Novel non-invasive algorithm to identify the origins of re-entry and ectopic foci in the atria from 64-lead ECGs: A computational study.

Atrial tachy-arrhytmias, such as atrial fibrillation (AF), are characterised by irregular electrical activity in the atria, generally associated with erratic excitation underlain by re-entrant scroll waves, fibrillatory conduction of multiple wavelets or rapid focal activity. Epidemiological studies have shown an increase in AF prevalence in the developed world associated with an ageing society, highlighting the need for effective treatment options. Catheter ablation therapy, commonly used in the treatment of AF, requires spatial information on atrial electrical excitation. The standard 12-lead electrocardiogram (ECG) provides a method for non-invasive identification of the presence of arrhythmia, due to irregularity in the ECG signal associated with atrial activation compared to sinus rhythm, but has limitations in providing specific spatial information. There is therefore a pressing need to develop novel methods to identify and locate the origin of arrhythmic excitation. Invasive methods provide direct information on atrial activity, but may induce clinical complications. Non-invasive methods avoid such complications, but their development presents a greater challenge due to the non-direct nature of monitoring. Algorithms based on the ECG signals in multiple leads (e.g. a 64-lead vest) may provide a viable approach. In this study, we used a biophysically detailed model of the human atria and torso to investigate the correlation between the morphology of the ECG signals from a 64-lead vest and the location of the origin of rapid atrial excitation arising from rapid focal activity and/or re-entrant scroll waves. A focus-location algorithm was then constructed from this correlation. The algorithm had success rates of 93% and 76% for correctly identifying the origin of focal and re-entrant excitation with a spatial resolution of 40 mm, respectively. The general approach allows its application to any multi-lead ECG system. This represents a significant extension to our previously developed algorithms to predict the AF origins in association with focal activities

Spatiotemporal Model-Based Estimation of High-Density Atrial Fibrillation Activation Map

Examination of activation maps using multi-electrode array (MEA) sensors can help to understand the mechanisms underlying atrial fibrillation (AF). Classically, creation of activation maps starts with detection of local activation times (LAT) based on recorded unipolar electrograms. LAT detection has a limited robustness and accuracy, and generally requires manual edition. In general, LAT detection ignores spatiotemporal information of activation embedded in the relation between electrode signals on the MEA mapping sensor. In this work, a unified approach to construct activation maps by simultaneous analysis of activation patterns from overlapping clusters of MEA electrodes is proposed. An activation model fits on the measured data by iterative optimization of the model parameters based on a cost function. The accuracy of the estimated activation maps was evaluated by comparison with audited maps created by expertelectrophysiologists during sinus rhythm (SR) and AF. During SR recordings, 25 activation maps (3100 LATs) were automatically determined resulting in an average LAT estimation error of -0.66 ±2.00msand a correlation of ¿s=0.98compared to the expert reference. During AF recordings (235 maps, 28226 LATs), the estimation error was -0.83 ±6.02mswith only a slightly lower correlation (¿s=0.93). In conclusion, complex spatial activation patterns can be decomposed into local activation patterns derived from fitting an activation model, allowing the creation of smooth and comprehensive high-density activation maps

