Abstract:

Models of cardiac tissue electrophysiology are an important component of the Cardiac Physiome Project, which is an international effort to build biophysically based multi-scale mathematical models of the heart. Models of tissue electrophysiology can provide a bridge between electrophysiological cell models at smaller scales, and tissue mechanics, metabolism and blood flow at larger scales. This paper is a critical review of cardiac tissue electrophysiology models, focussing on the micro-structure of cardiac tissue, generic behaviours of action potential propagation, different models of cardiac tissue electrophysiology, the choice of parameter values and tissue geometry, emergent properties in tissue models, numerical techniques and computational issues. We propose a tentative list of information that could be included in published descriptions of tissue electrophysiology models, and used to support interpretation and evaluation of simulation results. We conclude with a discussion of challenges and open questions.

Abstract:

In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field.

Abstract:

The specific absorption rate (SAR) is a limiting constraint in sequence design for high-field MRI. SAR estimation is typically performed by numerical simulations using generic human body models. This entails an intrinsic uncertainty in present SAR prediction. This study first investigates the required detail of human body models in terms of spatial resolution and the number of soft tissue classes required, based on finite-differences time-domain simulations of a 3 T body coil. The numerical results indicate that a resolution of 5 mm is sufficient for local SAR estimation. Moreover, a differentiation between fatty tissues, water-rich tissues, and the lungs was found to be essential to represent eddy current paths inside the human body. This study then proposes a novel approach for generating individualized body models from whole-body water-fat-separated MR data and applies it to volunteers. The SAR hotspots consistently occurred in the arms due to proximity to the body coil as well as in narrow regions of the muscles. An initial in vivo validation of the simulated fields in comparison with measured B(1) -field maps showed good qualitative and quantitative agreement. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc.

Abstract:

OBJECT: Parallel transmission facilitates a relatively direct control of the RF transmit field. This is usually applied to improve the RF field homogeneity but might also allow a reduction of the specific absorption rate (SAR) to increase freedom in sequence design for high-field MRI. However, predicting the local SAR is challenging as it depends not only on the multi-channel drive but also on the individual patient. MATERIALS AND METHODS: The potential of RF shimming for SAR management is investigated for a 3 T body coil with eight independent transmit elements, based on Finite-Difference Time-Domain (FDTD) simulations. To address the patient-dependency of the SAR, nine human body models were generated from volunteer MR data and used in the simulations. A novel approach to RF shimming that enforces local SAR constraints is proposed. RESULTS: RF shimming substantially reduced the local SAR, consistently for all volunteers. Using SAR constraints, a further SAR reduction could be achieved with only minor compromises in RF performance. CONCLUSION: Parallel transmission can become an important tool to control and manage the local SAR in the human body. The practical use of local SAR constraints is feasible with consistent results for a variety of body models.

Abstract:

The specific absorption rate (SAR) is an important safety criterion, limiting many MR protocols with respect to the achievable contrast and scan duration. Parallel transmission enables control of the radiofrequency field in space and time and hence allows for SAR management. However, a trade-off exists between radiofrequency pulse performance and SAR reduction. To overcome this problem, in this work, parallel transmit radiofrequency pulses are adapted to the position in sampling k-space. In the central k-space, highly homogeneous but SAR-intensive radiofrequency shim settings are used to achieve optimal performance and contrast. In the outer k-space, the homogeneity requirement is relaxed to reduce the average SAR of the scan. The approach was experimentally verified on phantoms and volunteers using field echo and spin echo sequences. A reduction of the SAR by 25-50% was achieved without compromising image quality.

Abstract:

Ventricular wall deformation is widely assumed to have an impact on the morphology of the T-wave that can be measured on the body surface. This study aims at quantifying these effects based on an in silico approach. To this end, we used a hybrid, static-dynamic approach: action potential propagation and repolarization were simulated on an electrophysiologically detailed but static 3-D heart model while the forward calculation accounted for ventricular deformation and the associated movement of the electrical sources (thus, it was dynamic). The displacement vectors that describe the ventricular motion were extracted from cinematographic and tagged MRI data using an elastic registration procedure. To probe to what extent the T-wave changes depend on the synchrony/asynchrony of mechanical relaxation and electrical repolarization, we created three electrophysiological configurations, each with a unique QT time: a setup with physiological QT time, a setup with pathologically short QT time (SQT), and pathologically long QT time (LQT), respectively. For all three electrophysiological configurations, a reduction of the T-wave amplitude was observed when the dynamic model was used for the forward calculations. The largest amplitude changes and the lowest correlation coefficients between the static and dynamic model were observed for the SQT setup, followed by the physiological QT and LQT setups.

Abstract:

BACKGROUND: The prevalence of atrial fibrillation is increased in patients with end-stage renal disease. Previous studies suggested that extracellular electrolyte alterations caused by hemodialysis (HD) therapy could be proarrhythmic. METHODS: Multiscale models were used for a consequent analysis of the effects of extracellular ion concentration changes on atrial electrophysiology. Simulations were based on measured electrolyte concentrations from patients with end-stage renal disease. RESULTS: Simulated conduction velocity and effective refractory period are decreased at the end of an HD session, with potassium having the strongest influence. P-wave is prolonged in patients undergoing HD therapy in the simulation as in measurements. CONCLUSIONS: Electrolyte concentration alterations impact atrial electrophysiology from the action potential level to the P-wave and can be proarrhythmic, especially because of induced hypokalemia. Analysis of blood electrolytes enables patient-specific electrophysiology modeling. We are providing a tool to investigate atrial arrhythmias associated with HD therapy, which, in the future, can be used to prevent such complications.

