Abstract:

BACKGROUND: Electrical impedance tomography (EIT) with indicator dilution may be clinically useful to measure relative lung perfusion, but there is limited information on the performance of this technique. METHODS: Thirteen pigs (50-66 kg) were anaesthetised and mechanically ventilated. Sequential changes in ventilation were made: (i) right-lung ventilation with left-lung collapse, (ii) two-lung ventilation with optimised PEEP, (iii) two-lung ventilation with zero PEEP after saline lung lavage, (iv) two-lung ventilation with maximum PEEP (20/25 cm HO to achieve peak airway pressure 45 cm HO), and (v) two-lung ventilation under unilateral pulmonary artery occlusion. Relative lung perfusion was assessed with EIT and central venous injection of saline 3%, 5%, and 10% (10 ml) during breath holds. Relative perfusion was determined by positron emission tomography (PET) using Gallium-labelled microspheres. EIT and PET were compared in eight regions of equal ventro-dorsal height (right, left, ventral, mid-ventral, mid-dorsal, and dorsal), and directional changes in regional perfusion were determined. RESULTS: Differences between methods were relatively small (95% of values differed by less than 8.7%, 8.9%, and 9.5% for saline 10%, 5%, and 3%, respectively). Compared with PET, EIT underestimated relative perfusion in dependent, and overestimated it in non-dependent, regions. EIT and PET detected the same direction of change in relative lung perfusion in 68.9-95.9% of measurements. CONCLUSIONS: The agreement between EIT and PET for measuring and tracking changes of relative lung perfusion was satisfactory for clinical purposes. Indicator-based EIT may prove useful for measuring pulmonary perfusion at bedside.

Abstract:

Local brain hypothermia is an attractive method for providing cerebral neuroprotection for ischemic stroke patients and at the same time reducing systemic side effects of cooling. In acute ischemic stroke patients with large vessel occlusion, combination with endovascular mechanical recanalization treatment could potentially allow for an alleviation of inflammatory and apoptotic pathways in the critical phase of reperfusion. The direct cooling of arterial blood by means of an intra-carotid heat exchange catheter compatible with recanalization systems is a novel promising approach. Focusing on the concept of "cold reperfusion", we developed an energetic model to calculate the rate of temperature decrease during intra-carotid cooling in case of physiological as well as decreased perfusion. Additionally, we discussed and considered the effect and biological significance of temperature decrease on resulting brain perfusion. Our model predicted a 2 °C brain temperature decrease in 8.3, 11.8 and 26.2 min at perfusion rates of 50, 30 and 10ml100g⋅min, respectively. The systemic temperature decrease - caused by the venous blood return to the main circulation - was limited to 0.5 °C in 60 min. Our results underline the potential of catheter-assisted, intracarotid blood cooling to provide a fast and selective brain temperature decrease in the phase of vessel recanalization. This method can potentially allow for a tissue hypothermia during the restoration of the physiological flow and thus a "cold reperfusion" in the setting of mechanical recanalization.

Abstract:

Each heartbeat is initiated by cyclic spontaneous depolarization of cardiomyocytes in the sinus node forming the primary natural pacemaker. In patients with end-stage renal disease undergoing hemodialysis, it was recently shown that the heart rate drops to very low values before they suffer from sudden cardiac death with an unexplained high incidence. We hypothesize that the electrolyte changes commonly occurring in these patients affect sinus node beating rate and could be responsible for severe bradycardia. To test this hypothesis, we extended the Fabbri et al. computational model of human sinus node cells to account for the dynamic intracellular balance of ion concentrations. Using this model, we systematically tested the effect of altered extracellular potassium, calcium, and sodium concentrations. Although sodium changes had negligible (0.15 bpm/mM) and potassium changes mild effects (8 bpm/mM), calcium changes markedly affected the beating rate (46 bpm/mM ionized calcium without autonomic control). This pronounced bradycardic effect of hypocalcemia was mediated primarily by I attenuation due to reduced driving force, particularly during late depolarization. This, in turn, caused secondary reduction of calcium concentration in the intracellular compartments and subsequent attenuation of inward I and reduction of intracellular sodium. Our in silico findings are complemented and substantiated by an empirical database study comprising 22,501 pairs of blood samples and in vivo heart rate measurements in hemodialysis patients and healthy individuals. A reduction of extracellular calcium was correlated with a decrease of heartrate by 9.9 bpm/mM total serum calcium (p < 0.001) with intact autonomic control in the cross-sectional population. In conclusion, we present mechanistic in silico and empirical in vivo data supporting the so far neglected but experimentally testable and potentially important mechanism of hypocalcemia-induced bradycardia and asystole, potentially responsible for the highly increased and so far unexplained risk of sudden cardiac death in the hemodialysis patient population.

