Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria

作者：Whittaker, Dominic G.; Ni, Haibo; El Harchi, Aziza; Hancox, Jules C.^*; Zhang, Henggui

来源：PLoS Computational Biology, 2017, 13(6): e1005593.

DOI：10.1371/journal.pcbi.1005593

• ACTION-POTENTIAL HETEROGENEITY
• PULMONARY VEIN CARDIOMYOCYTES
• IONIC MECHANISMS
• SINUS RHYTHM
• K+ CHANNEL
• MODEL
• FIBRILLATION
• CHLOROQUINE
• BLOCK
• REPOLARIZATION

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 I-K1 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 I-K1 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 I-K1 and I-Kr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas I-Kr block alone may be a safer alternative for the E299V mutation. Combined inhibition of I-Kr and produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhyth-mia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF.

• 出版日期2017-6
• 单位哈尔滨工业大学