title: Computational modelling of the initiation and development of spontaneous intracellular Ca2+ waves in ventricular myocytes.
abstract: Intracellular Ca(2+) dynamics provides excitation-contraction coupling in cardiac myocytes. Under pathological conditions, spontaneous Ca(2+) release events can lead to intracellular Ca(2+) travelling waves, which can break, giving transitory or persistent intracellular re-entrant Ca(2+) scroll waves. Intracellular Ca(2+) waves can trigger cellular delayed after-depolarizations of membrane potential, which if they occur in a cluster of a few hundred neighbouring myocytes may lead to cardiac arrhythmia. Quantitative prediction of the initiation and propagation of intracellular Ca(2+) waves requires the dynamics of Ca(2+)-induced Ca(2+) release, and the intracellular spatial distribution of Ca(2+) release units (CRUs). The spatial distribution of ryanodine receptor clusters within a few sarcomeres was reconstructed directly from confocal imaging measurements. It was then embedded into a three-dimensional ventricular cell model, with a resting membrane potential and simple stochastic Ca(2+)-induced Ca(2+) release dynamics. Isotropic global Ca(2+) wave propagation can be produced within the anisotropic intracellular architecture, by isotropic local Ca(2+) diffusion, and the branching Z-disc structure providing inter Z-disc pathways for Ca(2+) propagation. The branching Z-disc provides a broader spatial distribution of ryanodine receptor clusters across Z-discs, which reduces the likelihood of wave initiation by spontaneous Ca(2+) releases. Intracellular Ca(2+) dynamics during catecholaminergic polymorphic ventricular tachycardia (CPVT) was simulated phenomenologically by increasing the Ca(2+) sensitivity factor of the CRU, which results in an increased rate of Ca(2+) release events. Flecainide has been shown to prevent arrhythmias in a murine model of CPVT and in patients. The modelled actions of flecainide on the time course of Ca(2+) release events prevented the initiation of Ca(2+) waves.
authors.affiliation: Department of Biomedical Engineering and Cardiac Bioelectricity and Arrhythmia Center, Campus Box 1097, Washington University in St Louis, 1 Brookings Drive, St Louis, MO 63130, USA. panli@wustl.edu
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.forename: Wenjie
authors.initials: W
authors.lastname: Wei
authors.forename: Xing
authors.initials: X
authors.lastname: Cai
authors.forename: Christian
authors.initials: C
authors.lastname: Soeller
authors.forename: Mark B
authors.initials: MB
authors.lastname: Cannell
authors.forename: Arun V
authors.initials: AV
authors.lastname: Holden
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D003198:Computer Simulation; D003593:Cytoplasm / Q000502:physiology; D005424:Flecainide / Q000494:pharmacology; D006321:Heart / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D013269:Stochastic Processes
chemical_list: D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D005424:Flecainide; D002118:Calcium