Fibroblasts are abundant in cardiac tissue. Experimental studies suggested that fibroblasts are electrically coupled to myocytes and this coupling can impact cardiac electrophysiology. In this work, we present a novel approach for mathematical modeling of electrical conduction in cardiac tissue composed of myocytes, fibroblasts, and the extracellular space. The model is an extension of established cardiac bidomain models, which include a description of intra-myocyte and extracellular conductivities, currents and potentials in addition to transmembrane voltages of myocytes. Our extension added a description of fibroblasts, which are electrically coupled with each other and with myocytes. We applied the extended model in exemplary computational simulations of plane waves and conduction in a thin tissue slice assuming an isotropic conductivity of the intra-fibroblast domain. In simulations of plane waves, increased myocyte-fibroblast coupling and fibroblast-myocyte ratio reduced peak voltage and maximal upstroke velocity of myocytes as well as amplitudes and maximal downstroke velocity of extracellular potentials. Simulations with the thin tissue slice showed that inter-fibroblast coupling affected rather transversal than longitudinal conduction velocity. Our results suggest that fibroblast coupling becomes relevant for small intra-myocyte and/or large intra-fibroblast conductivity. In summary, the study demonstrated the feasibility of the extended bidomain model and supports the hypothesis that fibroblasts contribute to cardiac electrophysiology in various manners.
BACKGROUND AND PURPOSE: Atomoxetine is a selective noradrenaline reuptake inhibitor, recently approved for the treatment of attention-deficit/hyperactivity disorder. So far, atomoxetine has been shown to be well tolerated, and cardiovascular effects were found to be negligible. However, two independent cases of QT interval prolongation, associated with atomoxetine overdose, have been reported recently. We therefore analysed acute and subacute effects of atomoxetine on cloned human Ether-a-Go-Go-Related Gene (hERG) channels. EXPERIMENTAL APPROACH: hERG channels were heterologously expressed in Xenopus oocytes and in a human embryonic kidney cell line and hERG currents were measured using voltage clamp and patch clamp techniques. Action potential recordings were made in isolated guinea-pig cardiomyocytes. Gene expression and channel surface expression were analysed using quantitative reverse transcriptase polymerase chain reaction, Western blot and the patch clamp techniques. KEY RESULTS: In human embryonic kidney cells, atomoxetine inhibited hERG current with an IC(50) of 6.3 micromol.L(-1). Development of block and washout were fast. Channel activation and inactivation were not affected. Inhibition was state-dependent, suggesting an open channel block. No use-dependence was observed. Inhibitory effects of atomoxetine were attenuated in the pore mutants Y652A and F656A. In guinea-pig cardiomyocytes, atomoxetine lengthened action potential duration without inducing action potential triangulation. Overnight incubation with high atomoxetine concentrations resulted in a decrease of channel surface expression. CONCLUSIONS AND IMPLICATIONS: Whereas subacute effects of atomoxetine seem negligible under therapeutically relevant concentrations, hERG channel block should be considered in cases of atomoxetine overdose and when administering atomoxetine to patients at increased risk for the development of acquired long-QT syndrome.
D. L. Weiss, M. Ifland, F. B. Sachse, G. Seemann, and O. Dössel. Modeling of cardiac ischemia in human myocytes and tissue including spatiotemporal electrophysiological variations / Modellierung kardialer Ischämie in menschlichen Myozyten und Gewebe. In Biomedizinische Technik/Biomedical Engineering, vol. 54(3) , pp. 107-125, 2009
Cardiac tissue exhibits spatially heterogeneous electrophysiological properties. In cardiac diseases, these properties also change in time. This study introduces a framework to investigate their role in cardiac ischemia using mathematical modeling and computational simulations at cellular and tissue level. Ischemia was incorporated by reproducing effects of hyperkalemia, acidosis, and hypoxia with a human electrophysiological model. In tissue, spatial heterogeneous ischemia was described by central ischemic (CIZ) and border zone. Anisotropic conduction was simulated with a bidomain approach in an anatomical ventricle model including realistic fiber orientation and transmural, apico-basal, and interventricular electrophysiological heterogeneities. A model of electrical conductivity in a human torso served for ECG calculations. Ischemia increased resting but reduced peak voltage, action potential duration, and upstroke velocity. These effects were strongest in subepicardial cells. In tissue, conduction velocity decreased towards CIZ but effective refractory period increased. At 10 min of ischemia 19% of subepi- and 100% of subendocardial CIZ cells activated with a delay of 34.6+/-7.8 ms and 55.9+/-18.8 ms, respectively, compared to normal. Significant ST elevation and premature T wave end appeared only with the subepicardial CIZ. The model reproduced effects of ischemia at cellular and tissue level. The results suggest that the presented in silico approach can complement experimental studies, e.g., in understanding the role of ischemia or the onset of arrhythmia.
