Contents

📒 Heijman 2016

Computational models of atrial cellular electrophysiology and calcium handling, and their role in atrial fibrillation1

Sciwheel.

Introduction

  • Computational modelling was developed to complement experimental approaches to improve understanding of cardiac electrophysiology and arrhythmogenesis
  • a central role for Ca2+ handling abnormalities has been identified in promoting ectopic activity and re‐entry, the two major mechanisms underlying atrial fibrillation (AF)

Differences between atrial, ventricular and sinoatrial node cardiomyocytes

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  • Atrial cardiomyocytes possessing a number of ion currents that are largely absent in the ventricle (e.g. ultra‐rapid delayed‐rectifier K+ current IKur, or acetylcholine‐activated inward‐rectifying K+ current IK,ACh)
  • SAN cardiomyocytes additionally express more hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels but have relatively few Na+ channels. T‐type Ca2+ current is largest in the SAN.
  • ventricular cardiomyocytes have a larger basal inward‐rectifying K+ current (IK1)
  • differences in Ca2+ handling between cell types
    • ventricular myocytes having a well‐developed system of membrane invaginations (t‐tubules) => homogeneous activation
    • atrial myocytes: centripetal Ca2+ wave

Role of Ca2+ handling abnormalities in atrial arrhythmias

  • Ca2+ overload can activate NCX => EADs and DADs, cardiac alternans
  • Ca signalling pathways => remodeling

Computational modelling of atrial cellular electrophysiology and Ca2+ handling

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Types of ion‐channel models

  • instantaneous, time‐independent (rapid equilibrium): IK1
  • Hodgkin–Huxley gating variables
  • Markov models: states variables, more complex, additionally capture dependent state transitions

Atrial cardiomyocyte models and their principal findings

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Computational models based on experimental data from animals

See tbl1.html

Computational models of human atrial cardiomyocytes

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Spatial models of atrial Ca2+ handling

  • transverse segmentation allows simulation of the centripetal Ca2+ wave
  • subsarcolemmal SR Ca2+‐release sites influence AP shape, whereas the central release sites control centripetal Ca2+ wave propagation
  • However, common‐pool models also show alternans, as recently demonstrated for the Grandi model (Chang et al. 2014). This type of alternans critically depends on intrinsic RyR2 properties.
  • both transverse and longitudinal compartmentation of Ca2+ handling (Fig. 4 C), along with stochastic gating of RyR2s using a Markov‐model approach => The combination of changes produces sustained triggered activity = paroxysmal AF (pAF)

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Applications of computational modelling in AF research

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  • It’s not experimentally possible to modulate the function of a single channel or transporter in human atrial cardiomyocytes with high specificity. Computational assessment of potential mechanisms of atrial arrhythmogenesis could help to identify experimental findings about changes in ion‐channel function
  • The advances and applications of atrial cardiomyocyte models have been paralleled by advances in the development of models for other cell types (ventricular: common‐pool and spatial ‘local‐control’ models)

Gaps in knowledge and future directions

  • pronounced inter‐patient and regional variation: tissues surrounding the (PVs) have specific electrophysiological and Ca2+ handling properties, making them more likely to produce ectopic activity
  • multiscale understanding of AF
  • Channel modeling (e.g. RyR2) https://wol-prod-cdn.literatumonline.com/cms/attachment/a77de851-f73a-48a6-8f01-987eaa35d0df/tjp6968-fig-0007-m.jpg

Reference


  1. Heijman J, Erfanian Abdoust P, Voigt N, Nattel S, Dobrev D. Computational models of atrial cellular electrophysiology and calcium handling, and their role in atrial fibrillation. J Physiol (Lond) 2016;594(3):537-553. doi:10.1113/JP271404. PMC5341705↩︎