in aortic valve surgery: comparison of bicuspid aortic valve versus tricuspid aortic valve morphotype. Interact Cardiovasc Thorac Surg 2018; 26: 617622.
69. Park, CB, Greason, KL, Suri, RM, Michelena, HI, Schaff, H V, Sundt, TM 3rd. Fate of nonreplaced sinuses of Valsalva in bicuspid aortic valve disease. J Thorac Cardiovasc Surg 2011; 142: 278284.
70. Nazer, RI, Elhenawy, AM, Fazel, SS, Garrido-Olivares, LE, Armstrong, S, David, TE. The influence of operative techniques on the outcomes of bicuspid aortic valve disease and aortic dilatation. Ann Thorac Surg 2010; 89: 19181924.
71. Huntington, K, Hunter, AG, Chan, KL, et al. Left ventricular outflow tract obstruction: should cardiac screening be offered to first-degree relatives? Pediatrics 1997; 133: e12127.
72. Cozijnsen, L, van der Zaag-Loonen, HJ, Braam, RL, et al. Echocardiography screening of siblings of children with bicuspid aortic valve. Int J Cardiol 2011; 97: 12281232.
73. Kerstjens-Frederikse, WS, Du Marchie Sarvaas, GJ, Ruiter, JS, et al. Left ventricular outflow tract obstruction: should cardiac screening be offered to first-degree relatives? Heart 2011; 97: 12281232.
74. Hales, AR, Mahle, WT. Echocardiography screening of siblings of children with bicuspid aortic valve. Pediatrics 2014; 133: e12127.
75. Rodrigues, I, Agapito, AF, de Sousa, L, et al. Bicuspid aortic valve outcomes. Cardiol Young 2017; 27: 518529.
76. Cotter, AR, Vuong, K, Mustelin, L, et al. Do psychological harms result from being labelled with an unexpected diagnosis of abdominal aortic aneurysm or prostate cancer through screening? A systematic review. BMJ Open 2017; 7: e017565.
77. Harris, RP, Sheridan, SL, Lewis, CL, et al. The harms of screening: a proposed taxonomy and application to lung cancer screening. JAMA Intern Med 2014; 174: 281285.
78. Regitz-Zagrosek, V, Blomstrom Lundqvist, C, Borghi, C, et al. ESC guidelines on the management of cardiovascular diseases during pregnancy: the task force on the management of cardiovascular diseases during pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 31473197.
79. Orwat, S, Diller, G-P, van Hagen, IM, et al. Risk of pregnancy in moderate and severe aortic stenosis: from the multinational ROPAC registry. J Am Coll Cardiol 2016; 68: 17271737.
80. McKellar, SH, MacDonald, RJ, Michelena, HI, Connolly, HM, Sundt, TM 3rd. Frequency of cardiovascular events in women with a congenitally bicuspid aortic valve in a single community and effect of pregnancy on events. Am J Cardiol 2011; 107: 9699.
81. Groth, KA, Greisen, JR, Nielsen, BB, Andersen, NH. High-risk pregnancy in a woman with Marfan syndrome, a bicuspid aortic valve, and a dilated aortic sinus. Ugeskr Laeger 2015; 177: 8283; article in Danish.
82. Lawley, CM, Lain, SJ, Algert, CS, Ford, JB, Figtree, GA, Roberts, CL. Prosthetic heart valves in pregnancy, outcomes for women and their babies: a systematic review and meta-analysis. BJOG. 2015; 122: 14461455.
83. Kaza, AK, Pigula, FA. Are bioprosthetic valves appropriate for aortic valve replacement in young patients? Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2016; 19: 6367.
84. Mazine, A, David, TE, Rao, V, et al. Long-term outcomes of the Ross procedure versus mechanical aortic valve replacement: propensity-matched cohort study. Circulation 2016; 134: 576585.
85. Brown, JW, Ruzmetov, M, Shahriari, AP, Rodefeld, MD, Mahomed, Y, Turrentine, MW. Modification of the Ross aortic valve replacement to prevent late autograft dilatation. Eur J Cardiothorac Surg 2010; 37: 10021007.
86. Gillespie, MJ, McElhinney, DB, Kreutzer, J, et al. Transcatheter pulmonary valve replacement for right ventricular outflow tract conduit dysfunction after the Ross procedure. Ann Thorac Surg 2015; 100: 993996.
87. Chen, H, VanBuren, V. A provisional gene regulatory atlas for mouse heart development. PLoS One 2014; 9: e83364.
88. Sannino, A, Cedars, A, Stoler, RC, Szerlip, M, Mack, MJ, Grayburn, PA. Comparison of efficacy and safety of transcatheter aortic valve implantation in patients with bicuspid versus tricuspid aortic valves. Am J Cardiol 2017; 120: 16011606.
89. Popma, JJ, Ramadan, RCT. Imaging of bicuspid aortic valve disease for TAVR. JACC Cardiovasc Imaging 2016; 9: 11591163.
90. Yoon, S-H, Lefevre, T, Ahn, J-M, et al. Transcatheter aortic valve replacement with early- and new-generation devices in bicuspid aortic valve stenosis. J Am Coll Cardiol 2016; 68: 11951205.
91. Yoon, S-H, Bleiziffer, S, De Backer, O, et al. Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol 2017; 69: 25792589.
92. Luciani, GB, De Rita, F, Lucchese, G, et al. Repair of congenitally dysplastic aortic valve by bicuspidization: midterm results. Ann Thorac Surg 2012; 94: 11731179.
93. Schneider, U, Feldner, SK, Hofmann, C, et al. Two decades of experience with root remodeling and valve repair for bicuspid aortic valves. J Thorac Cardiovasc Surg 2017; 153: S65S71.
94. Thudt, M, Papadopoulos, N, Monsefi, N, et al. Long-term results following pericardial patch augmentation for incompetent bicuspid aortic valves: a single center experience. Ann Thorac Surg 2017; 103: 11861192.
95. Ozaki, S, Kawase, I, Yamashita, H, et al. Aortic valve reconstruction using autologous pericardium for patients aged less than 60 years. J Thorac Cardiovasc Surg 2014; 148: 934938.
96. Ozaki, S, Kawase, I, Yamashita, H, et al. Reconstruction of bicuspid aortic valve with autologous pericardium – usefulness of tricuspidization. Circ J 2014; 78: 11441151.
97. Reuthebuch, O, Koechlin, L, Schurr, U, Grapow, M, Fassl, J, Eckstein, FS. Aortic valve replacement using autologous pericardium: single centre experience with the Ozaki technique. Swiss Med Wkly 2018; 148: w14591.
98. Ozaki, S, Kawase, I, Yamashita, H, Uchida, S, Takatoh, M, Kiyohara, N. Midterm outcomes after aortic valve neocuspidization with glutaraldehyde-treated autologous pericardium. J Thorac Cardiovasc Surg 2018; 155: 23792387.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Cardiology in the Young
  • ISSN: 1047-9511
  • EISSN: 1467-1107
  • URL: /core/journals/cardiology-in-the-young
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed