In silico Study of Transmural Dispersion of Repolarization in Non-failing Human Ventricular Myocytes: Contribution to Cardiac Safety Pharmacology

Aims: To investigate the putative usefulness of the in silico determination of transmural dispersion of repolarization (TDR) for early cardiac safety pharmacology. Study Design: Computational simulations. Place and Duration of Study: SCAP Test, Belgium, between September 2014 and March 2015. Methodology: TDR was calculated as the difference between epicardial-midmyocardial action potential duration (APD95) determined in non-failing human ventricular myocytes using the O’Hara-Rudy dynamic algorithm. The role of each ionic current in TDR was investigated by modifying its conductance in the algorithm. The effects of each tested drug on TDR were studied by reducing the IKr, INa and ICaL conductances in the algorithm by a scaling factor which is a function of the IC50 of the drug for IKr, INa and ICaL ionic currents and the maximal effective free therapeutic plasma concentration (EFTPCmax) of the drug. Results: Our simulations showed that TDR was increased by a preferential midmyocardial APD95 prolongation which was induced by net repolarising current reduction via IKr or IKs inhibition and/or ICaL or INaL activation. Drugs’ effects on TDR were in good agreement with their torsade de pointes (TdP) risk according to the CredibleMeds or the Redfern classifications: most torsadogenic tested drugs induced a TDR increase via IKr vs. ICaL and/or INa selective inhibition; while most non-torsadogenic tested drugs induced a TDR decrease via ICaL vs. IKr and/or INa selective inhibition. Conclusion: Based on computer simulations within the human situation, the present study identified the effects of various cardiac ionic currents on TDR amplitude and suggested that in silico study of drugs’ effects on TDR could be informative for early cardiac safety pharmacology.