Modeling ventricular tachycardia in genetic long QT syndrome using engineered cardiac tissues

Richard Z. Zhuang, Georgia Doufexi, Marc Yehya, Margaretha A.J. Morsink, Xianghai Liao, Manu Ben-Johny, Gordana Vunjak-Novakovic

Congenital long QT syndrome (LQTS) predisposes patients to malignant ventricular tachycardias, yet existing in vitro models do not fully capture the clinical arrhythmic phenotypes that determine patient outcomes. We report the development of an engineered platform with mature, fully hiPSC-derived human cardiac tissues that reproduces genotype-specific ventricular tachycardia under physiologically relevant triggers. Using patient-derived and corrected hiPSCs, we engineered electromechanically matured cardiac tissues to model LQT8 and LQT2 syndromes. LQT8 tissues exhibited spontaneous early afterdepolarizations and sustained tachycardia, including monomorphic, polymorphic, and torsades de pointes-like waveforms. In contrast, LQT2 tissues remained stable under constant pacing but developed arrhythmias during dynamic rate acceleration, mirroring clinical trigger-dependent arrhythmogenicity. Frequency-domain analysis and activation mapping revealed re-entrant dynamics consistent with ventricular tachycardia-like activity. By unifying cellular-level electrophysiology with tissue-scale ECG-like arrhythmic activity, this platform enables physiologically inspired investigation of arrhythmogenic mechanisms in inherited arrhythmia syndromes.