Atrial fibrillation (AF) is a progressive arrhythmia characterized by structural alterations that... more Atrial fibrillation (AF) is a progressive arrhythmia characterized by structural alterations that increase its stability. Both clinical and experimental studies showed a concomitant loss of antiarrhythmic drug efficacy in later stages of AF. The mechanisms underlying this loss of efficacy are not well understood. We hypothesized that structural remodelling may explain this reduced efficacy by making the substrate more three-dimensional. To investigate this, we simulated the effect of sodium (Na þ)-channel block on AF in a model of progressive transmural uncoupling.
Collaborative Virtual Environments are of increasing interest to different user communities to su... more Collaborative Virtual Environments are of increasing interest to different user communities to support collaborative tasks of geographically dispersed teams. These tasks not only involve communication through speech and document exchange, but may also require some three-dimensional view on or interaction with the topic of interest. In this way discussion on design, architecture or integration can be supported. A platform for generic Collaborative Virtual Environment (CVE) applications has been proposed and is actually realized within the COVEN project. COVEN is part of the European Advanced Communication Technology and Services (ACTS) programme. The project mainly focuses on scalable networked architectures to support co-operative work between many users over large distances within a shared virtual environment. As part of the COVEN project, the requirements for a CVE reference architecture have been identified and are compared to the interoperability concepts offered by the High Lev...
During the past decade, requirements within the US defence community for simulation-based tools t... more During the past decade, requirements within the US defence community for simulation-based tools to support acquisition, planning, (team) training and analysis, have resulted in a standard for distributed simulation known as DIS (Distributed Interactive Simulation). The potential advantages of distributed simulation technologies are evident: increased flexibility, building on existing software and communications standards, maximisation of the use of existing simulation assets, and thus reduced costs. Although DIS was originally developed for military applications, the technology is well suited as a simulator interoperability standard for both the space domain and other civil application areas. The first international DIS experiments between space agencies have already taken place. As in other distributed computing areas, the military have expressed a need for standardisation on a higher abstraction level than the basic communication protocols such as DIS. This trend has led to a new ...
We introduce a method for predicting the network traffic that will be generated by Collaborative ... more We introduce a method for predicting the network traffic that will be generated by Collaborative Virtual Environment applications with varying numbers of participants. Statistical analysis of event logs from user trials results in a user behaviour model. Controlled traffic measurements combined with an analysis of the application architecture and network topology results in a system behaviour model. These two models are combined to produce a network traffic model. We describe the application of this method to a business game application that has been developed as part of the COVEN project. Finally, we make some general observations concerning the network traffic generated by CVEs including its bursty nature and the potential use of techniques such as multicasting and statistical multiplexing to reduce network load.
This documentation is actually the key to the success of the 're-use' of simulation compo... more This documentation is actually the key to the success of the 're-use' of simulation components: it is often the primary source of information on which the decision is based whether the component can be re-used as part of some other product. A well-defined verification and validation policy, in conjunction with a well conducted configuration management policy, is the most prominent precondition for the success of simulation component repositories and the concept of re-usability at large.
Background: P waves reported in electrocardiology literature uniformly appear smooth. Computer si... more Background: P waves reported in electrocardiology literature uniformly appear smooth. Computer simulation and signal analysis studies have shown much more complex shapes. Objective: We systematically investigated P-wave complexity in normal volunteers using highfidelity electrocardiographic techniques without filtering. Methods: We recorded 5-min multichannel ECGs in 16 healthy volunteers. Noise and interference were reduced by averaging over 300 beats per recording. In addition, normal P waves were simulated with a realistic model of the human atria. Results: Measured P waves had an average of 4.1 peaks (range 1-10) that were reproducible between recordings. Simulated P waves demonstrated similar complexity, which was related to structural discontinuities in the computer model of the atria. Conclusion: The true shape of the P wave is very irregular and is best seen in ECGs averaged over many beats.
Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie ... more Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie conduction disturbances predisposing to atrial fibrillation (AF). Putatively, disruption of electrical connections occurs not only within the epicardial layer but also between the epicardial layer and the endocardial bundle network, thus impeding transmural conductions ('breakthroughs'). However, both clinical and experimental studies have shown an enhancement of breakthroughs during later stages of AF. We tested the hypothesis that endo-epicardial uncoupling enhances endo-epicardial electrical dyssynchrony, breakthrough rate (BTR), and AF stability. Methods and results In a novel dual-layer computer model of the human atria, 100% connectivity between the two layers served as healthy control. Atrial structural remodelling was simulated by reducing the number of connections between the layers from 96 to 6 randomly chosen locations. With progressive elimination of connections, AF stability increased. Reduction in the number of connections from 96 to 24 resulted in an increase in endo-epicardial dyssynchrony from 6.6 + 1.9 to 24.6 + 1.3%, with a concomitant increase in BTR. A further reduction to 12 and 6 resulted in more pronounced endo-epicardial dyssynchrony of 34.4 + 1.15 and 40.2 + 0.52% but with BTR reduction. This biphasic relationship between endo-epicardial coupling and BTR was found independently from whether AF was maintained by re-entry or by ectopic focal discharges. Conclusion Loss of endo-epicardial coupling increases AF stability. There is a biphasic relation between endo-epicardial coupling and BTR. While at high degrees of endo-epicardial connectivity, the BTR is limited by the endo-epicardial synchronicity, at low degrees of connectivity, it is limited by the number of endo-epicardial connections.
Although the retina is one of the best understood parts of the central nervous system, manymyster... more Although the retina is one of the best understood parts of the central nervous system, manymysteries of this complex tissue have not yet been unraveled. We have used computationalmodeling to comprise knowledge from literature and gain more knowledge in the interactionsbetween neurons on two levels. Here we present two models: the network model, which describesthe whole neuronal network of the retina and the ephaptic model, which deals with aspecific feedback mechanism between neurons (cones and horizontal cells) in the first layers ofthe retina. In the network model we have included all known information on the pathways involved in colorvision in the primate retina. The behavior and output of this model depends on the spatial,temporal as well as the spectral information of the visual input. The model contains 20 typesof neurons, representing 3 types of cones (photoreceptors), 2 types of horizontal cells, 8 types ofbipolar cells and 7 types of ganglion cells. For each type of neuron there is a layer with cells ofthat type placed on a hexagonal grid. Each individual neuron is described by differential equationsbased on an electrical network of a capacitor in parallel with a number of resistors. Someof these resistors represent synaptic connections, for which the resistance can be controlled byadjacent neurons in the same layer as well as neurons in other layers. The ephaptic model provides a more detailed description of the interaction between cones andhorizontal cells. For long it has been known that cone type photoreceptors convert light stimuliinto a chemical signal that is received by horizontal cells and bipolar cells. There is also a feedbacksignal from horizontal cells to cones. With our ephaptic model we study the hypothesisthat this feedback is caused by an ephaptic phenomenon, i.e., by the local modulation of extracellular ion concentrations. The differential equations describing the behavior of neurons in thismodel resemble those in the network model, but contain much more physiological detail, as wellas a description of the extra cellular potential in a specific region of the synapse. Simulations with the network model show qualitative agreement with biological phenomena.Examples are differences in spatial resolution of the various pathways and the change in networkbehavior if one type of cone is missing (color blindness). However, the model lacks physiologicaldetail of the ephaptic interaction between cones and horizontal cells. This lack of physiologicaldetail can be filled in with our model of ephaptic feedback. The ephaptic model fits well withexperimental data and shows that ephaptic interaction can indeed explain feedback from horizontalcells to cones. Our network model can be used to study the whole retina as if it were an image processingunit, whereas the ephaptic model can be used to study the specific interaction between conesand horizontal cells. The combination of the two models yields a model that can explain bothphysiological and perceptual phenomena.