Abstract:

Ongoing developments in cardiac modelling have resulted, in particular, in the development of advanced and increasingly complex computational frameworks for simulating cardiac tissue electrophysiology. The goal of these simulations is often to represent the detailed physiology and pathologies of the heart using codes that exploit the computational potential of high-performance computing architectures. These developments have rapidly progressed the simulation capacity of cardiac virtual physiological human style models; however, they have also made it increasingly challenging to verify that a given code provides a faithful representation of the purported governing equations and corresponding solution techniques. This study provides the first cardiac tissue electrophysiology simulation benchmark to allow these codes to be verified. The benchmark was successfully evaluated on 11 simulation platforms to generate a consensus gold-standard converged solution. The benchmark definition in combination with the gold-standard solution can now be used to verify new simulation codes and numerical methods in the future.

Abstract:

The loss of cardiac pump function accounts for a significant increase in both mortality and morbidity in Western society, where there is currently a one in four lifetime risk, and costs associated with acute and long-term hospital treatments are accelerating. The significance of cardiac disease has motivated the application of state-of-the-art clinical imaging techniques and functional signal analysis to aid diagnosis and clinical planning. Measurements of cardiac function currently provide high-resolution datasets for characterizing cardiac patients. However, the clinical practice of using population-based metrics derived from separate image or signal-based datasets often indicates contradictory treatments plans owing to inter-individual variability in pathophysiology. To address this issue, the goal of our work, demonstrated in this study through four specific clinical applications, is to integrate multiple types of functional data into a consistent framework using multi-scale computational modelling.

Abstract:

The electric properties of human tissue can potentially be used as an additional diagnostic parameter, e.g., in tumor diagnosis. In the framework of radiofrequency safety, the electric conductivity of tissue is needed to correctly estimate the local specific absorption rate distribution during MR measurements. In this study, a recently developed approach, called electric properties tomography (EPT) is adapted for and applied to in vivo imaging. It derives the patient's electric conductivity and permittivity from the spatial sensitivity distributions of the applied radiofrequency coils. In contrast to other methods to measure the patient's electric properties, EPT does not apply externally mounted electrodes, currents, or radiofrequency probes, which enhances the practicability of the approach. This work shows that conductivity distributions can be reconstructed from phase images and permittivity distributions can be reconstructed from magnitude images of the radiofrequency transmit field. Corresponding numerical simulations using finite-difference time-domain methods support the feasibility of this phase-based conductivity imaging and magnitude-based permittivity imaging. Using this approximation, three-dimensional in vivo conductivity and permittivity maps of the human brain are obtained in 5 and 13 min, respectively, which can be considered a step toward clinical feasibility for EPT. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc.

Abstract:

In this paper, we present an efficient method to estimate changes in forward-calculated body surface potential maps (BSPMs) caused by variations in tissue conductivities. For blood, skeletal muscle, lungs, and fat, the influence of conductivity variations was analyzed using the principal component analysis (PCA). For each single tissue, we obtained the first PCA eigenvector from seven sample simulations with conductivities between ±75% of the default value. We showed that this eigenvector was sufficient to estimate the signal over the whole conductivity range of ±75%. By aligning the origins of the different PCA coordinate systems and superimposing the single tissue effects, it was possible to estimate the BSPM for combined conductivity variations in all four tissues. Furthermore, the method can be used to easily calculate confidence intervals for the signal, i.e., the minimal and maximal possible amplitudes for given conductivity uncertainties. In addition to that, it was possible to determine the most probable conductivity values for a given BSPM signal. This was achieved by probing hundreds of different conductivity combinations with a numerical optimization scheme. In conclusion, our method allows to efficiently predict forward-calculated BSPMs over a wide range of conductivity values from few sample simulations.

Abstract:

Conduction velocity (CV) and CV restitution are important substrate parameters for understanding atrial arrhythmias. The aim of this work is to (i) present a simple but feasible method to measure CV restitution in-vivo using standard circular catheters, and (ii) validate its feasibility with data measured during incremental pacing. From five patients undergoing catheter ablation, we analyzed 8 datasets from sinus rhythm and incremental pacing sequences. Every wavefront was measured with a circular catheter and the electrograms were analyzed with a cosine-fit method that calculated the local CV. For each pacing cycle length, the mean local CV was determined. Furthermore, changes in global CV were estimated from the time delay between pacing stimulus and wavefront arrival. Comparing local and global CV between pacing at 500 and 300 ms, we found significant changes in 7 of 8 pacing sequences. On average, local CV decreased by 2015% and global CV by 1713%. The method allows for in-vivo measurements of absolute CV and CV restitution during standard clinical procedures. Such data may provide valuable insights into mechanisms of atrial arrhythmias. This is important both for improving cardiac models and also for clinical applications, such as characterizing arrhythmogenic substrates during sinus rhythm.

Abstract:

Acute cardiac ischemia, which is caused by the occlusion of a coronary artery, often leads to lethal ventricular arrhythmias or heart failure. The early diagnosis of this pathology is based on changes of the electrocardiogram (ECG), i.e. mainly shifts of the ST segment. However, the underlying mechanisms responsible for these shifts are not completely understood. Furthermore, clinical observations indicate that some acute ischemia cases can hardly be detected using standard 12-lead ECG only. Therefore, multi-scale computer simulations of cardiac ischemia using realistic models of human ventricles were carried out in this work. For this purpose, the transmembrane voltage distributions in the heart and the corresponding body surface potentials were computed with varying transmural extent of the ischemic region at different ischemia stages. Some of the simulated ischemia cases were electrically silent, i.e. they could hardly be identified in the 12-lead ECG.

Abstract:

In guideline E14, the American Food and Drug Administration (FDA) requests for clinical studies to investigate the prolongation of the heart rate corrected QT-interval (QTc) of the ECG. As drug induced QT-prolongation can be caused by changes in the repolarisation of the ventricles, it is so far a thorough ECG biomarker of risk for ventricular tachyarrhythmias and Torsade de Pointes (TdP). Ventricular repolarisation changes not only change QT but also influence the morphology of the T-wave. In a (400 mg single dose) Moxifloxacin positive control study both, QTc and several descriptors describing the T-wave morphology have been measured. Moxifloxacin is changing two shape dependent descriptors significantly (P<0.05) about 3 to 4 hours after a 400 mg oral single dose of Moxifloxacin.

