Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models

Kurata, Yasutaka; Tsumoto, Kunichika; Hayashi, Kenshi; Hisatome, Ichiro; Tanida, Mamoru; Kuda, Yuhichi; Shibamoto, Toshishige

doi:10.1152/ajpheart.00115.2016

Cited by 38 publications

(84 citation statements)

References 75 publications

(129 reference statements)

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“…Although evaluations were made only at ETPC unbound , these results suggest that the evaluation of arrhythmogenicity is acceptable before reaching steady state (quasi‐steady state). In fact, in recent studies using single‐cell models (Dutta et al ., ; Kurata et al ., ), the authors examined the occurrence of EAD at fewer than 1000 beats (quasi‐steady state). Duttas et al .…”

Section: Discussionmentioning

confidence: 99%

“…Although evaluations were made only at ETPC unbound , these results suggest that the evaluation of arrhythmogenicity is acceptable before reaching steady state (quasi-steady state). In fact, in recent studies using single-cell models (Dutta et al, 2017;Kurata et al, 2017), the authors examined the occurrence of EAD at fewer than 1000 beats (quasi-steady state). Duttas et al found a strong correlation between their metrics of arrhythmogenicity (net charge constituting the net current during the stimulated beat) analysed at 1000 beats, and the I Kr reduction threshold for the induction of EAD checked at 100 beats (Dutta et al, 2017).…”

Section: Study Limitationsmentioning

confidence: 99%

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Arrhythmic hazard map for a 3D whole‐ventricle model under multiple ion channel block

Okada

Yoshinaga

Kurokawa

et al. 2018

British J Pharmacology

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Background and PurposeTo date, proposed in silico models for preclinical cardiac safety testing are limited in their predictability and usability. We previously reported a multi‐scale heart simulation that accurately predicts arrhythmogenic risk for benchmark drugs.Experimental ApproachWe created a comprehensive hazard map of drug‐induced arrhythmia based on the electrocardiogram (ECG) waveforms simulated under wide range of drug effects using the multi‐scale heart simulator described here, implemented with cell models of human cardiac electrophysiology.Key ResultsA total of 9075 electrocardiograms constitute the five‐dimensional hazard map, with coordinates representing the extent of the block of each of the five ionic currents (rapid delayed rectifier potassium current (I Kr), fast (I Na) and late (I Na,L) components of the sodium current, L‐type calcium current (I Ca,L) and slow delayed rectifier current (I Ks)), involved in arrhythmogenesis. Results of the evaluation of arrhythmogenic risk based on this hazard map agreed well with the risk assessments reported in the literature. ECG databases also suggested that the interval between the J‐point and the T‐wave peak is a superior index of arrhythmogenicity when compared to the QT interval due to its ability to characterize the multi‐channel effects compared with QT interval.Conclusion and ImplicationsBecause concentration‐dependent effects on electrocardiograms of any drug can be traced on this map based on in vitro current assay data, its arrhythmogenic risk can be evaluated without performing costly and potentially risky human electrophysiological assays. Hence, the map serves as a novel tool for use in pharmaceutical research and development.

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Section: Discussionmentioning

confidence: 99%

Section: Study Limitationsmentioning

confidence: 99%

Arrhythmic hazard map for a 3D whole‐ventricle model under multiple ion channel block

Okada

Yoshinaga

Kurokawa

et al. 2018

British J Pharmacology

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“…For each IKr reduction tested, EADs were defined as having a positive differential (dV/dt) during the plateau phase of the AP (between APD30 and APD90) after 100 beats. The cell model was pulsed for a 100 beats before checking for EADs to allow the system to reach quasi-steady state, as in Kurata et al (2017). The minimum IKr conductance reduction needed to trigger an EAD was named IKr reduction threshold, which reflects the system's repolarization robustness against, or distance from, EADs.…”

Section: Simulation Protocol For Metric Evaluationmentioning

confidence: 99%

“…In order to assess the physiological significance of the metric, we borrowed some concepts from non-linear dynamic theory, where EADs appear as membrane voltage oscillations when the equilibrium state at the plateau phase (membrane voltage between 0 and −40 mV) changes its stability via bifurcation Kurata et al, 2017). The robustness of the system could be evaluated by applying a specific perturbation with a series of strengths and measuring the range of the perturbation FIGURE 5 | qNet for the 12 CiPA training compounds for a range of doses (0.5-25x Cmax) at a pacing rate of 2,000 ms. (A) Optimized IKr-dyn ORd; (B) A model variation without the incorporation of the IKr dynamic model (note this is the same model as in Dutta et al, 2016) and; (C) A model variation without the optimized channel conductances to accurately quantify block effects of individual currents (note this is the same model as in Li et al, 2017).…”

