Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1-2% of the population. It is generally diagnosed late in adulthood when deterioration of the abnormal leaflet becomes clinically evident. BAV patients have an increased risk of developing serious complications, including stenosis, regurgitation, endocarditis, dilation of the aorta, aortic dissection, and aneurysm. BAV is a heritable trait, but the genetic basis underlying this cardiac malformation remains poorly understood. In the last decade, thanks to studies in animal models as well as genetic and biochemical approaches, a large number of genes that play important roles in heart development have been identified. These discoveries provided valuable insight into cardiac morphogenesis and uncovered congenital-heart-disease-causing genes. This paper will summarize the current knowledge of valve morphogenesis as well as our current understanding of the genetic pathways involved in BAV formation. The impact of these advances on human health including diagnosis of BAV and prevention of cardiovascular complications in individuals with BAV or with a family history of BAV is also discussed. 1. Overview of Valve Development In human and other mammals, cardiac valves are essential for unidirectional blood flow which is crucial for proper functioning and survival of the organism. Defects in valve structure or function can profoundly alter cardiovascular homeostasis and are among the leading causes of human morbidity and mortality. Thus, understanding the molecular basis of normal and pathologic valve development is of utmost importance and clinical relevance. The valves of the four chambered heart can be classified in 2 groups: atrioventricular valves (mitral and tricuspid) separate the atria from the ventricles while semilunar valves (aortic and pulmonary) divide the ventricles from the great arteries. Normal aortic valve is tricuspid, meaning it possesses three leaflets (or cusps) but defective development involving fusion of two of these produces bicuspid aortic valve (BAV). At 1-2% prevalence in the human population, BAV is the most common form of congenital heart disease and a significant risk factor for premature cardiovascular complications and valve replacement in young adults. In the embryo, the heart is the first organ to develop starting with the specification and migration of the anterior lateral plate mesoderm cells to form the cardiac crescent [1]. This is closely followed (embryonic day (E) 8.5 in the mouse and 3 weeks gestation in human) by migration of the cardiac
References
[1]
R. Abu-Issa and M. L. Kirby, “Heart field: from mesoderm to heart tube,” Annual Review of Cell and Developmental Biology, vol. 23, pp. 45–68, 2007.
[2]
R. R. Markwald, T. P. Fitzharris, and F. J. Manasek, “Structural development of endocardial cushions,” American Journal of Anatomy, vol. 148, no. 1, pp. 85–119, 1977.
[3]
A. D. Person, S. E. Klewer, and R. B. Runyan, “Cell biology of cardiac cushion development,” International Review of Cytology, vol. 243, pp. 287–335, 2005.
[4]
S. Chakraborty, M. D. Combs, and K. E. Yutzey, “Transcriptional regulation of heart valve progenitor cells,” Pediatric Cardiology, vol. 31, no. 3, pp. 414–421, 2010.
[5]
C. A. Loffredo, “Epidemiology of cardiovascular malformations: prevalence and risk factors,” American Journal of Medical Genetics, vol. 97, no. 4, pp. 319–325, 2000.
[6]
A. C. Braverman, H. Guven, M. A. Beardslee, M. Makan, A. M. Kates, and M. R. Moon, “The bicuspid aortic valve,” Current Problems in Cardiology, vol. 30, no. 9, pp. 470–522, 2005.
[7]
T. Friedman, A. Mani, and J. A. Elefteriades, “Bicuspid aortic valve: clinical approach and scientific review of a common clinical entity,” Expert Review of Cardiovascular Therapy, vol. 6, no. 2, pp. 235–248, 2008.
[8]
V. Sans-Coma, B. Fernández, A.C. Duran et al., “Fusion of valve cushions as a key factor in the formation of congenital bicuspid aortic valves in Syrian hamsters,” Anatomical Record, vol. 244, no. 4, pp. 490–498, 1996.
[9]
B. Fernandez, A.C. Duran, T. Fernandez-Gallego et al., “Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities,” Journal of the American College of Cardiology, vol. 54, no. 24, pp. 2312–2318, 2009.
