A new model of the human atrial myocyte with variable T-tubule organization for the study of atrial fibrillation

Atrial fibrillation is the most common arrhythmia, yet treatment strategies are sub-optimal due to incomplete understanding of the underlying mechanisms. Spatiotemporal sub-cellular calcium cycling may play a critical role in the development of alternans and spontaneous activity, which may underlie arrhythmia in the human atria. In this study, we construct a novel electrophysiological model of the human atrial myocyte which incorporates new data on atrial intracellular structure and explicitly accounts for variations in T-tubule organization. The model reproduces spatio-temporal calcium dynamics associated with normal cardiac excitation. In preliminary simulations, the model demonstrates that a loss of T-tubules can promote both alternans and spontaneous calcium waves. The model produced in this study provides novel insight into arrhythmia mechanisms in the human atria and provides a platform for future investigation of proarrhythmic calcium dynamics

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

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 Ca2+ 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.Postprint (published version

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

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

Modelling pathological effects in intracellular calcium dynamics leading to atrial fibrillation

The heart beating is produced by the synchronization of the cardiac cells' contraction. A dysregulation in this mechanism may produce episodes of abnormal heart contraction. The origin of these abnormalities often lies at the subcellular level where calcium is the most important ion that controls the cell contraction. The regulation of calcium concentration is determined by the ryanodine receptors (RyR), the calcium channels that connect the cytosol and the sarcoplasmic reticulum. RyRs open and close stochastically with calcium-dependent rates. The fundamental calcium release event is known as calcium spark, which refers to a local release of calcium through one or more RyRs. Thus, a deep knowledge on both the spatio-temporal characteristics of the calcium patterns and the role of the RyRs is crucial to understand the transition between healthy to unhealthy cells. The aim of this Thesis has been to figure out these changes at the submicron scale, which may induce the transition to Atrial Fibrillation (AF) in advanced stages. To address this issue, I have developed, and validated, a subcellular mathematical model of an atrial myocyte which includes the electro-physiological currents as well as the fundamental intracellular structures. The high resolution of the model has allowed me to study the spatio-temporal calcium features that arise from both the cell stimulation and the resting conditions. Simulations show the relevance of the assembly of RyRs into clusters, leading to the formation of macro-sparks for heterogeneous distributions. These macro-sparks may produce ectopic beats under pathophysiological conditions. The incorporation of RyR-modulators into the model produces a nonuniform spatial distribution of calcium sparks, a situation observed during AF. In this sense, calsequestrin (CSQ) has emerged as a key calcium buffer that modifies the calcium handling. The lack of CSQ produces an increase in the spark frequency and, during calcium overload, it also promotes the appearance of global calcium oscillations. Finally, I have also characterized the effect of detubulation, a common issue in cells with AF and heart failure. Thus, the present work represents a step forward in the understanding of the mechanisms leading to AF, with the development of computational models that, in the future, can be used to complement in vitro or in vivo studies, helping find therapeutic targets for this disease