Human induced pluripotent stem cell-derived closed-loop cardiac tissue for drug assessment

Area of Science:

• Cardiovascular Science
• Biomedical Engineering
• Drug Discovery

Background:

• Human iPSC-derived cardiomyocytes (hiPSC-CMs) display functional immaturity, limiting their use in drug proarrhythmic potential assessment.
• Previous traveling wave (TW) systems matured 3D cardiac tissue, but 2D models are needed for current drug testing paradigms.

Purpose of the Study:

• To develop a 2D cardiac tissue model for enhanced maturation of hiPSC-CMs.
• To integrate a TW system with a multi-electrode array for spontaneous wave initiation and pacing.
• To evaluate the utility of this system in assessing drug proarrhythmic potential.

Main Methods:

• Integration of a TW system with a multi-electrode array to create hiPSC-derived closed-loop cardiac tissue (iCT).
• Spontaneous TW initiation and rapid pacing of hiPSC-CMs from various cell lines.
• Assessment of cardiomyocyte maturation (sarcomeric and functional) and drug response.

Main Results:

• TW-paced hiPSC-CMs showed heightened sarcomeric and functional maturation, with an enhanced response to isoproterenol.
• Cells exhibited reduced sensitivity to verapamil and maintained low arrhythmia rates with ranolazine.
• Increased arrhythmia rates were observed with high/intermediate risk TdP drugs (quinidine, pimozide), validating the model's predictive capability.

Conclusions:

• The developed iCT system effectively promotes hiPSC-CM maturation in a 2D monolayer format.
• This system shows significant potential for accurate drug proarrhythmic risk assessment, aligning with CiPA and JiCSA guidelines.
• The model's ability to differentiate responses to various TdP-risk drugs highlights its utility in preclinical safety evaluations.