High Resolution Multi-parametric Diagnostics and Therapy of Atrial Fibrillation: Chasing Arrhythmia Vulnerabilities in the Spatial Domain

After a century of research, atrial fibrillation (AF) remains a challenging disease to study and exceptionally resilient to treatment. Unfortunately, AF is becoming a massive burden on the health care system with an increasing population of susceptible elderly patients and expensive unreliable treatment options. Pharmacological therapies continue to be disappointingly ineffective or are hampered by side effects due to the ubiquitous nature of ion channel targets throughout the body. Ablative therapy for atrial tachyarrhythmias is growing in acceptance. However, ablation procedures can be complex, leading to varying levels of recurrence, and have a number of serious risks. The high recurrence rate could be due to the difficulty of accurately predicting where to draw the ablation lines in order to target the pathophysiology that initiates and maintains the arrhythmia or an inability to distinguish sub-populations of patients who would respond well to such treatments. There are electrical cardioversion options but there is not a practical implanted deployment of this strategy. Under the current bioelectric therapy paradigm there is a trade-off between efficacy and the pain and risk of myocardial damage, all of which are positively correlated with shock strength. Contrary to ventricular fibrillation, pain becomes a significant concern for electrical defibrillation of AF due to the fact that a patient is conscious when experiencing the arrhythmia. Limiting the risk of myocardial injury is key for both forms of fibrillation. In this project we aim to address the limitations of current electrotherapy by diverging from traditional single shock protocols. We seek to further clarify the dynamics of arrhythmia drivers in space and to target therapy in both the temporal and spatial domain; ultimately culminating in the design of physiologically guided applied energy protocols. In an effort to provide further characterization of the organization of AF, we used transillumination optical mapping to evaluate the presence of three-dimensional electrical substrate variations within the transmural wall during acutely induced episodes of AF. The results of this study suggest that transmural propagation may play a role in AF maintenance mechanisms, with a demonstrated range of discordance between the epicardial and endocardial dynamic propagation patterns. After confirming the presence of epi-endo dyssynchrony in multiple animal models, we further investigated the anatomical structure to look for regional trends in transmural fiber orientation that could help explain the spectrum of observed patterns. Simultaneously, we designed and optimized a multi-stage, multi-path defibrillation paradigm that can be tailored to individual AF frequency content in the spatial and temporal domain. These studies continue to drive down the defibrillation threshold of electrotherapies in an attempt to achieve a pain-free AF defibrillation solution. Finally, we designed and characterized a novel platform of stretchable electronics that provide instrumented membranes across the epicardial surface or implanted within the transmural wall to provide physiological feedback during electrotherapy beyond just the electrical state of the tissue. By combining a spatial analysis of the arrhythmia drivers, the energy delivered and the resulting damage, we hope to enhance the biophysical understanding of AF electrical cardioversion and xiii design an ideal targeted energy delivery protocol to improve upon all limitations of current electrotherapy

Standardizing Single-Frame Phase Singularity Identification Algorithms and Parameters in Phase Mapping During Human Atrial Fibrillation

[EN] Purpose Recent investigations failed to reproduce the positive rotor-guided ablation outcomes shown by initial studies for treating persistent atrial fibrillation (persAF). Phase singularity (PS) is an important feature for AF driver detection, but algorithms for automated PS identification differ. We aim to investigate the performance of four different techniques for automated PS detection. Methods 2048-channel virtual electrogram (VEGM) and electrocardiogram signals were collected for 30 s from 10 patients undergoing persAF ablation. QRST-subtraction was performed and VEGMs were processed using sinusoidal wavelet reconstruction. The phase was obtained using Hilbert transform. PSs were detected using four algorithms: (1) 2D image processing based and neighbor-indexing algorithm; (2) 3D neighbor-indexing algorithm; (3) 2D kernel convolutional algorithm estimating topological charge; (4) topological charge estimation on 3D mesh. PS annotations were compared using the structural similarity index (SSIM) and Pearson's correlation coefficient (CORR). Optimized parameters to improve detection accuracy were found for all four algorithms usingF(beta)score and 10-fold cross-validation compared with manual annotation. Local clustering with density-based spatial clustering of applications with noise (DBSCAN) was proposed to improve algorithms 3 and 4. Results The PS density maps created by each algorithm with default parameters were poorly correlated. Phase gradient threshold and search radius (or kernels) were shown to affect PS detections. The processing times for the algorithms were significantly different (p< 0.0001). TheF(beta)scores for algorithms 1, 2, 3, 3 + DBSCAN, 4 and 4 + DBSCAN were 0.547, 0.645, 0.742, 0.828, 0.656, and 0.831. Algorithm 4 + DBSCAN achieved the best classification performance with acceptable processing time (2.0 +/- 0.3 s). Conclusion AF driver identification is dependent on the PS detection algorithms and their parameters, which could explain some of the inconsistencies in rotor-guided ablation outcomes in different studies. For 3D triangulated meshes, algorithm 4 + DBSCAN with optimal parameters was the best solution for real-time, automated PS detection due to accuracy and speed. Similarly, algorithm 3 + DBSCAN with optimal parameters is preferred for uniform 2D meshes. Such algorithms - and parameters - should be preferred in future clinical studies for identifying AF drivers and minimizing methodological heterogeneities. This would facilitate comparisons in rotor-guided ablation outcomes in future works.This work was supported by the NIHR Leicester Biomedical Research Centre, UK. XL received research grants from Medical Research Council UK (MRC DPFS Ref: MR/S037306/1). TA received research grants from the British Heart Foundation (BHF Project Grant No. PG/18/33/33780), BHF Research Accelerator Award funding and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Brazil, Grant No. 2017/00319-8). MG research was funded by a research grant from the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-00903). GN received funding from the British Heart Foundation (BHF Programme Grant, RG/17/3/32774).Li, X.; Almeida, TP.; Dastagir, N.; Guillem Sánchez, MS.; Salinet, J.; Chu, GS.; Stafford, PJ.... (2020). Standardizing Single-Frame Phase Singularity Identification Algorithms and Parameters in Phase Mapping During Human Atrial Fibrillation. Frontiers in Physiology. 11:1-16. https://doi.org/10.3389/fphys.2020.00869S11611ALHUSSEINI, 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.13177Allessie, M. A., de Groot, N. M. S., Houben, R. P. M., Schotten, U., Boersma, E., Smeets, J. L., & Crijns, H. J. (2010). Electropathological Substrate of Long-Standing Persistent Atrial Fibrillation in Patients With Structural Heart Disease. Circulation: Arrhythmia and Electrophysiology, 3(6), 606-615. doi:10.1161/circep.109.910125Benharash, P., Buch, E., Frank, P., Share, M., Tung, R., Shivkumar, K., & Mandapati, R. (2015). Quantitative Analysis of Localized Sources Identified by Focal Impulse and Rotor Modulation Mapping in Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology, 8(3), 554-561. doi:10.1161/circep.115.002721BRAY, M.-A., LIN, S.-F., ALIEV, R. R., ROTH, B. J., & WIKSWO, J. P. (2001). Experimental and Theoretical Analysis of Phase Singularity Dynamics in Cardiac Tissue. Journal of Cardiovascular Electrophysiology, 12(6), 716-722. doi:10.1046/j.1540-8167.2001.00716.xBray, M.-A., & Wikswo, J. P. (2002). Use of topological charge to determine filament location and dynamics in a numerical model of scroll wave activity. IEEE Transactions on Biomedical Engineering, 49(10), 1086-1093. doi:10.1109/tbme.2002.803516Buch, E., Share, M., Tung, R., Benharash, P., Sharma, P., Koneru, J., … Shivkumar, K. (2016). Long-term clinical outcomes of focal impulse and rotor modulation for treatment of atrial fibrillation: A multicenter experience. Heart Rhythm, 13(3), 636-641. doi:10.1016/j.hrthm.2015.10.031Canny, J. (1986). A Computational Approach to Edge Detection. IEEE Transactions on Pattern Analysis and Machine Intelligence, PAMI-8(6), 679-698. doi:10.1109/tpami.1986.4767851Clayton, R. H., & Nash, M. P. (2015). Analysis of Cardiac Fibrillation Using Phase Mapping. Cardiac Electrophysiology Clinics, 7(1), 49-58. doi:10.1016/j.ccep.2014.11.011Davis, J., & Goadrich, M. (2006). The relationship between Precision-Recall and ROC curves. Proceedings of the 23rd international conference on Machine learning - ICML ’06. doi:10.1145/1143844.1143874De Groot, N. M. S., Houben, R. P. M., Smeets, J. L., Boersma, E., Schotten, U., Schalij, M. J., … Allessie, M. A. (2010). Electropathological Substrate of Longstanding Persistent Atrial Fibrillation in Patients With Structural Heart Disease. Circulation, 122(17), 1674-1682. doi:10.1161/circulationaha.109.910901Earley, M. J., Abrams, D. J. R., Sporton, S. C., & Schilling, R. J. (2006). Validation of the Noncontact Mapping System in the Left Atrium During Permanent Atrial Fibrillation and Sinus Rhythm. Journal of the American College of Cardiology, 48(3), 485-491. doi:10.1016/j.jacc.2006.04.069Gianni, C., Mohanty, S., Di Biase, L., Metz, T., Trivedi, C., Gökoğlan, Y., … Natale, A. (2016). Acute and early outcomes of focal impulse and rotor modulation (FIRM)-guided rotors-only ablation in patients with nonparoxysmal atrial fibrillation. Heart Rhythm, 13(4), 830-835. doi:10.1016/j.hrthm.2015.12.028GOJRATY, S., LAVI, N., VALLES, E., KIM, S. J., MICHELE, J., & GERSTENFELD, E. P. (2009). Dominant Frequency Mapping of Atrial Fibrillation: Comparison of Contact and Noncontact Approaches. Journal of Cardiovascular Electrophysiology, 20(9), 997-1004. doi:10.1111/j.1540-8167.2009.01488.xGrandi, E., Pandit, S. V., Voigt, N., Workman, A. J., Dobrev, D., Jalife, J., & Bers, D. M. (2011). Human Atrial Action Potential and Ca 2+ Model. Circulation Research, 109(9), 1055-1066. doi:10.1161/circresaha.111.253955Gray, R. A., Pertsov, A. M., & Jalife, J. (1998). Spatial and temporal organization during cardiac fibrillation. Nature, 392(6671), 75-78. doi:10.1038/32164Guillem, 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.112.000167Guillem, 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/cvw011Gurevich, D. R., & Grigoriev, R. O. (2019). Robust approach for rotor mapping in cardiac tissue. Chaos: An Interdisciplinary Journal of Nonlinear Science, 29(5), 053101. doi:10.1063/1.5086936HAISSAGUERRE, 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.12075Iyer, A. N., & Gray, R. A. (2001). An Experimentalist’s Approach to Accurate Localization of Phase Singularities during Reentry. Annals of Biomedical Engineering, 29(1), 47-59. doi:10.1114/1.1335538Jalife, J. (2002). Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. Cardiovascular Research, 54(2), 204-216. doi:10.1016/s0008-6363(02)00223-7Jalife, J., Filgueiras Rama, D., & Berenfeld, O. (2015). Letter by Jalife et al Regarding Article, «Quantitative Analysis of Localized Sources Identified by Focal Impulse and Rotor Modulation Mapping in Atrial Fibrillation». Circulation: Arrhythmia and Electrophysiology, 8(5), 1296-1298. doi:10.1161/circep.115.003324Jarman, J. W. E., Wong, T., Kojodjojo, P., Spohr, H., Davies, J. E., Roughton, M., … Peters, N. S. (2012). Spatiotemporal Behavior of High Dominant Frequency During Paroxysmal and Persistent Atrial Fibrillation in the Human Left Atrium. Circulation: Arrhythmia and Electrophysiology, 5(4), 650-658. doi:10.1161/circep.111.967992Kuklik, P., Zeemering, S., Maesen, B., Maessen, J., Crijns, H. J., Verheule, S., … Schotten, U. (2015). Reconstruction of Instantaneous Phase of Unipolar Atrial Contact Electrogram Using a Concept of Sinusoidal Recomposition and Hilbert Transform. IEEE Transactions on Biomedical Engineering, 62(1), 296-302. doi:10.1109/tbme.2014.2350029Identification 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.2016.2554660Lee, Y.-S., Song, J.-S., Hwang, M., Lim, B., Joung, B., & Pak, H.-N. (2016). A New Efficient Method for Detecting Phase Singularity in Cardiac Fibrillation. PLOS ONE, 11(12), e0167567. doi:10.1371/journal.pone.0167567Li, X., Chu, G. S., Almeida, T. P., Salinet, J. L., Dastagir, N., Mistry, A. R., … André Ng, G. (2017). 5Characteristics of ablated rotors in terminating persistent atrial fibrillation using non-contact mapping. EP Europace, 19(suppl_1), i3-i3. doi:10.1093/europace/eux283.145Li, X., Salinet, J. L., Almeida, T. P., Vanheusden, F. J., Chu, G. S., Ng, G. A., & Schlindwein, F. S. (2017). An interactive platform to guide catheter ablation in human persistent atrial fibrillation using dominant frequency, organization and phase mapping. Computer Methods and Programs in Biomedicine, 141, 83-92. doi:10.1016/j.cmpb.2017.01.011Mandapati, R., Skanes, A., Chen, J., Berenfeld, O., & Jalife, J. (2000). Stable Microreentrant Sources as a Mechanism of Atrial Fibrillation in the Isolated Sheep Heart. Circulation, 101(2), 194-199. doi:10.1161/01.cir.101.2.194Narayan, S. M., Baykaner, T., Clopton, P., Schricker, A., Lalani, G. G., Krummen, D. E., … Miller, J. M. (2014). Ablation of Rotor and Focal Sources Reduces Late Recurrence of Atrial Fibrillation Compared With Trigger Ablation Alone. Journal of the American College of Cardiology, 63(17), 1761-1768. doi:10.1016/j.jacc.2014.02.543NARAYAN, S. M., KRUMMEN, D. E., & RAPPEL, W.-J. (2012). Clinical Mapping Approach To Diagnose Electrical Rotors and Focal Impulse Sources for Human Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 23(5), 447-454. doi:10.1111/j.1540-8167.2012.02332.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.2012.05.022Nattel, S. (2002). New ideas about atrial fibrillation 50 years on. Nature, 415(6868), 219-226. doi:10.1038/415219aNattel, S. (2003). Atrial Electrophysiology and Mechanisms of Atrial Fibrillation. Journal of Cardiovascular Pharmacology and Therapeutics, 8(1_suppl), S5-S11. doi:10.1177/107424840300800102Ortigosa, N., Fernández, C., Galbis, A., & Cano, Ó. (2015). Phase information of time-frequency transforms as a key feature for classification of atrial fibrillation episodes. Physiological Measurement, 36(3), 409-424. doi:10.1088/0967-3334/36/3/409Pandit, S. V., & Jalife, J. (2013). Rotors and the Dynamics of Cardiac Fibrillation. Circulation Research, 112(5), 849-862. doi:10.1161/circresaha.111.300158VII. Mathematical contributions to the theory of evolution.—III. Regression, heredity, and panmixia. (1896). Philosophical Transactions of the Royal Society of London. Series A, Containing Papers of a Mathematical or Physical Character, 187, 253-318. doi:10.1098/rsta.1896.0007Pertsov, A. M., Davidenko, J. M., Salomonsz, R., Baxter, W. T., & Jalife, J. (1993). Spiral waves of excitation underlie reentrant activity in isolated cardiac muscle. Circulation Research, 72(3), 631-650. doi:10.1161/01.res.72.3.631Podziemski, P., Zeemering, S., Kuklik, P., van Hunnik, A., Maesen, B., Maessen, J., … Schotten, U. (2018). Rotors Detected by Phase Analysis of Filtered, Epicardial Atrial Fibrillation Electrograms Colocalize With Regions of Conduction Block. Circulation: Arrhythmia and Electrophysiology, 11(10). doi:10.1161/circep.117.005858Wieser, L., Stühlinger, M. C., Hintringer, F., Tilg, B., Fischer, G., & Rantner, L. J. (2007). Detection of Phase Singularities in Triangular Meshes. Methods of Information in Medicine, 46(06), 646-654. doi:10.3414/me0427Ríos-Muñoz, G. R., Arenal, Á., & Artés-Rodríguez, A. (2018). Real-Time Rotational Activity Detection in Atrial Fibrillation. Frontiers in Physiology, 9. doi:10.3389/fphys.2018.00208Rodrigo, M., Climent, A. M., Liberos, A., Fernández-Avilés, F., Berenfeld, O., Atienza, F., & Guillem, M. S. (2017). Technical Considerations on Phase Mapping for Identification of Atrial Reentrant Activity in Direct- and Inverse-Computed Electrograms. Circulation: Arrhythmia and Electrophysiology, 10(9). doi:10.1161/circep.117.005008Rodrigo, 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.2014.05.013Roney, C. H., Cantwell, C. D., Bayer, J. D., Qureshi, N. A., Lim, P. B., Tweedy, J. H., … Ng, F. S. (2017). Spatial Resolution Requirements for Accurate Identification of Drivers of Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology, 10(5). doi:10.1161/circep.116.004899Salinet, J., Schlindwein, F. S., Stafford, P., Almeida, T. P., Li, X., Vanheusden, F. J., … Ng, G. A. (2017). Propagation of meandering rotors surrounded by areas of high dominant frequency in persistent atrial fibrillation. Heart Rhythm, 14(9), 1269-1278. doi:10.1016/j.hrthm.2017.04.031Salinet, J. L., Madeiro, J. P. V., Cortez, P. C., Stafford, P. J., André Ng, G., & Schlindwein, F. S. (2013). Analysis of QRS-T subtraction in unipolar atrial fibrillation electrograms. Medical & Biological Engineering & Computing, 51(12), 1381-1391. doi:10.1007/s11517-013-1071-4Salinet, J. L., Oliveira, G. N., Vanheusden, F. J., Comba, J. L. D., Ng, G. A., & Schlindwein, F. S. (2013). Visualizing intracardiac atrial fibrillation electrograms using spectral analysis. Computing in Science & Engineering, 15(2), 79-87. doi:10.1109/mcse.2013.37Schilling, R. J., Peters, N. S., & Davies, D. W. (1998). Simultaneous Endocardial Mapping in the Human Left Ventricle Using a Noncontact Catheter. Circulation, 98(9), 887-898. doi:10.1161/01.cir.98.9.887Schricker, A. A., Lalani, G. G., Krummen, D. E., & Narayan, S. M. (2014). Rotors as Drivers of Atrial Fibrillation and Targets for Ablation. Current Cardiology Reports, 16(8). doi:10.1007/s11886-014-0509-0Steinberg, J. S., Shah, Y., Bhatt, A., Sichrovsky, T., Arshad, A., Hansinger, E., & Musat, D. (2017). Focal impulse and rotor modulation: Acute procedural observations and extended clinical follow-up. Heart Rhythm, 14(2), 192-197. doi:10.1016/j.hrthm.2016.11.008THIAGALINGAM, A., WALLACE, E. M., BOYD, A. C., EIPPER, V. E., CAMPBELL, C. R., BYTH, K., … KOVOOR, P. (2004). Noncontact Mapping of the Left Ventricle:. Insights from Validation with Transmural Contact Mapping. Pacing and Clinical Electrophysiology, 27(5), 570-578. doi:10.1111/j.1540-8159.2004.00489.xUmapathy, K., Nair, K., Masse, S., Krishnan, S., Rogers, J., Nash, M. P., & Nanthakumar, K. (2010). Phase Mapping of Cardiac Fibrillation. Circulation: Arrhythmia and Electrophysiology, 3(1), 105-114. doi:10.1161/circep.110.853804WITTKAMPF, F. H. M., & NAKAGAWA, H. (2006). RF Catheter Ablation: Lessons on Lesions. Pacing and Clinical Electrophysiology, 29(11), 1285-1297. doi:10.1111/j.1540-8159.2006.00533.xWang, Z., Bovik, A. C., Sheikh, H. R., & Simoncelli, E. P. (2004). Image Quality Assessment: From Error Visibility to Structural Similarity. IEEE Transactions on Image Processing, 13(4), 600-612. doi:10.1109/tip.2003.81986

