Cellular Electrophysiological Mechanisms Research Articles

Computational modelling of mouse atrio ventricular node action potential and automaticity.

The atrioventricular node (AVN) is a crucial component of the cardiac conduction system. Despite its pivotal role in regulating the transmission of electrical signals between atria and ventricles, a comprehensive understanding of the cellular electrophysiological mechanisms governing AVN function has remained elusive. This paper presents a detailed computational model of mouse AVN cell action potential (AP). Our model builds upon previous work and introduces several key refinements, including accurate representation of membrane currents and exchangers, calcium handling, cellular compartmentalization, dynamic update of intracellular ion concentrations, and calcium buffering. We recalibrated and validated the model against existing and unpublished experimental data. In control conditions, our model reproduces the AVN AP experimental features, (e.g. rate=175bpm, experimental range [121, 191]bpm). Notably, our study sheds light on the contribution of L-type calcium currents, through both Cav1.2 and Cav1.3 channels, in AVN cells. The model replicates several experimental observations, including the cessation of firing upon block of Cav1.3 or INa,r current. If block induces a reduction in beating rate of 11%. In summary, this work presents a comprehensive computational model of mouse AVN cell AP, offering a valuable tool for investigating pacemaking mechanisms and simulating the impact of ionic current blockades. By integrating calcium handling and refining formulation of ionic currents, our model advances understanding of this critical component of the cardiac conduction system, providing a platform for future developments in cardiac electrophysiology. KEY POINTS: This paper introduces a comprehensive computational model of mouse atrioventricular node (AVN) cell action potentials (APs). Our model is based on the electrophysiological data from isolated mouse AVN cells and exhibits an action potential and calcium transient that closely match the experimental records. By simulating the effects of blocking specific ionic currents, the model effectively predicts the roles of L-type Cav1.2 and Cav1.3 channels, T-type calcium channels, sodium currents (TTX-sensitive and TTX-resistant), and the funny current (If) in AVN pacemaking. The study also emphasizes the significance of other ionic currents, including IKr, Ito, IKur, in regulating AP characteristics and cycle length in AVN cells. The model faithfully reproduces the rate dependence of action potentials under pacing, opening the possibility of use in impulse propagation models. The population-of-models approach showed the robustness of this new AP model in simulating a wide spectrum of cellular pacemaking in AVN.

Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current.

Aim: To assess the risk of sudden cardiac arrest (SCA) associated with the use of carbamazepine (CBZ) and establish the possible underlying cellular electrophysiological mechanisms. Methods: The SCA risk association with CBZ was studied in general population cohorts using a case–control design (n = 5,473 SCA cases, 21,866 non-SCA controls). Effects of 1–100 µM CBZ on action potentials (APs) and individual membrane currents were determined in isolated rabbit and human cardiomyocytes using the patch clamp technique. Results: CBZ use was associated with increased risk of SCA compared with no use (adjusted odds ratio 1.90 [95% confidence interval: 1.12–3.24]). CBZ reduced the AP upstroke velocity of rabbit and human cardiomyocytes, without prominent changes in other AP parameters. The reduction occurred at ≥30 µM and was frequency-dependent with a more pronounced reduction at high stimulus frequencies. The cardiac sodium current (INa) was reduced at ≥30 μM; this was accompanied by a hyperpolarizing shift in the voltage-dependency of inactivation. The recovery from inactivation was slower, which is consistent with the more pronounced AP upstroke velocity reduction at high stimulus frequencies. The main cardiac K+ and Ca2+ currents were unaffected, except reduction of L-type Ca2+ current by 100 µM CBZ. Conclusion: CBZ use is associated with an increased risk of SCA in the general population. At concentrations of 30 µM and above, CBZ reduces AP upstroke velocity and INa in cardiomyocytes. Since the concentration of 30 µM is well within the therapeutic range (20–40 µM), we conclude that CBZ increases the risk of SCA by a reduction of the cardiac INa.

GW26-e4459 Cellular Electrophysiological Mechanisms and Drug Intervention Study of the CACNA1C Gene Mutation Related to Early Repolarization

GW26-e4459 Cellular Electrophysiological Mechanisms and Drug Intervention Study of the CACNA1C Gene Mutation Related to Early Repolarization

Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective.

