Cell Biology of the Specialized Cardiac Conduction System

Acknowledgments

This work was supported by National Institutes of Health grants R01HL105983, R01HL142498, and R01HL146107 to G.I.F. and R01HL132073 to D.S.P.

The cardiac conduction system (CCS) consists of the impulse generating but slowly conducting sinoatrial node (SAN) and atrioventricular node (AVN) and the rapidly conducting ventricular conduction system (VCS). The SAN is the dominant pacemaker and is located at the junction between the superior vena cava (SVC) and the right atrium (RA). Cardiac impulses originating from the SAN rapidly propagate throughout the pectinated atrial myocardium (PAM) resulting in synchronous contraction of the atrial chambers. On reaching the AVN, which is located within the triangle of Koch (bordered by anteroseptal leaflet of the tricuspid valve, the tendon of Todaro, and the coronary sinus os) in the low RA, the cardiac impulse slows, giving the ventricles adequate time to fill. As the cardiac impulse enters the VCS, which consists of the His bundle, bundle branches, and the Purkinje fiber network (PFN), conduction accelerates, enabling synchronized ventricular chamber contraction. The His bundle and bundle branches are ensheathed in fibrous insulation with only the PFN coupled to the ventricular myocardium in a more apical and freewall location. This configuration allows for apex-to-base ventricular activation that optimizes blood propulsion toward the aorta and pulmonary artery. Therefore the CCS initiates each heartbeat, synchronizes atrial and ventricular chamber contraction, and optimizes the vector of myocardial contraction to maximize cardiac output.

The framework of the CCS is laid down early during heart development. Paff and coworkers noted that the chick electrocardiogram (ECG) converts from a sinusoidal waveform to the mature configuration before identifiable components of the CCS are formed ( Fig. 29.1 ). They also noted that atrioventricular (AV) block was achievable with digitalis at the 18-somite stage before a discernable PR interval is evident, suggesting that the AVN primordium develops with the early heart tube (see Fig. 29.1B ). After the 18-somite stage, cardiac chamber formation initiates and the ECG begins to manifest evidence of fast conduction, as demonstrated by the presence of high-frequency P waves and QRS complexes (see Fig. 29.1C ). The evolution of the chick ECG is indicative of the fact that the slowly conducting nodal elements are present in the early-looped heart and that the fast conducting elements are added during chamber formation. The interposition of slowly conducting AV canal (AVC) myocardium between the rapidly conducting atrial and ventricular chamber myocardium is what generates the mature ECG configuration. The fast conducting components are enriched in the α-subunit of the cardiac sodium channel, Na _V 1.5 (encoded by Scn5a ) and high conductance gap junction proteins, Connexin 40 (Cx40; encoded by Gja5 ) and Cx43 (encoded by Gja1 ). The slow conducting SAN and AVN express low conductance gap junction proteins, Cx30.2 (encoded by Gjd3 ) and Cx45 (encoded by Gja7 ) and express little to no Na _V 1.5. How these electrophysiologically distinct regions are specified and what defines the boundaries between slow and fast conduction have been the focus of intense research over the last 50 years. This chapter discusses the developmental origins of the CCS and the transcriptional networks that govern its formation.

Histological Analysis Of The Developing Mammalian Cardiac Conduction System

Viragh and Challice performed histologic analysis of the developing CCS in mouse embryos 8 to 12 days post-coitum (E8–E12). Conduction cells were distinguished from working cardiomyocytes by the following characteristics: (1) periodic acid–Schiff (PAS) positive staining, (2) poorly organized contractile apparatus, (3) enriched glycogen content, and (4) reduced number of T-tubules. Using these features, the temporal-spatial distribution of conduction cells was then tracked during cardiac development.

At E9 the origin of contraction was noted to be in the right sinus horn well before the appearance of the SAN primordium. Within the dorsolateral wall of the sinus horns, loose mesenchymal cells were noted to transform into the early sinus musculature, which covers the venous side of the sinoatrial venous valves. This aggregation of early sinus muscle tissue was the presumed site of SAN development. The SAN primordium was recognizable at E10–E11 in the medioanterior wall of the right SVC within the early sinus muscle. A left-sided SAN (L-SAN) developed simultaneously in the medioanterior region of the left common cardinal vein, but ultimately resorbed and incorporated into the wall of the left atrium.

The SAN and AV conduction systems develop simultaneously. At E9–E10, the AVC was a well-defined constriction with the inner cell layer making numerous interconnections with the trabecular compartment, which is the source of VCS myocytes. ^, At E11, the primordium of the AVN was identified as a PAS+ cell cluster in the inner, dorsal AVC. These PAS+ AVC cells were contiguous with the crest of the developing interventricular (IV) septum, positioning the AV nodal anlage in direct communication with the primordial His bundle and bundle branches. In the trabecular region, glycogen-rich PAS+ cells were seen immediately subjacent to the endocardium; these nascent Purkinje cells formed extensive connections with the developing bundle branches. ^, Consequently, all components of the AV conduction system were shown to be in contact with each other throughout cardiogenesis.

The work of Viragh and Challice demonstrated that conduction system development is inextricably linked to cardiogenesis. Yet significant questions remained regarding the cellular origins of the conduction system, the mechanism by which the pool of conduction cells expands, and the factors that dictate CCS specification and patterning.

Cellular Origins Of The Cardiac Conduction System

The neuronal qualities of the CCS led many to believe that its cellular origins were from neural crest derivatives. However, lineage-tracing studies in the chick and mouse have demonstrated that all conductive components of the CCS are myocardial in origin.

After gastrulation in the E7.5 mouse embryo, mesoderm originating from the primitive streak gives rise to two myocardial progenitor pools that fuse together to form the cardiac crescent (CC). The cardiogenic mesoderm in the CC is also referred to as the first heart field (FHF). Spontaneous calcium oscillations are first seen at this stage prior to overt beating. Subsequent fusion of the CC from a cranial to caudal direction gives rise to the primary heart tube at E8 when nascent myocardial contractions are first evident. FHF myocardial cells of the primary heart tube form the left ventricle (LV) and the AVC. The AVN derives from the AVC.

The second wave of cardiogenic mesoderm that is added to the primary heart tube via both venous and arterial poles is referred to as the second heart field (SHF). The SHF at the venous pole (inflow) contributes to the atria and the sinus venosus (SV). The SV is the confluence of venous drainage back to the heart and is composed of the right and left sinus horns and the venous side of the venous valves. SV myocardium gives rise to the SAN. The SHF at the arterial pole (outflow) contributes to the right ventricle (RV) and outflow tract. The His bundle derives from a mixture of LV and RV (both heart fields), the left bundle and left PFN derive from the LV (FHF origin) and the right bundle, and the right PFN derives mostly from the RV (SHF origin).

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