New Paradigm of Defibrillation: Towards Painless Therapy

Sudden cardiac death: SCD) causes approximately 300,000 - 400,000 deaths a year in the United States. It usually starts as ventricular tachycardia: VT) and then degenerates into ventricular fibrillation: VF). Implantable cardioverter defibrillator: ICD) therapy is the only reliable treatment of VT/VF and has been shown to effectively reduce mortality by many clinical trials. However, high-voltage ICD shocks could result in myocardial dysfunction and damage. The majority of patients receiving ICD therapy have a history of coronary disease; their hearts develop myocardium infarction, which could provide a substrate for reentrant tachy-arrhythmias. Other than lethal ventricular tachycardia, atrial fibrillation: AF) became the most common arrhythmia by affecting 2.2 to 5.6 millions of Americans. The complications of AF include an increased rate of mortality, heart failure, stroke, etc. In this dissertation, we explore mechanisms of sustained ventricular and atrial tachyarrhythmias and the mechanisms of defibrillation using the conventional high-voltage single shock. Through the use of novel fluorescent optical mapping techniques and several animal models of ventricular and atrial arrhythmias, we develop and validate several novel low-voltage defibrillation therapies for atrial and ventricular arrhythmias. Several important previous studies on mechanisms of arrhythmia maintenance and termination using mathematical and experimental models are overviewed in Chapter 2. A study on multiple monophasic shocks improving electrotherapy of ventricular tachycardia in rabbit model of chronic infarction is presented in Chapter 3. Ventricular arrhythmias and low-voltage defibrillation therapy are studied in a more clinically-relevent in vivo canine model of healing myocardial infarction in Chapter 4. Finally, Chapter 5 presents a novel multi-stage low-energy defibrillation therapy for atrial fibrillation in in vivo canine hearts