Conference Contributions (17)
G. Seemann. Modeling of cardiac Ischemia in human myocytes and tissue including spatiotemporal electrophysiological variations. In VPH Events - 4th Cardiac Physiome Workshop, 2009
Cardiac tissue exhibits spatially heterogeneous electrophysiological properties. In cardiac diseases, these properties change also in time. This study introduces a framework to investigate their role in cardiac ischemia using mathematical modeling and computational simulations at cellular and tissue level. Ischemia was incorporated by reproducing effects of hyperkalemia, acidosis, and hypoxia with a human electrophysiological model. In tissue, spatial heterogeneous ischemia was described by central ischemic (CIZ) and border zone. Anisotropic conduction was simulated with a bidomain approach in an anatomical ventricle model including realistic fiber orientation and transmural, apico-basal, and interventricular electrophysiological heterogeneities. A model of electrical conductivity in a human torso served for ECG calculations. Ischemia raised resting but reduced peak voltage, action potential duration and upstroke velocity. These effects were strongest in subepicardial cells. In tissue, conduction velocity decreased towards CIZ but effective refractory period increases. At 10 min of ischemia 19% of subepi- and 100% of subendocardial CIZ cells activated with a delay of 34.6±7.8 ms and 55.9±18.8 ms, respectively, compared to normal. Significant ST elevation and premature T wave end appeared only with the subepicardial CIZ. The model reproduced effects of ischemia at cellular and tissue level. The results suggest that the presented in-silico approach can complement experimental studies e.g. in understanding the role of ischemia or the onset of arrhythmia.
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the western world. Genetic variants in the cardiac I Kr channel have been identified to influence ventricular repolarization. The aim of this work is to investigate the effect of the mutation N588K on atrial repolarization and the predisposition to AF. Experimental data of N588K mutated hERG channel were incorporated in an atrial ionic model using parameter fitting. The effects of the mutation were analyzed in cell and tissue. N588K showed a gain of function effect, causing a rapid repolarization and a shortening of the action potential duration. Computer simulations of a schematic right atrial geometry were used to investigate the excitation conduction properties. The effective refractory period of mutant cells were reduced from 317 to 233 ms at 1 Hz. The conduction velocity is not significantly influenced by the mutation. Nevertheless, the wavelength of mutant cells is for all frequencies smaller, indicating that the mutation N588K predisposes the initiation and perpetuation of AF.
