In virtual human atria models, D172N and E299V KCNJ2 mutations decreased the wavelength for re-entry through reduced effective refractory period and conduction velocity, promoting atrial arrhythmogenesis.
Does simulated ion channel block (IK1, IKr, IKur) terminate re-entry in virtual human atria models of SQT3 KCNJ2 mutations?
Computational modeling reveals that targeted ion channel blockade, particularly combined IKr and IKur inhibition, may offer a synergistic anti-arrhythmic strategy for managing atrial fibrillation in patients with SQT3-linked KCNJ2 mutations.
Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF.
Whittaker et al. (Tue,) conducted a other in Short QT syndrome variant 3 (SQT3) and Atrial Fibrillation. Simulated KCNJ2 mutations (D172N and E299V) and ion channel block vs. Wild-type (WT) conditions was evaluated on Action potential duration, conduction velocity, effective refractory period, and wavelength of re-entry. In virtual human atria models, D172N and E299V KCNJ2 mutations decreased the wavelength for re-entry through reduced effective refractory period and conduction velocity, promoting atrial arrhythmogenesis.
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