A New Model of the Human Atrial Myocyte with Variable T:tubule Organization for the Study of Atrial Fibrillation

Colman, Michael A.; Sarathy, Prasanna Partha; MacQuiaide, Niall; Workman, Antony J.

doi:10.22489/cinc.2016.067-421

Cited by 8 publications

(20 citation statements)

References 2 publications

(2 reference statements)

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“…T-tubule disruption was also found to give rise to a steeper SR Ca release-load relationship, predisposing for the appearance of alternans. For atrial myocytes, on the contrary, Colman et al [23] found that alternans appears at low values of t-tubule density, since this results in alternating behavior of success and failure of inward calcium wave propagation. Spontaneous Ca waves originate from regions with no T-tubules, probably because the lack of NCX allows a local spontaneous release to trigger neighboring RyR2 clusters.…”

Section: Discussionmentioning

confidence: 97%

“…In this work we consider a fixed cell size. However, the amount of TAT is typically dependent on cell size [31], even within the same animal species, and it has been observed, in modeling studies, to modulate the effect of t-tubule disruption [22,23]. Finally, we have considered a voltage clamped cell and therefore do not allow for calcium-voltage coupling.…”

Section: Spark Properties Do Not Change With Detubulationmentioning

confidence: 99%

“…Besides, it has been observed that spontaneous Ca 2+ sparks do not appear uniformly in the cell, but they occur around the RyR2s close to the tubules [3]. Modeling studies have shown a relation between the density and spatial organization of t-tubules and the occurrence of alternans and triggered activity [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Marchena

Echebarria

2020

PLoS ONE

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Transverse and axial tubules (TATS) are an essential ingredient of the excitation-contraction machinery that allow the effective coupling of L-type Calcium Channels (LCC) and ryanodine receptors (RyR2). They form a regular network in ventricular cells, while their presence in atrial myocytes is variable regionally and among animal species We have studied the effect of variations in the TAT network using a bidomain computational model of an atrial myocyte with variable density of tubules. At each z-line the t-tubule length is obtained from an exponential distribution, with a given mean penetration length. This gives rise to a distribution of t-tubules in the cell that is characterized by the fractional area (F.A.) occupied by the t-tubules. To obtain consistent results, we average over different realizations of the same mean penetration length. To this, in some simulations we add the effect of a network of axial tubules. Then we study global properties of calcium signaling, as well as regional heterogeneities and local properties of sparks and RyR2 openings. In agreement with recent experiments in detubulated ventricular and atrial cells, we find that detubulation reduces the calcium transient and synchronization in release. However, it does not affect sarcoplasmic reticulum (SR) load, so the decrease in SR calcium release is due to regional differences in Ca 2+ release, that is restricted to the cell periphery in detubulated cells. Despite the decrease in release, the release gain is larger in detubulated cells, due to recruitment of orphaned RyR2s, i.e, those that are not confronting a cluster of LCCs. This probably provides a safeguard mechanism, allowing physiological values to be maintained upon small changes in the t-tubule density. Finally, we do not find any relevant change in spark properties between tubulated and detubulated cells, suggesting that the differences found in experiments could be due to differential properties of the RyR2s in the membrane and in the t-tubules, not incorporated in the present model. This work will help understand the effect of detubulation, that has been shown to occur in disease conditions such as heart failure (HF) in ventricular cells, or atrial fibrillation (AF) in atrial cells.

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Section: Discussionmentioning

confidence: 97%

Section: Spark Properties Do Not Change With Detubulationmentioning

confidence: 99%

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Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Marchena

Echebarria

2020

PLoS ONE

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“… Overview of hA-CM model lineages and most important changes implemented in model iterations. References: Courtemanche et al (1998) , Nygren et al (1998) , Maleckar et al (2009b) , Grandi et al (2010) , Grandi et al (2011) , Koivumäki et al (2011) , Colman et al (2013) , Voigt et al (2013a , b ), Koivumäki et al (2014b) , Colman et al (2016) , Skibsbye et al (2016) . …”

Section: In Silico Atrial Modelingmentioning

confidence: 99%

“…To account for the centripetal diffusion of calcium due to the lack of T-tubules in hA-CMs, Voigt et al (2013b) extended the Grandi model with a spatial representation of Ca 2+ handling based on longitudinal and transverse division of the intracellular space, and included stochastic RyR gating. Colman et al (2016) also presented an atrial model with spatial representation of the calcium handling system to assess the role of variable T-tubule density on intracellular calcium waves and alternans. These efforts have generally attempted to approach more realistic Ca 2+ handling representations by drawing on data describing the T-tubule structure in particular.…”

Section: In Silico Atrial Modelingmentioning

confidence: 99%

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

et al. 2018

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The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology.

