Human Ventricular Cell Model Research Articles

A stacking ensemble machine learning model for evaluating cardiac toxicity of drugs based on in silico biomarkers.

This study addresses the critical issue of drug-induced torsades de pointes (TdP) risk assessment, a vital aspect of new drug development due to its association with arrhythmia and sudden cardiac death. Existing methodologies, particularly those reliant on a single biomarker derived from CiPA O'Hara-Rudy (CiPAORdv1.0) ventricular cell model without the hERG dynamic as input to the individual machine learning model, have limitations in capturing the complexity inherent in the comprehensive range of factors influencing drug-induced TdP risk. This study aims to overcome these limitations by proposing a stacking ensemble machine learning approach by integrating multiple in silico biomarkers derived from the CiPAORdv1.0 with hERG dynamic characteristics. The ensemble machine learning model consisted of three artificial neural network (ANN) models as baseline model and support vector machine (SVM), logistic regression (LR), random forest (RF), and extreme gradient boosting (XGBoost) models as meta-classifier. The highest AUC score of 1.00 (0.90-1.00) for high risk, 0.97 (0.84-1.00) for intermediate risk, and 1.00 (0.87-1.00) for low risk were obtained using seven biomarkers derived from the CiPAORdv1.0 with hERG dynamic characteristics. Furthering our investigation, we explored the model's robustness by incorporating interindividual variability into the generation of in silico biomarkers from a population of human ventricular cell models. This study also enabled an analysis of TdP risk classification under high clinical exposure and therapeutic scenarios for several drugs. Additionally, from a sensitivity analysis, we revealed four important ion channels, namely, CaL, NaL, Na, and Kr channels that affect significantly the important biomarkers for TdP risk prediction.

Machine learning approach to evaluate TdP risk of drugs using cardiac electrophysiological model including inter-individual variability.

Introduction: Predicting ventricular arrhythmia Torsade de Pointes (TdP) caused by drug-induced cardiotoxicity is essential in drug development. Several studies used single biomarkers such as qNet and Repolarization Abnormality (RA) in a single cardiac cell model to evaluate TdP risk. However, a single biomarker may not encompass the full range of factors contributing to TdP risk, leading to divergent TdP risk prediction outcomes, mainly when evaluated using unseen data. We addressed this issue by utilizing multi-in silico features from a population of human ventricular cell models that could capture a representation of the underlying mechanisms contributing to TdP risk to provide a more reliable assessment of drug-induced cardiotoxicity. Method: We generated a virtual population of human ventricular cell models using a modified O'Hara-Rudy model, allowing inter-individual variation. and Hill coefficients from 67 drugs were used as input to simulate drug effects on cardiac cells. Fourteen features (, , , , , , , , , , , , qNet, qInward) could be generated from the simulation and used as input to several machine learning models, including k-nearest neighbor (KNN), Random Forest (RF), XGBoost, and Artificial Neural Networks (ANN). Optimization of the machine learning model was performed using a grid search to select the best parameter of the proposed model. We applied five-fold cross-validation while training the model with 42 drugs and evaluated the model's performance with test data from 25 drugs. Result: The proposed ANN model showed the highest performance in predicting the TdP risk of drugs by providing an accuracy of 0.923 (0.908-0.937), sensitivity of 0.926 (0.909-0.942), specificity of 0.921 (0.906-0.935), and AUC score of 0.964 (0.954-0.975). Discussion and conclusion: According to the performance results, combining the electrophysiological model including inter-individual variation and optimization of machine learning showed good generalization ability when evaluated using the unseen dataset and produced a reliable drug-induced TdP risk prediction system.

Prediction of anesthetic torsadogenicity using a human ventricular cell model.

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+ currents (IKs and IKr, respectively) by 50%, respectively. Action potential duration at 50% repolarization level (APD50) and diastolic intracellular Ca2+ concentration were measured in epicardial cell during administration of sevoflurane (1 ~ 5%) and propofol (1 ~ 10μM). Torsadogenicity can be predicted from the relationship between APD50 and diastolic intracellular Ca2+ 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 ≥ 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 IKr, such as LQT2 patients. Caution should be paid to the occurrence of arrhythmia during sevoflurane anesthesia in patients with reduced IKr.

