title: Arrhythmic potency of human ether-a-go-go-related gene mutations L532P and N588K in a computational model of human atrial myocytes.
abstract: OBJECTIVE
  Human ether-à-go-go-related gene (hERG) missense mutations N588K and L532P are both associated with atrial fibrillation (AF). However, the underlying gain-of-function mechanism is different. The aim of this computational study is to assess and understand the arrhythmogenic mechanisms of these genetic disorders on the cellular and tissue level as a basis for the improvement of therapeutic strategies.
  
  
  RESULTS
  The IKr formulation of an established model of human atrial myocytes was adapted by using the measurement data of wild-type and mutant hERG channels. Restitution curves of the action potential duration and its slope, effective refractory period (ERP), conduction velocity, reentry wavelength (WL), and the vulnerable window (VW) were determined in a one-dimensional (1D) tissue strand. Moreover, spiral wave inducibility and rotor lifetime in a 2D tissue patch were evaluated. The two mutations caused an increase in IKr regarding both peak amplitude and current integral, whereas the duration during which IKr is active was decreased. The WL was reduced due to a shorter ERP. Spiral waves could be initiated by using mutation models as opposed to the control case. The frequency dependency of the VW was reversed.
  
  
  CONCLUSIONS
  Both mutations showed an increased arrhythmogenicity due to decreased refractory time in combination with a more linear repolarization phase. The effects were more pronounced for mutation L532P than for N588K. Furthermore, spiral waves presented higher stability and a more regular pattern for L532P. These in silico investigations unveiling differences of mutations affecting the same ion channel may help to advance genotype-guided AF prevention and therapy strategies.
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Kaiserstr. 12, 76131 Karlsruhe, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Loewe
authors.forename: Mathias
authors.initials: M
authors.lastname: Wilhelms
authors.forename: Fathima
authors.initials: F
authors.lastname: Fischer
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
authors.forename: Olaf
authors.initials: O
authors.lastname: Dössel
authors.forename: Gunnar
authors.initials: G
authors.lastname: Seemann
mesh_terms: D000200:Action Potentials / Q000235:genetics; D001281:Atrial Fibrillation / Q000503:physiopathology*; D003198:Computer Simulation; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D006325:Heart Atria / Q000503:physiopathology*; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D008564:Membrane Potentials / Q000235:genetics; D008955:Models, Cardiovascular; D008957:Models, Genetic; D032342:Muscle Cells; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human
keywords: Atrial fibrillation; Channelopathy; Mathematical model; Repolarization; hERG channels