Non-invasive identification of atrial fibrillation drivers

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. Nowadays the fibrillatory process is known to be provoked by the high-frequency reentrant activity of certain atrial regions that propagates the fibrillatory activity to the rest of the atrial tissue, and the electrical isolation of these key regions has demonstrated its effectiveness in terminating the fibrillatory process. The location of the dominant regions represents a major challenge in the diagnosis and treatment of this arrhythmia. With the aim to detect and locate the fibrillatory sources prior to surgical procedure, non-invasive methods have been developed such as body surface electrical mapping (BSPM) which allows to record with high spatial resolution the electrical activity on the torso surface or the electrocardiographic imaging (ECGI) which allows to non-invasively reconstruct the electrical activity in the atrial surface. Given the novelty of these systems, both technologies suffer from a lack of scientific knowledge about the physical and technical mechanisms that support their operation. Therefore, the aim of this thesis is to increase that knowledge, as well as studying the effectiveness of these technologies for the localization of dominant regions in patients with AF. First, it has been shown that BSPM systems are able to noninvasively identify atrial rotors by recognizing surface rotors after band-pass filtering. Furthermore, the position of such surface rotors is related to the atrial rotor location, allowing the distinction between left or right atrial rotors. Moreover, it has been found that the surface electrical maps in AF suffer a spatial smoothing effect by the torso conductor volume, so the surface electrical activity can be studied with a relatively small number of electrodes. Specifically, it has been seen that 12 uniformly distributed electrodes are sufficient for the correct identification of atrial dominant frequencies, while at least 32 leads are needed for non-invasive identification of atrial rotors. Secondly, the effect of narrowband filtering on the effectiveness of the location of reentrant patterns was studied. It has been found that this procedure allows isolating the reentrant electrical activity caused by the rotor, increasing the detection rate for both invasive and surface maps. However, the spatial smoothing caused by the regularization of the ECGI added to the temporal filtering causes a large increase in the spurious reentrant activity, making it difficult to detect real reentrant patterns. However, it has been found that maps provided by the ECGI without temporal filtering allow the correct detection of reentrant activity, so narrowband filtering should be applied for intracavitary or surface signal only. Finally, we studied the stability of the markers used to detect dominant regions in ECGI, such as frequency maps or the rotor presence. It has been found that in the presence of alterations in the conditions of the inverse problem, such as electrical or geometrical noise, these markers are significantly more stable than the ECGI signal morphology from which they are extracted. In addition, a new methodology for error reduction in the atrial spatial location based on the curvature of the curve L has been proposed. The results presented in this thesis showed that BSPM and ECGI systems allows to non-invasively locate the presence of high-frequency rotors, responsible for the maintenance of AF. This detection has been proven to be unambiguous and robust, and the physical and technical mechanisms that support this behavior have been studied. These results indicate that both non-invasive systems provide information of great clinical value in the treatment of AF, so their use can be helpful for selecting and planning atrial ablation procedures.La fibrilación auricular (FA) es una de las arritmias cardiacas más frecuentes. Hoy en día se sabe que el proceso fibrilatorio está provocado por la actividad reentrante a alta frecuencia de ciertas regiones auriculares que propagan la actividad fibrilatoria en el resto del tejido auricular, y se ha demostrado que el aislamiento eléctrico de estas regiones dominantes permite detener el proceso fibrilatorio. La localización de las regiones dominantes supone un gran reto en el diagnóstico y tratamiento de la FA. Con el objetivo de poder localizar las fuentes fibrilatorias con anterioridad al procedimiento quirúrgico, se han desarrollado métodos no invasivos como la cartografía eléctrica de superficie (CES) que registra con gran resolución espacial la actividad eléctrica en la superficie del torso o la electrocardiografía por imagen (ECGI) que permite reconstruir la actividad eléctrica en la superficie auricular. Dada la novedad de estos sistemas, existe una falta de conocimiento científico sobre los mecanismos físicos y técnicos que sustentan su funcionamiento. Por lo tanto, el objetivo de esta tesis es aumentar dicho conocimiento, así como estudiar la eficacia de ambas tecnologías para la localización de regiones dominantes en pacientes con FA. En primer lugar, ha visto que los sistemas CES permiten identificar rotores auriculares mediante el reconocimiento de rotores superficiales tras el filtrado en banda estrecha. Además, la posición de los rotores superficiales está relacionada con la localización de dichos rotores, permitiendo la distinción entre rotores de aurícula derecha o izquierda. Por otra parte, se ha visto que los mapas eléctricos superficiales durante FA sufren una gran suavizado espacial por el efecto del volumen conductor del torso, lo que permite que la actividad eléctrica superficial pueda ser estudiada con un número relativamente reducido de electrodos. Concretamente, se ha visto que 12 electrodos uniformemente distribuidos son suficientes para una correcta identificación de frecuencias dominantes, mientras que son necesarios al menos 32 para una correcta identificación de rotores auriculares. Por otra parte, también se ha estudiado el efecto del filtrado en banda estrecha sobre la eficacia de la localización de patrones reentrantes. Así, se ha visto que este procedimiento permite aislar la actividad eléctrica reentrante provocada por el rotor, aumentando la tasa de detección tanto para señal obtenida de manera invasiva como para los mapas superficiales. No obstante, este filtrado temporal sobre la señal de ECGI provoca un gran aumento de la actividad reentrante espúrea que dificulta la detección de patrones reentrantes reales. Sin embargo, los mapas ECGI sin filtrado temporal permiten la detección correcta de la actividad reentrante, por lo el filtrado debería ser aplicado únicamente para señal intracavitaria o superficial. Por último, se ha estudiado la estabilidad de los marcadores utilizados en ECGI para detectar regiones dominantes, como son los mapas de frecuencia o la presencia de rotores. Se ha visto que en presencia de alteraciones en las condiciones del problema inverso, como ruido eléctrico o geométrico, estos marcadores son significativamente más estables que la morfología de la propia señal ECGI. Además, se ha propuesto una nueva metodología para la reducción del error en la localización espacial de la aurícula basado en la curvatura de la curva L. Los resultados presentados en esta tesis revelan que los sistemas de CES y ECGI permiten localizar de manera no invasiva la presencia de rotores de alta frecuencia. Esta detección es univoca y robusta, y se han estudiado los mecanismos físicos y técnicos que sustentan dicho comportamiento. Estos resultados indican que ambos sistemas no invasivos proporcionan información de gran valor clínico en el tratamiento de la FA, por lo que su uso puede ser de gran ayuda para la selección y planificaciLa fibril·lació auricular (FA) és una de les arítmies cardíaques més freqüents. Hui en dia es sabut que el procés fibrilatori està provocat per l'activitat reentrant de certes regions auriculars que propaguen l'activitat fibril·latoria a la resta del teixit auricular, i s'ha demostrat que l'aïllament elèctric d'aquestes regions dominants permet aturar el procés fibrilatori. La localització de les regions dominants suposa un gran repte en el diagnòstic i tractament d'aquesta arítmia. Amb l'objectiu de poder localitzar fonts fibril·latories amb anterioritat al procediment quirúrgic s'han desenvolupat mètodes no invasius com la cartografia elèctrica de superfície (CES) que registra amb gran resolució espacial l'activitat elèctrica en la superfície del tors o l'electrocardiografia per imatge (ECGI) que permet obtenir de manera no invasiva l'activitat elèctrica en la superfície auricular. Donada la relativa novetat d'aquests sistemes, existeix una manca de coneixement científic sobre els mecanismes físics i tècnics que sustenten el seu funcionament. Per tant, l'objectiu d'aquesta tesi és augmentar aquest coneixement, així com estudiar l'eficàcia d'aquestes tecnologies per a la localització de regions dominants en pacients amb FA. En primer lloc, s'ha vist que els sistemes CES permeten identificar rotors auriculars mitjançant el reconeixement de rotors superficials després del filtrat en banda estreta. A més, la posició dels rotors superficials està relacionada amb la localització d'aquests rotors, permetent la distinció entre rotors de aurícula dreta o esquerra. També s'ha vist que els mapes elèctrics superficials durant FA pateixen un gran suavitzat espacial per l'efecte del volum conductor del tors, el que permet que l'activitat elèctrica superficial pugui ser estudiada amb un nombre relativament reduït d'elèctrodes. Concretament, s'ha vist que 12 elèctrodes uniformement distribuïts són suficients per a una correcta identificació de freqüències dominants auriculars, mentre que són necessaris almenys 32 per a una correcta identificació de rotors auriculars. D'altra banda, també s'ha estudiat l'efecte del filtrat en banda estreta sobre l'eficàcia de la localització de patrons reentrants. Així, s'ha vist que aquest procediment permet aïllar l'activitat elèctrica reentrant provocada pel rotor, augmentant la taxa de detecció tant pel senyal obtingut de manera invasiva com per als mapes superficials. No obstant això, aquest filtrat temporal sobre el senyal de ECGI provoca un gran augment de l'activitat reentrant espúria que dificulta la detecció de patrons reentrants reals. A més, els mapes proporcionats per la ECGI sense filtrat temporal permeten la detecció correcta de l'activitat reentrant, per la qual cosa el filtrat hauria de ser aplicat únicament per a senyal intracavitària o superficial. Per últim, s'ha estudiat l'estabilitat dels marcadors utilitzats en ECGI per a detectar regions auriculars dominants, com són els mapes de freqüència o la presència de rotors. S'ha vist que en presència d'alteracions en les condicions del problema invers, com soroll elèctric o geomètric, aquests marcadors són significativament més estables que la morfologia del mateix senyal ECGI. A més, s'ha proposat una nova metodologia per a la reducció de l'error en la localització espacial de l'aurícula basat en la curvatura de la corba L. Els resultats presentats en aquesta tesi revelen que els sistemes de CES i ECGI permeten localitzar de manera no invasiva la presència de rotors d'alta freqüència. Aquesta detecció és unívoca i robusta, i s'han estudiat els mecanismes físics i tècnics que sustenten aquest comportament. Aquests resultats indiquen que els dos sistemes no invasius proporcionen informació de gran valor clínic en el tractament de la FA, pel que el seu ús pot ser de gran ajuda per a la selecció i planificació de procediments d'ablació auricular.Rodrigo Bort, M. (2016). Non-invasive identification of atrial fibrillation drivers [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/75346TESISPremios Extraordinarios de tesis doctorale

