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CC BY 4.0 · Aorta (Stamford) 2014; 02(05): 186-195
DOI: 10.12945/j.aorta.2014.14-032
Basic Science for the Clinician
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Heterogeneity in the Segmental Development of the Aortic Tree

Impact on Management of Genetically Triggered Aortic Aneurysms
Hisham M.F. Sherif
1   Department of Cardiac Surgery, Christiana Hospital, Christiana Care Health System, Newark, Delaware, USA
› Author Affiliations
Further Information

Publication History

27 May 2014

07 August 2014

Publication Date:
24 September 2018 (online)

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Abstract

An extensive search of the medical literature examining the development of the thoracic aortic tree reveals that the thoracic aorta does not develop as one unit or in one stage: the oldest part of the thoracic aorta is the descending aorta with the aortic arch being the second oldest, developing under influence from the neural crest cell. Following in chronological order are the proximal ascending aorta and aortic root, which develop from a conotruncal origin. Different areas of the thoracic aorta develop under the influence of different gene sets. These parts develop from different cell lineages: the aortic root (the conotruncus), developing from the mesoderm; the ascending aorta and aortic arch, developing from the neural crest cells; and the descending aorta from the mesoderm. Findings illustrate that the thoracic aorta is not a single entity, in developmental terms. It develops from three or four distinct areas, at different stages of embryonic life, and under different sets of genes and signaling pathways. Genetically triggered thoracic aortic aneurysms are not a monolithic group but rather share a multi-genetic origin. Identification of therapeutic targets should be based on the predilection of certain genes to cause aneurysmal disease in specific aortic segments.

Key Words

Aortic development - Aneurysms - Aortic dissection - Genetics - Developmental anatomy
 

