Congenital Short QT Syndrome (SQTS) is a rare but dangerous condition involving abbreviated ventricular repolarization and an increased risk of atrial and ventricular arrhythmias. Taking the example of the first identified SQTS mutation, N588K-hERG, we consider briefly the basic science approaches used to obtain an understanding of the mechanism(s) of arrhythmogenesis in this form of the syndrome. A combination of recombinant channel electrophysiology and in silico simulations has provided insights into causality between the identified mutation, accelerated repolarization and increased susceptibility to re-entry in N588K-hERG-linked SQTS. Subsequent studies employing a transgenic rabbit model or human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) have further demonstrated mechanisms predisposing to re-entry, spiral wave activity and arrhythmia in intact tissue. The complementarity between the findings made using these different approaches gives confidence that, collectively, they have identified major arrhythmia mechanisms and their potential mitigation by Class I antiarrhythmic drugs in this form of SQTS.
- potassium channel
- short QT syndrome