EFFECTS OF SPATIAL RESOLUTION ON ARRHYTHMIA DRIVERS’ DETECTION AND LOCALIZATION: INTER-ELECTRODE RECOMMENDATIONS FOR CARDIAC ELECTROPHYSIOLOGICAL MAPPING DEVICES

Arrhythmia is a cardiac rhythm disorder that can be fatal. Its treatment includes ablation of the cardiac tissue and/or defibrillation. Advances are being made for both treatment options to localize the culprit region and apply therapy directly where it is needed. However, success rates have been inconsistent, with frequent arrhythmia recurrence. A likely reason is the limited current resolution of mapping devices, that averages 4 mm. Higher resolution may improve localization of arrhythmia drivers, termed rotors, and consequently improve efficacy of treatment. This study evaluates the effects of spatial resolution on arrhythmia dynamics, rotor tracking, and rotor localization. Optical data from ex vivo human hearts was used, being clinically relevant and with ultra-high spatial resolution. To simulate different resolutions, original data was downsampled bymultiple factors and upsampled back to full resolution. Rotors were tracked for each sub-resolution and compared to the rotors in the original data. Further comparisons were made according to arrhythmia type, sex, anatomical region, and mapped surface. Accuracy profiles were created for both rotor detection and localization, describing how accuracy changed with spatial resolution and spatial accuracy. Rotor detection accuracy for currently used mapping devices was found to be 57±4%. Localization accuracy is 61±7%. Detection accuracy was above 80% only for a resolution of 1.4 mm. Moreover, the detection and localization accuracies were affected by arrhythmia type, and rotor incidence was found to be higher in the endocardium. Therefore, current clinical rotor detection and localization accuracies can be expected to fall within a confidence interval of 47-67% and 46-75%, respectively. This means that a higher spatial resolution is needed in cardiac mapping devices than what is currently available. For high accuracy, a resolution of at least 1.4 mm is required. The accuracy profiles provided in this thesis may serve as a guideline for future mapping device developmentArritmia é um distúrbio do ritmo cardíaco que pode ser fatal. O seu tratamento passa por ablação do tecido cardíaco e/ou desfibrilhação. Tem havido progressos em ambas as opções para localizar a região afetada e aplicar a terapia diretamente onde é requerida. Contudo, a taxa de sucesso tem sido inconsistente, com frequente recorrência das arritmias. Uma razão provável é a limitada resolução atual dos dispositivos de mapeamento, sendo, em média, de 4 mm. Uma maior resolução poderá melhorar a localização de catalisadores de arritmias, designados por rotores, e, consequentemente, melhorar a eficácia do tratamento. Este estudo avalia os efeitos da resolução espacial na dinâmica de arritmias e na localização e deteção de rotores. Dados óticos de corações humanos ex vivo foram usados, tendo alta resolução espacial e sendo clinicamente relevantes. De modo a simular diferentes resoluções, os dados recolhidos foram downsampled por vários fatores e upsampled de volta para a resolução original. Os rotores foram monitorizados para cada sub-resolução e comparados com os rotores dos dados originais. Outras comparações foram feitas em consideração com tipo de arritmia, sexo, região anatómica e superfície mapeada. Perfis de exatidão foram criados para a deteção e localização de rotores, de forma a descrever as alterações na exatidão face à resolução especial e exatidão espacial. A exatidão da deteção de rotores para os atuais dispositivos de mapeamento é de 57±4%. A exatidão da localização é de 61±7%. A precisão da deteção foi acima de 80% apenas para uma resolução de 1,4 mm. Adicionalmente, as exatidões de deteção e localização foram afetadas pelo tipo de arritmia e a incidência de rotores é maior no endocárdio. Portanto, as atuais exatidões clínicas de deteção e localização de rotores encontram-se num intervalo de confiança de 47-67% e 46-75%, respetivamente. Ou seja, é necessária uma maior resolução espacial nos dispositivos cardíacos de mapeamento do que existe atualmente. Para uma alta precisão, é necessária uma resolução de pelo menos 1.4 mm. Os perfis de exatidão disponibilizados nesta tese poderão servir como diretriz para o futuro desenvolvimento de dispositivos médicos de mapeamento cardíaco

