Computational models of ventricular- and atrial-like human induced pluripotent stem cell derived cardiomyocytes

Abstract

The clear importance of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as an in-vitro model highlights the relevance of studying these cells and their function also in-silico. Moreover, the phenotypical differences between the hiPSC-CM and adult myocyte action potentials (APs) call for understanding of how hiPSC-CMs are maturing towards adult myocytes. Using recently published experimental data, we developed two computational models of the hiPSC-CM action potential (AP), distinguishing between the ventricular-like and atrial-like phenotypes, emerging during the differentiation process of hiPSC-CMs. Also, we used the computational approach to quantitatively assess the role of ionic mechanisms which are likely responsible for the not completely mature phenotype of hiPSC-CMs. Our models reproduce the typical hiPSC-CM ventricular-like and atrial-like spontaneous APs and the response to prototypical current blockers, namely tetrodotoxine, nifedipine, E4041 and 3R4S-Chromanol 293B. Moreover, simulations using our ventricular-like model suggest that the interplay of immature INa, If and IK1 currents has a fundamental role in the hiPSC-CM spontaneous beating whereas a negative shift in ICaL activation causes the observed long lasting AP. In conclusion, this work provides two novel tools useful in investigating the electrophysiological features of hiPSC-CMs, whose importance is growing fast as in-vitro models for pharmacological studies.

COR specifics

Two different model versions are avaible, respectively marked as Atrial and Ventricular in the Files section.

The Ventricular version includes a compartment for the simulation of a stimulus current injection and one for the simulation of the effect of current blockers.

To simulate the presence of stimulus current:

• the 'stim_flag' constant in the 'stim_mode' compartment needs to be set to 1.
• 'i_stim_Amplitude' sets the stimulus intensity expressed in Ampere
• 'i_stim_start' sets the current injection starting time in Seconds
• 'i_stim_end' sets the current injection stop time in Seconds
• 'i_stim_frequency' sets the number of stimulation pulses per minute (es. 60 means 1Hz stimulation)
• 'i_stim_PulseDuration' sets the pulse duration in Seconds

To simulate the effects of current blockers, one of the corresponding flags in the 'current_blockers' compatment need to be set to 1. Only one flag at time must be active.

NOTE: The default parameter values suggested by COR for numerical integration proved insufficient to get correct results from simulations when including stimulus current. Possible solutions are changing the Iterator from 'Newton' to 'Functional' or setting the Maximum Time Step to 0.05.