Development of the cardiac conduction system.

The cardiac conduction system (CCS) is a specialized tissue network that initiates and maintains a rhythmic heartbeat. The CCS consists of several functional subcomponents responsible for producing a pacemaking impulse and distributing action potentials across the heart in a coordinated manner. The formation of the distinct subcomponents of the CCS occurs within a precise temporal and spatial framework; thereby assuring that as the system matures from a tubular to a complex chambered organ, a rhythmic heartbeat is always maintained. Therefore, a defect in differentiation of any CCS component would lead to severe rhythm disturbances. Recent molecular, cell biological and physiological approaches have provided fresh and unexpected perspectives of the relationships between cell fate, gene expression and differentiation of specialized function within the developing myocardium. In particular, biomechanical forces created by the heartbeat itself have important roles in the inductive patterning and functional integration of the developing conduction system. This new understanding of the cellular origin and molecular induction of CCS tissues during embryogenesis may provide the foundation for tissue engineering, replacement and repair of these essential cardiac tissues in the future.

[1]  C. Lo,et al.  Cx43 gap junctions in cardiac development. , 1998, Trends in cardiovascular medicine.

[2]  T. Mikawa,et al.  Fate diversity of primitive streak cells during heart field formation in ovo , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[3]  T. Mikawa,et al.  The fate diversity of mesodermal cells within the heart field during chicken early embryogenesis. , 1996, Developmental biology.

[4]  S. Schiaffino Protean patterns of gene expression in the heart conduction system. , 1997, Circulation research.

[5]  T. Mikawa,et al.  In vivo induction of cardiac Purkinje fiber differentiation by coexpression of preproendothelin-1 and endothelin converting enzyme-1. , 2000, Development.

[6]  M. Kirby,et al.  Neural crest and cardiovascular development: a 20-year perspective. , 2003, Birth defects research. Part C, Embryo today : reviews.

[7]  A. Moorman,et al.  T‐box transcription factor Tbx2 represses differentiation and formation of the cardiac chambers , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[8]  K Kamino,et al.  Optical approaches to ontogeny of electrical activity and related functional organization during early heart development. , 1991, Physiological reviews.

[9]  U. Hoppe,et al.  Endothelin induces differentiation of ANP‐EGFP expressing embryonic stem cells towards a pacemaker phenotype , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  F Davies,et al.  The Conducting System of the Bird's Heart. , 1930, Journal of anatomy.

[11]  W H Lamers,et al.  Spatial distribution of connexin43, the major cardiac gap junction protein, in the developing and adult rat heart. , 1991, Circulation research.

[12]  R. P. Thompson,et al.  The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. , 1993, Journal of cell science.

[13]  J E Saffitz,et al.  The Molecular Basis of Anisotropy: Role of Gap Junctions , 1995, Journal of cardiovascular electrophysiology.

[14]  Calum A MacRae,et al.  Notch1b and neuregulin are required for specification of central cardiac conduction tissue , 2006, Development.

[15]  J Jalife,et al.  Connexins and Impulse Propagation in the Mouse Heart , 1999, Journal of cardiovascular electrophysiology.

[16]  T. Mikawa,et al.  Retroviral analysis of cardiac morphogenesis: discontinuous formation of coronary vessels. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Yanagisawa,et al.  ECE-1: A membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1 , 1994, Cell.

[18]  J. Seidman,et al.  Congenital heart disease caused by mutations in the transcription factor NKX2-5. , 1998, Science.

[19]  Robert H. Anderson,et al.  Anatomic substrates for cardiac conduction. , 2005, Heart rhythm.

[20]  T. Sakurai,et al.  Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor , 1990, Nature.

[21]  T. Yada,et al.  Development of electrical rhythmic activity in early embryonic cultured chick double-heart monitored optically with a voltage-sensitive dye. , 1985, Developmental biology.

[22]  A Keith,et al.  The Form and Nature of the Muscular Connections between the Primary Divisions of the Vertebrate Heart. , 1907, Journal of anatomy and physiology.

[23]  M. Yanagisawa,et al.  Endothelin-converting Enzyme-2 Is a Membrane-bound, Phosphoramidon-sensitive Metalloprotease with Acidic pH Optimum (*) , 1995, The Journal of Biological Chemistry.

[24]  M. Kirby,et al.  Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart. , 2005, Developmental biology.

[25]  W. Denetclaw,et al.  Common epicardial origin of coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts in the avian heart. , 1998, Developmental biology.

[26]  Tomoki Nakamura,et al.  Neural Crest Cells Retain Multipotential Characteristics in the Developing Valves and Label the Cardiac Conduction System , 2006, Circulation research.