  • References

  • 1 Caglayan AO, Dundar M. Inherited diseases and syndromes leading to aortic aneurysms and dissections. Eur J Cardiothorac Surg 2009; 35: 931-940 . 10.1016/j.ejcts.2009.01.006
    CrossrefPubMedGoogle Scholar
  • 2 Jondeau G. Phenotypic heterogeneity and determinants in aortic aneurysm syndromes. . Proceedings, the Aortic Disease Summit. Baltimore, Maryland. September 22-23, 2009
    PubMedGoogle Scholar
  • 3 Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol 2010; 55: 841-857 . 10.1016/j.jacc.2009.08.084
    CrossrefPubMedGoogle Scholar
  • 4 Sherif HMF. In search of a new therapeutic target for the treatment of genetically triggered thoracic aortic aneurysms and cardiovascular conditions: insights from human and animal lathyrism. Interact CardioVasc Thorac Surg 2010; 11: 271-276 . 10.1510/icvts.2010.239681
    CrossrefPubMedGoogle Scholar
  • 5 Winstein B. What guides early embryonic blood vessel formation?. Dev Dyn 1999; 215: 2-11
    CrossrefPubMedGoogle Scholar
  • 6 Larsen W.. Development of the heart. In: Human Embryology. New York: Churchill Livingstone; 1997. , p. 135-161
    Google Scholar
  • 7 Abu-Issa R, Kirby ML. Heart field: from mesoderm to heart tube. Annu Rev Cell Dev Biol 2007; 23: 45-68 . 10.1146/annurev.cellbio.23.090506.123331
    CrossrefPubMedGoogle Scholar
  • 8 Siekmann AF, Standley C, Fogarty KE, Wolfe SA, Lawson ND. Chemokine signaling guides regional patterning of the first embryonic artery. Genes Dev 2009; 23: 2272-2277 . 10.1101/gad.1813509
    CrossrefPubMedGoogle Scholar
  • 9 Cleaver, Krieg P. VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. Development 1998; 125: 3905-3914
    PubMedGoogle Scholar
  • 10 McLean SE, Mecham BH, Kelleher CM, Mariani TJ, Mecham RP. Extracellular matrix gene expression in the developing mouse aorta. Adv Dev Biol 2005; 15: 81-128 . 10.1016/S1574-3349(05)15003-0
    PubMedGoogle Scholar
  • 11 Hungerford JE, Owens GK, Argraves WS, Little CD. Development of the aortic vessel wall as defined by vascular smooth muscle and extracellular matrix markers. Dev Biol 1996; 178: 375-392 . 10.1006/dbio.1996.0225
    CrossrefPubMedGoogle Scholar
  • 12 Eriksson J, Löfberg J. Development of the hypochord and dorsal aorta in the zebrafish embryo (Danio rerio). J Morphol 2000; 244: 167-176 . 10.1002/(SICI)1097-4687(200006)244:3<167::AID-JMOR2>3.0.CO;2-J
    CrossrefPubMedGoogle Scholar
  • 13 Hunt P, Clarke JD, Buxton P, Ferretti P, Thorogood P. Stability and plasticity of neural crest patterning and branchial arch Hox code after extensive cephalic crest rotation. Dev Biol 1998; 198: 82-104 . 10.1006/dbio.1998.8886
    CrossrefPubMedGoogle Scholar
  • 14 Bockman DE, Redmond ME, Kirby ML. Alteration of early vascular development after ablation of cranial neural crest. Anat Rec 1989; 225: 209-217 . 10.1002/ar.1092250306
    CrossrefPubMedGoogle Scholar
  • 15 Bockman DE, Redmond ME, Waldo K, Davis H, Kirby ML. Effect of neural crest ablation on development of the heart and arch arteries in the chick. Am J Anat 1987; 180: 332-341 . 10.1002/aja.1001800403
    CrossrefPubMedGoogle Scholar
  • 16 Bergwerff M, DeRuiter MC, Hall S, Poelmann RE, Gittenberger-de Groot AC. Unique vascular morphology of the fourth aortic arches: possible implications for pathogenesis of type-B aortic arch interruption and anomalous right subclavian artery. Cardiovasc Res 1999; 44: 185-196 . 10.1016/S0008-6363(99)00186-8
    CrossrefPubMedGoogle Scholar
  • 17 Kirby ML. Cellular and molecular contributions of the cardiac neural crest to cardiovascular development. Trends Cardiovasc Med 1993; 3: 18-23 . 10.1016/1050-1738(93)90023-Y
    CrossrefPubMedGoogle Scholar
  • 18 Porras D, Brown CB. Temporal-spatial ablation of neural crest in the mouse results in cardiovascular defects. Dev Dyn 2008; 237: 153-162 . 10.1002/dvdy.21382
    CrossrefPubMedGoogle Scholar
