Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment

Maria Camporesi1, Chiara Bartolucci1, Chon Lok Lei2, Gary R. Mirams3, Teun P. de Boer4, Stefano Severi1
1University of Bologna, 2University of Oxford, 3University of Nottingham, 4University Medical Center Utrecht


Aims: The Dynamic Clamp technique has been proposed for drug cardiac safety assessment as no mathematical description of drug is required. This project aimed to recreate a simulator of a multicellular dynamic action potential clamp (dAPC) system in Simulink and evaluate how artefacts from the acquisition system affect APD90 in dAPC. Lastly, we evaluated if it is possible to determine drug effects in dAPC.

Methods: We simulated each system component (in-vitro cells, acquisition system and AP model (O’Hara-Rudy)) and the protocols needed, such as the scaling factor estimation protocol required to scale the current’s amplitude acquired from the cell to a value consistent with the AP model, and the leakage current compensation.

Results: In the dAPC simulation, in a perfectly compensated acquisition system, APD90 = 268,3 ms close to APD90 = 270,6 ms in the O’Hara-Rudy model. Then, an analysis showing how artefacts from the acquisition system and their compensations affect the APD90, revealed that membrane capacitance, offset voltage and leakage current result to be the main responsible for changes in APD90. Lastly, we determined drug’s effects by calculating how APD90 changes (ΔAPD90) upon virtual administration of Verapamil to the cells: ΔAPD90 = - 19,5 ms in the dAPC simulation compared to ΔAPD90 = -14,8 ms in the O’Hara-Rudy model.

Conclusion: This study showed that it is possible, in a dAPC simulation, to reproduce an AP similar to the one in the in silico model and that sensible AP prolungation could be observed in a dAPC system when drugs are administrated.