Abstract:

Magnetic Particle Imaging (MPI) benefits from the non-linear magnetization curve of magnetic nano-particles. Magnetic fields applied in this new imaging modality are of fre- quencies in the kHz-range. Little research has been carried out upon absorbed power and temperature increase caused by time- varying fields in that frequency range. Presented here are tem- perature distributions in a human body model exposed to mag- netic fields of 10 kHz to 100 kHz. A numerical human model has been placed within field generating coils. The finite elements model for the field calculation and the Pennes Bio-heat equation for the temperature distribution with and without perfusion and heat transfer by convection have been used. The results indicate that the absorbed power does lead to local temperature increase but not up to a hazardous level, if certain thresholds for the mag- netic fields are considered.

Abstract:

A method to reconstruct integrals of transmembrane voltages in the heart from measured integrals of Body Surface Potential Maps (BSPM) is proposed. It is applied to localize the origin of premature beats in the heart (extrasystoles). In contrast to other proposals no specific assumption about the slope of the transmembrane voltage during depolarization is made, in particular it must not be a step function. This way the non-linear problem of localizing ectopic foci based on activation times is translated into a linear inverse problem. A Maximum-A-Posteriori (MAP) estimator is applied to solve the ill-posed linear inverse problem. Successful localization of ventricular extrasystoles is demonstrated using computer simulations. Even endocardial, midmyocardial and epicardial foci can be separated.

Abstract:

The objective of personalised modelling of the atria is to improve comprehension of the etiology of atrial arrhythmias, to enable specific diagnosis and to optimise therapy. We start with CT or MR datasets and use adapted segmentation procedures to build a patient-specific 3D-model of the atria. Then we include fibre direction based on the rules of atrial anatomy. Work in progress is also considering late enhancement MRI in order to add areas of fibrotic tissue. Next we can use BSPM data of the P-wave and solve the inverse problem of ECG to get a hypothesis about the spread of depolarisation. Finally we use intracardiac catheter signals (e.g. using a circular catheter) to measure direction and conduction velocity of depolarisation waves (sinus rhythm, atrial flutter, or following stimulation). All this is integrated into a personalised model of the atria of an individual patient. Our next goal will be to properly add ablation lines into the model.The research leading to these results has partly received funding from the European Communitys Seventh Framework Programme (FP7/2007-2013) under grant agreement n 224495 (euHeart project).

Abstract:

A framework for step-by-step personalization of a computational model of human atria is presented. Beginning with anatomical modeling based on CT or MRI data, next fiber structure is superimposed using a rule-based method. If available, late-enhancement-MRI images can be considered in order to mark fibrotic tissue. A first estimate of individual electrophysiology is gained from BSPM data solving the inverse problem of ECG. A final adjustment of electrophysiology is realized using intracardiac measurements. The framework is applied using several patient data. First clinical application will be computer assisted planning of RF-ablation for treatment of atrial flutter and atrial fibrillation.

Abstract:

The impact of transmural infarctions of the left ventricle on the cardiac mechanical dynamics is evaluated for all 17 AHA segments in a computer model. The simulation framework consists of two parts: an electrophysiological model and an elastomechanical model of the ventricles. The electrophysiological model is used to simulate the electrophysiological processes on cellular level, excitation propagation and the tension development. It is linked to the elastomechanical model, which is based on nonlinear finite element analysis for continuum mechanics. Altogether, 18 simulations of the contraction of the ventricles were performed, 17 with an infarction in the respective AHA segment and one simulation for the control case. For each simulation, the mechanical dynamics as well as the wall thickening of the infarct region were analyzed and compared to the corresponding region of the control case. The simulation revealed details of the impact of the myocardial infarction on wall thickening as well as on the velocity of the infarct region for most of the AHA segments

Abstract:

Elastomechanical modeling of the heart can help to gain a deeper insight into the mechanical dynamics of the heart. Furthermore it can help to enhance diagnostic strategies and to investigate new therapeutic approaches. Phase contrast magnetic resonance imaging allows to directly measure the velocity vector field of the myocardial motion over the cardiac cycle. Aim of this work was to analyze the impact of transmural myocardial infarction on the velocity vector field of the left ventricle in a numerical model of the heart. For this purpose a multi-scale electromechanical computer framework was used. It consisted of two parts: an electrophysiological model and an elastomechanical model. The electrophysiological model described the electrophysiological processes on cellular level, the excitation propagation as well as the tension development. It was was linked to an elastomechanical model which was based on nonlinear continuum mechanics using the finite element method. The computer framework was used to simulate the contraction of the heart with left ventricular transmural infarctions, differing in size, location and stiffness of the scar tissue. For each simulation, the velocity vector field of the infarct region was analyzed and compared to the corresponding region of the control case. The simulations revealed a direct impact of the myocardial infarction on the magnitude and orientation of the velocity vectors of the affected region.

Abstract:

The delineation of anatomical structures in medical images can be achieved in an efficient and robust manner using statistical anatomical organ models, which has been demonstrated for an already considerable set of organs, including the heart. While it is possible to provide models with sufficient shape variability to cope, to a large extent, with inter-patient variability, as long as object topology is conserved, it is a fundamental problem to cope with topological organ variability. We address this by creating a set of model variants and selecting the most appropriate model variant for the patient at hand. We propose a hybrid method combining model-based image analysis with a guided region growing approach for automated anatomical variant selection and apply it to the left atrium in cardiac CT images. Concerning the human heart, the left atrium is the most variable sub-structure with a variable number of pulmonary veins draining into it. It is of large clinical interest in the context of atrial fibrillation and related interventions.

