In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome

Lucia Romero, Beatriz Trenor, Pei Chi Yang, Javier Saiz, Colleen E Clancy

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)271-282
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume87
DOIs
StatePublished - Oct 1 2015

Fingerprint

Long QT Syndrome
Computer Simulation
Mutation
Action Potentials
Cardiac Arrhythmias
Pharmaceutical Preparations
Genetic Predisposition to Disease
Drug Interactions
Mutagenesis
Pharmacokinetics
Pharmacology
Phenotype
Therapeutics

Keywords

  • Computer modeling
  • Drug-induced arrhythmias
  • Drug-induced long-QT syndrome
  • Genetics
  • Mutations
  • Potassium channels

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome. / Romero, Lucia; Trenor, Beatriz; Yang, Pei Chi; Saiz, Javier; Clancy, Colleen E.

In: Journal of Molecular and Cellular Cardiology, Vol. 87, 01.10.2015, p. 271-282.

Research output: Contribution to journalArticle

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