[27]  C. Green,et al.  Evidence for a distinct gap-junctional phenotype in ventricular conduction tissues of the developing and mature avian heart. , 1993, Circulation research.

[28]  A. Moorman,et al.  Downregulation of connexin 45 gene products during mouse heart development. , 1999, Circulation research.

[29]  T. Mikawa,et al.  Constitutive expression of preproendothelin in the cardiac neural crest selectively promotes expansion of the adventitia of the great vessels in vivo. , 2002, Developmental biology.

[30]  V. García-Martínez,et al.  Primitive-streak origin of the cardiovascular system in avian embryos. , 1993, Developmental Biology.

[31]  T. Mikawa,et al.  Clonal analysis of cardiac morphogenesis in the chicken embryo using a replication‐defective retrovirus. III: Polyclonal origin of adjacent ventricular myocytes , 1992, Developmental dynamics : an official publication of the American Association of Anatomists.

[32]  T. Mikawa,et al.  The polyclonal origin of myocyte lineages. , 1996, Annual review of physiology.

[33]  W. Giles,et al.  Nkx2-5 Pathways and Congenital Heart Disease Loss of Ventricular Myocyte Lineage Specification Leads to Progressive Cardiomyopathy and Complete Heart Block , 2004, Cell.

[34]  Larry V. McIntire,et al.  DNA microarray reveals changes in gene expression of shear stressed human umbilical vein endothelial cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  B. M. Patten,et al.  The initiation of contraction in the embryonic chick heart , 1933 .

[36]  T Hiruma,et al.  Epicardial formation in embryonic chick heart: computer-aided reconstruction, scanning, and transmission electron microscopic studies. , 1989, The American journal of anatomy.

[37]  T. Mikawa,et al.  Purkinje fibers of the avian heart express a myogenic transcription factor program distinct from cardiac and skeletal muscle. , 2001, Developmental biology.

[38]  M. Lieberman,et al.  The Electrophysiological Organization of the Embryonic Chick Heart , 1965, The Journal of general physiology.

[39]  Takashi Mikawa,et al.  Induction and patterning of the cardiac conduction system. , 2002, The International journal of developmental biology.

[40]  P. Tam,et al.  Cardiac Fate Maps: Lineage Allocation, Morphogenetic Movement, and Cell Commitment , 1999 .

[41]  J Jalife,et al.  Visualization and functional characterization of the developing murine cardiac conduction system. , 2001, Development.

[42]  Y. Shimada,et al.  Formation of the epicardium studied with the scanning electron microscope. , 1978, Developmental biology.

[43]  田淵 淳,et al.  Das Reizleitungssystem des Säugetierherzens : eine anatomisch-histologische Studie über das Atrioventrikularbündel und die Purkinjeschen Fäden , 1906 .

[44]  Rüdiger Klein,et al.  Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor , 1995, Nature.

[45]  R. P. Thompson,et al.  Developmental transitions in electrical activation patterns in chick embryonic heart. , 2004, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[46]  G. Callewaert,et al.  Existence of a calcium-dependent potassium channel in the membrane of cow cardiac Purkinje cells , 1986, Pflügers Archiv European Journal of Physiology.

[47]  T. Mikawa,et al.  Cytoskeletal Gene Expression in the Developing Cardiac Conduction System , 2002 .

[48]  S. Rivkees,et al.  Neuregulin-1 promotes formation of the murine cardiac conduction system , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[49]  C. Eisenberg,et al.  Wnt11 and Wnt7a are up‐regulated in association with differentiation of cardiac conduction cells in vitro and in vivo , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[50]  T. Mikawa,et al.  The use of replication-defective retroviruses for cell lineage studies of myogenic cells. , 1997, Methods in cell biology.

[51]  T. Mikawa,et al.  Retroviral cell lineage analysis in the developing chick heart. , 2000, Methods in molecular biology.

[52]  M. Silverman,et al.  Why does the heart beat? The discovery of the electrical system of the heart. , 2006, Circulation.

[53]  P. R. Vassall-Adams The development of the atrioventricular bundle and its branches in the avian heart. , 1982, Journal of anatomy.

[54]  D. Roden,et al.  Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system. , 2004, The Journal of clinical investigation.

[55]  K W Hewett,et al.  The rate and anisotropy of impulse propagation in the postnatal terminal crest are correlated with remodeling of Cx43 gap junction pattern. , 2000, Cardiovascular research.

[56]  M. Lieberman,et al.  The Spread of Excitation in the Embryonic Chick Heart , 1965, The Journal of general physiology.

[57]  D. Opel,et al.  Neuregulins Promote Survival and Growth of Cardiac Myocytes , 1998, The Journal of Biological Chemistry.

