Abstract
The relative simplicity of the clinical presentation and management of an atrial septal defect belies the complexity of the developmental pathogenesis. Here, we describe the anatomic development of the atrial septum and the venous return to the atrial chambers. Experimental models suggest how mutations and naturally occurring genetic variation could affect developmental steps to cause a defect within the oval fossa, the so-called secundum defect, or other interatrial communications, such as the sinus venosus defect or ostium primum defect.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Anderson RH, Brown NA. The anatomy of the heart revisited. Anat Rec. 1996;246:1–7.
Rutland C, Warner L, Thorpe A, et al. Knockdown of alpha myosin heavy chain disrupts the cytoskeleton and leads to multiple defects during chick cardiogenesis. J Anat. 2009;214:905–15.
Deniz E, Jonas S, Khokha M, et al. Endogenous contrast blood flow imaging in embryonic hearts using hemoglobin contrast subtraction angiography. Opt Lett. 2012;37:2979–81.
Jahr M, Manner J. Development of the venous pole of the heart in the frog Xenopus laevis: a morphological study with special focus on the development of the venoatrial connections. Dev Dyn. 2011;240:1518–27.
Kelly RG. The second heart field. Curr Top Dev Biol. 2012;100:33–65.
Webb S, Brown NA, Anderson RH. Formation of the atrioventricular septal structures in the normal mouse. Circ Res. 1998;82:645–56.
Webb S, Kanani M, Anderson RH, et al. Development of the human pulmonary vein and its incorporation in the morphologically left atrium. Cardiol Young. 2001;11:632–42.
Webb S, Brown NA, Wessels A, et al. Development of the murine pulmonary vein and its relationship to the embryonic venous sinus. Anat Rec. 1998;250:325–34.
Mommersteeg MT, Soufan AT, de Lange FJ, et al. Two distinct pools of mesenchyme contribute to the development of the atrial septum. Circ Res. 2006;99:351–3.
Snarr BS, O’Neal JL, Chintalapudi MR, et al. Isl1 expression at the venous pole identifies a novel role for the second heart field in cardiac development. Circ Res. 2007;101:971–4.
Snarr BS, Wirrig EE, Phelps AL, et al. A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development. Dev Dyn. 2007;236:1287–94.
Anderson RH, Mohun TJ, Brown NA. Clarifying the morphology of the ostium primum defect. J Anat. 2015;226:244–57.
Loomba RS, Tretter JT, Mohun TJ, et al. Identification and morphogenesis of vestibular atrial septal defects. J Cardiovasc Dev Dis. 2020;7
van den Berg G, Moorman AF. Development of the pulmonary vein and the systemic venous sinus: an interactive 3D overview. PLoS One. 2011;6:e22055.
Sizarov A, Anderson RH, Christoffels VM, et al. Three-dimensional and molecular analysis of the venous pole of the develo** human heart. Circulation. 2010;122:798–807.
Basson CT, Bachinsky DR, Lin RC, et al. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997;15:30–5.
Garg V, Kathiriya IS, Barnes R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003;424:443–7.
Jay PY, Bielinska M, Erlich JM, et al. Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects. Dev Biol. 2007;301:602–14.
Li QY, Newbury-Ecob RA, Terrett JA, et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997;15:21–9.
Nadeau M, Georges RO, Laforest B, et al. An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation. Proc Natl Acad Sci U S A. 2010;107:19356–61.
**e L, Hoffmann AD, Burnicka-Turek O, et al. Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation. Dev Cell. 2012;23:280–91.
Feng Q, Song W, Lu X, et al. Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase. Circulation. 2002;106:873–9.
Frank D, Yusuf Rangrez A, Friedrich C, et al. Cardiac alpha-Actin (ACTC1) gene mutation causes atrial-septal defects associated with late-onset dilated cardiomyopathy. Circ Genom Precis Med. 2019;12:e002491.
Matsson H, Eason J, Bookwalter CS, et al. Alpha-cardiac actin mutations produce atrial septal defects. Hum Mol Genet. 2008;17:256–65.
Abdelwahid E, Pelliniemi LJ, Szucsik JC, et al. Cellular disorganization and extensive apoptosis in the develo** heart of mice that lack cardiac muscle alpha-actin: apparent cause of perinatal death. Pediatr Res. 2004;55:197–204.
Degenhardt K, Singh MK, Aghajanian H, et al. Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. Nat Med. 2013;19:760–5.
Epstein JA, Aghajanian H, Singh MK. Semaphorin signaling in cardiovascular development. Cell Metab. 2015;21:163–73.
He Z, Wang KC, Koprivica V, et al. Knowing how to navigate: mechanisms of semaphorin signaling in the nervous system. Sci STKE. 2002;2002:re1.
Cota CD, Bagher P, Pelc P, et al. Mice with mutations in Mahogunin ring finger-1 (Mgrn1) exhibit abnormal patterning of the left-right axis. Dev Dyn. 2006;235:3438–47.
Anderson RH, Wessels A, Vettukattil JJ. Morphology and morphogenesis of atrioventricular septal defect with common atrioventricular junction. World J Pediatr Congenit Heart Surg. 2010;1:59–67.
Kaski JP, Wolfenden J, Josen M, et al. Can atrioventricular septal defects exist with intact septal structures? Heart. 2006;92:832–5.
Lana-Elola E, Watson-Scales S, Slender A, et al. Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse map** panel. Elife. 2016;5
Jay PY, Akhirome E, Magnan RA, et al. Transgenerational cardiology: One way to a baby’s heart is through the mother. Mol Cell Endocrinol. 2016;435:94–102.
Akhirome E, Regmi SD, Magnan RA, et al. The genetic architecture of a congenital heart defect is related to its fitness cost. Genes (Basel). 2021;12
Bertrand N, Roux M, Ryckebusch L, et al. Hox genes define distinct progenitor sub-domains within the second heart field. Dev Biol. 2011;353:266–74.
Nguyen HH, Jay PY. A single misstep in cardiac development explains the co-occurrence of tetralogy of fallot and complete atrioventricular septal defect in Down syndrome. J Pediatr. 2014;165:194–6.
Eldar A, Dorfman R, Weiss D, et al. Robustness of the BMP morphogen gradient in Drosophila embryonic patterning. Nature. 2002;419:304–8.
McDowell GS, Lemire JM, Pare JF, et al. Conserved roles for cytoskeletal components in determining laterality. Integr Biol (Camb). 2016;8:267–86.
Vandenberg LN, Adams DS, Levin M. Normalized shape and location of perturbed craniofacial structures in the Xenopus tadpole reveal an innate ability to achieve correct morphology. Dev Dyn. 2012;241:863–78.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2024 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Magnan, R.A., Kang, L., Degenhardt, K.R., Anderson, R.H., Jay, P.Y. (2024). Molecular Pathways and Animal Models of Atrial Septal Defect. In: Rickert-Sperling, S., Kelly, R.G., Haas, N. (eds) Congenital Heart Diseases: The Broken Heart. Advances in Experimental Medicine and Biology, vol 1441. Springer, Cham. https://doi.org/10.1007/978-3-031-44087-8_25
Download citation
DOI: https://doi.org/10.1007/978-3-031-44087-8_25
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-44086-1
Online ISBN: 978-3-031-44087-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)