[10]
S. M. Fernandes, P. Khairy, S. P. Sanders, and S. D. Colan, “Bicuspid aortic valve morphology and interventions in the young,” Journal of the American College of Cardiology, vol. 49, no. 22, pp. 2211–2214, 2007.
[11]
M. D. Hope, T. A. Hope, S. E. S. Crook et al., “4D flow CMR in assessment of valve-related ascending aortic disease,” Journal of the American College of Cardiology, vol. 4, no. 7, pp. 781–787, 2011.
[12]
J. I. E. Hoffman and S. Kaplan, “The incidence of congenital heart disease,” Journal of the American College of Cardiology, vol. 39, no. 12, pp. 1890–1900, 2002.
[13]
P. De Mozzi, U. G. Longo, G. Galanti, and N. Maffulli, “Bicuspid aortic valve: a literature review and its impact on sport activity,” British Medical Bulletin, vol. 85, no. 1, pp. 63–85, 2008.
[14]
M. Silberbach, “Bicuspid aortic valve and thoracic aortic aneurysm: toward a unified theory,” Journal of the American College of Cardiology, vol. 53, no. 24, pp. 2296–2297, 2009.
[15]
T. E. Bunton, N. Jensen Biery, L. Myers, B. Gayraud, F. Ramirez, and H. C. Dietz, “Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome,” Circulation Research, vol. 88, no. 1, pp. 37–43, 2001.
[16]
K. Huntington, A. G. W. Hunter, and K. L. Chan, “A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve,” Journal of the American College of Cardiology, vol. 30, no. 7, pp. 1809–1812, 1997.
[17]
M. Clementi, L. Notari, A. Borghi, and R. Tenconi, “Familial congenital bicuspid aortic valve: a disorder of uncertain inheritance,” American Journal of Medical Genetics, vol. 62, no. 4, pp. 336–338, 1996.
[18]
B. N. Glick and W. C. Roberts, “Congenitally bicuspid aortic valve in multiple family members,” American Journal of Cardiology, vol. 73, no. 5, pp. 400–404, 1994.
[19]
L. Cripe, G. Andelfinger, L. J. Martin, K. Shooner, and D. W. Benson, “Bicuspid aortic valve is heritable,” Journal of the American College of Cardiology, vol. 44, no. 1, pp. 138–143, 2004.
[20]
L. J. Martin, V. Ramachandran, L. H. Cripe et al., “Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations,” Human Genetics, vol. 121, no. 2, pp. 275–284, 2007.
[21]
V. Garg, A. N. Muth, J. F. Ransom et al., “Mutations in NOTCH1 cause aortic valve disease,” Nature, vol. 437, no. 7056, pp. 270–274, 2005.
[22]
S. A. Mohamed, Z. Aherrahrou, H. Liptau et al., “Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve,” Biochemical and Biophysical Research Communications, vol. 345, no. 4, pp. 1460–1465, 2006.
[23]
S. H. McKellar, D. J. Tester, M. Yagubyan, R. Majumdar, M. J. Ackerman, and T. M. Sundt, “Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms,” Journal of Thoracic and Cardiovascular Surgery, vol. 134, no. 2, pp. 290–296, 2007.
[24]
X. Lin, Z. Huo, X. Liu et al., “A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect,” Journal of Human Genetics, vol. 55, no. 10, pp. 662–667, 2010.
[25]
K. Kodo, T. Nishizawa, M. Furutani et al., “GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 33, pp. 13933–13938, 2009.
[26]
M. Maitra, S. N. Koenig, D. Srivastava, and V. Garg, “Identification of GATA6 sequence variants in patients with congenital heart defects,” Pediatric Research, vol. 68, no. 4, pp. 281–285, 2010.
[27]
J. J. Lepore, P. A. Mericko, L. Cheng, M. M. Lu, E. E. Morrisey, and M. S. Parmacek, “GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis,” Journal of Clinical Investigation, vol. 116, no. 4, pp. 929–939, 2006.
[28]
H. C. Dietz, G. R. Cutting, R. E. Pyeritz et al., “Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene,” Nature, vol. 352, no. 6333, pp. 337–339, 1991.