Cisapride is a drug to help gastric problems. It is limited because of reports of the side-effect long QT syndrome which predisposes to arrhythmias. In this computatinal study, the effects of Cisapride on human ventricular myocytes are investigated in-silico. From literature reported effects of the drug on ion channel level are included into a virtual human ventricular cell. Cisapride has the most dominating effect on the rapid delayed rectifier current IKr. A shift in the activation and inactivation and mainly a reduction of conductivity is seen. This leads to the prolongation of the APD comparable to the long QT syndrome. In future studies, the stability of the heart under the influence of this drug will be evaluated
P. Carrillo, G. Seemann, E. Scholz, D. L. Weiss, and O. Dössel. Impact of the hERG Channel Mutation N588K on the Electrical Properties of the Human Atrium. In 4th European Conference of the International Federation for Medical and Biological Engineering, IFMBE Proc., vol. 22(22) , pp. 2583-2586, 2009
Atrial fibrillation is the most common cardiac arrhythmia in humans. The precise cellular mechanisms underlying atrial fibrillation are still poorly understood. Recent studies have identified several genetic defects as predisposing factors for this pathology. One of the identified genetic defects is the mutation N588K, which affects the cardiac IKr channel. Genetic variants in this channel have been identified to modify ventricular repolarization. The aim of this work is to investigate the effect of this mutation on atrial repolarization and the predisposition to atrial fibrillation.Measured data obtained with whole cell voltage clamp technique of wild-type and mutated hERG channel were implemented in the Courtemanche et al. ionic model. For this purpose, channel kinetics and density of the model were adjusted using parameter fitting to the measured data. By this way, the effects of the mutation in the hERG channel could be analyzed in the whole cell and in tissue, as well. The channel mutation N588K showed a gain of function effect, causing a rapid repolarization and consequently, a shortening of the action potential duration. Computer simulations of a schematic anatomical model of the right atrium were then carried out to investigate the excitation propagation and the repolarization.The action potential duration of the mutant cell was reduced to 116 ms and the effective refractory period to 220 ms. Both factors are linked to a shortening of the wavelength, indicating that the mutation N588K predisposes the initiation and perpetuation of atrial fibrillation.
R. Kalayciyan, D. U. J. Keller, G. Seemann, and O. Dössel. Creation of a realistic endocardial stimulation profile for the visible man dataset. In IFMBE Proceedings World Congress on Medical Physics and Biomedical Engineering, vol. 25/4, pp. 934-937, 2009
D. U. J. Keller, O. Dössel, and G. Seemann. Evaluation of rule-based approaches for the incorporation of skeletal muscle fiber orientation in patient-specific anatomies. In Proceedings Computers in Cardiology, vol. 36, pp. 181-184, 2009
Muscle anisotropy is important for the realistic solution of the forward problem of electrocardiography. Whenever computer models of patient-specific anatomies are created usually no information about the muscle fiber arrangement in the heart or skeletal muscle is available. As in-vivo imaging techniques that can determine fiber orientation like Diffusion Tensor MRI are time-consuming and susceptible to motion artifacts, cardiac fiber orientation is frequently described using simplified rules. However, for the skeletal muscle there are only few suggestions for a rule-based implementation of fiber orientation into patient-specific models. In this work we evaluated a rule-based approach from the literature together with two new methods by comparing the corresponding forward calculated body surface potential maps (BSPMs) with the BSPM resulting from a reference skeletal muscle fiber distribution extracted from the thin-section photos of the Visible Man dataset (Journal of Computing and Information Technology vol.6, pp. 95-101 1998). The skeletal muscle anisotropy ratio was set to 3:1. The following fiber orientation setups were evaluated: A) the torso is divided into twelve sectors (cross-section perspective) and fiber direction was assumed to be perpendicular to the bisector as proposed by Klepfer et al. (IEEE Trans. Biomed. Eng. vol. 44, no. 8, pp. 706-719 1997); B) A 3D Sobel filter was used on the torso geometry filled with a gradient from inside to outside which generated a vector that was normal to the thoracic surface in every voxel. Fiber orientation was assumed to be perpendicular to the plane formed by these normal vectors and the direction from head to feet (longitudinal torso orientation); C) Same procedure as in B) but additionally, the back muscles which are known to have a longitudinal orientation were integrated accordingly. Potentials were extracted at 64 electrode positions from the BSPMs. The RMS was calculated at these electrode positions between the reference fiber distribution and the respective rule-based approaches. The RMS was comparable between A) and B) (8.8e-5 vs. 8.9e-5) leading to the conclusion that the twelve discrete sectors introduced no significant error. A) and B) performed also well compared to a modified version of the reference dataset where the longitudinal component of the fiber vectors was set to zero (8.3e-5). Including the longitudinal components of the back muscles as done in C) enhances the RMS to 5.5e-5. If the skeletal muscle anisotropy was neglected and only cardiac fiber orientation was taken into account, the RMS improved (!) further to only 4.0e-5. Thus it can be concluded that neglecting the longitudinal component (A) and B)) or accounting for it with a highly simplified approach (C)) is not sufficient. In cases where no detailed information about the skeletal muscle fiber arrangement is available, it is better to entirely neglect its anisotropic influence.
