Skip to main content Accessibility help
  • Print publication year: 2020
  • Online publication date: October 2019

Chapter 12 - Structural Heart Disease: Embryology

from Structural Heart Disease in the Fetus


The prenatal detection of structural cardiac malformations has greatly benefited from the advances in echo Doppler technology and the in-depth training of specialists in this area. This opens up new possibilities, now and in the future, for developing in utero therapies. It also allows a better knowledge of the underlying mechanisms and developmental timing that lead to structural congenital heart disease (CHD), based on a marked progress involving genetic and epigenetic causes. Gene mutations are discovered in the fetus and parents, and pathways can be unraveled using mouse transgene technology. Epigenetic causes are also receiving attention, but have thus far been underestimated as approximately 85% of CHD is determined to have a multifactorial background that combines a genetic susceptibility with epigenetic influences. Studies in animal models, including chicken, quail, zebrafish, and even more primitive Chordates, contribute relevant data. In essence, cardiac development shows basic similarities of the major processes involved between species. Therefore mechanisms unraveled in animal models can be reliably used in understanding normal human cardiac development and CHD [1].

Related content

Powered by UNSILO
[1]Poelmann, RE, Gittenberger-de Groot, AC, Biermans, MWM, Dolfing, AI, Jagessar, A, van Hattum, S, et al. Outflow tract septation and the aortic arch system in reptiles: lessons for understanding the mammalian heart. Evodevo; 2017; 8: 9.
[2]DeRuiter, MC, Poelmann, RE, VanderPlas-de Vries, I, Mentink, MM, Gittenberger-de Groot, AC. The development of the myocardium and endocardium in mouse embryos. Fusion of two heart tubes? Anat Embryol (Berl). 1992; 185: 461–73.
[3]Buckingham, M, Meilhac, S, Zaffran, S. Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet. 2005; 6: 826–35.
[4]Cai, CL, Liang, X, Shi, Y, Chu, PH, Pfaff, SL, Chen, J, Evans, S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003; 5: 877–89.
[5]de la Cruz, M, Sanchez-Gomez, C, Palomino, MA. The primitive cardiac regions in the straight tube heart (Stage 9-) and their anatomical expression in the mature heart: an experimental study in the chick heart. J Anat. 1989; 165: 121–31.
[6]Miquerol, L, Kelly, RG. Organogenesis of the vertebrate heart. Wiley Interdiscip Rev Dev Biol. 2013; 2: 1729.
[7]Kirby, ML, Gale, TF, Stewart, DE. Neural crest cells contribute to normal aorticopulmonary septation. Science. 1983; 220: 1059–61.
[8]Bergwerff, M, Verberne, ME, DeRuiter, MC, Poelmann, RE, Gittenberger-de Groot, AC. Neural crest cell contribution to the developing circulatory system: implications for vascular morphology? Circ Res. 1998; 82: 221–31.
[9]Farrell, MJ, Burch, JL, Wallis, K, Rowley, L, Kumiski, D, Stadt, H, Godt, RE, Creazzo, TL, Kirby, ML. FGF-8 in the ventral pharynx alters development of myocardial calcium transients after neural crest ablation. J Clin Invest. 2001; 107: 1509–17.
[10]Lindsay, EA, Vitelli, F, Su, H, Morishima, M, Huynh, T, Pramparo, T, Jurecic, V, Ogunrinu, G, Sutherland, HF, Scambler, PJ, Bradley, A, Baldini, A. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature. 2001; 410: 97101.
[11]Poelmann, RE, Mikawa, T, Gittenberger-de Groot, AC. Neural crest cells in outflow tract septation of the embryonic chicken heart: differentiation and apoptosis. Dev Dyn. 1998; 212: 373–84.
[12]Poelmann, RE, Gittenberger-de Groot, AC. A dual pathway to the heart links neural crest to in- and outflow tract septation and to differentiation of the conduction system. Anat Embryol. 2000; 231–5.
