Mapping of the electrical activity of human atria. Multiscale modelling and simulations

La fibrilación auricular es una de las arritmias cardíacas más comunes observadas en la práctica clínica. Por lo tanto, es de vital importancia desarrollar nuevas tecnologías destinadas a diagnosticar y acabar con este tipo de arritmia, para mejorar la calidad de vida de los pacientes y reducir los costes de los sistemas nacionales de salud. En los últimos años ha aumentado el uso de las nuevas técnicas de mapeo auricular, basadas en sistemas multi-electrodo para mapear la actividad eléctrica en humanos. Dichas técnicas permiten localizar y ablacionar los impulsores de la fibrilación auricular, como son las fuentes focales o los rotores. Sin embargo, todavía existe incertidumbre sobre su precisión y los procedimientos experimentales para su análisis están limitados debido a su carácter invasivo. Por lo tanto, las simulaciones computacionales son una herramienta muy útil para superar estas limitaciones, al permitir reproducir con fidelidad las observaciones experimentales, dividir el problema bajo estudio en sub-estudios más simples, y realizar investigaciones preliminares imposibles de llevar a cabo en el práctica clínica. Esta tesis doctoral se centra en el análisis de la precisión de los sistemas de mapeo multi-electrodo a través de modelos y simulaciones computacionales. Para ello, desarrollamos modelos realistas multi-escala con el objetivo de simular actividad eléctrica auricular reentrante, en primer lugar en una lámina de tejido auricular, y en segundo lugar en las aurículas completas. Posteriormente, analizamos los efectos de las configuraciones geométricas multi-electrodo en la precisión de la localización de los rotores, mediante el uso de agrupaciones multi-electrodo con distancias inter-electrodo equidistantes, así como a través de catéteres de tipo basket con distancias inter-electrodo no equidistantes. Después de calcular los electrogramas unipolares intracavitarios, realizamos mapas de fase, detecciones de singularidad de fase para rastrear los rotores, y mapas de frecuencia dominantes. Finalmente, descubrimos que la precisión de los sistemas de mapeo multi-electrodo depende de su posición dentro de la cavidad auricular, de la distancia entre los electrodos y el tejido, de la distancia inter-electrodo, y de la contribución de las fuentes de campo lejano. Además, como consecuencia de estos factores que pueden afectar a la precisión de los sistemas de mapeo multi-electrodo, observamos la aparición de rotores falsos que podrían contribuir al fracaso de los procesos de ablación de la fibrilación auricular.Atrial fibrillation is one of the most common cardiac arrhythmias seen in clinical practice. Therefore, it is of vital importance to develop new technologies aimed at diagnosing and terminating this kind of arrhythmia, to improve the quality of life of patients and to reduce costs to national health systems. In the last years, new atrial mapping techniques based on multi-electrode systems are increasingly being used to map the atrial electrical activity in humans and localise and target atrial fibrillation drivers in the form of focal sources or rotors. However, significant concerns remain about their accuracy and experimental approaches to analyse them are limited due to their invasive character. Therefore, computer simulations are a helpful tool to overcome these limitations since they can reproduce with fidelity experimental observations, permit to split the problem to treat into more simple substudies, and allow the possibility of performing preliminary investigations impossible to carry out in the clinical practice. This PhD thesis is focused on