Endocardial activation mapping of human atrial fibrillation

Successful ablation of arrhythmias depends upon interpretation of the mechanism. However, in persistent atrial fibrillation (AF) ablation is currently directed towards the mechanism that initiates paroxysmal AF. We sought to address the hypothesis that atrial activation patterns during persistent AF may help determine the underlying mechanism. Activation mapping of AF wavefronts is labor intensive and often restricted to short time segments in limited atrial locations. RETRO-Mapping was developed to identify uniform wavefronts that occur during AF, and summate all wavefront vectors on to an orbital plot. Uniform wavefronts were mapped using RETRO-Mapping during sinus rhythm, atrial tachycardia, and atrial fibrillation, and validated against detailed manual analysis of the same wavefronts with conventional isochronal mapping. RETRO-Mapping was found to have comparable accuracy to isochronal mapping. RETRO-Mapping was then used to investigate atrial activation patterns during persistent AF. Atrial activation patterns demonstrated evidence of spatiotemporal stability over long time periods. Orbital plots created at different time points in the same location remained unchanged. Together with this important discovery, both fractionation and bipolar voltage were also demonstrated to express stability over time. Spatiotemporal stability during persistent AF enables sequential mapping as an acceptable technique. This property also allowed the development of a method for displaying sequentially mapped locations on a single map – RETRO-Choropleth Map. These findings go against the multiple wavelet hypothesis with random activation. Having gained insights in to these stable activation patterns, extensive analysis was undertaken to identify the presence of focal activation. Focal activations were identified during persistent AF. RETRO-Mapping was used to show that adjacent activation patterns were not related to focal activations. Lastly, the effect of pulmonary vein isolation (PVI) was studied by mapping atrial activation patterns before and after PVI. RETRO-Mapping showed that PVI leads to increased organisation of AF in most patients, supporting a mechanistic role of the pulmonary veins in persistent AF. In conclusion, a new technique has been developed and validated for automated activation mapping of persistent AF. These techniques could be used to guide additional ablation strategies beyond PVI for patients with persistent AF.Open Acces

Technical Considerations on Phase Mapping for Identification of Atrial Reentrant Activity in Direct- and Inverse-Computed Electrograms