[13]Gurjarpadhye, A, Hewett, KW, Justus, C, Wen, X, Stadt, H, Kirby, ML, Sedmera, D, Gourdie, RG. Cardiac neural crest ablation inhibits compaction and electrical function of conduction system bundles. Am J Physiol Heart Circ Physiol. 2007; 292: H1291–300.
[14]Bax, NA, Bleyl, SB, Gallini, R, Wisse, LJ, Hunter, J, van Oorschot, AAM, Mahtab, EAF, Lie-Venema, H, Goumans, M-J, Betsholtz, C, Gittenberger-de Groot, AC. Cardiac malformations in Pdgfralpha mutant embryos are associated with increased expression of WT1 and Nkx2.5 in the second heart field. Dev Dyn. 2010; 239: 2307–17.
[15]Kruithof, BP, van Wijk, B, Somi, S, Kruithof-de Julio, M, Pérez Pomares, JM, Weesie, F, Wessels, A, Moorman, AF, van den Hoff, MJ. BMP and FGF regulate the differentiation of multipotential pericardial mesoderm into the myocardial or epicardial lineage. Dev Biol. 2006; 295: 507–22.
[16]Pérez-Pomares, JM, Phelps, A, Sedmerova, M, Carmona, R, González-Iriarte, M, Muñoz-Chápuli, R, Wessels, A. Experimental studies on the spatiotemporal expression of WT1 and RALDH2 in the embryonic avian heart: a model for the regulation of myocardial and valvuloseptal development by epicardially derived cells (EPDCs). Dev Biol. 2002; 247: 307–26.
[17]Gittenberger-de Groot, AC, Winter, EM, Bartelings, MM, Goumans, MJ, DeRuiter, MC, Poelmann, RE. The arterial and cardiac epicardium in development, disease and repair. Differentiation. 2012 ; 84: 4153.
[18]Gittenberger-de Groot, AC, Vrancken Peeters, MP, Mentink, MM, Gourdie, RG, Poelmann, RE. Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions. Circ Res. 1998; 82: 1043–52.
[19]Lie-Venema, H, van den Akker, NM, Bax, NA, Winter, EM, Maas, S, Kekarainen, T, Hoeben, RC, deRuiter, MC, Poelmann, RE, Gittenberger-de Groot, AC. Origin, fate, and function of epicardium-derived cells (EPCDs) in normal and abnormal cardiac development. ScientificWorldJournal. 2007; 7: 1777–98.
[20]Red-Horse, K, Ueno, H, Weissman, IL, Krasnow, MA. Coronary arteries form by developmental reprogramming of venous cells. Nature. 2010; 464: 549–53.
[21]Palmquist-Gomes, P, Guadix, JA, Pérez-Pomares, JM. Avian embryonic coronary arterio-venous patterning involves the contribution of different endothelial and endocardial cell populations. Dev Dyn. 2018; 247: 686–98.
[22]Tian, X, Hu, T, He, L, Zhang, H, Huang, X, Poelmann, RE, Liu, W, Yang, Z, Yan, Y, Pu, WT, Zhou, B. Peritruncal coronary endothelial cells contribute to proximal coronary artery stems and their aortic orifices in the mouse heart. PLoS One. 2013; 8: e80857.
[23]Zhou, B, Ma, Q, Rajagopal, S, Wu, SM, Domian, I, Rivera-Feliciano, J, Jiang, D, von Gise, A, Ikeda, S, Chien, KR, Pu, WT. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature. 2008; 454: 109–13.
[24]Gittenberger-de Groot, AC, Winter, EM, Poelmann, RE. Epicardium-derived cells (EPDCs) in development, cardiac disease and repair of ischemia. J Cell Mol Med. 2010; 14: 1056–60.
[25]Goumans, MJ, de Boer, TP, Smits, AM, van Laake, LW, van Vliet, P, Metz, CH, et al. TGF-beta1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Res. 2007; 1: 138–49.
[26]Winter, EM, Van Oorschot, AA, Hogers, B, van der Graaf, LM, Doevendans, PA, Poelmann, RE, Atsma, DE, Gittenberger-de Groot, AC, Goumans, MJ. A new direction for cardiac regeneration therapy: application of synergistically acting epicardium-derived cells and cardiomyocyte progenitor cells. Circ Heart Fail. 2009; 2: 643–53.
