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

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.

Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network

The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we apply genetic fate mapping and temporal clonal analysis to identify murine cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.

Hearts are Poised Near the Edge of Chaos

The Cardiac Purkinje Fiber (CPF) is the last branch of the heart conduction system, which is meshed with the normal ventricular myocyte. Purkinje fiber plays a key role in the occurrence of ventricular arrhythmia and maintenance. Does the heart Purkinje fiber cells have the same memory function as the cerebral nerve? In this paper, the cardiac Hodgkin–Huxley equation is taken as the object of study. In particular, we find that the potassium ion-channel [Formula: see text] and the sodium ion-channel [Formula: see text] are memristors. We also derive the small-signal equivalent circuits about the equilibrium points of the CPF Hodgkin–Huxley model. According to the principle of local activity, the regions of Locally-Active domain, Edge of Chaos domain and Locally-Passive domain are partitioned under parameters [Formula: see text], and the domain exhibiting the normal human heartbeat frequency range (Goldilocks Zone) is identified. Meanwhile, the Super-Critical Hopf bifurcation of the CPF Hodgkin–Huxley model is identified. Finally, the migration changes between different state domains under external current [Formula: see text] excitation are analyzed in detail. All of the above complex nonlinear dynamics are distilled and mapped geometrically into a surreal union of intersecting two-dimensional manifolds, dubbed the Hodgkin–Huxley’s magic roof.

Nkx2-5 defines distinct scaffold and recruitment phases during formation of the cardiac Purkinje fiber network

The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. In this study, we apply genetic fate mapping and temporal clonal analysis to identify cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.