[EN] [Background] Phase mapping has become a broadly used technique to identify atrial reentrant circuits for ablative therapy guidance. This work studies the phase mapping process and how the signal nature and its filtering affect the reentrant pattern characterization in electrogram (EGM), body surface potential mapping, and electrocardiographic imaging signals. [Methods and Results] EGM, body surface potential mapping, and electrocardiographic imaging phase maps were obtained from 17 simulations of atrial fibrillation, atrial flutter, and focal atrial tachycardia. Reentrant activity was identified by singularity point recognition in raw signals and in signals after narrow band-pass filtering at the highest dominant frequency (HDF). Reentrant activity was dominantly present in the EGM recordings only for atrial fibrillation and some atrial flutter propagations patterns, and HDF filtering allowed increasing the reentrant activity detection from 60% to 70% of time in atrial fibrillation in unipolar recordings and from 0% to 62% in bipolar. In body surface potential mapping maps, HDF filtering increased from 10% to 90% the sensitivity, although provoked a residual false reentrant activity ¿30% of time. In electrocardiographic imaging, HDF filtering allowed to increase ¿100% the time with detected rotors, although provoked the apparition of false rotors during 100% of time. Nevertheless, raw electrocardiographic imaging phase maps presented reentrant activity just in atrial fibrillation recordings accounting for ¿80% of time. [Conclusions] Rotor identification is accurate and sensitive and does not require additional signal processing in measured or noninvasively computed unipolar EGMs. Bipolar EGMs and body surface potential mapping do require HDF filtering to detect rotors at the expense of a decreased specificity.This study was supported, in part, by Universitat Politecnica de Valencia through its research initiative program; Generalitat Valenciana Grants (ACIF/2013/021); the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882, PI13-00903, PI14/00857, PI16/01123, TEC2013-46067-R, DTS16/0160, and IJCI-2014-22178); Spanish Society of Cardiology (Grant for Clinical Research in Cardiology 2015); Spanish Ministry of Science and Innovation (Red RIC RD12.0042.0001); and the National Heart, Lung, and Blood Institute (P01-HL039707, P01-HL087226, and Q1 R01-HL118304) and cofounded by FEDER.Rodrigo Bort, M.; Martínez Climent, A.; Liberos Mascarell, A.; Fernández-Avilés, F.; Berenfeld, O.; Atienza, F.; Guillem Sánchez, MS. (2017). Technical Considerations on Phase Mapping for Identification of Atrial Reentrant Activity in Direct- and Inverse-Computed Electrograms. Circulation Arrhythmia and Electrophysiology. 10(9):1-13. https://doi.org/10.1161/CIRCEP.117.005008S113109Allessie, M., & de Groot, N. (2014). CrossTalk opposing view: Rotors have not been demonstrated to be the drivers of atrial fibrillation. The Journal of Physiology, 592(15), 3167-3170. doi:10.1113/jphysiol.2014.271809Narayan, S. M., & Zaman, J. A. B. (2016). Mechanistically based mapping of human cardiac fibrillation. The Journal of Physiology, 594(9), 2399-2415. doi:10.1113/jp270513Guillem, M. S., Climent, A. M., Rodrigo, M., Fernández-Avilés, F., Atienza, F., & Berenfeld, O. (2016). Presence and stability of rotors in atrial fibrillation: evidence and therapeutic implications. Cardiovascular Research, 109(4), 480-492. doi:10.1093/cvr/cvw011Narayan, S. M., Krummen, D. E., Clopton, P., Shivkumar, K., & Miller, J. M. (2013). Direct or Coincidental Elimination of Stable Rotors or Focal Sources May Explain Successful Atrial Fibrillation Ablation. Journal of the American College of Cardiology, 62(2), 138-147. doi:10.1016/j.jacc.2013.03.021Berenfeld, O., Ennis, S., Hwang, E., Hooven, B., Grzeda, K., Mironov, S., … Jalife, J. (2011). Time- and frequency-domain analyses of atrial fibrillation activation rate: The optical mapping reference. Heart Rhythm, 8(11), 1758-1765. doi:10.1016/j.hrthm.2011.05.007Gray, R. A., Pertsov, A. M., & Jalife, J. (1998). Spatial and temporal organization during cardiac fibrillation. Nature, 392(6671), 75-78. doi:10.1038/32164Rodrigo, M., Guillem, M. S., Climent, A. M., Pedrón-Torrecilla, J., Liberos, A., Millet, J., … Berenfeld, O. (2014). Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: A clinical-computational study. Heart Rhythm, 11(9), 1584-1591. doi:10.1016/j.hrthm.2014.05.013Vijayakumar, R., Vasireddi, S. K., Cuculich, P. S., Faddis, M. N., & Rudy, Y. (2016). Methodology Considerations in Phase Mapping of Human Cardiac Arrhythmias. Circulation: Arrhythmia and Electrophysiology, 9(11). doi:10.1161/circep.116.004409Guillem, M. S., Climent, A. M., Millet, J., Arenal, Á., Fernández-Avilés, F., Jalife, J., … Berenfeld, O. (2013). Noninvasive Localization of Maximal Frequency Sites of Atrial Fibrillation by Body Surface Potential Mapping. Circulation: Arrhythmia and Electrophysiology, 6(2), 294-301. doi:10.1161/circep.112.000167Haissaguerre, 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.113.005421Dössel, O., Krueger, M. W., Weber, F. M., Wilhelms, M., & Seemann, G. (2012). Computational modeling of the human atrial anatomy and electrophysiology. Medical & Biological Engineering & Computing, 50(8), 773-799. doi:10.1007/s11517-012-0924-6Koivumäki, J. T., Seemann, G., Maleckar, M. M., & Tavi, P. (2014). In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation. PLoS Computational Biology, 10(5), e1003620. doi:10.1371/journal.pcbi.1003620Garcia-Molla, V. M., Liberos, A., Vidal, A., Guillem, M. S., Millet, J., Gonzalez, A., … Climent, A. M. (2014). Adaptive step ODE algorithms for the 3D simulation of electric heart activity with graphics processing units. Computers in Biology and Medicine, 44, 15-26. doi:10.1016/j.compbiomed.2013.10.023Rodrigo, M., Climent, A. M., Liberos, A., Calvo, D., Fernández-Avilés, F., Berenfeld, O., … Guillem, M. S. (2016). Identification of Dominant Excitation Patterns and Sources of Atrial Fibrillation by Causality Analysis. Annals of Biomedical Engineering, 44(8), 2364-2376. doi:10.1007/s10439-015-1534-xPEDRÓN-TORRECILLA, J., RODRIGO, M., CLIMENT, A. M., LIBEROS, A., PÉREZ-DAVID, E., BERMEJO, J., … GUILLEM, M. S. (2016). Noninvasive Estimation of Epicardial Dominant High-Frequency Regions During Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 27(4), 435-442. doi:10.1111/jce.12931Zlochiver, S., Yamazaki, M., Kalifa, J., & Berenfeld, O. (2008). Rotor meandering contributes to irregularity in electrograms during atrial fibrillation. Heart Rhythm, 5(6), 846-854. doi:10.1016/j.hrthm.2008.03.010ALHUSSEINI, M., VIDMAR, D., MECKLER, G. L., KOWALEWSKI, C. A., SHENASA, F., WANG, P. J., … RAPPEL, W.-J. (2017). Two Independent Mapping Techniques Identify Rotational Activity Patterns at Sites of Local Termination During Persistent Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 28(6), 615-622. doi:10.1111/jce.1317

