Multi-scale approaches for the simulation of cardiac electrophysiology: I – Sub-cellular and stochastic calcium dynamics from cell to organ

Colman, Michael A.; Holmes, Maxx; Whittaker, Dominic G.; Jayasinghe, Izzy; Benson, Alan P.

doi:10.1016/j.ymeth.2020.02.011

Cited by 11 publications

(11 citation statements)

References 30 publications

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“…The top panel illustrates the processing of LTCC/RyR image data so that it can be aligned and registered on an idealized grid computational model, as presented in Sutanto et al (2018) . The lower panel illustrates the method of calculating the correlation length-scale (λ) in order to generate Gaussian-random field maps which match these parameters in order to describe sub-cellular heterogeneity, as presented in Colman et al (2020) . (B) Approaches for directly incorporating imaging data into realistic, sub-micron cell models.…”

Section: Modeling Variability In Sub-cellular Structure and Functionmentioning

confidence: 99%

“…In an alternative approach, a method was presented in Colman et al (2020) which involved the development of image-analysis techniques to extract parameters describing the spatial correlation and distribution of the channels ( Figure 7A ). This involved calculating the length-scale which describes the distance over which expression is correlated.…”

Section: Modeling Variability In Sub-cellular Structure and Functionmentioning

confidence: 99%

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Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

et al. 2022

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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.

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Section: Modeling Variability In Sub-cellular Structure and Functionmentioning

confidence: 99%

Section: Modeling Variability In Sub-cellular Structure and Functionmentioning

confidence: 99%

Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

et al. 2022

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“…Specifically, Ca 2+ -driven arrhythmia is known to involve criticality in the ensemble behavior of subcellular (micron scale) Ca 2+ -handling structures. Detailed models of sub-cellular Ca 2+ -dynamics have been developed (see, e.g., Colman et al, 2020 ) but application of these models in syncytium of myocytes remains challenging.…”

Section: Still Averagingmentioning

confidence: 99%

From Millimeters to Micrometers; Re-introducing Myocytes in Models of Cardiac Electrophysiology

et al. 2021

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Computational modeling has contributed significantly to present understanding of cardiac electrophysiology including cardiac conduction, excitation-contraction coupling, and the effects and side-effects of drugs. However, the accuracy of in silico analysis of electrochemical wave dynamics in cardiac tissue is limited by the homogenization procedure (spatial averaging) intrinsic to standard continuum models of conduction. Averaged models cannot resolve the intricate dynamics in the vicinity of individual cardiomyocytes simply because the myocytes are not present in these models. Here we demonstrate how recently developed mathematical models based on representing every myocyte can significantly increase the accuracy, and thus the utility of modeling electrophysiological function and dysfunction in collections of coupled cardiomyocytes. The present gold standard of numerical simulation for cardiac electrophysiology is based on the bidomain model. In the bidomain model, the extracellular (E) space, the cell membrane (M) and the intracellular (I) space are all assumed to be present everywhere in the tissue. Consequently, it is impossible to study biophysical processes taking place close to individual myocytes. The bidomain model represents the tissue by averaging over several hundred myocytes and this inherently limits the accuracy of the model. In our alternative approach both E, M, and I are represented in the model which is therefore referred to as the EMI model. The EMI model approach allows for detailed analysis of the biophysical processes going on in functionally important spaces very close to individual myocytes, although at the cost of significantly increased CPU-requirements.

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“…For the realistic 2D ventricular slice and the 3D bi-ventricle simulations, the spatial resolution was 0.2 mm kept from the geometry reconstructed from DT-MRI [22], [23]. Neumann boundary conditions with zero-flux were implemented at geometry boundaries [24].…”

Section: Numerical Detailsmentioning

confidence: 99%

In Silico Investigation of CACNA2D1 S755T Mutation Associated With Short QT Syndrome

et al. 2021

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Short QT syndrome (SQTS) is a genetic disease characterized by constantly short QT intervals and high risks of sudden death. SQTS6 is one of the identified SQTS genotype variants associated with the CACNA2D1 S755T mutation. However, the pathogenesis of SQTS induced arrhythmias remains unclear. To identify the underlying mechanisms of SQTS6 induced arrhythmias, a multi-scale human ventricle model comprising cell to organ levels was built. Cellular data was fitted at the cell level to reproduce the electrophysiological alterations reported in experiments. The influences were further explored at tissue and organ levels using idealized strand or tissue sheet models, and realistic ventricular slice and three-dimensional organ models. Simulation results suggested that, at the cellular level, the action potential duration (APD) and the effective refractory period (ERP) of myocytes were significantly abbreviated in the mutation condition. The unevenly changed APD and ERP led to transmural heterogeneity remodeling, and resulted in decreased temporal vulnerability. In addition, the S755T mutation shortened the critical length for initiating reentrant spiral waves, which enhanced the spatial vulnerability and provided substrates for reentry arrhythmias. Regarding the sustainability of arrhythmias, the evoked spiral waves or scroll waves persisted in the mutation condition but did not persist in the wild-type condition. The present study clearly suggested that the CACNA1DC S755T mutation can facilitate the initiation and maintenance of ventricular arrhythmias, and therefore contributes to higher risks of ventricular arrhythmias in SQTS6 patients.INDEX TERMS Inherited heart disease, short QT syndrome, simulation, ventricular arrhythmia.

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Multi-scale approaches for the simulation of cardiac electrophysiology: I – Sub-cellular and stochastic calcium dynamics from cell to organ

Abstract: This is a repository copy of Multi-scale approaches for the simulation of cardiac electrophysiology: I -sub-cellular and stochastic calcium dynamics from cell to organ.

Cited by 11 publications

References 30 publications

Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

From Millimeters to Micrometers; Re-introducing Myocytes in Models of Cardiac Electrophysiology

In Silico Investigation of CACNA2D1 S755T Mutation Associated With Short QT Syndrome

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