Simulation and evaluation of freeze-thaw cryoablation scenarios for the treatment of cardiac arrhythmias.

BACKGROUND: Cardiac cryoablation is a minimally invasive procedure to treat cardiac arrhythmias by cooling cardiac tissues responsible for the cardiac arrhythmia to freezing temperatures. Although cardiac cryoablation offers a gentler treatment than radiofrequency ablation, longer interventions and higher recurrence rates reduce the clinical acceptance of this technique. Computer models of ablation scenarios allow for a closer examination of temperature distributions in the myocardium and evaluation of specific effects of applied freeze-thaw protocols in a controlled environment. METHODS: In this work multiple intervention scenarios with two freeze-thaw cycles were simulated with varying durations and starting times of the interim thawing phase using a finite element model verified by in-vivo measurements and data from literature. To evaluate the effects of different protocols, transmural temperature distributions and iceball dimensions were compared over time. Cryoadhesion durations of the applicator were estimated in the interim thawing phase with varying thawing phase starting times. In addition, the increase of cooling rates was compared between the freezing phases, and the thawing rates of interim thawing phases were analyzed over transmural depth. RESULTS: It could be shown that the increase of cooling rate, the regions undergoing additional phase changes and depths of selected temperatures depend on the chosen ablation protocol. Only small differences of the estimated cryoadhesion duration were found for ablation scenarios with interim thawing phase start after 90 s freezing. CONCLUSIONS: By the presented model a quantification of effects responsible for cell death is possible, allowing for the analysis and optimization of cryoablation scenarios which contribute to a higher clinical acceptance of cardiac cryoablation.

Non-invasive imaging of cardiac electrophysiology in a cardiac resynchronization therapy defibrillator patient with a quadripolar left ventricular lead.

AIMS: The present study was aimed to assess epi- and endocardial ventricular electroanatomical activation during cardiac resynchronization therapy (CRT) by means of non-invasive imaging of cardiac electrophysiology (NICE) in a patient with a novel quadripolar LV lead. METHODS AND RESULTS: Non-invasive imaging of cardiac electrophysiology is a novel imaging tool which works by fusing data from high-resolution electrocardiogram (ECG) mapping with a model of the patient's individual cardiothoracic anatomy created from magnetic resonance imaging. This was performed in a cardiac resynchronization therapy defribrillator (CRT-D) patient with a quadripolar left ventricular (LV) lead. Beat-to-beat endocardial and epicardial ventricular activation sequences were computed using NICE during intrinsic conduction as well as during different pacing modes with different LV and biventricular (biV) pacing vectors. The spatial resolution of NICE enabled discrimination of the different pacing vectors during LV and biV pacing. Biventricular pacing resulted in a marked shortening of the total activation duration (TAD) of both ventricles when compared with intrinsic conduction and RV and LV pacing. CONCLUSION: Non-invasive imaging of cardiac electrophysiology facilitates non-invasive imaging of ventricular activation, which may be useful in CRT patients to locate the area of latest ventricular activation as the target area for LV lead placement. Moreover, especially in non-responders to CRT NICE may be further useful to determine the best electrical repositioning option.

Beyond the Status Quo: Density Functional Tight Binding and Neural Network Potentials as a Versatile Simulation Strategy to Characterize Host-Guest Interactions in Metal- and Covalent Organic Frameworks.

In recent years, research focused on synthesis, characterization, and application of metal-organic frameworks (MOFs) has attracted increased interest, from both an experimental as well as a theoretical perspective. Self-consistent charge density functional tight binding (SCC DFTB) in conjunction with a suitable constrained molecular dynamics (MD) simulation protocol provides a versatile and flexible platform for the study of pristine MOFs as well as guest@MOF systems. Although being a semi-empirical quantum mechanical method, SCC DFTB inherently accounts for polarization and many-body contributions, which may become a limiting factor in purely force field-based simulation studies. A number of examples such as CO2, indigo, and drug molecules embedded in various MOF hosts are discussed to highlight the capabilities of the presented simulation approach. Furthermore, a promising extension of the outlined simulation strategy toward the treatment of covalent organic frameworks utilizing state-of-the-art neural network potentials providing a description at DFT accuracy and force field cost is outlined.

The effect of gender on force, muscle activity, and frontal plane knee alignment during maximum eccentric leg-press exercise.

