Development of the Cardiac Conduction System

Abstract

The cardiac conduction system initiates and propagates each heartbeat. Specialized conducting cells are a well-conserved phenomenon across vertebrate evolution, although mammalian and avian species harbor specific components unique to organisms with four-chamber hearts. Early histological studies in mammals provided evidence for a dominant pacemaker within the right atrium and clarified the existence of the specialized muscular axis responsible for atrioventricular conduction. Building on these seminal observations, contemporary genetic techniques in a multitude of model organisms has characterized the developmental ontogeny, gene regulatory networks, and functional importance of individual anatomical compartments within the cardiac conduction system. This review describes in detail the transcriptional and regulatory networks that act during cardiac conduction system development and homeostasis with a particular emphasis on networks implicated in human electrical variation by large genome-wide association studies. We conclude with a discussion of the clinical implications of these studies and describe some future directions.

Figure 1.

Functional anatomy of the cardiac conduction system (CCS). Red dotted lines indicate the direction of the electric impulse from sinoatrial node (SAN), to atrioventricular node (AVN), and then propagation through the ventricular conduction system (VCS), leading to ventricular contraction. Unique action potential tracings for each CCS compartment are shown in blue.

Figure 2.

Cellular and molecular networks for sinoatrial node (SAN) development. Upward pointing red arrows indicate high expression of genes. Yellow arrows indicate developmental stages of SAN specification, although additional contributions to the SAN are likely. Black arrows indicate activation of genes. Blue lines with blunt ends indicate suppression of gene expression by respective transcription factors (TFs). The blue dotted box represents a gene program that shuts down and the brown dotted box indicates a gene program that is activated during SAN maturation. The large continuous brown box indicates the gene regulatory networks at play during SAN development.

Figure 3.

Molecular and signaling networks for atrioventricular conduction system (AVCS) development. Light green inset shows the definitive atrioventricular node (AVN). Black arrows indicate activation of genes. Blue lines with blunt ends indicate suppression of gene expression by respective transcription factors (TFs). The blue dotted box represents a gene program that shuts down, and the light dotted box indicates a gene program that is activated for maturation of the AVN. The large continuous light green box indicates the role of players in AVN development and function. (BMP2) bone morphogenetic protein 2.

Figure 4.

Molecular signaling networks for ventricular conduction system (VCS) development. The orange inset shows the atrioventricular bundle/bundle branches (AVB/BBs) and the green inset shows the Purkinje fiber network (PFN). Black arrows indicate activation of genes. Blue lines with blunt ends indicate suppression of gene expression by respective transcription factor (TFs). The blue dotted box represents gene program that shuts down. Orange and green dotted boxes indicate gene programs that are activated for maturation of the AVB/BB and PFN, respectively. Large continuous orange and green boxes represent the network of players in AVB/BB and PFN development, respectively. (MAPK) mitogen-activated protein kinase.

Figure 5.

The anatomical location of each cardiac conduction system (CCS) compartment is shown with its corresponding electrophysiological activity on an electrocardiogram (ECG). The (HR)/RR interval for sinoatrial node (SAN) activity, PR parameters for atrial/atrioventricular node (AVN) activity, and QRS/QT parameters for ventricular conduction system (VCS) activity. Loci associated with various ECG traits are outlined by distinct colors: orange, SAN; light green, atrioventricular conduction system (AVCS) rhythm and disease; dark green, VCS activity or disease. Many of the genomic loci are associated with one or more of the above traits. (AVB) atrioventricular bundle, (BBs) bundle branches, (PFN) Purkinje fiber network.