L-type calcium current in human ventricular myocytes at a physiological temperature from children with tetralogy of Fallot

Pelzmann, Brigitte; Schäffer, Péter; Bernhart, Eva; Lang, Petra; Mächler, Heinrich; Rigler, B; Koidl, Bernd

doi:10.1016/s0008-6363(98)00002-9

Cited by 42 publications

(40 citation statements)

References 39 publications

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“…Figure 1b shows the different current-voltage curves, where it can be observed that the new definition of I CaL is in good agreement with the available experimental data [14][15][16], with the additional benefit of contributing to physiological model response in terms of S1S2 APD 90 restitution and APD 90 rate adaptation dynamics.…”

Section: (I) the Gpb Modelsupporting

confidence: 72%

“…where Frdy is Faraday's constant, FoRT is the ratio between Faraday's constant and the product of the gas constant and the absolute temperature,Ī k m is the maximal current for ion k in the compartment m, and p k is the relative permeability of ion k. The current-voltage curve obtained with the new definition of the I CaL current was compared with the experimental data [14][15][16] and with the original definition of the GPB model. Figure 1b shows the different current-voltage curves, where it can be observed that the new definition of I CaL is in good agreement with the available experimental data [14][15][16], with the additional benefit of contributing to physiological model response in terms of S1S2 APD 90 restitution and APD 90 rate adaptation dynamics.…”

Section: (I) the Gpb Modelmentioning

confidence: 99%

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A human ventricular cell model for investigation of cardiac arrhythmias under hyperkalaemic conditions

Carro

Rodrı́guez

Laguna

et al. 2011

Phil. Trans. R. Soc. A.

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In this study, several modifications were introduced to a recently proposed human ventricular action potential (AP) model so as to render it suitable for the study of ventricular arrhythmias. These modifications were driven by new sets of experimental data available from the literature and the analysis of several well-established cellular arrhythmic risk biomarkers, namely AP duration at 90 per cent repolarization (APD 90 ), AP triangulation, calcium dynamics, restitution properties, APD 90 adaptation to abrupt heart rate changes, and rate dependence of intracellular sodium and calcium concentrations. The proposed methodology represents a novel framework for the development of cardiac cell models. Five stimulation protocols were applied to the original model and the ventricular AP model developed here to compute the described arrhythmic risk biomarkers. In addition, those models were tested in a one-dimensional fibre in which hyperkalaemia was simulated by increasing the extracellular potassium concentration, [K + ] o . The effective refractory period (ERP), conduction velocity (CV) and the occurrence of APD alternans were investigated. Results show that modifications improved model behaviour as verified by: (i) AP triangulation well within experimental limits (the difference between APD at 50 and 90 per cent repolarization being 78.1 ms); (ii) APD 90 rate adaptation dynamics characterized by fast and slow time constants within physiological ranges (10.1 and 105.9 s); and (iii) maximum S1S2 restitution slope in accordance with experimental data (S S1S2 = 1.0). In simulated tissues under hyperkalaemic conditions, APD 90 progressively shortened with the degree of hyperkalaemia, whereas ERP increased once a threshold in of AP models on the computation of arrhythmic risk biomarkers, as opposed to joining together independently derived ion channel descriptions to produce a whole-cell AP model, with the new framework providing a better picture of the model performance under a variety of stimulation conditions. On top of replicating experimental data at single-cell level, the model developed here was able to predict the occurrence of APD 90 alternans and areas of conduction block associated with high [K + ] o in tissue, which is of relevance for the investigation of the arrhythmogenic substrate in ischaemic hearts.

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Section: (I) the Gpb Modelsupporting

confidence: 72%

Section: (I) the Gpb Modelmentioning

confidence: 99%

A human ventricular cell model for investigation of cardiac arrhythmias under hyperkalaemic conditions

Carro

Rodrı́guez

Laguna

et al. 2011

Phil. Trans. R. Soc. A.