Directed networks as a novel way to describe and analyze cardiac excitation : directed graph mapping

Networks provide a powerful methodology with applications in a variety of biological, technological and social systems such as analysis of brain data, social networks, internet search engine algorithms, etc. To date, directed networks have not yet been applied to characterize the excitation of the human heart. In clinical practice, cardiac excitation is recorded by multiple discrete electrodes. During (normal) sinus rhythm or during cardiac arrhythmias, successive excitation connects neighboring electrodes, resulting in their own unique directed network. This in theory makes it a perfect fit for directed network analysis. In this study, we applied directed networks to the heart in order to describe and characterize cardiac arrhythmias. Proof-of-principle was established using in-silico and clinical data. We demonstrated that tools used in network theory analysis allow determination of the mechanism and location of certain cardiac arrhythmias. We show that the robustness of this approach can potentially exceed the existing state-of-the art methodology used in clinics. Furthermore, implementation of these techniques in daily practice can improve the accuracy and speed of cardiac arrhythmia analysis. It may also provide novel insights in arrhythmias that are still incompletely understood

High-Throughput Analysis of Optical Mapping Data Using ElectroMap

Optical mapping is an established technique for high spatio-temporal resolution study of cardiac electrophysiology in multi-cellular preparations. Here we present, in a step-by-step guide, the use of ElectroMap for analysis, quantification, and mapping of high-resolution voltage and calcium datasets acquired by optical mapping. ElectroMap analysis options cover a wide variety of key electrophysiological parameters, and the graphical user interface allows straightforward modification of pre-processing and parameter definitions, making ElectroMap applicable to a wide range of experimental models. We show how built-in pacing frequency detection and signal segmentation allows high-throughput analysis of entire experimental recordings, acute responses, and single beat-to-beat variability. Additionally, ElectroMap incorporates automated multi-beat averaging to improve signal quality of noisy datasets, and here we demonstrate how this feature can help elucidate lectrophysiological changes that might otherwise go undetected when using single beat analysis. Custom modules are included within the software for detailed investigation of conduction, single file analysis, and alternans, as demonstrated here. This software platform can be used to enable and accelerate the processing, analysis, and mapping of complex cardiac electrophysiology

