Nature, significance, and mechanisms of electrical heterogeneities in ventricle

Previously, dispersion of repolarization (DOR) has been extensively linked to the development of arrhythmias and sudden cardiac death. The electrical heterogeneities that cause DOR between transmural myocyte layers have been reported in a wide variety of animals and humans. The underlying causes of transmural electrical heterogeneities are in part due to heterogeneous functional expression of proteins responsible for ion handling. Recently, we found that electrophysiologic heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias. However, cell-to-cell coupling through gap junctions is expected to attenuate transmural heterogeneities between cell types spanning the ventricular wall. In this article we review a hypothesis that regional uncoupling resulting from expression patterns of gap junctions across the ventricular wall underlies DOR, and DOR can be amplified under disease conditions which remodel gap junctions. We find the principle gap junction protein, connexin43 (Cx43), is selectively reduced in the subepicardium (by 24%) compared to deeper layers of normal canine left ventricle. Additionally, the greatest DOR occurs within the subepicardial-midmyocardial interface, precisely where Cx43 expression is reduced. The present data suggests that ion channel and gap junction heterogeneities act in conjunction to form and maintain transmural DOR. Importantly, both ion channel and gap junction remodeling occurs during many disease states such as heart failure. Importantly, in the absence of ion channel remodeling, pharmacological uncoupling increases transmural DOR, particularly within the epicardial-midmyocardial interface, to values observed in heart failure. Therefore, these data suggest that heterogeneous Cx43 expression produces functionally significant electrophysiologic heterogeneities across the ventricular wall and may be a mechanism for promoting DOR which underlie arrhythmias in heart failure.