Cardiotoxicity assessment using 3D vascularized cardiac tissue consisting of human iPSC-derived cardiomyocytes and...

Area of Science:

• Cardiovascular Research
• Stem Cell Biology
• Drug Discovery and Development

Background:

• Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are valuable for cardiac safety assessment but have limitations in evaluating drug-induced contractility.
• Three-dimensional (3D) cardiac tissues mimic native tissue structure and are ideal for contractility assessment, but traditional methods require significant time and specialized equipment.
• A previously developed rapid method for generating 3D cardiac tissue by coating cell surfaces with extracellular matrix proteins offers a potential solution.

Purpose of the Study:

• To investigate the utility of the rapid 3D cardiac tissue model for the simultaneous evaluation of drug-induced repolarization and contractility.
• To assess the model's ability to detect the effects of various cardiovascular drugs with different mechanisms of action.

Main Methods:

• Development of a simplified 3D cardiac tissue model using extracellular matrix protein coating for rapid generation.
• Utilized cell motion imaging to examine the effects of multiple compounds on cardiac tissue contractility and waveform.
• Tested known human ether-a-go-go-related gene (HERG) channel blockers, positive inotropic drugs (ouabain, pimobendane), and negative inotropic drugs (verapamil).

Main Results:

• Human ether-a-go-go-related gene (HERG) channel blockers induced prolonged contraction-relaxation duration and arrhythmia-like waveforms, indicating arrhythmogenic risk.
• Positive inotropic agents increased maximum contraction speed (MCS) or average deformation distance (ADD) (e.g., ouabain 138% for MCS, pimobendane 132% for ADD).
• Negative inotropic agents, like verapamil, reduced both MCS and ADD (e.g., 61% reduction at 100 nM).

Conclusions:

• The rapid 3D cardiac tissue model effectively detected expected pharmacological effects of diverse cardiovascular drugs.
• This model shows significant promise for efficient and comprehensive cardiotoxicity evaluation in drug development.
• The model enables simultaneous assessment of drug-induced repolarization and contractility, addressing limitations of current hiPSC-CM assays.