Abstract
Spontaneous sub-cellular calcium release events (SCRE) are conjectured to promote rapid arrhythmias associated with conditions such as heart failure and atrial fibrillation: they can underlie the emergence of spontaneous action potentials in single cells which can lead to arrhythmogenic triggers in tissue. The multi-scale mechanisms of the development of SCRE into arrhythmia triggers, and their dynamic interaction with the tissue substrate, remain elusive; rigorous and simultaneous study of dynamics from the nanometre to the centimetre scale is a major challenge. The aim of this study was to develop a computational approach to overcome this challenge and study potential bi-directional coupling between sub-cellular and tissue-scale arrhythmia phenomena. A framework comprising a hierarchy of computational models was developed, which includes detailed single-cell models describing spatio-temporal calcium dynamics in 3D, efficient non-spatial cell models, and both idealised and realistic tissue models. A phenomenological approach was implemented to reproduce SCRE morphology and variability in the efficient cell models, comprising the definition of analytical Spontaneous Release Functions (SRF) whose parameters may be randomly sampled from appropriate distributions in order to match either the 3D cell models or experimental data. Pro-arrhythmogenic pacing protocols were applied to initiate re-entry and promote calcium overload, leading to the emergence of SCRE. The SRF accurately reproduced the dynamics of SCRE and its dependence on environment variables under multiple different conditions. Sustained re-entrant excitation promoted calcium overload, and led to the emergence of focal excitations after termination. A purely functional mechanism of re-entry and focal activity localisation was demonstrated, related to the unexcited spiral wave core. In conclusion, a novel approach has been developed to dynamically model SCRE at the tissue scale, which facilitates novel, detailed multi-scale mechanistic analysis. It was revealed that complex re-entrant excitation patterns and SCRE may be bi-directionally coupled, promoting novel mechanisms of arrhythmia perpetuation.
Highlights
Cardiovascular disease is one of the major healthcare problems faced by the developed world, with increasing prevalence associated with aging populations [1,2,3]
Is first described validation of the Dynamic Fit Spontaneous Release Functions (SRF) approach for the three Ca2+ system conditions before application of the framework, in order to: (i) demonstrate the mechanism of stochastically mediated sub-cellular calcium release events (SCRE)-induced ectopic beats; (ii) examine the complexities underlying the Sarcoplasmic Reticulum (SR)-Ca2+ dependence of focal excitation; (iii) demonstrate two independent mechanisms of conduction block associated with SCRE; and (iv) study the potential multiscale, pro-arrhythmic interactions between SCRE and re-entrant excitation
The 0D model implementing the Dynamic Fit SRF model was first validated by comparison of whole-cell SCRE under Ca2+ clamp conditions with a second set of simulations of the 3D cell model, for the control and remodelling conditions (S2 Text (Validation and Results))
Summary
Cardiovascular disease is one of the major healthcare problems faced by the developed world, with increasing prevalence associated with aging populations [1,2,3]. The underlying rapid and irregular electrical activation of cardiac tissue may be mediated by abnormal spontaneous pacing (focal ectopic activity; “arrhythmia triggers”), self-perpetuating re-entrant excitation (“arrhythmia substrate”), or a complex interplay between both mechanisms (trigger-substrate interactions) [4,5]. Management of these arrhythmias is typically challenging, often requiring invasive procedures such as implanted defibrillators or catheter ablation; even these interventions have limited success rates [6,7]. Understanding of the mechanisms underlying the genesis, perpetuation and recurrence of rapid arrhythmias will lead to the development of improved treatment strategies
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