Role of sinoatrial node architecture in maintaining a balanced source-sink relationship and synchronous cardiac pacemaking

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.

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

“…Importantly, SAN failure is associated with increased mortality in heart failure patients, in which bradyarrhythmias account for >40% of sudden deaths 45. Underlying causes of SAN dysfunction likely involve changes in tissue structure (eg, fibrosis), ion channel defects (eg, mutations in Scn5a or HCN genes), and neurohumoral dysregulation, although the precise molecular and cellular pathways leading to aberrant pacemaking remain unknown 46, 47. Moreover, despite the prevalence of SAN dysfunction, available therapies are limited by their efficacy or risk of procedural complication.…”

Sinus Node and Atrial Arrhythmias

“…Although temporary SND can result from a number of extrinsic factors (Figure 2), permanent dysfunction is more commonly attributable to intrinsic factors such as progressive fibrosis and ischemia, and infiltrative and inflammatory processes can also act as triggers and substrates for atrial arrhythmia. 25,34 Parasympathetic stimulation, although more likely to produce SN dysfunction, can also provoke AF (see below).…”

“…46 A Schematic of sinoatrial anatomy and factors that lead to sinus node dysfunction. 25,34 The extent of the rabbit sinus node (SN) with central region (CN, dark brown) and peripheral region (PN, blue) as determined by computer 3-dimensional reconstruction is shown in the central figure. CAMKII indicates calcium/calmodulin-dependent protein kinase II; IVC, inferior vena cava; RAA, right atrial appendage; SERCA, sarcoendoplasmic reticulum calcium transport ATPase; and SVC, superior vena cava.…”

Synchronization of Pacemaking in the Sinoatrial Node: A Mathematical Modeling Study

“…One challenge for studying synchronization of cardiac pacemaking activity is the multiscalar and heterogeneous nature of the sinus node. Pacemaking is governed by a delicate sourcesink relationship between the SAN and surrounding atria defined by the need for a relatively small structure (SAN) to excite a much larger tissue mass (surrounding atria) [9,10]. This sourcesink relationship is altered in disease due to increased fibrosis and/or cell loss leading to a shift of the primary pacemaker site, emergent behavior of ectopic foci, or otherwise reduced capacity for SAN pacemaking [11][12][13].…”