Abstract:

Atrial myofiber orientation is complex and has multiple discrete layers and bundles. A novel robust semi-automatic method to incorporate atrial anisotropy and heterogeneities into patient-specific models is introduced. The user needs to provide 22 distinct seed-points from which a network of auxiliary lines is constructed. These are used to define fiber orientation and myocardial bundles. The method was applied to 14 patient-specific volumetric models derived from CT, MRI and photographic data. Initial electrophysiological simulations show a significant influence of anisotropy and heterogeneity on the excitation pattern and P-wave duration (20.7% shortening). Fiber modeling results show good overall correspondence with anatomical data. Minor modeling errors are observed if more than four pulmonary veins exist in the model. The method is an important step towards creating realistic patient-specific atrial models for clinical applications.

Abstract:

Atrial fibre architecture has complex patterns of bundles and layers and is known to impact on atrial electrophysiology, especially in fast-conducting bundles like Crista Terminalis, Bachmanns bundle and pectinate muscles. Based on a priori knowledge of atrial fibre structure, we incorporated rule-based fibre orientation in seven volumetric models of human atria using a semi-automatic approach. We were able to introduce multiple layers of myofibres and regional heterogeneities of ion channels in the models. We evaluated the influence of complete atrial fibre architecture on multiple modelling scales. First, we simulated atrial excitation in the isotropic and anisotropic models using the model of Courtemanche et al. in combination with the monodomain approach. Second, we computed body surface potentials from the simulated transmembrane voltages and compared these to measured ECGs from the respective patients. Temporal behaviour of the atrial excitation sequences was significantly altered in the anisotropic models compared to the sequences in the isotropic models. Complete atrial activation was achieved approximately 20% faster in the anisotropic models mostly due to fast conducting myofibre bundles. Electrophysiological heterogeneities influenced right atrial transmembrane voltage distribution over time due to a less negative action potential plateau in Crista Terminalis cells. P-wave duration was significantly shorted by the introduction of atrial anisotropy and the error to measured P-wave duration was reduced. Furthermore, a pattern change in body surface potential distribution over time was observed. The anisotropic patterns showed a better match to the measurements. Thus, the modelling error by using generalised fibre architecture for patient-specific models was smaller than by using isotropic models. The results highlight the necessity to incorporate atrial anisotropy in personalised models to produce more realistic simulations. The semi-automatic approach allows the use of these models for future clinical applications.

Abstract:

Background: Patients with end-stage renal disease show an increased prevalence of atrial fibrillation. A combined simulation and electrocardio- gram analysis study revealed a correlation between the changes in plasma electrolytes and intra-atrial conduction velocity related to hemodialysis (HD) session. A recognized limitation of the study is that simulations were performed on single-cell level. We present a computer study to investigate the influence of HD-related electrolyte modifications on atrial electrophys- iology in a volumetric environment.Methods: Based on the Courtemanche-Ramirez-Nattel model and its parameterization for different atrial tissues, we studied action potential, effective refractory period, conduction velocity (CV) restitution, and wave length restitution for common atrial myocardium (CAM) and fast conducting Crista Terminalis (CT). We used isotropic, homogeneous tissue patches. External stimuli were applied with 184 different pacing rates (PRs) from 330 to 1250 milliseconds.Results: The effect of temporary HD- related electrolyte changes on the action potential morphology and effective refractory period showed results consistent with the previous single-cell study. Action potential morphology was not significantly altered both in CAM and CT, but resting potential decreased from &#9251;82.6 to &#9251;88.2 mV for CAM and from &#9251;81.7 to &#9251;87.3 mV for CT. Effective refractory period decreased from 32 (pre-HD) to 308 milliseconds (end-HD). At a PR of 832 milliseconds, CV dropped by &#9251;6.3% for both types of tissue (CAM: 741 694 mm/s; CT: 746 699 mm/s). Wave length increased slightly with higher PR, but rapidly fell off below a PR of 450 milliseconds. Wave length was &#9251;30 mm shorter in the end-HD condition.Conclusions: Conduction velocity decrease and consequent wave length shortening increases vulnerability for atrial fibrillation onset, especially in conjunction with structural dilation often present in atria of end-stage renaldisease patients. Temporary HD-caused electrical remodeling has equal effects on regular and fast-conducting tissue. Although there is no biophysical model for fast interatrial condition pathways (eg, Bachmann dundle) available, the HD influence on them should also be similar and therefore slow down interatrial conduction significantly. It has been suggested that constantly repeating alteration of atrial electrophysiology may lead to a longer lasting electrical atrial remodeling; future studies should therefore investigate the long-term HD effects.

Abstract:

IntroductionAtrial fibrillation (AF) is the most common cardiac arrhythmia. Over 4.5 million people in the European Union suffer from AF. The mechanisms leading to AF are still not completely understood although various theories were proposed. Numerical models of the human atria can help to understand these mechanisms. Personalized atrial models may in fu- ture be used to set up patient-specific therapies.MethodsPersonalization of atrial models splits into different tasks. The individual atrial and thorax anatomy are derived from various imaging modalities (CT, MRI). Valuable information is hidden in these data, such as atrial wall thickness and myocardial fiber structure. The missing parts are added to the geometric model using rule-based approaches. Atrial electrophysiology is adapted to different pathologies (e.g. remodeling, genetic defects) and to ECG and intracardiac measurements of the individual patient by tuning model parameters (e.g. conductivity).ResultsPersonalization of atrial anatomy enables a realistic simulation of atrial excitation propagation during sinus rhythm. Ad- justment of the generalized electrophysiology model to the according patient group provides insights into the substrate of the known global effects. Adaption of these model parameters to the individual patient results in a better fit of simu- lated intracardiac and ECG signals to the measurements.ConclusionWith the help of various personalization techniques, generalized atrial models can be adapted to patient data. These models may in future be used for personalized model-based AF-treatment planning.

