title: Atrial proarrhythmia due to increased inward rectifier current (I(K1)) arising from KCNJ2 mutation--a simulation study.
abstract: Atrial fibrillation (AF) has been linked to increased inward rectifier potassium current, I(K1), either due to AF-induced electrical remodelling, or from functional changes due to the Kir2.1 V93I mutation. The aim of this simulation study was to identify at cell and tissue levels' mechanisms by which increased I(K1) facilitates and perpetuates AF. The Courtemanche et al. human atrial cell action potential (AP) model was modified to incorporate reported changes in I(K1) induced by the Kir2.1 V93I mutation in both heterozygous (Het) and homozygous (Hom) mutant forms. The modified models for wild type (WT), Het and Hom conditions were incorporated into homogeneous 1D, 2D and 3D tissue models. Restitution curves of AP duration (APD), effective refractory period (ERP) and conduction velocity (CV) were computed and both the temporal and the spatial vulnerability of atrial tissue to re-entry were measured. The lifespan and tip meandering pattern of re-entry were also characterised. For comparison, parallel simulations were performed by incorporating into the Courtmanche et al. model a linear increase in maximal I(K1) conductance. It was found that the gain-in-function of V93I 'mutant'I(K1) led to abbreviated atrial APs and flattened APD, ERP and CV restitution curves. It also hyperpolarised atrial resting membrane potential and slowed down intra-atrial conduction. V93I 'mutant'I(K1) reduced the tissue's temporal vulnerability but increased spatial vulnerability to initiate and sustain re-entry, resulting in an increased overall susceptibility of atrial tissue to arrhythmogenesis. In the 2D model, spiral waves self-terminated for WT (lifespan < 3.3 s) tissue, but persisted in Het and Hom tissues for the whole simulation period (lifespan > 10 s). The tip of the spiral wave meandered more in WT tissue than in Het and Hom tissues. Increased I(K1) due to augmented maximal conductance produced similar results to those of Het and Hom Kir2.1 V93I mutant conditions. In the 3D model the dynamic behaviour of scroll waves was stabilized by increased I(K1). In conclusion, increased I(K1) current, either by the Kir2.1 V93I mutation or by augmented maximal conductance, increases atrial susceptibility to arrhythmia by increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue, thereby facilitating initiation and maintenance of re-entrant circuits.
authors.affiliation: Biological Physics Group, The University of Manchester, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kharche
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Garratt
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boyett
authors.forename: Shin
authors.initials: S
authors.lastname: Inada
authors.forename: Arun V
authors.initials: AV
authors.lastname: Holden
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials; D000465:Algorithms; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D006325:Heart Atria / Q000473:pathology / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D021621:Imaging, Three-Dimensional; D008955:Models, Cardiovascular; D009154:Mutation; D032383:Myocytes, Cardiac / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology*
chemical_list: C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying