Abstract
The atria and the ventricles of the heart contract rhythmically and sequentially to achieve efficient blood flow. This contraction pattern is orchestrated by the cardiac conduction system, comprising specialized cardiomyocytes that initiate and propagate the cardiac electrical impulse. Genetic defects cause dysfunction of the cardiac conduction system leading to arrhythmias, emphasizing the need to understand the molecular and cellular mechanisms involved in its development and function. In the adult heart, the electrical impulse is generated in the sinoatrial node and traverses slowly through the atrioventricular node and rapidly through the atrioventricular bundle, the left and right bundle branches, and the peripheral ventricular conduction system. All components have a unique function, shape, and molecular composition but share particular properties acquired during embryogenesis. During embryonic development, the components are gradually formed from embryonic cardiomyocytes involving conserved molecular regulatory networks. In this chapter, the developmental origin, known signaling pathways, transcription factors, ion channels, and gap junctions involved in the development and functioning of the cardiac conduction system will be addressed.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Mangoni ME, Nargeot J (2008) Genesis and regulation of the heart automaticity. Physiol Rev 88:919–982
de Haan RL (1961) Differentiation of the atrioventricular conducting system of the heart. Circulation 24:458–470
Moorman AFM, Christoffels VM (2003) Cardiac chamber formation: development, genes and evolution. Physiol Rev 83:1223–1267
de Jong F, Opthof T, Wilde AA et al (1992) Persisting zones of slow impulse conduction in developing chicken hearts. Circ Res 71:240–250
Buckingham M, Meilhac S, Zaffran S (2005) Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 6:826–837
Davis DL, Edwards AV, Juraszek AL et al (2001) A GATA-6 gene heart-region-specific enhancer provides a novel means to mark and probe a discrete component of the mouse cardiac conduction system. Mech Dev 108:105–119
Aanhaanen WT, Brons JF, Dominguez JN et al (2009) The Tbx2+ primary myocardium of the atrioventricular canal forms the atrioventricular node and the base of the left ventricle. Circ Res 104:1267–1274
van den Berg G, Abu-Issa R, de Boer BA et al (2009) A caudal proliferating growth center contributes to both poles of the forming heart tube. Circ Res 104:179–188
Christoffels VM, Habets PEMH, Franco D et al (2000) Chamber formation and morphogenesis in the developing mammalian heart. Dev Biol 223:266–278
Soufan AT, van den Berg G, Ruijter JM et al (2006) Regionalized sequence of myocardial cell growth and proliferation characterizes early chamber formation. Circ Res 99:545–552
van Mierop LHS (1967) Localization of pacemaker in chick embryo heart at the time of initiation of heartbeat. Am J Physiol 212:407–415
Hoff EC, Kramer TC, DuBois D et al (1939) The development of the electrocardiogram of the embryonic heart. Am Heart J 17:470–488
Bleeker WK, Mackaay AJC, Masson-Pevet M et al (1980) Functional and morphological organization of the rabbit sinus node. Circ Res 46:11–22
Liu J, Dobrzynski H, Yanni J et al (2007) Organisation of the mouse sinoatrial node: structure and expression of HCN channels. Cardiovasc Res 73:729–738
Fedorov VV, Schuessler RB, Hemphill M et al (2009) Structural and functional evidence for discrete exit pathways that connect the canine sinoatrial node and atria. Circ Res 104:915–923
Kreuzberg MM, Willecke K, Bukauskas FF (2006) Connexin-mediated cardiac impulse propagation: connexin 30.2 slows atrioventricular conduction in mouse heart. Trends Cardiovasc Med 16:266–272
Gros D, Theveniau-Ruissy M, Bernard M et al (2009) Connexin 30 is expressed in the mouse sino-atrial node, and modulates heart rate. Cardiovasc Res 85:45–55
Dobrzynski H, Boyett MR, Anderson RH (2007) New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation 115:1921–1932
Verheijck EE, van Kempen MJ, Veereschild M et al (2001) Electrophysiological features of the mouse sinoatrial node in relation to connexin distribution. Cardiovasc Res 52:40–50
Hoogaars WM, Engel A, Brons JF et al (2007) Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria. Genes Dev 21:1098–1112
Gros D, Dupays L, Alcolea S et al (2004) Genetically modified mice: tools to decode the functions of connexins in the heart-new models for cardiovascular research. Cardiovasc Res 62:299–308
Tellez JO, Dobrzynski H, Greener ID et al (2006) Differential expression of ion channel transcripts in atrial muscle and sinoatrial node in rabbit. Circ Res 99:1384–1393
Stieber J, Herrmann S, Feil S et al (2003) The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc Natl Acad Sci U S A 100:15235–15240
Mommersteeg MTM, Hoogaars WMH, Prall OWJ et al (2007) Molecular pathway for the localized formation of the sinoatrial node. Circ Res 100:354–362
Virágh S, Challice CE (1980) The development of the conduction system in the mouse embryo heart. III. The development of sinus muscle and sinoatrial node. Dev Biol 80:28–45
Mommersteeg MT, Dominguez JN, Wiese C et al (2010) The sinus venosus progenitors separate and diversify from the first and second heart fields early in development. Cardiovasc Res 87:92–101
Wiese C, Grieskamp T, Airik R et al (2009) Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by tbx18 and tbx3. Circ Res 104:388–397
Ma Q, Zhou B, Pu WT (2008) Reassessment of Isl1 and Nkx2-5 cardiac fate maps using a Gata4-based reporter of Cre activity. Dev Biol 323:98–104
Zhou B, von Gise A, Ma Q et al (2008) Nkx2-5- and Isl1-expressing cardiac progenitors contribute to proepicardium. Biochem Biophys Res Commun 375:450–453
Hoogaars WMH, Tessari A, Moorman AFM et al (2004) The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart. Cardiovasc Res 62:489–499
Frank DU, Carter KL, Thomas KR et al (2011) Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis. Proc Natl Acad Sci U S A 109:E154–E163
Blaschke RJ, Hahurij ND, Kuijper S et al (2007) Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation 115:1830–1838
Espinoza-Lewis RA, Yu L, He F et al (2009) Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5. Dev Biol 327:376–385
Hoffmann S, Berger IM, Glaser A et al (2013) Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia. Basic Res Cardiol 108:339
Tessadori F, van Weerd JH, Burkhard SB et al (2012) Identification and functional characterization of cardiac pacemaker cells in zebrafish. PLoS One 7:e47644
Mori AD, Zhu Y, Vahora I et al (2006) Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis. Dev Biol 297:566–586
Puskaric S, Schmitteckert S, Mori AD et al (2010) Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart. Hum Mol Genet 19:4625–4633
Mommersteeg MTM, Hoogaars WMH, Prall OWJ et al (2007) Molecular pathway for the localized formation of the sinoatrial node. Circ Res 100:354–362
Li J, Greener ID, Inada S et al (2008) Computer three-dimensional reconstruction of the atrioventricular node. Circ Res 102:975–985
Ko YS, Yeh HI, Ko YL et al (2004) Three-dimensional reconstruction of the rabbit atrioventricular conduction axis by combining histological, desmin, and connexin mapping data. Circulation 109:1172–1179
Christoffels VM, Moorman AFM (2009) Development of the cardiac conduction system. Why are some regions of the heart more arrhythmogenic than others? Circ Arrhythm Electrophysiol 2:195–207
Wessels A, Markman MWM, Vermeulen JLM et al (1996) The development of the atrioventricular junction in the human heart. Circ Res 78:110–117
Pennisi DJ, Rentschler S, Gourdie RG et al (2002) Induction and patterning of the cardiac conduction system. Int J Dev Biol 46:765–775
Cheng G, Litchenberg WH, Cole GJ et al (1999) Development of the cardiac conduction system involves recruitment within a multipotent cardiomyogenic lineage. Development 126:5041–5049
de Lange FJ, Moorman AFM, Anderson RH et al (2004) Lineage and morphogenetic analysis of the cardiac valves. Circ Res 95:645–654
Yamada M, Revelli JP, Eichele G et al (2000) Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2. Dev Biol 228:95–105
Singh R, Hoogaars WM, Barnett P et al (2012) Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation. Cell Mol Life Sci 69:1377–1389
Habets PEMH, Moorman AFM, Clout DEW et al (2002) Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev 16:1234–1246
Bakker ML, Boukens BJ, Mommersteeg MTM et al (2008) Transcription factor Tbx3 is required for the specification of the atrioventricular conduction system. Circ Res 102:1340–1349
Ma L, Lu MF, Schwartz RJ et al (2005) Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development 132:5601–5611
Gaussin V, Morley GE, Cox L et al (2005) Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus. Circ Res 97:219–226
Stroud DM, Gaussin V, Burch JB et al (2007) Abnormal conduction and morphology in the atrioventricular node of mice with atrioventricular canal-targeted deletion of Alk3/Bmpr1a receptor. Circulation 116:2535–2543
Verhoeven MC, Haase C, Christoffels VM et al (2011) Wnt signaling regulates atrioventricular canal formation upstream of BMP and Tbx2. Birth Defects Res A Clin Mol Teratol 91:435–440
Schott J-J, Benson DW, Basson CT et al (1998) Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281:108–111
Basson CT, Bachinsky DR, Lin RC et al (1997) Mutations in human TBX5 (corrected) cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15:30–35
Munshi NV, McAnally J, Bezprozvannaya S et al (2009) Cx30.2 enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay. Development 136:2665–2674
Moskowitz IP, Kim JB, Moore ML et al (2007) A molecular pathway including id2, tbx5, and nkx2-5 required for cardiac conduction system development. Cell 129:1365–1376