the analysis for accuracy of the multielectrode mapping systems through computational models and simulations. For this purpose, we developed realistic multiscale models in order to simulate atrial electrical reentrant activity, first in a sheet of atrial tissue and, then, in the whole atria. Then, we analysed the effects of the multi-electrode geometrical configurations on the accuracy of localizing rotors, by using multi-electrode arrays with equidistant inter-electrode distances, as well as multi-electrode basket catheters with non-equidistant inter-electrode distances. After computing the intracavitary unipolar electrograms, we performed phase maps, phase singularity detections to track rotors, and dominant frequency maps. We finally found out that the accuracy of multi-electrode mapping systems depends on their position inside the atrial cavity, the electrode-to-tissue distance, the inter-electrode distance, and the contribution of far field sources. Furthermore, as a consequence of these factors, false rotors might appear and could contribute to failure of atrial fibrillation ablation procedures.La fibril·lació auricular és una de les arítmies cardíaques més comuns observades en la pràctica clínica. Per tant, és de vital importància desenvolupar noves tecnologies destinades a diagnosticar i acabar amb aquest tipus d'arítmia, per tal de millorar la qualitat de vida dels pacients i reduir els costos dels sistemes nacionals de salut. En els últims anys, ha augmentat l'ús de les noves tècniques de mapeig auricular, basades en sistemes multielèctrode per a mapejar l'activitat elèctrica auricular en humans. Aquestes tècniques permeten localitzar i ablacionar els impulsors de la fibril·lació auricular, com són les fonts focals o els rotors. No obstant això, encara hi ha incertesa sobre la seua precisió i els procediments experimentals per al seu anàlisi estan limitats a causa del seu caràcter invasiu. Per tant, les simulacions computacionals són una eina molt útil per a superar aquestes limitacions, en permetre reproduir amb fidelitat les observacions experimentals, dividir el problema sota estudi en subestudis més simples, i realitzar investigacions preliminars impossibles de dur a terme en el pràctica clínica. Aquesta tesi doctoral es centra en l'anàlisi de la precisió del sistemes de mapeig multielèctrode mitjançant els models i les simulacions computacionals. Per a això, desenvolupàrem models realistes multiescala per tal de simular activitat elèctrica auricular reentrant, en primer lloc en una làmina de teixit auricular, i en segon lloc a les aurícules completes. Posteriorment, analitzàrem els efectes de les configuracions geomètriques multielèctrode en la precisió de la localització dels rotors, mitjançant l'ús d'agrupacions multielèctrode amb distàncies interelèctrode equidistants, així com catèters de tipus basket amb distàncies interelèctrode no equidistants. Després de calcular els electrogrames unipolars intracavitaris, vam realitzar mapes de fase, deteccions de singularitat de fase per a rastrejar els rotors, i mapes de freqüència dominants. Finalment, vam descobrir que la precisió dels sistemes de mapeig multielèctrode depèn de la seua posició dins de la cavitat auricular, de la distància entre els elèctrodes i el teixit, de la distància interelèctrode, i de la contribució de les fonts de camp llunyà. A més, com a conseqüència d'aquests factors, es va observar l'aparició de rotors falsos que podrien contribuir al fracàs de l'ablació de la fibril·lació auricular.Martínez Mateu, L. (2018). Mapping of the electrical activity of human atria. Multiscale modelling and simulations [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/104604TESI

