SUMMARY
Recent progress in search of mechanisms regulating the spatio-temporal formation of specialized
conduction tissues pushes us further in our understanding of the developmental molecular mechanisms
of myocardial patterning. It is not clear which mechanisms direct the fates of chamber myocytes to
differentiate into ventricular cardiac conduction system (CCS). Similarly, the formation and nature of
connections between its most distal component, the Purkinje fibers, and the working myocytes, is
unresolved. The process of remodelling of originally ring-like AV junction into AV node and
accompanying fibrous insulation between the atria and ventricles is poorly understood, especially on
the molecular level. Perturbation of this process can result in abnormal atrio-ventricular connections,
manifesting as Wolf-Parkinson-White syndrome of ventricular pre-excitation. Understanding the
signalling mechanisms involved in CCS development may be of significance to clinicians and basic
researchers studying adult cardiac disease. Congenital abnormalities in CCS, as well as ectopic or
inappropriate induction of CCS tissue in the mature heart, may be processes that contribute to, or
cause, cardiac conduction disturbance and arrhythmia in adults. Understanding the signalling
mechanisms that give rise to normal development of the CCS may thus provide insight into cardiac
disease.
KEY WORDS
myocyte; AV junction; Wolf-Parkinson-White syndrome; ventricular CCS; cardiac disease
REFERENCES
Alanis J, Benitez D, Lopez E, Martinez-Palomo A:
Impulse propagation through the cardiac
junctional regions of the axolotl and the turtle.
Jpn J Physiol 23:149-164, 1973.
Anderson RH, Ho SY: The architecture of the sinus
node, the atrioventricular conduction axis, and
the internodal atrial myocardium. J
Cardiovasc Electrophysiol 9:1233-1248, 1998.
Arbel ER, Liberthson R, Langendorf R, Pick A,
Lev M, Fishman AP: Electrophysiological and
anatomical observations on the heart of the
African lungfish. Am J Physiol 232:H24-H34, 1977.
Arguello C, Alanis J, Pantoja O, Valenzuela B:
Electrophysiological and ultrastructural study
of the atrioventricular canal during the
development of the chick embryo. J Mol
Cell Cardiol 18:499-510, 1986.
Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S,
Smalls O, Johnson MC, Watson MS, Seidman
JG, Seidman CE, Plowden J, Kugler JD:
Mutations in the cardiac transcription factor
Nkx2.5 affect diverse cardiac developmental
pathways. J Clin Invest 104:1567-1573, 1999.
Benson DW: Genetics of atrioventricular
conduction disease in humans. Anat Rec A Discov Mol Cell Evol Biol 280:934-939, 2004.
Cheng G, Litchenberg WH, Cole GJ, Mikawa T,
Thompson RP, Gourdie RG: Development of
the cardiac conduction system involves
recruitment within a multipotent
cardiomyogenic lineage. Development
126:5041-5049, 1999.
Christian E, Grigg GC: Electrical activation of the
ventricular myocardium of the crocodile
Crocodylus johnstoni: a combined
microscopic and electrophysiological study.
Comp Biochem Physio, Part A Mol Integr
Physiol 123:17-23, 1999.
Christoffels VM, Burch JB, Moorman AF:
Architectural plan for the heart: Early
patterning and delineation of the chambers and
the nodes. Trends Cardiovasc Med 14:301-307, 2004.
Chuck ET, Freeman DM, Watanabe M, Rosenbaum
DS: Changing activation sequence in the
embryonic chick heart. Implications for the
development of the His-Purkinje system. Circ
Res 81:470-476, 1997.
Coppen SR, Severs NJ, Gourdie RG: Connexin45
(alpha 6) expression delineates an extended
conduction system in the embryonic and
mature rodent heart. Dev Genet 24:82-90, 1999.
Coppen SR, Kaba RA, Halliday D, Dupont E,
Skepper JN, Elneil S, Severs NJ: Comparison
of connexin expression patterns in the
developing mouse heart and human foetal
heart. Mol Cell Biochem 242:121-127, 2003.
Davis DL, Edwards AV, Juraszek AL, Phelps A,
Wessels A, Burch JB: A GATA-6 gene heartregion-
specific enhancer provides a novel
means to mark and probe a discrete
component of the mouse cardiac conduction
system. Mech Dev 108:105-119, 2001.
de Jong F, Opthof T, Wilde AA, Janse MJ, Charles
R, Lamers WH, Moorman AF: Persisting
zones of slow impulse conduction in
developing chicken hearts. Circ Res 71:240-250, 1992.