[29]
H. C. Dietz and R. E. Pyeritz, “Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders,” Human Molecular Genetics, vol. 4, pp. 1799–1809, 1995.
[30]
P. N. Robinson, P. Booms, S. Katzke et al., “Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies,” Human Mutation, vol. 20, no. 3, pp. 153–161, 2002.
[31]
P. W. M. Fedak, M. P. L. De Sa, S. Verma et al., “Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation,” Journal of Thoracic and Cardiovascular Surgery, vol. 126, no. 3, pp. 797–806, 2003.
[32]
L. Pereira, K. Andrikopoulos, J. Tian et al., “Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome,” Nature Genetics, vol. 17, no. 2, pp. 218–222, 1997.
[33]
L. Pereira, S. Y. Lee, B. Gayraud et al., “Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 3819–3823, 1999.
[34]
C. M. Ng, A. Cheng, L. A. Myers et al., “TGF-β-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome,” Journal of Clinical Investigation, vol. 114, no. 11, pp. 1586–1592, 2004.
[35]
G. Matyas, E. Arnold, T. Carrel et al., “Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders,” Human Mutation, vol. 27, no. 8, pp. 760–769, 2006.
[36]
B. L. Loeys, J. Chen, E. R. Neptune et al., “A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2,” Nature Genetics, vol. 37, no. 3, pp. 275–281, 2005.
[37]
E. Girdauskas, S. Schulz, M. A. Borger, M. Mierzwa, and T. Kuntze, “Transforming growth factor-beta receptor type II mutation in a patient with bicuspid aortic valve disease and intraoperative aortic Dissection,” Annals of Thoracic Surgery, vol. 91, no. 5, pp. e70–e71, 2011.
[38]
D. C. Guo, H. Pannu, V. Tran-Fadulu et al., “Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections,” Nature Genetics, vol. 39, no. 12, pp. 1488–1493, 2007.
[39]
M. A. Tischfield, T. M. Bosley, M. A. M. Salih et al., “Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development,” Nature Genetics, vol. 37, no. 10, pp. 1035–1037, 2005.
[40]
N. Makki and M.R. Capecchi, “Cardiovascular defects in a mouse model of Hoxa1 syndrome,” Human Molecular Genetics, vol. 21, no. 1, Article ID ddr434, pp. 26–31, 2012.
[41]
G. Andelfinger, A. R. Tapper, R. C. Welch, C. G. Vanoye, A. L. George Jr, and D. W. Benson, “KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes,” American Journal of Human Genetics, vol. 71, no. 3, pp. 663–668, 2002.
[42]
T. C. Lee, Y. D. Zhao, D. W. Courtman, and D. J. Stewart, “Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase,” Circulation, vol. 101, no. 20, pp. 2345–2348, 2000.
[43]
B. C. W. Groenendijk, B. P. Hierck, A. C. Gittenberger-De Groot, and R. E. Poelmann, “Development-related changes in the expression of shear stress responsive genes KLF-2, ET-1, and NOS-3 in the developing cardiovascular system of chicken embryos,” Developmental Dynamics, vol. 230, no. 1, pp. 57–68, 2004.
[44]
D. Aicher, C. Urbich, A. Zeiher, S. Dimmeler, and H. J. Sch？fers, “Endothelial nitric oxide synthase in bicuspid aortic valve disease,” Annals of Thoracic Surgery, vol. 83, no. 4, pp. 1290–1294, 2007.
[45]
Z. German, K. L. Chambliss, M. C. Pace, U. A. Arnet, C. J. Lowenstein, and P. W. Shaul, “Molecular basis of cell-specific endothelial nitric-oxide synthase expression in airway epithelium,” Journal of Biological Chemistry, vol. 275, no. 11, pp. 8183–8189, 2000.
[46]
G. Nemer and M. Nemer, “Cooperative interaction between GATA5 and NF-ATc regulates endothelial-endocardial differentiation of cardiogenic cells,” Development, vol. 129, no. 17, pp. 4045–4055, 2002.