Analysis And Comparison Of Ventricular Cardiac Arrhythmia Classification Using Sodium Channel Parameters With ANN And KNN Classifier

Aim: Aim of this research is to analyze and compare ventricular Cardiac Arrhythmia (CA) classification using Sodium Channel (Na+) parameters with Artificial Neural Network (ANN) and K-Nearest Neighbour (KNN) classifiers. Materials and Methods: Ten Tusscher Human Ventricular Cell Model (THVCM) (data) is used for arrhythmias classification. THVCM has well defined sodium (Na+) channel dynamics. Sample size was calculated by keeping threshold 0.05, G Power 80%, confidence interval 95% and enrolment ratio as 1. Number of samples considered is 20 for each analysis and will be imported to the classifier, K-Nearest Neighbour (KNN) and Artificial Neural Network (ANN) classifier to find better accuracy. Finally, the results (accuracy) will be validated by using Statistical Package for the Social Science (SPSS) software. Result: Ventricular normal, tachycardia and bradycardia data are fed into novel ANN and KNN classifiers. The results obtained from classifiers for 20 samples are fed to SPSS. In that ANN shows accuracy of 35.6% with standard deviation (3.17822) and Standard error mean (0.71067). Similarly KNN produces an accuracy value of 18.05% with standard deviation (1.19593) and Standard error mean (0.26739). Conclusion: As per the results, it clearly shows that the novel ANN has better accuracy for classification than KNN.

Acetylcholine Reduces L-Type Calcium Current without Major Changes in Repolarization of Canine and Human Purkinje and Ventricular Tissue.

Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect of acetylcholine (ACh) on repolarization in Purkinje and ventricular cardiac preparations to identify the advantages, risks, and underlying cellular mechanisms of VNS. Here, we studied the effect of ACh on the action potential (AP) of canine Purkinje fibers (PFs) and several human ventricular preparations. In addition, we characterized the effects of ACh on the L-type Ca2+ current (ICaL) and AP of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and performed computer simulations to explain the observed effects. Using microelectrode recordings, we found a small but significant AP prolongation in canine PFs. In the human myocardium, ACh slightly prolonged the AP in the midmyocardium but resulted in minor AP shortening in subepicardial tissue. Perforated patch-clamp experiments on hiPSC-CMs demonstrated that 5 µM ACh caused an ≈15% decrease in ICaL density without changes in gating properties. Using dynamic clamp, we found that under blocked K+ currents, 5 µM ACh resulted in an ≈23% decrease in AP duration at 90% of repolarization in hiPSC-CMs. Computer simulations using the O'Hara-Rudy human ventricular cell model revealed that the overall effect of ACh on AP duration is a tight interplay between the ACh-induced reduction in ICaL and ACh-induced changes in K+ currents. In conclusion, ACh results in minor changes in AP repolarization and duration of canine PFs and human ventricular myocardium due to the concomitant inhibition of inward ICaL and outward K+ currents, which limits changes in net repolarizing current and thus prevents major changes in AP repolarization.

Disrupted CaV1.2 selectivity causes overlapping long QT and Brugada syndrome phenotypes in the CACNA1C-E1115K iPS cell model

A missense mutation in the α1c subunit of voltage-gated L-type Ca2+ channel-coding CACNA1C-E1115K, located in the Ca2+ selectivity site, causes a variety of arrhythmogenic phenotypes. We aimed to investigate the electrophysiological features and pathophysiological mechanisms of CACNA1C-E1115K in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). We generated iPSCs from a patient carrying heterozygous CACNA1C-E1115K with overlapping phenotypes of long QT syndrome, Brugada syndrome, and mild cardiac dysfunction. Electrophysiological properties were investigated using iPSC-CMs. We used iPSCs from a healthy individual and an isogenic iPSC line corrected using CRISPR-Cas9-mediated gene editing as controls. A mathematical E1115K-CM model was developed using a human ventricular cell model. Patch-clamp analysis revealed that E1115K-iPSC-CMs exhibited reduced peak Ca2+ current density and impaired Ca2+ selectivity with an increased permeability to monovalent cations. Consequently, E1115K-iPSC-CMs showed decreased action potential plateau amplitude, longer action potential duration (APD), and a higher frequency of early afterdepolarization compared with controls. In optical recordings examining the antiarrhythmic drug effect, late Na+ channel current (INaL) inhibitors (mexiletine and GS-458967) shortened APDs specifically in E1115K-iPSC-CMs. The AP-clamp using a voltage command obtained from E1115K-iPSC-CMs with lower action potential plateau amplitude and longer APD confirmed the upregulation of INaL. An in silico study recapitulated the invitro electrophysiological properties. Our iPSC-based analysis in CACNA1C-E1115K with disrupted CaV1.2 selectivity demonstrated that the aberrant currents through the mutant channels carried by monovalent cations resulted in specific action potential changes, which increased endogenous INaL, thereby synergistically contributing to the arrhythmogenic phenotype.