Cardiac Resynchronization Therapy (CRT) has emerged as an important therapy to improve pump funct... more Cardiac Resynchronization Therapy (CRT) has emerged as an important therapy to improve pump function in heart failure patients with left bundle branch block (LBBB). Using a multi-scale modeling approach, we investigated the effect of mechano-electrical feedback (MEF) during LBBB and CRT on cardiac function and dispersion of repolarization. Our model describes cellular electrophysiology and calcium handling as well as cardiac mechanics and hemodynamics. Ventricular electromechanics is represented by a single cardiac fiber, while physiological pressure-volume loops are obtained by simulating the systemic circulation. LBBB was simulated by activating the fiber at one end and CRT by simultaneous activation at both ends. Systolic function improved with onset of CRT, but diastolic function only improved after MEF. We conclude that MEF during LBBB may lead to an increase in dispersion of repolarization during onset of CRT, which may lead to impaired diastolic function and to ventricular arrhythmia.
Atrial fibrillation is a progressive arrhythmia with increase in AF stability during its progress... more Atrial fibrillation is a progressive arrhythmia with increase in AF stability during its progression. AF progression goes in line with structural and electrophysiological changes. These alterations can make changes in electrophysiological parameters such as increase in number of waves, decrease in wave sizes, and increase in transmural conductions. In order to investigate which parameter has the largest effects on AF stability, we made a novel dual layer computer model and measured different read out parameters. Afterwards, a statistical test, multivariate logistic tests, was performed to extract contributions of different parameters on AF stability. Our study revealed endo-epicardial electrical activity dissociation is the most determinant parameter associate with AF stability.
Atrial fibrillation is the most common cardiac arrhythmia. Structural cardiac defects such as fib... more Atrial fibrillation is the most common cardiac arrhythmia. Structural cardiac defects such as fibrosis and gap junction remodeling lead to a reduced cellular electrical coupling and are known to promote atrial fibrillation. It has been observed that the expression of the hyperpolarization-activated current f is increased under pathological conditions. Recent experimental data indicate a possible contribution of f to arrhythmogenesis. In this paper, the role of f in action potential propagation in normal and in pathological tissue is investigated by means of computer simulations. The effect of diffuse fibrosis and gap junction remodeling is simulated by reducing cellular coupling nonuniformly. As expected, the conduction velocity decreases when cellular coupling is reduced. In the presence of f the conduction velocity increases both in normal and in pathological tissue. In our simulations, ectopic activity is present in regions with high expression of f and is facilitated by cellular uncoupling. We conclude that an increased f may facilitate propagation of the action potential. Hence, f may prevent conduction slowing and block. Overexpression of f may lead to ectopic activity, especially when cellular coupling is reduced under pathological conditions.
Structural alterations during atrial fibrillation (AF) not only lead to electrical dissociation w... more Structural alterations during atrial fibrillation (AF) not only lead to electrical dissociation within the epicardial layer, but also between the epicardial layer and the endocardial bundle network. The aim of the study was to investigate the role of transmural conduction in the stability of AF episodes using a dual-layer computer model. Methods and results A proof-of-principle dual-layer model was developed in which connections between the layers can be introduced or removed at any time during the simulation. Using an S1-S2 protocol, a spiral wave was initiated in one of the layers, which degenerated into a complex AF pattern after connection with the other layer at six randomly chosen sites. After 6 s, connections were either retained (dual-layer simulations) or removed (single-layer simulations). Duallayer simulations were more complex, as indicated by the higher number of waves and phase singularities. Tracking waves through both layers revealed that the number of waves in dual-layer simulations was significantly higher than in the single-layer simulations, reflecting more opportunities for reentry and a concomitant increase in AF stability. In the dual-layer model, only 12% of the AF episodes died out within 6 s, while 59% died out in the single-layer model. Conclusion Atrial fibrillation patterns are more complex and AF episodes are more stable in a dual-layer model. This study indicates an important role for endo-epicardial conduction for the stabilization of AF.