Abstract:

Ectopic beats are a common cause of cardiac arrhythmia. In order to automatically detect and classify ectopic beats in the ECG a new method based on a Support Vector Machine (SVM) was developed. The numerical patterns needed for this classification task were obtained from rhythmical and morphological characteristics of the QRS complexes. The SVM was trained and tested using the MIT-BIH Arrythmia Database and the MIT-BIH Supraventricular Arrythmia Database. A sensitivity of 92.46% was achieved.

Abstract:

The early detection of myocardial ischemia is an essential lever for its successful treatment. We investigated an ECG monitoring system with 3 electrodes. Optimal electrode positions are determined using a cellular automaton. The spatially heterogeneous effects of myocardial ischemia were modeled by altering 4 electrophysiological parameters: action potential amplitude and duration, conduction velocity as well as resting membrane voltage. Both, transmural heterogeneity and the influence of the border zone were considered in the simulations on three patient models. The detection of myocardial ischemia is based on ST segment deviation from the physiological case. The signals used to find the best electrode positions comprise ischemic regions with different transmural extents in all 17 AHA segments. We show which ischemic ECGs can be detected given a realistic signal-to-noise ratio, false positive rate and maximum response time of the system.

Abstract:

Electrophysiological simulations of the atria could improve diagnosis and treatment of cardiac arrhythmia, like atrial fibrillation or flutter. For this purpose, a precise segmentation of both atria is needed. However, the atrial epicardium and the electrophysiological structures needed for electrophysiological simulations are barely or not at all detectable in CT-images. Therefore, a model based segmentation of only the atrial endocardium was developed as a landmark generator to facilitate the registration of a finite wall thickness model of the right and left atrial myocardium. It further incorporates atlas information about tissue structures relevant for simulation purposes like Bachmanns bundle, terminal crest, sinus node and the pectinate muscles. The correct model based segmentation of the atrial endocardium was achieved with a mean vertex to surface error of 0.53 mm for the left and 0.18 mm for the right atrium respectively. The atlas based myocardium segmentation yields physiologically correct results well suited for electrophysiological simulations.

Abstract:

Biosignal analysis is aiming at analyzing physiological parameters for improved diagnosis and treatment. In this paper, the use of multivariate autoregressive models is proposed as a new method to analyze ECG data and to gain further information about the functionality of the heart. This application is demonstrated on myocarditis patients, where cure and diagnosis was observed. Timeseries of RR and QT intervals are analyzed by an autoregressive (AR) model, whose parameters are found dependent on the condition of the inflammation. The heart muscle inflammation is known as potentially lethal and an invasive biopsy still is the gold standard. Due to the variety of its symptoms, detailled non-invasive diagnosis is rather difficult and thus a highly challenging topic.

Abstract:

In spite of the considerable medical and technical progress during the last years, catheter ablation of atrial fibrillation is still challenging. For a successful execution of the ablation and the avoidance of intricacies the catheter must be in contact with the endocardium, which is still difficult to assure with existent techniques. It would be desirable to detect the endocardial catheter contact directly from the signal shape and its properties. In this work, significant signal property changes were detected and investigated, which allow an automatic contact detection. Furthermore, atrial electrograms were simulated and compared with a database of measured and annotated signals. During these simulations, the distance between endocardium and the catheter tip could be chosen discretionary. The simulated signals revealed themselves to be very accurate. Simulations can now be used to analyse intracardiac signals more closely. The exact position of the catheter will hereby always be assured, which is not always granted in clinical practice.

Abstract:

Background: Catheter ablation of persistent atrial fibrillation (AF) is challenging. The underlying mechanisms are mostly unknown and discussed very controversially. Automated detection and signal analysis of complex fractionated atrial electrograms (CFAEs) is essential in supporting the physicians during the ablation procedure. To investigate the clinical value of descriptors for CFAEs, we calculate their value before and after pulmonary vein isolation (PVI). Pulmonary vein isolation effects the excitation propagation of AF. This should be detected by every descriptor. We calculated the dominant frequency (DF), the fractionation index (CFE-Idx), and the activity ratio (AR) before and after PVI.Methods: (1) A common analysis technique of AF is DF analysis. It is an estimation of the atrial activation rates. (2) Ensite-NavX provides an algorithm that delivers a CFE-Idx based on the cycle length of distinguishable local activities in one electrogram. (3) A third method calculates atrial activity with a segmentation algorithm based on a nonlinear energy operator. Complex fractionated atrial electrograms are marked as active segments. The AR is then defined as the ratio between the length of active segments and the total length of the signal [2]. Dominant frequency, CFE-Idx, and AR were compared on data sets of 17 patients suffering from persistent AF. All patients were sent to hospital for catheter ablation. Electrograms of 5 seconds were recorded before and after PVI at customary 46 locations per patient in the left atrium. Nine patients terminated during ablation (A), whereas 8 patients did not terminate (B) and underwent an external cardioversion. Results: The mean DF decreased from 5.7 ± 0.6 to 5.5 ± 0.3 Hz (A) and increased from 5.3 ± 0.5 to 5.5 ± 0.5 Hz (B). Mean CFE-Idx increased from 157 ± 68 to 223 ± 51 milliseconds (A) and from 222 ± 88 to 273 ± 72 milliseconds (B). Mean AR decreased from 0.65 ± 0.1 to 0.63 ± 0.04 (A) and increased from 0.69 ± 0.5 to 0.72 ± 0.1 (B).Conclusion: More regular excitation should result in higher CFE-Idx and lower DF and AR. We found intergroup differences and could show the influence of PVI on the excitation during AF. The fractionation index of CFE has shown the most distinct results in differentiation of the 2 states of PVI (before/after) and also in differentiation of group A to B. Nevertheless, AR and DF are promising alternatives. Removal of outliers will increase performance of AR and DF.

