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Short QT syndrome (SQTS) is a new congenital and heterozygous entity associated with familial atrial and/or ventricular fibrillation. Electrocardiographically, it is characterized by a shortened QT interval of less than 320 ms. However, to our knowledge, ionic mechanisms underlying cardiac arrhythmias of SQTS are incompletely understood. One form of the SQTS (SQT3) has been linked to a new gain-in-function mutation (KCNJ2 M301K), which results in larger outward currents than through Kir2.1 channels responsible for inward rectifier potassium current (IK1). Therefore, this study used computational modelling to investigate mechanism by which the KCNJ2 M301K mutation facilitates and perpetuates ventricular arrhythmias.
The mathematical model developed by ten Tusscher et al. for human ventricular actin potentials (APs) was modified to incorporate the channel kinetics of M301K mutation to Kir2.1 function based on experimentally observed data: both wild-type (WT) and heterozygous (WT-M301K) scenarios were studied. Cell models were incorporated into one-dimensional (1D) and 2D models with transmural heterogeneities to compute the pseudo-ECG. Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behavior of re-entrant excitation waves was characterized.
Incorporating the M301K mutation into 1D simulations reproduced defining feature of the SQTS: abbreviation of the QT interval (from 363 ms in the WT condition to 292 ms in the WT-M301K condition), and increases in T wave amplitude. In the single-cell model, the M301K mutant IK1 led to abbreviated ventricular cell AP duration at 90% repolarization (APD90) (from 302 ms for ENDO cells in the WT condition to 250 ms in the WT-M301K condition). In the tissue simulation, the M301K mutant IK1 increased tissue temporal vulnerability of initiating re-entry, but reduced the minimum substrate size necessary to sustain re-entry. It also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry.
KCNJ2 M301K mutation in SQT3 abbreviated APD90 and increased vulnerable window for unidirectional conduction block, which generates an electrical substrate favorable to ventricular re-entrant arrhythmia.