Reentry in cardiac ventricular epicardial tissue due to SCN5A L812Q gene mutation: a computational study

Cardiovascular diseases are the major cause of sudden death. Brugada syndrome is an inherited rare disease, that leads to death due to ventricular fibrillation (VF). Brugada Syndrome is related to mutations in the genes that encode SCN5A, a subunit of sodium ion channel (NaV). This computational study investigates the mechanism of loss of function gene mutation (SCN5A L812Q) in sodium ion channel that leads to spiral wave and further develops into VF in an epicardial tissue with homozygous condition. Study was made on wild type, L812Q heterozygous mutated and homozygous mutated ventricular tissues. Ten Tusscher human ventricular cell model (TP06) was used for the simulation study. VF is developed when a spiral wave that causes ventricular arrhythmia breaks. This leads to the formation of multiple spiral waves that are activated on different regions of the ventricles called wave break. This is observed in the epicardial tissue with homozygous condition as the effect of SCN5A L812Q gene mutation. This indicates that VF occurs in the SCN5A L812Q gene mutated homozygous ventricular epicardial tissue that may further lead to Brugada syndrome.

A computationally efficient dynamic model of human epicardial tissue.

We present a new phenomenological model of human ventricular epicardial cells and we test its reentry dynamics. The model is derived from the Rogers-McCulloch formulation of the FitzHugh-Nagumo equations and represents the total ionic current divided into three contributions corresponding to the excitatory, recovery and transient outward currents. Our model reproduces the main characteristics of human epicardial tissue, including action potential amplitude and morphology, upstroke velocity, and action potential duration and conduction velocity restitution curves. The reentry dynamics is stable, and the dominant period is about 270 ms, which is comparable to clinical values. The proposed model is the first phenomenological model able to accurately resemble human experimental data by using only 3 state variables and 17 parameters. Indeed, it is more computationally efficient than existing models (i.e., almost two times faster than the minimal ventricular model). Beyond the computational efficiency, the low number of parameters facilitates the process of fitting the model to the experimental data.

Adaptation of the Calcium-dependent Tension Development in Ventricular Cardiomyocytes

Abstract Today a variety of models describe the physiological behavior of the heart on a cellular level. The intracellular calcium concentration plays an important role, since it is the main driver for the active contraction of the heart. Due to different implementations of the calcium dynamics, simulating cardiac electromechanics can lead to severely different behaviors of the active tension when coupling the same tension model with different electrophysiological models. To handle these variations, we present an optimization tool that adapts the parameters of the most recent, human based tension model. The goal is to generate a physiologically valid tension development when coupled to an electrophysiological cellular model independent of the specifics of that model's calcium transient. In this work, we focus on a ventricular cell model. In order to identify the calcium-sensitive parameters, a sensitivity analysis of the tension model was carried out. In a further step, the cell model was adapted to reproduce the sarcomere length-dependent behavior of troponin C. With a maximum relative deviation of 20.3% per defined characteristic of the tension development, satisfactory results could be obtained for isometric twitch tension. Considering the length-dependent troponin handling, physiological behavior could be reproduced. In conclusion, we propose an algorithm to adapt the tension development model to any calcium transient input to achieve a physiologically valid active contraction on a cellular level. As a proof of concept, the algorithm is successfully applied to one of the most recent human ventricular cell models. This is an important step towards fully coupled electromechanical heart models, which are a valuable tool in personalized health care.

