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Author(s): Akiko Kojima [sup.1], Yutaka Fukushima [sup.1], Hiroshi Matsuura [sup.2] Author Affiliations: (1) https://ror.org/00d8gp927, grid.410827.8, 0000 0000 9747 6806, Department of Anesthesiology, Shiga University of Medical Science, , 520-2192, Otsu, [...], This simulation study was designed to predict the torsadogenicity of sevoflurane and propofol in healthy control, as well as type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), using the O'Hara-Rudy dynamic model. LQT1 and LQT2 models were simulated by decreasing the conductances of slowly and rapidly activating delayed rectifier K.sup.+ currents (I.sub.Ks and I.sub.Kr, respectively) by 50%, respectively. Action potential duration at 50% repolarization level (APD.sub.50) and diastolic intracellular Ca.sup.2+ concentration were measured in epicardial cell during administration of sevoflurane (1 ~ 5%) and propofol (1 ~ 10 [mu]M). Torsadogenicity can be predicted from the relationship between APD.sub.50 and diastolic intracellular Ca.sup.2+ concentration, which is classified by the decision boundary. Whereas the relationships in control and LQT1 models were distributed on nontorsadogenic side in the presence of sevoflurane at all tested concentrations, those in LQT2 models were shifted to torsadogenic side by concentrations of [greater than or equal to] 2%. In all three models, propofol shifted the relationships in a direction away from the decision boundary on nontorsadogenic side. Our findings suggest that sevoflurane, but not propofol, exerts torsadogenicity in patients with reduced I.sub.Kr, such as LQT2 patients. Caution should be paid to the occurrence of arrhythmia during sevoflurane anesthesia in patients with reduced I.sub.Kr.

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is a problem of growing proportions. Recent studies have increased interest in fast-unbinding [Na.sup.+] channel blockers like vernakalant (RSD1235) and ranolazine for AF therapy, but the mechanism of efficacy is poorly understood. To study how fast-unbinding [I.sub.Na] blockers affect AF, we developed realistic mathematical models of state-dependent [Na.sup.+] channel block, using a lidocaine model as a prototype, and studied the effects on simulated cholinergic AF in two-and three-dimensional atrial substrates. We then compared the results with in vivo effects of lidocaine on vagotonic AF in dogs. Lidocaine action was modeled with the Hondeghem-Katzung modulatedreceptor theory and maximum affinity for activated [Na.sup.+] channels. Lidocaine produced frequency-dependent [Na.sup.+] channel blocking and conduction slowing effects and terminated AF in both two- and three-dimensional models with concentration-dependent efficacy (maximum ~89% at 60 [micro]M). AF termination was not related to increases in wavelength, which tended to decrease with the drug, but rather to decreased source [Na.sup.+] current in the face of large ACh-sensitive [K.sup.+] current-related sinks, leading to the destabilization of primary generator rotors and a great reduction in wavebreak, which caused primary rotor annihilations in the absence of secondary rotors to resume generator activity. Lidocaine also reduced the variability and maximum values of the dominant frequency distribution during AF. Qualitatively similar results were obtained in vivo for lidocaine effects on vagal AF in dogs, with an efficacy of 86% at 2 mg/kg iv, as well as with simulations using the guarded-receptor model of lidocaine action. These results provide new insights into the mechanisms by which rapidly unbinding class I antiarrhythmic agents, a class including several novel compounds of considerable promise, terminate AF. state-dependent channel; cardiac action potential; antiarrhythmic drug therapy; computer simulations; heart arrhythmia models

Ablation strategies to prevent episodes of paroxysmal atrial fibrillation (AF) have been subject to many clinical studies. The issues mainly concern pattern and transmurality of the lesions. This paper investigates ten different ablation strategies on a multilayered 3-D anatomical model of the atria with respect to 23 different setups of AF initiation in a biophysical computer model. There were 495 simulations carried out showing that circumferential lesions around the pulmonary veins (PVs) yield the highest success rate if at least two additional linear lesions are carried out. The findings compare with clinical studies as well as with other computer simulations. The anatomy and the setup of ectopic beats play an important role in the initiation and maintenance of AF as well as the resulting therapy. The computer model presented in this paper is a suitable tool to investigate different ablation strategies. By including individual patient anatomy and electrophysiological measurement, the model could be parameterized to yield an effective tool for future investigation of tailored ablation strategies and their effects on atrial fibrillation. Index Terms--Catheter ablation strategies, computer simulation, supraventricular arrhythmia.

