Simulation of ventricular rate control during atrial fibrillation using ionic channel blockers.

Background: The atrioventricular (AV) node is the only compartment that conducts an electrical impulse between the atria and the ventricles. The main role of the AV node is to facilitate efficient pumping by conducting excitation slowly between the two chambers as well as reduce the ventricular rate during atrial fibrillation (AF).

Methods: Using computer simulations, we investigated excitation conduction from the right atrium to the bundle of His during high-rate atrial excitation with or without partial blocking of the calcium or potassium ionic current.

Characterization and influence of cardiac background sodium current in the atrioventricular node.

Background inward sodium current (IB,Na) that influences cardiac pacemaking has been comparatively under-investigated. The aim of this study was to determine for the first time the properties and role of IB,Na in cells from the heart's secondary pacemaker, the atrioventricular node (AVN). Myocytes were isolated from the AVN of adult male rabbits and mice using mechanical and enzymatic dispersion.

Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.

Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A.

Three-dimensional computer model of the right atrium including the sinoatrial and atrioventricular nodes predicts classical nodal behaviours.

The aim of the study was to develop a three-dimensional (3D) anatomically-detailed model of the rabbit right atrium containing the sinoatrial and atrioventricular nodes to study the electrophysiology of the nodes. A model was generated based on 3D images of a rabbit heart (atria and part of ventricles), obtained using high-resolution magnetic resonance imaging. Segmentation was carried out semi-manually.

Importance of gradients in membrane properties and electrical coupling in sinoatrial node pacing.

The sinoatrial node (SAN) is heterogeneous in terms of cell size, ion channels, current densities, connexins and electrical coupling. For example, Nav1.5 (responsible for INa) and Cx43 (responsible for electrical coupling) are absent from the centre of the SAN (normally the leading pacemaker site), but present in the periphery (at SAN-atrial muscle junction).

Simulation study of complex action potential conduction in atrioventricular node.

The atrioventricular (AV) node, which is located between the atria and ventricles of the heart, acts as important roles in cardiac excitation conduction between the two chambers. Although there are multiple conduction pathways in the AV node, the structure of the AV node has not been clarified. In this study, we constructed a one-dimensional model of the AV node and simulated excitation conduction between the right atrium and the bundle of His via the AV node.

Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues.

It is now over 100years since the discovery of the cardiac conduction system, consisting of three main parts, the sinus node, the atrioventricular node and the His-Purkinje system. The system is vital for the initiation and coordination of the heartbeat. Over the last decade, immense strides have been made in our understanding of the cardiac conduction system and these recent developments are reviewed here.

Connexins and the atrioventricular node.

The structure and functioning of the atrioventricular (AV) node has remained mysterious owing to its high degree of complexity. In this review article, we integrate advances in knowledge regarding connexin expression in the AV node. Complex patterning of 4 different connexin isoforms with single channel conductances ranging from ultralow to high explains the dual pathway electrophysiology of the AV node, the presence of 2 nodal extensions, longitudinal dissociation in the penetrating bundle, and, most importantly, how the AV node maintains slow conduction between the atria and the ventricles.

Pharmacological blockade of IKs destabilizes spiral-wave reentry under β-adrenergic stimulation in favor of its early termination.

We tested a hypothesis that an enhancement of I(Ks) may play a pivotal role in ventricular proarrhythmia under high sympathetic activity. A 2-dimensional ventricular muscle layer was prepared in rabbit hearts, and action potential signals were analyzed by optical mapping. During constant stimulation, isoproterenol (ISP, 0.

Anatomical and molecular mapping of the left and right ventricular His-Purkinje conduction networks.

Functioning of the cardiac conduction system depends critically on its structure and its complement of ion channels. Therefore, the aim of this study was to document both the structure and ion channel expression of the left and right ventricular His-Purkinje networks, as we have previously done for the sinoatrial and atrioventricular nodes. A three-dimensional (3D) anatomical computer model of the His-Purkinje network of the rabbit heart was constructed after staining the network by immunoenzyme labelling of a marker protein, middle neurofilament.