Abstract:

Changes of serum and extracellular ion concentrations occur regularly in patients with chronic kidney disease (CKD). Recently, hypocalcemia, i.e. a decrease of the extra-cellular calcium concentration [Ca2+]o, has been suggested as potential pathomechanism contributing to the unexplained high rate of sudden cardiac death (SCD) in CKD patients. In particular, there is a hypothesis that hypocalcaemia could slow down natural pacemaking in the human sinus node to fatal degrees. Here, we address the question whether there are inter-species differences in the response of cellular sinus node pacemaking to changes of [Ca2+]o. Towards this end, we employ computational models of mouse, rabbit and human sinus node cells. The Fabbri et al. human model was updated to consider changes of intracellular ion concentrations. We identified crucial inter-species differences in the response of cellular pacemaking in the sinus node to changes of [Ca2+]o with little changes of cycle length in mouse and rabbit models (<83 ms) in contrast to a pronounced bradycardic effect in the human model (up to > 1000 ms). Our results suggest that experiments with human sinus node cells are required to investigate the potential mechanism of hypocalcaemia-induced bradycardic SCD in CKD patients and small animal models are not well suited.

Abstract:

Atypical atrial flutter (AFlut) is a reentrant arrhythmia which patients frequently develop after ablation for atrial fibrillation (AF). Indeed, substrate modifications during AF ablation can increase the likelihood to develop AFlut and it is clinically not feasible to reliably and sensitively test if a patient is vulnerable to AFlut. Here, we present a novel method based on personalized computational models to identify pathways along which AFlut can be sustained in an individual patient. We build a personalized model of atrial excitation propagation considering the anatomy as well as the spatial distribution of anisotropic conduction velocity and repolarization characteristics based on a combination of a priori knowledge on the population level and information derived from measurements performed in the individual patient. The fast marching scheme is employed to compute activation times for stimuli from all parts of the atria. Potential flutter pathways are then identified by tracing loops from wave front collision sites and constricting them using a geometric snake approach under consideration of the heterogeneous wavelength condition. In this way, all pathways along which AFlut can be sustained are identified. Flutter pathways can be instantiated by using an eikonal-diffusion phase extrapolation approach and a dynamic multifront fast marching simulation. In these dynamic simulations, the initial pattern eventually turns into the one driven by the dominant pathway, which is the only pathway that can be observed clinically. We assessed the sensitivity of the flutter pathway maps with respect to conduction velocity and its anisotropy. Moreover, we demonstrate the application of tailored models considering disease-specific repolarization properties (healthy, AF-remodeled, potassium channel mutations) as well as applicabiltiy on a clinical dataset. Finally, we tested how AFlut vulnerability of these substrates is modulated by exemplary antiarrhythmic drugs (amiodarone, dronedarone). Our novel method allows to assess the vulnerability of an individual patient to develop AFlut based on the personal anatomical, electrophysiological, and pharmacological characteristics. In contrast to clinical electrophysiological studies, our computational approach provides the means to identify all possible AFlut pathways and not just the currently dominant one. This allows to consider all relevant AFlut pathways when tailoring clinical ablation therapy in order to reduce the development and recurrence of AFlut.

Abstract:

Atrial fibrillation (AF) is the most prevalent form of cardiac arrhythmia. The atrial wall thickness (AWT) can potentially improve our understanding of the mechanism underlying atrial structure that drives AF and provides important clinical information. However, most existing studies for estimating AWT rely on ruler-based measurements performed on only a few selected locations in 2D or 3D using digital calipers. Only a few studies have developed automatic approaches to estimate the AWT in the left atrium, and there are currently no methods to robustly estimate the AWT of both atrial chambers. Therefore, we have developed a computational pipeline to automatically calculate the 3D AWT across bi-atrial chambers and extensively validated our pipeline on both ex vivo and in vivo human atria data. The atrial geometry was first obtained by segmenting the atrial wall from the MRIs using a novel machine learning approach. The epicardial and endocardial surfaces were then separated using a multi-planar convex hull approach to define boundary conditions, from which, a Laplace equation was solved numerically to automatically separate bi-atrial chambers. To robustly estimate the AWT in each atrial chamber, coupled partial differential equations by coupling the Laplace solution with two surface trajectory functions were formulated and solved. Our pipeline enabled the reconstruction and visualization of the 3D AWT for bi-atrial chambers with a relative error of 8% and outperformed existing algorithms by >7%. Our approach can potentially lead to improved clinical diagnosis, patient stratification, and clinical guidance during ablation treatment for patients with AF.