Delorme B, Dahl E, Jarry-Guichard T, Marics I,
Briand JP, Willecke K, Gros D, Theveniau-
Ruissy M: Developmental regulation of
connexin 40 gene expression in mouse heart
correlates with the differentiation of the
conduction system. Dev Dyn 204:358-371, 1995.
Dillon S, Morad M: A new laser scanning system
for measuring action potential propagation in
the heart. Science 214:453-456, 1981.
Dobrzynski H, Boyett MR, Anderson RH: New
insights into pacemaker activity: promoting
understanding of sick sinus syndrome.
Circulation 115:1921-1932, 2007.
Efimov IR, Aguel F, Cheng Y, Wollenzier B,
Trayanova N: Virtual electrode polarization in
the far field: implications for external
defibrillation. Am J Physiol Heart Circ
Physiol 279:H1055-H1070, 2007.
Franco D, Icardo JM: Molecular characterization of
the ventricular conduction system in the
developing mouse heart: topographical
correlation in normal and congenitally
malformed hearts. Cardiovasc Res 49:417-429, 2001.
Gassanov N, Er F, Zagidullin N, Hoppe UC:
Endothelin induces differentiation of ANPEGFP
expressing embryonic stem cells
towards a pacemaker phenotype. FASEB J
18:1710-1712, 2004.
Gorza L, Schiaffino S, Vitadello M: Heart
conduction system: a neural crest derivative?
Brain Res 457:360-366, 1988.
Gorza L, Vettore S, Vitadello M: Molecular and
cellular diversity of heart conduction system
myocytes. Trends Cardiovasc Med 4:153-159, 1994.
Gourdie RG, Mima T, Thompson RP, Mikawa T:
Terminal diversification of the myocyte
lineage generates Purkinje fibers of the cardiac
conduction system. Development 121:1423-1431, 1995.
Gourdie RG, Wei Y, Kim D, Klatt SC, Mikawa T:
Endothelin-induced conversion of embryonic
heart muscle cells into impulse-conducting
Purkinje fibers. Proc Natl Acad Sci U.S.A.
95:6815-6818, 1998.
Gourdie RG, Harris BS, Bond J, Justus C, Hewett
KW, O'Brien TX, Thompson RP, Sedmera D:
Development of the cardiac pacemaking and
conduction system. Birth Defects Res
69C:46-57, 2003.
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 292:H1291-H1300, 2007.
Harris BS, Spruill L, Edmonson AM, Rackley MS,
Benson DW, O'Brien TX, Gourdie RG:
Differentiation of cardiac Purkinje fibers
requires precise spatiotemporal regulation of
Nkx2.5 expression. Dev Dyn 235:38-49, 2006.
Hoogaars WM, Engel A, Brons JF, Verkerk AO, de
Lange FJ, Wong LY, Bakker ML, Clout DE,
Wakker V, Barnett P, Ravesloot JH, Moorman
AF, Verheijck EE, Christoffels VM: Tbx3
controls the sinoatrial node gene program and imposes pacemaker function on the atria.
Genes Dev 21:1098-1112, 2007.
Irisawa H: Comparative physiology of the cardiac
pacemaker mechanism. Physiol Rev 58:461-498, 1978.
Jay PY, Berul CI, Tanaka M, Ishii M, Kurachi Y,
Izumo S: Cardiac conduction and arrhythmia:
insights from Nkx2.5 mutations in mouse and
humans. In Chadwick DJ, Goode J (eds.):
Development of the Cardiac Conduction
System. Wiley, Chicheter 2003, pp. 227-241.
Jay PY, Harris BS, Maguire CT, Buerger A,
Wakimoto H, Tanaka M, Kupershmidt S,
Roden DM, Schultheiss TM, O'Brien TX,
Gourdie RG, Berul CI, Izumo S: Nkx2.5
mutation causes anatomic hypoplasia of the
cardiac conduction system. J Clin Invest
113:1130-1137, 2004.
Kamino K: Optical approaches to ontogeny of
electrical activity and related functional
organization during early heart development.
Physiol Rev 71:53-91, 1991.
Kokubo H, Tomita-Miyagawa S, Hamada Y, Saga
Y: Hesr1 and Hesr2 regulate atrioventricular
boundary formation in the developing heart
through the repression of Tbx2. Development
134:747-755, 2007.
Kolditz DP, Wijffels MC, Blom NA, van der
Laarse A, Markwald RR, Schalij MJ,
Gittenberger-de Groot AC: Persistence of
functional atrioventricular accessory pathways
in postseptated embryonic avian hearts:
implications for morphogenesis and functional
maturation of the cardiac conduction system.