Interactive 3D Human Heart Simulations on Segmented Human MRI Hearts.

Understanding cardiac arrhythmic mechanisms and developing new strategies to control and terminate them using computer simulations requires realistic physiological cell models with anatomically accurate heart structures. Furthermore, numerical simulations must be fast enough to study and validate model and structure parameters. Here, we present an interactive parallel approach for solving detailed cell dynamics in high-resolution human heart structures with a local PC's GPU. In vitro human heart MRI scans were manually segmented to produce 3D structures with anatomically realistic electrophysiology. The Abubu.js library was used to create an interactive code to solve the OVVR human ventricular cell model and the FDA extension of the model in the human MRI heart structures, allowing the simulation of reentrant waves and investigation of their dynamics in real time. Interactive simulations of a physiological cell model in a detailed anatomical human heart reveals propagation of waves through the fine structures of the trabeculae and pectinate muscle that can perpetuate arrhythmias, thereby giving new insights into effects that may need to be considered when planning ablation and other defibrillation methods.

In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle

The macrolide antibiotic azithromycin (AZM) is widely used for respiratory infections and has been suggested to be a possible treatment for the Coronavirus Disease of 2019 (COVID-19). However, AZM-associated QT interval prolongation and arrhythmias have been reported. Integrated mechanistic information on AZM actions on human ventricular excitation and conduction is lacking. Therefore, this study was undertaken to investigate the actions of AZM on ventricular cell and tissue electrical activity. The O'Hara- Virag-Varro-Rudy dynamic (ORd) model of human ventricular cells was modified to incorporate experimental data on the concentration-dependent actions of AZM on multiple ion channels, including INa, ICaL, IKr, IKs, IK1 and INaL in both acute and chronic exposure conditions. In the single cell model, AZM prolonged the action potential duration (APD) in a concentration-dependent manner, which was predominantly attributable to IKr reduction in the acute condition and potentiated INaL in the chronic condition. High concentrations of AZM also increased action potential (AP) triangulation (determined as an increased difference between APD30 and APD90) which is a marker of arrhythmia risk. In the chronic condition, the potentiated INaL caused a modest intracellular Na + concentration accumulation at fast pacing rates. At the 1D tissue level, the AZM-prolonged APD at the cellular level was reflected by an increased QT interval in the simulated pseudo-ECG, consistent with clinical observations. Additionally, AZM reduced the conduction velocity (CV) of APs in the acute condition due to a reduced INa, and it augmented the transmural APD dispersion of the ventricular tissue, which is also pro-arrhythmic. Such actions were markedly augmented when the effects of chronic exposure of AZM were also considered, or with additional IKr block, as may occur with concurrent use of other medications. This study provides insights into the ionic mechanisms by which high concentrations of AZM may modulate ventricular electrophysiology and susceptibility to arrhythmia.

Post myocardial infarction ionic remodelling promotes repolarisation dispersions and abnormalities in acute and chronic stages

