Fig. 2
From: Learning from studying very rare cardiac conditions: the example of short QT syndrome
A schematic diagram of the main pro-arrhythmic mechanisms of the N588K-hERG short QT syndrome (SQTS) mutation identified by experiments and modelling. The upper panel shows experimental voltage and action potential (AP) clamp characterisations of wild type (WT) and N588K mutant hERG currents at the ion channel level. The N588K mutation was found to increase greatly the current over the physiological range of membrane potentials due to impaired inactivation [43] causing increased maximal IhERG to occur earlier during a simulated human ventricular AP waveform [148]. These changes were integrated into a mathematical models of the human ventricular AP in which the N588K mutation was shown to shorten the action potential duration (APD) whilst increasing the transmural dispersion of repolarisation (TDR) across the ventricular wall [67, 132]. At the tissue level this had the effect of shortening the QT interval whilst increasing the amplitude of the T wave, as has been observed clinically in SQTS patients. When integrated into a human left ventricular wedge model with realistic geometry, the combined pro-arrhythmic substrate of shortened AP with increased heterogeneity of repolarisation due to the N588K-hERG mutation rendered ventricular tachycardia/fibrillation (VT/VF) inducible. Modified with permission from [132]