β-Adrenergic Stimulation Synchronizes a Broad Spectrum of Action Potential Firing Rates of Cardiac Pacemaker Cells toward a Higher Population Average

Abstract

The heartbeat is initiated by pacemaker cells residing in the sinoatrial node (SAN). SAN cells generate spontaneous action potentials (APs), i.e., normal automaticity. The sympathetic nervous system increases the heart rate commensurate with the cardiac output demand via stimulation of SAN β-adrenergic receptors (βAR). While SAN cells reportedly represent a highly heterogeneous cell population, the current dogma is that, in response to βAR stimulation, all cells increase their spontaneous AP firing rate in a similar fashion. The aim of the present study was to investigate the cell-to-cell variability in the responses of a large population of SAN cells. We measured the βAR responses among 166 single SAN cells isolated from 33 guinea pig hearts. In contrast to the current dogma, the SAN cell responses to βAR stimulation substantially varied. In each cell, changes in the AP cycle length were highly correlated (R2 = 0.97) with the AP cycle length before βAR stimulation. While, as expected, on average, the cells increased their pacemaker rate, greater responses were observed in cells with slower basal rates, and vice versa: cells with higher basal rates showed smaller responses, no responses, or even decreased their rate. Thus, βAR stimulation synchronized the operation of the SAN cell population toward a higher average rate, rather than uniformly shifting the rate in each cell, creating a new paradigm of βAR-driven fight-or-flight responses among individual pacemaker cells.

Functional Heterogeneity of Cell Populations Increases Robustness of Pacemaker Function in a Numerical Model of the Sinoatrial Node Tissue

“…A substantial cell-to-cell variability in phospholamban phosphorylation is expected based on a substantial variability of both basal AP firing rates and responses to β-adrenergic stimulation among isolated SAN cells ( Kim et al, 2021 ). However, in contrast to g CaL , there is no single-cell data in the literature to set up cell populations in the model within an exact P up range.…”

“…This results in a large degree of functional heterogeneity among individual cells, ranging from frequently and rhythmic AP firing to infrequently and dysrhythmic firing, to nonfiring cells (recently dubbed “dormant” cells) ( Kim et al, 2018 ; Tsutsui et al, 2018 ; Tsutsui et al, 2021 ). The SAN cell population is also extremely heterogeneous with respect to the AP firing rate increase in response to β-adrenergic stimulation ( Kim et al, 2021 ).…”

L-Type Cav1.3 Calcium Channels Are Required for Beta-Adrenergic Triggered Automaticity in Dormant Mouse Sinoatrial Pacemaker Cells

“…However, SANC with different ion channel expression span the whole SAN and represent a reserve pool of SANC capable of reaching normal frequency upon multiple external stimuli, ensuring SAN adaptability. Indeed, a recent study showed that all SANC with various basal rates tend to reach the same frequency under β-adrenergic stimulation [ 23 ]. In this regard, our data indicate that in dormant SANC, Ca v 1.3 channels are essential to reach this synchronized average rate among SANC during the fight-or-flight response.…”

“…This β-adrenergic effect was also observed in isolated dormant human SANC [ 22 ]. Interestingly, a recent study showed that the chronotropic response is actually different among SANC with various basal firing rates which results, ultimately, in a synchronized average rate for all SANC under β-adrenergic stimulation [ 23 ].…”

Coupling and heterogeneity modulate pacemaking capability in healthy and diseased two-dimensional sinoatrial node tissue models

“…Despite the many insights obtained by these studies, important questions remain unresolved, particularly with respect to how heterogeneity between SAN myocytes and inter-cellular coupling combine to influence coordinated beating in tissue. For example, although it has recently been shown experimentally that not all SAN cells fire spontaneously when they are enzymatically isolated [8][9][10], we do not know how non-firing cells behave when they are electrically coupled in tissue, nor how the percentage of non-firing cells influences the overall electrical activity of the SAN.…”