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The paradigm shift: heartbeat initiation without “the pacemaker cell”

View ORCID ProfileVictor A. Maltsev, View ORCID ProfileMichael D. Stern
doi: https://doi.org/10.1101/2022.11.04.515227
Victor A. Maltsev
Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, United States
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Michael D. Stern
Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, United States
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  • For correspondence: SternMi@mail.nih.gov
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Abstract

The current dogma about the heartbeat origin is based on “the pacemaker cell”, a specialized cell residing in the sinoatrial node (SAN) that exhibits spontaneous diastolic depolarization triggering rhythmic action potentials (APs). Recent high-resolution imaging, however, demonstrated that Ca signals and APs in the SAN are heterogeneous, with many cells generating APs of different rates and rhythms or even remaining non-firing (dormant cells), i.e. generating only subthreshold signals. Here we numerically tested a hypothesis that a community of dormant cells can generate normal automaticity, i.e. “the pacemaker cell” is not required to initiate rhythmic cardiac impulses. Our model includes (i) non-excitable cells generating oscillatory local Ca releases and (ii) an excitable cell lacking automaticity. While each cell in isolation was not “the pacemaker cell”, the cell system generated rhythmic APs: the subthreshold signals of non-excitable cells were transformed into respective membrane potential oscillations via electrogenic Na/Ca exchange and further transferred and integrated (computed) by the excitable cells to reach its AP threshold, generating rhythmic pacemaking. Conclusions: Cardiac impulse is an emergent property of the SAN cellular network and can be initiated by cells lacking intrinsic automaticity. Cell heterogeneity, weak coupling, subthreshold signals, and their summation are critical properties of the new pacemaker mechanism, i.e cardiac pacemaker can operate via a signaling process basically similar to that of “temporal summation” happening in a neuron with input from multiple presynaptic cells. The new mechanism, however, does not refute the classical pacemaker cell-based mechanism: both mechanisms can co-exist and interact within SAN tissue.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • 1. We performed sensitivity analysis for connectivity conductance (new Figure 1B) to illustrate importance of weak coupling 2. We report results with a more complex model with 4 layers of dormant cells (new Figure 2) to illustrate that the subpopulation of CaOsc cells can drive more than just one excitable cell and the emergent automaticity can spread within further layers of dormant excitable cells. 3. We added new supplemental figure S1 with our previously published patch clamp data demonstrating substantial cell-to-cell variability of ICaL and If. 4. We added a new diagram (Figure 2C) illustrating possible importance (prevalence) and shifts between different pacing modes in different conditions.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted November 21, 2022.
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The paradigm shift: heartbeat initiation without “the pacemaker cell”
Victor A. Maltsev, Michael D. Stern
bioRxiv 2022.11.04.515227; doi: https://doi.org/10.1101/2022.11.04.515227
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The paradigm shift: heartbeat initiation without “the pacemaker cell”
Victor A. Maltsev, Michael D. Stern
bioRxiv 2022.11.04.515227; doi: https://doi.org/10.1101/2022.11.04.515227

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