The Heart’s Pacemaker Mimics Brain Cytoarchitecture and Function

Bychkov, Rostislav; Juhaszova, Magdalena; Barrera, Miguel Calvo-Rubio; Donald, Lorenzo A.H.; Coletta, Christopher; Shumaker, Chad; Moorman, Kayla; Sirenko, Syevda; Maltsev, Alexander V.; Sollott, Steven J.; Lakatta, Edward G.

doi:10.1016/j.jacep.2022.07.003

Cited by 20 publications

(33 citation statements)

References 47 publications

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“…Yet, our BIs were in the range of previous publications of mouse SAN tissue measurements [ 6 , 35 , 36 , 37 ]. Others have published shorter BIs [ 38 , 39 ], but based on their illustration, the tissue was stretched, which could shorten the BI [ 40 ]. Moreover, their tissue had multiple rhythms while we only used tissues with synchronically beating cells.…”

Section: Discussionmentioning

confidence: 99%

Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue

Ganon

Davoodi

Alexandrovich

et al. 2023

IJMS

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Bradycardia is initiated by the sinoatrial node (SAN), which is regulated by a coupled-clock system. Due to the clock coupling, reduction in the ‘funny’ current (If), which affects SAN automaticity, can be compensated, thus preventing severe bradycardia. We hypothesize that this fail-safe system is an inherent feature of SAN pacemaker cells and is driven by synergy between If and other ion channels. This work aimed to characterize the connection between membrane currents and their underlying mechanisms in SAN cells. SAN tissues were isolated from C57BL mice and Ca2+ signaling was measured in pacemaker cells within them. A computational model of SAN cells was used to understand the interactions between cell components. Beat interval (BI) was prolonged by 54 ± 18% (N = 16) and 30 ± 9% (N = 21) in response to If blockade, by ivabradine, or sodium current (INa) blockade, by tetrodotoxin, respectively. Combined drug application had a synergistic effect, manifested by a BI prolonged by 143 ± 25% (N = 18). A prolongation in the local Ca2+ release period, which reports on the level of crosstalk within the coupled-clock system, was measured and correlated with the prolongation in BI. The computational model predicted that INa increases in response to If blockade and that this connection is mediated by changes in T and L-type Ca2+ channels.

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Section: Discussionmentioning

confidence: 99%

Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue

Ganon

Davoodi

Alexandrovich

et al. 2023

IJMS

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“…The phase shifts between the times of appearance of large-scale Ca 2+ signals in these regions of the SAN are large enough such that the last area to activate over the course of a beat has not fully subsided by the time the earliest activity emerges for the beat after it. This may be another tissue-level mechanism that preserves the robustness of SAN activity: if impulses overlap and are not completely synchronized in time, there is no timepoint at which the entire SAN tissue is deactivated [21].…”

Section: (C) Local Calcium Releases Within and Among Sinoatrial Node ...mentioning

confidence: 99%

“…( d ) 3D reconstructions of different distributional patterns of neuronal projections, with tyrosine hydroxylase (TH) in green and vesicular acetylcholine transporter (VAChT) in blue. ( a ) Adapted from [20]; ( b – d ) adapted from [21]. …”

Section: From Single Pacemaker Cells To Sinoatrial Node Tissuementioning

confidence: 99%

“…Recent experiments employing confocal microscopy and virtual slicing of immunolabelled mouse SAN preparations have added nuance to the study of the intrinsic cardiac nervous system (ICNS) by demonstrating in microscale 3D reconstructions the noteworthy heterogeneity of sympathetic and parasympathetic innervation within any given SAN as well as between those of different mice [21] (figure 2 c ). These variable distribution patterns create areas of dominant excitatory or inhibitory input, the functional implications of which are still to be uncovered [21].…”

Section: From Single Pacemaker Cells To Sinoatrial Node Tissuementioning

confidence: 99%

“…Next, we will describe how novel 3D confocal immunohistochemical studies of SAN cytoarchitecture have uncovered complex, brain-like arrangements of multiple pacemaker cell types as well as neurons, glial cells and more [20,21]. We will then discuss how this complex cytoarchitecture contextualizes the recent discovery that LCRs are heterogeneous in phase, frequency and amplitude, not only within individual cells, but also among pacemaker cells embedded in SAN tissue.…”

Section: Introductionmentioning

confidence: 99%

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What makes the sinoatrial node tick? A question not for the faint of heart

Donald

Lakatta

2023

Phil. Trans. R. Soc. B

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Even before the sinoatrial node (SAN) was discovered, cardiovascular science was engaged in an active investigation of when and why the heart would beat. After the electrochemical theory of bioelectric membrane potentials was formulated and the first action potentials were measured in contracting muscle cells, the field became divided: some investigators studied electrophysiology and ion channels, others studied muscle contraction. It later became known that changes in intracellular Ca 2+ cause contraction. The pacemaking field was reunited by the coupled-clock theory of pacemaker cell function, which integrated intracellular Ca 2+ cycling and transmembrane voltage into one rhythmogenic system. In this review, we will discuss recent discoveries that contextualize the coupled-clock system, first described in isolated SAN cells, into the complex world of SAN tissue: heterogeneous local Ca 2+ releases, generated within SAN pacemaker cells and regulated by the other cell types within the SAN cytoarchitecture, variably co-localize and synchronize to give rise to relatively rhythmic impulses that emanate from the SAN to excite the heart. We will ultimately conceptualize the SAN as a brain-like structure, composed of intercommunicating meshworks of multiple types of pacemaker cells and interstitial cells, intertwined networks of nerves and glial cells and more. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

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Emergent activity, heterogeneity, and robustness in a calcium feedback model of the sinoatrial node

Moise

Weinberg

2023

Biophysical Journal

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The Heart’s Pacemaker Mimics Brain Cytoarchitecture and Function

Cited by 20 publications

References 47 publications

Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue

Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue

What makes the sinoatrial node tick? A question not for the faint of heart

Emergent activity, heterogeneity, and robustness in a calcium feedback model of the sinoatrial node

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