Determinants of Heterogeneity, Excitation and Conduction in the Sinoatrial Node: A Model Study

Oren, Ronit V.; Clancy, Colleen E.

doi:10.1371/journal.pcbi.1001041

Cited by 62 publications

(70 citation statements)

References 43 publications

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“…This study showed that both fibroblast density and heterocellular coupling conductance exhibit a biphasic effect on the frequency of spiral waves and that both impact the wave stability. Similar results were obtained in the sinoatrial node by Oren et al [100] and in ventricular tissue.…”

Section: Consequences Of Fibrosis Derived From Computational Studiessupporting

confidence: 88%

Intermittent Failure Dynamics Characterization

et al. 2012

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Heart failure constitutes a major public health problem worldwide. Affected patients experience a number of changes in the electrical function of the heart that predispose to potentially lethal cardiac arrhythmias. Due to the multitude of electrophysiological changes that may occur during heart failure, the scientific literature is complex and sometimes ambiguous, perhaps because these findings are highly dependent on the etiology, the stage of heart failure, and the experimental model used to study these changes. Nevertheless, a number of common features of failing hearts have been documented. Prolongation of the action potential (AP) involving ion channel remodeling and alterations in calcium handling have been established as the hallmark characteristics of myocytes isolated from failing hearts. Intercellular uncoupling and fibrosis are identified as major arrhythmogenic factors. Multi-scale computational simulations are a powerful tool that complements experimental and clinical research. The development of biophysically detailed computer models of single myocytes and cardiac tissues has contributed greatly to our understanding of processes underlying excitation and repolarization in the heart. The electrical, structural, and metabolic remodeling that arises in cardiac tissues during heart failure has been addressed from different computational perspectives to further understand the arrhythmogenic substrate. This review summarizes the contributions from computational modeling and simulation to predict the underlying mechanisms of heart failure phenotypes and their implications for arrhythmogenesis, ranging from the cellular level to whole-heart simulations. The main aspects of heart failure are presented in several related sections. An overview of the main electrophysiological and structural changes that have been observed experimentally in failing hearts is followed by the description and discussion of the simulation work in this field at the cellular level, and then in 2D and 3D cardiac structures. The implications for arrhythmogenesis in heart failure are also discussed including therapeutic measures, such as drug effects and cardiac resynchronization therapy. Finally, the future challenges in heart failure modeling and simulation will be discussed.

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Section: Consequences Of Fibrosis Derived From Computational Studiessupporting

confidence: 88%

Intermittent Failure Dynamics Characterization

et al. 2012

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“…Previous SAN models to date have been 1D or a thin radial slice (8,30) and are, thus, unable to capture the phenomenon studied herein. Building upon histological, anatomical, and mapping studies, our SAN model captured a broad array of experimentally observed behavior and offers comprehensive mechanistic insight into SAN function and neurally induced AF genesis.…”

Section: Discussionmentioning

confidence: 97%

“…Recent SAN modeling studies have been limited to one dimension or a thin radial slice (8,30), and thus the inferior/superior LPS shifting has not been a target of study. Furthermore, extension of these one-dimensional (1D) gradient models to three-dimensional (3D) is ambiguous, as it can be performed by either rotation or translation.…”

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confidence: 99%

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Munoz

Kaur

Vigmond

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Muñoz MA, Kaur J, Vigmond EJ. Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study. Am J Physiol Heart Circ Physiol 301: H1974-H1983, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00059.2011.-Neuronal modulation of the sinoatrial node (SAN) plays a crucial role in the initiation and maintenance of atrial arrhythmias (AF), although the exact mechanisms remain unclear. We used a computer model of a rabbit right atrium (RA) with a heterogeneous SAN and detailed ionic current descriptions for atrial and SAN myocytes to explore reentry initiation associated with autonomic activity. Heterogeneous acetylcholine (ACh)-dependent ionic responses along with L-type Ca current (ICa,L) upregulation were incorporated in the SAN only. During control, activation was typical with the leading pacemaker site located close to the superior vena cava or the intercaval region. With cholinergic stimulation, activation patterns frequently included caudal shifts of the leading pacemaker site and occasional double breakouts. The model became increasingly arrhythmogenic for the ACh concentration Ͼ20 nM and for large ICa,L conductance. Reentries obtained included counterclockwise rotors in the free wall, clockwise reentry circulating between the SAN and free wall, and typical flutter. The SAN was the cause of reentry with a common leading sequence of events: a bradycardic beat with shifting in the caudal direction, followed by a premature beat or unidirectional block within the SAN. Electrotonic loading, and not just overdrive pacing, squelches competing pacemaker sites in the SAN. Cholinergic stimulation concomitant with I Ca,L upregulation shifts leading pacemaker site and can lead to reentry. A heterogeneous response to autonomic innervation, a large myocardial load, and an extensive SAN in the intercaval region are required for neurally induced SAN-triggered reentry. electrophysiology; reentry; autonomic innervation ATRIAL FIBRILLATION (AF) is the most common and diverse cardiac arrhythmia (21). Experimental observations have illustrated the crucial role that neuronal mechanisms have in its initiation and maintenance (33). Atrial arrhythmias can be induced in dogs by localized electrical stimuli applied to nerve branches of the thoracic vagosympathetic complex (31) or mediastinal nerves (2, 31). Experiments show that acetylcholine (ACh) can trigger reentry and AF in the right atrium (RA) and that adrenergic stimulation facilitates both AF initiation and maintenance (33). Atropine completely abolishes bradycardia and subsequent tachyarrhythmias, indicating that cholinergic efferents play a predominant role in induction (33).Different studies describe a similar sequence of events for arrhythmias originating in the RA that were induced by neural stimulation: cycle length (CL) prolongation, often with leading pacemaker site (LPS) shifting, followed by an atrial premature beat (APB), and subsequent tachyarrhythmia (1, 2, 31, 33). The escape beat initiating the tachyarr...

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“…fibroblasts, neurons, etc. The interested reader is referred to the most recent achievements in the numerical modeling in this exciting area of research (137, 138), including pathological aspects of SA node function (139, 140). …”

Section: Summary and Future Directionsmentioning

confidence: 99%

Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

et al. 2014

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Cardiac pacemaking is a complex phenomenon that is still not completely understood. Together with experimental studies, numerical modeling has been traditionally used to acquire mechanistic insights in this research area. This review summarizes the present state of numerical modeling of the cardiac pacemaker, including approaches to resolve present paradoxes and controversies. Specifically we discuss the requirement for realistic modeling to consider symmetrical importance of both intracellular and cell membrane processes (within a recent “coupled-clock” theory). Promising future developments of the complex pacemaker system models include the introduction of local calcium control, mitochondria function, and biochemical regulation of protein phosphorylation and cAMP production. Modern numerical and theoretical methods such as multi-parameter sensitivity analyses within extended populations of models and bifurcation analyses are also important for the definition of the most realistic parameters that describe a robust, yet simultaneously flexible operation of the coupled-clock pacemaker cell system. The systems approach to exploring cardiac pacemaker function will guide development of new therapies, such as biological pacemakers for treating insufficient cardiac pacemaker function that becomes especially prevalent with advancing age.

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Determinants of Heterogeneity, Excitation and Conduction in the Sinoatrial Node: A Model Study

Cited by 62 publications

References 43 publications

Intermittent Failure Dynamics Characterization

Intermittent Failure Dynamics Characterization

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

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