Mathematical modeling approaches for the diagnosis and treatment of reentrant atrial tachyarrhythmias

[EN] Atrial tachyarrhythmias present a high prevalence in the developed world, and several studies predict that in the coming decades it will be increased. Micro or macro-reentrant mechanisms of the electrical wavefronts that govern the mechanical behavior of the heart are one of the main responsibles for the maintenance of these arrhythmias. Atrial flutter is maintained by a macro-reentry around an anatomical or functional obstacle located in the atria. In the case of atrial fibrillation, the hypothesis which describes high frequency rotors as dominant sources of the fibrillation and responsible for the maintenance of the arrhythmia, has been gaining relevance in the last years. However, the therapies that target high frequency sources have a limited efficacy with current techniques. Radiofrequency ablation allows the destruction of parts of the cardiac tissue resulting in the interruption of the reentrant circuit in case of macro-reentries or the isolation of micro-reentrant circuits. The non-invasive location of reentrant circuits would increment the efficacy of these therapies and would shorten surgery interventions. In parallel, pharmacological therapies modify ionic expressions associated to the excitability and electrical refractoriness of the cardiac tissue with the objective of hindering the maintenance of reentrant behaviors. These therapies require a deep knowledge of the ionic mechanisms underlying the reentrant behavior and its properties in order to be effective. The research in these mechanisms allows the evaluation of new targets for the treatment and thus may improve the efficacy in atrial fibrillation termination. In this thesis, mathematical modeling is used to go forward in the minimization of the limitations associated to these treatments. Body surface potential mapping has been evaluated, both clinically and by means of mathematical simulations for the diagnosis and location of macro-reentrant circuits. The analysis of phase maps obtained from multiple lead electrocardiographic recordings distributed in the whole torso allowed the discrimination between different reentrant circuits. It is the reason why this technique is presented as a tool for the non-invasive location of macro and micro-reentrant circuits. A population of mathematical models designed in this thesis based on the action potentials recordings of atrial cardiomyocites from 149 patients, allowed the evaluation of the ionic mechanisms defining the properties of reentrant behaviors. This study has allowed us defining the blockade of ICaL as a target for the pharmacological treatment. The blockade of this current is associated with the increase of the movement in the core of the rotor which easies the collision of the rotor with other wavefronts or anatomical obstacles promoting the extinction of the reentry. The variability observed between patients modeled in our population has allowed showing and explaining the mechanisms promoting divergent results of a single treatment. This is why the introduction of populations of models will allow the prevention of side effects associated to inter-subject variability and to go forward in the development of individualized therapies. These works are built through a simulation platform of cardiac electrophysiology based in Graphic Processing Units (GPUs) and developed in this thesis. The platform allows the simulation of cellular models, tissues and organs with a realistic geometry and shows features comparable to that of the platforms used by the most relevant electrophysiology research groups at the moment.[ES] Las taquiarritmias auriculares tienen una alta prevalencia en el mundo desarrollado, además diversos estudios poblacionales indican que en las próximas décadas ésta se verá incrementada. Los mecanismos de micro o macro-reentrada de los frentes de onda eléctricos que rigen el comportamiento mecánico del corazón, se presentan como una de las principales causas del mantenimiento de estas arritmias. El flutter auricular es mantenido por un macro-reentrada alrededor de un obstáculo anatómico o funcional en las aurículas, mientras que en el caso de la fibrilación auricular la hipótesis que define a los rotores de alta frecuencia como elementos dominantes y responsables del mantenimiento de la arritmia se ha ido imponiendo al resto en los últimos años. Sin embargo, las terapias que tienen como objetivo finalizar o aislar estas reentradas tienen todavía una eficacia limitada. La ablación por radiofrecuencia permite eliminar zonas del tejido cardiaco resultando en la interrupción del circuito de reentrada en el caso de macro-reentradas o el aislamiento de comportamientos micro-reentrantes. La localización no invasiva de los circuitos reentrantes incrementaría la eficacia de estas terapias y reduciría la duración de las intervenciones quirúrgicas. Por otro lado, las terapias farmacológicas alteran las expresiones iónicas asociadas a la excitabilidad y la refractoriedad del tejido con el fin de dificultar el mantenimiento de comportamientos reentrantes. Este tipo de terapias exigen incrementar el conocimiento de los mecanismos subyacentes que explican el proceso de reentrada y sus propiedades, la investigación de estos mecanismos permite definir las dianas terapéuticas que mejoran la eficacia en la extinción de estos comportamientos. En esta tesis el modelado matemático se utiliza para dar un paso importante en la minimización de las limitaciones asociadas a estos tratamientos. La cartografía eléctrica de superficie ha sido