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

Daniel Gratz,Alyssa Dalic,Birce Onal,Thomas J Hund

doi:10.3389/fphy.2018.00063

Daniel Gratz, Alyssa Dalic + Show 2 more

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https://doi.org/10.3389/fphy.2018.00063

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Abstract

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 1/Ω-cm to 0.00033 1/Ω-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, 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 nonlinear 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.

Highlights

The sinoatrial node (SAN) generates the electrical impulse that coordinates mechanical contraction of the heart [1, 2]
We use mathematical modeling to explore the role of coupling on spontaneous action potential (AP) dynamics and synchronization of pacemaking
Our simulations led to a number of important findings, including: (1) While parameter sensitivity analysis reveals a similar relationship between ion channel conductances and AP properties in single and coupled cells, our simulations predict small but potentially important differences, including complicated effects of coupling on the influence of ICa,L and IKr; (2) a specific coupling range in simulations promoted complex emergent behavior and at values higher than this coupling range cells fired together synchronously; (3) We define an approach for first defining groups of related cells and characterizing their synchrony, which facilitates quantification and visualization of synchronous behavior in a two-dimensional heterogeneous grid of SAN cells

Summary

Introduction

The sinoatrial node (SAN) generates the electrical impulse that coordinates mechanical contraction of the heart [1, 2]. Pacemaking is governed by a delicate sourcesink relationship between the SAN and surrounding atria defined by the need for a relatively small structure (SAN) to excite a much larger tissue mass (surrounding atria) [9, 10]. 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]

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