Cellular and Molecular Mechanisms of Functional Hierarchy of Pacemaker Clusters in the Sinoatrial Node: New Insights into Sick Sinus Syndrome

Abstract

The sinoatrial node (SAN), the primary pacemaker of the heart, consists of a heterogeneous population of specialized cardiac myocytes that can spontaneously produce action potentials, generating the rhythm of the heart and coordinating heart contractions. Spontaneous beating can be observed from very early embryonic stage and under a series of genetic programing, the complex heterogeneous SAN cells are formed with specific biomarker proteins and generate robust automaticity. The SAN is capable to adjust its pacemaking rate in response to environmental and autonomic changes to regulate the heart’s performance and maintain physiological needs of the body. Importantly, the origin of the action potential in the SAN is not static, but rather dynamically changes according to the prevailing conditions. Changes in the heart rate are associated with a shift of the leading pacemaker location within the SAN and accompanied by alterations in P wave morphology and PQ interval on ECG. Pacemaker shift occurs in response to different interventions: neurohormonal modulation, cardiac glycosides, pharmacological agents, mechanical stretch, a change in temperature, and a change in extracellular electrolyte concentrations. It was linked with the presence of distinct anatomically and functionally defined intranodal pacemaker clusters that are responsible for the generation of the heart rhythm at different rates. Recent studies indicate that on the cellular level, different pacemaker clusters rely on a complex interplay between the calcium (referred to local subsarcolemmal Ca2+ releases generated by the sarcoplasmic reticulum via ryanodine receptors) and voltage (referred to sarcolemmal electrogenic proteins) components of so-called “coupled clock pacemaker system” that is used to describe a complex mechanism of SAN pacemaking. In this review, we examine the structural, functional, and molecular evidence for hierarchical pacemaker clustering within the SAN. We also demonstrate the unique molecular signatures of intranodal pacemaker clusters, highlighting their importance for physiological rhythm regulation as well as their role in the development of SAN dysfunction, also known as sick sinus syndrome.

RyR2 and Calcium Release in Heart Failure

“…This is consistent with a study in isolated SAN cells from rabbit HF model of pressure and volume overload, which concluded that SAN Ca 2+ cycling properties are conserved despite bradycardic effects (Verkerk et al, 2015). However, the latest study did not take into account the presence of hierarchical pacemaker clustering within the SAN that might be modified in HF (Sanders et al, 2004;Lang and Glukhov, 2021). Preliminary data from our group, using TACinduced HF in the mouse indicate impairment of "Ca 2+ clock, " characterized by slower spontaneous [Ca 2+ ] i transients, as well as less frequent and smaller Ca 2+ sparks, supported by a mechanism including depression in the CaMKII signaling pathway (Xue et al, 2020).…”

Drivers of Sinoatrial Node Automaticity in Zebrafish: Comparison With Mechanisms of Mammalian Pacemaker Function

“…A shift in the leading pacemaker site with electrical stimulation of extracardiac inputs or during pharmacologic activation of autonomic receptors has been demonstrated in a variety of mammals (Opthof, 1988;Boyett et al, 2000;Lang and Glukhov, 2021), including rabbit (West, 1955;Toda and West, 1967;Bouman et al, 1968;Toda, 1968;Toda and Shimamoto, 1968;Spear et al, 1979;Mackaay et al, 1980;Shibata et al, 2001;Lang et al, 2011). In general, sympathetic stimulation tends to shift the leading pacemaker site superiorly, while parasympathetic Thollon et al, 1994Thollon et al, , 2007Bucchi et al, 2007;Yaniv et al, 2012Yaniv et al, , 2013Yaniv et al, , 2014 Noma et al, 1983;Dennis and Williams, 1986;Denyer and Brown, 1990;Leitch et al, 1995;Nikmaram et al, 1997;Zhang and Vassalle, 2000;Bogdanov et al, 2006;Thollon et al, 2007 I Ca,T Nickel 165 µM* −10% 40 -100 µM −14 -−18% Hagiwara et al, 1988;Satoh, 1995 Kawai et al, 1981;Senges et al, 1983;Satoh and Tsuchida, 1993;Masumiya et al, 1997;Budriesi et al, 1998;Bogdanov et al, 2006 RyR Ryanodine 1 µM −45% 1 -3 µM −14 -−50% Hata et al, 1996;Satoh, 1997;Bogdanov et al,...…”

The Role of POPDC Proteins in Cardiac Pacemaking and Conduction

“…The heart consists of two different kinds of myocytes, i.e., the working or forceproducing cardiac myocytes found in the atrial and ventricular chambers, and the nodal and conducting myocytes forming the cardiac conduction system (CCS). The CCS spontaneously generates and propagates electrical activity to trigger the synchronous and consecutive contraction of the atrial and ventricular chambers [1,2]. Atrial and ventricular myocytes are characterized by the presence of stable resting membrane potential, while CCS myocytes are characterized by spontaneous diastolic depolarization.…”

“…Atrial and ventricular myocytes are characterized by the presence of stable resting membrane potential, while CCS myocytes are characterized by spontaneous diastolic depolarization. During each cardiac cycle, myocytes of the sinoatrial node (SAN) are the fastest to depolarize and first to generate action potential [1]. From the SAN, the electrical activation spreads to the atrial myocardium and subsequently to the ventricular chambers via the atrioventricular node (AVN).…”