Abstract:

Aims Chronic left atrial enlargement (LAE) increases the risk of atrial fibrillation. Electrocardiogram (ECG) criteria might provide a means to diagnose LAE and identify patients at risk; however, current criteria perform poorly. We seek to characterize the potentially differential effects of atrial dilation vs. hypertrophy on the ECG P-wave. Methods and results We predict effects on the P-wave of (i) left atrial dilation (LAD), i.e. an increase of LA cavity volume without an increase in myocardial volume, (ii) left atrial concentric hypertrophy (LACH), i.e. a thickened myocardial wall, and (iii) a combination of the two. We performed a computational study in a cohort of 72 anatomical variants, derived from four human atrial anatomies. To model LAD, pressure was applied to the LA endocardium increasing cavity volume by up to 100%. For LACH, the LA wall was thickened by up to 3.3 mm. P-waves were derived by simulating atrial excitation propagation and computing the body surface ECG. The sensitivity regarding changes beyond purely anatomical effects was analysed by altering conduction velocity by 25% in 96 additional model variants. Left atrial dilation prolonged P-wave duration (PWd) in two of four subjects; in one subject a shortening, and in the other a variable change were seen. Left atrial concentric hypertrophy, in contrast, consistently increased P-wave terminal force in lead V1 (PTF-V1) in all subjects through an enlarged amplitude while PWd was unaffected. Combined hypertrophy and dilation generally enhanced the effect of hypertrophy on PTF-V1. Conclusion Isolated LAD has moderate effects on the currently used P-wave criteria, explaining the limited utility of PWd and PTF-V1 in detecting LAE in clinical practice. In contrast, PTF-V1 may be a more sensitive indicator of LA myocardial hypertrophy.

Abstract:

The cardiac muscarinic receptor (M2R) regulates heart rate, in part, by modulating the acetylcholine (ACh) activated K+ current IK,ACh through dissociation of G-proteins, that in turn activate KACh channels. Recently, M2Rs were noted to exhibit intrinsic voltage sensitivity, i.e. their affinity for ligands varies in a voltage dependent manner. The voltage sensitivity of M2R implies that the affinity for ACh (and thus the ACh effect) varies throughout the time course of a cardiac electrical cycle. The aim of this study was to investigate the contribution of M2R voltage sensitivity to the rate and shape of the human sinus node action potentials in physiological and pathophysiological conditions. We developed a Markovian model of the IK,ACh modulation by voltage and integrated it into a computational model of human sinus node. We performed simulations with the integrated model varying ACh concentration and voltage sensitivity. Low ACh exerted a larger effect on IK,ACh at hyperpolarized versus depolarized membrane voltages. This led to a slowing of the pacemaker rate due to an attenuated slope of phase 4 depolarization with only marginal effect on action potential duration and amplitude. We also simulated the theoretical effects of genetic variants that alter the voltage sensitivity of M2R. Modest negative shifts in voltage sensitivity, predicted to increase the affinity of the receptor for ACh, slowed the rate of phase 4 depolarization and slowed heart rate, while modest positive shifts increased heart rate. These simulations support our hypothesis that altered M2R voltage sensitivity contributes to disease and provide a novel mechanistic foundation to study clinical disorders such as atrial fibrillation and inappropriate sinus tachycardia.

Abstract:

Electrocardiographic imaging (ECGI) reconstructs the electrical activity of the heart from a dense array of body-surface electrocardiograms and a patient-specific heart-torso geometry. Depending on how it is formulated, ECGI allows the reconstruction of the activation and recovery sequence of the heart, the origin of premature beats or tachycardia, the anchors/hotspots of re-entrant arrhythmias and other electrophysiological quantities of interest. Importantly, these quantities are directly and noninvasively reconstructed in a digitized model of the patient’s three-dimensional heart, which has led to clinical interest in ECGI’s ability to personalize diagnosis and guide therapy. Despite considerable development over the last decades, validation of ECGI is challenging. Firstly, results depend considerably on implementation choices, which are necessary to deal with ECGI’s ill-posed character. Secondly, it is challenging to obtain (invasive) ground truth data of high quality. In this review, we discuss the current status of ECGI validation as well as the major challenges remaining for complete adoption of ECGI in clinical practice. Specifically, showing clinical benefit is essential for the adoption of ECGI. Such benefit may lie in patient outcome improvement, workflow improvement, or cost reduction. Future studies should focus on these aspects to achieve broad adoption of ECGI, but only after the technical challenges have been solved for that specific application/pathology. We propose ‘best’ practices for technical validation and highlight collaborative efforts recently organized in this field. Continued interaction between engineers, basic scientists and physicians remains essential to find a hybrid between technical achievements, pathological mechanisms insights, and clinical benefit, to evolve this powerful technique towards a useful role in clinical practice.

Abstract:

Electrocardiographic imaging (ECGI) strongly relies on a priori assumptions and additional information to overcome ill-posedness. The major challenge of obtaining good reconstructions consists in finding ways to add information that effectively restricts the solution space without violating properties of the sought solution. In this work, we attempt to address this problem by constructing a spatio-temporal basis of body surface potentials (BSP) from simulations of many focal excitations. Measured BSPs are projected onto this basis and reconstructions are expressed as linear combinations of corresponding transmembrane voltage (TMV) basis vectors. The novel method was applied to simulations of 100 atrial ectopic foci with three different conduction velocities. Three signal-to-noise ratios (SNR) and bases of six different temporal lengths were considered. Reconstruction quality was evaluated using the spatial correlation coefficient of TMVs as well as estimated local activation times (LAT). The focus localization error was assessed by computing the geodesic distance between true and reconstructed foci. Compared with an optimally parameterized Tikhonov-Greensite method, the BSP basis reconstruction increased the mean TMV correlation by up to 22, 24, and 32% for an SNR of 40, 20, and 0 dB, respectively. Mean LAT correlation could be improved by up to 5, 7, and 19% for the three SNRs. For 0 dB, the average localization error could be halved from 15.8 to 7.9 mm. For the largest basis length, the localization error was always below 34 mm. In conclusion, the new method improved reconstructions of atrial ectopic activity especially for low SNRs. Localization of ectopic foci turned out to be more robust and more accurate. Preliminary experiments indicate that the basis generalizes to some extent from the training data and may even be applied for reconstruction of non-ectopic activity.