testada, clínicamente y con simulaciones matemática,s como técnica de diagnóstico y localización de circuitos macro-reentrantes. El análisis de mapas de fase obtenidos a partir de los registros multicanal de derivaciones electrocardiográficas distribuidas en la superficie del torso permite diferenciar distintos circuitos de reentrada. Es por ello que esta técnica de registro y análisis se presenta como una herramienta para la localización no invasiva de circuitos macro y micro-reentrantes. Una población de modelos matemáticos, diseñada en esta tesis a partir de los registros de los potenciales de acción de 149 pacientes, ha permitido evaluar los mecanismos iónicos que definen las propiedades asociadas a los procesos de reentrada. Esto ha permitido apuntar al bloqueo de la corriente ICaL como diana terapéutica. Ésta se asocia al incremento del movimiento del núcleo que facilita el impacto del rotor con otros frentes de onda u obstáculos extinguiéndose así el comportamiento reentrante. La variabilidad entre pacientes reflejada en la población de modelos ha permitido además mostrar los mecanismos por los cuales un mismo tratamiento puede mostrar efectos divergentes, así el uso de poblaciones de modelos matemáticos permitirá prevenir efectos secundarios asociados a la variabilidad entre pacientes y profundizar en el desarrollo de terapias individualizadas. Estos trabajos se cimientan sobre una plataforma de simulación de electrofisiología cardiaca de basado en Unidades de Procesado Gráfico (GPUs) y desarrollada en esta tesis. La plataforma permite la simulación de modelos celulares cardiacos así como de tejidos u órganos con geometría realista, mostrando unas prestaciones comparables con las de las utilizadas por los grupos de investigación más potentes en el campo de la electrofisiología.[CA] Les taquiarítmies auriculars tenen una alta prevalença en el món desenvolupat, a més diversos estudis poblacionals indiquen que en les pròximes dècades aquesta es veurà incrementada. Els mecanismes de micro o macro-reentrada dels fronts d'ona elèctrics que regeixen el comportament mecànic del cor, es presenten com una de les principals causes del manteniment d'aquestes arítmies. El flutter auricular és mantingut per una macro-reentrada al voltant d'un obstacle anatòmic o funcional en les aurícules, mentre que en el cas de la fibril·lació auricular la hipòtesi que defineix als rotors d'alta freqüència com a elements dominants i responsables del manteniment de l'arítmia s'ha anat imposant a la resta en els últims anys. No obstant això, les teràpies que tenen com a objectiu finalitzar o aïllar aquestes reentrades tenen encara una eficàcia limitada. L'ablació per radiofreqüència permet eliminar zones del teixit cardíac resultant en la interrupció del circuit de reentrada en el cas de macro-reentrades o l'aïllament de comportaments micro-reentrants. La localització no invasiva dels circuits reentrants incrementaria l'eficàcia d'aquestes teràpies i reduiria la durada de les intervencions quirúrgiques. D'altra banda, les teràpies farmacològiques alteren les expressions iòniques associades a la excitabilitat i la refractaritat del teixit amb la finalitat de dificultar el manteniment de comportaments reentrants. Aquest tipus de teràpies exigeixen incrementar el coneixement dels mecanismes subjacents que expliquen el procés de reentrada i les seues propietats, la recerca d'aquests mecanismes permet definir les dianes terapèutiques que milloren l'eficàcia en l'extinció d'aquests comportaments. En aquesta tesi el modelatge matemàtic s'utilitza per a fer un pas important en la minimització de les limitacions associades a aquests tractaments. La cartografia elèctrica de superfície ha sigut testada, clínicament i amb simulacions matemàtiques com a tècnica de diagnòstic i localització de circuits macro-reentrants. L'anàlisi de mapes de fase obtinguts a partir dels registres multicanal de derivacions electrocardiogràfiques distribuïdes en la superfície del tors permet diferenciar diferents circuits de reentrada. És per açò que aquesta tècnica de registre i anàlisi es presenta com una eina per a la localització no invasiva de circuits macro i micro-reentrants. Una població de models matemàtics, dissenyada en aquesta tesi a partir dels registres dels potencials d'acció de 149 pacients, ha permès avaluar els mecanismes iònics que defineixen les propietats associades als processos de reentrada. Açò ha permès apuntar al bloqueig del corrent ICaL com a diana terapèutica. Aquesta s'associa a l'increment del moviment del nucli que facilita l'impacte del rotor amb altres fronts d'ona o obstacles extingint-se així el comportament reentrant. La variabilitat entre pacients reflectida en la població de models ha permès a més mostrar els mecanismes pels quals un mateix tractament pot mostrar efectes divergents, així l'ús de poblacions de models matemàtics permetrà prevenir efectes secundaris associats a la variabilitat entre pacients i aprofundir en el desenvolupament de teràpies individualitzades. Aquests treballs es fonamenten sobre una plataforma de simulació de electrofisiologia cardíaca basat en Unitats de Processament Gràfic (GPUs) i desenvolupada en aquesta tesi. La plataforma permet la simulació de models cel·lulars cardíacs així com de teixits o òrgans amb geometria realista, mostrant unes prestacions comparables amb les de les utilitzades per els grups de recerca més importants en aquesta área.Liberos Mascarell, A. (2016). Mathematical modeling approaches for the diagnosis and treatment of reentrant atrial tachyarrhythmias [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62166TESI