American Journal of Physiology-Heart and Circulatory Physiology, 2014
It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of card... more It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of cardiac function is followed by a further gradual deterioration of function, whereas most adverse cardiac events lead to compensatory adaptations. We investigated whether mechano-electrical coupling (MEC) can explain long-term remodeling with LBBB and cardiac resynchronization therapy (CRT). To this purpose, we used an integrative modeling approach relating local ventricular electrophysiology, calcium handling, and excitation-contraction coupling to global cardiovascular mechanics and hemodynamics. Each ventricular wall was composed of multiple mechanically and electrically coupled myocardial segments. MEC was incorporated by allowing adaptation of L-type Ca2+ current aiming at minimal dispersion of local external work, an approach that we previously applied to replicate T-wave memory in a synchronous heart after a period of asynchronous activation. LBBB instantaneously decreased left-ventri...
American Journal of Physiology-Heart and Circulatory Physiology, 2007
Atrial fibrillation, a common cardiac arrhythmia, is promoted by atrial dilatation. Acute atrial ... more Atrial fibrillation, a common cardiac arrhythmia, is promoted by atrial dilatation. Acute atrial dilatation may play a role in atrial arrhythmogenesis through mechanoelectric feedback. In experimental studies, conduction slowing and block have been observed in acutely dilated atria. In the present study, the influence of the stretch-activated current ( Isac) on impulse propagation is investigated by means of computer simulations. Homogeneous and inhomogeneous atrial tissues are modeled by cardiac fibers composed of segments that are electrically and mechanically coupled. Active force is related to free Ca2+ concentration and sarcomere length. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and Isac under stretch. In our model, conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Conduction block can be unidirectional in an inh...
American Journal of Physiology-Heart and Circulatory Physiology, 2012
At present, it is unknown why patients suffering from severe pulmonary hypertension (PH) benefit ... more At present, it is unknown why patients suffering from severe pulmonary hypertension (PH) benefit from atrial septostomy (AS). Suggested mechanisms include enhanced filling of the left ventricle, reduction of right ventricular preload, increased oxygen availability in the peripheral tissue, or a combination. A multiscale computational model of the cardiovascular system was used to assess the effects of AS in PH. Our model simulates beat-to-beat dynamics of the four cardiac chambers with valves and the systemic and pulmonary circulations, including an atrial septal defect (ASD). Oxygen saturation was computed for each model compartment. The acute effect of AS on systemic flow and oxygen delivery in PH was assessed by a series of simulations with combinations of different ASD diameters, pulmonary flows, and degrees of PH. In addition, blood pressures at rest and during exercise were compared between circulations with PH before and after AS. If PH did not result in a right atrial pressu...
The cytoskeleton is a dynamic scaffold in living cells even in the absence of externally imposed ... more The cytoskeleton is a dynamic scaffold in living cells even in the absence of externally imposed forces. In this study on cytoskeletal deformation, the applicability of hierarchical feature vector matching (HFVM), a new matching method, currently applied in space research and three-dimensional surface reconstruction, was investigated. Stably transfected CHO-K1 cells expressing green fluorescent protein (GFP) coupled to vimentin were used to visualize spontaneous movement of the vimentin cytoskeleton of individual cells using a confocal laser scanning system. We showed that, with proper parameter and configuration settings, HFVM could recognize and trace 60–70% of all image points in artificially translated, rotated, or deformed images. If only points belonging to the cytoskeleton were selected for matching purposes, the percentage of matched points increased to 98%. This high percentage of recognition also could be reached in a time series of images, in which a certain degree of ble...