Circulation 115:17-26, 2007.
Litchenberg WH, Norman LW, Holwell AK,
Martin KL, Hewett KW, Gourdie RG: The
rate and anisotropy of impulse propagation in
the postnatal terminal crest are correlated with
remodeling of Cx43 gap junction pattern.
Cardiovasc Res 45:379-387, 2000.
Liu J, Dobrzynski H, Yanni J, Boyett MR, Lei M:
Organisation of the mouse sinoatrial node:
structure and expression of HCN channels.
Cardiovasc Res 73:729-738, 2007.
Lyons GE, Schiaffino S, Sassoon D, Barton P,
Buckingham M: Developmental regulation of
myosin gene expression in mouse cardiac
muscle. J Cell Biol 111:2427-2436, 1990.
Lyons I, Parsons LM, Hartley L, Li R, Andrews JE,
Robb L, Harvey RP: Myogenic and
morphogenetic defects in the heart tubes of
murine embryos lacking the homeo box gene
Nkx2.5. Genes Dev 9:1654-1666, 1995.
Meilhac SM, Kelly RG, Rocancourt D, Eloy-
Trinquet S, Nicolas JF, Buckingham ME: A
retrospective clonal analysis of the
myocardium reveals two phases of clonal
growth in the developing mouse heart.
Development 130:3877-3889, 2003.
Meysen S, Marger L, Hewett KW, Jarry-Guichard
T, Agarkova I, Chauvin JP, Perriard JC,
Izumo S, Gourdie RG, Mangoni ME, Nargeot
J, Gros D, Miquerol L: Nkx2.5 cellautonomous
gene function is required for the
postnatal formation of the peripheral
ventricular conduction system. Dev Biol 303:740-753, 2007.
Miquerol L, Meysen S, Mangoni M, Bois P, van
Rijen HV, Abran P, Jongsma H, Nargeot J,
Gros D: Architectural and functional
asymmetry of the His-Purkinje system of the
murine heart. Cardiovasc Res 63:77-86, 2004.
Mommersteeg MT, Hoogaars WM, Prall OW, de
Gier-de Vries C, Wiese C, Clout DE,
Papaioannou VE, Brown NA, Harvey RP,
Moorman AF, Christoffels VM: Molecular
pathway for the localized formation of the
sinoatrial node. Circ Res 100:354-362, 2007.
Moorman AF, de Jong F, Denyn MM, Lamers WH:
Development of the cardiac conduction
system. Circ. Res. 82:629-644, 1998.
Moorman AF, Christoffels VM: Cardiac chamber
formation: development, genes, and evolution.
Physiol Rev 83:1223-1267, 2003.
Moskowitz IP, Pizard A, Patel VV, Bruneau BG,
Kim JB, Kupershmidt S, Roden D, Berul CI,
Seidman CE, Seidman JG: The T-Box
transcription factor Tbx5 is required for the
patterning and maturation of the murine
cardiac conduction system. Development 131:4107-4116, 2004.
Myers DC, Fishman GI: Toward an understanding
of the genetics of murine cardiac pacemaking
and conduction system development. Anat
Rec 280A:1018-1021, 2004.
Nakamura T, Colbert MC, Robbins J: Neural crest
cells retain multipotential characteristics in the
developing valves and label the cardiac
conduction system. Circ Res 98:1547-1554, 2006.
Nygren A, Clark RB, Belke DD, Kondo C, Giles
WR, Witkowski FX: Voltage-sensitive dye
mapping of activation and conduction in adult
mouse hearts. Ann Biomed Eng 28:958-967, 2000.
Ozcelik C, Erdmann B, Pilz B, Wettschureck N,
Britsch S, Hubner N, Chien KR, Birchmeier
C, Garratt AN: Conditional mutation of the
ErbB2 (HER2) receptor in cardiomyocytes
leads to dilated cardiomyopathy. Proc Natl
Acad Sci U.S.A. 99:8880-8885, 2002.
Pashmforoush M, Lu JT, Chen H, Amand TS,
Kondo R, Pradervand S, Evans SM, Clark B,
Feramisco JR, Giles W, Ho SY, Benson DW, Silberbach M, Shou W, Chien KR: 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, 2004.
Patel R, Kos L: Endothelin-1 and Neuregulin-1
convert embryonic cardiomyocytes into cells
of the conduction system in the mouse. Dev
Dyn 233:20-28, 2005.
