Atrial conduction velocity mapping: clinical tools, algorithms and approaches for understanding the arrhythmogenic substrate

Characterizing patient-specific atrial conduction properties is important for understanding arrhythmia drivers, for predicting potential arrhythmia pathways, and for personalising treatment approaches. One metric that characterizes the health of the myocardial substrate is atrial conduction velocity, which describes the speed and direction of propagation of the electrical wavefront through the myocardium. Atrial conduction velocity mapping algorithms are under continuous development in research laboratories and in industry. In this review article, we give a broad overview of different categories of currently published methods for calculating CV, and give insight into their different advantages and disadvantages overall. We classify techniques into local, global, and inverse methods, and discuss these techniques with respect to their faithfulness to the biophysics, incorporation of uncertainty quantification, and their ability to take account of the atrial manifold

Formation of Intracardiac Electrograms under Physiological and Pathological Conditions

This work presents methods to advance electrophysiological simulations of intracardiac electrograms (IEGM). An experimental setup is introduced, which combines electrical measurements of extracellular potentials with a method for optical acquisition of the transmembrane voltage in-vitro. Thereby, intracardiac electrograms can be recorded under defined conditions. Using experimental and clinical signals, detailed simulations of IEGMs are parametrized, which can support clinical diagnosis

Uncertainty Quantification and Reduction in Cardiac Electrophysiological Imaging

Cardiac electrophysiological (EP) imaging involves solving an inverse problem that infers cardiac electrical activity from body-surface electrocardiography data on a physical domain defined by the body torso. To avoid unreasonable solutions that may fit the data, this inference is often guided by data-independent prior assumptions about different properties of cardiac electrical sources as well as the physical domain. However, these prior assumptions may involve errors and uncertainties that could affect the inference accuracy. For example, common prior assumptions on the source properties, such as fixed spatial and/or temporal smoothness or sparseness assumptions, may not necessarily match the true source property at different conditions, leading to uncertainties in the inference. Furthermore, prior assumptions on the physical domain, such as the anatomy and tissue conductivity of different organs in the thorax model, represent an approximation of the physical domain, introducing errors to the inference. To determine the robustness of the EP imaging systems for future clinical practice, it is important to identify these errors/uncertainties and assess their impact on the solution. This dissertation focuses on the quantification and reduction of the impact of uncertainties caused by prior assumptions/models on cardiac source properties as well as anatomical modeling uncertainties on the EP imaging solution. To assess the effect of fixed prior assumptions/models about cardiac source properties on the solution of EP imaging, we propose a novel yet simple Lp-norm regularization method for volumetric cardiac EP imaging. This study reports the necessity of an adaptive prior model (rather than fixed model) for constraining the complex spatiotemporally changing properties of the cardiac sources. We then propose a multiple-model Bayesian approach to cardiac EP imaging that employs a continuous combination of prior models, each re-effecting a specific spatial property for volumetric sources. The 3D source estimation is then obtained as a weighted combination of solutions across all models. Including a continuous combination of prior models, our proposed method reduces the chance of mismatch between prior models and true source properties, which in turn enhances the robustness of the EP imaging solution. To quantify the impact of anatomical modeling uncertainties on the EP imaging solution, we propose a systematic statistical framework. Founded based on statistical shape modeling and unscented transform, our method quantifies anatomical modeling uncertainties and establish their relation to the EP imaging solution. Applied on anatomical models generated from different image resolutions and different segmentations, it reports the robustness of EP imaging solution to these anatomical shape-detail variations. We then propose a simplified anatomical model for the heart that only incorporates certain subject-specific anatomical parameters, while discarding local shape details. Exploiting less resources and processing for successful EP imaging, this simplified model provides a simple clinically-compatible anatomical modeling experience for EP imaging systems. Different components of our proposed methods are validated through a comprehensive set of synthetic and real-data experiments, including various typical pathological conditions and/or diagnostic procedures, such as myocardial infarction and pacing. Overall, the methods presented in this dissertation for the quantification and reduction of uncertainties in cardiac EP imaging enhance the robustness of EP imaging, helping to close the gap between EP imaging in research and its clinical application