Gap junction channels are required for normal cardiac impulse propagation, and gap junction remodeling is associated with enhanced arrhythmic risk. Oculodentodigital dysplasia (ODDD) is a multisystem syndrome due to mutations in the connexin43 (Cx43) gap junction channel gene. To determine the effects of a human connexin channelopathy on cardiac electrophysiology and arrhythmogenesis, we generated a murine model of ODDD by introducing the disease-causing I130T mutant allele into the mouse genome. Cx43 abundance was markedly reduced in mutant hearts with preferential loss of phosphorylated forms that interfered with trafficking and assembly of gap junctions in the junctional membrane. Dual whole-cell patch--clamp studies showed significantly lower junctional conductance between neonatal cell pairs from mutant hearts, and optical mapping of isolated-perfused hearts with voltage-sensitive dyes demonstrated significant slowing of conduction velocity. Programmed electrical stimulation revealed a markedly increased susceptibility to spontaneous and inducible ventricular tachyarrhythmias. In summary, our data demonstrate that the 1130T mutation interferes with Cx43 posttranslational processing, resulting in diminished cell--cell coupling, slowing of impulse propagation, and a proarrhythmic substrate. arrhythmia | connexin43 | transgenic | channel | mouse

Recent experimental and theoretical results have stressed the importance of modeling studies of reentrant arrhythmias in cardiac tissue and at the whole heart level. We introduce a six-variable model obtained by a reformulation of the Priebe-Beuckelmann model of a single human ventricular cell. The reformulated model is 4.9 times faster for numerical computations and it is more stable than the original model. It retains the action potential shape at various frequencies, restitution of action potential duration, and restitution of conduction velocity. We were able to reproduce the main properties of epicardial, endocardial, and M cells by modifying selected ionic currents. We performed a simulation study of spiral wave behavior in a two-dimensional sheet of human ventricular tissue and showed that spiral waves have a frequency of 3.3 Hz and a linear core of ~50-mm diameter that rotates with an average frequency of 0.62 rad/s. Simulation results agreed with experimental data. In conclusion, the proposed model is suitable for efficient and accurate studies of reentrant phenomena in human ventricular tissue. action potential; computer simulation; mathematical model; reentrant arrhythmia; spiral wave

The complex dynamics of cardiac arrhythmia can be analyzed based on mathematical models. The nonlinear dynamics of heart rhythms based on electrocardiogram analysis can be utilized to control cardiac arrythmia.

Bifurcation analysis, simulation methods and model construction were utilized to explain the effects of ion channel blockers on arrhythmias in the heart. Modeling considered the proarrhythmic and antiarrhythmic actions of antiarrhythmic drugs and their effects on ion channels. An animal model showing two inward currents was developed to explain the mechanism of cycle length oscillation.

Action potential propagation simulations with physiologic membrane currents and macroscopic tissue dimensions are computationally expensive. We, therefore, analyzed distributed computing schemes to reduce execution time in workstation clusters by parallelizing solutions with message passing. Four schemes were considered in two-dimensional monodomain simulations with the Beeler-Reuter membrane equations. Parallel speedups measured with each scheme were compared to theoretical speedups, recognizing the relationship between speedup and code portions that executed serially. A data decomposition scheme based on total ionic current provided the best performance. Analysis of communication latencies in that scheme led to a load-balancing algorithm in which measured speedups at 89 [+ or -] 2% and 75 [+ or -] 8% of theoretical speedups were achieved in homogeneous and heterogeneous clusters of workstations. Speedups in this scheme with the Luo-Rudy dynamic membrane equations exceeded 3.0 with eight distributed workstations. Cluster speedups were comparable to those measured during parallel execution on a shared memory machine. Index Terms--Arrhythmia, heart, numerical simulations.

A trial fibrillation is the most frequent arrhythmia, provoking discomfort, heart failure and arterial embolisms. The aim of this work is to develop a simplified anatomical computer model of human atria for the study of atrial arrhythmias and the understanding of electrical propagation mechanisms. With the model we propose, up to 40 s of real-time propagation have been simulated on a single-processor computer. The size and the electrophysiological properties of the simulated atria are within realistic values and information about anatomy has been taken into account in a three-dimensional structure. Besides normal sinus beat, pathological phenomena such as flutter and fibrillation have been induced using a programmed stimulation protocol. One important observation in our model is that atrial arrhythmias are a combination of functional and anatomical reentries and that the geometry plays an important role. This virtual atrium can reproduce electrophysiological observations made in humans but with the advantage of showing in great detail how arrhythmias are initiated and sustained. Such details are difficult or impossible to study in humans. This model will serve us as a tool to evaluate the impact of new therapeutic strategies and to improve them. Index Terms--Atrial arrhythmias, computer modeling, electrical propagation, fibrillation, flutter, human atria.