Abstract:

Optical mapping is widely used as a tool to investigate cardiac electrophysiology in ex vivo preparations. Digital filtering of fluorescence-optical data is an important requirement for robust subsequent data analysis and still a challenge when processing data acquired from thin mammalian myocardium. Therefore, we propose and investigate the use of an adaptive spatio-temporal Gaussian filter for processing optical mapping signals from these kinds of tissue usually having low signal-to-noise ratio (SNR). We demonstrate how filtering parameters can be chosen automatically without additional user input. For systematic comparison of this filter with standard filtering methods from the literature, we generated synthetic signals representing optical recordings from atrial myocardium of a rat heart with varying SNR. Furthermore, all filter methods were applied to experimental data from an ex vivo setup. Our developed filter outperformed the other filter methods regarding local activation time detection at SNRs smaller than 3 dB which are typical noise ratios expected in these signals. At higher SNRs, the proposed filter performed slightly worse than the methods from literature. In conclusion, the proposed adaptive spatio-temporal Gaussian filter is an appropriate tool for investigating fluorescence-optical data with low SNR. The spatio-temporal filter parameters were automatically adapted in contrast to the other investigated filters.

Abstract:

Promising results have been reported in noninvasive estimation of cardiac activation times (AT) using the equivalent dipole layer (EDL) source model in combination with the boundary element method (BEM). However, the assumption of equal anisotropy ratios in the heart that underlies the EDL model does not reflect reality. In the present study, we quantify the errors of the nonlinear AT imaging based on the EDL approximation. Nine different excitation patterns (sinus rhythm and eight ectopic beats) were simulated with the monodomain model. Based on the bidomain theory, the body surface potential maps (BSPMs) were calculated for a realistic finite element volume conductor with an anisotropic heart model. For the forward calculations, three cases of bidomain conductivity tensors in the heart were considered: isotropic, equal, and unequal anisotropy ratios in the intra- and extracellular spaces. In all inverse reconstructions, the EDL model with BEM was employed: AT were estimated by solving the nonlinear optimization problem with the initial guess provided by the fastest route algorithm. Expectedly, the case of unequal anisotropy ratios resulted in larger localization errors for almost all considered activation patterns. For the sinus rhythm, all sites of early activation were correctly estimated with an optimal regularization parameter being used. For the ectopic beats, all but one foci were correctly classified to have either endo- or epicardial origin with an average localization error of 20.4 mm for unequal anisotropy ratio. The obtained results confirm validation studies and suggest that cardiac anisotropy might be neglected in clinical applications of the considered EDL-based inverse procedure.

Abstract:

BACKGROUND: Complementary to clinical and experimental studies, computational cardiac modeling serves to obtain a comprehensive understanding of the cardiovascular system in order to analyze dysfunction, evaluate existing, and develop novel treatment strategies. OBJECTIVES: We describe the basics of multiscale computational modeling of cardiac electrophysiology from the molecular ion channel to the whole body scale. By modeling cardiac ischemia, we illustrate how in silico experiments can contribute to our understanding of how the pathophysiological mechanisms translate into changes observed in diagnostic tools such as the electrocardiogram (ECG). MATERIALS AND METHODS: Quantitative in silico modeling spans a wide range of scales from ion channel biophysics to ECG signals. For each of the scales, a set of mathematical equations describes electrophysiology in relation to the other scales. Integration of ischemia-induced changes is performed on the ion channel, single-cell, and tissue level. This approach allows us to study how effects simulated at molecular scales translate to changes in the ECG. RESULTS: Ischemia induces action potential shortening and conduction slowing. Hence, ischemic myocardium has distinct and significant effects on propagation and repolarization of excitation, depending on the intramural extent of the ischemic region. For transmural and subendocardial ischemic regions, ST segment elevation and depression, respectively, were observed, whereas intermediate ischemic regions were found to be electrically silent (NSTEMI). CONCLUSIONS: In silico modeling contributes quantitative and mechanistic insight into fundamental ischemia-related arrhythmogenic mechanisms. In addition, computational modeling can help to translate experimental findings at the (sub-)cellular level to the organ and body context (e. g., ECG), thereby providing a thorough understanding of this routinely used diagnostic tool that may translate into optimized applications.

