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

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…