New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function

Abstract

The rapid propagation of electrical activity through the ventricular conduction system (VCS) controls spatiotemporal contraction of the ventricles. Cardiac conduction defects or arrhythmias in humans are often associated with mutations in key cardiac transcription factors that have been shown to play important roles in VCS morphogenesis in mice. Understanding of the mechanisms of VCS development is thus crucial to decipher the etiology of conduction disturbances in adults. During embryogenesis, the VCS, consisting of the His bundle, bundle branches, and the distal Purkinje network, originates from two independent progenitor populations in the primary ring and the ventricular trabeculae. Differentiation into fast-conducting cardiomyocytes occurs progressively as ventricles develop to form a unique electrical pathway at late fetal stages. The objectives of this review are to highlight the structure-function relationship between VCS morphogenesis and conduction defects and to discuss recent data on the origin and development of the VCS with a focus on the distal Purkinje fiber network.

Keywords: Purkinje fiber network; cardiac morphogenesis; cardiac progenitors; conduction defects; ventricular conduction system.

Figure 1

Morphological and cytoarchitectural similarities between human and mouse left ventricular Purkinje network. (A) Drawing of the human left ventricular conduction system from Tawara [1]. (B) Fluorescent image showing the mouse left ventricular conduction system of a Cx40-GFP heart [13]; The complexity of the PF network formed by ellipsoidal structures are indicated by stars. AVB: Atrioventricular bundle; LBB: Left Bundle branch; PF: Purkinje fibers. (C) Purkinje network (P) and muscular trabeculae (T) in the human heart. Purkinje cells running in parallel within the trabeculae are continuous with a delicate network of polygonal or stellate cells ×120 (a gift from Dr Shimada with permission) [14]. (D) Cytoarchitecture of the mouse Purkinje network from a high-magnification image of a Cx40-GFP heart shows similar organization with parallel fascicles (T) and Purkinje network (P) ×80.

Figure 2

Correlation between structural defects of specific components of the VCS and conduction abnormalities. (A) Representation of the ventricular conduction system of healthy mice, with a corresponding surface ECG. (B) Representation of morphological abnormalities of one or several components of the ventricular conduction system with the corresponding mouse genotype indicated vertically. Abnormal ECGs are indicated with an increased PR interval associated with hypoplasia of the AVN and/or AVB; a fragmented QRS also referred as RsR’ pattern associated with hypoplasia of bundle branches and a prolonged QRS duration associated with both hypoplasia and hyperplasia of the Purkinje network. AVN: Atrioventricular node, AVB: Atrioventricular bundle, RBB and LBB: right and left bundle branch, PF: Purkinje Fibers, OE: overexpression, ΔLV: mutation of the left ventricle specific enhancer.

Figure 3

Model of the ventricular conduction system lineage and morphogenesis. (A) Within the early heart tube, a subset of cardiac progenitors localized in the primary ring or emerging trabeculae is already specified to the conductive lineage (green cells) and represents the primary scaffold of the VCS network. During trabeculation and compaction of the ventricles, trabecular progenitors (gray cells) are progressively fate-restricted, and many conductive cells are recruited to the primary scaffold to build a complex PF network. At late fetal stage, trabecular cells enter the conductive lineage in a massive Nkx2-5-dependent recruitment to contribute to ellipsoidal structures of the PF network. In Nkx2-5^+/− mice, the conductive potency is progressively lost leading to a hypoplastic PF network with very rare ellipsoidal structures. (B) Whole-mount fluorescence images of the left PF network from Mesp1-Cre::R26R-Confetti mice at P21. Immunostaining for Contactin-2 (CNTN2) is used to label the mature PF network. Multicolor confetti cells show the polyclonal morphogenesis of the PF network. (C) Schematic representation of chimeric PF network where Nkx2-5^+/− cells (red) are not recruited nor recruiting and do not form ellipsoidal structures of the PF network unlike Nkx2-5^+/+ cells (green) which cell autonomously participate to the PF network.