PURPOSE: To investigate for gender differences during eccentric leg-press exercise. Tears of the anterior cruciate ligament (ACL) are considered to be related to eccentric tasks, altered neuromuscular control (e.g., reduced co-contraction of hamstrings), and increased knee abduction (valgus alignment). Based on these observations and the fact that ACL tears are more common in women, it was hypothesized that men and women differ significantly with regard to key parameters of force, knee stabilization, and muscle activity when exposed to maximum eccentric leg extension. METHODS: Thirteen women and thirteen men were matched for age and physical activity. They performed maximum isokinetic eccentric leg-pressing against footplates of varied stability. The latter was done because earlier studies had shown that perturbational test conditions might be relevant in respect of ACL injuries. Key parameters of force, frontal plane knee stabilization, and muscle recruitment of significant muscles crossing the knee were recorded. RESULTS: The 'force stabilization deficit' (difference between maximum forces under normal and perturbed leg-pressing) did not differ significantly between genders. Likewise, parameters of muscle activity and frontal plane leg stabilization revealed no significant differences between men and women. CONCLUSION: This study is novel, in that gender differences in parameters of force, muscle activity, and leg kinematic were investigated during functional conditions of eccentric leg-pressing. No gender differences were observed in the measured parameters. However, the conclusion should be viewed with caution because the findings concurred with, but also contrasted, previous research in this field. LEVEL OF EVIDENCE: Diagnostic study, Level III.

Unsupervised Learning for Hydrogen Breath Tests.

Hydrogen breath tests are a well-established method to help diagnose functional intestinal disorders such as carbohydrate malabsorption or small intestinal bacterial overgrowth. In this work we apply unsupervised machine learning techniques to analyze hydrogen breath test datasets. We propose a method that uses 26 internal cluster validation measures to determine a suitable number of clusters. In an induced external validation step we use a predefined categorization proposed by a medical expert. The results indicate that the majority of the considered internal validation indexes was not able to produce a reasonable clustering. Considering a predefined categorization performed by a medical expert, a novel shape-based method obtained the highest external validation measure in terms of adjusted rand index. The predefined clusterings constitute the basis of a supervised machine learning step that is part of our ongoing research.

A Computer Model for Patient Individual Parametrizing of Ventricular Tachycardia Termination Algorithms.

BACKGROUND: Antitachycardial pacing (ATP) is a painless method for terminating ventricular tachycardias (VT) which would otherwise be treated using a painful high energy shock. However, it is well known that not each VT can be successfully terminated by ATP. Furthermore, ATP can be parametrized in several ways using scan, ramp or scan ramp approaches and can be applied in the right ventricle or in both ventricles (biventricular). In this work, we investigate the therapeutically most convenient ATP protocol based on a computer simulation using a patient individual model. METHODS: A patient individual model generated from a 3D/4D data set and a hybrid automaton was used for modeling and simulation of different VT scenarios. On the different VTs (from cycle length 288 ms up to 408 ms) different ATP approaches derived from the ADVANCE-CRT trial were applied in order to determine the effectiveness of these approaches. RESULTS: In this computer simulation study we were able to verify and validate the results from the ADVANCE-CRT trial. Biventricular ATP does not prove to be more effective than RV ATP but has a slight advantage in terminating fast VTs. CONCLUSIONS: The availability of a patient individual model and knowledge about the ischemic area and the underlying mechanism of the VTs will allow the use of these models to optimize ATP management.

Ensemble Based Approach for Time Series Classification in Metabolomics.

BACKGROUND: Machine learning is one important application in the area of health informatics, however classification methods for longitudinal data are still rare. OBJECTIVES: The aim of this work is to analyze and classify differences in metabolite time series data between groups of individuals regarding their athletic activity. METHODS: We propose a new ensemble-based 2-tier approach to classify metabolite time series data. The first tier uses polynomial fitting to generate a class prediction for each metabolite. An induced classifier (k-nearest-neighbor or naïve bayes) combines the results to produce a final prediction. Metabolite levels of 47 individuals undergoing a cycle ergometry test were measured using mass spectrometry. RESULTS: In accordance with our previous work the statistical results indicate strong changes over time. We found only small but systematic differences between the groups. However, our proposed stacking approach obtained a mean accuracy of 78% using 10-fold cross-validation. CONCLUSION: Our proposed classification approach allows a considerable classification performance for time series data with small differences between the groups.

Impact of a single, short morning bright light exposure on tryptophan pathways and visuo- and sensorimotor performance: a crossover study.