Abstract:

OBJECTIVE: Atrial tachycardia (AT) still pose a major challenge in catheter ablation. Although state-of-the-art electroanatomical mapping systems allow to acquire several thousand intracardiac electrograms (EGMs), algorithms for diagnostic analysis are mainly limited to the amplitude of the signal (voltage map) and the local activation time~(LAT map). We applied spatio-temporal analysis of EGM activity to generate maps indicating reentries and diastolic potentials, thus identifying and localizing the driving mechanism of AT. METHODS: First, the time course of active surface area (ASA) is determined during one basic cycle length (BCL). The global cycle length coverage (gCLC) reflects the relative duration within one BCL for which activity was present in each individual atrium. A local cycle length coverage (lCLC) is computed for circular sub-areas with 20mm diameter. The simultaneous active surface area sASA is determined to indicate the spatial extent of depolarizing tissue. RESULTS: Combined analysis of these spatial scales allowed to correctly identify and localize the driving mechanism: gCLC values of 100% were indicative for atria harbouring a reentrant driver. lCLC could detect micro reentries within an area of 1.651.28cm in simulated data and differentiate them against focal sources. Mid-diastolic potentials, being potential targets for catheter ablation, were identified as the areas showing confined activity based on sASA values. CONCLUSION: The concept of spatio-temporal activity analysis proved successful and correctly indicated the tachycardia mechanism in 20 simulated AT scenarios and three clinical data sets. SIGNIFICANCE: Automatic interpretation of intracardiac mapping data could help to improve the treatment strategy in complex cases of AT.

Abstract:

Catheter ablation is a curative therapeutic approach for atrial fibrillation (AF). Ablation of rotational sources based on basket catheter measurements has been proposed as a promising approach in patients with persistent AF to complement pulmonary vein isolation. However, clinically reported success rates are equivocal calling for a mechanistic investigation under controlled conditions. We present a computational framework to benchmark ablation strategies considering the whole cycle from excitation propagation to electrogram acquisition and processing to virtual therapy. Fibrillation was induced in a patient-specific 3D volumetric model of the left atrium, which was homogeneously remodelled to sustain reentry. The resulting extracellular potential field was sampled using models of grid catheters as well as realistically deformed basket catheters considering the specific atrial anatomy. Virtual electrograms were processed to compute phase singularity density maps to target rotor tips with up to three circular ablations. Stable rotors were successfully induced in different regions of the homogeneously remodelled atrium showing that rotors are not constrained to unique anatomical structures or locations. Phase singularity density maps correctly identified and located the rotors (deviation < 10 mm) based on catheter recordings only for sufficient resolution (inter-electrode distance = 3 mm) and proximity to the wall (< 10 mm). Targeting rotor sites with ablation did not stop reentries in the homogeneously remodelled atria independent from lesion size (1-7 mm radius), from linearly connecting lesions with anatomical obstacles, and from the number of rotors targeted sequentially (up to 3). Our results show that phase maps derived from intracardiac electrograms can be a powerful tool to map atrial activation patterns, yet they can also be misleading due to inaccurate localization of rotor tips depending on electrode resolution and distance to the wall. This should be considered to avoid ablating regions that are in fact free of rotor sources of AF. In our experience, ablation of rotor sites was not successful to stop fibrillation. Our comprehensive simulation framework provides the means to holistically benchmark ablation strategies in silico under consideration of all steps invol

Abstract:

AIMS: To test the ability of four circulating biomarkers of fibrosis, and of low left atrial voltage, to predict recurrence of atrial fibrillation after catheter ablation. BACKGROUND: Circulating biomarkers potentially may be used to improve patient selection for atrial fibrillation ablation. Low voltage areas in the left atrium predict arrhythmia recurrence when mapped in sinus rhythm. This study tested type III procollagen N terminal peptide (PIIINP), galectin-3 (gal-3), fibroblast growth factor 23 (FGF-23), and type I collagen C terminal telopeptide (ICTP), and whether low voltage areas in the left atrium predicted atrial fibrillation recurrence, irrespective of the rhythm during mapping. METHODS: 92 atrial fibrillation ablation patients were studied. Biomarker levels in peripheral and intra-cardiac blood were measured with enzyme-linked immunosorbent assay. Low voltage (<0.5mV) was expressed as a proportion of the mapped left atrial surface area. Follow-up was one year. The primary endpoint was recurrence of arrhythmia. The secondary endpoint was a composite of recurrence despite two procedures, or after one procedure if no second procedure was undertaken. RESULTS: The biomarkers were not predictive of either endpoint. After multivariate Cox regression analysis, high proportion of low voltage area in the left atrium was found to predict the primary endpoint in sinus rhythm mapping (hazard ratio 4.323, 95% confidence interval 1.337-13.982, p = 0.014) and atrial fibrillation mapping (hazard ratio 5.195, 95% confidence interval 1.032-26.141, p = 0.046). This effect was also apparent for the secondary endpoint. CONCLUSION: The studied biomarkers do not predict arrhythmia recurrence after catheter ablation. Left atrial voltage is an independent predictor of recurrence, whether the left atrium is mapped in atrial fibrillation or sinus rhythm.

