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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.
    Pflügers Archiv - European Journal of Physiology 02/2014; 466(2):183-193.
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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.
    Annals of Biomedical Engineering 12/2013;
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    ABSTRACT: Cardiac imaging is routinely used to evaluate cardiac tissue properties prior to therapy. By integrating the structural information with electrophysiological data from e.g. electroanatomical mapping systems, knowledge of the properties of the cardiac tissue can be further refined. However, as in other clinical modalities, electrophysiological data are often sparse and noisy, and this results in high levels of uncertainty in the estimated quantities. In this study, we develop a methodology based on Bayesian inference, coupled with a computationally efficient model of electrical propagation to achieve two main aims: (1) to quantify values and associated uncertainty for different tissue conduction properties inferred from electroanatomical data, and (2) to design strategies to optimize the location and number of measurements required to maximize information and reduce uncertainty. The methodology is validated in an in silico study performed using simulated data obtained from a human image-based ventricular model, including realistic fibre orientation and a transmural scar. We demonstrate that the method provides a simultaneous description of clinically-relevant electrophysiological conduction properties and their associated uncertainty for various levels of noise. By using the developed methodology to investigate how the uncertainty decreases in response to added measurements, we then derive an a priori index for placing electrophysiological measurements in order to optimize the information content of the collected data. Results show that the derived index has a clear benefit in minimizing the uncertainty of inferred conduction properties compared to a random distribution of measurements, reducing the number of required measurements by over 50% in several of the investigated settings. This suggests that the methodology presented in this work provides an important step towards improving the quality of the spatiotemporal information obtained using electroanatomical mapping.
    Medical image analysis 10/2013; 18(1):228-240.
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    ABSTRACT: The diastolic function (i.e., blood filling) of the left ventricle (LV) is determined by its capacity for relaxation, or the decay in residual active tension (AT) generated during systole, and its constitutive material properties, or myocardial stiffness. The clinical determination of these two factors (diastolic residual AT and stiffness) is thus essential for assessing LV diastolic function. To quantify these two factors, in our previous work, a novel model-based parameter estimation approach was proposed and successfully applied to multiple cases using clinically acquired motion and invasively measured ventricular pressure data. However, the need to invasively acquire LV pressure limits the wide application of this approach. In this study, we address this issue by analyzing the feasibility of using two kinds of non-invasively available pressure measurements for the purpose of inverse mechanical parameter estimation. The prescription of pressure based on a generic pressure-volume (P-V) relationship reported in literature is first evaluated in a set of 18 clinical cases (10 healthy and 8 diseased), finding reasonable results for stiffness but not for residual active tension. We then investigate the use of non-invasive pressure measures, now available through imaging techniques and limited by unknown or biased offset values. Specifically, three sets of physiologically realistic synthetic data with three levels of diastolic residual active tension (i.e., impaired relaxation capability) are designed to quantify the percentage error in the parameter estimation against the possible pressure offsets within the physiological limits. Maximum errors are quantified as 11 % for the magnitude of stiffness and 22 % for AT, with averaged 0.17 kPa error in pressure measurement offset using the state-of-the-art non-invasive pressure estimation method. The main cause for these errors is the limited temporal resolution of clinical imaging data currently available. These results demonstrate the potential feasibility of the estimation diastolic biomarkers with non-invasive assessment of pressure through medical imaging data.
    Biomechanics and Modeling in Mechanobiology 10/2013;
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    ABSTRACT: Cellular and ionic causes of variability in the electrophysiological activity of hearts from individuals of the same species are unknown. However, improved understanding of this variability is key to enable prediction of the response of specific hearts to disease and therapies. Limitations of current mathematical modeling and experimental techniques hamper our ability to provide insight into variability. Here, we describe a methodology to unravel the ionic determinants of intersubject variability exhibited in experimental recordings, based on the construction and calibration of populations of models. We illustrate the methodology through its application to rabbit Purkinje preparations, because of their importance in arrhythmias and safety pharmacology assessment. We consider a set of equations describing the biophysical processes underlying rabbit Purkinje electrophysiology, and we construct a population of over 10,000 models by randomly assigning specific parameter values corresponding to ionic current conductances and kinetics. We calibrate the model population by closely comparing simulation output and experimental recordings at three pacing frequencies. We show that 213 of the 10,000 candidate models are fully consistent with the experimental dataset. Ionic properties in the 213 models cover a wide range of values, including differences up to ±100% in several conductances. Partial correlation analysis shows that particular combinations of ionic properties determine the precise shape, amplitude, and rate dependence of specific action potentials. Finally, we demonstrate that the population of models calibrated using data obtained under physiological conditions quantitatively predicts the action potential duration prolongation caused by exposure to four concentrations of the potassium channel blocker dofetilide.
