title: Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents.
abstract: Gap junction redistribution and reduced expression, a phenomenon termed gap junction remodeling (GJR), is often seen in diseased hearts and may predispose toward arrhythmias. We have recently shown that short-term pacing in the mouse is associated with changes in connexin43 (Cx43) expression and localization but not with increased inducibility into sustained arrhythmias. We hypothesized that short-term pacing, if imposed on murine hearts with decreased Cx43 abundance, could serve as a model for evaluating the electrophysiological effects of GJR. We paced wild-type (normal Cx43 abundance) and heterozygous Cx43 knockout (Cx43+/-; 66% mean reduction in Cx43) mice for 6 h at 10-15% above their average sinus rate. We investigated the electrophysiological effects of pacing on the whole animal using programmed electrical stimulation and in isolated ventricular myocytes with patch-clamp studies. Cx43+/- myocytes had significantly shorter action potential durations (APD) and increased steady-state (Iss) and inward rectifier (I(K1)) potassium currents compared with those of wild-type littermate cells. In Cx43+/- hearts, pacing resulted in a significant prolongation of ventricular effective refractory period and APD and significant diminution of Iss compared with unpaced Cx43+/- hearts. However, these changes were not seen in paced wild-type mice. These data suggest that Cx43 abundance plays a critical role in regulating currents involved in myocardial repolarization and their response to pacing. Our study may aid in understanding how dyssynchronous activation of diseased, Cx43-deficient myocardial tissue can lead to electrophysiological changes, which may contribute to the worsened prognosis often associated with pacing in the failing heart.
authors.affiliation: Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Andrianos
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authors.lastname: Kontogeorgis
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authors.forename: Eunice Y
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authors.lastname: Kang
authors.forename: Jonathan E
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authors.forename: Guoxin
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authors.lastname: Kang
authors.forename: Riyaz A
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authors.lastname: Kaba
authors.forename: Andrew L
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authors.forename: Edward A
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authors.forename: Gregory E
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authors.lastname: Morley
authors.forename: Nicholas S
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authors.lastname: Peters
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: David E
authors.initials: DE
authors.lastname: Gutstein