Relationship between body surface potential maps and atrial electrograms in patients with atrial fibrillation

PhD ThesisAtrial fibrillation (AF) is the most common cardiac arrhythmia. It is distinguished by fibrillating or trembling of the atrial muscle instead of normal contraction. Patients in AF have a much higher risk of stroke. AF is often driven by the left atrium (LA) and the diagnosis of AF is normally made from lead V1 in a 12-lead electrocardiogram (ECG). However, lead V1 is dominated by right atrial activity due to its proximal location to the right atrium (RA). Consequently it is not well understood how electrical activity from the LA contributes to the ECG. Studies of the AF mechanisms from the LA are typically based on invasive recording techniques. From a clinical point of view it is highly desirable to have an alternative, non-invasive characterisation of AF. The aim of this study was to investigate how the LA electrical activity was expressed on the body surface, and if it could be observed preferentially in different sites on the body surface. For this purpose, electrical activity of the heart from 20 patients in AF were recorded simultaneously using 64-lead body surface potential mapping (BSPM) and bipolar 10-electrode catheters located in the LA and coronary sinus (CS). Established AF characteristics such as amplitude, dominant frequency (DF) and spectral concentration (SC) were estimated and analysed. Furthermore, two novel AF characteristics (intracardiac DF power distribution, and body surface spectral peak type) were proposed to investigate the relationship between the BSPM and electrogram (EGM) recordings. The results showed that although in individual patients there were body surface sites that preferentially represented the AF characteristics estimated from the LA, those sites were not consistent across all patients. It was found that the left atrial activity could be detected in all body surface sites such that all sites had a dominant or non-dominant spectral peak corresponding to EGM DF. However, overall the results suggested that body surface site 22 (close to lead V1) was more closely representative of the CS activity, and site 49 (close to the posterior lower central right) was more closely representative of the left atrial activity. There was evidence of more accurate estimation of AF characteristics using additional electrodes to lead V1

Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: A clinical-computational study

