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Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations.

Corrias A, Jie X, Romero L, Bishop MJ, Bernabeu M, Pueyo E, Rodriguez B - Philos Trans A Math Phys Eng Sci (2010)

Bottom Line: To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels.Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market.We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.

View Article: PubMed Central - PubMed

Affiliation: Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford OX1 3QD, UK.

ABSTRACT
In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.

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Related in: MedlinePlus

(a) Endocardial activation seen in a sliced whole heart. (b) Snapshot of AP propagation across the epicardial surface. (c) Representative AP traces in control and IKr block conditions at nodes located in the epicardial (red line), mid-myocardial (green line) and endocardial (blue line) layers. (d) Pseudo-ECG computed at a distance of approximately 3 cm from the epicardium (IKr block, red line; control, green line).
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RSTA20100083F6: (a) Endocardial activation seen in a sliced whole heart. (b) Snapshot of AP propagation across the epicardial surface. (c) Representative AP traces in control and IKr block conditions at nodes located in the epicardial (red line), mid-myocardial (green line) and endocardial (blue line) layers. (d) Pseudo-ECG computed at a distance of approximately 3 cm from the epicardium (IKr block, red line; control, green line).

Mentions: Figure 6a shows a transverse slice of the whole heart 3 ms after endocardial stimulation. The depolarizing wave reaches the epicardium and starts propagating towards the apex (figure 6b). Figure 6c shows representative APs from three nodes (location shown in the inset) under control conditions and under the effect of IKr block. The differences in AP shape and duration between epicardial, mid-myocardial and endocardial layers are less marked than with a single-cell situation (figure 5b) owing to cell-to-cell electrotonic interactions. APD prolongation caused by IKr block was 40, 39 and 40 ms in the epicardial, mid-myocardial and endocardial representative nodes, respectively. These variations in AP duration are reflected in variations in the QT interval at the ECG level (figure 6d) where the QT interval was prolonged by 42 ms.


Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations.

Corrias A, Jie X, Romero L, Bishop MJ, Bernabeu M, Pueyo E, Rodriguez B - Philos Trans A Math Phys Eng Sci (2010)

(a) Endocardial activation seen in a sliced whole heart. (b) Snapshot of AP propagation across the epicardial surface. (c) Representative AP traces in control and IKr block conditions at nodes located in the epicardial (red line), mid-myocardial (green line) and endocardial (blue line) layers. (d) Pseudo-ECG computed at a distance of approximately 3 cm from the epicardium (IKr block, red line; control, green line).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2944395&req=5

RSTA20100083F6: (a) Endocardial activation seen in a sliced whole heart. (b) Snapshot of AP propagation across the epicardial surface. (c) Representative AP traces in control and IKr block conditions at nodes located in the epicardial (red line), mid-myocardial (green line) and endocardial (blue line) layers. (d) Pseudo-ECG computed at a distance of approximately 3 cm from the epicardium (IKr block, red line; control, green line).
Mentions: Figure 6a shows a transverse slice of the whole heart 3 ms after endocardial stimulation. The depolarizing wave reaches the epicardium and starts propagating towards the apex (figure 6b). Figure 6c shows representative APs from three nodes (location shown in the inset) under control conditions and under the effect of IKr block. The differences in AP shape and duration between epicardial, mid-myocardial and endocardial layers are less marked than with a single-cell situation (figure 5b) owing to cell-to-cell electrotonic interactions. APD prolongation caused by IKr block was 40, 39 and 40 ms in the epicardial, mid-myocardial and endocardial representative nodes, respectively. These variations in AP duration are reflected in variations in the QT interval at the ECG level (figure 6d) where the QT interval was prolonged by 42 ms.

Bottom Line: To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels.Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market.We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.

View Article: PubMed Central - PubMed

Affiliation: Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford OX1 3QD, UK.

ABSTRACT
In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.

Show MeSH
Related in: MedlinePlus