BACKGROUND: Bright light (BL) has been shown to be effective in enhancing both cognitive and physical performances. Alterations in nighttime melatonin levels have also been observed. However, evaluations of light-induced changes in the preceding biochemical processes are absent. Therefore, the impact of a single morning BL exposure on sensorimotor and visuomotor performance, as well as tryptophan (trp) and trp metabolites, was evaluated in this study. METHODS: In a crossover design, 33 healthy volunteers were randomly exposed to 30 min of < 150 lx at eye level (office light, OL) and 5000 lx at eye level (bright light, BL) of 6500 K in the morning hours. Trp, sulfatoxymelatonin (aMT6s), and kynurenine (kyn) courses over the morning hours were analyzed, and changes in sensori- and visuomotor measures were examined. RESULTS: Motoric performance increased in both setups, independent of light intensity. aMT6s and kyn decreased equally under both lighting conditions. Trp levels decreased from a mean (95% confidence interval) of 82.0 (77.2-86.9) to 66.5 (62.5-70.1) in the OL setup only. CONCLUSION: These data suggest that BL in the morning hours has a limited effect on visuo- and sensorimotor performance. Nevertheless, trp degradation pathways in the morning show diverse courses after OL and BL exposure. This suggests that trp courses can potentially be altered by BL exposure.

Modeling hypothermia induced effects for the heterogeneous ventricular tissue from cellular level to the impact on the ECG.

Hypothermia has a profound impact on the electrophysiological mechanisms of the heart. Experimental investigations provide a better understanding of electrophysiological alterations associated with cooling. However, there is a lack of computer models suitable for simulating the effects of hypothermia in cardio-electrophysiology. In this work, we propose a model that describes the cooling-induced electrophysiological alterations in ventricular tissue in a temperature range from 27°C to 37°C. To model the electrophysiological conditions in a 3D left ventricular tissue block it was essential to consider the following anatomical and physiological parameters in the model: the different cell types (endocardial, M, epicardial), the heterogeneous conductivities in longitudinal, transversal and transmural direction depending on the prevailing temperature, the distinct fiber orientations and the transmural repolarization sequences. Cooling-induced alterations on the morphology of the action potential (AP) of single myocardial cells thereby are described by an extension of the selected Bueno-Orovio model for human ventricular tissue using Q10 temperature coefficients. To evaluate alterations on tissue level, the corresponding pseudo electrocardiogram (pECG) was calculated. Simulations show that cooling-induced AP and pECG-related parameters, i.e. AP duration, morphology of the notch of epicardial AP, maximum AP upstroke velocity, AP rise time, QT interval, QRS duration and J wave formation are in good accordance with literature and our experimental data. The proposed model enables us to further enhance our knowledge of cooling-induced electrophysiological alterations from cellular to tissue level in the heart and may help to better understand electrophysiological mechanisms, e.g. in arrhythmias, during hypothermia.

Cardiac anisotropy: is it negligible regarding noninvasive activation time imaging?

The aim of this study was to quantify the effect of cardiac anisotropy in the activation-based inverse problem of electrocardiography. Differences of the patterns of simulated body surface potential maps for isotropic and anisotropic conditions were investigated with regard to activation time (AT) imaging of ventricular depolarization. AT maps were estimated by solving the nonlinear inverse ill-posed problem employing spatio-temporal regularization. Four different reference AT maps (sinus rhythm, right-ventricular and septal pacing, accessory pathway) were calculated with a bidomain theory based anisotropic finite-element heart model in combination with a cellular automaton. In this heart model a realistic fiber architecture and conduction system was implemented. Although the anisotropy has some effects on forward solutions, effects on inverse solutions are small indicating that cardiac anisotropy might be negligible for some clinical applications (e.g., imaging of focal events) of our AT imaging approach. The main characteristic events of the AT maps were estimated despite neglected electrical anisotropy in the inverse formulation. The worst correlation coefficient of the estimated AT maps was 0.810 in case of sinus rhythm. However, all characteristic events of the activation pattern were found. The results of this study confirm our clinical validation studies of noninvasive AT imaging in which cardiac anisotropy was neglected.

Brief Morning Light Exposure, Visuomotor Performance, and Biochemistry in Sport Shooters.