Pennisi DJ, Rentschler S, Gourdie RG, Fishman GI,
Mikawa T: Induction and patterning of the
cardiac conduction system. Int J Dev Biol
46:765-775 2002.
Reckova M, Rosengarten C, deAlmeida A, Stanley
CP, Wessels A, Gourdie RG, Thompson RP,
Sedmera D: Hemodynamics is a key
epigenetic factor in development of the
cardiac conduction system. Circ Res 93:77-85, 2003.
Rentschler S, Vaidya DM, Tamaddon H,
Degenhardt K, Sassoon D, Morley GE, Jalife
J, Fishman GI: Visualization and functional
characterization of the developing murine
cardiac conduction system. Development 128:1785-1792, 2001.
Rentschler S, Zander J, Meyers K, France D,
Levine R, Porter G, Rivkees SA, Morley GE,
Fishman GI: Neuregulin-1 promotes formation
of the murine cardiac conduction system.
Proc Natl Acad Sci U.S.A. 99:10464-10469, 2002.
Robb JS: Comparative Basic Cardiology. Grune &
Stratton, New York and London 1965.
Rosen MR, Robinson RB, Brink P, Cohen IS:
Recreating the biological pacemaker. Anat
Rec A Discov Mol Cell Evol Biol 280:1046-1052, 2004.
Rothenberg F, Nikolski V, Watanabe M, Efimov I:
Electrophysiology and anatomy of embryonic
rabbit hearts before and after septation. Am J
Physiol Heart Circ Physiol 288:H344-H351, 2005.
Sanders E, de Groot IJ, Geerts WJ, de Jong F, van
Horssen AA, Los JA, Moorman AF: The local
expression of adult chicken heart myosins
during development. II. Ventricular
conducting tissue. Anat Embryol 174:187-193, 1986.
Sedmera D, Reckova M, DeAlmeida A, Sedmerova
M, Biermann M, Volejnik J, Sarre A,
Raddatz E, McCarthy RA, Gourdie RG,
Thompson RP: Functional and morphological
evidence for a ventricular conduction system
in the zebrafish and Xenopus heart. Am J
Physiol Heart Circ Physiol 284:H1152-H1160, 2003a.
Sedmera D, Reckova M, DeAlmeida A, Coppen
SR, Kubalak SW, Gourdie RG, Thompson
RP: Spatiotemporal pattern of commitment to
slowed proliferation in the embryonic mouse
heart indicates progressive differentiation of
the cardiac conduction system. Anat Rec
274A:773-777, 2003b.
Sedmera D, Reckova M, Rosengarten C, Torres MI,
Gourdie RG, Thompson RP: Optical mapping
of electrical activation in developing heart.
Microsc Microanal 11:209-215, 2005.
Takebayashi-Suzuki K, Yanagisawa M, Gourdie
RG, Kanzawa N, Mikawa T: In vivo induction
of cardiac Purkinje fiber differentiation by
coexpression of preproendothelin-1 and
endothelin converting enzyme-1.
Development 127:3523-3532, 2000.
Tamaddon HS, Vaidya D, Simon AM, Paul DL,
Jalife J, Morley GE: High-resolution optical
mapping of the right bundle branch in
connexin40 knockout mice reveals slow
conduction in the specialized conduction
system. Circ Res 87:929-936, 2000.
Thompson RP, Lindroth JR, Allen AJ, Fazel AR:
Cell differentiation birthdates in the
embryonic rat heart. Ann N.Y. Acad Sci
588:446-448, 1990.
van Veen TA, van Rijen HV, van Kempen MJ,
Miquerol L, Opthof T, Gros D, Vos MA,
Jongsma HJ, de Bakker JM: Discontinuous
conduction in mouse bundle branches is
caused by bundle-branch architecture.
Circulation 112:2235-2244, 2005.
Viswanathan S, Burch JB, Fishman GI, Moskowitz
IP, Benson DW: Characterization of sinoatrial
node in four conduction system marker mice.
J Mol Cell Cardiol 42:946-953, 2007.
Wessels A, Markman MW, Vermeulen JL,
Anderson RH, Moorman AF, Lamers WH:
The development of the atrioventricular
junction in the human heart. Circ Res 78:110-117, 1996.
Wolf CM, Berul CI: Inherited conduction system
abnormalities-one group of diseases, many
genes. J Cardiovasc Electrophysiol 17:446-455, 2006.
|
CITED
Sedmera D, McQuinn T: Embryogenesis of the Heart Muscle. Heart Failure Clinics 4:235-245, 2008.
|