  • 19 Kirby ML, Hunt P, Wallis K, Thorogood P. Abnormal patterning of the aortic arch arteries does not evoke cardiac malformations. Dev Dyn 1997; 208: 34-47 . 10.1002/(SICI)1097-0177(199701)208:1<34::AID-AJA4>3.0.CO;2-2
    CrossrefPubMedGoogle Scholar
  • 20 Yashiro K, Shiratori H, Hamada H. Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 2007; 450: 285-288 . 10.1038/nature06254
    PubMedGoogle Scholar
  • 21 Larsen W.. Development of the heart. In: Human Embryology. New York: Churchill Livingstone; 1997. , p. 169-187
    Google Scholar
  • 22 Bruneau B. The developmental genetics of congenital heart disease. Nature 2008; 451: 943-948 . 10.1038/nature06801
    CrossrefPubMedGoogle Scholar
  • 23 Nishibatake M, Kirby ML, Van Mierop LH. Pathogenesis of persistent truncus arteriosus and dextroposed aorta in the chick embryo after neural crest ablation. Circulation 1987; 75: 255-264 . 10.1161/01.CIR.75.1.255
    CrossrefPubMedGoogle Scholar
  • 24 Hutson MR, Kirby ML. Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations. Semin Cell Dev Biol 2007; 18: 101-110 . 10.1016/j.semcdb.2006.12.004
    CrossrefPubMedGoogle Scholar
  • 25 Restivo A, Piacintini G, Placidi S, Saffirio C, Marino B. Cardiac outflow tract: a review of some embryogenetic aspects of the conotruncal region of the heart. Anat Rec A Discov Mol Cell Evol Biol 2006; 288: 936-943 . 10.1002/ar.a.20367
    PubMedGoogle Scholar
  • 26 Beall AC, Rosenquist TH. Smooth muscle cells of neural crest origin form the aorticopulmonary septum in the avian embryo. Anat Rec 1990; 226: 360-366 . 10.1002/ar.1092260313
    CrossrefPubMedGoogle Scholar
  • 27 Kappetein A, Gittenberger-de Groot A, Zwinderman A, Rohmer J, Poelmann R, Huysmans H. The neural crest as a possible pathogenetic factor in coarctation of the aorta and bicuspid aortic valve. J Thorac Cardiovasc Surg 1991; 102: 830-836
    PubMedGoogle Scholar
  • 28 Anderson RH, Webb S, Brown NA, Lamers W, Moorman A. Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks. Heart 2003; 89: 1110-1118 . 10.1136/heart.89.9.1110
    CrossrefPubMedGoogle Scholar
  • 29 Qayyum SR, Webb S, Anderson RH, Verbeek FJ, Brown NA, Richardson MK. Septation and valvar formation in the outflow tract of the embryonic chick heart. Anat Rec 2001; 264: 273-283 . 10.1002/ar.1162
    CrossrefPubMedGoogle Scholar
  • 30 Webb S, Qayyum SR, Anderson RH, Lamers WH, Richardson MK. Septation and separation within the outflow tract of the developing heart. J Anat 2003; 202: 327-342 . 10.1046/j.1469-7580.2003.00168.x
    CrossrefPubMedGoogle Scholar
  • 31 Maron B, Hutchins G. The development of the semilunar valves in the human heart. Am J Pathol 1974; 74: 333-344
    PubMedGoogle Scholar
  • 32 Fernández B, Durán AC, Fernández-Gallego T, Fernández MC, Such M, Arqué JM. , et al. Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiologic entities. J Am Coll Cardiol 2009; 54: 2312-2318 . 10.1016/j.jacc.2009.07.044
    CrossrefPubMedGoogle Scholar
  • 33 Cho H, Harrison K, Schwartz O, Kehrl JH. The aorta and heart differentially express RGS (regulators of G-protein signalling) proteins that selectively regulate sphingosine 1-phosphate, angiotensin II and endothelin-1 signalling. Biochem J 2003; 371: 973-980 . 10.1042/BJ20021769
    CrossrefPubMedGoogle Scholar
  • 34 Downes M, Koopman P. SOX18 and the transcriptional regulation of blood vessel development. Trends Cardiovasc Med 2001; 11: 318-324 . 10.1016/S1050-1738(01)00131-1
    CrossrefPubMedGoogle Scholar
  • 35 Yang X, Castilla LH, Xu X, Li C, Gotay J, Weinstein M. , et al. Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development 1999; 126: 1571-1580
    PubMedGoogle Scholar
  • 36 Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC. gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science 2000; 287: 1820-1824 . 10.1126/science.287.5459.1820
    CrossrefPubMedGoogle Scholar
  • 37 Jaffe M, Sesti C, Washington IM, Du L, Dronadula N, Chin MT. , et al. Transforming growth factor β signaling in myogenic cells regulates vascular morphogenesis, differentiation and matrix synthesis. Arterioscler Thromb Vasc Biol 2012; 23: e1-e11 . 10.1161/ATVBAHA.111.238410
