title: Cardiac conduction is required to preserve cardiac chamber morphology.
abstract: Electrical cardiac forces have been previously hypothesized to play a significant role in cardiac morphogenesis and remodeling. In response to electrical forces, cultured cardiomyocytes rearrange their cytoskeletal structure and modify their gene expression profile. To translate such in vitro data to the intact heart, we used a collection of zebrafish cardiac mutants and transgenics to investigate whether cardiac conduction could influence in vivo cardiac morphogenesis independent of contractile forces. We show that the cardiac mutant dco(s226) develops heart failure and interrupted cardiac morphogenesis following uncoordinated ventricular contraction. Using in vivo optical mapping/calcium imaging, we determined that the dco cardiac phenotype was primarily due to aberrant ventricular conduction. Because cardiac contraction and intracardiac hemodynamic forces can also influence cardiac development, we further analyzed the dco phenotype in noncontractile hearts and observed that disorganized ventricular conduction could affect cardiomyocyte morphology and subsequent heart morphogenesis in the absence of contraction or flow. By positional cloning, we found that dco encodes Gja3/Cx46, a gap junction protein not previously implicated in heart formation or function. Detailed analysis of the mouse Cx46 mutant revealed the presence of cardiac conduction defects frequently associated with human heart failure. Overall, these in vivo studies indicate that cardiac electrical forces are required to preserve cardiac chamber morphology and may act as a key epigenetic factor in cardiac remodeling.
authors.affiliation: Departments of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA. nchi@ucsd.edu
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
authors.forename: Markus
authors.initials: M
authors.lastname: Bussen
authors.forename: Koroboshka
authors.initials: K
authors.lastname: Brand-Arzamendi
authors.forename: Chunhua
authors.initials: C
authors.lastname: Ding
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Olgin
authors.forename: Robin M
authors.initials: RM
authors.lastname: Shaw
authors.forename: Gail R
authors.initials: GR
authors.lastname: Martin
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017630:Connexins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D004562:Electrocardiography; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000196:embryology / Q000502:physiology*; D006329:Heart Conduction System / Q000502:physiology*; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017630:Connexins; D029961:Zebrafish Proteins; C082917:GJA3 protein, human; D049452:Green Fluorescent Proteins