📒 Heijman 2016

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



  • 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

  • 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

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

Computational models based on experimental data from animals

See tbl1.html

Computational models of human atrial cardiomyocytes

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)

Applications of computational modelling in AF research

  • 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)


  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↩︎