Abstract:

Computational modeling is an important tool to advance our knowledge on cardiac diseases and their underlying mechanisms. Computational models of conduction in cardiac tissues require identification of parameters. Our knowledge on these parameters is limited, especially for diseased tissues. Here, we assessed and quantified parameters for computational modeling of conduction in cardiac tissues. We used a rabbit model of myocardial infarction (MI) and an imaging-based approach to derive the parameters. Left ventricular tissue samples were obtained from fixed control hearts (animals: 5) and infarcted hearts (animals: 6) within 200 μm (region 1), 250-750 μm (region 2) and 1,000-1,250 μm (region 3) of the MI border. We assessed extracellular space, fibroblasts, smooth muscle cells, nuclei and gap junctions by a multi-label staining protocol. With confocal microscopy we acquired three-dimensional (3D) image stacks with a voxel size of 200 × 200 × 200 nm. Image segmentation yielded 3D reconstructions of tissue microstructure, which were used to numerically derive extracellular conductivity tensors. Volume fractions of myocyte, extracellular, interlaminar cleft, vessel and fibroblast domains in control were (in %) 65.03 ± 3.60, 24.68 ± 3.05, 3.95 ± 4.84, 7.71 ± 2.15, and 2.48 ± 1.11, respectively. Volume fractions in regions 1 and 2 were different for myocyte, myofibroblast, vessel, and extracellular domains. Fibrosis, defined as increase in fibrotic tissue constituents, was (in %) 21.21 ± 1.73, 16.90 ± 9.86, and 3.58 ± 8.64 in MI regions 1, 2, and 3, respectively. For control tissues, image-based computation of longitudinal, transverse and normal extracellular conductivity yielded (in S/m) 0.36 ± 0.11, 0.17 ± 0.07, and 0.1 ± 0.06, respectively. Conductivities were markedly increased in regions 1 (+75, +171, and +100%), 2 (+53, +165, and +80%), and 3 (+42, +141, and +60%). Volume fractions of the extracellular space including interlaminar clefts strongly correlated with conductivities in control and MI hearts. Our study provides novel quantitative data for computational modeling of conduction in normal and MI hearts. Notably, our study introduces comprehensive statistical information on tissue composition and extracellular conductivities on a microscopic scale in the MI border zone. We suggest that the presented data fill a significant gap in modeling parameters and extend our foundation for computational modeling of cardiac conduction.

Abstract:

Objectives: This study hypothesized that P-wave morphology and timing under left atrial appendage (LAA) pacing change characteristically immediately upon anterior mitral line (AML) block. Background: Perimitral flutter commonly occurs following ablation of atrial fibrillation and can be cured by an AML. However, confirmation of bidirectional block can be challenging, especially in severely fibrotic atria. Methods: The study analyzed 129 consecutive patients (66 ± 8 years, 64% men) who developed perimitral flutter after atrial fibrillation ablation. We designed electrocardiography criteria in a retrospective cohort (n = 76) and analyzed them in a validation cohort (n = 53). Results: Bidirectional AML block was achieved in 110 (85%) patients. For ablation performed during LAA pacing without flutter (n = 52), we found a characteristic immediate V1 jump (increase in LAA stimulus to P-wave peak interval in lead V1) as a real-time marker of AML block (V1 jump ≥30 ms: sensitivity 95%, specificity 100%, positive predictive value 100%, negative predictive value 88%). As V1 jump is not applicable when block coincides with termination of flutter, absolute V1 delay was used as a criterion applicable in all cases (n = 129) with a delay of 203 ms indicating successful block (sensitivity 92%, specificity 84%, positive predictive value 90%, negative predictive value 87%). Furthermore, an initial negative P-wave portion in the inferior leads was observed, which was attenuated in case of additional cavotricuspid isthmus ablation. Computational P-wave simulations provide mechanistic confirmation of these findings for diverse ablation scenarios (pulmonary vein isolation ± AML ± roof line ± cavotricuspid isthmus ablation). Conclusions: V1 jump and V1 delay are novel real-time electrocardiography criteria allowing fast and straightforward assessment of AML block during ablation for perimitral flutter.

Abstract:

Background: During atrial fibrillation, heterogeneities and anisotropies result in a chaotic propagation of the depolarization wavefront. The electrophysiological parameter called conduction velocity (CV) influences the propagation pattern over the atrium. We present a method that determines the regional CV for deformed catheter shapes, which result due to the catheter movement and changing wall contact.Methods: The algorithm selects stable catheter positions, finds the local activation times (LAT), considers the wall contact and calculates all CV estimates within the area covered by the catheter. The method is evaluated with simulated data and then applied to four clinical data sets. Both sinus rhythm activity as well as depolarization wavefronts initiated by stimulation are analyzed. The regional CV is compared with the fractionation duration (FD) and peak-to-peak (P2P) voltages. A speed of 0.5 m/s was defined to create the simulated LAT.Results: After analyzing the simulated LAT with clinical catheter spatial coordinates, the median CV of 0.5 m/s with an interquartile range of 0.22 and exact CV direction vectors were obtained. For clinical cases, the CV magnitude range of 0.08 m/s to 1.0 m/s was obtained. The P2P amplitude of 0.7 mV to 3.7 mV and the mean FD from 40.79ms to 48.66ms was obtained. The correlation of 0.86 was observed between CV and P2P amplitude, and 0.62 between CV and FD.Conclusion: In this paper, a method is presented and validated which calculates the CV for the deformed catheter and changing wall contact. In an exemplary clinical data set correlation between regional CV with FD and the P2P voltage was observed.

