Predicting the cardiac toxicity of drugs using a novel multiscale exposure-response simulator

Computer Methods in Biomechanics and Biomedical Engineering
Francisco Sahli CostabalEllen Kuhl

Abstract

A common but serious side effect of many drugs is torsades de pointes, a rhythm disorder that can have fatal consequences. Torsadogenic risk has traditionally been associated with blockage of a specific potassium channel and an increased recovery period in the electrocardiogram. However, the mechanisms that trigger torsades de pointes remain incompletely understood. Here we establish a computational model to explore how drug-induced effects propagate from the single channel, via the single cell, to the whole heart level. Our mechanistic exposure-response simulator translates block-concentration characteristics for arbitrary drugs into three-dimensional excitation profiles and electrocardiogram recordings to rapidly assess torsadogenic risk. For the drug of dofetilide, we show that this risk is highly dose-dependent: at a concentration of 1x, QT prolongation is 55% but the heart maintains its regular sinus rhythm; at 5.7x, QT prolongation is 102% and the heart spontaneously transitions into torsades de points; at 30x, QT prolongation is 132% and the heart adapts a quasi-depolarized state with numerous rapidly flickering local excitations. Our simulations suggest that neither potassium channel blockage nor QT interval prolongatio...Continue Reading

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Citations

Jan 14, 2018·Circulation. Arrhythmia and Electrophysiology·Junaid A B ZamanNicholas S Peters
Jun 18, 2020·APL Bioengineering·Minki HwangEun Bo Shim
Nov 6, 2020·Médecine sciences : M/S·Aurélie Jean
Jan 4, 2021·Journal of Biomechanics·Denisa MartonováSigrid Leyendecker
Feb 2, 2021·International Journal for Numerical Methods in Biomedical Engineering·Lucas A WoodworthMichael Kaliske
Nov 30, 2018·Progress in Biophysics and Molecular Biology·Francisco Sahli CostabalEllen Kuhl
Jan 11, 2019·Acta Biomaterialia·F Sahli CostabalE Kuhl
Apr 15, 2021·Cardiovascular Engineering and Technology·Steven M KreuzerJorge A Ochoa

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Software Mentioned

Zygote
Abaqus

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