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ABSTRACT: The function of the ventricular specialized conduction system in the heart is to ensure the coordinated electrical activation of the ventricles. It is therefore critical to the overall function of the heart, and has also been implicated as an important player in various diseases, including lethal ventricular arrhythmias such as ventricular fibrillation and drug-induced torsades de pointes. However, current ventricular models of electrophysiology usually ignore, or include highly simplified representations of the specialized conduction system. Here, we describe the development of an image-based, species-consistent, anatomically-detailed model of rabbit ventricular electrophysiology that incorporates a detailed description of the free-running part of the specialized conduction system. Techniques used for the construction of the geometrical model of the specialized conduction system from a magnetic resonance dataset and integration of the system model into a ventricular anatomical model, developed from the same dataset, are described. Computer simulations of rabbit ventricular electrophysiology are conducted using the novel anatomical model and rabbit-specific membrane kinetics to investigate the importance of the components and properties of the conduction system in determining ventricular function under physiological conditions. Simulation results are compared to panoramic optical mapping experiments for model validation and results interpretation. Full access is provided to the anatomical models developed in this study.
Progress in Biophysics and Molecular Biology 06/2011; 107(1):90-100. · 3.20 Impact Factor
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ABSTRACT: The electrocardiogram (ECG) is widely used as a clinical tool for the evaluation of cardiac conditions caused by drugs, mutations
and diseases. However, the ionic basis underlying changes in the ECG are often unclear. In the present study, we present a
computational model of the human ECG capable of representing drug-induced effects from the ionic to the surface potential
level. Bidomain simulations are conducted to simulate the electrophysiological activity of the heart and extracellular potentials
in the whole body. Membrane kinetics are represented by the most recent version of a human action potential model, modified
to include representation of HERG block by dofetilide, a known class III anti-arrhythmic drug with potential pro-arrhythmic
effects. Simulation results are presented showing how dofetilide administration results in the prolongation of the action
potential duration in the ventricles and the QT interval measured on the surface of the thorax, in agreement with clinical
results. The state-of-the-art tools and methodologies presented here could be useful in the investigation and assessment of
drug cardiotoxicity and can also be extended to the investigation of the effect of mutations or disease on the ECG.
05/2011: pages 259-266;
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ABSTRACT: This paper describes the design and deployment of a large scale wireless sensor network (WSN) for monitoring the health of power equipment in a substation. The sensor network consists of 122 low power nodes that that are spread over an area approximately 1000 × 400 feet in size and perform monitoring of equipment such as transformers, circuit breakers, and compressors. All nodes communicate over a multihop wireless mesh network that uses a dynamic link-quality based routing protocol. A primary objective of this project is to develop effective monitoring applications for the substation using low-cost wireless sensor nodes that can sustain long periods of battery life. We study the battery consumption in the network and present a transmission scheme that conserves communication cost by enabling the sensor nodes to transmit observation samples only when their values are significantly different from those transmitted previously. Experimental results that demonstrate the performance of the sensor network for several monitoring applications are presented.
Local Computer Networks (LCN), 2010 IEEE 35th Conference on; 11/2010
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ABSTRACT: Increased beat-to-beat variability of repolarization (BVR) has been suggested to indicate increased susceptibility to drug-induced arrhythmia. This study aimed to characterize BVR in patients before and after administration of sotalol, a torsadogenic antiarrhythmic drug, in the search for new biomarkers of proarrhythmic risk. ECG Recordings pre and post sotalol injection in two groups of patients (with and without history of drug-induced torsades de pointes) were obtained from THEW. ECG wave detection and delineation were performed via dyadic wavelet transform. BVR was evaluated by short-term variability (STV) of QTc interval and JT area. In both groups, sotalol resulted in significant increase in STV of JT area, while no significant change occurred in STV of QTc interval. Thus, STV of JT area, as a measure of BVR, has the potential to be a biomarker for drug toxicity.