Abstract:

This study examines the effect of mental workload on the electrocardiogram (ECG) of participants driving the Lane Change Task (LCT). Different levels of mental workload were induced by a secondary task (n-back task) with three levels of difficulty. Subjective data showed a significant increase of the experienced workload over all three levels. An exploratory approach was chosen to extract a large number of rhythmical and morphological features from the ECG signal thereby identifying those which differentiated best between the levels of mental workload. No single rhythmical or morphological feature was able to differentiate between all three levels. A group of parameters were extracted which were at least able to discriminate between two levels. For future research, a combination of features is recommended to achieve best diagnosticity for different levels of mental workload.

Abstract:

Heart rate variability (HRV) plays an important role in medicine and psychology because it is used to quantify imbalances of the autonomic nervous system (ANS). An important manifestations of the ANS on HRV is also directly related to respiration and it is called respiratory sinus arrhythmia (RSA). This is a controlled phenomenon that leads to a synchronized coupling between respiration and instantaneous heart rate. Thus, the portion of HRV that is not related to respiration, and could potentially contain undiscovered diagnostic value, is overlapped and remains hidden in a standard HRV analysis. In such cases, a decoupling procedure would deliver a discriminated HRV analysis and possible new insights about the regulation of the cardiovascular system. In this work, we propose an algorithm based on Granger's causality to measure coupling between respiration and HRV. In the case of significant coupling, we estimate and cancel the respiration driven HRV component using a linear filtering approach. We tested the method using synthetic signals and prove it to deliver a reliable coupling measurement in 96.3% of the cases and reconstruct respiration free signals with a median correlation coefficient of 0.992. Afterwards, we applied our method to signals recorded during paced respiration and during natural breathing. We demonstrated that coupling is dependent on respiratory frequency and that it maximizes at 0.3 Hz. Furthermore, the HRV parameters measured during paced respiration tend to level among subjects after decoupling. The intersubject variability of HRV parameter is also decreased after the separation process. During natural breathing, coupling is notoriously lower to non-existing and decoupling has little impact on HRV. We conclude that the method proposed here can be used to investigate the diagnostic value of respiration independent HRV parameters.

Abstract:

The most important ECG marker for the diagnosis of ischemia or infarction is a change in the ST segment. Baseline wander is a typical artifact that corrupts the recorded ECG and can hinder the correct diagnosis of such diseases. For the purpose of finding the best suited filter for the removal of baseline wander, the ground truth about the ST change prior to the corrupting artifact and the subsequent filtering process is needed. In order to create the desired reference, we used a large simulation study that allowed us to represent the ischemic heart at a multiscale level from the cardiac myocyte to the surface ECG. We also created a realistic model of baseline wander to evaluate five filtering techniques commonly used in literature. In the simulation study, we included a total of 5.5 million signals coming from 765 electrophysiological setups. We found that the best performing method was the wavelet-based baseline cancellation. However, for medical applications, the Butterworth high-pass filter is the better choice because it is computationally cheap and almost as accurate. Even though all methods modify the ST segment up to some extent, they were all proved to be better than leaving baseline wander unfiltered.

Abstract:

Radiofrequency ablation has become a first-line approach for curative therapy of many cardiac arrhythmias. Various existing catheter designs provide high spatial resolution to identify the best spot for performing ablation and to assess lesion formation. However, creation of transmural and nonconducting ablation lesions requires usage of catheters with larger electrodes and improved thermal conductivity, leading to reduced spatial sensitivity. As trade-off, an ablation catheter with integrated mini electrodes was introduced. The additional diagnostic benefit of this catheter is still not clear. In order to solve this issue, we implemented a computational setup with different ablation scenarios. Our in silico results show that peak-to-peak amplitudes of unipolar electrograms from mini electrodes are more suitable to differentiate ablated and nonablated tissue compared to electrograms from the distal ablation electrode. However, in orthogonal mapping position, no significant difference was observed between distal electrode and mini electrodes electrograms in the ablation scenarios. In conclusion, catheters with mini electrodes bring about additional benefit to distinguish ablated tissue from nonablated tissue in parallel position with high spatial resolution. It is feasible to detect conduction gaps in linear lesions with this catheter by evaluating electrogram data from mini electrodes.

