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    ABSTRACT: The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the systems biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies.
    Full-text · Article · Feb 2014 · Pflügers Archiv - European Journal of Physiology
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    ABSTRACT: System level biological behaviour typically arises from highly dynamic, strongly nonlinear, tightly coupled interactions between component processes occurring across multiple space and time scales. The interdependent nature of these processes often makes it difficult to apply standard mathematical techniques to separate out the scales, uncouple the physical processes or average over contributions from discrete components. To make rapid progress we need to address interoperability challenges: to build integrated models from reusable components, and to relate simulation results to experimental data both for parameter fitting and model analysis. In this paper we describe how work we have done to address these issues in the domain of cardiac electrophysiology can be applied in a completely different field: multicellular models of intestinal crypts, with cells treated as discrete entities, and the sub-cellular, cellular, and tissue scales interacting. In this application the model and simulation are intertwined in software, with no suitable markup language model representation. Different modelling paradigms are available for each of the scales, and comparing their predictions is of particular interest. We use our concept of ‘functional curation’ to separate the experimental protocols applied to models from the model descriptions themselves, allowing easier comparison of model behaviour with experimental data. We also describe the use of ontological annotation for providing semantically rich model interfaces, facilitating coupling models to each other and to protocol descriptions. Finally, we show how these uses of semantic annotation and markup languages may be mixed incrementally with legacy code. This work suggests that the ideas we have developed have the potential to be useful across computational science, and we discuss these wider implications.
    Full-text · Article · Dec 2013 · Procedia Computer Science
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    ABSTRACT: A method to extract myocardial coronary permeabilities appropriate to parameterise a continuum porous perfusion model using the underlying anatomical vascular network is developed. Canine and porcine whole-heart discrete arterial models were extracted from high-resolution cryomicrotome vessel image stacks. Five parameterisation methods were considered that are primarily distinguished by the level of anatomical data used in the definition of the permeability and pressure-coupling fields. Continuum multi-compartment porous perfusion model pressure results derived using these parameterisation methods were compared quantitatively via a root-mean-square metric to the Poiseuille pressure solved on the discrete arterial vasculature. The use of anatomical detail to parameterise the porous medium significantly improved the continuum pressure results. The majority of this improvement was attributed to the use of anatomically-derived pressure-coupling fields. It was found that the best results were most reliably obtained by using porosity-scaled isotropic permeabilities and anatomically-derived pressure-coupling fields. This paper presents the first continuum perfusion model where all parameters were derived from the underlying anatomical vascular network.
    Full-text · Article · Dec 2013 · Annals of Biomedical Engineering
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