Computational modelling of the initiation and development of spontaneous intracellular Ca 2+ 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.