Validation and Opportunities of Electrocardiographic Imaging: From Technical chievements to Clinical Applications

[EN] 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 non-invasively 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 toward a useful role in clinical practice.This study received financial support from the Hein Wellens Fonds, the Cardiovascular Research and Training Institute (CVRTI), the Nora Eccles Treadwell Foundation, the National Institute of General Medical Sciences of the National Institutes of Health (P41GM103545), the National Institutes of Health (NIH HL080093), the French government as part of the Investments of the Future program managed by the National Research Agency (ANR-10-IAHU-04), from the VEGA Grant Agency in Slovakia (2/0071/16), from the Slovak Research and Development Agency (APVV-14-0875), the Fondo Europeo de Desarrollo Regional (FEDER), the Instituto de Salud Carlos III (PI17/01106) and from Conselleria d'Educacio, Investigacio, Cultura i Esport de la Generalitat Valenciana (AICO/2018/267) and NIH grant (HL125998) and National Science Foundation (ACI-1350374).Cluitmans, M.; Brooks, D.; Macleod, RS.; Dossel, O.; Guillem Sánchez, MS.; Van Dam, P.; Svehlikova, J.... (2018). Validation and Opportunities of Electrocardiographic Imaging: From Technical chievements to Clinical Applications. Frontiers in Physiology. 9. https://doi.org/10.3389/fphys.2018.01305S9Andrews, C. M., Srinivasan, N. T., Rosmini, S., Bulluck, H., Orini, M., Jenkins, S., … Rudy, Y. (2017). Electrical and Structural Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging. Circulation: Arrhythmia and Electrophysiology, 10(7). doi:10.1161/circep.116.005105Aras, K., Good, W., Tate, J., Burton, B., Brooks, D., Coll-Font, J., … MacLeod, R. (2015). Experimental Data and Geometric Analysis Repository—EDGAR. Journal of Electrocardiology, 48(6), 975-981. doi:10.1016/j.jelectrocard.2015.08.008Austen, W., Edwards, J., Frye, R., Gensini, G., Gott, V., Griffith, L., … Roe, B. (1975). A reporting system on patients evaluated for coronary artery disease. 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Acta Crystallographica Section B Structural Science, 52(5), 753-769. doi:10.1107/s0108768196005599Haissaguerre, M., Hocini, M., Denis, A., Shah, A. J., Komatsu, Y., Yamashita, S., … Dubois, R. (2014). Driver Domains in Persistent Atrial Fibrillation. Circulation, 130(7), 530-538. doi:10.1161/circulationaha.113.005421HAISSAGUERRE, M., HOCINI, M., SHAH, A. J., DERVAL, N., SACHER, F., JAIS, P., & DUBOIS, R. (2013). Noninvasive Panoramic Mapping of Human Atrial Fibrillation Mechanisms: A Feasibility Report. Journal of Cardiovascular Electrophysiology, 24(6), 711-717. doi:10.1111/jce.12075Han, C., Pogwizd, S. M., Killingsworth, C. R., & He, B. (2011). Noninvasive imaging of three-dimensional cardiac activation sequence during pacing and ventricular tachycardia. Heart Rhythm, 8(8), 1266-1272. doi:10.1016/j.hrthm.2011.03.014Bin He, Guanglin Li, & Xin Zhang. (2003). Noninvasive imaging of cardiac transmembrane potentials within three-dimensional myocardium by means of a realistic geometry anisotropic heart model. IEEE Transactions on Biomedical Engineering, 50(10), 1190-1202. doi:10.1109/tbme.2003.817637Bin He, & Dongsheng Wu. (2001). Imaging