D. U. J. Keller, R. Kalayciyan, O. Dössel, and G. Seemann. Fast creation of endocardial stimulation profiles for the realistic simulation of body surface ECGs. In IFMBE Proceedings World Congress on Medical Physics and Biomedical Engineering, vol. 25/4, pp. 145-148, 2009
The Purkinje network plays a major role for realistically simulating the activation sequence of the ventricles. In this work, we describe a method to create an endocardial stimulation profile that describes the location and time instant of ventricular stimulation, thus mimicking the His-Purkinje conduction system. By adapting model parameters stimulation profiles can be generated for different ventricular anatomies with minimal manual interaction. The stimulation profile parameters are evaluated by analyzing the excitation propagation in a three-dimensional, heterogeneous and anisotropic model of the human ventricles which are embedded in an anatomically detailed torso geometry. The calculated QRS complexes are in good agreement with the corresponding clinical recordings on the same proband.
M. W. Krueger, F. M. Weber, G. Seemann, and O. Dössel. Influence of myocardial structures on electrophysiologic simulations in patient specific atrial models. In The Cardiac Physiome: Multi-scale and Multi-physics Mathematical Modelling Applied to the Heart, 2009
M. W. Krueger, F. M. Weber, G. Seemann, and O. Dössel. Semi-automatic segmentation of sinus node, Bachmann's Bundle and Terminal Crest for patient specific atrial models. In World Congress on Medical Physics and Biomedical Engineering. IFMBE Proceedings, vol. 25/4, pp. 673-676, 2009
The human atria contain fine structures, which can hardly be distinguished with common medical imaging techniques. However, some of these structures play an important role in the electrophysiologic depolarisation sequence of the atria. We present a semi-automatic algorithm to segment the sinus node, Bachmann’s Bundle and the Terminal Crest in given anatomical shape models of the atria. The algorithm bases on anatomical knowledge of the atria and only requires the user to provide few distinct landmarks in the atria as input. Incorporation of these structures into patient individual atrial geometries augments the electrophysiological correctness of the models.
C. A. Otto, D. U. J. Keller, G. Seemann, and O. Dössel. Integrating Beta-Adrenergic Signaling into a Computational Model of Human Cardiac Electrophysiology. In IFMBE Proceedings World Congress on Medical Physics and Biomedical Engineering, vol. 25/4, pp. 1033-1036, 2009
Orthogonal recursive bisection (ORB) algorithm can be used as data decomposition strategy to distribute a large data set of a cardiac model to a distributed memory supercomputer. It has been shown previously that good scaling results can be achieved using the ORB algorithm for data decomposition. However, the ORB algorithm depends on the distribution of computational load of each element in the data set. In this work we investigated the dependence of data decomposition and load balancing on different rotations of the anatomical data set to achieve optimization in load balancing. The anatomical data set was given by both ventricles of the Visible Female data set in a 0.2 mm resolution. Fiber orientation was included. The data set was rotated by 90 degrees around x, y and z axis, respectively. By either translating or by simply taking the magnitude of the resulting negative coordinates we were able to create 14 data sets of the same anatomy with different orientation and position in the overall volume. Computation load ratios for non tissue vs. tissue elements used in the data decomposition were 1:1, 1:2, 1:5, 1:10, 1:25, 1:38.85, 1:50 and 1:100 to investigate the effect of different load ratios on the data decomposition. The ten Tusscher et al. (2004) electrophysiological cell model was used in monodomain simulations of 1 ms simulation time to compare performance using the different data sets and orientations. The simulations were carried out for load ratio 1:10, 1:25 and 1:38.85 on a 512 processor partition of the IBM Blue Gene/L supercomputer. The results show that the data decomposition does depend on the orientation and position of the anatomy in the global volume. The difference in total run time between the data sets is 10 s for a simulation time of 1 ms. This yields a difference of about 28 h for a simulation of 10 s simulation time. However, given larger processor partitions, the difference in run time decreases and becomes less significant. Depending on the processor partition size, future work will have to consider the orientation of the anatomy in the global volume for longer simulation runs.