Computing in Cardiology, 2010; 10/2010
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ABSTRACT: Ionic mechanisms underlying atrial fibrillation (AF) generation and propagation are unclear. In this study, we investigate the dependence of AF related properties to changes in human atrial ion channel characteristics by systematically conducting a sensitivity analysis. Cell and tissue simulations are performed using the Maleckar action potential computational model for control and AF remodeling conditions, and are validated using experimental data from the literature. Inward rectifier K<sup>+</sup> current is shown to play a key role in many of the analyzed cell properties: action potential duration (APD), resting membrane potential and APD restitution slopes; as well as in tissue refractory period and wavelength. Na<sup>+</sup>/K<sup>+</sup> pump is essential in APD adaptation to heart rate changes and important in the tissue refractory period as well. FastNa<sup>+</sup> current is proven to be of great significance in tissue simulations, especially altering tissue excitability and, consequently, conduction velocity. Ionic mechanisms underlying electrophysiological properties are similar in control and AF. Sensitivity of AF related properties to changes in ion channel characteristics can help in the design and screening of new multi-channel action anti-AF drugs.
Computing in Cardiology, 2010; 10/2010
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ABSTRACT: Purkinje fibres play an important role in cardiac conduction and have been implicated in arrhythmia in presence of diseased states, genetic mutations, or adverse side effects of drugs. For these reasons, the Purkinje assay is commonly used in pre-clinical in vitro drug assessment of arrhythmic risk. Several investigators have pointed out that rabbit Purkinje cells, compared to other species, have a better sensitivity in detecting arrhythmic risk.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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ABSTRACT: Experimental studies of pro-arrhythmic mechanisms are scarcely performed in humans due to the limited availability of human cardiomyocytes. Subsequently, extrapolation of animal experimental research to humans is widely extended. Our aim is to systematically compare the ionic mechanisms of the main cellular biomarkers of arrhythmic risk between human and rabbit using computer simulations. For this purpose four stimulation protocols were applied to the Mahajan et al. rabbit ventricular action potential (AP) model for control conditions and for ±15 and ±30% variations in the ionic current conductances of the main repolarization currents to quantify cellular biomarkers. Sensitivity of every simulated biomarker to every parameter modification was compared to that obtained for human in our previous work. Our results show that the ionic mechanisms involved in AP triangulation, systolic intracellular calcium concentration and AP duration (APD) accommodation to abrupt changes of pacing rate are very similar in both species. Unfortunately, significant differences were found in the ionic mechanisms related to APD, restitution properties and rate dependence of intracellular calcium and sodium concentrations. In conclusion, extrapolation of experimental research in rabbit to humans is limited by the existence of species dependent ionic mechanisms. In addition, this analysis is very useful for understanding and improvement of mathematical models.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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ABSTRACT: QT prolongation is the only clinically proven, yet insufficient, electrocardiogram (ECG) biomarker for drug-induced cardiac toxicity. The goal of this study is to evaluate whether JT area, i.e., total area of the T-wave, can serve as an ECG biomarker for drug-induced cardiac toxicity using both signal processing and computational modeling approaches. An ECG dataset that contained recordings from patients under control and sotalol condition was analyzed. In order to relate sotalol-induced ECG changes to its effect on ion channel level, i.e., blockade of the rapid component of the delayed rectifier potassium channel (I<sub>Kr</sub>), varied degrees of I<sub>Kr</sub> blockade were simulated in a slab of ventricular tissue. The mean JT area increased by 36.5% following the administration of sotalol in patients. Simulations in the slab tissue showed that sotalol increased action potential duration preferentially in the midmyocardium, which led to increased transmural dispersion of repolarization and JT area. In conclusion, JT area reflects the transmural dispersion of repolarization and may be a potentially useful surrogate/supplemental ECG biomarker to assess drug safety.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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ABSTRACT: Electrical defibrillation by application of a strong shock to the heart is the only effective treatment against lethal cardiac arrhythmias such as ventricular fibrillation. A large body of experimental and computational research has been devoted to understanding shock-induced effects on the heart in an attempt to improve defibrillation efficacy. However, most of the research has been performed in small animal hearts, and in particular rabbits. The difference in size between rabbits and humans might limit the extrapolation of the results to the clinical setting. In this paper, we present, for the first time, computer simulations of shock-induced effects on a human ventricular model with realistic ion channel dynamics and fibre architecture. Bidomain simulations using the human ventricular model were performed using the Chaste open source simulation package. The parallel performance of the software package was highly improved in order to meet the computational requirements of these kind of studies.