Abstract
Regulation of intracellular calcium is a critical component of cardiac electrophysiology and excitation-contraction coupling. The calcium spark, the fundamental element of the intracellular calcium transient, is initiated in specialized nanodomains which co-locate the ryanodine receptors and L-type calcium channels. However, calcium homeostasis is ultimately regulated at the cellular scale, by the interaction of spatially separated but diffusively coupled nanodomains with other sub-cellular and surface-membrane calcium transport channels with strong non-linear interactions; and cardiac electrophysiology and arrhythmia mechanisms are ultimately tissue-scale phenomena, regulated by the interaction of a heterogeneous population of coupled myocytes. Recent advances in imaging modalities and image-analysis are enabling the super-resolution reconstruction of the structures responsible for regulating calcium homeostasis, including the internal structure of nanodomains themselves. Extrapolating functional and imaging data from the nanodomain to the whole-heart is non-trivial, yet essential for translational insight into disease mechanisms. Computational modeling has important roles to play in relating structural and functional data at the sub-cellular scale and translating data across the scales. This review covers recent methodological advances that enable image-based modeling of the single nanodomain and whole cardiomyocyte, as well as the development of multi-scale simulation approaches to integrate data from nanometer to whole-heart. Firstly, methods to overcome the computational challenges of simulating spatial calcium dynamics in the nanodomain are discussed, including image-based modeling at this scale. Then, recent whole-cell models, capable of capturing a range of different structures (such as the T-system and mitochondria) and cellular heterogeneity/variability are discussed at two different levels of discretization. Novel methods to integrate the models and data across the scales and simulate stochastic dynamics in tissue-scale models are then discussed, enabling elucidation of the mechanisms by which nanodomain remodeling underlies arrhythmia and contractile dysfunction. Perspectives on model differences and future directions are provided throughout.
Highlights
Intracellular calcium (Ca2+) handling is a critical component of cardiac electrophysiology (Cheng et al, 1993; Bers, 2002; Song et al, 2015): it governs excitation-contraction coupling (ECC), is involved in multiple signaling pathways, and its impairment has been causally linked to both mechanical and electrical dysfunction of the heart (Eisner et al, 2009; Voigt et al, 2014; Clarke et al, 2015)
We focus on methods and approaches, in particular those for image-based and multi-scale modeling, how these differ between models, and the implications of these model differences
This study demonstrated the importance of specific ryanodine receptors (RyRs) arrangement – not just total number – on Ca2+ spark dynamics and highlighted the importance of Ca2+ diffusion within the dyad
Summary
Intracellular calcium (Ca2+) handling is a critical component of cardiac electrophysiology (Cheng et al, 1993; Bers, 2002; Song et al, 2015): it governs excitation-contraction coupling (ECC), is involved in multiple signaling pathways, and its impairment has been causally linked to both mechanical and electrical dysfunction of the heart (Eisner et al, 2009; Voigt et al, 2014; Clarke et al, 2015). Ca2+ sparks, the fundamental element of Ca2+-induced-Ca2+-release (CICR; see sub-section), are controlled at the nanometer-scale in localized nanodomains referred to as dyads or couplons, yet Ca2+ homeostasis occurs inherently at the cellular-scale where flux balance through the membrane and subcellular transporters determines the total Ca2+ levels in the cell and in the Sarcoplasmic Reticulum (SR, the intracellular Ca2+ store). Structure-function relationships from the nanometer- to the whole-heart-scales and dynamics occurring over nanoseconds to hours all contribute to the macroscopic behavior of the heartbeat
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