Defining the cellular electrophysiological mechanisms for ventricular tachyarrhythmias is difficult, given the wide array of potential mechanisms, ranging from abnormal automaticity to various types of reentry and kk activity. The degree of difficulty is increased further by the fact that any particular mechanism may be influenced by the evolving ionic and anatomic environments associated with many forms of heart disease. Consequently, static measures of a single electrophysiological characteristic are unlikely to be useful in establishing mechanisms. Rather, the dynamics of the electrophysiological triggers and substrates that predispose to arrhythmia development need to be considered. Moreover, the dynamics need to be considered in the context of a system, one that displays certain predictable behaviors, but also one that may contain seemingly stochastic elements. It also is essential to recognize that even the predictable behaviors of this complex nonlinear system are subject to small changes in the state of the system at any given time. Here we briefly review some of the short-, medium-, and long-term alterations of the electrophysiological substrate that accompany myocardial disease and their potential impact on the initiation and maintenance of ventricular arrhythmias. We also provide examples of cases in which small changes in the electrophysiological substrate can result in rather large differences in arrhythmia outcome. These results suggest that an interrogation of cardiac electrical dynamics is required to provide a meaningful assessment of the immediate risk for arrhythmia development and for evaluating the effects of putative antiarrhythmic interventions.

Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AF

Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear. This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF. Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique. The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 +/- 8 ms; 52 cells, 18 patients vs 233 +/- 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% +/- 4%, n = 15) than in those without LVSD (62% +/- 2%, n = 31; P <0.05). In cells from patients with LVEF <or= 45%, the ERP and action potential duration at 90% repolarization were shorter than in those from patients with LVEF > 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics. LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF.

Dynamical and cellular electrophysiological mechanisms of ECG changes during ischaemia

The interpretation of normal and pathological electrocardiographic (ECG) patterns in terms of the underlying cellular and tissue electrophysiology is rudimentary, as the existing theories rely on geometrical aspects. We relate effects of sub-endocardial ischaemia on the ST-segment depression in ECG to patterns of transmural action potential propagation in a one-dimensional virtual ventricular wall. Our computational study exposes two electrophysiological mechanisms of ST depression: dynamic—predominantly positive spatial gradients in the membrane potential during abnormal repolarization of the wall, produced by action potential duration changes in the ischaemic region; and static—a negative spatial gradient of the resting membrane potential between the normal and ischaemic regions. Hyperkalaemia is the major contributor to both these mechanisms at the cellular level. These results complement simulations of the effects of cardiac geometry on the ECG, and dissect spatio-temporal and cellular electrophysiological mechanisms of ST depression seen in sub-endocardial ischaemia.

Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue.

T-wave alternans, which is associated with the genesis of cardiac fibrillation, has recently been related to discordant action potential duration (APD) alternans. However, the cellular electrophysiological mechanisms responsible for discordant alternans are poorly understood. We simulated a 2D sheet of cardiac tissue using phase 1 of the Luo-Rudy cardiac action potential model. A steep (slope >1) APD restitution curve promoted concordant APD alternans and T-wave alternans without QRS alternans. When pacing was from a single site, discordant APD alternans occurred only when the pacing rate was fast enough to engage conduction velocity (CV) restitution, producing both QRS and T-wave alternans. Tissue heterogeneity was not required for this effect. Discordant alternans markedly increases dispersion of refractoriness and increases the ability of a premature stimulus to cause localized wavebreak and induce reentry. In the absence of steep APD restitution and of CV restitution, sustained discordant alternans did not occur, but reentry could be induced if there was marked electrophysiological heterogeneity. Both discordant APD alternans and preexisting APD heterogeneity facilitate reentry by causing the waveback to propagate slowly. Discordant alternans arises dynamically from APD and CV restitution properties and markedly increases dispersion of refractoriness. Preexisting and dynamically induced (via restitution) dispersion of refractoriness independently increase vulnerability to reentrant arrhythmias. Reduction of dynamically induced dispersion by appropriate alteration of electrical restitution has promise as an antiarrhythmic strategy.

Ischemic preconditioning: antiarrhythmic effects and electrophysiological mechanisms in isolated ventricle.

The objective of this study was to identify cellular electrophysiological mechanisms by which ischemic preconditioning decreases arrhythmias in an isolated ventricular tissue model of ischemia and reperfusion. Electrical activity was recorded with microelectrodes from endocardium and epicardium of paced guinea pig right ventricular free walls. Control preparations were exposed for 15 min to Tyrode solution modified to simulate selected ischemic conditions and then were reperfused for 30 min with normal solution. Preconditioned tissues were exposed to a 2- or 5-min period of simulated ischemia before this same protocol. Neither preconditioning protocol affected incidence of ventricular tachycardia (VT) in ischemia; however, the 5-min protocol significantly decreased premature beats (PVB) and transmural conduction block. Preconditioning for 5 min, but not 2 min, significantly decreased reperfusion-induced VT and PVB. Ischemic preconditioning did not change effects of ischemia or reperfusion on action potential duration, effective refractory period, or endocardial conduction time. However, preconditioning markedly attenuated depression of transmural conduction by ischemia and early reperfusion and thereby prevented conduction delays necessary for transmural reentry.