and visualization of 3-D cardiac electric activity. IEEE Transactions on Information Technology in Biomedicine, 5(3), 181-186. doi:10.1109/4233.945288Horáček, B. M., Sapp, J. L., Penney, C. J., Warren, J. W., & Wang, J. J. (2011). Comparison of epicardial potential maps derived from the 12-lead electrocardiograms with scintigraphic images during controlled myocardial ischemia. Journal of Electrocardiology, 44(6), 707-712. doi:10.1016/j.jelectrocard.2011.08.009Horáček, B. M., Wang, L., Dawoud, F., Xu, J., & Sapp, J. L. (2015). Noninvasive electrocardiographic imaging of chronic myocardial infarct scar. Journal of Electrocardiology, 48(6), 952-958. doi:10.1016/j.jelectrocard.2015.08.035Jamil-Copley, S., Vergara, P., Carbucicchio, C., Linton, N., Koa-Wing, M., Luther, V., … Kanagaratnam, P. (2015). Application of Ripple Mapping to Visualize Slow Conduction Channels Within the Infarct-Related Left Ventricular Scar. Circulation: Arrhythmia and Electrophysiology, 8(1), 76-86. doi:10.1161/circep.114.001827Janssen, A. M., Potyagaylo, D., Dössel, O., & Oostendorp, T. F. (2017). Assessment of the equivalent dipole layer source model in the reconstruction of cardiac activation times on the basis of BSPMs produced by an anisotropic model of the heart. Medical & Biological Engineering & Computing, 56(6), 1013-1025. doi:10.1007/s11517-017-1715-xKnecht, S., Sohal, M., Deisenhofer, I., Albenque, J.-P., Arentz, T., Neumann, T., … Rostock, T. (2017). Multicentre evaluation of non-invasive biatrial mapping for persistent atrial fibrillation ablation: the AFACART study. EP Europace, 19(8), 1302-1309. doi:10.1093/europace/euw168Kuck, K.-H., Schaumann, A., Eckardt, L., Willems, S., Ventura, R., Delacrétaz, E., … Hansen, P. S. (2010). Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. The Lancet, 375(9708), 31-40. doi:10.1016/s0140-6736(09)61755-4Identification of Rotors during Human Atrial Fibrillation Using Contact Mapping and Phase Singularity Detection: Technical Considerations. (2017). IEEE Transactions on Biomedical Engineering, 64(2), 310-318. doi:10.1109/tbme.2016.2554660Leong, K. M. W., Ng, F. S., Yao, C., Roney, C., Taraborrelli, P., Linton, N. W. F., … Varnava, A. M. (2017). ST-Elevation Magnitude Correlates With Right Ventricular Outflow Tract Conduction Delay in Type I Brugada ECG. Circulation: Arrhythmia and Electrophysiology, 10(10). doi:10.1161/circep.117.005107Chenguang Liu, Eggen, M. D., Swingen, C. M., Iaizzo, P. A., & Bin He. (2012). Noninvasive Mapping of Transmural Potentials During Activation in Swine Hearts From Body Surface Electrocardiograms. IEEE Transactions on Medical Imaging, 31(9), 1777-1785. doi:10.1109/tmi.2012.2202914MacLeod, R. S., Ni, Q., Punske, B., Ershler, P. R., Yilmaz, B., & Taccardi, B. (2000). Effects of heart position on the body-surface electrocardiogram. Journal of Electrocardiology, 33, 229-237. doi:10.1054/jelc.2000.20357Metzner, A., Wissner, E., Tsyganov, A., Kalinin, V., Schlüter, M., Lemes, C., … Kuck, K.-H. (2017). Noninvasive phase mapping of persistent atrial fibrillation in humans: Comparison with invasive catheter mapping. Annals of Noninvasive Electrocardiology, 23(4), e12527. doi:10.1111/anec.12527Modre, R., Tilg, B., Fischer, G., Hanser, F., Messnarz, B., Seger, M., … Roithinger, F. X. (2003). Atrial Noninvasive Activation Mapping of Paced Rhythm Data. Journal of Cardiovascular Electrophysiology, 14(7), 712-719. doi:10.1046/j.1540-8167.2003.02558.xNarayan, S. M., Krummen, D. E., Shivkumar, K., Clopton, P., Rappel, W.