Differential Modulation of I-K and I-Ca,I-L Channels in High-Fat Diet-Induced Obese Guinea Pig Atria

[EN] Obesity mechanisms that make atrial tissue vulnerable to arrhythmia are poorly understood. Voltage-dependent potassium (I-K, I-Kur, and I-K1) and L-type calcium currents (I-Ca,I- L) are electrically relevant and represent key substrates for modulation in obesity. We investigated whether electrical remodeling produced by high-fat diet (HFD) alone or in concert with acute atrial stimulation were different. Electrophysiology was used to assess atrial electrical function after short-term HFD-feeding in guinea pigs. HFD atria displayed spontaneous beats, increased I-K (I-Kr + I-Ks) and decreased I-Ca,I- L densities. Only with pacing did a reduction in I-Kur and increased I-K1 phenotype emerge, leading to a further shortening of action potential duration. Computer modeling studies further indicate that the measured changes in potassium and calcium current densities contribute prominently to shortened atrial action potential duration in human heart. Our data are the first to show that multiple mechanisms (shortened action potential duration, early after depolarizations and increased incidence of spontaneous beats) may underlie initiation of supraventricular arrhythmias in obese guinea pig hearts. These results offer different mechanistic insights with implications for obese patients harboring supraventricular arrhythmias.This study was supported by an AHA (13SDG16850065 to AA), NIH (R01 HL147044 to AA), and Programa Prometeu de la Conselleria d Educació, Formació I Ocupació de la Generalitat Valenciana, award number PROMETEU/2016/088.Martínez-Mateu, L.; Saiz Rodríguez, FJ.; Aromolaran, A. (2019). Differential Modulation of I-K and I-Ca,I-L Channels in High-Fat Diet-Induced Obese Guinea Pig Atria. Frontiers in Physiology. 10:1-18. https://doi.org/10.3389/fphys.2019.01212S11810Abed, H. S., & Wittert, G. A. (2013). Obesity and atrial fibrillation. 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Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture. PLOS ONE, 10(8), e0133052. doi:10.1371/journal.pone.0133052OCHI, R., MOMOSE, Y., OYAMA, K., & GILES, W. (2006). Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents. Cardiovascular Research, 70(1), 88-96. doi:10.1016/j.cardiores.2006.01.010O’Hara, T., & Rudy, Y. (2012). Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species. American Journal of Physiology-Heart and Circulatory Physiology, 302(5), H1023-H1030. doi:10.1152/ajpheart.00785.2011Osadchii, O. E. (2012). Electrophysiological determinants of arrhythmic susceptibility upon endocardial and epicardial pacing in guinea-pig heart. Acta Physiologica, 205(4), 494-506. doi:10.1111/j.1748-1716.2012.02428.xPatoine, D., Levac, X., Pilote, S., Drolet, B., & Simard, C. (2013). Decreased CYP3A Expression and Activity in Guinea Pig Models of Diet-Induced Metabolic Syndrome: Is Fatty Liver Infiltration Involved? Drug Metabolism and Disposition, 41(5), 952-957. doi:10.1124/dmd.112.050641Paulino, E. C., Ferreira, J. C. B., Bechara, L. R., Tsutsui, J. M., Mathias, W., Lima, F. B., … Negrão, C. E. (2010). Exercise Training and Caloric Restriction Prevent Reduction in Cardiac Ca 2+ -Handling Protein Profile in Obese Rats. Hypertension, 56(4), 629-635. doi:10.1161/hypertensionaha.110.156141Pérez-Hernández, M., Matamoros, M., Barana, A., Amorós, I., Gómez, R., Núñez, M., … Caballero, R. (2015). Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancingIKsand decreasingICa,L. Cardiovascular Research, 109(3), 431-441. doi:10.1093/cvr/cvv280A, P., H, C., MC, F., L, B., JN, W., & HS, K. (2018). Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Eff

Public Health Innovations Program tailored to Master on Telecommunications’ Students

[EN] Developed and under-developed countries are facing several challenges related to public health and sustainability of health care systems. New challenges demand of the collaborative action of multiple stakeholders with different backgrounds. In the late years, telecommunication engineers are involved in a wide range of companies and institutions to help designing and building innovative and efficient solutions, among which public health is a paradigmatic example. In this paper authors introduce a program for teaching public health principles and tools focused at telecommunications master students. The program is presented in five practices of three hours duration (fifteen hours overall). The sessions are structured in the classic problem-solving methodology in which the students must respond to concrete and general questions by the application of knowledge, practice and reasoning. Each practice includes theoretical framework introduction, provision of tools and use of open repositories to complete the assignments. The covered topics are: mobile health and usability, open data, data mining, Internet of Things and wearable and process mining.Martínez Millana, A.; Martínez Mateu, L.; Guillem Sánchez, MS.; Traver Salcedo, V. (2021). Public Health Innovations Program tailored to Master on Telecommunications’ Students. En Proceedings INNODOCT/20. International Conference on Innovation, Documentation and Education. Editorial Universitat Politècnica de València. 137-144. https://doi.org/10.4995/INN2020.2020.11860OCS13714

Simulation Study of the Arrhythmogenic Effects of Two Missense Mutations in Human Atrial Fibrillation

