title: In silico screening of the impact of hERG channel kinetic abnormalities on  channel block and susceptibility to acquired long QT syndrome.
abstract: Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of I(Kr) blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in I(Kr) channel gating that would be expected to result from benign genetic variants.Weused themodel to predict themost potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed “in silico mutagenesis” by altering discrete kinetic transition rates of the Fink et al. Markov model of human I(Kr) channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of I(Kr) channels. We then screened and identified the properties of I(Kr) blockers that caused acquired long QT and therefore unmasked mutant phenotypes formild,moderate and severe variants. Mutant I(Kr) channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of I(Kr)-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and I(Kr) mutated cells. Our results show that drugs with disparate affinities to conformation states of the I(Kr) channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical formulation of the M54T MiRP1 latent mutation and simulated a provocative test. In this setting, application of dofetilide dramatically amplified the predicted QT interval duration in the M54T hMiRP1 mutation compared to wild-type.
authors: Lucia
authors: L
authors: Romero
authors: Beatriz
authors: B
authors: Trenor
authors: Pei-Chi
authors: PC
authors: Yang
authors: Javier
authors: J
authors: Saiz
authors: Colleen E
authors: CE
authors: Clancy
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000235:genetics* / Q000473:pathology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000075224:Cardiac Conduction System Disease; D003198:Computer Simulation; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000235:genetics; D009154:Mutation
chemical_list: D051638:Ether-A-Go-Go Potassium Channels