Atrioventricuiar Node Reentry: Current Concepts and New Perspectives

With the advent of RF catheter modification of AV node conduction for the treatment of AV node reentrant tachycardia, considerable advances have been made with better understanding of the AV junctional anatomy, electrophysiology, and mechanism responsible for AV node reentrant tachycardia. Future studies should be designed to uncover the basic cellular electrophysiological mechanisms responsible for fast and slow AV node conduction, to define the exact tissue components of the reentrant circuit in order to make ablative procedures safer, and to study the long-term effects of RF catheter ablation on AV conduction. Special caution should be directed toward pediatric patients with more stringent indications for catheter ablation of the AV junctional area in these patients.

Dynamics of circus movement re-entry across canine Purkinje fibre-muscle junctions.

1. To determine the cellular electrophysiological mechanisms for unidirectional conduction block and re-entrant excitation, single cycles of circus movement re-entry were induced in canine Purkinje fibre-papillary muscle preparations containing two Purkinje fibre-muscle junctions (PMJs). The preparations were mounted in a partitioned tissue bath that permitted independent superfusion of each PMJ. The pre-existing dispersion of refractoriness between PMJs was accentuated by superfusing PMJ1 with normal Tyrode solution or Tyrode solution containing 6-8 mM KCl and superfusing PMJ2 with Tyrode solution containing 0.5 mM heptanol and 4-10 mM KCl. 2. Premature stimuli delivered to the Purkinje fibre induced unidirectional anterograde conduction block at PMJ2. Conduction proceeded from Purkinje cells to papillary muscle at PMJ1 and from papillary muscle retrogradely across the previously blocked PMJ2. 3. The difference in refractory periods between the two PMJs defined a range of premature coupling intervals within which re-entry was inducible. Conduction block at the PMJ occurred in papillary muscle at short coupling intervals and in the Purkinje fibre at longer intervals. 4. Once initiated, re-entry could be reset or annihilated by properly timed subthreshold current pulses delivered to cells at the PMJ. 5. To define better the mechanisms for conduction block and re-entry, an analytical model was developed using non-linear regression analysis to derive equations from the experimental results. Varying parameters within the constraints of the model reproduced the key features of the rate-dependent conduction block observed experimentally. Critical elements of the model included the induction of significant activation delays at short diastolic intervals and a reduction in the rate of action potential duration restitution after exposure to heptanol. 6. These results help to establish the conditions necessary for induction of one-dimensional circus movement re-entry and to define the roles of non-linearities of activation delay and excitability in the dynamics of conduction block at the PMJ.

Mechanisms for cardiac arrhythmias.

Possible cellular electrophysiological mechanisms for arrhythmias have been investigated through studies of isolated cardiac tissues. Records through extracellular and intracellular electrodes indicate that arrhythmias may result from either focal or non-focal mechanisms. Focal mechanisms include abnormal impulse initiation (normal or abnormal automaticity), triggering from either early or delayed afterdepolarizations and reflection, whereas the non-focal mechanisms are various forms of reentry due to circus movement. It is reasonable to assume that these mechanisms also occur in vivo. Although it is safe to identify macro-re-entry as the cause of some atrial and ventricular arrhythmias, for the most part direct proof of mechanism usually is lacking for the focal arrhythmias. If 'on line' activation sequence mapping techniques can be developed to quickly and specifically locate arrhythmogenic foci in the in situ heart, it may be possible to use unipolar extracellular recording techniques to identify the exact cellular electrophysiological mechanisms operating within them.

Spontaneous and induced cardiac arrhythmias in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs.

The cellular electrophysiological mechanisms underlying the ventricular arrhythmias that accompany myocardial infarction were studied in isolated, superfused infarcted myocardium excised from dogs previously subjected to a two-stage ligation of the anterior descending coronary artery. Ventricular arrhythmias frequently occurred in the intact heart 24 hours after coronary occlusion. Surviving subendocardial Purkinje fibers in infarcts excised at this time were highly arrhythmic when they were studied with intracellular microelectrodes in vitro. These arrhythmias consisted of rapid, repetitive depolarizations and occurred spontaneously or could be induced by premature electrical stimulation. Premature stimulation also resulted in single unstimulated responses. In such instances, premature impulses conducted extremely slowly through the infarcted region where surviving Purkinje fiber action potential durations were extraordinarily prolonged. Conduction block at some sites in the infarct caused phenomena which were interpreted as reentrant beats. Some surviving subendocardial Purkinje fibers in the infarct demonstrated spontaneous diastolic depolarization and appeared to function as pacemakers in the absence of electrical stimulation. In some instances, these fibers constituted typical parasystolic foci, demonstrating both entrance and exit block. These results suggest that subendocardial Purkinje fibers which survive in an infarct may be the site of origin of some of the ventricular arrhythmias that accompany myocardial infarction.