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

Rotor detection in atrial fibrillation

Atrial fibrillation (AF) is one of the most common arrhythmias in the clinical practice. Catheter ablation method was developed more than 20 years ago as an approach to terminate this rhythm disorder. Since its outbreak, this technique obtained international acceptance among the clinicians, and technological advances in this field increased its safety while reducing the procedure duration. However, there is no perfect AF treatment procedure described yet, since the understanding of the driving and sustaining AF mechanisms remains poor, with pulmonary vein isolation being the most common ablation strategy. Several theories try to explain the initiating and maintenance mechanisms of the AF, ranging from multiple wavelets propagating at random in the atria to ectopic focus fired from the pulmonary veins. Alternatively, spatiotemporal stable sources (rotors) have been proposed as the maintenance mechanism of AF. The most representative characteristic of a rotor is the re-entry spiral-like propagation pattern that the electrical wavefront exhibits as it propagates. The assessment of its presence and posterior ablation of the sites where rotors anchor might improve the success of AF ablation. Technical solutions emerged focusing on the rotor assessment problem. They base their methods on the reconstruction of the atrial activity using multi-electrode catheters and phase maps, in which they detect singularity points, the sites where rotors spin. The ablation of these sites showed promising results, but the difficulty to reproduce the results by other authors increased the controversy on this technique. In this Thesis we address the rotor detection problem in the time domain as opposed to current methods based on the phase domain of the signals. We develop a new method to identify local activation times (LATs) in unipolar electrograms (EGMs) recorded with multi-electrode catheters. We propose a new filtering scheme to enhance the activation component of the EGM while considerably reducing the presence of noise in the signal. This signal processing method reects the real activity of the tissue in contact with the electrode. It opposes the Hilbert transform (HT) used to extract the phase component of the signal, that do not correlate well with the temporal activations. With the EGM LATs we perform a spatial interpolation translating the electrode positions of the catheter into a regular 2D grid. This way we generate isochronal maps revealing the electrical wavefronts in the atrium. What is more, this step guarantees compatibility with multi-electrode catheters, not restricting the method to specific models. With the isochronal maps, we develop a new rotor detection algorithm based on the optical flow of the wavefront dynamics, and a rotation pattern match. Additionally, we develop a new method based on Granger's causality to estimate the directionality of the wavefronts, that provides an additional indicator for rotational patterns. We validate the methods using in silico and real AF signals. We implement these methods into a system that can assess the presence of rotational activation sites in the atrium. Our system is able to operate in realtime with multi-electrode catheters of different topologies in contact with the atrial wall. We integrate signal acquisition and processing in our system, allowing direct acquisition of the signals without requiring signal exportation from a recording device, which delays the clinical procedure. We address the computational time handicap by designing parallelizable signal processing steps. We employ multi-core processors and GPU based code to distribute the computations and minimize the processing times, achieving near real-time results. The results presented in this Thesis provide a new technical solution to detect the presence of rotational activity (rotors) in AF patients in real-time. Although the presence of rotational activity is itself controversial, we individually validate each of the steps of the procedure and obtain evidence of the presence of rotational activity in AF patients. The system has been also found useful to characterize the atrial sites where rotational activity was found in terms of spatial and voltage distribution. The results of this Thesis provide a new alternative to existing methods based on phase analysis and open a new research line in the detection of the mechanisms sustaining AF.La fibrilación auricular (FA) es una de las arritmias más comunes en la práctica clínica. Para tratar de terminar esta fibrilación en pacientes se desarrollo el método de ablación con catéter hace ya más de 20 años. Desde su puesta en marchar esta técnica ha ido ganando aceptación internacional por parte de la comunidad médica, y los avances tecnológicos desarrollados en esta línea han aumentado la seguridad y disminuido la duración del procedimiento. Sin embargo todavía no existe un tratamiento perfecto para tratar la FA, debido en parte a que el conocimiento de los mecanismos que inician y sostienen la fibrilación son limitados. Como método de ablación el aislamiento de las venas pulmonares prevalece como el más empleado en la práctica, pero se hace necesario el desarrollo de nuevos métodos para hacer frente al problema de la FA. Distintas teorías tratan de explicar los mecanismos de inicio y mantenimiento de la FA, desde unas basadas en la propagación de múltiples frentes de onda aleatorios en las aurículas, hasta las que basan su hipótesis en focos ectópicos disparados principalmente desde las venas pulmonares, entre otras teorías. Recientemente, una de estas teorías basada en fuentes espacio-temporalmente estables (rotores) se propuso como mecanismo de mantenimiento de la FA. La característica más representativa de un rotor es su patrón de reentrada en forma de espiral que realiza el frente de onda eléctrico en el tejido auricular. La evaluación de la presencia de rotores y la posterior de los sitios en los que se encuentren puede mejorar el éxito de la ablación en pacientes con FA. En vista de esta tendencia por la búsqueda de rotores se desarrollaron soluciones técnicas para la evaluación de zonas que alberguen actividad rotacional. Sus técnicas se basan en la reconstrucción de la actividad auricular empleando catéteres multi-electrodo y detectando puntos de singularidad en mapas de phase, esto es la posición en la aurícula en la que el rotor gira. La ablación de estos puntos mostró resultados prometedores, pero la dificultad por replicar los resultados por parte de otros autores incremento la controversia con respecto a esta técnica. En esta Tesis abordamos el problema de la detección de rotores en el dominio del tiempo, oponiéndonos a las técnicas actuales basadas en el dominio de la fase de las señales. Para ello hemos desarrollado un nuevo para identificar tiempos de activación local en electrogramas unipolares registrados con catéteres multi-electrodo. Para ello proponemos un nuevo método de filtrado para realzar la activación del electrograma reduciendo considerablemente la presencia de ruido en la señal. Con este procesado de la señal extraemos y reflejamos la actividad real del tejido en contacto con el electrodo. Al mismo tiempo nos oponemos a la transformada de Hilbert empleada para calcular la componente de fase de la señal, que es sabido no tiene una buena correlación con las activaciones temporales. Con los electrogramas y los tiempos de activación locales aplicamos una interpolación espacial logrando trasladar la posición de los electrodos en el catéter a una rejilla regular en 2D. Mediante este paso generamos mapas isócronos que reconstruyen los frentes de onda eléctricos que se propagan en la aurícula. Además, la interpolación nos permite garantizar una compatibilidad con otros catéteres multi-electrodos, no restringiendo el uso de nuestro método a modelos específicos. Con los mapas isócronos hemos desarrollado un nuevo algoritmo de detección de rotores basado en el flujo óptico de la dinámica del frente de onda que hacemos coincidir con un patrón de rotación. Adicionalmente hemos desarrollado un nuevo método basad en la causalidad propuesta por Granger para estimar la dirección de los frentes de propagación, que sirve como indicador adicional para encontrar patrones de activación rotacional. Hemos validado todos y cada uno de los métodos empleando señales in silico así como señales reales de pacientes con FA. En la parte de aplicación, hemos implementado los métodos en un sistema que evalúa la presencia de actividad rotacional en la aurícula. Nuestro sistema opera en tiempo real siendo compatible con catéteres multi-electrodo de diferentes topologías asegurando contacto con la pared auricular. Para evitar sobreextender el procedimiento clínico, hemos integrado las partes de adquisición y procesado de señal conjuntamente, lo que nos permite un registro de las señales directo sin viii necesidad de requerir un exportado adicional desde un sistema de registro. Para hacer frente al objetivo de presentar los resultados en tiempo real hemos diseñado todos los pasos de procesado de señal para que sean paralelizables. Para ello empleamos procesadores multinúcleo y código para ejecutar en tarjetas gráficas (GPUs) para distribuir las computaciones y minimizar el tiempo de procesado, logrando resultados en quasi tiempo real. Hemos empleado el sistema de detección de rotores para estudiar la distribución espacial y de voltaje de los sitios que muestran actividad rotacional en la aurícula. Aunque la presencia de actividad rotacional es en sí misma controvertida, hemos validad individualmente todos y cada uno de los pasos descritos obteniendo evidencia de la presencia de actividad rotacional en pacientes con FA.Programa Oficial de Doctorado en Multimedia y ComunicacionesPresidente: Pablo Laguna Lasaosa.- Secretario: Pablo Martínez Olmos.- Vocal: Batiste Andreu Martínez Climen