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 (APD(95)) 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 I-Kr, I-Na and I-CaL conductances in the algorithm by a scaling factor which is a function of the IC50 of the drug for I-Kr, I-Na and I-CaL 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 APD(95) prolongation which was induced by net repolarising current reduction via I-Kr or I-Ks inhibition and/or I-CaL or I-NaL 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 I-Kr vs. I-CaL and/or I-Na selective inhibition; while most non-torsadogenic tested drugs induced a TDR decrease via I-CaL vs. I-Kr and/or I-Na 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.