title: Electrotonic suppression of early afterdepolarizations in the neonatal rat ventricular myocyte monolayer.
abstract: Pathologies that result in early afterdepolarizations (EADs) are a known trigger for tachyarrhythmias, but the conditions that cause surrounding tissue to conduct or suppress EADs are poorly understood. Here we introduce a cell culture model of EAD propagation consisting of monolayers of cultured neonatal rat ventricular myocytes treated with anthopleurin-A (AP-A). AP-A-treated monolayers display a cycle length dependent prolongation of action potential duration (245 ms untreated, vs. 610 ms at 1 Hz and 1200 ms at 0.5 Hz for AP-A-treated monolayers). In contrast, isolated single cells treated with AP-A develop prominent irregular oscillations with a frequency of 2.5 Hz, and a variable prolongation of the action potential duration of up to several seconds. To investigate whether electrotonic interactions between coupled cells modulates EAD formation, cell connectivity was reduced by RNA silencing gap junction Cx43. In contrast to well-connected monolayers, gap junction silenced monolayers display bradycardia-dependent plateau oscillations consistent with EADs. Further, simulations of a cell displaying EADs electrically connected to a cell with normal action potentials show a coupling strength-dependent suppression of EADs consistent with the experimental results. These results suggest that electrotonic effects may play a critical role in EAD-mediated arrhythmogenesis.
authors.affiliation: G. Bub: Department of Physiology Anatomy and Genetics, Sherrington Building Room C-33, University of Oxford, Oxford, Oxfordshire, UK, OX1 3PT. gil.bub@dpag.ox.ac.uk.
authors.forename: Herman D
authors.initials: HD
authors.lastname: Himel
authors.forename: Alan
authors.initials: A
authors.lastname: Garny
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Noble
authors.forename: Raj
authors.initials: R
authors.lastname: Wadgaonkar
authors.forename: Joseph
authors.initials: J
authors.lastname: Savarese
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.forename: Gil
authors.initials: G
authors.lastname: Bub
authors.forename: Nabil
authors.initials: N
authors.lastname: El-Sherif
mesh_terms: D000200:Action Potentials; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology* / Q000254:growth & development; D036341:Intercellular Signaling Peptides and Proteins; D008564:Membrane Potentials; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats
chemical_list: D002316:Cardiotonic Agents; D018031:Connexin 43; C580592:Gja1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C012746:anthopleurin-A
references.citation: Circ Res. 1994 Jun;74(6):1097-113
references.pmid: 7514510
references.citation: Circulation. 1991 Nov;84(5):1915-23
references.pmid: 1657447
references.citation: Biophys J. 2008 Nov 1;95(9):4469-80
references.pmid: 18658226
references.citation: Heart Rhythm. 2012 Apr;9(4):600-7
references.pmid: 22100711
references.citation: Circ Res. 2003 Sep 5;93(5):421-8
references.pmid: 12893743
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):2983-8
references.pmid: 19218447
references.citation: Heart Rhythm. 2012 Dec;9(12):2077-82
references.pmid: 23108055
references.citation: Proc Natl Acad Sci U S A. 1988 May;85(10):3431-4
references.pmid: 2453059
references.citation: Circ Res. 1989 May;64(5):977-90
references.pmid: 2468430
references.citation: Cardiovasc Res. 2012 Apr 1;94(1):58-65
references.pmid: 22287588
references.citation: Circ Res. 1988 Aug;63(2):286-305
references.pmid: 3396153
references.citation: J Gen Physiol. 1995 Oct;106(4):617-40
references.pmid: 8576700
references.citation: J Physiol. 1972 Nov;226(3):593-618
references.pmid: 4637625
references.citation: J Am Coll Cardiol. 1996 May;27(6):1526-33
references.pmid: 8626969
references.citation: J Physiol. 1998 May 1;508 ( Pt 3):811-23
references.pmid: 9518735
references.citation: Cardiovasc Res. 1992 May;26(5):543-8
references.pmid: 1280184
references.citation: Heart Rhythm. 2006 Jan;3(1):58-66
references.pmid: 16399055
references.citation: J Physiol. 2002 Sep 1;543(Pt 2):615-31
references.pmid: 12205194
references.citation: Circ Res. 1995 Jan;76(1):102-9
references.pmid: 8001267
references.citation: Eur Biophys J. 2008 Apr;37(4):509-14
references.pmid: 17687549
references.citation: Circ Res. 1992 Feb;70(2):285-301
references.pmid: 1346508
references.citation: J Physiol. 1972 Oct;226(2):573-91
references.pmid: 5085347
references.citation: Cardiovasc Res. 1994 Aug;28(8):1277-84
references.pmid: 7954634
references.citation: Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1636-44
references.pmid: 22307670
references.citation: J Cardiovasc Electrophysiol. 1994 Jul;5(7):609-20
references.pmid: 7987531
references.citation: Prog Biophys Mol Biol. 2008 Jan-Apr;96(1-3):258-80
references.pmid: 17888503