Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents

Kontogeorgis A, Li X, Kang EY, Feig JE, Ponzio M, Kang G, Kaba RA, Wit AL, Fisher EA, Morley GE, Peters NS, Coetzee WA, Gutstein DE. Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents. Am J Physiol Heart Circ Physiol 295: H1905-H1916, 2008. First published August 29, 2008; doi:10.1152/ajpheart.590.2008. - 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 (I-ss) 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.