[EN] Genetic mutations affecting genes encoding for ion channel protein structures have been associated with the presence of atrial fibrillation (AF) in healthy individuals. The aim of this study is to model and simulate the effects of two gain-of-function mutations found in literature, T895M and T436M, and affecting the rapid delayed rectifier potassium current. Courtemanche human atrial model has been chosen to reproduce myocytes behaviour and an optimization algorithm has been employed to fit model parameters to experimental data. Single cell and tissue patch simulations have been performed to study the effects of the two mutations in control, paroxysmal and permanent AF conditions, both in right and left atrium. 0D simulations revealed that both mutations cause an increase in IKr current, leading to action potential duration shortening and flattening of restitution curves, especially in presence of the mutation T895M. Initiation of a re-entrant activity in 2D simulations were possible both in case of T895M and T436M. The study reports the arrhythmogenicity of the two mutants and reveals T895M having a stronger effect with respect to T436M, in particular in control rather than in paroxysmal and permanent AF conditions. Differences in the dynamics of the two mutations highlight the importance of a patient-specific approach in planning targeted drug therapies.I acknowledge this work to the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie gran agreement No.766082 and to Generalitat Valenciana, Prometeo programme 2020/043Belletti, R.; Martínez-Mateu, L.; Romero Pérez, L.; Saiz Rodríguez, FJ. (2020). Simulation Study of the Arrhythmogenic Effects of Two Missense Mutations in Human Atrial Fibrillation. IEEE. 1-4. https://doi.org/10.22489/CinC.2020.420S1

Far-field contributions in multi-electrodes atrial recordings blur distinction between anatomical and functional reentries and may cause imaginary phase singularities A computational study

[EN] Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and the most important cause of embolic stroke, requiring new technologies for its better understanding and therapies. Recent approaches to map the electrical activity during AF with multi-electrode systems aim at localizing patient-specific ablation targets of reentrant patterns. However, there is a critical need to determine the accuracy of those mapping systems. We performed computer simulations as a numerical approach of systematically evaluating the influence of far-field sources on the electrical recordings and detection of rotors. Methods We constructed 2 computer models of atrial tissue: (i) a 2D sheet model with varying non-active cells area in its center, and (ii) a whole realistic 3D atrial model. Phase maps were built based on the Hilbert transform of the unipolar electrograms recorded by virtual 2D and 3D multi-electrode systems and rotors were tracked through phase singularities detections. Results Analysis of electrograms recorded away from the 2D atrial model shows that the larger the distance between an electrode and the tissue model, the stronger the far-field sources contribution to the electrogram is. Importantly, even if an electrode is positioned in contact with the tissue, the electrogram contains significant contributions from distal sources that blur the distinction between anatomical and functional reentries. Moreover, when mapping the 3D atrial model, remote activity generated false phase singularities at locations without local reentrant excitation patterns. Conclusions Far-field contributions to electrograms during AF reduce the accuracy of detecting and interpreting reentrant activity.This work was supported in part by Programa Prometeu de la Conselleria d'Educacio, Formacio I Ocupacio de la Generalitat Valenciana, award number PROMETEU/2016/088; Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016 del Ministerio de Economia, Industria y Competitividad of Spain, Agencia Estatal de Investigacion and the European Commission (European Regional Development Funds - ERDF -FEDER), award number DPI2016-75799-R; The National Heart, Lung, and Blood Institute grant ROl-HL118304; the Gelman Award from the Cardiovascular Division at the University of Michigan; and the Coulter Program Award from the Dept. of Biomed Eng. at the University of Michigan.Martínez-Mateu, L.; Romero Pérez, L.; Saiz Rodríguez, FJ.; Berenfeld, O. (2019). Far-field contributions in multi-electrodes atrial recordings blur distinction between anatomical and functional reentries and may cause imaginary phase singularities A computational study. Computers in Biology and Medicine. 108:276-287. https://doi.org/10.1016/j.compbiomed.2019.02.022S27628710

Unipolar Electrogram Eigenvalue Distribution Analysis for the Identification of Atrial Fibrosis

