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 IKr blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in IKr channel gating that would be expected to result from benign genetic variants. We used the model to predict the most 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 IKr channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of IKr channels. We then screened and identified the properties of IKr blockers that caused acquired long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant IKr 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 IKr-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the IKr 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.affiliation: Instituto de Investigación Interuniversitario en Bioingeniería y Tecnología Orientada al Ser Humano (I3BH), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain. Electronic address: lurope@eln.upv.es.
authors.forename: Lucia
authors.initials: L
authors.lastname: Romero
authors.affiliation: Instituto de Investigación Interuniversitario en Bioingeniería y Tecnología Orientada al Ser Humano (I3BH), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain. Electronic address: btrenor@eln.upv.es.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Trenor
authors.affiliation: Department of Pharmacology, University of California, Davis, Genome Building Rm 3503, Davis, CA 95616-8636, USA. Electronic address: pcyang@ucdavis.edu.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Instituto de Investigación Interuniversitario en Bioingeniería y Tecnología Orientada al Ser Humano (I3BH), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain. Electronic address: jsaiz@gbio.i3bh.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Saiz
authors.affiliation: Department of Pharmacology, University of California, Davis, Genome Building Rm 3503, Davis, CA 95616-8636, USA. Electronic address: ceclancy@ucdavis.edu.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D016589:Astemizole / Q000009:adverse effects; D020117:Cisapride / Q000009:adverse effects; D003198:Computer Simulation; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015233:Models, Statistical; D009154:Mutation; D010627:Phenethylamines / Q000009:adverse effects; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D024642:Potassium Channels, Voltage-Gated / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D012720:Severity of Illness Index; D013015:Sotalol / Q000009:adverse effects; D013449:Sulfonamides / Q000009:adverse effects; D016593:Terfenadine / Q000009:adverse effects
chemical_list: D000889:Anti-Arrhythmia Agents; C489619:KCNE2 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D016593:Terfenadine; D016589:Astemizole; D013015:Sotalol; C063533:dofetilide; D020117:Cisapride
keywords: Computer modeling; Drug-induced arrhythmias; Drug-induced long-QT syndrome; Genetics; Mutations; Potassium channels