Abstract
The cardiac conduction system is a network of distinct cell types necessary for the coordinated contraction of the cardiac chambers. The distal portion, known as the ventricular conduction system, allows for the rapid transmission of impulses from the atrio-ventricular node to the ventricular myocardium and plays a central role in cardiac function as well as disease when perturbed. Notably, its patterning during embryogenesis is intimately linked to that of ventricular wall formation, including trabeculation and compaction. Here, we review our current understanding of the underlying mechanisms responsible for the development and maturation of these interdependent processes.
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References
Miquerol L, Moreno-Rascon N, Beyer S et al (2010) Biphasic development of the mammalian ventricular conduction system. Circ Res 107:153–161. https://doi.org/10.1161/CIRCRESAHA.110.218156
Haissaguerre M, Vigmond E, Stuyvers B et al (2016) Ventricular arrhythmias and the His-Purkinje system. Nat Rev Cardiol 13:155–166. https://doi.org/10.1038/nrcardio.2015.193
van Weerd JH, Christoffels VM (2016) The formation and function of the cardiac conduction system. Development 143:197–210. https://doi.org/10.1242/dev.124883
Steiner I (1988) History of Purkinje’s fibers. Cesk Fysiol 37:509–512
Davies F (1930) The conducting system of the bird’s heart. J Anat 64:129–146
Sommer JR, Johnson EA (1968) Cardiac muscle. A comparative study of Purkinje fibers and ventricular fibers. J Cell Biol 36:497–526
Samsa LA, Yang B, Liu J (2013) Embryonic cardiac chamber maturation: trabeculation, conduction, and cardiomyocyte proliferation. Am J Med Genet C 163C:157–168. https://doi.org/10.1002/ajmg.c.31366
Rentschler S, Vaidya DM, Tamaddon H et al (2001) Visualization and functional characterization of the developing murine cardiac conduction system. Development 128:1785–1792
Sedmera D, Reckova M, DeAlmeida A et al (2003) Spatiotemporal pattern of commitment to slowed proliferation in the embryonic mouse heart indicates progressive differentiation of the cardiac conduction system. Anat Rec 274:773–777. https://doi.org/10.1002/ar.a.10085
Meysen S, Marger L, Hewett KW et al (2007) Nkx2.5 cell-autonomous gene function is required for the postnatal formation of the peripheral ventricular conduction system. Dev Biol 303:740–753. https://doi.org/10.1016/j.ydbio.2006.12.044
Kim K-H, Rosen A, Hussein SMI et al (2016) Irx3 is required for postnatal maturation of the mouse ventricular conduction system. Sci Rep 6:19197. https://doi.org/10.1038/srep19197
Sedmera D, Pexieder T, Vuillemin M et al (2000) Developmental patterning of the myocardium. Anat Rec 258:319–337
Moorman AFM, Christoffels VM (2003) Cardiac chamber formation: development, genes, and evolution. Physiol Rev 83:1223–1267. https://doi.org/10.1152/physrev.00006.2003
Zhang W, Chen H, Qu X et al (2013) Molecular mechanism of ventricular trabeculation/compaction and the pathogenesis of the left ventricular noncompaction cardiomyopathy (LVNC). Am J Med Genet C 163C:144–156. https://doi.org/10.1002/ajmg.c.31369
Gorza L, Schiaffino S, Vitadello M (1988) Heart conduction system: a neural crest derivative? Brain Res 457:360–366
Gourdie RG, Mima T, Thompson RP, Mikawa T (1995) Terminal diversification of the myocyte lineage generates Purkinje fibers of the cardiac conduction system. Development 121:1423–1431
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
Jiang X, Rowitch DH, Soriano P et al (2000) Fate of the mammalian cardiac neural crest. Development 127:1607–1616
Delorme B, Dahl E, Jarry-Guichard T et al (1995) Developmental regulation of connexin 40 gene expression in mouse heart correlates with the differentiation of the conduction system. Dev Dyn 204:358–371. https://doi.org/10.1002/aja.1002040403
Delorme B, Dahl E, Jarry-Guichard T et al (1997) Expression pattern of connexin gene products at the early developmental stages of the mouse cardiovascular system. Circ Res 81:423–437
Erokhina IL, Rumyantsev PP (1988) Proliferation and biosynthetic activities of myocytes from conductive system and working myocardium of the developing mouse heart. Light microscopic autoradiographic study. Acta Histochem 84:51–66. https://doi.org/10.1016/S0065-1281(88)80010-2