    PubMedGoogle Scholar
  • 38 Topouzis S, Majesky M. Smooth muscle lineage diversity in the chick embryo: two types of aortic smooth muscle cell differ in growth and receptor-mediated transcriptional responses to transforming growth factor-β. Dev Biol 1996; 178: 430-445 . 10.1006/dbio.1996.0229
    CrossrefPubMedGoogle Scholar
  • 39 Patterson LJ, Gering M, Patient R. Scl is required for dorsal aorta as well as blood formation in zebrafish embryos. Blood 2005; 105: 3502-3511 . 10.1182/blood-2004-09-3547
    CrossrefPubMedGoogle Scholar
  • 40 Cha YI, Kim SH, Solnica-Krezel L, DuBois RN. Cyclooxygenase-1 signaling is required for vascular tube formation during development. Dev Biol 2005; 282: 274-283 . 10.1016/j.ydbio.2005.03.014
    CrossrefPubMedGoogle Scholar
  • 41 Ben Abdelkhalek H, Beckers A, Schuster-Gossler K, Pavlova MN, Burkhardt H, Lickert H. , et al. The mouse homeobox gene Not is required for caudal notochord development and affected by the truncate mutation. Genes Dev 2004; 18: 1725-1736 . 10.1101/gad.303504
    CrossrefPubMedGoogle Scholar
  • 42 Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS. , et al. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 1997; 11: 1048-1060 . 10.1101/gad.11.8.1048
    CrossrefPubMedGoogle Scholar
  • 43 Holzenberger M, Ayer-Le Lièvre, Robert L. Tropoelastin gene expression in the developing vascular system of the chicken: an in situ hybridization study. Anat Embryol 1993; 188: 481-492
    PubMedGoogle Scholar
  • 44 Abdulla RI, Slott EF, Kirby ML. Proteins associated with cardiac neural crest in the pharyngeal region of early chick embryos. Pediatr Res 1993; 33: 43-47 . 10.1203/00006450-199301000-00009
    CrossrefPubMedGoogle Scholar
  • 45 Biben C, Hatzistavrou T, Harvey R. Expression of NK-2 class homeobox gene Nkx2-6 in foregut endoderm and heart. Mech Dev 1998; 73: 125-127 . 10.1016/S0925-4773(98)00037-9
    CrossrefPubMedGoogle Scholar
  • 46 Calmont A, Ivins S, Van Bueren KL, Papangeli I, Kyriakopoulou V, Andrews WD. , et al. Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm. Development 2009; 136: 3173-3183 . 10.1242/dev.028902
    CrossrefPubMedGoogle Scholar
  • 47 Gittenberger-de Groot AC, Azhar M, Molin DG. Transforming growth factor beta-SMAD2 signaling and aortic arch development. Trends Cardiovasc Med 2006; 16: 1-6 . 10.1016/j.tcm.2005.09.006
    CrossrefPubMedGoogle Scholar
  • 48 Waldo KL, Lo CW, Kirby ML. Connexin 43 expression reflects neural crest patterns during cardiovascular development. Dev Biol 1999; 208: 307-323 . 10.1006/dbio.1999.9219
    CrossrefPubMedGoogle Scholar
  • 49 Yanagisawa H, Hammer RE, Richardson JA, Williams SC, Clouthier DE, Yanagisawa M. Role of endothelin-1/endothelin-A-receptor-mediated signaling pathway in the aortic arch patterning in mice. J Clin Invest 1998; 102: 22-33 . 10.1172/JCI2698
    CrossrefPubMedGoogle Scholar
  • 50 Morishima M, Yanagisawa H, Yanagisawa M, Baldini A. Ece1 and Tbx1 define distinct pathways to aortic arch morphogenesis. Dev Dyn 2003; 228: 95-104 . 10.1002/dvdy.10358
    CrossrefPubMedGoogle Scholar
  • 51 Gavalas A, Trainor P, Ariza-McNaughton L, Krumlauf R. Synergy between Hoxa1 and Hoxb1: the relationship between arch patterning and the generation of cranial neural crest. Development 2001; 128: 3017-3027
    PubMedGoogle Scholar
  • 52 Kameda Y. Hoxa3 and signaling molecules involved in aortic arch patterning and remodeling. Cell Tissue Res 2009; 336: 165-178 . 10.1007/s00441-009-0760-7
    CrossrefPubMedGoogle Scholar
  • 53 Liao J, Aggarwal VS, Nowotschin S, Bondarev A, Lipner S, Morrow BE. Identification of downstream genetic pathways of Tbx1 in the second heart field. Dev Biol 2008; 316: 524-537 . 10.1016/j.ydbio.2008.01.037
    CrossrefPubMedGoogle Scholar
