scholarly journals In Silico Comparison of Phase Maps Based on Action Potential and Extracellular Potential

2018 ◽  
Author(s):  
Konstantin Ushenin ◽  
Artem Razumov ◽  
Vitaly Kalinin ◽  
Olga Solovyova
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Extracellular Potential

scholarly journals Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

2021 ◽  
Author(s):  
Yangyang Lin ◽  
Sam Z. Grinter ◽  
Zhongju Lu ◽  
Xianjin Xu ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Therapeutic Efficacy ◽  
Torsade De Pointes ◽  
Computational Prediction ◽  
Chemical Library ◽  
Drug Induced ◽  
Voltage Dependent ◽  
Life Threatening ◽  
Approved Drugs

AbstractCardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD) either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs, a slowly activating K+ current plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage sensing domain (VSD) of the IKs channel. Here we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.Significance statementC28, identified by in silico screening, specifically facilitated voltage dependent activation of a cardiac potassium ion channel, IKs. C28 reversed drug-induced prolongation of action potentials, but minimally affected the normal action potential at the same dosage. This outcome supports a computational prediction of modulating IKs activation as a potential therapy for all forms of action potential prolongation, and could expand therapeutic efficacy of many currently approved drugs that may trigger arrhythmias.

scholarly journals Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico Study

2022 ◽  
Vol 9 (1) ◽  
pp. 28
Author(s):  
Henry Sutanto
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
In Silico ◽  
Computational Study ◽  
Surrogate Marker ◽  
Cardiac Ion Channels ◽  
Atrial Electrophysiology ◽  
In Silico Study ◽  
In Silico Models ◽  
Atrial Repolarization

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (INa, Ito, ICaL, IKur, IKr, IKs, IK1, INCX and INaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of ICaL and INCX resulted in AP shortening, while the inhibition of IKur, IKr, IKs, IK1 and INaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of IKr and IKs only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of IKr and IKs significantly prolonged APD and vice versa. Additionally, a 50% reduction of Ito density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable IK1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca2+ concentration, promoting a repolarization failure in ICaL upregulation above 150% and facilitating reentrant spiral waves stabilization by ICaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of IKr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model’s accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.

Focal extracellular potential: a means to monitor electrical activity in single cardiac myocytes

2000 ◽  
Vol 278 (4) ◽  
pp. H1383-H1394 ◽  
Author(s):  
Tara L. Riemer ◽  
Leslie Tung
Keyword(s):  
Action Potential ◽  
Cardiac Myocytes ◽  
Transmembrane Potential ◽  
Membrane Conductance ◽  
Electrical Activation ◽  
Ventricular Myocyte ◽  
Extracellular Potential ◽  
Whole Cell ◽  
Cell Recording ◽  
Electrophysiological Signal

The focal extracellular potential (FEP) described in this study is an electrophysiological signal related to the transmembrane potential ( V m) of cardiac myocytes that avoids the mechanical fragility, interference with contraction, and intracellular contact associated with conventional whole cell recording. One end of a frog ventricular myocyte was secured into a glass holding pipette. The FEP was measured differentially between this pipette and a bath pipette while the cell was voltage- or current-clamped by a third whole cell pipette. The FEP appeared as an amplitude-truncated action potential, while FEP duration accurately reflected the action potential duration (APD) at 90% repolarization (APD90). FEP magnitude increased as the holding pipette K+ concentration ([K+]) was increased. The FEP-voltage relation was quasi-linear at negative V m with a slope that increased with elevated holding pipette [K+]. Increasing the membrane conductance inside the holding pipette by adding amphotericin B or cromakalim linearized the FEP-voltage relation across all V m. The FEP accurately reported electrical activation and APD90 during changes of stimulation frequency and episodes of cellular stretch.