CONTEXT: Demands on concentrative and cognitive performance are high in sport shooting and vary in a circadian pattern, aroused by internal and external stimuli. The most prominent external stimulus is light. Bright light (BL) has been shown to have a certain impact on cognitive and physical performance. PURPOSE: To evaluate the impact of a single half hour of BL exposure in the morning hours on physical and cognitive performance in 15 sport shooters. In addition, courses of sulfateoxymelatonin (aMT6s), tryptophan (TRP), and kynurenine (KYN) were monitored. METHODS: In a crossover design, 15 sport shooters were exposed to 30 min of BL and dim light (DL) in the early-morning hours. Shooting performance, balance, visuomotor performance, and courses of aMT6s, TRP, and KYN were evaluated. RESULTS: Shooting performance was 365.4 (349.7-381.0) and 368.5 (353.9-383.1), identical in both light setups. Numbers of right reactions (sustained attention) and deviations from the horizontal plane (balance-related measure) were higher after BL. TRP concentrations decreased from 77.5 (73.5-81.4) to 66.9 (60.7-67.0) in the DL setup only. CONCLUSIONS: The 2 light conditions generated heterogeneous visuomotor and physiological effects in sport shooters. The authors therefore suggest that a single half hour of BL exposure is effective in improving cognitive aspects of performance, but not physical performance. Further research is needed to evaluate BL's impact on biochemical parameters.

Model-based imaging of cardiac electrical excitation in humans.

Activation time (AT) imaging from electrocardiographic (ECG) mapping data has been developing for several years. By coupling ECG mapping and three-dimensional (3-D) + time anatomical data, the electrical excitation sequence can be imaged completely noninvasively in the human heart. In this paper, a bidomain theory-based surface heart model AT imaging approach was applied to single-beat data of atrial and ventricular depolarization in two patients with structurally normal hearts. In both patients, the AT map was reconstructed from sinus and paced rhythm data. Pacing sites were the apex of the right ventricle and the coronary sinus (CS) ostium. For CS pacing, the reconstructed AT pattern on the endocardium of the right atrium was compared with the CARTO map in both patients. The localization errors of the origins of the initial endocardial breakthroughs were determined to be 6 and 12 mm. The sites of early activation and the areas with late activation were estimated with sufficient accuracy. The reconstructed sinus rhythm sequence was in good qualitative agreement with the pattern previously published for the isolated Langendorff-perfused human heart.

A new spatiotemporal regularization approach for reconstruction of cardiac transmembrane potential patterns.

The single-beat reconstruction of electrical cardiac sources from body-surface electrocardiogram data might become an important issue for clinical application. The feasibility and field of application of noninvasive imaging methods strongly depend on development of stable algorithms for solving the underlying ill-posed inverse problems. We propose a novel spatiotemporal regularization approach for the reconstruction of surface transmembrane potential (TMP) patterns. Regularization is achieved by imposing linearly formulated constraints on the solution in the spatial as well as in the temporal domain. In the spatial domain an operator similar to the surface Laplacian, weighted by a regularization parameter, is used. In the temporal domain monotonic nondecreasing behavior of the potential is presumed. This is formulated as side condition without the need of any regularization parameter. Compared to presuming template functions, the weaker temporal constraint widens the field of application because it enables the reconstruction of TMP patterns with ischemic and infarcted regions. Following the line of Tikhonov regularization, but considering all time points simultaneously, we obtain a linearly constrained sparse large-scale convex optimization problem solved by a fast interior point optimizer. We demonstrate the performance with simulations by comparing reconstructed TMP patterns with the underlying reference patterns.

A comparison of noninvasive reconstruction of epicardial versus transmembrane potentials in consideration of the null space.

We compare two source formulations for the electrocardiographic forward problem in consideration of their implications for regularizing the ill-posed inverse problem. The established epicardial potential source model is compared with a bidomain-theory-based transmembrane potential source formulation. The epicardial source approach is extended to the whole heart surface including the endocardial surfaces. We introduce the concept of the numerical null and signal space to draw attention to the problems associated with the nonuniqueness of the inverse solution and show that reconstruction of null-space components is an important issue for physiologically meaningful inverse solutions. Both formulations were tested with simulated data generated with an anisotropic heart model and with clinically measured data of two patients. A linear and a recently proposed quasi-linear inverse algorithm were applied for reconstructions of the epicardial and transmembrane potential, respectively. A direct comparison of both formulations was performed in terms of computed activation times. We found the transmembrane potential-based formulation is a more promising source formulation as stronger regularization by incorporation of biophysical a priori information is permitted.

On modeling the Wilson terminal in the boundary and finite element method.