Jay PY, Harris BS, Maguire CT et al (2004) Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system. J Clin Invest 113:1130–1137
Moskowitz IPG, Pizard A, Patel VV et al (2004) The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system. Development 131:4107–4116
Rutenberg JB, Fischer A, Jia H et al (2006) Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development 133:4381–4390
Kokubo H, Miyagawa-Tomita S, Nakazawa M et al (2005) Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Dev Biol 278:301–309
Stennard FA, Harvey RP (2005) T-box transcription factors and their roles in regulatory hierarchies in the developing heart. Development 132:4897–4910
Singh R, Horsthuis T, Farin HF et al (2009) Tbx20 interacts with smads to confine tbx2 expression to the atrioventricular canal. Circ Res 105:442–452
Hahurij ND, Gittenberger-de Groot AC, Kolditz DP et al (2008) Accessory atrioventricular myocardial connections in the developing human heart: relevance for perinatal supraventricular tachycardias. Circulation 117:2850–2858
Aanhaanen WT, Boukens BJ, Sizarov A et al (2011) Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice. J Clin Invest 121:534–544
Anderson RH, Ho SY, Gillette PC et al (1996) Mahaim, Kent and abnormal atrioventricular conduction. Cardiovasc Res 31:480–491
Gollob MH, Green MS, Tang AS et al (2001) Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med 344:1823–1831
Lalani SR, Thakuria JV, Cox GF et al (2009) 20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits. J Med Genet 46:168–175
Rentschler S, Harris BS, Kuznekoff L et al (2011) Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways. J Clin Invest 121:525–533
Gourdie RG, Severs NJ, Green CR et al (1993) The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. J Cell Sci 105:985–991
Miquerol L, Moreno-Rascon N, Beyer S et al (2010) Biphasic development of the mammalian ventricular conduction system. Circ Res 107:153–161
Wessels A, Vermeulen JLM, Verbeek FJ et al (1992) Spatial distribution of “tissue-specific” antigens in the developing human heart and skeletal muscle: III. An immunohistochemical analysis of the distribution of the neural tissue antigen G1N2 in the embryonic heart; implications for the development of the atrioventricular conduction system. Anat Rec 232:97–111
Virágh S, Challice CE (1977) The development of the conduction system in the mouse embryo heart. II. Histogenesis of the atrioventricular node and bundle. Dev Biol 56:397–411
Arnolds DE, Liu F, Fahrenbach JP et al (2012) TBX5 drives Scn5a expression to regulate cardiac conduction system function. J Clin Invest 122:2509–2518
Zhang SS, Kim KH, Rosen A et al (2011) Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network. Proc Natl Acad Sci U S A 108:13576–13581
Sedmera D, Reckova M, DeAlmeida A et al (2003) Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts. Am J Physiol Heart Circ Physiol 284:H1152–H1160
Bruneau BG, Logan M, Davis N et al (1999) Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol 211:100–108
Gourdie RG, Wei Y, Kim D et al (1998) Endothelin-induced conversion of embryonic heart muscle cells into impulse-conducting Purkinje fibers. Proc Natl Acad Sci U S A 95:6815–6818
Rentschler S, Zander J, Meyers K et al (2002) Neuregulin-1 promotes formation of the murine cardiac conduction system. Proc Natl Acad Sci U S A 99:10464–10469
Grego-Bessa J, Luna-Zurita L, del Monte G et al (2007) Notch signaling is essential for ventricular chamber development. Dev Cell 12:415–429
Chen H, Shi S, Acosta L et al (2004) BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131:2219–2231
Rentschler S, Yen AH, Lu J et al (2012) Myocardial Notch signaling reprograms cardiomyocytes to a conduction-like phenotype. Circulation 126:1058–1066
Christoffels VM, Smits GJ, Kispert A et al (2010) Development of the pacemaker tissues of the heart. Circ Res 106:240–254
Munshi NV (2012) Gene regulatory networks in cardiac conduction system development. Circ Res 110:1525–1537
de Laat W, Duboule D (2013) Topology of mammalian developmental enhancers and their regulatory landscapes. Nature 502:499–506
Wu M, Peng S, Yang J et al (2014) Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node. Cell Res 24:1201–1213
Stefanovic S, Barnett P, Van Duijvenboden K et al (2014) GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development. Nat Commun 5:3680
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer-Verlag Wien
About this chapter
Cite this chapter
Mohan, R., Christoffels, V.M. (2016). Cardiac Conduction System. In: Rickert-Sperling, S., Kelly, R., Driscoll, D. (eds) Congenital Heart Diseases: The Broken Heart. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1883-2_8
Download citation
DOI: https://doi.org/10.1007/978-3-7091-1883-2_8
Publisher Name: Springer, Vienna
Print ISBN: 978-3-7091-1882-5
Online ISBN: 978-3-7091-1883-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)