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Wellcome Trust Background Sudden cardiac death after a myocardial infarction (MI) was reported in both the acute stage and the chronic stage with the development of heart failure (HF). Around 50% of these deaths were due to ventricular tachyarrhythmia which is related to the temporal dispersion of repolarisation caused by the post-MI remodelling of ionic currents. While variable extent of ionic current changes was observed in multiple animal species in different post-MI phases, the proarrhythmic effects of such remodelling in post infarction human hearts is not fully explored. Purpose The goal of this study is to explore the proarrhythmic effects of post-MI ionic remodelling in human ventricular myocyte models of electrophysiology for both the acute and the chronic stages. Methods The ToR-ORd human ventricular cellular model was used as the baseline model, and a new formulation of the calcium activated potassium current was implemented. We constructed and calibrated a population of 253 human ventricular cell models (POM) to represent electrophysiological variability of normal zone (NZ) myocytes. For the acute phase, three types of border zone (BZ) remodelling (Acute BZ1-3) were introduced based on dog experimental data collected within one week after infarction. For the chronic phase with the development of HF, BZ (Chronic BZ) and one type of remote zone (RZ) remodelling (Chronic RZ1) were introduced based on minipig data collected 5 months post-MI. Another type of RZ remodelling (Chronic RZ2) was introduced based on experimental data from failing human hearts. The cellular models were paced at cycle lengths of 1000ms, 500ms, 400ms and 300ms for 500 beats before the analysis of repolarization abnormalities. Results For both the acute and the chronic stages post-MI, the extent of repolarisation dispersion between BZ and the corresponding NZ and RZ varied from 2ms up to 120ms, and largely depended on the level of potassium current remodelling. A weaker calcium transient was always observed in the BZ. Early after depolarisations (EADs) and repolarisation failure (RF) were observed in the chronic stages, caused by the reactivation of L-type calcium current due to the augmentation of late sodium current and the inhibition of hERG current. Beat-to-beat repolarization alternans was observed in both the acute and the chronic stages, with the key ionic mechanisms being the inhibition of SERCA activity and the slower calcium release due to enhanced CaMKII. Conclusions Post-MI ionic remodelling of the acute and chronic stages can cause a substantial dispersion of repolarisation in human hearts by inducing the prolongation of action potential durations, EADs, RFs, and alternans, providing substrates for the generation and maintenance of lethal reentrant waves. Abstract Figure. BZ and RZ ionic current remodelling

Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under \u03b2-adrenergic stimulation

The variant c.926C > T (p.T309I) in KCNQ1 gene was identified in 10 putatively unrelated Czech families with long QT syndrome (LQTS). Mutation carriers (24 heterozygous individuals) were more symptomatic compared to their non-affected relatives (17 individuals). The carriers showed a mild LQTS phenotype including a longer QTc interval at rest (466 ± 24 ms vs. 418 ± 20 ms) and after exercise (508 ± 32 ms vs. 417 ± 24 ms), 4 syncopes and 2 aborted cardiac arrests. The same haplotype associated with the c.926C > T variant was identified in all probands. Using the whole cell patch clamp technique and confocal microscopy, a complete loss of channel function was revealed in the homozygous setting, caused by an impaired channel trafficking. Dominant negativity with preserved reactivity to β-adrenergic stimulation was apparent in the heterozygous setting. In simulations on a human ventricular cell model, the dysfunction resulted in delayed afterdepolarizations (DADs) and premature action potentials under β-adrenergic stimulation that could be prevented by a slight inhibition of calcium current. We conclude that the KCNQ1 variant c.926C > T is the first identified LQTS-related founder mutation in Central Europe. The dominant negative channel dysfunction may lead to DADs under β-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to β-blocker therapy.

Mechanisms of the occurrence, maintenance and propagation of EADs in a human ventricular cell model

Mechanisms of the occurrence, maintenance and propagation of EADs in a human ventricular cell model

A computational analysis of the effect of sevoflurane in a human ventricular cell model of long QT syndrome: Importance of repolarization reserve in the QT-prolonging effect of sevoflurane

The slowly and rapidly activating delayed rectifier K+ channels (IKs and IKr, respectively) contribute to the repolarization of ventricular action potential in human heart and thereby determine QT interval on an electrocardiogram. Loss-of-function mutations in genes encoding IKs and IKr cause type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), accompanied by a high risk of malignant ventricular arrhythmias and sudden cardiac death. This study was designed to investigate which cardiac electrophysiological conditions exaggerate QT-prolonging and arrhythmogenic effects of sevoflurane. We used the O'Hara-Rudy dynamic model to reconstruct human ventricular action potential and a pseudo-electrocardiogram, and simulated LQT1 and LQT2 phenotypes by decreasing conductances of IKs and IKr, respectively. Sevoflurane, but not propofol, prolonged ventricular action potential duration and QT interval in wild-type, LQT1 and LQT2 models. The QT-prolonging effect of sevoflurane was more profound in LQT2 than in wild-type and LQT1 models. The potent inhibitory effect of sevoflurane on IKs was primarily responsible for its QT-prolonging effect. In LQT2 model, IKs was considerably enhanced during excessive prolongation of ventricular action potential duration by reduction of IKr and relative contribution of IKs to ventricular repolarization was markedly elevated, which appears to underlie more pronounced QT-prolonging effect of sevoflurane in LQT2 model, compared with wild-type and LQT1 models. This simulation study clearly elucidates the electrophysiological basis underlying the difference in QT-prolonging effect of sevoflurane among wild-type, LQT1 and LQT2 models, and may provide important information for developing anesthetic strategies for patients with long QT syndrome in clinical settings.

