A mathematical model of hiPSC cardiomyocytes electromechanics
Mohamadamin Forouzandehmehr1, Jussi T Koivumäki1, Jari Hyttinen1
1Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Insights
We developed a novel computational model, hiPSC-CM-CE, for human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This model accurately simulates cardiac electrophysiology and contractility, aiding cardiotoxicity testing and personalized medicine.
Area of Science:
- Cardiovascular Research
- Computational Biology
- Biomedical Engineering
Background:
- Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are crucial for cardiac research and drug testing.
- Accurate modeling of hiPSC-CMs is needed to understand their electromechanical behavior.
- Existing models may not fully capture the complex contractility of hiPSC-CMs.
Purpose of the Study:
- To introduce a novel electromechanical computational model, hiPSC-CM-CE, for hiPSC-CMs.
- To integrate a new passive force formulation with existing hiPSC-CM electrophysiology.
- To validate the model's predictive capabilities against experimental data.
Main Methods:
- Reparameterization of the contractile element (CE) model by Rice et al. (2008).
- Integration of a new passive force formulation into the CE.
- Incorporation of the modified CE into the hiPSC-CM electrophysiology model by Paci et al. (2020).
- Validation against in vitro data for action potential, calcium transient, cell shortening, and tension.
Main Results:
- The hiPSC-CM-CE model accurately simulated key action potential and calcium transient biomarkers within experimental ranges.
- Simulated cell shortening, contraction-relaxation kinetics, and tension amplitude matched in vitro data.
- The model correctly predicted inotropic effects and simulated drug responses (Verapamil, Bay-K 8644) and aftercontractions.
Conclusions:
- The hiPSC-CM-CE model provides a validated platform for studying hiPSC-CM electromechanical function.
- The model's passive force formulation enhances its ability to predict inter-scale effects.
- Future applications include pharmacological trials, genetic mutation studies, and arrhythmia research.
Abstract:
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are becoming instrumental in cardiac research, human-based cell level cardiotoxicity tests, and developing patient-specific care. As one of the principal functional readouts is contractility, we propose a novel electromechanical hiPSC-CM computational model named the hiPSC-CM-CE. This model comprises a reparametrized version of contractile element (CE) by Rice et al., 2008, with a new passive force formulation, integrated into a hiPSC-CM electrophysiology formalism by Paci et al. in 2020. Our simulated results were validated against in vitro data reported for hiPSC-CMs at matching conditions from different labs. Specifically, key action potential (AP) and calcium transient (CaT) biomarkers simulated by the hiPSC-CM-CE model were within the experimental ranges. On the mechanical side, simulated cell shortening, contraction-relaxation kinetic indices (RT50 and RT25 ), and the amplitude of tension fell within the experimental intervals. Markedly, as an inter-scale analysis, correct classification of the inotropic effects due to non-cardiomyocytes in hiPSC-CM tissues was predicted on account of the passive force expression introduced to the CE. Finally, the physiological inotropic effects caused by Verapamil and Bay-K 8644 and the aftercontractions due to the early afterdepolarizations (EADs) were simulated and validated against experimental data. In the future, the presented model can be readily expanded to take in pharmacological trials and genetic mutations, such as those involved in hypertrophic cardiomyopathy, and study arrhythmia trigger mechanisms.