Abstract:

In den Lebenswissenschaften ist die Individualisierte Medizin aktuell ein zentrales Thema, vielleicht ein Hype. Das bestätigen auch synonyme, erweiternde und klärende Begriffe wie Personalisierte Medizin, Customized Medicine, Stratifizierende Medizin oder Präzisionsmedizin. In einer State of the Union Address an die Bevölkerung der Vereinigten Staaten von Amerika hat Präsident Barack Obama 2015 die Bedeutung der Präzisionsmedizin hervorgehoben [1]. Diese Initiative wurde inhaltlich wesentlich vom Direktor des National Institute of Health, dem Genetiker Francis Collins, vorangetrieben [2]. Individualisierte Medizin, das ist eine gute Botschaft, betont sie doch die Wertigkeit des einzelnen Patienten. Für klinisch tätige Ärzte ist das bereits eine Selbstverständlichkeit. Die Bedeutung eines Wortes, und das sei mit einem Lächeln hinzugefügt, zeigt sich nach Wittgenstein im Gebrauch der Sprache [3].Die Nationale Akademie der Wissenschaften Leopoldina, die acatech Deutsche Akademie der Technikwissenschaften und die Union der Deutschen Akademien der Wissenschaften haben im Dezember 2014 eine Stellungnahme über Voraussetzungen und Konsequenzen der Individualisierten Medizin publiziert. Darin wird der Fokus, wie im Vorwort ausgeführt, auf molekulare, genetische und pharmakologische Aspekte der Onkologie gelegt, einen Bereich, in dem die Individualisierung am weitesten fortgeschritten ist. Diese Beschränkung bedeutet, dass andere eng assoziierte Themen, wie die Patienten- und Versorgungsperspektiven, der Bereich der Medizintechnik oder neue Erkrankungen, beispielsweise in der Psychiatrie, in dieser Studie nicht beleuchtet werden. Die Behandlung dieser Gebiete bedarf einer separaten nachfolgenden Betrachtung. [4].Vor einer Betrachtung wesentlicher Beiträge allein der Bildgebung in der Individualisierten Medizin seien wenige vorausschickende Bemerkungen zu zwei Grenz-Fragen der Wissenschaft gemacht. Was steht für und gegen Stellungnahmen der genannten Akademien? Erfüllt die Beschäftigung mit der Bildgebung Kriterien der Wissenschaft?Eine der Aufgaben der Akademien ist es, Ordnung in die vorhandenen Aussagen und auch damit vorhandene Daten zu bringen, die in unterschiedlichen Disziplinen hervorgebracht werden, um daraus ein Gesamtbild zu formen. Weiterhin sollen Empfehlungen gegeben werden, wie die Entwicklungen günstig zu beeinflussen sind [5]. Wichtige Grenzen der wissenschaftlichen Politik- bzw. Gesellschaftsberatung bilden etwa Katastrophenwarnungen und Heilsverheißungen, andererseits nicht-altruistische, sondern dem Eigeninteresse dienende, wie auch politisierende Verlautbarungen. Das setzt eine Selbstbegrenzung voraus.Wünschenswert ist bei wissenschaftlichem Handeln der Respekt von und vor Grenzen, ist die Distanz zur Macht. Diese Macht kann der Politik, der Ökonomie und auch den Medien zugeschrieben werden; fatal sind Nähe oder gar Einfluss von Ideologien. Dabei wird nicht nur ein behutsamer Umgang mit Empfehlungen angesprochen; im wissenschaftlichen Handeln sind gerade beim Gegenstand der Bildgebung Berührungen mit der und sogar Überlappungen mit Interessen der Industrie möglich, teilweise gewünscht und fruchtbar. Letztlich ist es ja immer die Industrialisierung, die medizinischen Fortschritt, sei er pharmakologisch oder technologisch abbildbar, breiten Bevölkerungsgruppen und entlegenen Standorten zugänglich macht. Das bedarf immer einer gegenseitigen kritischen Begleitung.Die Wissenschaft dient dem Erkenntnisgewinn. Dazu gehört eine methodische Suche nach Wahrheit, die alle Befähigten überprüfen und nachvollziehen können. Wenn dieses angenommen, akzeptiert werden kann, dann sind die Technikwissenschaften Wissenschaften, dann betreiben Radiologie und Nuklearmedizin Wissenschaft (science). Dann bedarf es nicht der Aufzählung von Nobelpreisen oder ähnlichen Anerkennungen in der Scientific Community. Dann bedarf es nicht der Aufzählung fachlicher Beispiele; die Methoden und die Technologien fallen nicht vom Himmel. Wissenschaft wird von Menschen betrieben und getragen. An Pioniere der Bildgebung, an Personen, wie Wilhelm Conrad Röntgen, Marie Curie, Godfrey Hounsfield, Peter Mansfield, Paul Lauterbur oder Stephan Hell sei erinnert.* Dieses Editorial wird zeitgleich in Nuklearmedizin publiziert. Schober O, Dössel O, Ermert H et al. Bildgebung in Klinik und Forschung: Beitrag zur Individualisierten Medizin? Nuklearmedizin 2017; 56: 157-161; https://doi.org/10.3413/2017-05-0002.