[27]van Vliet, P, Smits, AM, de Boer, TP, Korfage, TH, Metz, CH, Roccio, M, van der Heyden, MA, van Veen, TA, Sluijter, JP, Doevendans, PA, Goumans, MJ. Foetal and adult cardiomyocyte progenitor cells have different developmental potential. J Cell Mol Med. 2010; 14: 861–70.
[28]Poelmann, RE, Jongbloed, MR, Gittenberger-de Groot, AC. Pitx2: a challenging teenager. Circ Res. 2008; 102: 749–51.
[29]Franco, D, Campione, M. The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases. Trends Cardiovasc Med. 2003; 13: 157–63.
[30]Manasek, FJ, Monroe, RG. Early cardiac morphogenesis is independent of function. Dev Biol. 1972; 27: 584–8.
[31]Bouman, HG, Broekhuizen, ML, Baasten, AM, Gittenberger-de Groot, AC, Wenink, AC. Spectrum of looping disturbances in stage 34 chicken hearts after retinoic acid treatment. Anat Rec. 1995; 243: 101–8.
[32]Blom, NA, Gittenberger-de Groot, AC, DeRuiter, MC, Poelmann, RE, Mentink, MM, Ottenkamp, J. Development of the cardiac conduction tissue in human embryos using HNK-1 antigen expression: possible relevance for understanding of abnormal atrial automaticity. Circulation. 1999; 99: 800–6.
[33]Gittenberger-de Groot, AC, Calkoen, EE, Poelmann, RE, Bartelings, MM, Jongbloed, MR. Morphogenesis and molecular considerations on congenital cardiac septal defects. Ann Med. 2014; 46: 640–52.
[34]Scherptong, RW, Jongbloed, MR, Wisse, LJ, Vicente-Steijn, R, Bartelings, MM, Poelmann, RE, Schalij, MJ, Gittenberger-de Groot, AC. Morphogenesis of outflow tract rotation during cardiac development: the pulmonary push concept. Dev Dyn. 2012; 241: 1413–22.
[35]Bartelings, MM, Gittenberger-de Groot, AC, Wenink, ACG, et al. The morphogenesis of common arterial trunk reconsidered. Recent and classical views. Cardia Selectief. 1992; 5: 10-10.
[36]Conway, SJ, Bundy, J, Chen, J, Dickman, E, Rogers, R, Will, BM. Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Cardiovasc Res. 2000; 47: 314–28.
[37]Kirby, ML, Waldo, KL. Role of neural crest in congenital heart disease. Circulation. 1990; 82: 332–40.
[38]Baardman, ME, Zwier, MV, Wisse, LJ, Gittenberger-de Groot, AC, Kerstjens-Frederikse, WS, Hofstra, RM, et al. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development. Dis Model Mech. 2016; 9: 413–25.
[39]Bogers, AJ, Bartelings, MM, Bökenkamp, R, Stijnen, T, van Suylen, RJ, Poelmann, RE, Gittenberger-de Groot, AC. Common arterial trunk, uncommon coronary arterial anatomy. J Thorac Cardiovasc Surg. 1993; 106: 1133–7.
[40]Gittenberger-de Groot, AC, Bartelings, MM, Bogers, AJJC, Boot, MJ, Poelmann, RE. The embryology of the common arterial trunk. Progr Pediatr Cardiol. 2002; 15: 18.
[41]Van Den Akker, NM, Molin, DG, Peters, PP, Maas, S, Wisse, LJ, van Brempt, R, et al. Tetralogy of Fallot and alterations in vascular endothelial growth factor-A signaling and notch signaling in mouse embryos solely expressing the VEGF120 isoform. Circ Res. 2007; 100: 842–9.
[42]Molin, DG, Roest, PA, Nordstrand, H, Wisse, LJ, Poelmann, RE, Eriksson, UJ, Gittenberger-de Groot, AC. Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic rats. Birth Defects Res A Clin Mol Teratol. 2004; 70: 927–38.