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Mechanisms of spontaneous Ca²⁺ release-mediated arrhythmia in a novel 3D human atrial myocyte model: I. Transverse-axial tubule variation

Zhang

Morotti

et al. 2022

Preprint

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Intracellular calcium (Ca2+) cycling is tightly regulated in the healthy heart ensuring effective contraction. This is achieved by transverse (t)-tubule membrane invaginations that facilitate close coupling of key Ca2+-handling proteins such as the L-type Ca2+ channel (LCC) and Na+-Ca2+ exchanger (NCX) on the cell surface with ryanodine receptors (RyRs) on the intracellular Ca2+ store. Though less abundant and regular than in the ventricle, t-tubules also exist in atrial myocytes as a network of transverse invaginations with axial extensions known as the transverse-axial tubule system (TATS). In heart failure and atrial fibrillation there is TATS remodeling that is associated with aberrant Ca2+-handling and Ca2+-induced arrhythmic activity, however the mechanism underlying this is not fully understood. To address this, we developed a novel 3D human atrial myocyte model that couples electrophysiology and Ca2+-handling with variable TATS organization and density. We extensively parameterized and validated our model against experimental data to build a robust tool examining TATS regulation of subcellular Ca2+ release. We found that varying TATS density and thus the localization of key Ca2+-handling proteins has profound effects on Ca2+ handling. Following TATS loss there is reduced NCX that results in increased cleft Ca2+ concentration through decreased Ca2+ extrusion. This elevated Ca2+ increases RyR open probability causing spontaneous Ca2+ releases and promotion of arrhythmogenic waves (especially in the cell interior) that leads to voltage instabilities through delayed afterdepolarizations. In summary, this study demonstrates a mechanistic link between TATS remodeling and Ca2+-driven proarrhythmic behavior that likely reflects the arrhythmogenic state observed in disease.Key PointsTransverse-axial tubule systems (TATS) modulate Ca2+ handling and excitation-contraction coupling in atrial myocytes, with TATS remodeling in heart failure and atrial fibrillation associated with altered Ca2+ cycling and subsequent arrhythmogenesis.To investigate the poorly understood mechanisms linking TATS variation and spontaneous Ca2+ release, we built, parameterized and validated a 3D human atrial myocyte model coupling electrophysiology and spatially-detailed subcellular Ca2+ handling governed by the TATS.Simulated TATS loss causes diastolic Ca2+ and voltage instabilities through reduced NCX-mediated Ca2+ removal, cleft Ca2+ accumulation and increased RyR open probability, resulting in spontaneous Ca2+ release and promotion of arrhythmogenic waves and delayed afterdepolarizations.At fast electrical rates typical of atrial tachycardia/fibrillation, spontaneous Ca2+ releases are larger and more frequent in the cell interior than at the periphery.Our work provides mechanistic insight into how atrial TATS remodeling can lead to Ca2+- driven instabilities that may ultimately contribute to the arrhythmogenic state in disease.

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A New Model of the Human Atrial Myocyte with Variable T:tubule Organization for the Study of Atrial Fibrillation

Abstract: Atrial fibrillation is the most common arrhythmia, yet treatment strategies are sub-optimal due to incomplete understanding of the underlying mechanisms. Spatiotemporal sub-cellular

Cited by 8 publications

References 2 publications

Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

Mechanisms of spontaneous Ca²⁺ release-mediated arrhythmia in a novel 3D human atrial myocyte model: I. Transverse-axial tubule variation

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A New Model of the Human Atrial Myocyte with Variable T:tubule Organization for the Study of Atrial Fibrillation

Abstract: Atrial fibrillation is the most common arrhythmia, yet treatment strategies are sub-optimal due to incomplete understanding of the underlying mechanisms. Spatiotemporal sub-cellular

Cited by 8 publications

References 2 publications

Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: I. Transverse-axial tubule variation

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Mechanisms of spontaneous Ca²⁺ release-mediated arrhythmia in a novel 3D human atrial myocyte model: I. Transverse-axial tubule variation