Abstract 19799: Slowed Activation in Acute Myocardial Infarction: Role of Lateralized Connexin43
Background: In acute myocardial infarction (MI) Connexin43 (Cx43) structural remodeling occurs by 30 min. However functional remodeling during this period has not been explored. We hypothesized that lateralized Cx43 is non-functional even at these early time points forming regions of slowed activation forming an arrhythmogenic substrate.
Objective: To determine remodeled Cx43 channel function and the electrophysiological consequences thereof in acute MI.
Methods: Using a canine model of coronary occlusion (CO) we examined epicardial tissue from normal hearts and hearts subjected to 30 min, 1 hr and 3 hrs CO. Sections were coimmunostained for total Cx43 and “undocked” Cx43 (with an extracellular loop antibody which only binds to Cx43 that does not form intercellular channels). Using a modified scrape-loading technique and epicardial mapping we examined the correlation between Cx43 remodeling and electrophysiological changes following acute MI.
Results: Lateralization of Cx43 started by 30 min post-CO and became more pronounced over time. Percent of undocked Cx43 increased after CO (13.9+/−1% (norm); 19.9+/−4.5% (30 min); 21.3+/−5% (1hr); 27+/−4% (3 hr p<0.05)) with the lateralized Cx43 predominantly consisting of “undocked” Cx43. Assessment of Cx43 channel function showed significant decrease in transverse dye spread after CO at all time points (118+/− 18.8 μm (normal); 32 +/− 7.8 μm (30 min); 56.7+/− 22.5 μm (1 hr); 46 +/− 15.7 μm (3 hr) p<0.05) indicating that gap junctions on the lateral membranes were closed. Longitudinal dye spread was also significantly decreased, suggesting that overall Cx43 channel function was diminished. Analysis of activation times in epicardial border zone showed significant slowing as early as 30 min of CO (13.9+/−0.67ms (norm) vs. 17+/−0.88ms, p<0.05) which was more prominent by 1hr (19.5+/−1.0ms) and 3 hrs post-CO (19.4+/−1.0ms).
Conclusions: Our studies suggest that Cx43 on the lateral membrane does not form intercellular channels therefore coupling in the transverse direction does not aid in maintaining conduction in the post-MI heart and with the overall reduced Cx43 channel function contributes to the formation of arrhythmogenic substrate.
- © 2010 by American Heart Association, Inc.