DOI to the publisher's website. • The final author version and the galley proof are versions of t... more DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the "Taverne" license above, please follow below link for the End User Agreement:
Atrial fibrillation (AF) is a progressive arrhythmia characterized by structural alterations that... more Atrial fibrillation (AF) is a progressive arrhythmia characterized by structural alterations that increase its stability. Both clinical and experimental studies showed a concomitant loss of antiarrhythmic drug efficacy in later stages of AF. The mechanisms underlying this loss of efficacy are not well understood. We hypothesized that structural remodelling may explain this reduced efficacy by making the substrate more three-dimensional. To investigate this, we simulated the effect of sodium (Na þ)-channel block on AF in a model of progressive transmural uncoupling.
Collaborative Virtual Environments are of increasing interest to different user communities to su... more Collaborative Virtual Environments are of increasing interest to different user communities to support collaborative tasks of geographically dispersed teams. These tasks not only involve communication through speech and document exchange, but may also require some three-dimensional view on or interaction with the topic of interest. In this way discussion on design, architecture or integration can be supported. A platform for generic Collaborative Virtual Environment (CVE) applications has been proposed and is actually realized within the COVEN project. COVEN is part of the European Advanced Communication Technology and Services (ACTS) programme. The project mainly focuses on scalable networked architectures to support co-operative work between many users over large distances within a shared virtual environment. As part of the COVEN project, the requirements for a CVE reference architecture have been identified and are compared to the interoperability concepts offered by the High Lev...
During the past decade, requirements within the US defence community for simulation-based tools t... more During the past decade, requirements within the US defence community for simulation-based tools to support acquisition, planning, (team) training and analysis, have resulted in a standard for distributed simulation known as DIS (Distributed Interactive Simulation). The potential advantages of distributed simulation technologies are evident: increased flexibility, building on existing software and communications standards, maximisation of the use of existing simulation assets, and thus reduced costs. Although DIS was originally developed for military applications, the technology is well suited as a simulator interoperability standard for both the space domain and other civil application areas. The first international DIS experiments between space agencies have already taken place. As in other distributed computing areas, the military have expressed a need for standardisation on a higher abstraction level than the basic communication protocols such as DIS. This trend has led to a new ...
We introduce a method for predicting the network traffic that will be generated by Collaborative ... more We introduce a method for predicting the network traffic that will be generated by Collaborative Virtual Environment applications with varying numbers of participants. Statistical analysis of event logs from user trials results in a user behaviour model. Controlled traffic measurements combined with an analysis of the application architecture and network topology results in a system behaviour model. These two models are combined to produce a network traffic model. We describe the application of this method to a business game application that has been developed as part of the COVEN project. Finally, we make some general observations concerning the network traffic generated by CVEs including its bursty nature and the potential use of techniques such as multicasting and statistical multiplexing to reduce network load.
This documentation is actually the key to the success of the 're-use' of simulation compo... more This documentation is actually the key to the success of the 're-use' of simulation components: it is often the primary source of information on which the decision is based whether the component can be re-used as part of some other product. A well-defined verification and validation policy, in conjunction with a well conducted configuration management policy, is the most prominent precondition for the success of simulation component repositories and the concept of re-usability at large.
Background: P waves reported in electrocardiology literature uniformly appear smooth. Computer si... more Background: P waves reported in electrocardiology literature uniformly appear smooth. Computer simulation and signal analysis studies have shown much more complex shapes. Objective: We systematically investigated P-wave complexity in normal volunteers using highfidelity electrocardiographic techniques without filtering. Methods: We recorded 5-min multichannel ECGs in 16 healthy volunteers. Noise and interference were reduced by averaging over 300 beats per recording. In addition, normal P waves were simulated with a realistic model of the human atria. Results: Measured P waves had an average of 4.1 peaks (range 1-10) that were reproducible between recordings. Simulated P waves demonstrated similar complexity, which was related to structural discontinuities in the computer model of the atria. Conclusion: The true shape of the P wave is very irregular and is best seen in ECGs averaged over many beats.
Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie ... more Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie conduction disturbances predisposing to atrial fibrillation (AF). Putatively, disruption of electrical connections occurs not only within the epicardial layer but also between the epicardial layer and the endocardial bundle network, thus impeding transmural conductions ('breakthroughs'). However, both clinical and experimental studies have shown an enhancement of breakthroughs during later stages of AF. We tested the hypothesis that endo-epicardial uncoupling enhances endo-epicardial electrical dyssynchrony, breakthrough rate (BTR), and AF stability. Methods and results In a novel dual-layer computer model of the human atria, 100% connectivity between the two layers served as healthy control. Atrial structural remodelling was simulated by reducing the number of connections between the layers from 96 to 6 randomly chosen locations. With progressive elimination of connections, AF stability increased. Reduction in the number of connections from 96 to 24 resulted in an increase in endo-epicardial dyssynchrony from 6.6 + 1.9 to 24.6 + 1.3%, with a concomitant increase in BTR. A further reduction to 12 and 6 resulted in more pronounced endo-epicardial dyssynchrony of 34.4 + 1.15 and 40.2 + 0.52% but with BTR reduction. This biphasic relationship between endo-epicardial coupling and BTR was found independently from whether AF was maintained by re-entry or by ectopic focal discharges. Conclusion Loss of endo-epicardial coupling increases AF stability. There is a biphasic relation between endo-epicardial coupling and BTR. While at high degrees of endo-epicardial connectivity, the BTR is limited by the endo-epicardial synchronicity, at low degrees of connectivity, it is limited by the number of endo-epicardial connections.
Although the retina is one of the best understood parts of the central nervous system, manymyster... more Although the retina is one of the best understood parts of the central nervous system, manymysteries of this complex tissue have not yet been unraveled. We have used computationalmodeling to comprise knowledge from literature and gain more knowledge in the interactionsbetween neurons on two levels. Here we present two models: the network model, which describesthe whole neuronal network of the retina and the ephaptic model, which deals with aspecific feedback mechanism between neurons (cones and horizontal cells) in the first layers ofthe retina. In the network model we have included all known information on the pathways involved in colorvision in the primate retina. The behavior and output of this model depends on the spatial,temporal as well as the spectral information of the visual input. The model contains 20 typesof neurons, representing 3 types of cones (photoreceptors), 2 types of horizontal cells, 8 types ofbipolar cells and 7 types of ganglion cells. For each type of neuron there is a layer with cells ofthat type placed on a hexagonal grid. Each individual neuron is described by differential equationsbased on an electrical network of a capacitor in parallel with a number of resistors. Someof these resistors represent synaptic connections, for which the resistance can be controlled byadjacent neurons in the same layer as well as neurons in other layers. The ephaptic model provides a more detailed description of the interaction between cones andhorizontal cells. For long it has been known that cone type photoreceptors convert light stimuliinto a chemical signal that is received by horizontal cells and bipolar cells. There is also a feedbacksignal from horizontal cells to cones. With our ephaptic model we study the hypothesisthat this feedback is caused by an ephaptic phenomenon, i.e., by the local modulation of extracellular ion concentrations. The differential equations describing the behavior of neurons in thismodel resemble those in the network model, but contain much more physiological detail, as wellas a description of the extra cellular potential in a specific region of the synapse. Simulations with the network model show qualitative agreement with biological phenomena.Examples are differences in spatial resolution of the various pathways and the change in networkbehavior if one type of cone is missing (color blindness). However, the model lacks physiologicaldetail of the ephaptic interaction between cones and horizontal cells. This lack of physiologicaldetail can be filled in with our model of ephaptic feedback. The ephaptic model fits well withexperimental data and shows that ephaptic interaction can indeed explain feedback from horizontalcells to cones. Our network model can be used to study the whole retina as if it were an image processingunit, whereas the ephaptic model can be used to study the specific interaction between conesand horizontal cells. The combination of the two models yields a model that can explain bothphysiological and perceptual phenomena.