Characterization of Spatio-Temporal Cardiac Action Potential Variability at Baseline and Under $\beta$-Adrenergic Stimulation by Combined Unscented Kalman Filter and Double Greedy Dimension Reduction

Elevated spatio-temporal variability of human ventricular repolarization has been related to increased risk for ventricular arrhythmias and sudden cardiac death, particularly under β-adrenergic stimulation ( β-AS). This work presents a methodology for theoretical characterization of temporal and spatial repolarization variability at baseline conditions and in response to β-AS. For any measured voltage trace, the proposed methodology estimates the parameters and state variables of an underlying human ventricular action potential (AP) model by combining Double Greedy Dimension Reduction (DGDR) with automatic selection of biomarkers and the Unscented Kalman Filter (UKF). Such theoretical characterization can facilitate subsequent characterization of underlying variability mechanisms. Given an AP trace, initial estimates for the ionic conductances in a stochastic version of the baseline human ventricular O'Hara etal. model were obtained by DGDR. Those estimates served to initialize and update model parameter estimates by the UKF method based on formulation of an associated nonlinear state-space representation and joint estimation of model parameters and state variables. Similarly, β-AS-induced phosphorylation levels of cellular substrates were estimated by the DGDR-UKF methodology. Performance was tested by building an experimentally-calibrated population of virtual cells, from which synthetic AP traces were generated for baseline and β-AS conditions. The combined DGDR-UKF methodology led to 25% reduction in the error associated with estimation of ionic current conductances at baseline conditions and phosphorylation levels under β-AS with respect to individual DGDR and UKF methods. This improvement was not at the expense of higher computational load, which was diminished by 90% with respect to the individual UKF method. Both temporal and spatial AP variability of repolarization were accurately characterized by the DGDR-UKF methodology. A combined DGDR-UKF methodology is proposed for parameter and state variable estimation of human ventricular cell models from available AP traces at baseline and under β-AS. This methodology improves the estimation performance and reduces the convergence time with respect to individual DGDR and UKF methods and renders a suitable approach for computational characterization of spatio-temporal repolarization variability to be used for ascertainment of variability mechanisms and its relation to arrhythmogenesis.

Late Sodium Current in Canine, Guinea Pig and Human Left Ventricular Myocardium

The late sodium current (INa,late) has been known to contribute to cardiac action potentials (AP), and lately it was also considered as a possible antiarrhythmic target. However, many aspects of this current are still poorly understood. Our aim was to study the true profile of INa,late in canine and guinea pig left ventricular cells and compare them to INa,late recorded in undiseased human cardiomyocytes. INa,late was defined as a tetrodotoxin-sensitive current, recorded under action potential voltage clamp (APVC) conditions using either canonic- or self-action potentials as command signals. INa,late was also recorded using conventional voltage clamp. Under APVC conditions the density of canine and human INa,late monotonically decreased, whereas in guinea pig, it continuously increased during the AP plateau. The “decreasing” profile of canine INa,late could not be converted to an “increasing” morphology by application of isoproterenol, calmodulin, AP-like ramp voltage command or command APs recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the “increasing” INa,late profile in guinea pig is determined by the slow decay of INa,late in this species. INa,late was increased by isoproterenol but not by calmodulin in canine myocytes. When APs were recorded from multicellular ventricular preparations with sharp microelectrode, tetrodotoxin decreased AP duration in a reverse rate-dependent manner, which effect was the largest in human, while smaller in canine and the smallest in guinea pig preparations. The shape of INa,late under the AP is likely determined by the different inactivation kinetics of the sodium channels that generate INa,late. Variances between different species in the actual sodium channel subtypes that contribute to INa,late might underlie the differences observed in the macroscopic current. Canine myocytes seems to be the best model of human ventricular cells regarding INa,late.