Section: Physiological Significance Of Qnetmentioning

confidence: 99%

“…Based on ideas from non-linear dynamic theory and studies demonstrating mechanisms of EAD generation (Guo et al, 2007;Weiss et al, 2010;Xie et al, 2010;Chang et al, 2013;Kurata et al, 2017), we established a theoretical framework to quantitatively evaluate the physiological consequences of the change of the qNet (and in principle any) metric. A key concept here is the system robustness (Kurata et al, 2008), which is defined as the level of a specific perturbation the system can tolerate without a qualitative change of stability (e.g., emergence or annihilation of oscillations).…”

Section: Qnet Correlates With the System's Robustness Against Eadsmentioning

confidence: 99%

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Optimization of an In Silico Cardiac Cell Model for Proarrhythmia Risk Assessment

Dutta¹,

Strauss²,

Colatsky³

et al. 2016

2016 Computing in Cardiology Conference (CinC)

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Drug-induced Torsade-de-Pointes (TdP) has been responsible for the withdrawal of many drugs from the market and is therefore of major concern to global regulatory agencies and the pharmaceutical industry. The Comprehensive in vitro Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using in silico models and in vitro multi-channel pharmacology data as integral parts of this initiative. Previously, we reported that combining dynamic interactions between drugs and the rapid delayed rectifier potassium current (IKr) with multi-channel pharmacology is important for TdP risk classification, and we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model). We also developed a novel metric that could separate drugs with different TdP liabilities at high concentrations based on total electronic charge carried by the major inward ionic currents during the action potential. In this study, we further optimized the IKr-dynamic ORd model by refining model parameters using published human cardiomyocyte experimental data under control and drug block conditions. Using this optimized model and manual patch clamp data, we developed an updated version of the metric that quantifies the net electronic charge carried by major inward and outward ionic currents during the steady state action potential, which could classify the level of drug-induced TdP risk across a wide range of concentrations and pacing rates. We also established a framework to quantitatively evaluate a system's robustness against the induction of early afterdepolarizations (EADs), and demonstrated that the new metric is correlated with the cell's robustness to the pro-EAD perturbation of IKr conductance reduction. In summary, in this work we present an optimized model that is more consistent with experimental data, an improved metric that can classify drugs at concentrations both near and higher than clinical exposure, and a physiological framework to check the relationship between a metric and EAD. These findings provide a solid foundation for using in silico models for the regulatory assessment of TdP risk under the CiPA paradigm.

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Integrative and theoretical research on the architecture of a biological system and its disorder

et al. 2019

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An organism stems from assemblies of a variety of cells and proteins. This complex system serves as a unit, and it exhibits highly sophisticated functions in response to exogenous stimuli that change over time. The complete sequencing of the entire human genome has allowed researchers to address the enigmas of life and disease at the gene- or molecular-based level. The consequence of such studies is the rapid accumulation of a multitude of data at multiple levels, ranging from molecules to the whole body, that has necessitated the development of entirely new concepts, tools, and methodologies to analyze and integrate these data. This necessity has given birth to systems biology , an advanced theoretical and practical research framework that has totally changed the directions of not only basic life science but also medicine. During the symposium of the 95th Annual Meeting of The Physiological Society of Japan 2018, five researchers reported on their respective studies on systems biology. The topics included reactions of drugs, ion-transport architecture in an epithelial system, multi-omics in renal disease, cardiac electrophysiological systems, and a software platform for computer simulation. In this review article these authors have summarized recent achievements in the field and discuss next-generation studies on health and disease. Electronic supplementary material The online version of this article (10.1007/s12576-019-00667-8) contains supplementary material, which is available to authorized users.

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Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models

Cited by 38 publications

References 75 publications

Arrhythmic hazard map for a 3D whole‐ventricle model under multiple ion channel block

Arrhythmic hazard map for a 3D whole‐ventricle model under multiple ion channel block

Optimization of an In Silico Cardiac Cell Model for Proarrhythmia Risk Assessment

Integrative and theoretical research on the architecture of a biological system and its disorder

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