[EN] Atrial fibrosis plays an important role in the pathogenesis of atrial fibrillation (AF). Low bipolar electrograms (b-EGMs) peak-to-peak voltage areas indicate scar tissue and are considered targets for AF substrate ablation. However, this approach ignores the spatiotemporal information embedded in the signal and the dependence of b-EGMs on catheter orientation. This work proposes an approach to detect fibrosis based on the eigenvalue dominance ratio (EIGDR) in an ensemble (clique) of unipolar electrograms (u-EGMs). A 2-D tissue with a central circular patch of fibrosis has been simulated using the Courtemanche cellular model. Maps of EIGDR have been computed using two sizes of electrode cliques, from the original u-EGMs within the ensemble or after a time alignment of these signals. Performance of each map in detecting fibrosis has been evaluated using receiver operating characteristic curves and detection accuracy. Best results achieve an area under the curve (AUC) of 0.98 and an accuracy (ACC) of 1 when we use as marker the gain in eigenvalue dominance produced by the ensemble alignmentFunding comes from EU Programme H2020 under the Marie Sklodowska-Curie Grant No 766082 (MY-ATRIA), Gobierno de Aragon (BSICoS Group T39-20R) cofunded by FEDER 2014-2020 "Building Europe from Aragon", fellowship ACIF/2018/174 from Generalitat Valenciana, and PID2019-104881RB-I00 from MICINN, SpainRiccio, J.; Rocher-Ventura, S.; Martínez-Mateu, L.; Alcaine, A.; Saiz Rodríguez, FJ.; Martínez, JP.; Laguna, P. (2020). Unipolar Electrogram Eigenvalue Distribution Analysis for the Identification of Atrial Fibrosis. IEEE. 1-4. https://doi.org/10.22489/CinC.2020.434S1

Macrophage-Dependent Interleukin-6-Production and Inhibition of I-K Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart

[EN] In the heart, the delayed rectifier K current, I-K, composed of the rapid (I-Kr) and slow (I-Ks) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel I-K, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered I-K in the heart, using electrophysiology to evaluate changes in I-K in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of I-Kr and I-Ks densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of I-Kr did a proarrhythmic phenotype of I-Ks depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.This study was supported by an AHA (13SDG16850065 to A.S.A), NIH (R01 HL147044 to A.S.A), and Programa Prometeu de la Conselleria d'innovacio, Universitats, Ciencia i Societat Digital de la Generalitat Valenciana (Award number prometeu/2020/043 to J.S).Chowdhury, MKH.; Martínez-Mateu, L.; Do, J.; Aromolaran, KA.; Saiz Rodríguez, FJ.; Aromolaran, A. (2021). Macrophage-Dependent Interleukin-6-Production and Inhibition of I-K Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart. International Journal of Molecular Sciences. 22(20):1-15. https://doi.org/10.3390/ijms222011249S115222

Characterization of Atrial Propagation Patterns and Fibrotic Substrate With a Modified Omnipolar Electrogram Strategy in Multi-Electrode Arrays

[EN] Introduction: The omnipolar electrogram method was recently proposed to try to generate orientation-independent electrograms. It estimates the electric field from the bipolar electrograms of a clique, under the assumption of locally plane and homogeneous propagation. The local electric field evolution over time describes a loop trajectory from which omnipolar signals in the propagation direction, substrate and propagation features, are derived. In this work, we propose substrate and conduction velocity mapping modalities based on a modified version of the omnipolar electrogram method, which aims to reduce orientation-dependent residual components in the standard approach. Methods: A simulated electrical propagation in 2D, with a tissue including a circular patch of diffuse fibrosis, was used for validation. Unipolar electrograms were calculated in a multi-electrode array, also deriving bipolar electrograms along the two main directions of the grid. Simulated bipolar electrograms were also contaminated with real noise, to assess the robustness of the mapping strategies against noise. The performance of the maps in identifying fibrosis and in reproducing unipolar reference voltage maps was evaluated. Bipolar voltage maps were also considered for performance comparison. Results: Results show that the modified omnipolar mapping strategies are more accurate and robust against noise than bipolar and standard omnipolar maps in fibrosis detection (accuracies higher than 85 vs. 80% and 70%, respectively). They present better correlation with unipolar reference voltage maps than bipolar and original omnipolar maps (Pearson's correlations higher than 0.75 vs. 0.60 and 0.70, respectively). Conclusion: The modified omnipolar method improves fibrosis detection, characterization of substrate and propagation, also reducing the residual sensitivity to directionality over the standard approach and improving robustness against noise. Nevertheless, studies with real electrograms will elucidate its impact in catheter ablation interventions.This study has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 766082 (MY-ATRIA project), from projects PID2019-104881RB-I00, and PID2019-105674RB-I00 from MICINN, Spain, from Gobierno de Aragon (BSICoS Group T39-20R) cofunded by FEDER 20142020 Building Europe from Aragon and from Generalitat Valenciana through the fellowship ACIF/2018/174 and the grant PROMETEO/2020/043.Riccio, J.; Alcaine, A.; Rocher-Ventura, S.; Martínez-Mateu, L.; Laranjo, S.; Saiz Rodríguez, FJ.; Laguna, P.... (2021). Characterization of Atrial Propagation Patterns and Fibrotic Substrate With a Modified Omnipolar Electrogram Strategy in Multi-Electrode Arrays. Frontiers in Physiology. 12:1-21. https://doi.org/10.3389/fphys.2021.674223S1211

