Human-engineered heart tissues recapitulate tissue-scale mechanisms underlying ventricular tachycardia

Area of Science:

• Cardiovascular Research
• Biomedical Engineering
• Arrhythmology

Background:

• Human induced pluripotent stem cell-derived engineered heart tissues (EHTs) are valuable for modeling cardiac physiology and drug responses.
• Assessing tissue-scale mechanisms of ventricular arrhythmias in EHTs has been limited by inadequate electrophysiological recording frameworks.

Purpose of the Study:

• To develop and validate a high-resolution optical mapping workflow for characterizing electrophysiology in perfused EHTs.
• To investigate the tissue-scale mechanisms of ventricular tachycardia (VT) in EHTs using a proarrhythmic perturbation model.

Main Methods:

• Fabrication of EHTs using milliPillar technology.
• High-resolution (22 µm spatial, 1 ms temporal) dual-channel optical mapping of voltage (RH-237) and calcium (Rhod-2 AM).
• Application of a proarrhythmic perturbation (hERG inhibition, hypokalemia, hypomagnesemia) to induce VT-like activity.

Main Results:

• The platform successfully reproduced baseline cardiac electrophysiology, including rate-dependent restitution and conduction properties.
• Treated EHTs exhibited VT mechanisms: APD dispersion, long-short APD zones, triggered activity, conduction block, wavebreak, and reentry.
• Phase singularity tracking identified rotors, characteristic of VT, in treated EHTs.

Conclusions:

• Human iPSC-derived EHTs, coupled with advanced optical mapping, can recapitulate key tissue-scale mechanisms of VT associated with acquired long QT syndrome.
• This scalable, non-animal platform provides a powerful tool for mechanistic arrhythmia research and drug screening.