A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window

Abstract

Background and objective

In silico human models are being used more and more to predict the potential proarrhythmic risk of compounds. It has been shown that incorporation of the dynamics of drug-hERG channel interactions can have an important impact on the action potential duration (APD) at normal heart rates. Our aim is to investigate the relevance of drug dynamics on other important biomarkers of proarrhythmic risk.

Methods

We use the state-of-the-art mathematical models of the cardiac electrophysiological activity to simulate TRIaD biomarkers, namely Triangulation, Reverse use-dependency, electrical Instability of the action potential and Dispersion, together with the vulnerable window to unidirectional block. They were simulated in control conditions and in the presence of an extensive set of 114 in silico I_Kr blockers with different kinetics and affinities to conformational states of the channel and 10 well-known real I_Kr blockers at the concentration leading to a 25 % prolongation of the APD.

Results

Our results show that drug binding dynamics to hERG are crucial for the reverse use-dependence of APD, the slope of the APD restitution curve as a function of the root square of the cycle length ranging from 0 to 5.6 ms/$\sqrt{ms}$ (2.1 ms/$\sqrt{ms}$ in control conditions). The vulnerable window for unidirectional block and the transmural action potential duration dispersion markedly depended on the drug binding mechanisms and kinetics, although to a lesser extent. Virtual drugs led to increments of these two biomarkers from 25 % to 200 %. On the contrary, temporal instability and, beat-to-beat instability, are less dependent on the dynamics of drug binding. The results obtained with the models of real I_Kr blockers are in line with those obtained with the virtual drugs.

Conclusions

Our study highlights the importance of considering the drug binding mechanism, as well as the kinetics, to assess the effects of I_Kr blockers. Moreover, adoption of in silico models mimicking these characteristics would contribute to the improvement of the prediction of the proarrhythmic risk of new compounds.