Cardiac Resynchronization Therapy (CRT) has emerged as an important therapy to improve pump funct... more Cardiac Resynchronization Therapy (CRT) has emerged as an important therapy to improve pump function in heart failure patients with left bundle branch block (LBBB). Using a multi-scale modeling approach, we investigated the effect of mechano-electrical feedback (MEF) during LBBB and CRT on cardiac function and dispersion of repolarization. Our model describes cellular electrophysiology and calcium handling as well as cardiac mechanics and hemodynamics. Ventricular electromechanics is represented by a single cardiac fiber, while physiological pressure-volume loops are obtained by simulating the systemic circulation. LBBB was simulated by activating the fiber at one end and CRT by simultaneous activation at both ends. Systolic function improved with onset of CRT, but diastolic function only improved after MEF. We conclude that MEF during LBBB may lead to an increase in dispersion of repolarization during onset of CRT, which may lead to impaired diastolic function and to ventricular arrhythmia.
Atrial fibrillation is a progressive arrhythmia with increase in AF stability during its progress... more Atrial fibrillation is a progressive arrhythmia with increase in AF stability during its progression. AF progression goes in line with structural and electrophysiological changes. These alterations can make changes in electrophysiological parameters such as increase in number of waves, decrease in wave sizes, and increase in transmural conductions. In order to investigate which parameter has the largest effects on AF stability, we made a novel dual layer computer model and measured different read out parameters. Afterwards, a statistical test, multivariate logistic tests, was performed to extract contributions of different parameters on AF stability. Our study revealed endo-epicardial electrical activity dissociation is the most determinant parameter associate with AF stability.
Atrial fibrillation is the most common cardiac arrhythmia. Structural cardiac defects such as fib... more Atrial fibrillation is the most common cardiac arrhythmia. Structural cardiac defects such as fibrosis and gap junction remodeling lead to a reduced cellular electrical coupling and are known to promote atrial fibrillation. It has been observed that the expression of the hyperpolarization-activated current f is increased under pathological conditions. Recent experimental data indicate a possible contribution of f to arrhythmogenesis. In this paper, the role of f in action potential propagation in normal and in pathological tissue is investigated by means of computer simulations. The effect of diffuse fibrosis and gap junction remodeling is simulated by reducing cellular coupling nonuniformly. As expected, the conduction velocity decreases when cellular coupling is reduced. In the presence of f the conduction velocity increases both in normal and in pathological tissue. In our simulations, ectopic activity is present in regions with high expression of f and is facilitated by cellular uncoupling. We conclude that an increased f may facilitate propagation of the action potential. Hence, f may prevent conduction slowing and block. Overexpression of f may lead to ectopic activity, especially when cellular coupling is reduced under pathological conditions.
Structural alterations during atrial fibrillation (AF) not only lead to electrical dissociation w... more Structural alterations during atrial fibrillation (AF) not only lead to electrical dissociation within the epicardial layer, but also between the epicardial layer and the endocardial bundle network. The aim of the study was to investigate the role of transmural conduction in the stability of AF episodes using a dual-layer computer model. Methods and results A proof-of-principle dual-layer model was developed in which connections between the layers can be introduced or removed at any time during the simulation. Using an S1-S2 protocol, a spiral wave was initiated in one of the layers, which degenerated into a complex AF pattern after connection with the other layer at six randomly chosen sites. After 6 s, connections were either retained (dual-layer simulations) or removed (single-layer simulations). Duallayer simulations were more complex, as indicated by the higher number of waves and phase singularities. Tracking waves through both layers revealed that the number of waves in dual-layer simulations was significantly higher than in the single-layer simulations, reflecting more opportunities for reentry and a concomitant increase in AF stability. In the dual-layer model, only 12% of the AF episodes died out within 6 s, while 59% died out in the single-layer model. Conclusion Atrial fibrillation patterns are more complex and AF episodes are more stable in a dual-layer model. This study indicates an important role for endo-epicardial conduction for the stabilization of AF.
