Miguel O Bernabeu is currently working at Centre for Computational Science, University College London, London WC1H 0AJ, UK, and CoMPLEX, University College London, London WC1E 6BT, UK.
Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials
Article first published online: 16 JAN 2013
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Volume 168, Issue 3, pages 718–733, February 2013
How to Cite
Zemzemi, N., Bernabeu, M. O., Saiz, J., Cooper, J., Pathmanathan, P., Mirams, G. R., Pitt-Francis, J. and Rodriguez, B. (2013), Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials. British Journal of Pharmacology, 168: 718–733. doi: 10.1111/j.1476-5381.2012.02200.x
- Issue published online: 16 JAN 2013
- Article first published online: 16 JAN 2013
- Accepted manuscript online: 5 SEP 2012 04:36AM EST
- Manuscript Accepted: 14 AUG 2012
- Manuscript Revised: 6 AUG 2012
- Manuscript Received: 14 DEC 2011
- European Commission preDiCT. Grant Number: DG-INFSO-224381
- ECG modelling;
- computer simulation;
- sodium blockers;
- QT prolongation;
- QRS widening
Background and Purpose
Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential.
We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC50 value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions.
Introducing a 50% hERG-channel current block results in 8% prolongation of the APD90 and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD90 is not affected.
Conclusions and Implications
Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.