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Quantitative prediction of the arrhythmogenic effects of de novo hERG mutations in computational models of human ventricular tissues

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Abstract

Mutations to hERG which result in changes to the rapid delayed rectifier current I Kr can cause long and short QT syndromes and are associated with an increased risk of cardiac arrhythmias. Experimental recordings of I Kr reveal the effects of mutations at the channel level, but how these changes translate to the cell and tissue levels remains unclear. We used computational models of human ventricular myocytes and tissues to predict and quantify the effects that de novo hERG mutations would have on cell and tissue electrophysiology. Mutations that decreased I Kr maximum conductance resulted in an increased cell and tissue action potential duration (APD) and a long QT interval on the electrocardiogram (ECG), whereas those that caused a positive shift in the inactivation curve resulted in a decreased APD and a short QT. Tissue vulnerability to re-entrant arrhythmias was correlated with transmural dispersion of repolarisation, and any change to this vulnerability could be inferred from the ECG QT interval or T wave peak-to-end time. Faster I Kr activation kinetics caused cell APD alternans to appear over a wider range of pacing rates and with a larger magnitude, and spatial heterogeneity in these cellular alternans resulted in discordant alternans at the tissue level. Thus, from channel kinetic data, we can predict the tissue-level electrophysiological effects of any hERG mutations and identify how the mutation would manifest clinically, as either a long or short QT syndrome with or without an increased risk of alternans and re-entrant arrhythmias.

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Abbreviations

APD:

Action potential duration

cNBD:

Cyclic nucleotide binding domain

ECG:

Electrocardiogram

hERG:

Human ether-a-go-go-related gene

I Kr :

Rapid delayed rectifier potassium current

LQTS:

Long QT syndrome

M:

Midmyocardial

PAS:

Per-Arnt-Sim

SQTS:

Short QT syndrome

TDR:

Transmural dispersion of repolarisation

VF:

Ventricular fibrillation

WT:

Wild type

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Acknowledgments

This work was supported by the European Union through the BioSim Network of Excellence (contract number LSHB-CT-2004-005137). A.P.B. is supported by a Medical Research Council special training fellowship in biomedical informatics (G0701776). We acknowledge Professor Denis Wray (deceased), who initiated the research presented in this paper with support from the British Heart Foundation.

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Authors and Affiliations

  1. Institute of Membrane & Systems Biology, and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK

    Alan P. Benson & Arun V. Holden

  2. Division of Cardiovascular & Neuronal Remodelling, and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK

    Moza Al-Owais

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  1. Alan P. Benson
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  2. Moza Al-Owais
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Correspondence to Alan P. Benson.

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A. P. Benson and M. Al-Owais have contributed equally to this work.

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Benson, A.P., Al-Owais, M. & Holden, A.V. Quantitative prediction of the arrhythmogenic effects of de novo hERG mutations in computational models of human ventricular tissues. Eur Biophys J 40, 627–639 (2011). https://doi.org/10.1007/s00249-010-0663-2

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  • DOI: https://doi.org/10.1007/s00249-010-0663-2

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