American Journal of Physiology-Heart and Circulatory Physiology, 2014
It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of card... more It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of cardiac function is followed by a further gradual deterioration of function, whereas most adverse cardiac events lead to compensatory adaptations. We investigated whether mechano-electrical coupling (MEC) can explain long-term remodeling with LBBB and cardiac resynchronization therapy (CRT). To this purpose, we used an integrative modeling approach relating local ventricular electrophysiology, calcium handling, and excitation-contraction coupling to global cardiovascular mechanics and hemodynamics. Each ventricular wall was composed of multiple mechanically and electrically coupled myocardial segments. MEC was incorporated by allowing adaptation of L-type Ca2+ current aiming at minimal dispersion of local external work, an approach that we previously applied to replicate T-wave memory in a synchronous heart after a period of asynchronous activation. LBBB instantaneously decreased left-ventri...
American Journal of Physiology-Heart and Circulatory Physiology, 2007
Atrial fibrillation, a common cardiac arrhythmia, is promoted by atrial dilatation. Acute atrial ... more Atrial fibrillation, a common cardiac arrhythmia, is promoted by atrial dilatation. Acute atrial dilatation may play a role in atrial arrhythmogenesis through mechanoelectric feedback. In experimental studies, conduction slowing and block have been observed in acutely dilated atria. In the present study, the influence of the stretch-activated current ( Isac) on impulse propagation is investigated by means of computer simulations. Homogeneous and inhomogeneous atrial tissues are modeled by cardiac fibers composed of segments that are electrically and mechanically coupled. Active force is related to free Ca2+ concentration and sarcomere length. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and Isac under stretch. In our model, conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Conduction block can be unidirectional in an inh...
American Journal of Physiology-Heart and Circulatory Physiology, 2012
At present, it is unknown why patients suffering from severe pulmonary hypertension (PH) benefit ... more At present, it is unknown why patients suffering from severe pulmonary hypertension (PH) benefit from atrial septostomy (AS). Suggested mechanisms include enhanced filling of the left ventricle, reduction of right ventricular preload, increased oxygen availability in the peripheral tissue, or a combination. A multiscale computational model of the cardiovascular system was used to assess the effects of AS in PH. Our model simulates beat-to-beat dynamics of the four cardiac chambers with valves and the systemic and pulmonary circulations, including an atrial septal defect (ASD). Oxygen saturation was computed for each model compartment. The acute effect of AS on systemic flow and oxygen delivery in PH was assessed by a series of simulations with combinations of different ASD diameters, pulmonary flows, and degrees of PH. In addition, blood pressures at rest and during exercise were compared between circulations with PH before and after AS. If PH did not result in a right atrial pressu...
The cytoskeleton is a dynamic scaffold in living cells even in the absence of externally imposed ... more The cytoskeleton is a dynamic scaffold in living cells even in the absence of externally imposed forces. In this study on cytoskeletal deformation, the applicability of hierarchical feature vector matching (HFVM), a new matching method, currently applied in space research and three-dimensional surface reconstruction, was investigated. Stably transfected CHO-K1 cells expressing green fluorescent protein (GFP) coupled to vimentin were used to visualize spontaneous movement of the vimentin cytoskeleton of individual cells using a confocal laser scanning system. We showed that, with proper parameter and configuration settings, HFVM could recognize and trace 60–70% of all image points in artificially translated, rotated, or deformed images. If only points belonging to the cytoskeleton were selected for matching purposes, the percentage of matched points increased to 98%. This high percentage of recognition also could be reached in a time series of images, in which a certain degree of ble...
DOI to the publisher's website. • The final author version and the galley proof are versions of t... more DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the "Taverne" license above, please follow below link for the End User Agreement:
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