Connexin 43 Expression Delineates Two Discrete Pathways in the Human Atrioventricular Junction

Gap junction expression has been studied in the atrioventricular junction (AVJ) of many species, however, their distribution in the human AVJ is unknown. The AVJ expression of the gap junction protein connexin 43 (Cx43) is species dependent; therefore we investigated its distribution in the human AVJ. Using Masson trichrome histology, we reconstructed the AVJ of three normal human hearts and one with dilated cardiomyopathy in three dimensions. Cx43 was immunolabeled with vimentin and α‐actinin to determine the cellular origin of Cx43 and was quantified in the following structures: interatrial septum (IAS), His bundle, compact node (CN), lower nodal bundle (LNB), leftward and rightward nodal extensions (LE and RE), and inferior, endocardial, and left‐sided transitional cells. Histology revealed two nodal extensions in three of four hearts. Cx43 was found in the myocytes, but not fibroblasts, of the AVJ. LE and CN Cx43 was lower than the IAS (P < 0.05) and the RE, LNB, and His all expressed Cx43 similarly, with approximately half of IAS expression (RE: 44 ± 36%; LNB: 50 ± 26%; His: 48 ± 12%, P = NS compared with IAS). Cx43 levels in transitional cells were similar to the IAS (P = not significant). Cx43 was found in myocytes of the human AVJ, and its expression pattern delineates two separate continuous structures: one consists of the LE and CN with little Cx43, and the other consists of the His, LNB, and RE expressing approximately half the Cx43 of the IAS. The differential Cx43 expression may provide each structure with unique conduction properties, contributing to arrhythmias arising from the AVJ. Anat Rec, 2007. © 2007 Wiley‐Liss, Inc.

[1]  T. Borg,et al.  Structural and functional characterisation of cardiac fibroblasts. , 2005, Cardiovascular research.

[2]  Paul A Iaizzo,et al.  Excitation of the Intrinsic Conduction System Through His and Interventricular Septal Pacing , 2006, Pacing and clinical electrophysiology : PACE.

[3]  I. Efimov,et al.  Three-dimensional anatomy of the conduction system of the early embryonic rabbit heart. , 2006, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[4]  J E Saffitz,et al.  Gap Junction Protein Phenotypes of the Human Heart and Conduction System , 1995, Journal of cardiovascular electrophysiology.

[5]  J. B. Preston,et al.  Physiologic Evidence for a Dual A‐V Transmission System , 1956, Circulation research.

[6]  Robert H. Anderson,et al.  A Combined Morphological and Electrophysiological Study of the Atrioventricular Node of the Rabbit Heart , 1974, Circulation research.

[7]  W. Staines,et al.  Reduction of Lipofuscin-like Autofluorescence in Fluorescently Labeled Tissue , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

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

[9]  Alex McFadden,et al.  Organization of fibroblasts in the heart , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[10]  P. Tchou,et al.  His Electrogram Alternans Reveal Dual-Wavefront Inputs Into and Longitudinal Dissociation Within the Bundle of His , 2001, Circulation.

[11]  Y Rudy,et al.  Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. , 1997, Circulation research.

[12]  I. Efimov,et al.  Autonomic control and innervation of the atrioventricular junctional pacemaker. , 2007, Heart rhythm.

[13]  Alexander Ghanem,et al.  Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Billette,et al.  Atrioventricular nodal activation during periodic premature stimulation of the atrium. , 1987, The American journal of physiology.

[15]  Yu-Chun Hsu,et al.  Three-Dimensional Reconstruction of the Rabbit Atrioventricular Conduction Axis by Combining Histological, Desmin, and Connexin Mapping Data , 2004, Circulation.

[16]  Robert H. Anderson,et al.  The Morphology of the Specialized Atrioventricular Junctional Area: The Evolution of Understanding , 2002, Pacing and clinical electrophysiology : PACE.

[17]  J. Billette What is the Atrioventricular Node? Some Clues in Sorting out its Structure‐Function Relationship , 2002, Journal of cardiovascular electrophysiology.

[18]  I. Efimov,et al.  Cx43 and Dual-Pathway Electrophysiology of the Atrioventricular Node and Atrioventricular Nodal Reentry , 2003, Circulation research.

[19]  M. Yacoub,et al.  Altered connexin expression in human congestive heart failure. , 2001, Journal of molecular and cellular cardiology.

[20]  D. Sigg,et al.  Focal Pharmacological Modulation of Atrioventricular Nodal Conduction via Implantable Catheter: A Novel Therapy for Atrial Fibrillation? , 2006, Circulation.

[21]  N. Billinton,et al.  Seeing the wood through the trees: a review of techniques for distinguishing green fluorescent protein from endogenous autofluorescence. , 2001, Analytical biochemistry.

[22]  G. Rigatelli,et al.  A Feasible Approach for Direct His‐Bundle Pacing Using a New Steerable Catheter to Facilitate Precise Lead Placement , 2005, Cardiovascular Electrophysiology.

[23]  I. Efimov,et al.  Site of Origin and Molecular Substrate of Atrioventricular Junctional Rhythm in the Rabbit Heart , 2003, Circulation research.

[24]  A. Becker,et al.  The atrioventricular nodal reentrant tachycardia circuit: a proposal. , 2007, Heart rhythm.

[25]  F. Cosío,et al.  Living anatomy of the atrioventricular junctions. A guide to electrophysiologic mapping. A Consensus Statement from the Cardiac Nomenclature Study Group, Working Group of Arrhythmias, European Society of Cardiology, and the Task Force on Cardiac Nomenclature from NASPE. , 1999, Circulation.

[26]  J. Skepper,et al.  Comparison of connexin expression patterns in the developing mouse heart and human foetal heart , 2004, Molecular and Cellular Biochemistry.

[27]  N. Severs,et al.  Diversity of Connexin Expression Patterns in the Atrioventricular Node: Vestigial Consequence or Functional Specialization? , 2002, Journal of cardiovascular electrophysiology.

[28]  A E Becker,et al.  Anatomic and functional characteristics of a slow posterior AV nodal pathway: role in dual-pathway physiology and reentry. , 1998, Circulation.

[29]  H. Zhang,et al.  Connexins in the sinoatrial and atrioventricular nodes. , 2006, Advances in cardiology.

[30]  A. Becker,et al.  Posterior extensions of the human compact atrioventricular node: a neglected anatomic feature of potential clinical significance. , 1998, Circulation.

[31]  Igor R Efimov,et al.  Atrioventricular conduction with and without AV nodal delay: two pathways to the bundle of His in the rabbit heart. , 2007, American journal of physiology. Heart and circulatory physiology.

[32]  F. Gaita,et al.  Interruption of the Inferior Extension of the Compact Atrioventricular Node Underlies Successful Radio Frequency Ablation of Atrioventricular Nodal Reentrant Tachycardia , 1999, Journal of Interventional Cardiac Electrophysiology.

[33]  P. Iaizzo,et al.  Dynamic obstruction to coronary sinus access: the Thebesian valve. , 2006, Heart rhythm.