Cycle Length Restitution in Sinoatrial Node Cells: A Theory for Understanding Spontaneous Action Potential Dynamics

Glynn, Patric; Önal, Birce; Hund, Thomas J.

doi:10.1371/journal.pone.0089049

Cited by 20 publications

(15 citation statements)

References 31 publications

(46 reference statements)

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“…However, this activity also relies on the excitability of the membrane, which depends on the properties of ion channels; these are not well represented by FHN-like models and have important effects on propagation [41]. A quiescent version of the NRVM ionic model has been published [42] and could be modified to exhibit spontaneous activity more similar to real cardiomyocytes in culture with complex spontaneous activity [43].…”

Section: Discussionmentioning

confidence: 99%

Multicellular automaticity of cardiac cell monolayers: effects of density and spatial distribution of pacemaker cells

et al. 2014

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The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi-continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activation for similar spatial patterns, but more variability in those same variables for dissimilar spatial patterns. Compared to their isotropic counterparts, in silico anisotropic monolayers had less central foci and displayed more variability in cycle lengths and synchronization of electrical activation for both similar and dissimilar spatial patterns. The present study established a link between microscopic structure and macroscopic behavior of the biological pacemaker, and may provide crucial information for optimized biological pacemaker therapies.

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Section: Discussionmentioning

confidence: 99%

Multicellular automaticity of cardiac cell monolayers: effects of density and spatial distribution of pacemaker cells

et al. 2014

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“…Computer code was written in C++ and compiled using Intel Composer XE 2011 for Linux. Computer simulations were performed on a Dell PowerEdge R515 server (dual 6 core, 32 GB RAM running CentOS 6.2), as described 21, 22, 27, 28, 29, 30. Regression was performed using MATLAB R2014b (MathWorks) on a MacBook Pro with a 2.5‐GHz Intel Core i7 processor (Apple Inc).…”

Section: Methodsmentioning

confidence: 99%

Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

Unudurthi

Lei

et al. 2016

JAHA

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BackgroundTwo‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability.Methods and ResultsCardiac‐specific TREK‐1–deficient mice (αMHC‐Kcnk f/f) were generated and found to have a prevalent sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐Kcnk2 f/f sinoatrial node cells demonstrated decreased background K+ current and abnormal sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and sinoatrial node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin (qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of sinoatrial node dysfunction and in human cardiac disease.ConclusionsThese findings identify a TREK‐1–dependent pathway essential for normal sinoatrial node cell excitability that serves as a potential target for selectively regulating sinoatrial node cell function.

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“…This sourcesink relationship is altered in disease due to increased fibrosis and/or cell loss leading to a shift of the primary pacemaker site, emergent behavior of ectopic foci, or otherwise reduced capacity for SAN pacemaking [11][12][13]. There is a critical need to expand knowledge regarding regulation of membrane ion channels in the SAN, as well as to further develop quantitative tools to assess the sensitivity of the SAN to changes in coupling and ion channel regulation [14].…”

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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Cycle Length Restitution in Sinoatrial Node Cells: A Theory for Understanding Spontaneous Action Potential Dynamics

Cited by 20 publications

References 31 publications

Multicellular automaticity of cardiac cell monolayers: effects of density and spatial distribution of pacemaker cells

Multicellular automaticity of cardiac cell monolayers: effects of density and spatial distribution of pacemaker cells

Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

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

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Cycle Length Restitution in Sinoatrial Node Cells: A Theory for Understanding Spontaneous Action Potential Dynamics

Cited by 20 publications

References 31 publications

Multicellular automaticity of cardiac cell monolayers: effects of density and spatial distribution of pacemaker cells

Multicellular automaticity of cardiac cell monolayers: effects of density and spatial distribution of pacemaker cells

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

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

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Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability