Biphasic Development of the Mammalian Ventricular Conduction System

Abstract

Rationale: The ventricular conduction system controls the propagation of electric activity through the heart to coordinate cardiac contraction. This system is composed of specialized cardiomyocytes organized in defined structures including central components and a peripheral Purkinje fiber network. How the mammalian ventricular conduction system is established during development remains controversial. Objective: To define the lineage relationship between cells of the murine ventricular conduction system and surrounding working myocytes. Methods and Results: A retrospective clonal analysis using the ␣-cardiac actin nlaacZ/؉ mouse line was carried out in three week old hearts. Clusters of clonally related myocytes were screened for conductive cells using Key Words: conduction system Ⅲ cell lineage Ⅲ clonal analysis Ⅲ nlaacZ Ⅲ Purkinje fibers T he cardiac conduction system controls the generation and propagation of electric activity through the heart to coordinate cardiac contraction. Atrial contraction is initiated by the sinoatrial node or pacemaker. After a delay mediated by the atrioventricular node (AVN), the ventricular conduction system (VCS) ensures rapid propagation of electric activity to the ventricular apex. 1 The VCS is comprised of a central component, the atrioventricular (AV or His) bundle and right and left bundle branches, and a peripheral component composed of a dense ellipsoid network of Purkinje fibers. These structures have been well characterized in adult mouse and human hearts by their specific histological and electrophysiological properties. 2,3 However, despite the clinical importance of the VCS in regulating cardiac rhythm, important questions remain as to the origin and the mode of development of the mammalian VCS. 4 Existing views of VCS development are largely based on data obtained in avian embryos, despite major anatomic differences within the VCS between birds and mammals. In the avian system, lineage analysis using replication defective retroviral labeling has demonstrated that conductive cells share common progenitors with working cardiomyocytes and that the VCS develops by a process of induction and recruitment of myocytes through endothelial derived signals. 5,6 According to this model, conductive myocytes are nonproliferative and subsequent growth of the conduction system occurs by accretional recruitment of new myocytes (or ingrowth). However, in the chick, a perivascular network of Purkinje fibers is localized deep in the myocardium in proximity to coronary vessels, whereas in the mouse, as in humans, Purkinje fibers are present only at the subendocardial ventricular surface 1,7,8 and it is unclear whether the chick model is applicable to the mammalian VCS. In mammals an outgrowth model has been proposed for development of the central VCS, by which conductive cells develop independently of the working myocardium from a pool of conductive Original

Cardiac Cell Lineages that Form the Heart

“…In contrast to the central conduction system, the peripheral conduction system shares common ventricular progenitors for contractile and conductive cardiomyocytes until E16.5 (Miquerol et al 2010). After segregation, cells of both lineages continue to proliferate, although to a lesser extent for the conductive cardiomyocytes.…”

The formation and function of the cardiac conduction system

“…5A). Elegant clonal and lineage analyses, based on the labelling and tracing of Cx40 + cells, have provided proof for this assumption (Miquerol et al, 2010(Miquerol et al, , 2013. When Cx40 + cells are irreversibly pulse labelled at E10.5, when the still-thin trabecular left ventricular wall is entirely positive for Cx40 and the right ventricular wall is only partially so, labelled descendants are found both in the Purkinje fibres and in the compact wall.…”

“…The ventricular conduction system (VCS), which makes up only 1% of the total muscle mass of the ventricles (Miquerol et al, 2010), comprises the AVB (or bundle of His), the left and right BBs running from the crest of the septum towards the apex, and the Purkinje fibre network. The VCS is of myocardial origin (Gourdie et al, 1995;Cheng et al, 1999).…”

“…It arises from the trabecular myocardium; during embryogenesis, the embryonic ventricles are largely composed of trabecular myocardium that acts as both the functional equivalent and cellular precursor of the Purkinje fibre network. It expresses Cx40, Irx3 and other VCS markers and rapidly conducts the impulse (Rentschler et al, 2001;Miquerol et al, 2010;Zhang et al, 2011). In fish, amphibians and reptiles, the Cx40 + trabecular myocardial wall is maintained into adulthood.…”

High Resolution Imaging of the Human Cardiac Conduction System Using Reflectance Confocal Microscopy

“…In the most recent studies with genetically modified mice, where green fluorescent protein and red fluorescent protein had been expressed under the control of the gap junction connexin 40 gene, the precise localization of the conduction system was demonstrated Beyer et al 2011). However, the signal was also observed in the coronary arteries and the atria (Miquerol et al 2004(Miquerol et al , 2010. In most cases, the precise identification of a particular tissue could be performed by histological examination, in which a thin tissue section is stained and studied under a microscope.…”