Dynamics of drug binding to the hERG channel: An in silico cardiac action potential model for early safety assessment

2012 ◽  
Vol 66 (2) ◽  
pp. 171
Author(s):  
Giovanni Y. Di Veroli ◽  
Mark Davies ◽  
Chris E. Pollard ◽  
Jean-Pierre Valentin ◽  
Henggui Zhang ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Safety Assessment ◽  
Potential Model ◽  
Drug Binding ◽  
Herg Channel ◽  
Cardiac Action Potential ◽  
Cardiac Action

DYNAMICAL EFFECTS OF MYOCARDIAL ISCHEMIA IN ANISOTROPIC CARDIAC MODELS IN THREE DIMENSIONS

2007 ◽  
Vol 17 (12) ◽  
pp. 1965-2008 ◽  
Author(s):  
PIERO COLLI FRANZONE ◽  
LUCA F. PAVARINO ◽  
SIMONE SCACCHI
Keyword(s):  
Myocardial Ischemia ◽  
Action Potential ◽  
Numerical Simulations ◽  
Cardiac Muscle ◽  
Action Potential Duration ◽  
Three Dimensions ◽  
Extracellular Potential ◽  
Anisotropic Structure ◽  
Orthogonal Components ◽  
Cardiac Excitation

The interaction between the presence of moderate or severe subendocardial ischemic regions and the anisotropic structure of the cardiac muscle is investigated here by means of numerical simulations based on anisotropic Bidomain and Monodomain models. The ischemic effects on cardiac excitation, recovery and distribution of action potential duration are discussed, showing the presence of ischemic epicardial markers. Extracellular potential distributions during the ST and TQ intervals are computed separately using non-stationary models. During the ST interval, the extracellular potential patterns differ from those simulated with stationary models used in the literature. These differences are explained by decomposing the cardiac current sources into conormal, axial and orthogonal components and by determining which component is dominant during the ST and TQ intervals.

scholarly journals Lead and Carbon Monoxide Effects on Human Atrial Action Potential. In Silico Study

2017 ◽  
Author(s):  
Catalina Tobon ◽  
Diana C Pachajoa ◽  
Juan P Ugarte ◽  
Andres Orozco-Duque ◽  
Javier Saiz
Keyword(s):  
Carbon Monoxide ◽  
Action Potential ◽  
In Silico ◽  
In Silico Study

scholarly journals Large-Scale Simulation of the Phenotypical Variability Induced by Loss-of-Function Long QT Mutations in Human Induced Pluripotent Stem Cell Cardiomyocytes

2018 ◽  
Vol 19 (11) ◽  
pp. 3583 ◽  
Author(s):  
Michelangelo Paci ◽  
Simona Casini ◽  
Milena Bellin ◽  
Jari Hyttinen ◽  
Stefano Severi
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Pluripotent Stem Cell ◽  
Large Scale ◽  
Induced Pluripotent Stem Cell ◽  
Loss Of Function ◽  
Prolonged Action ◽  
Long Qt ◽  
Induced Pluripotent

Loss-of-function long QT (LQT) mutations inducing LQT1 and LQT2 syndromes have been successfully translated to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) used as disease-specific models. However, their in vitro investigation mainly relies on experiments using small numbers of cells. This is especially critical when working with cells as heterogeneous as hiPSC-CMs. We aim (i) to investigate in silico the ionic mechanisms underlying LQT1 and LQT2 hiPSC-CM phenotypic variability, and (ii) to enable massive in silico drug tests on mutant hiPSC-CMs. We combined (i) data of control and mutant slow and rapid delayed rectifying K+ currents, IKr and IKs respectively, (ii) a recent in silico hiPSC-CM model, and (iii) the population of models paradigm to generate control and mutant populations for LQT1 and LQT2 cardiomyocytes. Our four populations contain from 1008 to 3584 models. In line with the experimental in vitro data, mutant in silico hiPSC-CMs showed prolonged action potential (AP) duration (LQT1: +14%, LQT2: +39%) and large electrophysiological variability. Finally, the mutant populations were split into normal-like hiPSC-CMs (with action potential duration similar to control) and at risk hiPSC-CMs (with clearly prolonged action potential duration). At risk mutant hiPSC-CMs carried higher expression of L-type Ca2+, lower expression of IKr and increased sensitivity to quinidine as compared to mutant normal-like hiPSC-CMs, resulting in AP abnormalities. In conclusion, we were able to reproduce the two most common LQT syndromes with large-scale simulations, which enable investigating biophysical mechanisms difficult to assess in vitro, e.g., how variations of ion current expressions in a physiological range can impact on AP properties of mutant hiPSC-CMs.

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