Abstract
Anomalous action potential conduction through the atrial chambers of the heart can lead to severe cardiac arrhythmia. To date, however, little is known regarding the mechanisms that pattern proper atrial conduction during development. Here we demonstrate that atrial muscle functionally diversifies into at least two heterogeneous subtypes, thin-walled myocardium and rapidly conducting muscle bundles, during a developmental window just following cardiac looping. During this process, atrial muscle bundles become enriched for the fast conduction markers Cx40 and Nav1.5, similar to the precursors of the fast conduction Purkinje fiber network located within the trabeculae of the ventricles. In contrast to the ventricular trabeculae, however, atrial muscle bundles display an increased proliferation rate when compared to the surrounding myocardium. Interestingly, mechanical loading of the embryonic atrial muscle resulted in an induction of Cx40, Nav1.5 and the cell cycle marker Cyclin D1, while decreasing atrial pressure via in vivo ligation of the vitelline blood vessels results in decreased atrial conduction velocity. Taken together, these data establish a novel model for atrial conduction patterning, whereby hemodynamic stretch coordinately induces proliferation and fast conduction marker expression, which in turn promotes the formation of large diameter muscle bundles to serve as preferential routes of conduction.
Highlights
Whether the atrial musculature of the heart contains specialized tracts of cells capable of rapid electrical impulse propagation has been a topic of investigationPLOS ONE | DOI:10.1371/journal.pone.0115207 December 12, 2014Patterning of the Atrial Conduction System for more than 100 years [1,2,3,4,5,6,7]
The specialized cells of the ventricular conduction system (VCS) have been characterized based on their distinct histological appearance [46], the presence of insulating connective tissue separating these cells from the working myocardium [11], and by the unique molecular expression profile that they exhibit [26, 29, 40, 47,48,49]
Anisotropic propagation through mature atrial tissue has been reported in multiple species [13, 15, 20, 50,51,52,53], with preferential routes of conduction proposed to coincide with the developing pectinate muscle bundles along the atrial roof [15, 35]
Summary
Patterning of the Atrial Conduction System for more than 100 years [1,2,3,4,5,6,7]. To date, a definitive fast conduction system, meeting the criteria first proposed by Aschoff and Monckeberg [7,8,9] has yet to be identified in the atria [10,11,12]. Our data demonstrate that the patterning of fast conducting muscle bundles in the atria is associated with increased myocardial proliferation as opposed to the slower proliferation rate previously reported during VCS formation [31, 32]. These findings suggest a previously unrecognized mechanism for atrial conduction patterning in which hemodynamic stretch activates both cell proliferation and the expression of molecular components of fast conduction resulting in the formation of large diameter, fast conducting muscle bundles
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