Development of a Biophysically Detailed Mathematical Model of a Mouse Atrial Cell for the Study of Cellular Proarrhythmic Mechanisms

  • Weijian Shen

Student thesis: Phd


Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with abnormal intracellular Ca2+ handling. Understanding AF requires comprehensive understanding of ionic currents, Ca2+ handling, phosphorylation regulation and related signalling pathways, but appropriate models are limited. The aim of this thesis is to develop an ionic model of the mouse atrial myocyte to investigate the cellular proarrhythmic mechanisms. We have developed the first mouse atrial myocyte model that incorporates mathematically detailed ion channels, cellular Ca2+ and Na+ handling and their regulation by Ca2+-calmodulin-dependent protein kinase II (CaMKII) and protein kinase A. For the first time, the inositol 1,4,5-trisphosphate (IP3) production system and its effects on excitation-contraction coupling have also been described. The validated model predicted that: 1) hyperactivity of CaMKII and elevated intracellular Na+ concentration are the crucial factors that induce sarcoplasmic reticulum (SR) Ca2+ spontaneous release and delayed afterdepolarisations; 2) β-adrenergic stimulation may have proarrhythmic effects by exacerbating Ca2+ overload; and 3) enhanced activity in ryanodine receptors during IP3-induced Ca2+ release is the major cause of the arrhythmogenesis in IP3 signalling.
Date of Award1 Aug 2016
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorHenggui Zhang (Supervisor)


  • Mouse Atrial Model
  • CaMKII
  • ß-adrenergic signalling
  • IP3 signalling

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