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1 The Heart and Vascular Research Center and Department of Biomedical Engineering, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, USA
* To whom correspondence should be addressed. E-mail: drosenbaum{at}metrohealth.org.
Recently, we found that repolarization heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias in failing myocardium. We hypothesized that the mechanism responsible for maintaining transmural action potential duration heterogeneities in heart failure is related to intercellular uncoupling from down-regulation of cardiac gap junction protein connexin43 (Cx43). Methods: Using the canine model of pacing induced heart failure; left ventricles were sectioned in order to expose the transmural surface (n=5). To determine if heterogeneous Cx43 expression influenced electrophysiologic function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure conduction velocity (
TM), effective transmural space constant (
TM), and transmural gradients of action potential duration (APD). Results: Relative Cx43 expression in failing myocardium, quantified by confocal immunofluorescence, was uniformly reduced (by 40±3%, p<0.01) compared to control. Relative Cx43 expression was heterogeneously distributed and lower (by 32±18%, p<0.05) in the subepicardium compared to deeper layers. Reduced Cx43 expression in heart failure was associated with significant reductions in intercellular coupling between transmural muscle layers as evidenced by reduced TM (by 18.9 ±4.9%) and TM (by 17.2±1.4%, p<0.01) compared to control. Heterogeneous transmural distribution of Cx43 in failing myocardium was associated with lower subepicardial TM (by 12±10%) and TM (by 13±7%) compared to deeper transmural layers (p<0.05). APD dispersion was greatest in failing myocardium, and the largest transmural APD gradients were consistently found in regions exhibiting lowest relative Cx43 expression. Conclusions: These data demonstrate that reduced Cx43 expression produces uncoupling between transmural muscle layers leading to slowed conduction and marked dispersion of repolarization between epicardial and deeper myocardial layers. Therefore, Cx43 expression patterns can potentially contribute to an arrhythmic substrate in failing myocardium.
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