  • 54 Molin DG, Poelmann RE, DeRuiter MC, Azhar M, Doetschman T, Gittenberger-de Groot AC. Transforming growth factor beta-SMAD2 signaling regulates aortic arch innervation and development. Circ Res 2004; 95: 1109-1117 . 10.1161/01.RES.0000150047.16909.ab
    CrossrefPubMedGoogle Scholar
  • 55 Ohnemus S, Kanzler B, Jerome-Majewska L, Papaioannou VE, Boehm T, Mallo M. Aortic arch and pharyngeal phenotype in the absence of BMP-dependent neural crest in the mouse. Mech Dev 2002; 119: 127-135 . 10.1016/S0925-4773(02)00345-3
    CrossrefPubMedGoogle Scholar
  • 56 Schäfer K, Neuhaus P, Kruse J, Braun T. The homeobox gene Lbx1 specifies a subpopulation of cardiac neural crest necessary for normal heart development. Circ Res 2002; 92: 73-80 . 10.1161/01.RES.0000050587.76563.A5
    PubMedGoogle Scholar
  • 57 Thomas T, Kurihara H, Yamagishi H, Kurihara Y, Yazaki Y, Olson EN. , et al. A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme. Development 1998; 125: 3005-3014
    PubMedGoogle Scholar
  • 58 Hutson MR, Zhang P, Stadt HA, Sato AK, Li YX, Burch J. , et al. Cardiac arterial pole alignment is sensitive to FGF8 signaling in the pharynx. Dev Biol 2006; 295: 486-497 . 10.1016/j.ydbio.2006.02.052
    CrossrefPubMedGoogle Scholar
  • 59 van Gijn M, Blankesteijn W, Smits J, Hierck B, Gittenberger-de Groot A. Frizzled 2 is transiently expressed in neural crest-containing areas during development of the heart and great arteries in the mouse. Anat Embryol 2001; 203: 185-192
    CrossrefPubMedGoogle Scholar
  • 60 Vitelli F, Zhang Z, Huynh T, Sobotka A, Mupo A, Baldini A. Fgf8 expression in the Tbx1 domain causes skeletal abnormalities and modifies the aortic arch but not the outflow tract phenotype of Tbx1 mutants. Dev Biol 2006; 295: 559-570 . 10.1016/j.ydbio.2006.03.044
    CrossrefPubMedGoogle Scholar
  • 61 Vitelli F, Taddei I, Morishima M, Meyers EN, Lindsay EA, Baldini A. A genetic link between Tbx1 and fibroblast growth factor signaling. Development 2002; 129: 4605-4611
    PubMedGoogle Scholar
  • 62 Randall V, McCue K, Roberts C, Kyriakopoulou V, Beddow S, Barrett AN. , et al. Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice. J Clin Invest 2009; 119: 3301-3310 . 10.1172/JCI37561
    PubMedGoogle Scholar
  • 63 Scambler PJ. 22q11 deletion syndrome: a role for TBX1 in pharyngeal and cardiovascular development. Pediatr Cardiol 2010; 31: 378-390 . 10.1007/s00246-009-9613-0
    CrossrefPubMedGoogle Scholar
  • 64 Bergwerff M, Gittenberger-de Groot AC, Wisse LJ, DeRuiter MC, Wessels A, Martin JF. , et al. Loss of function of the Prx1 and Prx2 homeobox genes alters architecture of the great elastic arteries and ductus arteriosus. Virchows Arch 2000; 436: 12-19 . 10.1007/PL00008193
    CrossrefPubMedGoogle Scholar
  • 65 Farrell MJ, Stadt H, Wallis KT, Scambler P, Hixon RL, Wolfe R. , et al. HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation. Circ Res 1999; 84: 127-135 . 10.1161/01.RES.84.2.127
    CrossrefPubMedGoogle Scholar
  • 66 Heathcote K, Braybrook C, Abushaban L, Guy M, Khetyar ME, Patton MA. , et al. Common arterial trunk associated with a homeodomain mutation of NKX2.6. Hum Mol Genet 2005; 14: 585-593 . 10.1093/hmg/ddi055
    CrossrefPubMedGoogle Scholar
  • 67 Mesbah K, Harrelson Z, Théveniau-Ruissy M, Papaioannou VE, Kelly RG. Tbx3 is required for outflow tract development. Circ Res 2008; 103: 743-750 . 10.1161/CIRCRESAHA.108.172858
    CrossrefPubMedGoogle Scholar
  • 68 Nie X, Brown CB, Wang Q, Jiao K. Inactivation of Bmp4 from the Tbx1 expression domain causes abnormal pharyngeal artery and cardiac outflow tract remodeling. Cells Tissue Organs 2011; 193: 393-403 . 10.1159/000321170
    PubMedGoogle Scholar
  • 69 Washington Smoak I, Byrd NA, Abu-Issa R, Goddeeris MM, Anderson R, Morris J. , et al. Sonic hedgehog is required for cardiac outflow tract and neural crest cell development. Dev Biol 2005; 283: 357-372 . 10.1016/j.ydbio.2005.04.029
    CrossrefPubMedGoogle Scholar
  • 70 Kim RY, Robertson EJ, Solloway MJ. Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart. Dev Biol 2001; 235: 449-466 . 10.1006/dbio.2001.0284
