Torsade De Pointes in a Dish - The 65th Annual Conference of the Israel Heart Society & The Israel Society of Cardiothoracic Surgery, 24-25 April 2018

Assad Shiti Physiology, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel Naim Shaheen Physiology, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel Irit Huber Physiology, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel Gil Arbil Physiology, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel Amira Gepstein Physiology, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel Lior Gepstein Physiology, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel

Background: Torsade de pointe (TdP) is a specific form of life-threatening polymorphic ventricular tachycardia occurring in the context of QT prolongation. TdP is the leading cause for withdrawal of already approved drugs from the market. Several recent studies have demonstrated the ability of human pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to detect action potential (AP) prolongation and early after depolarisations (EADs) – a perquisites for TdP development- in small cellular clusters. However, mapping the initiation and perpetuation of the arrhythmia at the tissue level is crucial to gain insights regarding TdP pathophysiology and management.

Objective: To establish a two-dimensional model derived from hiPSC-CMs to study the mechanisms underlying and the treatment of drug-induced TdP.

Methods and Results: Transgenic hiPSC line expressing a genetically encoded voltage indicator ArcLight was coaxed to differentiate into the cardiac lineage. Following cardiomyocyte differentiation, cell populations containing >85% cardiomyocytes were enzymatically dissociated and seeded as circular hiPSC-cardiac cell sheets (hiPSC-CS). The generated hiPSC-CS’ electrical activity was mapped using a customized optical mapping system, which also allowed revealing dofetilide (I_Kr blocker) effects on cardiac repolarization in a dose-response manner. Application of high-doses of dofetilide caused significant prolongation of the AP diffusely throughout the cardiac sheets that led to the development of EADs, which could cause triggered activity (TA) and this in turn could initiate re-entry that stabilizes as a spiral-wave. Administration of magnesium-sulphate supplementation was able to reverse AP prolongation caused by dofetilide and decrease the torsadogenic risk. Moreover, rapid pacing of the dofetilide-treated cardiac sheets was able to eliminate the generation of EADs and TA and thus the risk of arrhythmia development despite presence of long AP.

Conclusions: hiPSC-CS offer the ability to map and evaluate the consequences of torsadogenic drugs on the cardiac tissue, study TdP mechanisms and test novel chemical and electrical antiarrhythmic approaches.