The output data generated in whole heart simula- tions are usually single or multiple parameters at each point in the simulation space. Visualizing data sets of gigabyte size puts great stress on the hardware and can be slow and tedious. Creating animated movies to analyze the excitation propaga- tion can take hours on standard systems. We present two par- allel visualization techniques to improve rendering of large datasets from cardiac simulations.The Scalable Parallel Visualization Networking (SPVN) toolkit provides the ability to assist in optimizing the utility and functionality of the aggregate resources in visualization clusters. Run time visualization offers the opportunity to visu- alize the results of cardiac simulations on the fly on High Per- formance Computers. Parallel visualization techniques enable fast manipulation of high resolution whole heart data sets and simulation results. The SPVN system has the potential to be linked with the simulation environment similar to the run time visualization described.Future efforts will focus on creating a simulation and visu- alization environment with appropriate characteristics for clinical setting. Specifically, speed, intuitive control and the ability to render diverse signals will likely be critical to drive adoption in the clinical setting.
Patient-specific model adaptation and validation requires a comparison of simulations with measured patient data. For patients suffering from atrial fibrillation, such data is mainly available as intracardiac catheter signals. In this work, we demonstrate the simulation of clinically relevant catheter data as measured using circular mapping catheters (such as Lasso or Orbiter) and coronary sinus catheters using atrial simulations on a realistic geometry. Four circular catheters are modeled using a projection technique for two distinct types of application. We show that in sinus rhythm, the choice of a distinct electrophysiological model does not impair the signal quality. Finally, we compare simulated potentials to a real clinical measurement. In the future, with patient- specific models available, such comparisons can constitute an important interface for personalizing cardiac models.
Intracardiac catheter recordings are available in common clinical practice. They can therefore be employed to adapt and validate atrial computer models of individual patients. Hence, their information content needs to be analyzed quantitatively. During treatment of atrial arrhythmia such as atrial flutter or fibrillation, the location of ectopic foci in the pulmonary veins is of special interest. In this study, virtual catheter signals are extracted from an atrial simulation on a realistic geometry with normal sinus rhythm as well as ectopic stimuli in all four pulmonary veins. Using a simplified Pan-Tompkins algorithm, the activation times are determined. Based on the analysis of the activation sequence in a circular mapping catheter simulated on the posterior left atrial wall, all four ectopic foci can clearly be associated with the pulmonary vein they came from. For a catheter on the anterior wall, this is possible for three of the four ectopic beats. Despite the knowledge gathered for the personalization of patient models, such simulations may help cardiologists to better classify measured signals.
Patient-specific cardiac simulations are approaching clinical applications. They could for example improve the treatment of atrial fibrillation (AF). Currently, many patients suffering from AF are treated with minimally-invasive catheter ablation. Using this technique, trigger sources for AF (mainly the pulmonary veins), are electrically isolated from the rest of the atrium. However, a large set of different ablation strategies is currently used in clinical practice. Therefore, the choice of a certain ablation strategy as well as the probability for successful and sustained AF termination are strongly dependent on the experience of the cardiologist. Atrial simulations could assist the cardiologist in the choice of a suitable method for an individual patient. For this, the atrial models have to be adapted to the patient. Besides anatomical modeling, several challenges must be faced in this process. First, an appropriate model of cellular electrophysiology and excitation conduction must be chosen. The model must provide the necessary accuracy and at the same time be fast enough for clinical applications. As a trade-off between accuracy and speed, we propose a minimal model adapted to atrial electrophysiology. Second, a main problem is the adaptation of physiological parameters in the patient-specific model as well as its validation. Therefore, an interface between clinical data and the model is needed. Data collected in standard clinical workflow are mainly intracardiac catheter ECGs. We therefore present techniques to model such catheter measurements. Signals from both circular mapping catheters (such as Lasso or Orbiter) as well as Coronary Sinus catheters can be simulated and compared to clinical signals. These are important steps towards clinical applications of atrial models. The long-term goal then is to assist the cardiologist in the choice of the best treatment for an individual patient.