Ageing-dependent remodelling of ion channel and Ca2+ clock genes underlying sino-atrial node pacemaking.

The function of the sino-atrial node (SAN), the pacemaker of the heart, is known to decline with age, resulting in pacemaker disease in the elderly. The aim of the study was to investigate the effects of ageing on the SAN by characterizing electrophysiological changes and determining whether changes in gene expression are involved. In young and old rats, SAN function was characterized in the anaesthetized animal, isolated heart and isolated right atrium using ECG and action potential recordings; gene expression was characterized using quantitative PCR.

Computer three-dimensional anatomical reconstruction of the human sinus node and a novel paranodal area.

We have previously shown in rabbit that the pacemaker of the heart (the sinus node) is widespread and matches the wide distribution of the leading pacemaker site within the right atrium. There is, however, uncertainty about the precise location of the pacemaker in human heart, and its spatial relationships with the surrounding right atrial muscle. Therefore, the aim of the current study was to investigate the distribution of the sinus node tissue in a series of healthy human hearts and, for one of the hearts to construct a computer three-dimensional anatomical model of the sinus node, including the likely orientation of myocytes.

Mechanistic links between Na+ channel (SCN5A) mutations and impaired cardiac pacemaking in sick sinus syndrome.

Rationale: Familial sick sinus syndrome (SSS) has been linked to loss-of-function mutations of the SCN5A gene, which result in decreased inward Na(+) current, I(Na). However, the functional role of I(Na) in cardiac pacemaking is controversial, and mechanistic links between mutations and sinus node dysfunction in SSS are unclear.

Objective: To determine mechanisms by which the SCN5A mutations impair cardiac pacemaking.

Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.

Background: Although we know much about the molecular makeup of the sinus node (SN) in small mammals, little is known about it in humans. The aims of the present study were to investigate the expression of ion channels in the human SN and to use the data to predict electrical activity.

Methods And Results: Quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence were used to analyze 6 human tissue samples.

Atrial proarrhythmia due to increased inward rectifier current (I(K1)) arising from KCNJ2 mutation--a simulation study.

Atrial fibrillation (AF) has been linked to increased inward rectifier potassium current, I(K1), either due to AF-induced electrical remodelling, or from functional changes due to the Kir2.1 V93I mutation. The aim of this simulation study was to identify at cell and tissue levels' mechanisms by which increased I(K1) facilitates and perpetuates AF.

Computer three-dimensional reconstruction of the atrioventricular node.

Because of its complexity, the atrioventricular node (AVN), remains 1 of the least understood regions of the heart. The aim of the study was to construct a detailed anatomic model of the AVN and relate it to AVN function. The electric activity of a rabbit AVN preparation was imaged using voltage-dependent dye.

Imaging the heart: computer 3-dimensional anatomic models of the heart.

Since the 1960s, models of the action potential in various cardiac cell types have been developed, and since the 1990s, 3-dimensional anatomic (or geometric) models of various cardiac structures have been developed. We are approaching the time when, for one species, we should have a complete set of action potential and anatomic models for the various cardiac tissues and then we will have realized the aim of constructing a "virtual heart" with accurate anatomy and electrophysiology. However, already the two types of model are beginning to be used in tandem to reconstruct the activation sequence of the heart both during sinus rhythm and arrhythmias.

Pacing-induced spontaneous activity in myocardial sleeves of pulmonary veins after treatment with ryanodine.

Background: Recent clinical electrophysiology studies and successful results of radiofrequency catheter ablation therapy suggest that high-frequency focal activity in the pulmonary veins (PVs) plays important roles in the initiation and perpetuation of atrial fibrillation, but the mechanisms underlying the focal arrhythmogenic activity are not understood.

Methods And Results: Extracellular potential mapping of rabbit right atrial preparations showed that ryanodine (2 micromol/L) caused a shift of the leading pacemaker from the sinoatrial node to an ectopic focus near the right PV-atrium junction. The transmembrane potential recorded from the isolated myocardial sleeve of the right PV showed typical atrial-type action potentials with a stable resting potential under control conditions.