Developmental Origin, Growth, and Three-Dimensional Architecture of the Atrioventricular Conduction Axis of the Mouse Heart

Abstract

Rationale:The clinically important atrioventricular conduction axis is structurally complex and heterogeneous, and its molecular composition and developmental origin are uncertain.Objective: To assess the molecular composition and 3D architecture of the atrioventricular conduction axis in the postnatal mouse heart and to define the developmental origin of its component parts. Methods and Results:We generated an interactive 3D model of the atrioventricular junctions in the mouse heart using the patterns of expression of Tbx3, Hcn4, Cx40, Cx43, Cx45, and Nav1.5, which are important for conduction system function. We found extensive figure-of-eight rings of nodal and transitional cells around the mitral and tricuspid junctions and in the base of the atrial septum. The rings included the compact node and nodal extensions. We then used genetic lineage labeling tools (Tbx2 ؉/Cre , Mef2c-AHF-Cre, Tbx18 ؉/Cre ), along with morphometric analyses, to assess the developmental origin of the specific components of the axis. The majority of the atrial components, including the atrioventricular rings and compact node, are derived from the embryonic atrioventricular canal. The atrioventricular bundle, including the lower cells of the atrioventricular node, in contrast, is derived from the ventricular myocardium. No contributions to the conduction system myocardium were identified from the sinus venosus, the epicardium, or the dorsal mesenchymal protrusion. Key Words: atrioventricular canal Ⅲ atrioventricular node Ⅲ three-dimensional reconstruction Ⅲ lineage analysis Ⅲ heart development Ⅲ transgenic mice T he atria and ventricles are separated by the connective tissues of the atrioventricular junction that insulate the atrial and ventricular muscle masses. A small part of the musculature, however, the atrioventricular conduction axis, crosses the plane of insulation, thus allowing conduction of the impulse generated by the sinus node to the ventricles. The axis has atrial parts, including the atrioventricular node and atrioventricular ring bundles, and ventricular parts, the atrioventricular bundle and the bundle branches. 1,2 The atrioventricular node delays the electric impulse, thus permitting the ventricles to fill before ventricular contraction. The node can also function as a subsidiary pacemaker. Several arrhythmias, such as atrioventricular block and reentrant tachycardia, have their anatomic substrates within the axis, 2-5 which is complex and heterogeneous in terms of its morphology. [2][3][4][5][6] Insight into the mechanisms of the arrhythmias can be provided by an understanding of development. Of the transcription factors implicated in the regulation of the developmental process, transcription factor Tbx3 is expressed specifically in the central conduction system, thus providing a key marker with which to delineate these tissues throughout development and in the adult. 7-9 The origin and lineages of the atrioventricular junctions, however, have still to be clarified. It is currently thought that the atrial component...

Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways

“…AV node volume was measured in 3 control Mlc2v +/+ DNMAML and 3 Mlc2v Cre/+ DNMAML adult hearts using Masson's trichrome staining of sections through the entire AV node, including the compact AV node, inferior nodal extension, and lower nodal cells (34). The presence of connective tissue located between AV nodal tissue and the surrounding atrial and AV ring myocardium as well as the distinct morphology of the AV nodal cells allowed identification of the AV node.…”

“…However, Mlc2v Cre/+ DNMAML mice had a significantly smaller AV node volume indexed to heart weight when compared with that of controls (16 ± 5.1 × 10 6 vs. 30 ± 1.8 × 10 6 μm 3 /g; n = three 5-month-old mice of each genotype; P < 0.01), as demonstrated by 3D reconstruction of the AV node from a representative control and Notch-inactivated mutant (Figure 1 Cx30.2 is a low conductance gap junction isoform expressed in the murine compact AV node and inferior nodal extension that decelerates electrical impulse propagation, while Cx40 expression within the AV node is confined to the lower AV nodal cells that are contiguous with the His bundle and contribute to faster electrical conduction (3,34). Myocytes of the compact AV node and inferior nodal extension are derived from AV canal myocardium, while Cx40-positive lower AV nodal cells and the His bundle are derived from ventricular myocardium (3,34). Mlc2v Cre/+ DNMAML mice demon- Notch inhibition disrupts AV nodal delay.…”

Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice

“…Usually, these strands do not lead to preexcitation, indicating they maintain slow conduction properties of the AV myocardium. Furthermore, in the adult heart, after formation of the annulus fibrosus has been completed, slow-conducting AV canal-type myocardium remains present around the orifices of the mitral and tricuspid valve (12)(13)(14). Together, these data suggest that AV canal myocardium plays a central role in the AV delay and that defects in AV canal myocardium could underlie formation of functional accessory pathways.…”

Expression of Id2 in the second heart field and cardiac defects in Id2 knock‐out mice

“…In the murine embryonic heart, it is expressed in the developing sinus venosus myocardium and the SAN (Garcia-Frigola et al, 2003). Furthermore, in early stages it is expressed in components of the mouse atrioventricular conduction axis in both mouse (Aanhaanen et al, 2010;Yanni et al, 2009) and chicken (Vicente-Steijn et al, 2011).…”