-J., & Miller, J. M. (2012). Treatment of Atrial Fibrillation by the Ablation of Localized Sources. Journal of the American College of Cardiology, 60(7), 628-636. doi:10.1016/j.jacc.2012.05.022NG, J., KADISH, A. H., & GOLDBERGER, J. J. (2007). Technical Considerations for Dominant Frequency Analysis. Journal of Cardiovascular Electrophysiology, 18(7), 757-764. doi:10.1111/j.1540-8167.2007.00810.xOosterhoff, P., Meijborg, V. M. F., van Dam, P. M., van Dessel, P. F. H. M., Belterman, C. N. W., Streekstra, G. J., … Oostendorp, T. F. (2016). Experimental Validation of Noninvasive Epicardial and Endocardial Activation Imaging. Circulation: Arrhythmia and Electrophysiology, 9(8). doi:10.1161/circep.116.004104Oster, H. S., Taccardi, B., Lux, R. L., Ershler, P. R., & Rudy, Y. (1997). Noninvasive Electrocardiographic Imaging. 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Noninvasive Localization of Ectopic Foci: A New Optimization Approach for Simultaneous Reconstruction of Transmembrane Voltages and Epicardial Potentials. Lecture Notes in Computer Science, 166-173. doi:10.1007/978-3-642-38899-6_20Punshchykova, O., Švehlíková, J., Tyšler, M., Grünes, R., Sedova, K., Osmančík, P., … Kneppo, P. (2016). Influence of Torso Model Complexity on the Noninvasive Localization of Ectopic Ventricular Activity. Measurement Science Review, 16(2), 96-102. doi:10.1515/msr-2016-0013RAMANATHAN, C., & RUDY, Y. (2001). Electrocardiographic Imaging: II. Effect of Torso Inhomogeneities on Noninvasive Reconstruction of Epicardial Potentials, Electrograms, and Isochrones. Journal of Cardiovascular Electrophysiology, 12(2), 241-252. doi:10.1046/j.1540-8167.2001.00241.xReddy, V. Y., Reynolds, M. R., Neuzil, P., Richardson, A. W., Taborsky, M., Jongnarangsin, K., … Josephson, M. E. (2007). Prophylactic Catheter Ablation for the Prevention of Defibrillator Therapy. 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K., & Rudy, Y. (2008). Noninvasive electrocardiographic imaging (ECGI) of epicardial activation before and after catheter ablation of the accessory pathway in a patient with Ebstein anomaly. Heart Rhythm, 5(6), 857-860. doi:10.1016/j.hrthm.2008.03.011Rudy, Y., Plonsey, R., & Liebman, J. (1979). The effects of variations in conductivity and geometrical parameters on the electrocardiogram, using an eccentric spheres model. Circulation Research, 44(1), 104-111. doi:10.1161/01.res.44.1.104SALINET, J. L., TUAN, J. H., SANDILANDS, A. J., STAFFORD, P. J., SCHLINDWEIN, F. S., & NG, G. A. (2013). Distinctive Patterns of Dominant Frequency Trajectory Behavior in Drug-Refractory Persistent Atrial Fibrillation: Preliminary Characterization of Spatiotemporal Instability. Journal of Cardiovascular Electrophysiology, 25(4), 371-379. doi:10.1111/jce.12331Dalu, Y. (1978). Relating the multipole moments of the heart to activated parts of the epicardium and endocardium. 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Characterizing Cardiac Electrophysiology during Radiofrequency Ablation : An Integrative Ex vivo, In silico, and In vivo Approach

