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 mol/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. Treatment with ryanodine (0.5 to 2 mol/L) resulted in a depolarization of the resting potential and a development of pacemaker depolarization. These changes were enhanced transiently after an increase in the pacing rate: a self-terminating burst of spontaneous action potentials (duration, 33.6Ϯ5.0 s; nϭ32) was induced by a train of rapid stimuli (3. A trial fibrillation (AF) is the most common of all sustained tachyarrhythmias and is one of the major causes of stroke. The most widely accepted mechanism of AF is multiple reentrant wavelets. 1 However, recent clinical studies have shown that paroxysmal AF is initiated by bursts of premature excitations originating primarily in the pulmonary veins (PVs), and radiofrequency ablation or electrical isolation of these foci can eliminate AF. 2,3 More recently, Haïs-saguerre et al 4 reported that in patients with drug-resistant chronic AF and structural heart disease, after electrical cardioversion, the PVs are also the dominant trigger reinitiating AF. Therefore, the PVs are important not only for the initiation of AF but also for its maintenance. 5 The myocardial fibers of the left atrium wrap around the PVs entering the left atrium to form "myocardial sleeves" (MSs), 6,7 and this structure is the origin of focal activity. 8 Previous studies have suggested that PVMSs show a variety of spontaneous activities such as sinoatrial (SA) node-type automaticity, rapid spontaneous activities via early or delayed afterdepolarizations, 8 -12 and microreentry based on a marked heterogeneous tissue structure. 12,13 However, the electrophysiological properties of PVMSs have not been fully characterized.In the present study, we investigated the electrophysiological properties of rabbit PVMSs. The results show that addition of 0.5 to 2 mol/L ryanodine to PVMSs uncovers pacing-induced spontaneous activity. Ryanodine at low concentrations locks the sarcoplasmic reticulum (SR) Ca 2ϩ release channel, the ryanodine receptor (RyR), in a subconductance state, causing a Ca 2ϩ -independent Ca 2ϩ release from the SR. 14 MethodsRabbits weighing 1.5 to 2.0 kg (Chubu-Kagaku-Shizai, Nagoya, Japan) were anesthetized with pentobarbital (30 to 40 mg/kg IV), and the heart was quickly excised. The right atrium, including the SA...

Abstract-Recent work on isolated sinoatrial node cells from rabbit has suggested that sarcoplasmic reticulum Ca 2ϩ release plays a dominant role in the pacemaker potential, and ryanodine at a high concentration (30 mol/L blocks sarcoplasmic reticulum Ca 2ϩ release) abolishes pacemaking and at a lower concentration abolishes the chronotropic effect of ␤-adrenergic stimulation. The aim of the present study was to test this hypothesis in the intact sinoatrial node of the rabbit. Spontaneous activity and the pattern of activation were recorded using a grid of 120 pairs of extracellular electrodes. Ryanodine 30 mol/L did not abolish spontaneous activity or shift the position of the leading pacemaker site, although it slowed the spontaneous rate by 18.9Ϯ2.5% (nϭ6). After ryanodine treatment, ␤-adrenergic stimulation still resulted in a substantial chronotropic effect (0.3 mol/L isoproterenol increased spontaneous rate by 52.6Ϯ10.5%, nϭ5). In isolated sinoatrial node cells from rabbit, 30 mol/L ryanodine slowed spontaneous rate by 21.5Ϯ2.6% (nϭ13). It is concluded that sarcoplasmic reticulum Ca 2ϩ release does not play a dominating role in pacemaking in the sinoatrial node. The full text of this article is available at http://www.circresaha.org. release activates inward Na ϩ -Ca 2ϩ exchange current, and this helps to generate the pacemaker depolarization. Two studies by Lakatta and coinvestigators 1,2 published recently in Circulation Research have placed the spotlight on this mechanism: Bogdanov et al 1 suggested that SR Ca 2ϩ release may be obligatory for pacemaking, because they observed that a high concentration (30 mol/L) of ryanodine, which blocks the SR Ca 2ϩ release channel, abolishes the spontaneous activity of isolated SA node cells from rabbit. Vinogradova et al 2 boldly suggested that the positive chronotropic effect of ␤-adrenergic stimulation is the result of the increase in the Ca 2ϩ transient caused by ␤-adrenergic stimulation, because they observed that the chronotropic effect in isolated SA node cells from rabbit is abolished or greatly reduced after the suppression of the Ca 2ϩ transient by a submaximal concentration of ryanodine (3 mol/L). These recent reports are surprising. Previously, the role of SR Ca 2ϩ release was thought to be more minor, because in isolated SA node cells from rabbit and guinea pig, suppression of the Ca 2ϩ transient by a variety of interventions (including up to 10 mol/L ryanodine) did not abolish pacemaking and just decreased spontaneous rate by 21% to 37%. [3][4][5] In this scenario, it is assumed that multiple ionic currents (I Na , I Ca,L , I Ca,T , I K,r , I b,Na , and I f as well as I NaCa ) are involved in the generation of the pacemaker potential. 6 As highlighted by DiFrancesco and Robinson, 7 the conclusion that the chronotropic effect of ␤-adrenergic stimulation is the result of an increase in the Ca 2ϩ transient is also surprising, because the chronotropic effect of ␤-adrenergic stimulation has been previously attributed to actions on ionic currents such as I Ca,...