    CrossrefPubMedGoogle Scholar
  • 71 Xu H, Morishima M, Wylie JN, Schwartz RJ, Bruneau BG, Lindsay EA. , et al. Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development 2004; 131: 3217-3227 . 10.1242/dev.01174
    CrossrefPubMedGoogle Scholar
  • 72 Vincentz JW, McWhirter JR, Murre C, Baldini A, Furuta Y. Fgf15 is required for proper morphogenesis of the mouse cardiac outflow tract. Genesis 2005; 41: 192-201 . 10.1002/gene.20114
    CrossrefPubMedGoogle Scholar
  • 73 Chen YH, Ishii M, Sun J, Sucov HM, Maxson Jr RE. Msx1 and Msx2 regulate survival of secondary heart field precursors and post-migratory proliferation of cardiac neural crest in the outflow tract. Dev Biol 2007; 308: 421-437 . 10.1016/j.ydbio.2007.05.037
    CrossrefPubMedGoogle Scholar
  • 74 Liao J, Aggarwal VS, Nowotschin S, Bondarev A, Lipner S, Morrow BE. Identification of downstream genetic pathways of Tbx1 in the second heart field. Dev Biol 2008; 316: 524-537 . 10.1016/j.ydbio.2008.01.037
    CrossrefPubMedGoogle Scholar
  • 75 Parisot P, Mesbah K, Théveniau-Ruissy M, Kelly RG. Tbx1, subpulmonary myocardium and conotruncal congenital heart defects. Birth Defects Res A Clin Mol Teratol 2011; 91: 477-484 . 10.1002/bdra.20803
    CrossrefPubMedGoogle Scholar
  • 76 Raid R, Krinka D, Bakhoff L, Abdelwahid E, Jokinen E, Kärner M. , et al. Lack of Gata3 results in conotruncal heart anomalies in mouse. Mech Dev 2009; 126: 80-89 . 10.1016/j.mod.2008.10.001
    CrossrefPubMedGoogle Scholar
  • 77 Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM. Fate of the mammalian cardiac neural crest. Development 2000; 127: 1607-1616
    PubMedGoogle Scholar
  • 78 Hove JR, Köster RW, Forouhar AS, Acevedo-Bolton G, Fraser SE, Gharib M. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 2003; 421: 172-177 . 10.1038/nature01282
    PubMedGoogle Scholar
  • 79 Ewart AK, Morris CA, Ensing GJ, Loker J, Moore C, Leppert M. , et al. A human vascular disorder, supravalvular aortic stenosis, maps to chromosome 7. Proc Natl Acad Sci U S A 1993; 90: 3226-3230 . 10.1073/pnas.90.8.3226
    CrossrefPubMedGoogle Scholar
  • 80 Galvin KM, Donovan MJ, Lynch CA, Meyer RI, Paul RJ, Lorenz JN. , et al. A role for Smad6 in development and homeostasis of the cardiovascular system [Letter]. Nat Genet 2000; 24: 171-174 . 10.1038/72835
    CrossrefPubMedGoogle Scholar
  • 81 Martin LJ, Ramachandran V, Cripe LH, Hinton RB, Andelfinger G, Tabangin M. , et al. Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Hum Genet 2007; 121: 275-284 . 10.1007/s00439-006-0316-9
    CrossrefPubMedGoogle Scholar
  • 82 Sans-Coma V, Cardo M, Durán AC, Franco D, Fernández B, Arqué JM. Evidence for quantitative genetic influence on the formation of aortic valves with 2 leaflets in the Syrian hamster. Cardiol Young 1993; 3: 132-140
    PubMedGoogle Scholar
  • 83 Olson TM, Michels VV, Urban Z, Csiszar K, Christiano AM, Driscoll DJ. , et al. A 30kb deletion within the elastin gene results in familial supravalvular aortic stenosis. Hum Mol Genet 1995; 9: 1677-1679
    PubMedGoogle Scholar
  • 84 Ruddy JM, Jones JA, Spinale FG, Ikonomidis JS. Regional heterogeneity within the aorta: relevance to aneurysm disease. J Thorac Cardiovasc Surg 2008; 136: 1123-1130 . 10.1016/j.jtcvs.2008.06.027
    CrossrefPubMedGoogle Scholar
  • 85 Milewicz DM, Guo DC, Tran-Fadulu V, Lafont AL, Papke CL, Inamoto S. , et al. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genom Hum Genet 2008; 9: 283-302 . 10.1146/annurev.genom.8.080706.092303
    CrossrefPubMedGoogle Scholar
  • 86 Wang L, Guo DC, Cao J, Gong L, Kamm KE, Regalado E. , et al. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet 2010; 87: 701-707 . 10.1016/j.ajhg.2010.10.006
    CrossrefPubMedGoogle Scholar
  • 87 The National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Available online at: https://gentac.rti.org/Home.aspx
    PubMedGoogle Scholar