[43]Bartram, U, Molin, DG, Wisse, LJ, Mohamad, A, Sanford, LP, Doetschman, T, Speer, CP, Poelmann, RE, Gittenberger-de Groot, AC. Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGFß2-knockout mice. Circulation. 2001; 103: 2745–52.
[44]Jenkins, SJ, Hutson, DR, Kubalak, SW. Analysis of the proepicardium-epicardium transition during the malformation of the RXRalpha-/- epicardium. Dev Dyn. 2005; 233: 1091–101.
[45]Hogers, B, DeRuiter, MC, Gittenberger-de Groot, AC, Poelmann, RE. Unilateral vitelline vein ligation alters intracardiac blood flow patterns and morphogenesis in the chick embryo. Circ Res. 1997; 80: 473–81.
[46]Van Loo, PF, Mahtab, EA, Wisse, LJ, Hou, J, Grosveld, F, Suske, G, Philipsen, S, Gittenberger-de Groot, AC. Transcription Factor Sp3 knockout mice display serious cardiac malformations. Mol Cell Biol. 2007; 27: 8571–82.
[47]Gittenberger-de Groot, AC, Vrancken Peeters, MP, Bergwerff, M, Mentink, MM, Poelmann, RE. Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and abnormal cardiac septation and coronary formation. Circ Res. 2000; 87: 969–71.
[48]Nakajima, Y, Morishima, M, Nakazawa, M, Momma, K. Inhibition of outflow cushion mesenchyme formation in retinoic acid-induced complete transposition of the great arteries. Cardiovasc Res. 1996; 31: E77–85.
[49]Moazzen, H, Lu, X, Ma, NL, Velenosi, TJ, Urquhart, BL, Wisse, LJ, Gittenberger-de Groot, AC, Feng, Q. N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes. Cardiovasc Diabetol. 2014; 18: 1346.
[50]Blom, NA, Ottenkamp, J, Jongeneel, TH, DeRuiter, MC, Gittenberger-de Groot, AC. Morphogenetic differences of secundum atrial septal defects. Pediatr Cardiol. 2005; 26: 338–43.
[51]Benson, DW, Silberbach, GM, Kavanaugh-McHugh, A, Cottrill, C, Zhang, Y, Riggs, S, et al. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999; 104: 1567–73.
[52]Moskowitz, IP, Kim, JB, Moore, ML, Wolf, CM, Peterson, MA, Shendure, J, Nobrega, MA, Yokota, Y, Berul, C, Izumo, S, Seidman, JG, Seidman, CE. A molecular pathway including Id2, Tbx5, and Nkx2–5 required for cardiac conduction system development. Cell. 2007; 129: 1365–76.
[53]Blaschke, RJ, Hahurij, ND, Kuijper, S, Just, S, Wisse, LJ, Deissler, K, et al. Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation 2007; 115: 1830–8.
[54]Barlow, GM, Chen, X-N, Shi, ZY, Lyons, GE, Kurnit, DM, Celle, L, et al. Down syndrome congenital heart disease: a narrowed region and a candidate gene. Genet Med. 2001; 3: 91101.
[55]Blom, NA, Ottenkamp, J, Wenink, AG, Gittenberger-de Groot, AC. Deficiency of the vestibular spine in atrioventricular septal defects in human fetuses with down syndrome. Am J Cardiol. 2003; 91: 180–4.
[56]Mahtab, EA, Wijffels, MC, van den Akker, NM, Hahurij, ND, Lie-Venema, H, Wisse, LJ, et al. Cardiac malformations and myocardial abnormalities in podoplanin knockout mouse embryos: correlation with abnormal epicardial development. Dev Dyn. 2008; 237: 847–57.
[57]Steimle, JD, Moskowitz, IP. TBX5: A Key Regulator of Heart Development. Curr Top Dev Biol. 2017; 122: 195221.
[58]Hinton, RB Jr., Martin, LJ, Tabangin, ME, Mazwi, ML, Cripe, LH, Benson, DW. Hypoplastic left heart syndrome is heritable. J Am Coll Cardiol. 2007; 50: 1590–5.
