The Subcellular Distribution of Ryanodine Receptors and L-Type Ca2+ Channels Modulates Ca2+-Transient Properties and Spontaneous Ca2+-Release Events in Atrial Cardiomyocytes

Sutanto, Henry; Sloun, Bart van; Schönleitner, Patrick; Zandvoort, Marc A. M. J. van; Antoons, Gudrun; Heijman, Jordi

doi:10.3389/fphys.2018.01108

Cited by 27 publications

(41 citation statements)

References 50 publications

(100 reference statements)

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“…In particular, previous studies have provided conflicting results about functional consequences of facilitation of SERCA-mediated SR Ca uptake in the setting of dysregulated, i.e. "leaky" cardiac RyR2s in arrhythmia and HF [15][16][17][18]35,36]. The overall deleterious effects on Ca handling and arrhythmogenesis observed in the present study with conditional overexpression of SERCA in CPVT (i.e.…”

Section: Discussioncontrasting

confidence: 67%

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Liu

Lou

Smith

et al. 2020

IJMS

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Ryanodine receptor 2 (RyR2) and SERCA2a are two major players in myocyte calcium (Ca) cycling that are modulated physiologically, affected by disease and thus considered to be potential targets for cardiac disease therapy. However, how RyR2 and SERCA2a influence each others’ activities, as well as the primary and secondary consequences of their combined manipulations remain controversial. In this study, we examined the effect of acute upregulation of SERCA2a on arrhythmogenesis by conditionally overexpressing SERCA2a in a mouse model featuring hyperactive RyR2s due to ablation of calsequestrin 2 (CASQ2). CASQ2 knock-out (KO) mice were crossbred with doxycycline (DOX)-inducible SERCA2a transgenic mice to generate KO-TG mice. In-vivo ECG studies have shown that induction of SERCA2a (DOX+) overexpression markedly exacerbated both ventricular and atrial arrhythmias in vivo, compared with uninduced KO-TG mice (DOX-). Consistent with that, confocal microscopy in both atrial and ventricular myocytes demonstrated that conditional upregulation of SERCA2a enhanced the rate of occurrence of diastolic Ca release events. Additionally, deep RNA sequencing identified 17 downregulated genes and 5 upregulated genes in DOX+ mice, among which Ppp1r13l, Clcn1, and Agt have previously been linked to arrhythmias. Our results suggest that conditional upregulation of SERCA2a exacerbates hyperactive RyR2-mediated arrhythmias by further elevating diastolic Ca release.

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Section: Discussioncontrasting

confidence: 67%

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Liu

Lou

Smith

et al. 2020

IJMS

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“…In this study, we used both CRN and Grandi models to simulate the AP of human atrial myocytes. Although these models were developed based on experimental data on human atrial myocytes and validated by their ability to reproduce APs and calcium transients, there were several limitations discussed elsewhere (Wilhelms et al, 2013; Voigt et al, 2014; Sutanto et al, 2018). Here, the limitations special to the present study are summarized.…”

Section: Discussionmentioning

confidence: 99%

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

Bai

et al. 2019

Front. Physiol.

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Functional analysis has shown that the p.Met207Val mutation was linked to atrial fibrillation and caused an increase in transactivation activity of PITX2c, which caused changes in mRNA synthesis related to ionic channels and intercellular electrical coupling. We assumed that these changes were quantitatively translated to the functional level. This study aimed to investigate the potential impact of the PITX2c p.Met207Val mutation on atrial electrical activity through multiscale computational models. The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial cell action potentials (APs) was modified to incorporate experimental data on the expected p.Met207Val mutation-induced changes in ionic channel currents (INaL, IKs, and IKr) and intercellular electrical coupling. The cell models for wild-type (WT), heterozygous (Mutant/Wild type, MT/WT), and homozygous (Mutant, MT) PITX2c cases were incorporated into homogeneous multicellular 1D and 2D tissue models. Effects of this mutation-induced remodeling were quantified as changes in AP profile, AP duration (APD) restitution, conduction velocity (CV) restitution and wavelength (WL). Temporal and spatial vulnerabilities of atrial tissue to the genesis of reentry were computed. Dynamic behaviors of re-entrant excitation waves (Life span, tip trajectory and dominant frequency) in a homogeneous 2D tissue model were characterized. Our results suggest that the PITX2c p.Met207Val mutation abbreviated atrial APD and flattened APD restitution curves. It reduced atrial CV and WL that facilitated the conduction of high rate atrial excitation waves. It increased the tissue's temporal vulnerability by increasing the vulnerable window for initiating reentry and increased the tissue spatial vulnerability by reducing the substrate size necessary to sustain reentry. In the 2D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained reentry. In conclusion, electrical and structural remodeling arising from the PITX2c p.Met207Val mutation may increase atrial susceptibility to arrhythmia due to shortened APD, reduced CV and increased tissue vulnerability, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.