Abstract:

Tikhonov methods usually lead to solutions of low amplitude that are distributed around zero. When reconstructing transmembrane voltages (TMVs) in the myocardium, the signal is therefore often not in the physiological range of between around -80mV and 10mV. In this article, we propose an adjusted Tikhonov method that reconstructs TMVs in the correct range, given an estimate of one polarized node in the heart and an estimated set of nodes that have depolarized in the preceding time step. It is shown that when feeding the reconstructed TMVs into a simple cellular automaton recursively, and when using the computed excitation propagation as a prior for the Tikhonov method, it is possible to reconstruct the excitation propagation throughout the ventricular myocardium. The method requires an estimate of the region of initial activation.

Abstract:

# BackgroundMethods for the non-invasive imaging of atrial activation times could provide cardiologists with valuable information on pathological excitation conduction patterns, e.g. for treatment planning.In this study, the source representation functions used in the critical times method (Greensite et al. 1997) are expanded with a range adjustment to generate more accurate activation time maps from ECG measurements.# Materials and methodsExcitation conduction in the atria was simulated for various excitation origins with a cellular automaton. Body surface potential maps were obtained from forward calculations using a bidomain approach.As introduced in Greensite et al. 1995, the method of critical times can be used to quantitatively localize critical point locations and times, and to reconstruct surface activation in a qualitative manner. To this end, all atrial surface nodes were treated as critical points and the corresponding critical times were reconstructed using the zero-crossing method by Greensite, which is the subtraction of the two representation functions.For the heart surface nodes, it was observed that the minuend representation function in the zero-crossing term is often by magnitudes greater than the subtrahend. For the minuend to not dominate the subtrahend before the desired zero-crossing, which is supposed to occur at the time of depolarization, the minuend was therefore weighted with a sigmoid function and normalized to the range of the subtrahend.# ResultsAtrial activation times were reconstructed with both the zero-crossing method by Greensite and the sigmoid-weighted zero-crossing. Two effects were observed. The overall reconstruction quality of the established method improves in the presence of 30dB additive white Gaussian noise. This effect results from a gradual offset that is imposed on the reconstructed critical times under these circumstances (see Huiskamp and Greensite 1997). Second, it could be shown that a significant reduction of reconstruction error can be achieved in the absence of noise with the sigmoid-weighted adaptation of the formula.# ConclusionWith the newly introduced sigmoidal normalization, the quality of reconstruction can be improved significantly if noise levels are below 30dB. Clinical studies need to be made in order to validate the method and assess its performance in a realistic environment.

Abstract:

Magnetic resonance imaging (MRI) is a valuable diagnostic method for many cardiovascular diseases. To date, patients with pacemakers are contra-indicated for cardiac MRI exams due to several effects that can occur during the MRI procedure: a) heating of the lead-tip, and b) less hazardous sensing errors and device malfunctions. Almost all measurements on MRI pacemaker compatibility have been conducted on classic 1.5 or 3T cylindrical whole-body MRI systems. In contrast, this study focused on the use of a high field open MRI (HFO) system due to its advantageous properties of RF fields which are commonly made responsible for the induction of lead heating.

Abstract:

As of today, the use of MRI procedures on patients with implanted cardiac pacemakers is prohibited due to safety issues. The implants can interact with the RF fields of the MRI device. The most hazardous effect is heating at the tip of the lead, less dangerous are sensing errors and malfunctions of the devices, because they disappear completely after the procedure. The majority of the previous studies used classic cylindrical whole-body MRI systems. The influence of different alignments of the pacemaker/lead system and the RF fields were evaluated by comparing temperature changes occurring in a cylindrical device with the effects induced in a high field open MRI (HFO) system.

Abstract:

Background: Catheter ablation of complex atrial arrhythmias, such as atrial fibrillation and atypical atrial flutter, is still challenging. Clinically evaluated ablation methods are leading to moderate success rates. Assessments of intracardiac electrograms are often done subjectively by the physician. Automatic algorithms can therefore improve the analysis of complex atrial electrograms (EGMs). In this work, we demonstrate a quantitative analysis of intracardiac EGMs from circular mapping catheters in humans. Both the wave direction and the local conduction velocity (CV) were calculated from individual wave fronts passing the catheter.Methods: Intracardiac EGMs measured with circular mapping catheters in humans were retrospectively analyzed. Five data sets from 3 patients undergoing catheter ablation of atrial fibrillation or flutter were available. Using a nonlinear energy operator, activation times from 9 bipolar catheter signals were calculated for each atrial activity. The resulting activation pattern was fitted to a cosine-shaped data model that has been validated in a previous simulation study. The cosine phase represented the wave direction. From the cosine amplitude and the catheter radius, the conduction velocity was calculated.Results: The wave directions in all five measurements were stable with a standard deviation below 10°. Calculated CVs were in the range of 70 to 110 cm/s, which is in accordance with published values. In one patient, electrograms were recorded during atrial stimulation. Stimulation cycle length was decreased from 500 to 300 milliseconds. Conduction velocity decreased by approximately 10% at a cycle length of 300 milliseconds compared with the CV at 500 milliseconds.Conclusion: The results show the ability to reliably extract wave direction and conduction velocity from intracardiac EGMs recorded with circular mapping catheters. Detected directions were stable, and the CV values were in a physiological range. As individual beats are analyzed, the method will also enable the quantitative study of singular events such as ectopic beats and facilitate the localization of tachycardia origins. Further, it will help to measure substrate parameters such as the CV and even CV restitution behavior. This way, the method can help to identify patient-specific physiological parameters that can be integrated into patient-specific models. Furthermore, it can directly provide quantitative data of high diagnostic value to the examiner and thereby improve clinical success rates.