[59]Wenink, AC, Gittenberger-de Groot, AC, Brom, AG. Developmental considerations of mitral valve anomalies. Int J Cardiol. 1986; 11: 8598.
[60]Elzenga, N, Gittenberger-de Groot, AC. Coarctation and related aortic arch anomalies in hypoplastic left heart syndrome. Int J Cardiol. 1985; 8: 379–89.
[61]Sedmera, D, Pexieder, T, Rychterova, V, Hu, N, Clark, EB. Remodeling of chick embryonic ventricular myoarchitecture under experimentally changed loading conditions. Anat Rec. 1999; 254: 238–52.
[62]Sizarov, A, Boudjemline, Y. Valve Interventions in utero: understanding the timing, indications, and approaches. Can J Cardiol. 2017; 33: 1150–8.
[63]Bartram, U, Bartelings, MM, Kramer, HH, Gittenberger-de Groot, AC. Congenital polyvalvular disease: a review. Pediatr Cardiol. 2001; 22: 93101.
[64]Garg, V, Muth, AN, Ransom, JF, Schluterman, MK, Barnes, R, King, IN, Grossfeld, PD, Srivastava, D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005; 437: 270–4.
[65]Grewal, N, DeRuiter, MC, Jongbloed, MR, Goumans, MJ, Klautz, RJ, Poelmann, RE, Gittenberger-de Groot, AC. Normal and abnormal development of the aortic wall and valve: correlation with clinical entities. Neth Heart J. 2014; 22: 363–9.
[66]Fernández, B, Durán, AC, Fernández-Gallego, T, Fernández, MC, Such, M, Arqué, JM, Sans-Coma, V. Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities. J Am Coll Cardiol. 2009; 54: 2312–18.
[67]Gittenberger-de Groot, AC, Tennstedt, C, Chaoui, R, Lie-Venema, H, Sauer, U, Poelmann, RE. Ventriculo coronary arterial communications (VCAC) and myocardial sinusoids in hearts with pulmonary artresia with intact ventricular septum: two different diseases. Progr Pediatr Cardiol. 2001; 13: 157–64.
[68]Chaoui, R, Tennstedt, C, Göldner, B, Bollmann, R. Prenatal diagnosis of ventriculo-coronary communications in a second-trimester fetus using transvaginal and transabdominal color Doppler sonography. Ultrasound Obstet Gynecol. 1997; 9: 194–7.
[69]Oosthoek, PW, Wenink, ACG, Macedo, AJ, Gittenberger-de Groot, AC. The parachute-like asymmetric mitral valve and its two papillary muscles. J Thorac Cardiovasc Surg. 1997; 114: 915.
[70]Wu, B, Wang, Y, Lui, W, Langworthy, M, Tompkins, KL, Hatzopoulos, AK, Baldwin, HS, Zhou, B. Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation. Circ Res. 2011; 109: 183–92.
[71]Lie-Venema, H, Eralp, I, Markwald, RR, van den Akker, NM, Wijffels, MC, Kolditz, DP, et al. Periostin expression by epicardium-derived cells (EPDCs) is involved in the development of the atrioventricular valves and fibrous heart skeleton. Differentiation. 2008; 76: 809–19.
[72]Jongbloed, MR, Vicente Steijn, R, Hahurij, ND, Kelder, TP, Schalij, MJ, Gittenberger-de Groot, AC, Blom, NA. Normal and abnormal development of the cardiac conduction system; implications for conduction and rhythm disorders in the child and adult. Differentiation. 2012; 84: 131–48.
[73]Haïssaguerre, M, Jaïs, P, Shah, DC, Takahashi, A, Hocini, M, Quiniou, G, Garrigue, S, Le Mouroux, A, Le Métayer, P, Clémenty, J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. New Engl J Med. 1998; 339: 659–66.
[74]Syeda, F, Kirchhof, P, Fabritz, L. PITX2-dependent gene regulation in atrial fibrillation and rhythm control. J Physiol. 2017; 595: 4019–26.