Computational modelling of the initiation and development of spontaneous intracellular Ca2+ waves in ventricular myocytes

P Li, W Wei, X Cai, C Soeller, MB Cannell, A V Holden

Research output: Contribution to journalArticle (Academic Journal)

11 Citations (Scopus)

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.
Translated title of the contributionComputational modelling of the initiation and development of spontaneous intracellular Ca2+ waves in ventricular myocytes
Original languageEnglish
Pages (from-to)3953 - 3965
Number of pages12
JournalPhilosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences
Volume368
DOIs
Publication statusPublished - Aug 2010

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