Background: Ablation is an effective therapy in atrial fibrillation (AF) patients in which an electrical driver can be identified. Objective: The aim of this study is to present and discuss a novel and strictly non-invasive approach to map and identify atrial regions responsible for AF perpetuation. Methods: Surface potential recordings of 14 patients with AF were recorded using a 67-lead recording system. Singularity points (SPs) were identified in surface phase maps after band-pass filtering at the highest dominant frequency (HDF). Mathematical models of combined atria and torso were constructed and used to investigate the ability of surface phase maps to estimate rotor activity in the atrial wall. Results: The simulations show that surface SPs originate at atrial SPs, but not all atrial SPs are reflected at the surface. Stable SPs were found in AF signals during 8.3±5.7% vs. 73.1±16.8% of the time in unfiltered vs. HDF-filtered patient data respectively (p<0.01). The average duration of each rotational pattern was also lower in unfiltered than in HDF-filtered AF signals (160±43 vs. 342±138 ms, p<0.01) resulting in 2.8±0.7 rotations per rotor. Band-pass filtering reduced the apparent meandering of surface HDF rotors by reducing the effect of the atrial electrical activity taking place at different frequencies. Torso surface SPs representing HDF rotors during AF were reflected at specific areas corresponding to the fastest atrial location. Conclusion: Phase analysis of surface potential signals after HDF-filtering during AF shows reentrant drivers localized to either the LA or RA, helping in localizing ablation targetsThis work was supported in part by the Spanish Society of Cardiology (Becas Investigacion Clinica 2009); the Universitat Politecnica de Valencia through its research initiative program; the Generalitat Valenciana grant (ACIF/2013/021); the Ministerio de Economia y Competitividad, Rod RIC; the Centro Nacional de Investigaciones Cardiovasculares (proyecto CNIC-13); the Coulter Foundation from the Biomedical Engineering Department, University of Michigan; the Gelman Award from the Cardiovascular Division, University of Michigan; the National Heart, Lung, and Blood Institute grants (P01411.039707, P01-1111187226, and R01-11L118304); and the Leducq Foundation. Dr Femandez-Aviles served on the advisory board of Medtronic and has received research funding from St Jude Medical Spain. Dr Berenfeld has received research support from Medtronic and St Jude Medical; he is a colbunder and scientific officer of Rhythm Solutions. None of the companies disclosed financed the research described in this article.Rodrigo Bort, M.; Guillem Sánchez, MS.; Climent, AM.; Pedrón Torrecilla, J.; Liberos Mascarell, A.; Millet Roig, J.; Fernandez-Aviles, F.... (2014). Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: A clinical-computational study. Heart Rhythm. 11(9):1584-1591. https://doi.org/10.1016/j.hrthm.2014.05.013S1584159111

The contact electrogram and its architectural determinants in atrial fibrillation

The electrogram is the sine qua non of excitable tissues, yet classification in atrial fibrillation (AF) remains poorly related to substrate factors. The objective of this thesis was to establish the relationship between electrograms and two commonly implicated substrate factors, connexin 43 and fibrosis in AF. The substrates and methods chosen to achieve this ranged from human acutely induced AF using open chest surgical mapping (Chapter 6), ex vivo whole heart Langendorff (Chapter 7) with in vivo telemetry confirming spontaneous AF in a new species of rat, the Brown Norway and finally isolated atrial preparations from an older cohort of rats using orthogonal pacing and novel co-localisation methods at sub-millimetre resolution and in some atria, optical mapping (Chapter 8). In rodents, electrode size and spacing was varied (Chapters 5, 10) to study its effects on structure function correlations (Chapter 9). Novel indices of AF organisation and automated electrogram morphology were used to quantify function (Chapter 4). Key results include the discoveries that humans without any history of prior AF have sinus rhythm electrograms with high spectral frequency content, that wavefront propagation velocities correlated with fibrosis and connexin phosphorylation ratios, that AF heterogeneity of conduction correlates to fibrosis and that orthogonal pacing in heavily fibrosed atria causes anisotropy in electrogram-fibrosis correlations. Furthermore, fibrosis and connexin 43 have differing and distinct spatial resolutions in their relationship with AF organisational indices. In conclusion a new model of AF has been found, and structure function correlations shown on an unprecedented scale, but with caveats of electrode size and direction dependence. These findings impact structure function methods and prove the effect of substrate on AF organisation.Open Acces