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Am J Physiol Heart Circ Physiol (April 13, 2007). doi:10.1152/ajpheart.00079.2007
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Submitted on January 18, 2007
Accepted on April 12, 2007

Dynamic Changes in Conduction Velocity and Gap Junction Properties During Development of Pacing Induced Heart Failure

Fadi G Akar1*, Robert D Nass1, Samuel Hahn1, Eugenio Cingolani1, Manish Shah1, Geoffrey G Hesketh1, Deborah DiSilvestre1, Richard S Tunin1, David A Kass1, and Gordon F Tomaselli1

1 Cardiology, Johns Hopkins University, Baltimore, Maryland, United States

* To whom correspondence should be addressed. E-mail: fakar1{at}jhmi.edu.

End-stage heart failure (HF) is characterized by changes in conduction velocity (CV) that predispose to arrhythmias. Here, we investigate the time-course of conduction changes with respect to alterations in Cx43 properties and mechanical function during the development of HF. Methods: We perform high-resolution optical mapping in arterially perfused myocardial preparations from dogs subjected to 0, 3, 7, 14, and 21-days of rapid pacing to produce variable degrees of remodeling. CV is compared to an index of mechanical function (LVEDP) and to dynamic changes in the expression, distribution, and phosphorylation of Cx43. Results: Unlike repolarization, CV was preserved during early stages of remodeling (3- and 7-day), and underwent significant reduction at later stages, which were associated with marked increases in LVEDP. Measurements of differentially phosphorylated Cx43 isoforms revealed early, sustained down-regulation of panCx43 that preceded changes in CV and LVEDP, a gradual rise in a dephosphorylated (DP) Cx43 isoform to over 2-fold baseline levels in end-stage HF, and a late abrupt increase in pan- but not DP-Cx43 lateralization. Conclusions: These data demonstrate that: 1) CV slowing occurs only at advanced stages of remodeling, 2) total reduction of PanCx43 is an early event that precedes mechanical dysfunction and CV slowing, 3) changes in Cx43 phosphorylation are more closely associated with the onset of HF, and 4) Cx43 lateralization is a late event which coincides with marked CV reduction. These data reveal a novel paradigm of remodeling based on the timing of conduction abnormalities relative to changes in Cx43 isoforms and mechanical dysfunction.




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