Abstract
Normal heart rhythm (sinus rhythm) depends on regular activity of the sinoatrial node (SAN), a heterogeneous collection of specialized myocytes in the right atrium. SAN cells, in general, possess a unique electrophysiological profile that promotes spontaneous electrical activity (automaticity). However, while automaticity is required for normal pacemaking, it is not necessarily sufficient. Less appreciated is the importance of the elaborate structure of the SAN complex for proper pacemaker function. Here, we review the important structural features of the SAN with a focus on how these elements help manage a precarious balance between electrical charge generated by the SAN (“source”) and the charge needed to excite the surrounding atrial tissue (“sink”). We also discuss how compromised “source-sink” balance due, for example to fibrosis, may promote SAN dysfunction, characterized by slow and/or asynchronous pacemaker activity and even failure, in the setting of cardiovascular disease (e.g., heart failure, atrial fibrillation). Finally, we discuss implications of the “source-sink” balance in the SAN complex for cell and gene therapies aimed at creating a biological pacemaker as replacement or bridge to conventional electronic pacemakers.
Highlights
The sinoatrial node (SAN), located in the right atrium, serves as the primary site for initiation of the normal heartbeat (Figure 1)
Together with the cardiac conduction system [the atrioventricular node (AVN) and the His–Purkinje system], the SAN is responsible for orchestrating the precise sequence of electrical events underlying the normal heart rhythm
The His–Purkinje system supports rapid conduction with action potential (AP) propagation velocities up to ten-fold higher than in the ventricular mass to ensure synchronous activation of the ventricular muscle (Boyett, 2009). This sequence of electrical events is essential for normal heart function and depends on a number of distinguishing cell and tissue properties shared by each component of the pacemaker and conduction system
Summary
The sinoatrial node (SAN), located in the right atrium, serves as the primary site for initiation of the normal heartbeat (sinus rhythm) (Figure 1). Together with the cardiac conduction system [the atrioventricular node (AVN) and the His–Purkinje system], the SAN is responsible for orchestrating the precise sequence of electrical events underlying the normal heart rhythm. The His–Purkinje system supports rapid conduction with action potential (AP) propagation velocities up to ten-fold higher than in the ventricular mass to ensure synchronous activation of the ventricular muscle (Boyett, 2009) This sequence of electrical events is essential for normal heart function and depends on a number of distinguishing cell and tissue properties shared by each component of the pacemaker and conduction system. The major focus of this review, aside from active cell membrane properties (e.g., voltage-gated ion channel activity), tissue structure and cell-to-cell communication are tightly controlled in these tissues to handle the unique energetic demands placed on them during the excitation cycle These tissues are designed to balance the supply of depolarizing current generated by activating cells (“sources”) with the demand of downstream quiescent cells (“sinks”). Sinoatrial node architecture and pacemaking around which the SAN cells are organized (Sanchez-Quintana et al, 2005)
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