Blinded In Silico Drug Trial Reveals the Minimum Set of Ion Channels for Torsades de Pointes Risk Assessment.

Torsades de Pointes (TdP) is a type of ventricular arrhythmia which could be observed as an unwanted drug-induced cardiac side effect, and it is associated with repolarization abnormalities in single cells. The pharmacological evaluations of TdP risk in previous years mainly focused on the hERG channel due to its vital role in the repolarization of cardiomyocytes. However, only considering drug effects on hERG led to false positive predictions since the drug action on other ion channels can also have crucial regulatory effects on repolarization. To address the limitation of only evaluating hERG, the Comprehensive in Vitro Proarrhythmia Assay initiative has proposed to systematically integrate drug effects on multiple ion channels into in silico drug trial to improve TdP risk assessment. It is not clear how many ion channels are sufficient for reliable TdP risk predictions, and whether differences in IC50 and Hill coefficient values from independent sources can lead to divergent in silico prediction outcomes. The rationale of this work is to investigate the above two questions using a computationally efficient population of human ventricular cells optimized to favor repolarization abnormality. Our blinded results based on two independent data sources confirm that simulations with the optimized population of human ventricular cell models enable efficient in silico drug screening, and also provide direct observation and mechanistic analysis of repolarization abnormality. Our results show that 1) the minimum set of ion channels required for reliable TdP risk predictions are Nav1.5 (peak), Cav1.2, and hERG; 2) for drugs with multiple ion channel blockage effects, moderate IC50 variations combined with variable Hill coefficients can affect the accuracy of in silico predictions.

Late sodium current in human, canine and guinea pig ventricular myocardium

Although late sodium current (INa-late) has long been known to contribute to plateau formation of mammalian cardiac action potentials, lately it was considered as possible target for antiarrhythmic drugs. However, many aspects of this current are still poorly understood. The present work was designed to study the true profile of INa-late in canine and guinea pig ventricular cells and compare them to INa-late recorded in undiseased human hearts. INa-late was defined as a tetrodotoxin-sensitive current, recorded under action potential voltage clamp conditions using either canonic- or self-action potentials as command signals. Under action potential voltage clamp conditions the amplitude of canine and human INa-late monotonically decreased during the plateau (decrescendo-profile), in contrast to guinea pig, where its amplitude increased during the plateau (crescendo profile). The decrescendo-profile of canine INa-late could not be converted to a crescendo-morphology by application of ramp-like command voltages or command action potentials recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the crescendo INa-late profile in guinea pig was due to the slower decay of INa-late in this species. When action potentials were recorded from multicellular ventricular preparations with sharp microelectrode, action potentials were shortened by tetrodotoxin, which effect was the largest in human, while smaller in canine, and the smallest in guinea pig preparations. It is concluded that important interspecies differences exist in the behavior of INa-late. At present canine myocytes seem to represent the best model of human ventricular cells regarding the properties of INa-late. These results should be taken into account when pharmacological studies with INa-late are interpreted and extrapolated to human. Accordingly, canine ventricular tissues or myocytes are suggested for pharmacological studies with INa-late inhibitors or modifiers. Incorporation of present data to human action potential models may yield a better understanding of the role of INa-late in action potential morphology, arrhythmogenesis, and intracellular calcium dynamics.

A method for reduction of human ventricular action potential model

ABSTRACTMathematical modelling and computer simulations are important tools in the field of cardiac electrophysiology. High computational costs of complex models make them difficult to apply in large-scale simulations like tissue. Therefore, model reduction are of particular importance in heart studies. In this paper, we introduce a technique for simplification of ventricular cell(VC) complex models. By using this technique, starting with a complex model of human VC including 17state variables, we reduce the number of state variables to two. Our simplified model is compared with the original one via several electrophysiological features and computational efficiency. Results show that the reduced model has acceptable behaviours in single cell and one-dimensional simulation, moreover, is 55 times faster than the original one. As the presented method does not depend on the reference model, it may be applied to every cardiac cell models or each complex excitable dynamical systems with the same dynamics as VC.