In scilico assessment of drugs action on the heart electrical activity

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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 IC(50) value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions.

ECG Modelling and Simulation

Meaningful computer based simulations of the electrocardiogram ( ECG), linking models of the electrical activity of the heart to ECG signals, are a necessary step towards the development of cardiac models from clinical ECG data.
An ECG simulator is, in addition, a valuable tool for building a virtual data base of pathological conditions, to test and train medical devices but also to improve the knowledge on the clinical significance of some ECG signals.
The heart-torso mathematical model is based on partial differential equations : a reaction diffusion system in the heart (called bidomain model) and the Laplace equation in the torso. These equations are coupled on the heart-torso interface to obtain the ECG model. The bidomain model it self is coupled to a dynamic system governing the electrical activation of the cell membrane. The drug acts directely on the ion channels conductance, we model the drug action by modifiyng the mathematical formulation of ion channels conductances (see papers bellow for more details about modelling).
The mathematical models are then solved folowing different numerical schemes: in space we use finite element methods and in time we use semi-implicit schemes based on Backward differentiation formula.

Examples of Simulation Results

Full details about the following simulations including mathematical models numerical schemes anatomical geometries simulation softwares could be found in the papers below.

Control case

In this video (right) we show the spread of the electrical wave inside the heart and in the body. The change in the color explains the change of the electrical potential magnitude. The ECG is measured on the standard 9 electrodes psitions. In this movie (left), we show the first lead of the ECG which is the difference between the left and the right arm electrical potentials.

hERG block case

We studied the effect of compounds that act on sodium potassium and L-type calcium ion channels.
Here is an example of a hERG block simulation. This simulation is supposed to show the effect of 10 nMol of the compound “Dofetilide” on the ECG.

Details about simulation could be found in these papers:

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