title: Quantitative prediction of the arrhythmogenic effects of de novo hERG mutations in computational models of human ventricular tissues.
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.
authors.affiliation: Institute of Membrane & Systems Biology, and Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK. a.p.benson@leeds.ac.uk
authors.forename: Alan P
authors.initials: AP
authors.lastname: Benson
authors.forename: Moza
authors.initials: M
authors.lastname: Al-Owais
authors.forename: Arun V
authors.initials: AV
authors.lastname: Holden
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D003198:Computer Simulation; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009712:Nucleotides, Cyclic / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009712:Nucleotides, Cyclic