Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents.
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.
Kontogeorgis
Andrianos
A
Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Li
Xiaodong
X
Kang
Eunice Y
EY
Feig
Jonathan E
JE
Ponzio
Marc
M
Kang
Guoxin
G
Kaba
Riyaz A
RA
Wit
Andrew L
AL
Fisher
Edward A
EA
Morley
Gregory E
GE
Peters
Nicholas S
NS
Coetzee
William A
WA
Gutstein
David E
DE