    Proceedings of the National Academy of Sciences 05/2013;
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    ABSTRACT: This paper discusses the need for interconnecting computational cancer models from different sources and scales within clinically relevant scenarios to increase the accuracy of the models and speed up their clinical adaptation, validation, and eventual translation. We briefly review current interoperability efforts drawing upon our experiences with the development of in silico models for predictive oncology within a number of European Commission Virtual Physiological Human initiative projects on cancer. A clinically relevant scenario, addressing brain tumor modeling that illustrates the need for coupling models from different sources and levels of complexity, is described. General approaches to enabling interoperability using XML-based markup languages for biological modeling are reviewed, concluding with a discussion on efforts towards developing cancer-specific XML markup to couple multiple component models for predictive in silico oncology.
    Cancer informatics 05/2013; 12:115-124.
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    ABSTRACT: INTRODUCTION: Unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for pharmaceutical safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the development of automated and high-throughput screening assays using cell lines. As a result of screening multiple ion-channels there is a need to integrate information, particularly for compounds affecting more than one current, and mathematical electrophysiology in-silico action potential models are beginning to be used for this. METHODS: We quantified the variability associated with concentration-effect curves fitted to recordings from high-throughput Molecular Devices IonWorks® Quattro™ screens when detecting block of trmIKr (hERG), INa (NaV1.5), ICaL (CaV1.2), IKs (KCNQ1/minK) and Ito (Kv4.3/KChIP2.2), and the Molecular Devices FLIPR® Tetra fluorescence screen for ICaL (CaV1.2), for control compounds used at AstraZeneca and GlaxoSmithKline. We examined how screening variability propagates through in-silico action potential models for whole cell electrical behaviour, and how confidence intervals on model predictions can be estimated with repeated simulations. RESULTS: There are significant levels of variability associated with high-throughput ion channel electrophysiology screens. This variability is of a similar magnitude for different cardiac ion currents and different compounds. Uncertainty in the Hill coefficients of reported concentration-effect curves is particularly high. Depending on a compound's ion channel blocking profile, the uncertainty introduced into whole-cell predictions can become significant. DISCUSSION: Our technique allows confidence intervals to be placed on computational model predictions that are based on high-throughput ion channel screens. This allows us to suggest when repeated screens should be performed to reduce uncertainty in a compound's action to acceptable levels, to allow a meaningful interpretation of the data.
    Journal of pharmacological and toxicological methods 05/2013;
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    ABSTRACT: We investigate the complexity of model checking (finite) interval-valued discrete time Markov chains, that is, discrete time Markov chains where each transition is associated with an interval in which the actual transition probability must lie. Two semantics are considered, the uncertain Markov chain (UMC) semantics and the interval Markov decision process (IMDP) semantics. We show that, for reachability, these two semantics coincide and the problem is P-complete. This entails that PCTL model checking problem under the IMDP semantics is also P-complete. We also show that model checking PCTL under the UMC semantics is Square-Root-Sum hard, meaning that one can reduce the Square-Root-Sum problem to it.
    Information Processing Letters 04/2013; 113(7):210–216.
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    ABSTRACT: The development of new models of biological tissues that consider cells in a discrete manner is becoming increasingly popular as an alternative to continuum methods based on partial differential equations, although formal relationships between the discrete and continuum frameworks remain to be established. For crystal mechanics, the discrete-to-continuum bridge is often made by assuming that local atom displacements can be mapped homogeneously from the mesoscale deformation gradient, an assumption known as the Cauchy-Born rule (CBR). Although the CBR does not hold exactly for noncrystalline materials, it may still be used as a first-order approximation for analytic calculations of effective stresses or strain energies. In this work, our goal is to investigate numerically the applicability of the CBR to two-dimensional cellular-scale models by assessing the mechanical behavior of model biological tissues, including crystalline (honeycomb) and noncrystalline reference states. The numerical procedure involves applying an affine deformation to the boundary cells and computing the quasistatic position of internal cells. The position of internal cells is then compared with the prediction of the CBR and an average deviation is calculated in the strain domain. For center-based cell models, we show that the CBR holds exactly when the deformation gradient is relatively small and the reference stress-free configuration is defined by a honeycomb lattice. We show further that the CBR may be used approximately when the reference state is perturbed from the honeycomb configuration. By contrast, for vertex-based cell models, a similar analysis reveals that the CBR does not provide a good representation of the tissue mechanics, even when the reference configuration is defined by a honeycomb lattice. The paper concludes with a discussion of the implications of these results for concurrent discrete and continuous modeling, adaptation of atom-to-continuum techniques to biological tissues, and model classification.
    Physical Review E 04/2013; 87(4-1):042724.
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    ABSTRACT: Membrane systems (P systems) are distributed computing models inspired by living cells where a collection of processors jointly achieves a computing task. The problem of maximal independent set (MIS) selection in a graph is to choose a set of nonadjacent nodes to which no further nodes can be added. In this letter, we design a class of simple neural-like P systems to solve the MIS selection problem efficiently in a distributed way. This new class of systems possesses two features that are attractive for both distributed computing and membrane computing: first, the individual processors do not need any information about the overall size of the graph; second, they communicate using only one-bit messages.
    Neural Computation 03/2013;
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