Sedmera D, Thompson RP (2011) Myocyte proliferation in the developing heart. Dev Dyn 240:1322–1334. https://doi.org/10.1002/dvdy.22650
Miquerol L, Bellon A, Moreno N et al (2013) Resolving cell lineage contributions to the ventricular conduction system with a Cx40-GFP allele: a dual contribution of the first and second heart fields. Dev Dyn 242:665–677. https://doi.org/10.1002/dvdy.23964
Später D, Abramczuk MK, Buac K et al (2013) A HCN4 + cardiomyogenic progenitor derived from the first heart field and human pluripotent stem cells. Nat Cell Biol 15:1098–1106. https://doi.org/10.1038/ncb2824
Liang X, Wang G, Lin L et al (2013) HCN4 dynamically marks the first heart field and conduction system precursors. Circ Res 113:399–407. https://doi.org/10.1161/CIRCRESAHA.113.301588
Tsai S-Y, Maass K, Lu J et al (2015) Efficient generation of cardiac Purkinje cells from ESCs by activating cAMP signaling. Stem Cell Rep 4:1089–1102. https://doi.org/10.1016/j.stemcr.2015.04.015
Maass K, Shekhar A, Lu J et al (2015) Isolation and characterization of embryonic stem cell-derived cardiac Purkinje cells. Stem Cells 33:1102–1112. https://doi.org/10.1002/stem.1921
Li G, Xu A, Sim S et al (2016) Transcriptomic profiling maps anatomically patterned subpopulations among single embryonic cardiac cells. Dev Cell 39:491–507. https://doi.org/10.1016/j.devcel.2016.10.014
Paige SL, Plonowska K, Xu A, Wu SM (2015) Molecular regulation of cardiomyocyte differentiation. Circ Res 116:341–353. https://doi.org/10.1161/CIRCRESAHA.116.302752
Munshi NV (2012) Gene regulatory networks in cardiac conduction system development. Circ Res 110:1525–1537. https://doi.org/10.1161/CIRCRESAHA.111.260026
de la Pompa JL, Epstein JA (2012) Coordinating tissue interactions: notch signaling in cardiac development and disease. Dev Cell 22:244–254. https://doi.org/10.1016/j.devcel.2012.01.014
Christoffels VM, Smits GJ, Kispert A, Moorman AFM (2010) Development of the pacemaker tissues of the heart. Circ Res 106:240–254. https://doi.org/10.1161/CIRCRESAHA.109.205419
Hatcher CJ, Basson CT (2009) Specification of the cardiac conduction system by transcription factors. Circ Res 105:620–630. https://doi.org/10.1161/CIRCRESAHA.109.204123
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. https://doi.org/10.1016/j.devcel.2006.12.011
Rentschler S, Morley GE, Fishman GI (2002) Molecular and functional maturation of the murine cardiac conduction system. In: Cold Spring Harbor symposia on quantitative biology, vol 67. Cold Spring Harbor Laboratory Press, New York, pp 353–361
Hertig CM, Kubalak SW, Wang Y, Chien KR (1999) Synergistic roles of neuregulin-1 and insulin-like growth factor-I in activation of the phosphatidylinositol 3-kinase pathway and cardiac chamber morphogenesis. J Biol Chem 274:37362–37369
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 USA 95:6815–6818
Chen H, Zhang W, Sun X et al (2013) Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity. Development 140:1946–1957. https://doi.org/10.1242/dev.089920
Rentschler S, Yen AH, Lu J et al (2012) Myocardial Notch signaling reprograms cardiomyocytes to a conduction-like phenotype. Circulation 126:1058–1066. https://doi.org/10.1161/CIRCULATIONAHA.112.103390
Khandekar A, Springer S, Wang W et al (2016) Notch-mediated epigenetic regulation of voltage-gated potassium currents. Circ Res 119:1324–1338. https://doi.org/10.1161/CIRCRESAHA.116.309877
Moskowitz IPG, 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. https://doi.org/10.1016/j.cell.2007.04.036
Jongbloed MRM, Vicente-Steijn R, Douglas YL et al (2011) Expression of Id2 in the second heart field and cardiac defects in Id2 knock-out mice. Dev Dyn 240:2561–2577. https://doi.org/10.1002/dvdy.22762
Zhang S-S, Kim K-H, Rosen A et al (2011) Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network. Proc Natl Acad Sci USA 108:13576–13581. https://doi.org/10.1073/pnas.1106911108
Koizumi A, Sasano T, Kimura W et al (2016) Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. Eur Heart J 37:1469–1475. https://doi.org/10.1093/eurheartj/ehv449
Thomas PS, Kasahara H, Edmonson AM et al (2001) Elevated expression of Nkx-2.5 in developing myocardial conduction cells. Anat Rec 263:307–313
Pashmforoush M, Lu JT, Chen H et al (2004) Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell 117:373–386
