Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling.
OBJECTIVE
One form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K(+) current (I(K1)). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias.


RESULTS
The ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to I(K1) based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N 'mutant' I(K1) led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 'mutant' I(K1) also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry.


CONCLUSIONS
Increased I(K1) due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits.
Biological Physics Group,  School of Physics and Astronomy, The University of Manchester, Manchester M60 1QD,  UK.
Ismail
I
Adeniran
Aziza
A
El Harchi
Jules C
JC
Hancox
Henggui
H
Zhang
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016466:CHO Cells; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008955:Models, Cardiovascular; D009154:Mutation; D018408:Patch-Clamp Techniques; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying