title: Reduced intercellular coupling leads to paradoxical propagation across the Purkinje-ventricular junction and aberrant myocardial activation.
abstract: Ventricular tachycardia is a common heart rhythm disorder and a frequent cause of sudden cardiac death. Aberrant cell-cell coupling through gap junction channels, a process termed gap junction remodeling, is observed in many of the major forms of human heart disease and is associated with increased arrhythmic risk in both humans and in animal models. Genetically engineered mice with cardiac-restricted knockout of Connexin43, the major cardiac gap junctional protein, uniformly develop sudden cardiac death, although a detailed electrophysiological understanding of their profound arrhythmic propensity is unclear. Using voltage-sensitive dyes and high resolution optical mapping techniques, we found that uncoupling of the ventricular myocardium results in ectopic sites of ventricular activation. Our data indicate that this behavior reflects alterations in source-sink relationships and paradoxical conduction across normally quiescent Purkinje-ventricular muscle junctions. The aberrant activation profiles are associated with wavefront collisions, which in the setting of slow conduction may account for the highly arrhythmogenic behavior of Connexin43-deficient hearts. Thus, the extent of gap junction remodeling in diseased myocardium is a critical determinant of cardiac excitation patterns and arrhythmia susceptibility.
authors.affiliation: The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Morley
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Danik
authors.forename: Scott
authors.initials: S
authors.lastname: Bernstein
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Sun
authors.forename: Gregg
authors.initials: G
authors.lastname: Rosner
authors.forename: David E
authors.initials: DE
authors.lastname: Gutstein
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
mesh_terms: D000818:Animals; D004562:Electrocardiography; D017930:Genes, Reporter; D006352:Heart Ventricles / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011690:Purkinje Fibers / Q000378:metabolism*; D013610:Tachycardia / Q000378:metabolism