Tanaka M, Berul CI, Ishii M et al (2002) A mouse model of congenital heart disease: cardiac arrhythmias and atrial septal defect caused by haploinsufficiency of the cardiac transcription factor Csx/Nkx2.5. In: Cold Spring Harbor symposia on quantitative biology, vol 67, pp 317–325
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. https://doi.org/10.1172/JCI19846
Schott JJ, Benson DW, Basson CT et al (1998) Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281:108–111
Chen H, Shi S, Acosta L et al (2004) BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131:2219–2231. https://doi.org/10.1242/dev.01094
Shin CH, Liu Z-P, Passier R et al (2002) Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. Cell 110:725–735
Ismat FA, Zhang M, Kook H et al (2005) Homeobox protein Hop functions in the adult cardiac conduction system. Circ Res 96:898–903. https://doi.org/10.1161/01.RES.0000163108.47258.f3
Benjamin EJ, Blaha MJ, Chiuve SE et al (2017) Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 135:e146–e603. https://doi.org/10.1161/CIR.0000000000000485
John RM, Tedrow UB, Koplan BA et al (2012) Ventricular arrhythmias and sudden cardiac death. Lancet 380:1520–1529. https://doi.org/10.1016/S0140-6736(12)61413-5
Scheinman MM (2009) Role of the His-Purkinje system in the genesis of cardiac arrhythmia. Heart Rhythm 6:1050–1058. https://doi.org/10.1016/j.hrthm.2009.03.011
Kim EE, Shekhar A, Lu J et al (2014) PCP4 regulates Purkinje cell excitability and cardiac rhythmicity. J Clin Invest 124:5027–5036. https://doi.org/10.1172/JCI77495
Herron TJ, Milstein ML, Anumonwo J et al (2010) Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 7:1122–1128. https://doi.org/10.1016/j.hrthm.2010.06.010
Morley GE, Danik SB, Bernstein S et al (2005) Reduced intercellular coupling leads to paradoxical propagation across the Purkinje-ventricular junction and aberrant myocardial activation. Proc Natl Acad Sci USA 102:4126–4129. https://doi.org/10.1073/pnas.0500881102
Behradfar E, Nygren A, Vigmond EJ (2014) The role of Purkinje-myocardial coupling during ventricular arrhythmia: a modeling study. PLoS ONE 9:e88000. https://doi.org/10.1371/journal.pone.0088000
Gude NA, Emmanuel G, Wu W et al (2008) Activation of Notch-mediated protective signaling in the myocardium. Circ Res 102:1025–1035. https://doi.org/10.1161/CIRCRESAHA.107.164749
Bezzina CR, Barc J, Mizusawa Y et al (2013) Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet 45:1044–1049. https://doi.org/10.1038/ng.2712
Benson DW, Silberbach GM, Kavanaugh-McHugh A et al (1999) Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest 104:1567–1573. https://doi.org/10.1172/JCI8154
Xie H, Chen X, Chen N, Zhou Q (2017) Sudden death in a male infant due to histiocytoid cardiomyopathy: an autopsy case and review of the literature. Am J Forensic Med Pathol 38:32–34. https://doi.org/10.1097/PAF.0000000000000289
Finsterer J (2008) Histiocytoid cardiomyopathy: a mitochondrial disorder. Clin Cardiol 31:225–227. https://doi.org/10.1002/clc.20224
Acknowledgements
This work was supported by the NIH Office of Director’s Pioneer Award LM012179-03, the American Heart Association Established Investigator Award 17EIA33410923, the Department of Pediatrics and Division of Pediatric Cardiology at Lucille Packard Children’s Hospital, the Stanford Cardiovascular Institute, the Stanford Division of Cardiovascular Medicine, Department of Medicine, the Institute for Stem Cell Biology and Regenerative Medicine, and an endowed faculty scholar award from the Stanford Child Health Research Institute/Lucile Packard Foundation for Children (S.M.W). This was also supported by the Training Grant (T32) entitled Research Training in Myocardial Biology at Stanford (NIH 2 T32 HL094274) (W.R.G.).
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W.R.G. declares that he has no conflict of interest. S.M.W. declares that he has no conflict of interest.
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Goodyer, W.R., Wu, S.M. Fates Aligned: Origins and Mechanisms of Ventricular Conduction System and Ventricular Wall Development. Pediatr Cardiol 39, 1090–1098 (2018). https://doi.org/10.1007/s00246-018-1869-9
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DOI: https://doi.org/10.1007/s00246-018-1869-9