Abstract:

Diagnosis of acute cardiac ischemia depends on characteristic shifts of the ST segment. The transmural extent of the ischemic region and the temporal stage of ischemia have an impact on these changes. In this work, computer simulations of realistic ventricles with different transmural extent of the ischemic region were carried out. Furthermore, three stages within the first half hour after the occlusion of the distal left anterior descending coronary artery were regarded. The transmembrane voltage distributions and the corresponding body surface ECGs were calculated. It was observed how the electrophysiological properties worsen in the course of ischemia, so that almost no excitation was initiated in the central ischemic zone 30 minutes after the occlusion. In addition to these temporal effects, also the transmural extent of the ischemic region had an impact on the direction and intensity of the ST segment shift.

Abstract:

This work concentrates on in silico methods to investigate the impact of dronedarone on human myocytes. Here, two different atrial cells using the CRN model were simulated: firstly, the model of a healthy and secondly the model of an electrically remodeled myocyte, which possesses the electrophysiological behavior of a myocyte suffering from AF. In order to regard natural fluctuations of the agent, two drug concentrations were taken into account.Dronedarone is a new antiarrhythmic drug, which is similar to its parent agent amiodarone. Therefore, it is a multi channel blocker and is classified as class three antiarrhythmic drug. Nevertheless, properties of all Vaughan-Williams classes are exhibited. Blocking of channels, which is equivalent to a decrease of their conductivity, is dependent on the drug dosage. This link between the drug dosage and the inhibition of the channels is described by the Hill equation. However, only two values are needed to characterize the Hill function. Hence, in order to describe the impact of dronedarone, these values were obtained from literature. But, due to the spread of data, three setups were created. Here, each setup individually describes the effect of the drug.Afterwards, simulations using single cells were carried out, during which the drug related APD prolongations were investigated. Though based on experimental studies, it became clear that the created setups missed data. Therefore, unpublished data of the Kur channel was included, which resulted in much more realistic results. Hence, these expanded setups were also used in the further simulations.During the investigation of the different impacts of the setups on the ERP, CV and WL as well, setup 3 turned out to be the most successful one, since the prolongations were superior to those of the other setups. In contrast, setup 1 is the only one, which was successful in reducing the width of the VW, even though only in case of using the lower drug concentration.Finally, a two-dimensional tissue patch was created, within which four rotatory excitations were artificially placed in order to simulate AF. Thus, the effect of dronedarone on AF could be investigated during a simulation period of about 5 seconds. The investigation included the tracking of the rotor centers as well as the measurement of pseudo ECGs, from which the characteristic frequencies were extracted. Hence, information about the propagation progress as well as the possibility of AF to terminate of its own volition were gained. Unfortunately, no setup was able to terminate one or more rotors, but both the rotor propagation as well as the characteristic frequency were influenced. The biggest decrease of the characteristic frequency and therefore the highest possibility of AF to terminate of its own volition was achieved by using setup 3. The characteristic frequency in case of the higher drug concentration was lowered from 8.98 Hz to 7.81 Hz. Based on this outcome, further simulations with both drug concentrations using setup 3 were started. These simulations lasted 25 seconds, in order to investigate the long-term effect. Yet, no changes of the characteristic frequency appeared.Finally, dronedarone was found to be eventually effective in preventing the onset of AF in electrically remodeled cells and tissue but it is not able to terminate chronic AF.

Abstract:

This work is focused on different aspects within the loop of multiscale modeling:On the cellular level, effects of adrenergic regulation and the Long-QT syndrome have been investigated.On the organ level, a model for the excitation conduction system was developed and the role of electrophysiological heterogeneities was analyzed.On the torso level a dynamic model of a deforming heart was created and the effects of tissue conductivities on the solution of the forward problem were evaluated.

Abstract:

In this computer based work, the dose-dependent effect of 4-Aminopyridine on chronic atrial fibrillation in a virtual model was investigated. The CRN model was used and adjusted to do so. Additionally, a method of detection of the Vulnerable Window was de- veloped and the effect of 4-AP on it was examined. Furthermore, the minimal stimulation amplitude for a better comparison of various simulations was introduced.4-AP is a potent inhibitor of those potassium channels, which determine repolarization. The dose-dependent effects on these ion channels can be described by the reduction of their conductances. In order to modify the conductances, it was necessary to fit data from literature to the Hill equation.Afterwards, the effects on the restitution properties and on VW for normal and remodeled tissue could be examined. The simulations were performed for seven different concentra- tions in each case. The two lowest concentrations did not deviate from the control cases for any simulation, whereas the two highest concentrations caused very unphysiological effects.The other doses of 4-AP prolonged APD, ERP and WL, especially in remodeled tissue. The conduction velocity was almost unaffected. Thus, 4-AP shows antiarrhythmic prop- erties for doses between 10 &#956;M and 1mM.The Vulnerable Window is about the width of 1.2 ms, both in normal and remodeled tissue, if the tissue is stimulated by twice the minimal stimulation amplitude. The width of VW depends strongly on the stimulation amplitude. For smaller BCLs, the width of VW is constant in the remodeled case, but in the normal case the width increases. This effect is much more pronounced under the influence of 4-AP. By that, the risk of occur- rence of an unidirectional block increases in healthy tissue, which is a proarrhythmic effect.Finally, 2D simulations of atrial fibrillation in remodeled tissue were realized. After the initiation of four stable rotors, the effect of the various concentrations on the persistence of these rotors were observed and the time course of the rotor wave tips was evaluated. Doses between 10 &#956;M and 100 &#956;M can reduce the number of rotors, but they cannot prevent perpetuation. At doses of 100 &#956;M and higher, 4-AP is able to stop perpetuation of reentries. However, the side effects of these doses are lethal.At clinical doses such as in MS therapy, no effects of 4-AP for any simulations are found, neither antiarrhythmic nor proarrhythmic.

