ORCID Profile
0000-0001-6361-3339
Current Organisation
University of Oxford
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Numerical Solution of Differential and Integral Equations | Numerical Analysis | Numerical and Computational Mathematics |
Publisher: Wiley
Date: 10-11-2019
DOI: 10.1002/CPT.1647
Publisher: Public Library of Science (PLoS)
Date: 20-02-2013
Publisher: Elsevier BV
Date: 2015
Publisher: American Physiological Society
Date: 05-2018
DOI: 10.1152/AJPHEART.00477.2017
Abstract: Variability refers to differences in physiological function between in iduals, which may translate into different disease susceptibility and treatment efficacy. Experiments in human cardiomyocytes face wide variability and restricted tissue access under these conditions, computational models are a useful complementary tool. We conducted a computational and experimental investigation in cardiomyocytes isolated from s les of the right atrial appendage of patients undergoing cardiac surgery to evaluate the impact of variability in action potentials (APs) and subcellular ionic densities on Ca 2+ transient dynamics. Results showed that 1) variability in APs and ionic densities is large, even within an apparently homogenous patient cohort, and translates into ±100% variation in ionic conductances 2) experimentally calibrated populations of models with wide variations in ionic densities yield APs overlapping with those obtained experimentally, even if AP characteristics of the original generic model differed significantly from experimental APs 3) model calibration with AP recordings restricts the variability in ionic densities affecting upstroke and resting potential, but redundancy in repolarization currents admits substantial variability in ionic densities and 4) model populations constrained with experimental APs and ionic densities exhibit three Ca 2+ transient phenotypes, differing in intracellular Ca 2+ handling and Na + /Ca 2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology. NEW & NOTEWORTHY Variability in human atrial electrophysiology is investigated by integrating for the first time cellular-level and ion channel recordings in computational electrophysiological models. Ion channel calibration restricts current densities but not cellular phenotypic variability. Reduced Na + /Ca 2+ exchanger is identified as a primary mechanism underlying diastolic Ca 2+ fluctuations in human atrial myocytes.
Publisher: IEEE
Date: 08-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-01-2016
DOI: 10.1161/CIRCRESAHA.115.307836
Abstract: Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors. To characterize in vivo RA in human and to investigate in silico using human models, the ionic mechanisms underlying the frequency-dependent differences in RA behavior identified in vivo. In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600–350 ms). In silico investigations were conducted using a population of biophysically detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, 2 types of RA were identified, with Fork- and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show that RA are strongly correlated with fluctuations in sarcoplasmic reticulum calcium, because of strong release and weak reuptake. Large L-type calcium current conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type versus Fork-type P .01), because of sarcoplasmic reticulum Ca 2+ ATPase pump potentiation caused by frequency-induced increase in intracellular calcium. Large Na + /Ca 2+ exchanger current is the main driver in translating Ca 2+ fluctuations into RA. In human in vivo and in silico, 2 types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, L-type calcium current and Na + /Ca 2+ exchanger current determine RA human cell-to-cell differences through intracellular and sarcoplasmic reticulum calcium regulation.
Publisher: IEEE
Date: 08-2010
Publisher: Public Library of Science (PLoS)
Date: 28-02-2014
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 12-2011
Publisher: Elsevier BV
Date: 04-2020
Publisher: American Physiological Society
Date: 15-07-2012
DOI: 10.1152/AJPHEART.01151.2011
Abstract: Computational models in physiology often integrate functional and structural information from a large range of spatiotemporal scales from the ionic to the whole organ level. Their sophistication raises both expectations and skepticism concerning how computational methods can improve our understanding of living organisms and also how they can reduce, replace, and refine animal experiments. A fundamental requirement to fulfill these expectations and achieve the full potential of computational physiology is a clear understanding of what models represent and how they can be validated. The present study aims at informing strategies for validation by elucidating the complex interrelations among experiments, models, and simulations in cardiac electrophysiology. We describe the processes, data, and knowledge involved in the construction of whole ventricular multiscale models of cardiac electrophysiology. Our analysis reveals that models, simulations, and experiments are intertwined, in an assemblage that is a system itself, namely the model-simulation-experiment (MSE) system. We argue that validation is part of the whole MSE system and is contingent upon 1) understanding and coping with sources of biovariability 2) testing and developing robust techniques and tools as a prerequisite to conducting physiological investigations 3) defining and adopting standards to facilitate the interoperability of experiments, models, and simulations 4) and understanding physiological validation as an iterative process that contributes to defining the specific aspects of cardiac electrophysiology the MSE system targets, rather than being only an external test, and that this is driven by advances in experimental and computational methods and the combination of both.
Publisher: Elsevier BV
Date: 09-2020
Publisher: The Royal Society
Date: 28-08-2010
Abstract: Cardiac electrophysiology is a mature discipline, with the first model of a cardiac cell action potential having been developed in 1962. Current models range from single ion channels, through very complex models of in idual cardiac cells, to geometrically and anatomically detailed models of the electrical activity in whole ventricles. A critical issue for model developers is how to choose parameters that allow the model to faithfully reproduce observed physiological effects without over-fitting. In this paper, we discuss the use of a parametric modelling toolkit, called N imrod , that makes it possible both to explore model behaviour as parameters are changed and also to tune parameters by optimizing model output. Importantly, N imrod leverages computers on the Grid, accelerating experiments by using available high-performance platforms. We illustrate the use of N imrod with two case studies, one at the cardiac tissue level and one at the cellular level.
Publisher: Elsevier BV
Date: 2016
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000382140
Publisher: Springer Science and Business Media LLC
Date: 02-06-2010
DOI: 10.1038/CLPT.2010.95
Abstract: Side effects account for most of the instances of failure of candidate drugs at late stages of development. These development failures contribute to the exorbitant cost of bringing new compounds to market: a single withdrawal can represent a loss of more than $1 billion. Many unwanted actions of drugs affect the heart, resulting in potentially proarrhythmic alteration of ion channel function. Because these can be fatal, potential electrophysiological cardiotoxicity is among the most stringent exclusion criteria in the licensing process.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-01-2018
Abstract: We describe a statistically informed calibration of in silico populations to explore variability in complex systems.
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 08-2022
End Date: 08-2025
Amount: $396,000.00
Funder: Australian Research Council
View Funded Activity