[47]
B. Laforest, G. Andelfinger, and M. Nemer, “Loss of Gata5 in mice leads to bicuspid aortic valve,” Journal of Clinical Investigation, vol. 121, no. 7, pp. 2876–2887, 2011.
[48]
K. Niessen and A. Karsan, “Notch signaling in cardiac development,” Circulation Research, vol. 102, no. 10, pp. 1169–1181, 2008.
[49]
L. A. Timmerman, J. Grego-Bessa, A. Raya et al., “Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation,” Genes and Development, vol. 18, no. 1, pp. 99–115, 2004.
[50]
V. Nigam and D. Srivastava, “Notch1 represses osteogenic pathways in aortic valve cells,” Journal of Molecular and Cellular Cardiology, vol. 47, no. 6, pp. 828–834, 2009.
[51]
A. Acharya, C.P. Hans, S.N. Koenig et al., “Inhibitory role of Notch1 in calcific aortic valve disease,” PLoS ONE, vol. 6, no. 11, Article ID e27743, 2011.
[52]
B. Laforest and M. Nemer, “GATA5 interacts with GATA4 and GATA6 in outflow tract development,” Developmental Biology, vol. 358, no. 2, pp. 368–378, 2011.
[53]
C. Biben, R. Weber, S. Kesteven et al., “Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5,” Circulation Research, vol. 87, no. 10, pp. 888–895, 2000.
[54]
R. Majumdar, M. Yagubyan, G. Sarkar, M. E. Bolander, and T. M. Sundt, “Bicuspid aortic valve and ascending aortic aneurysm are not associated with germline or somatic homeobox NKX2-5 gene polymorphism in 19 patients,” Journal of Thoracic and Cardiovascular Surgery, vol. 131, no. 6, pp. 1301–1305, 2006.
[55]
M. Ponticos, T. Partridge, C. M. Black, D. J. Abraham, and G. Bou-Gharios, “Regulation of collagen type I in vascular smooth muscle cells by competition between Nkx2.5 and δEF1/ZEB1,” Molecular and Cellular Biology, vol. 24, no. 14, pp. 6151–6161, 2004.
[56]
F. Malfait, S. Symoens, P. Coucke, L. Nunes, S. De Almeida, and A. De Paepe, “Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems,” Journal of Medical Genetics, vol. 43, no. 7, p. e36, 2006.
[57]
V. Garg, I. S. Kathiriya, R. Barnes et al., “GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5,” Nature, vol. 424, no. 6947, pp. 443–447, 2003.
[58]
H. Hamanoue, S. E. Rahayuningsih, Y. Hirahara et al., “Genetic screening of 104 patients with congenitally malformed hearts revealed a fresh mutation of GATA4 in those with atrial septal defects,” Cardiology in the Young, vol. 19, no. 5, pp. 482–485, 2009.
[59]
S. K. Rajagopal, Q. Ma, D. Obler et al., “Spectrum of heart disease associated with murine and human GATA4 mutation,” Journal of Molecular and Cellular Cardiology, vol. 43, no. 6, pp. 677–685, 2007.
[60]
H. K. Gill, M. Splitt, G. K. Sharland, and J. M. Simpson, “Patterns of recurrence of congenital heart disease: an analysis of 6,640 consecutive pregnancies evaluated by detailed fetal echocardiography,” Journal of the American College of Cardiology, vol. 42, no. 5, pp. 923–929, 2003.
[61]
B. G. Bruneau, G. Nemer, J. P. Schmitt et al., “A murine model of Holt-Oram syndrome defines roles of the T-Box transcription factor Tbx5 in cardiogenesis and disease,” Cell, vol. 106, no. 6, pp. 709–721, 2001.
[62]
J. B. Winston, J. M. Erlich, C. A. Green et al., “Heterogeneity of genetic modifiers ensures normal cardiac development,” Circulation, vol. 121, no. 11, pp. 1313–1321, 2010.
[63]
A. Croquelois, A. A. Domenighetti, M. Nemir et al., “Control of the adaptive response of the heart to stress via the Notchl receptor pathway,” Journal of Experimental Medicine, vol. 205, no. 13, pp. 3173–3185, 2008.