In clinical electrocardiography, the zero-potential is commonly defined by the Wilson central terminal. In the electrocardiographic forward and inverse problem, the zero-potential is often defined in a different way, e.g., by the sum of all node potentials yielding zero. This study presents relatively simple to implement techniques, which enable the incorporation of the Wilson Terminal in the boundary element method (BEM) and finite element method (FEM). For the BEM, good results are obtained when properly adopting matrix deflation for modeling the Wilson terminal. Applying other zero-potential-definitions, the obtained solutions contained a remarkable offset with respect to the reference defined by the Wilson terminal. In the inverse problem (nonlinear dipole fit), errors introduced by an erroneous zero-potential-definition can lead to displacements of more than 5 mm in the computed dipole location. For the FEM, a method similar to matrix deflation is proposed in order to properly consider the Wilson central terminal. The matrix obtained from this manipulation is symmetric, sparse and positive definite enabling the application of standard FEM-solvers.

Electrocardiographic imaging of atrial and ventricular electrical activation.

Inverse electrocardiography has been developing for several years. By combining measurements obtained by electrocardiographic body surface mapping with three-dimensional anatomical data, one can non-invasively image the electrical activation sequence in the human heart. In this study, an imaging approach that uses a bidomain theory-based surface heart model was applied to single-beat data of atrial and ventricular activation. We found that for sinus and paced rhythms, the sites of early activation and the areas with late activation were estimated with sufficient accuracy. In particular, for focal arrhythmias, this model-based imaging approach might allow the guidance and evaluation of antiarrhythmic interventions, for instance, in case of catheter ablation or drug therapy.

ECG mapping and imaging of cardiac electrical function.

Inverse electrocardiography has been developed for several years. By coupling electrocardiographic mapping and 3D-time anatomical data, the electrical excitation sequence can be imaged completely non-invasively in the human heart. In this study, a bidomain theory based surface heart model activation time imaging approach was applied to single beat data of atrial and ventricular depolarization. For sinus and paced rhythms, the sites of early activation and the areas with late activation were estimated with sufficient accuracy. In particular for focal arrhythmias, this model-based imaging approach might allow the guidance and evaluation of antiarrhythmic interventions, for instance, in case of catheter ablation or drug therapy.

Single-beat noninvasive imaging of ventricular endocardial and epicardial activation in patients undergoing CRT.

BACKGROUND: Little is known about the effect of cardiac resynchronization therapy (CRT) on endo- and epicardial ventricular activation. Noninvasive imaging of cardiac electrophysiology (NICE) is a novel imaging tool for visualization of both epi- and endocardial ventricular electrical activation. METHODOLOGY/PRINCIPAL FINDINGS: NICE was performed in ten patients with congestive heart failure (CHF) undergoing CRT and in ten patients without structural heart disease (control group). NICE is a fusion of data from high-resolution ECG mapping with a model of the patient's individual cardiothoracic anatomy created from magnetic resonance imaging. Beat-to-beat endocardial and epicardial ventricular activation sequences were computed during native rhythm as well as during ventricular pacing using a bidomain theory-based heart model to solve the related inverse problem. During right ventricular (RV) pacing control patients showed a deterioration of the ventricular activation sequence similar to the intrinsic activation pattern of CHF patients. Left ventricular propagation velocities were significantly decreased in CHF patients as compared to the control group (1.6±0.4 versus 2.1±0.5 m/sec; p<0.05). CHF patients showed right-to-left septal activation with the latest activation epicardially in the lateral wall of the left ventricle. Biventricular pacing resulted in a resynchronization of the ventricular activation sequence and in a marked decrease of total LV activation duration as compared to intrinsic conduction and RV pacing (129±16 versus 157±28 and 173±25 ms; both p<0.05). CONCLUSIONS/SIGNIFICANCE: Endocardial and epicardial ventricular activation can be visualized noninvasively by NICE. Identification of individual ventricular activation properties may help identify responders to CRT and to further improve response to CRT by facilitating a patient-specific lead placement and device programming.

Semiautomatic volume conductor modeling pipeline for imaging the cardiac electrophysiology noninvasively.

In this paper we present an approach for extracting patient individual volume conductor models (VCM) using volume data acquired from Magnetic Resonance Imaging (MRI) for computational biology of electrical excitation in the patient's heart. The VCM consists of the compartments chest surface, lung surfaces, the atrial and ventricular myocardium, and the blood masses. For each compartment a segmentation approach with no or little necessity of user interaction was implemented and integrated into a VCM segmentation pipeline to enable the inverse problem of electrocardiography to become clinical applicable. The segmentation pipeline was tested using volume data from ten patients with structurally normal hearts.