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“…Additional studies into drug antagonism of these ion channels have further shown that the current density and activation properties of the channels for INa, ICa, IKr, IKs, IKr, IKi, If and Ito in hiPSC-CMs (Moretti et al, 2010;Ma et al, 2011) are quantitatively similar to those in human cardiomyocytes (Sakakibara et al, 1993;Feng et al, 1996;Pelzmann et al, 1998;Jost et al, 2009).…”

Section: Figurementioning

confidence: 94%

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Khan

Lyon

Harding

2013

British J Pharmacology

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The current drug screening models are deficient, particularly in detecting cardiac side effects. Human stem cell-derived cardiomyocytes could aid both early cardiotoxicity detection and novel drug discovery. Work over the last decade has generated human embryonic stem cells as potentially accurate sources of human cardiomyocytes, but ethical constraints and poor efficacy in establishing cell lines limit their use. Induced pluripotent stem cells do not require the use of human embryos and have the added advantage of producing patient-specific cardiomyocytes, allowing both generic and disease-and patient-specific pharmacological screening, as well as drug development through disease modelling. A critical question is whether sufficient standards have been achieved in the reliable and reproducible generation of 'adult-like' cardiomyocytes from human fibroblast tissue to progress from validation to safe use in practice and drug discovery. This review will highlight the need for a new experimental system, assess the validity of human induced pluripotent stem cell-derived cardiomyocytes and explore what the future may hold for their use in pharmacology. LINKED ARTICLESThis article is part of a themed section on Regenerative Medicine and Pharmacology: A Look to the Future. To view the other articles in this section visit http://dx

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“…3, A and B). ICaL voltage-clamp experiments indicate the presence of both a fast and slow voltage-dependent recovery process (32,35,46). Therefore, we incorporate both a slow voltage inactivation gate f and a fast voltage inactivation gate f 2, similar to the approach taken by Hund and Rudy (19).…”

Section: Model Developmentmentioning

confidence: 99%

Alternans and spiral breakup in a human ventricular tissue model

Tusscher¹,

Panfilov²

2006

American Journal of Physiology-Heart and Circulatory Physiology

939

1,142

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According to one hypothesis, the chaotic excitation dynamics during VF are the result of dynamical instabilities in action potential duration (APD) the occurrence of which requires that the slope of the APD restitution curve exceeds 1. Other factors such as electrotonic coupling and cardiac memory also determine whether these instabilities can develop. In this paper we study the conditions for alternans and spiral breakup in human cardiac tissue. Therefore, we develop a new version of our human ventricular cell model, which is based on recent experimental measurements of human APD restitution and includes a more extensive description of intracellular calcium dynamics. We apply this model to study the conditions for electrical instability in single cells, for reentrant waves in a ring of cells, and for reentry in two-dimensional sheets of ventricular tissue. We show that an important determinant for the onset of instability is the recovery dynamics of the fast sodium current. Slower sodium current recovery leads to longer periods of spiral wave rotation and more gradual conduction velocity restitution, both of which suppress restitution-mediated instability. As a result, maximum restitution slopes considerably exceeding 1 (up to 1.5) may be necessary for electrical instability to occur. Although slopes necessary for the onset of instabilities found in our study exceed 1, they are within the range of experimentally measured slopes. Therefore, we conclude that steep APD restitution-mediated instability is a potential mechanism for VF in the human heart. reentrant arrhythmias; human ventricular myocytes; restitution properties; spiral waves; computer simulation ONE OF THE MOST extensively investigated hypotheses for ventricular fibrillation (VF) is the so-called restitution hypothesis. In its initial form the hypothesis stated that if the action potential duration (APD) restitution curve has a maximum slope steeper than 1, it will lead to APD alternans (16,41). In tissue this APD alternans can result in the fragmentation of a spiral wave, leading to fibrillation-like excitation patterns (21,22,45,48). Modeling studies have confirmed that a steep restitution curve indeed promotes instability. However, modeling studies have also shown that the criterion of an APD restitution slope Ͼ1 is an oversimplification that only holds for very simple models. In more realistic and complex models, it has been shown that other factors such as short-term cardiac memory, electrotonic interactions between cells, conduction velocity (CV) restitution, the range of diastolic intervals (DIs) over which restitution is steeper than 1, and the range of DIs visited during spiral wave rotation all play an important role in determining whether alternans and spiral breakup will occur (5,7,10,11,42,48,64). In an extensive study of restitutioninduced instability, Cherry and Fenton (6), for example, showed that because of strong electrotonic interactions and gradual CV restitution, spiral breakup may not occur even if the APD restitution curve has ...

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L-type calcium current in human ventricular myocytes at a physiological temperature from children with tetralogy of Fallot

Cited by 42 publications

References 39 publications

A human ventricular cell model for investigation of cardiac arrhythmias under hyperkalaemic conditions

A human ventricular cell model for investigation of cardiac arrhythmias under hyperkalaemic conditions

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Alternans and spiral breakup in a human ventricular tissue model

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