Atrial low voltage areas: A comparison between atrial fibrillation and sinus rhythm

[EN] Background: Atrial fibrosis can promote atrial fibrillation (AF). Electroanatomic mapping (EAM) can provide information regarding local voltage abnormalities that may be used as a surrogate marker for fibrosis. Specific voltage cut-off values have been reproduced accurately to identify fibrosis in the ventricles, but these values are not well defined in atrial tissue. Methods: This study is a prospective single-center study. Patients with persistent AF referred for ablation were included. EAM was performed before ablation. We recorded bipolar signals, first in AF and later in sinus rhythm (SR). Two thresholds delimited low-voltage areas (LVA), 0.5 and 0.3 mV. We compared LVA extension between maps in SR and AF in each patient. Results: A total of 23 patients were included in the study. The percentage of points with voltage lower than 0.5 mV and 0.3 mV was significantly higher in maps in AF compared with maps in SR: 38.2% of points < 0.5 mV in AF vs. 22.9% in SR (p < 0.001); 22.3% of points < 0.3 mV in AF vs. 14% in SR (p < 0.001). Areas with reduced voltage were significantly larger in maps in AF (0.5 mV threshold, mean area in AF 41.3 ± 42.5 cm2 vs. 11.7 ± 17.9 cm2 in SR, p < 0.001; 0.3 mV threshold, mean area in AF 15.6 ± 22.1 cm2 vs. 6.2 ± 11.5 cm2 in SR, p < 0.001). Conclusions: Using the same voltage thresholds, LVA extension in AF is greater than in SR in patients with persistent AF. These findings provide arguments for defining a different atrial fibrosis threshold based on EAM rhythm.Andrés Lahuerta, A.; Roberto, C.; Saiz Rodríguez, FJ.; Cano, Ó.; Martínez-Mateu, L.; Alonso, P.; Saurí, A.... (2022). Atrial low voltage areas: A comparison between atrial fibrillation and sinus rhythm. Cardiology Journal. 29(2):252-262. https://doi.org/10.5603/CJ.a2021.0125S25226229

Atrial fibrosis identification with unipolar electrogram eigenvalue distribution analysis in multi-electrode arrays

Atrial fbrosis plays a key role in the initiation and progression of atrial fbrillation (AF). Atrial fbrosis is typically identifed by a peak-to-peak amplitude of bipolar electrograms (b-EGMs) lower than 0.5 mV, which may be considered as ablation targets. Nevertheless, this approach disregards signal spatiotemporal information and b-EGM sensitivity to catheter orientation. To overcome these limitations, we propose the dominant-to-remaining eigenvalue dominance ratio (EIGDR) of unipolar electrograms (u-EGMs) within neighbor electrode cliques as a waveform dispersion measure, hypothesizing that it is correlated with the presence of fbrosis. A simulated 2D tissue with a fbrosis patch was used for validation. We computed EIGDR maps from both original and time-aligned u-EGMs, denoted as R and RA, respectively, also mapping the gain in eigenvalue concentration obtained by the alignment, ΔRA. The performance of each map in detecting fbrosis was evaluated in scenarios including noise and variable electrode-tissue distance. Best results were achieved by RA, reaching 94% detection accuracy, versus the 86% of b-EGMs voltage maps. The proposed strategy was also tested in real u-EGMs from fbrotic and non-fbrotic areas over 3D electroanatomical maps, supporting the ability of the EIGDRs as fbrosis markers, encouraging further studies to confrm their translation to clinical settings