Modelling of the Short QT Syndrome Using Human Induced Pluripotent Stem Cells

Introduction: The congenital short QT syndrome (SQTS) is a familial arrhythmogenic syndrome caused by abnormal ion channel function leading to action-potential shortening and life-threatening arrhythmias and sudden cardiac death.

Aims: To establish a patient-specific hiPSC disease model of the congenital SQTS and to characterize the electrical properties of the generated patient-specific hiPSC cardiomyocytes at the single- and multi- cellular levels at baseline and following drug interventions.

Results: Patient/disease-specific hiPSC lines were established from a healthy individual and symptomatic SQTS patient carrying missense mutation (N588K) in the hERG gene, leading to gain of function in the rapidly activating delayed rectifier potassium currents (I_Kr). The SQTS-hiPSCs and healthy-control hiPSCs were coaxed to differentiate into cardiomyocytes. Whole cell patch clamp recordings revealed that the SQTS-hiPSC-CMs recapitulated the disease phenotype showing abbreviated action potential duration (198.2±15.5 ms) compared to healthy-control hiPSC-CMs (279.7±20.9 ms; p<0.05) at 1Hz pacing. Furthermore, the SQTS-hiPSC-CMs recapitulated the characteristic reduced rate adaptation of QT-interval noted in SQTS patients; with the healthy-control hiPSC-CMs showing steeper slope of action potential duration-pacing rate (-33.4±3.3 ms/Hz) when compared to the SQTS-hiPSC-CMs (-17.16±3.2 ms/Hz; p<0.05). As well, SQTS-hiPSC-CMs demonstrated shortened effective refractory period. Voltage clamp experiments revealed higher I_Kr currents in the SQTS-hiPSC-CMs compared to the healthy control cells. Additionally, microelectrode array recordings from the SQTS-hiPSC-derived cardiac-tissues revealed shortened field potential duration, which were normalized by addition of 1uM of Quinidine. Finally, optical mapping revealed the development of spontaneous stable reentrant activity (rotors) in cardiac myocyte monolayers derived from the SQTS-hiPSC-CMs

Conclusions: A novel hiPSC-based model of the SQTS was established. This model allowed recapitulating the disease phenotype (shortened action-potential, impaired rate adaptation, shortened effective refractory period, higher I_Kr density, and development of reentry) at the ionic-current, single-cell, and multicellular levels. The response to quinidine demonstrated the potential of the model for drug screening.