[58]  T. Mikawa,et al.  Endothelin-induced conversion of embryonic heart muscle cells into impulse-conducting Purkinje fibers. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Robert P. Thompson,et al.  Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts. , 2003, American journal of physiology. Heart and circulatory physiology.

[60]  A. G. Gittenberger-de Groot,et al.  A subpopulation of apoptosis-prone cardiac neural crest cells targets to the venous pole: multiple functions in heart development? , 1999, Developmental biology.

[61]  D. M. Freeman,et al.  Changing activation sequence in the embryonic chick heart. Implications for the development of the His-Purkinje system. , 1997, Circulation research.

[62]  D. Benson,et al.  Differentiation of cardiac Purkinje fibers requires precise spatiotemporal regulation of Nkx2‐5 expression , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[63]  D. Roden,et al.  Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. , 1999, Circulation research.

[64]  A. Moorman,et al.  The development of the avian conduction system, a review. , 1991, European journal of morphology.

[65]  M. Rosen,et al.  Electrophysiologic Characteristics of Human Ventricular and Purkinje Fibers , 1982, Circulation.

[66]  Robert G. Gourdie,et al.  Hemodynamics Is a Key Epigenetic Factor in Development of the Cardiac Conduction System , 2003, Circulation research.

[67]  G. Fischbach,et al.  Neuregulin stimulates DNA synthesis in embryonic chick heart cells. , 1999, Developmental biology.

[68]  T. Mikawa,et al.  Competency of embryonic cardiomyocytes to undergo Purkinje fiber differentiation is regulated by endothelin receptor expression. , 2002, Development.

[69]  R. P. Thompson,et al.  Expression of homeobox genes Msx‐1 (Hox‐7) and Msx‐2 (Hox‐8) during cardiac development in the chick , 1993, Developmental dynamics : an official publication of the American Association of Anatomists.

[70]  S. Nakanishi,et al.  Cloning and expression of a cDNA encoding an endothelin receptor , 1990, Nature.

[71]  J. Seidman,et al.  Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. , 1999, Developmental biology.

[72]  J. Seidman,et al.  Summary The T-Box transcription factor Tbx 5 is required for the patterning and maturation of the murine cardiac conduction system , 2004 .

[73]  T. Mikawa,et al.  Clonal analysis of cardiac morphogenesis in the chicken embryo using a replication‐defective retrovirus: I. Formation of the ventricular myocardium , 1992, Developmental dynamics : an official publication of the American Association of Anatomists.

[74]  Lamers Wh,et al.  The development of the avian conduction system, a review. , 1991 .

[75]  Michiko Watanabe,et al.  Differential expression of PSA‐NCAM and HNK‐1 epitopes in the developing cardiac conduction system of the chick , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[76]  S. Vettore,et al.  Molecular and cellular diversity of heart conduction system myocytes. , 1994, Trends in cardiovascular medicine.

[77]  W H Lamers,et al.  Persisting zones of slow impulse conduction in developing chicken hearts. , 1992, Circulation research.

[78]  A. B. Brown,et al.  A Novel Genetic Pathway for Sudden Cardiac Death via Defects in the Transition between Ventricular and Conduction System Cell Lineages , 2000, Cell.

[79]  T. Opthof,et al.  If Current and Spontaneous Activity in Mouse Embryonic Ventricular Myocytes , 2001, Circulation research.

[80]  G. Breithardt,et al.  Pacemaker channel dysfunction in a patient with sinus node disease. , 2003, The Journal of clinical investigation.

[81]  C. E. Challice,et al.  The structure of the atrioventricular conducting system in the avian heart , 1986, The Anatomical record.

[82]  M. Yacoub,et al.  Elevated expression of Nkx‐2.5 in developing myocardial conduction cells , 2001, The Anatomical record.

[83]  M. Buckingham,et al.  A retrospective clonal analysis of the myocardium reveals two phases of clonal growth in the developing mouse heart , 2003, Development.

[84]  A. McMahon,et al.  Fate of the mammalian cardiac neural crest. , 2000, Development.

[85]  T. Mikawa,et al.  Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. , 1996, Developmental biology.

[86]  H Honjo,et al.  The sinoatrial node, a heterogeneous pacemaker structure. , 2000, Cardiovascular research.

[87]  Y. Yazaki,et al.  Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. , 1989, Biochemical and biophysical research communications.

[88]  T. Mikawa,et al.  Hemodynamic-dependent patterning of endothelin converting enzyme 1 expression and differentiation of impulse-conducting Purkinje fibers in the embryonic heart , 2004, Development.

[89]  Sadao Kimura,et al.  A novel potent vasoconstrictor peptide produced by vascular endothelial cells , 1988, Nature.

