title: Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2.
abstract: The heart rhythm disorder long QT syndrome (LQTS) can result in sudden death in the young or remain asymptomatic into adulthood. The features of the surface electrocardiogram (ECG), a measure of the electrical activity of the heart, can be equally variable in LQTS patients, posing well-described diagnostic dilemmas. Here we report a correlation between QT interval prolongation and T-wave notching in LQTS2 patients and use a novel computational framework to investigate how individual ionic currents, as well as cellular and tissue level factors, contribute to notched T waves. Furthermore, we show that variable expressivity of ECG features observed in LQTS2 patients can be explained by as little as 20% variation in the levels of ionic conductances that contribute to repolarization reserve. This has significant implications for interpretation of whole-genome sequencing data and underlies the importance of interpreting the entire molecular signature of disease in any given individual.
authors.affiliation: 1] Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Arash
authors.initials: A
authors.lastname: Sadrieh
authors.affiliation: CSIRO eResearch and Computational and Simulation Sciences, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Domanski
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Pitt-Francis
authors.affiliation: 1] Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Mann
authors.affiliation: 1] Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Hodkinson
authors.affiliation: 1] Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Chai-Ann
authors.initials: CA
authors.lastname: Ng
authors.affiliation: 1] Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Perry
authors.affiliation: CSIRO eResearch and Computational and Simulation Sciences, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Taylor
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Gavaghan
authors.affiliation: 1] Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Rajesh N
authors.initials: RN
authors.lastname: Subbiah
authors.affiliation: 1] Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.affiliation: 1] Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Hill
mesh_terms: D015716:Electrocardiography, Ambulatory; D005838:Genotype; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*