In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome. (October 2015)

• Record Type: Journal Article
• Authors: Romero, Lucia; Trenor, Beatriz; Yang, Pei-Chi; Saiz, Javier; Clancy, Colleen E.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 87(2015:Oct.)
• Page Start: 271
• Page End: 282
• Publication Date: 2015-10
• Subjects: aLQTS drug-induced or acquired long-QT syndrome -- AP action potential -- APD action potential duration -- APD90 action potential duration at 90% repolarization -- C1 closed state 1 -- C2 closed state 2 -- C3 closed state 3 -- EAD early-afterdepolarization -- ECG electrocardiogram -- I inactivated state -- IKr rapid component of the delayed rectifier current -- LQTS long-QT syndrome -- O open state -- RFI recovery from inactivation -- TdP torsade de pointes -- WT wild-type -- Actilide_Oc drug binding simultaneously to both the open and closed states with lower affinity to the open state -- Inactilide_Oi drug binding simultaneously to both the open and inactivated states with lower affinity to the open state -- Actilide_Co drug binding simultaneously to both the closed and open states with lower affinity to the closed state -- Inactilide_Io drug binding simultaneously to both the inactivated and open states with lower affinity to the inactivated state; Mutations -- Drug-induced long-QT syndrome -- Drug-induced arrhythmias -- Computer modeling -- Potassium channels -- Genetics; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.08.015
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: A provocative test that can selectively differenciate IKr mutations has been proposed. Drugs with disparate affinities in the binding states of IKr channels are key for drug-induced LQT2. This mechanism could be adapted to selectively unmask mutations in other ionic channels. Defective deactivation of IKr plays a relevant role in drug-induced LQT2 and arrhythmias. A Markovian model of the M54T hMiRP1 mutation has been proposed.