[90]  T. Mikawa,et al.  Retroviral vectors to study cardiovascular development. , 1996, Trends in cardiovascular medicine.

[91]  M. Biel,et al.  The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[92]  C. Birchmeier,et al.  Multiple essential functions of neuregulin in development , 1995, Nature.

[93]  S. Siegelbaum,et al.  Hyperpolarization-activated cation currents: from molecules to physiological function. , 2003, Annual review of physiology.

[94]  M. Vitadello,et al.  Distribution of conduction system fibers in the developing and adult rabbit heart revealed by an antineurofilament antibody. , 1989, Circulation research.

[95]  Vassall-Adams Pr The development of the atrioventricular bundle and its branches in the avian heart. , 1982 .

[96]  Kuo-Fen Lee,et al.  Requirement for neuregulin receptor erbB2 in neural and cardiac development , 1995, Nature.

[97]  J. Epstein,et al.  Homeobox Protein Hop Functions in the Adult Cardiac Conduction System , 2005, Circulation research.

[98]  Rita R. Patel,et al.  Endothelin‐1 and Neuregulin‐1 convert embryonic cardiomyocytes into cells of the conduction system in the mouse , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[99]  W. Aird,et al.  A vascular bed-specific pathway. , 1999, The Journal of clinical investigation.

[100]  T. Mikawa,et al.  Evidence for an extracellular matrix bridge guiding proepicardial cell migration to the myocardium of chick embryos , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[101]  R. P. Thompson,et al.  Development of the cardiac conduction system involves recruitment within a multipotent cardiomyogenic lineage. , 1999, Development.

[102]  J. Epstein,et al.  Migration of cardiac neural crest cells in Splotch embryos. , 2000, Development.

[103]  H. Jockusch,et al.  Patterns of myocardial histogenesis as revealed by mouse chimeras. , 2005, Developmental biology.

[104]  K. Chien,et al.  Neurofilament M mRNA is expressed in conduction system myocytes of the developing and adult rabbit heart. , 1996, Journal of molecular and cellular cardiology.

[105]  J. Epstein,et al.  Cardiac neural crest. , 2005, Seminars in cell & developmental biology.

[106]  A. Moorman,et al.  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 , 1992, The Anatomical record.

[107]  A. Moorman,et al.  Spatial distribution of “tissue‐specific” antigens in the developing human heart and skeletal muscle. I. An immunohistochemical analysis of creatine kinase isoenzyme expression patterns , 1990, The Anatomical record.

[108]  M. Kirby Role of extracardiac factors in heart development , 1988, Experientia.

[109]  N. Severs,et al.  Connexin45 (alpha 6) expression delineates an extended conduction system in the embryonic and mature rodent heart. , 1999, Developmental genetics.

[110]  M. Runge,et al.  Principles of molecular cardiology , 2005 .

[111]  R. Hammer,et al.  Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. , 1998, Development.

[112]  M. Matteoli,et al.  Neurofilament proteins are co-expressed with desmin in heart conduction system myocytes. , 1990, Journal of cell science.

[113]  H. Morita,et al.  Functional Characterization of a Trafficking-defective HCN4 Mutation, D553N, Associated with Cardiac Arrhythmia* , 2004, Journal of Biological Chemistry.

[114]  W H Lamers,et al.  Development of the cardiac conduction system. , 1998, Circulation research.

[115]  S. Schiaffino,et al.  Heart conduction system: a neural crest derivative? , 1988, Brain Research.

[116]  T. Mikawa,et al.  Skeletal muscle-specific myosin binding protein-H is expressed in Purkinje fibers of the cardiac conduction system. , 1997, Circulation research.

[117]  W. Aird,et al.  A vascular bed–specific pathway regulates cardiac expression of endothelial nitric oxide synthase , 1999 .

[118]  Induction and Patterning of the Impulse Conducting Purkinje Fiber Network , 2007 .

[119]  T. Mikawa,et al.  Terminal diversification of the myocyte lineage generates Purkinje fibers of the cardiac conduction system. , 1995, Development.

[120]  U. Kaupp,et al.  Molecular diversity of pacemaker ion channels. , 2001, Annual review of physiology.

[121]  M. Kirby,et al.  Induction of Purkinje fiber differentiation by coronary arterialization. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[122]  J. Männer Experimental study on the formation of the epicardium in chick embryos , 1993, Anatomy and Embryology.

[123]  Kohtaro Kamino,et al.  Localization of pacemaking activity in early embryonic heart monitored using voltage-sensitive dye , 1981, Nature.

[124]  H. Jongsma,et al.  Connexins in mammalian heart function , 1996, BioEssays : news and reviews in molecular, cellular and developmental biology.