Abstract:

The large amount of data in the Karlsruhe 3D Ultrasound Computed Tomography (USCT) has to be reduced. For compression of ultrasound signals, cascading bit-wise run length method and adjacent A-scans or samples based method as new lossless methods were developed. Lossy compression methods are evaluated with an image quality based scheme using the newly designed optical flow based and committee model based estimators. Finally, an optimal method with a feasible compression ratio was suggested

Abstract:

The aim of this work was to identify the patterns that can induce heating around implanted cardiac pacemakers during MRI and to develop strategies to counteract them. Two approaches were taken: computer simulations of the occurring electromagnetic field distributions and in-vitro experiments using phantoms in real MRI devices, both for conventional bore-hole and new open MRI systems. Using the open MRI, the observed heating could be reduced significantly.

Abstract:

This work presents three new quantitative methods for magnetic resonance imaging. A method for simultaneous mapping of B1 and T1 (MTM) is developed and validated. Electric Properties Tomography (EPT), a method for quantitative imaging of dielectric properties of tissue, is presented. Based on EPT, separate (phase-based) conductivity and (amplitude-based) permittivity measurements are introduced. Finally, a B1-based method for patient-specific local SAR measurements is presented.

Abstract:

This work addresses major challenges of heart model personalization. Analysis techniques for clinical intracardiac electrograms determine wave direction and conduction velocity from single beats. Electrophysiological measurements are simulated to validate the models. Uncertainties in tissue conductivities impact on simulated ECGs. A minimal model of cardiac myocytes is adapted to the atria. This makes personalized cardiac models a promising technique to improve treatment of atrial arrhythmias.

Abstract:

This work covers several fields of studies. Biological techniques, knowledge of imaging systems and their features as well as a background in system theory and digital image processing were combined. Biopsy punches from six rat hearts and one rabbit heart were obtained providing seven biopsies from rat and three from rabbit. The tissue was sectioned and quad-labelled in a three day procedure to make extracellular space, intracellular space of fibroblasts, cellular nuclei and gap junctions visible. Afterwards three to four three-dimensional image stacks per biopsy were produced by confocal microscopy. The image stacks were preprocessed including depth-dependent attenuation correction, noise reduction, and deconvolution. The resulting data after this final step is used for analysis or further processing (segmentation). My exemplary analysis surveyed the orientation of Cx43 covered membrane surface.Image stacks of rat hearts samples provided good results. The different channels were distinguish- able and allowed analysis of ventricular histology. In contrast the quad-labelling protocol did not work as well for rabbit but crosstalk was visible. Confer Figs. 4.4 and 4.5. Analysis of the orien- tation of the membrane surface covered with Cx43 showed that the relatively highest percentage of Cx43 is found in orientation of the principal axis.

Abstract:

Anatomische und elektrophysiologische Modelle des menschlichen Vorhofs ermöglichen die Untersuchung verschiedener physiologischer und pathologischer Zusammenhänge. Beispielsweise kann die Entstehung von Vorhofflimmern oder die Wirkung einer Ablation vor der Operation untersucht werden. Die Qualität solcher Untersuchungen hängt davon ab, wie genau das verwendete Modell die Wirklichkeit abbildet.In früheren Arbeiten wurden bereits elektrophysiologische Heterogenitäten für Strukturen im rechten Vorhof in das Zellmodell von Courtemanche et al. implementiert. Darauf aufbauend wurde dieses Modell nun um Strukturen aus dem linken Vorhof, sowie dem interatrialen Septum, erweitert. Das Modell enthält nun ein breites Spektrum von Aktionspotentialmorphologien im menschlichen Vorhof. Es reicht von fast dreieckigen Aktionspotentialen im Septum mit einer Aktionspotentialdauer von 200ms bis zu Aktionspotentialen mit einer ausgeprägten Plateauphase und Aktionspotentialdauern von 300ms in der Crista Terminalis. Diese Vielfalt könnte eine mögliche Erklörung für die verschiedenen vorhandenen elektrophysiologischen Modelle des Vorhofmyokards sein.Die in dieser und früheren Arbeiten implementierten Heterogenitäten wurden auf zwei anatomische Modelle übertragen. In Simulationen der Erregungsausbreitung konnte gezeigt werden, dass die Heterogenitäten des Vorhofmyokards zu einer gleichmäßigeren Repolarisation der Vorhöfe führen. Dies ist darauf zurückzuführen, dass diese Heterogenitäten zu einer stetigen Abnahme der APD mit dem Abstand zum Sinusknoten führen. Des weiteren ist, bedingt durch die kürzere APD einiger Heterogenitäten verglichen mit dem originalen CRN-Modell, die Repolarisationszeit in den heterogenen Modellen kürzer als in den homogenen Modellen. Um sprunghafte Änderungen der elektrophysiologischen Eigenschaften an den Gewebegrenzen in den Modellen zu vermeiden, wurden Gradienten zwischen diesen in die Modelle implementiert. Für diese Aufgabe wurde ein Skript erstellt, welches die benötigten Operationen automatisiert durchführt. Dieses Skript kann leicht auf weitere anatomische Vorhofmodelle angewendet werden. In den Simulationen führten diese Gradienten nochmals zu einer leicht gleichmäßigeren Repolarisation verglichen mit den Modellen ohne Gradienten.Um die Auswirkungen der Heterogenitäten auf die Repolarisation der Vorhöfe weiter zu untersuchen wurden aus den Simulationsergebnissen der Erregungsausbreitung Vektorkardiogramme erstellt. Auch in diesen zeigte sich, dass die implementierten Heterogenitäten zu einer Verringerung der Amplitude der Ta-Welle und damit zu einer gleichmäßigeren Repolarisation der Vorhöfe führen.