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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ABSTRACT: Experimental action potential (AP) recordings in isolated ventricular myoctes display significant temporal beat-to-beat variability in morphology and duration. Furthermore, significant cell-to-cell differences in AP also exist even for isolated cells originating from the same region of the same heart. However, current mathematical models of ventricular AP fail to replicate the temporal and cell-to-cell variability in AP observed experimentally. In this study, we propose a novel mathematical framework for the development of phenomenological AP models capable of capturing cell-to-cell and temporal variability in cardiac APs. A novel stochastic phenomenological model of the AP is developed, based on the deterministic Bueno-Orovio/Fenton model. Experimental recordings of AP are fit to the model to produce AP models of individual cells from the apex and the base of the guinea-pig ventricles. Our results show that the phenomenological model is able to capture the considerable differences in AP recorded from isolated cells originating from the location. We demonstrate the closeness of fit to the available experimental data which may be achieved using a phenomenological model, and also demonstrate the ability of the stochastic form of the model to capture the observed beat-to-beat variability in action potential duration.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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ABSTRACT: The aim of this study was to investigate sex and age related differences in drug induced QT prolongation by dofetilide under reduced repolarization reserve in simulated ventricular cells. Left ventricular endocardial action potentials were simulated using a modified Luo Rudy model. Sex, age and regional differences in currents I<sub>CaL</sub>, IK<sub>r</sub>, IK<sub>s</sub>, and I<sub>to</sub> were incorporated into the model by modifying the equations representing them. A model of dofetilide, a class III antiarrhythmic drug, was developed and included into a ventricular cell models. The reduced repolarization reserve was reproduced decreasing the IKs current. Our results shown that the adult female cells had longer action potentials, a steeper APD-BCL relationship and a higher susceptibility to EADs than adult male cells, under control, drug induced and reduced repolarization reserve conditions. On the other hand, young female and young male cells had similar action potentials under control conditions. However, young male cells had longer action potentials and higher susceptibility to EADs than young female cells under drug induced and reduced repolarization reserve conditions. Sex and age dependent differences in I<sub>CaL</sub>, IKr, IKs, and Ito may explain the age and sex disparities in prolongation of APD by the action of dofetilide.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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ABSTRACT: The ordered electrical stimulation of the ventricles is achieved by a specialized network of fibres known as the Purkinje system. The gross anatomy and basic functional role of the Purkinje system is well understood. However, very little is known about the detailed anatomy of the Purkinje system, its inter-individual variability and the implications of the variability in ventricular function, in part due to limitations in experimental techniques. In this study, we aim to provide new insight into the inter-individual variability of the free running Purkinje system anatomy and its impact on ventricular electrophysiological function. As a first step towards achieving this aim, high resolution magnetic resonance imaging (MRI) datasets of rat and the rabbit ventricles are obtained and analysed using a novel semi-automatic image processing algorithm for segmentation of the free-running Purkinje system. Segmented geometry from the MRI datasets is used to construct a computational model of the Purkinje system, which is incorporated in to an anatomically-based ventricular geometry to simulate ventricular electrophysiological activity.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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ABSTRACT: Computational models for cardiomyocyte action potentials (AP) often make use of a large parameter set. This parameter set can contain some elements that are fitted to experimental data independently of any other element, some elements that are derived concurrently with other elements to match experimental data, and some elements that are derived purely from phenomenological fitting to produce the desired AP output. Furthermore, models can make use of several different data sets, not always derived for the same conditions or even the same species. It is consequently uncertain whether the parameter set for a given model is physiologically accurate. Furthermore, it is only recently that the possibility of degeneracy in parameter values in producing a given simulation output has started to be addressed. In this study, we examine the effects of varying two parameters (the L-type calcium current (I<sub>CaL</sub>) and the delayed rectifier potassium current (I<sub>Ks</sub>)) in a computational model of a rabbit ventricular cardiomyocyte AP on both the membrane potential (V<sub>m</sub>) and calcium (Ca<sup>2+</sup>) transient. It will subsequently be determined if there is degeneracy in this model to these parameter values, which will have important implications on the stability of these models to cell-to-cell parameter variation, and also whether the current methodology for generating parameter values is flawed. The accuracy of AP duration (APD) as an indicator of AP shape will also be assessed.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
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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.
Clinical Pharmacology & Therapeutics 07/2010; 88(1):130-4. · 6.04 Impact Factor
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ABSTRACT: In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.
Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences 06/2010; 368(1921):3001-25. · 2.77 Impact Factor
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ABSTRACT: This paper presents the design and implementation of a portable base station for a wireless sensor network (WSN) for monitoring power substations. Apart from serving as the sink for all sensor data in the WSN, this node is also capable of high-speed data acquisition, image capture, and connection to the Internet via a cellular modem. In particular, we demonstrate its capabilities for performing high data rate voltage sampling for monitoring the health of transformer bushings from a power substation. Laboratory experiments demonstrate that the samples can be used to estimate phase differences with errors below 0.03° for 60 Hz voltage signals, which is lower than the requirement of a commercial transformer bushing monitoring system. Additional features of the advanced wireless node that are appropriate for substation monitoring applications are also described.
IEEE SoutheastCon 2010 (SoutheastCon), Proceedings of the; 04/2010
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ABSTRACT: The paper describes the design, test, and development of vibration sensing nodes for a wireless sensor network (WSN) that is used for health monitoring of high voltage (HV) equipment in power substations. The principal objective of the project is to investigate the viability of using inexpensive and low-power wireless sensors for power system monitoring applications. Laboratory tests and experimental results that demonstrate the performance of the sensors are presented.
IEEE SoutheastCon 2010 (SoutheastCon), Proceedings of the; 04/2010
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[show abstract]
[hide abstract]
ABSTRACT: The ordered electrical stimulation of the ventricles is achieved by a specialized network of fibres known as the Purkinje system. The gross anatomy and basic functional role of the Purkinje system is well understood. However, very little is known about the detailed anatomy of the Purkinje system, its inter-individual variability and the implications of the variability in ventricular function, in part due to limitations in experimental techniques. In this study, we aim to provide new insight into the inter-individual variability of the free running Purkinje system anatomy and its impact on ventricular electrophysiological function. As a first step towards achieving this aim, high resolution magnetic resonance imaging (MRI) datasets of rat and the rabbit ventricles are obtained and analysed using a novel semi-automatic image processing algorithm for segmentation of the free-running Purkinje system. Segmented geometry from the MRI datasets is used to construct a computational model of the Purkinje system, which is incorporated in to an anatomically-based ventricular geometry to simulate ventricular electrophysiological activity.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 01/2010; 2010:6793-6.
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[show abstract]
[hide abstract]
ABSTRACT: Experimental studies of pro-arrhythmic mechanisms are scarcely performed in humans due to the limited availability of human cardiomyocytes. Subsequently, extrapolation of animal experimental research to humans is widely extended. Our aim is to systematically compare the ionic mechanisms of the main cellular biomarkers of arrhythmic risk between human and rabbit using computer simulations. For this purpose four stimulation protocols were applied to the Mahajan et al. rabbit ventricular action potential (AP) model for control conditions and for ± 15 and ± 30% variations in the ionic current conductances of the main repolarization currents to quantify cellular biomarkers. Sensitivity of every simulated biomarker to every parameter modification was compared to that obtained for human in our previous work. Our results show that the ionic mechanisms involved in AP triangulation, systolic intracellular calcium concentration and AP duration (APD) accommodation to abrupt changes of pacing rate are very similar in both species. Unfortunately, significant differences were found in the ionic mechanisms related to APD, restitution properties and rate dependence of intracellular calcium and sodium concentrations. In conclusion, extrapolation of experimental research in rabbit to humans is limited by the existence of species dependent ionic mechanisms. In addition, this analysis is very useful for understanding and improvement of mathematical models.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 01/2010; 2010:3253-6.
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M.O. Bernabeu,
A. Corrias,
J. Pitt-Francis, B. Rodriguez,
B. Bethwaite,
C. Enticott,
S. Garic,
T. Peachey,
J. Tan,
D. Abramson,
D. Gavaghan
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ABSTRACT: In this study, a computational framework combining state-of-the-art cardiac simulation software and Grid computing is used to investigate the impact of the block of the HERG current on the ECG waveform using state-of-the-art 3D ventricular models of electrophysiology. The technology developed enables (i) automated parameter sweeping using multiscale models (from ion channel to ECG) and (ii) reduced execution time of the simulations performed.
Computers in Cardiology, 2009; 10/2009