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“…The effect of adding axial TTs to the Voigt & Heijman human CM model was also studied by Sutanto et al ( 2018 ). Their simulations with variable axial TT density and distribution shows a progressive synchronization of the intracellular Ca 2+ release in the radial direction.…”

Section: Discussionmentioning

confidence: 98%

“…Another relevant model limitation is the use of a deterministic RyR model, which implicitly assumes homogeneous distribution and behavior of CRUs. Therefore, this simplification does not include stochastic Ca 2+ release events and subcellular fluctuations in calcium-handling proteins, which may influence the results (Sutanto et al, 2018 ) and limit the applicability of the model to describe pathological conditions. Using a stochastic formulation would allow the incorporation of spatial heterogeneity in Ca 2+ release, which constitutes an important trigger for spontaneous Ca 2+ waves, and consequently for abnormal Ca 2+ -wave propagation patterns.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Computational Model of the Rabbit Atrial Cardiomyocyte With Spatial Calcium Dynamics

et al. 2020

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Models of cardiac electrophysiology are widely used to supplement experimental results and to provide insight into mechanisms of cardiac function and pathology. The rabbit has been a particularly important animal model for studying mechanisms of atrial pathophysiology and atrial fibrillation, which has motivated the development of models for the rabbit atrial cardiomyocyte electrophysiology. Previously developed models include detailed representations of membrane currents and intracellular ionic concentrations, but these so-called “common-pool” models lack a spatially distributed description of the calcium handling system, which reflects the detailed ultrastructure likely found in cells in vivo . Because of the less well-developed T-tubular system in atrial compared to ventricular cardiomyocytes, spatial gradients in intracellular calcium concentrations may play a more significant role in atrial cardiomyocyte pathophysiology, rendering common-pool models less suitable for investigating underlying electrophysiological mechanisms. In this study, we developed a novel computational model of the rabbit atrial cardiomyocyte incorporating detailed compartmentalization of intracellular calcium dynamics, in addition to a description of membrane currents and intracellular processes. The spatial representation of calcium was based on dividing the intracellular space into eighteen different compartments in the transversal direction, each with separate systems for internal calcium storage and release, and tracking ionic fluxes between compartments in addition to the dynamics driven by membrane currents and calcium release. The model was parameterized employing a population-of-models approach using experimental data from different sources. The parameterization of this novel model resulted in a reduced population of models with inherent variability in calcium dynamics and electrophysiological properties, all of which fall within the range of observed experimental values. As such, the population of models may represent natural variability in cardiomyocyte electrophysiology or inherent uncertainty in the underlying experimental data. The ionic model population was also able to reproduce the U-shaped waveform observed in line-scans of triggered calcium waves in atrial cardiomyocytes, characteristic of the absence of T-tubules, resulting in a centripetal calcium wave due to subcellular calcium diffusion. This novel spatial model of the rabbit atrial cardiomyocyte can be used to integrate experimental findings, offering the potential to enhance our understanding of the pathophysiological role of calcium-handling abnormalities under diseased conditions, such as atrial fibrillation.

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The Subcellular Distribution of Ryanodine Receptors and L-Type Ca2+ Channels Modulates Ca2+-Transient Properties and Spontaneous Ca2+-Release Events in Atrial Cardiomyocytes

Cited by 27 publications

References 50 publications

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

A Novel Computational Model of the Rabbit Atrial Cardiomyocyte With Spatial Calcium Dynamics

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