A causal discovery approach for streamline ion channels selection to improve drug-induced TdP risk assessment

Torsade de Pointes (TdP) is an extremely serious drug-induced cardiac side effect, which is related to abnormal repolarizations in single cells, and the minimum set of ion channels needed to correctly assess TdP risk is still an open question. In this work, we propose to apply the causal discovery method ICA-Linear Non-Gaussian Acyclic Model (ICA-LiNGAM) to uncover the relations across the 7 ion channels identified by the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative as potentially related to the induction of TdP. We identify I\(_{Kr}\), I\(_{NaL}\) and I\(_{CaL}\) as the ones which directly affect TdP-risk assessment, and suggest that I\(_{Na}\) perturbations could potentially have a high impact on proarrhythmic risk induction.

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Recommended citation: Al-Ali S., Llopis-Lorente J., Mora M. T., Sermesant M., Trénor B., Balelli I. (2023). Accepted for publication in Computing in Cardiology. A causal discovery approach for streamline ion channels selection to improve drug-induced TdP risk assessment. Preprint. [hal-04105144]