Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

Maltsev, Victor A.; Yaniv, Yael; Maltsev, Anna; Stern, Michael D.; Lakatta, Edward G.

doi:10.1254/jphs.13r04cr

Cited by 35 publications

(27 citation statements)

References 135 publications

(281 reference statements)

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“…S2A), compared to optimal clock coupling (fig. S2, B and C) (19,20). Another possibility is a reduction in cell and SR Ca 2+ loading due to the absence of action potentials and resulting Ca 2+ transients (4).…”

Section: Discussionmentioning

confidence: 99%

A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells

et al. 2018

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The spontaneous rhythmic action potentials generated by the sinoatrial node (SAN), the primary pacemaker in the heart, dictate the regular and optimal cardiac contractions that pump blood around the body. Although the heart rate of humans is substantially slower than that of smaller experimental animals, current perspectives on the biophysical mechanisms underlying the automaticity of sinoatrial nodal pacemaker cells (SANCs) have been gleaned largely from studies of animal hearts. Using human SANCs, we demonstrated that spontaneous rhythmic local Ca2+ releases generated by a Ca2+ clock were coupled to electrogenic surface membrane molecules (the M clock) to trigger rhythmic action potentials, and that Ca2+–cAMP–protein kinase A (PKA) signaling regulated clock coupling. When these clocks became uncoupled, SANCs failed to generate spontaneous action potentials, showing a depolarized membrane potential and disorganized local Ca2+ releases that failed to activate the M clock. β-Adrenergic receptor (β-AR) stimulation, which increases cAMP concentrations and clock coupling in other species, restored spontaneous, rhythmic action potentials in some nonbeating “arrested” human SANCs by increasing intracellular Ca2+ concentrations and synchronizing diastolic local Ca2+ releases. When β-AR stimulation was withdrawn, the clocks again became uncoupled, and SANCs reverted to a nonbeating arrested state. Thus, automaticity of human pacemaker cells is driven by a coupled-clock system driven by Ca2+-cAMP-PKA signaling. Extreme clock uncoupling led to failure of spontaneous action potential generation, which was restored by recoupling of the clocks. Clock coupling and action potential firing in some of these arrested cells can be restored by β-AR stimulation–induced augmentation of Ca2+-cAMP-PKA signaling.

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Section: Discussionmentioning

confidence: 99%

A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells

et al. 2018

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“…Recognition of the limitations of the traditional common-pool model approach have led to novel pacemaker cell models featuring local Ca 2+ control mechanisms (for review see Maltsev et al, 2014 ). Thus, newer local control models are more accurate vs. old common pool models: the scale of amplitudes for Ca 2+ dynamics attained locally is higher by as much as two orders of magnitude vs. that predicted by the old models.…”

Section: Numerical Modeling: From One Clock To One Coupled Systemmentioning

confidence: 99%

From two competing oscillators to one coupled-clock pacemaker cell system

2015

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At the beginning of this century, debates regarding “what are the main control mechanisms that ignite the action potential (AP) in heart pacemaker cells” dominated the electrophysiology field. The original theory which prevailed for over 50 years had advocated that the ensemble of surface membrane ion channels (i.e., “M-clock”) is sufficient to ignite rhythmic APs. However, more recent experimental evidence in a variety of mammals has shown that the sarcoplasmic reticulum (SR) acts as a “Ca2+-clock” rhythmically discharges diastolic local Ca2+ releases (LCRs) beneath the cell surface membrane. LCRs activate an inward current (likely that of the Na+/Ca2+ exchanger) that prompts the surface membrane “M-clock” to ignite an AP. Theoretical and experimental evidence has mounted to indicate that this clock “crosstalk” operates on a beat-to-beat basis and determines both the AP firing rate and rhythm. Our review is focused on the evolution of experimental definition and numerical modeling of the coupled-clock concept, on how mechanisms intrinsic to pacemaker cell determine both the heart rate and rhythm, and on future directions to develop further the coupled-clock pacemaker cell concept.

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“…Models have been particularly helpful in elucidating the ionic basis of SAN activity and cardiac pacemaking [16,17]. For example, SAN cell models have furthered our understanding of the relative importance of coupling between Ca 2+ cycling and membrane ion channels in automaticity [18] and the genetic basis of human SAN disease [19].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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Computational studies using mathematical models of the sinoatrial node (SAN) cardiac action potential (AP) have provided important insight into the fundamental nature of cell excitability, cardiac arrhythmias, and potential therapies. While the impact of ion channel dynamics on SAN pacemaking has been studied, the governing dynamics responsible for regulating spatial and temporal control of SAN synchrony remain elusive. Here, we attempt to develop methods to explore cohesion in a network of coupled spontaneously active SAN cells. We present the updated version of a previously published graphical user interface LongQt: a cross-platform, threaded application for advanced cardiac electrophysiology studies that does not require advanced programming skills. We incorporated additional features to the existing LongQt platform that allows users to (1) specify heterogeneous gap junction conductivity across a multicellular grid, and (2) set heterogeneous ion channel conductance across a multicellular grid. We developed two methods of characterizing the synchrony of SAN tissue based on alignment of activation in time and similarity of voltage peaks among clusters of functionally related cells. In pairs and two-dimensional grids of coupled cells, we observed a range of conductivities (0.00014-0.00033 1/ -cm) in which the tissue was more susceptible to developing asynchronous spontaneous pro-arrhythmic behavior (e.g., spiral wave formation). We performed parameter sensitivity analysis to determine the relative impact of ion channel conductances on cycle length (CL), diastolic and peak voltage, and synchrony measurements in isolated and coupled cell pairs. We also defined measurements of evaluating synchrony based on peak AP voltage and the rate of wave propagation. Cell-to-cell coupling had a non-linear effect on the relationship between ion channel conductances, AP properties, and synchrony measurements. Our simulations demonstrate that conductivity plays an important role in regulating synchronous firing of heterogeneous SAN tissue, and demonstrate how to evaluate the role of coupling and ion channel conductance in pairs and grids of SAN cells. We anticipate that the approach outlined here will facilitate identification of key cell-and tissue-level factors responsible for cardiac disease.

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Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

Cited by 35 publications

References 135 publications

A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells

A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells

From two competing oscillators to one coupled-clock pacemaker cell system

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

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