Effects of brief postganglionic vagal nerve stimulation on the activation sequence of the rabbit sinoatrial (SA) node were investigated. Activation sequences in a small area (7 mm × 7 mm) on the epicardial surface were measured in a beat‐to‐beat manner using an extracellular potential mapping system composed of 64 modified bipolar electrodes with high‐gain and low‐frequency band‐pass filtering. The leading pacemaker site was recognised clearly from both the activation sequence and the characteristic morphology of the potentials. Vagal stimulation resulted in a short‐lasting initial slowing of spontaneous rate followed by a long‐lasting secondary slowing; a brief period of relative or absolute acceleration was interposed between the two slowing phases. During these changes of spontaneous rate, the leading pacemaker site shifted in a complex beat‐to‐beat manner by 1‐6 mm alongside the crista terminalis in the superior or inferior direction. For the first spontaneous excitation following stimulation, the greater the slowing, the larger the distance of the pacemaker shift. There was no such linear relationship between the extent of slowing and the distance of pacemaker shift for the subsequent beats. These changes in the leading pacemaker site in response to vagal stimulation may be the result of the functional and morphological heterogeneity of the mammalian SA node in terms of innervation, receptor distribution and ion channel densities.

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 I Na) 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). To test whether the heterogeneity is important for the functioning of the SAN, one- and two-dimensional models of the SAN and surrounding atrial muscle were created. Normal functioning of the SAN (in terms of cycle length, position of leading pacemaker site, conduction times, activation and repolarization sequences and space constants) was observed when, from the centre to the periphery, (i) cell characteristics (cell size and ionic current densities) were changed in a gradient fashion from a central-type (lacking I Na) to a peripheral-type (possessing I Na) and (ii) coupling conductance was increased in a gradient fashion. We conclude that the heterogeneous nature of the node is important for its normal functioning. The presence of Nav1.5 and Cx43 in the periphery may be essential for the node to be able to drive the atrial muscle: Nav1.5 provides the necessary depolarizing current and Cx43 delivers it to the atrial muscle.

To clarify the mechanisms underlying cardiac dysfunction after electrical defibrillation, we investigated the effects of direct current field stimulation (10 ms, 1-80 V/cm) on isolated guinea pig papillary muscles. Shocks (S2) > 15 V/cm lowered the plateau height of the S2-induced action potential and inhibited its terminal repolarization. Subsequent responses to basic stimuli (S1, 1.0 Hz) for 1-3 min were characterized by a decrease in the maximum diastolic potential, a shortening of action potential duration, and an increase of the developed tension. With S2 > 30 V/cm, a marked delay in repolarization of the S2-induced action potential was followed by oscillation of membrane potential, resulting in repetitive spontaneous activity and often refractoriness to S1 stimulation. The aftereffects were independent of the phase of S2 application. Most of the aftereffects were preserved in the presence of nifedipine (1 microM) or ryanodine (1 microM). Only sodium channel blockade by tetrodotoxin (10 microM) modified the aftereffects by depressing the generation of spontaneous activity. These findings suggest that strong shocks (> 15 V/cm) will produce abnormal arrhythmogenic responses probably through a transient rupture of sarcolemmal membrane (electroporation) leading to a disturbance of the ionic equilibrium of the myocyte.

BackgroundThe 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).MethodsUsing 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.ResultsOur simulations revealed differences in rate reduction and repolarization effects between calcium and potassium current blocking and high degree of potassium current blocking required to reduce the ventricular rate during AF.ConclusionsOur simulation results explain why potassium current blockers are not recommended for controlling ventricular rate during AF.

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. We also investigated several characteristics of the AV node: (1) responses of the AV node to high-rate excitation in the right atrium, (2) the AV nodal reentrant beat induced by premature stimulus, and (3) ventricular rate control during atrial fibrillation with various methods. Our simulation results suggest that multiple conduction pathways act as important roles in controlling the ventricular rate. The one-dimensional model constructed in this study may be useful to analyze complex conduction patterns in the AV node.

Purpose There is a growing interest in minimally invasive surgery as interventional radiology (IVR), which decreases the burden on a patient. However, occupational exposure is a problem because the treatment is performed using X-ray fluoroscopic images. This problem can be solved by the development of a teleoperation system, but rapid force presentation is important to perform safe surgery. The purpose of this study is to develop a new teleoperation system that can be controlled at a high speed and can provide feedback force sensation within 20 ms delay. Methods A master–slave-type remote-control system for catheterization was developed. A compact and high-speed force feedback system is realized using a novel electro-attractive material (EAM) device by which the resistance force is generated by the magnitude of the voltage applied. The linear and rotational movement of master is transferred to the slave device by UDP communication with the LAN cable, and the same movement is performed by two motors. The collision force of catheter or guidewire, detected by the sensor inside the slave device, is also transmitted to the master device. Two voltage-based methods for EAM: the ON/OFF and linear control methods, were implemented. Results After the collision force is detected by the slave sensor, the voltage is applied to the EAM in the master device for an average of 10.33 ms and 15.64 ms by the ON/OFF and linear control methods, respectively. These delays are less than required 20 ms. The movement of the master was stopped by the resistance force of EAM, and that of the slave was also stopped accordingly. Conclusion A master–slave-type remote-control system for catheterization that is capable of high-speed force feedback was developed. With a low delay, the developed system achieved the requirements of 20 ms that was aimed for this study. Therefore, this system may facilitate the realization of IVR surgery that is safe for both doctors and patients.