Catheter ablation is a major treatment for atrial tachycardias. Hereby, the precise monitoring of the lesion formation is an important success factor. This book presents computational, wet-lab, and clinical studies with the aim of evaluating the signal characteristics of the intracardiac electrograms (IEGMs) recorded around ablation lesions from different perspectives. The detailed analysis of the IEGMs can optimize the description of durable and complex lesions during the ablation procedure

Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation

Transcranial electric stimulation aims to stimulate the brain by applying weak electrical currents at the scalp. However, the magnitude and spatial distribution of electric fields in the human brain are unknown. We measured electric potentials intracranially in ten epilepsy patients and estimated electric fields across the entire brain by leveraging calibrated current-flow models. When stimulating at 2 mA, cortical electric fields reach 0.8 V/m, the lower limit of effectiveness in animal studies. When individual whole-head anatomy is considered, the predicted electric field magnitudes correlate with the recorded values in cortical (r = 0.86) and depth (r = 0.88) electrodes. Accurate models require adjustment of tissue conductivity values reported in the literature, but accuracy is not improved when incorporating white matter anisotropy or different skull compartments. This is the first study to validate and calibrate current-flow models with in vivo intracranial recordings in humans, providing a solid foundation to target stimulation and interpret clinical trials

Personalizing Simulations of the Human Atria : Intracardiac Measurements, Tissue Conductivities, and Cellular Electrophysiology

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

Doctor of Philosophy

dissertationAtrial fibrillation (AF) is the leading cause of ischemic stroke and is the most commonly observed arrhythmia in clinical cardiology. Catheter ablation of AF, in which specific regions of cardiac anatomy associated with AF are intenionally injured to create scar tissue, has been honed over the last 15 years to become a relatively common and safe treatment option. However, the success of these anatomically driven ablation strategies, particularly in hearts that have been exposed to AF for extended periods, remains poor. AF induces changes in the electrical and structural properties of the cardiac tissue that further promotes the permanence of AF. In a process known as electroanatomical (EAM) mapping, clinicians record time signals known as electrograms (EGMs) from the heart and the locations of the recording sites to create geometric representations, or maps, of the electrophysiological properties of the heart. Analysis of the maps and the individual EGM morphologies can indicate regions of abnormal tissue, or substrates that facilitate arrhythmogenesis and AF perpetuation. Despite this progress, limitations in the control of devices currently used for EAM acquisition and reliance on suboptimal metrics of tissue viability appear to be hindering the potential of treatment guided by substrate mapping. In this research, we used computational models of cardiac excitation to evaluate param- eters of EAM that affect the performance of substrate mapping. These models, which have been validated with experimental and clinical studies, have yielded new insights into the limitations of current mapping systems, but more importantly, they guided us to develop new systems and metrics for robust substrate mapping. We report here on the progress in these simulation studies and on novel measurement approaches that have the potential to improve the robustness and precision of EAM in patients with arrhythmias. Appropriate detection of proarrhythmic substrates promises to improve ablation of AF beyond rudimentary destruction of anatomical targets to directed targeting of complicit tissues. Targeted treatment of AF sustaining tissues, based on the substrate mapping approaches described in this dissertation, has the potential to improve upon the efficacy of current AF treatment options

Non-Invasive Electrocardiographic Imaging of Ventricular Activities: Data-Driven and Model-Based Approaches

Die vorliegende Arbeit beleuchtet ausgewählte Aspekte der Vorwärtsmodellierung, so zum Beispiel die Simulation von Elektro- und Magnetokardiogrammen im Falle einer elektrisch stillen Ischämie sowie die Anpassung der elektrischen Potentiale unter Variation der Leitfähigkeiten. Besonderer Fokus liegt auf der Entwicklung neuer Regularisierungsalgorithmen sowie der Anwendung und Bewertung aktuell verwendeter Methoden in realistischen in silico bzw. klinischen Studien