Optical imaging of voltage and calcium in isolated hearts: Linking spatiotemporal heterogeneities and ventricular fibrillation initiation

[EN] Background Alternans have been associated with the development of ventricular fibrillation and its control has been proposed as antiarrhythmic strategy. However, cardiac arrhythmias are a spatiotemporal phenomenon in which multiple factors are involved (e.g. calcium and voltage spatial alternans or heterogeneous conduction velocity) and how an antiarrhythmic drug modifies these factors is poorly understood. Objective The objective of the present study is to evaluate the relation between spatial electrophysiological properties (i.e. spatial discordant alternans and conduction velocity) and the induction of ventricular fibrillation (VF) when a calcium blocker is applied. Methods The mechanisms of initiation of VF were studied by simultaneous epicardial voltage and calcium optical mapping in isolated rabbit hearts using an incremental fast pacing protocol. The additional value of analyzing spatial phenomena in the generation of unidirectional blocks and reentries as precursors of VF was depicted. Specifically, the role of action potential duration (APD), calcium transients (CaT), spatial alternans and conduction velocity in the initiation of VF was evaluated during basal conditions and after the administration of verapamil. Results Our results enhance the relation between (1) calcium spatial alternans and (2) slow conduction velocities with the dynamic creation of unidirectional blocks that allowed the induction of VF. In fact, the administration of verapamil demonstrated that calcium and not voltage spatial alternans were the main responsible for VF induction. Conclusions VF induction at high activation rates was linked with the concurrence of a low conduction velocity and high magnitude of calcium alternans, but not necessarily related with increases of APD. Verapamil can postpone the development of cardiac alternans and the apparition of ventricular arrhythmias.This work was funded in part by the CIBERCV (Centro de Investigacion Biomedica en Red Enfermedades Cardiovasculares), Instituto de Salud Carlos III (PI14/00857, PI16/01123, DTS16/0160, PI17/01059, PI17/01106 and IJCI-2014-22178); Spanish Ministry of Ecomomy (TEC2013-46067-R); Generalitat Valenciana Grants (APOSTD/2017 and APOSTD/2018) and projects (GVA/2018/103), EIT-Health 19600 AFFINE and cofound by FEDER.Hernández-Romero, I.; Guillem Sánchez, MS.; Figuera, C.; Atienza, F.; Fernández-Avilés, F.; Martínez Climent, BA. (2019). Optical imaging of voltage and calcium in isolated hearts: Linking spatiotemporal heterogeneities and ventricular fibrillation initiation. PLoS ONE. 14(5):1-15. https://doi.org/10.1371/journal.pone.0215951S115145Hayashi, M., Shimizu, W., & Albert, C. M. (2015). The Spectrum of Epidemiology Underlying Sudden Cardiac Death. 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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

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

Minimal configuration of body surface potential mapping for discrimination of left versus right dominant frequencies during atrial fibrillation

[EN] Background: Ablation of drivers maintaining atrial fibrillation (AF) has been demonstrated as an effective therapy. Drivers in the form of rapidly activated atrial regions can be noninvasively localized to either left or right atria (LA, RA) with body surface potential mapping (BSPM) systems. This study quantifies the accuracy of dominant frequency (DF) measurements from reduced-leads BSPM systems and assesses the minimal configuration required for ablation guidance. Methods: Nine uniformly distributed lead sets of eight to 66 electrodes were evaluated. BSPM signals were registered simultaneously with intracardiac electrocardiograms (EGMs) in 16 AF patients. DF activity was analyzed on the surface potentials for the nine leads configurations, and the noninvasive measures were compared with the EGM recordings. Results: Surface DF measurements presented similar values than panoramic invasive EGM recordings, showing the highest DF regions in corresponding locations. The noninvasive DFs measures had a high correlation with the invasive discrete recordings; they presented a deviation of 0.8 for leads configurations with 12 or more electrodes. Conclusions: Reduced-leads BSPM systems enable noninvasive discrimination between LA versus RA DFs with similar results as higher-resolution 66-leads system. Our findings demonstrate the possible incorporation of simplified BSPM systems into clinical planning procedures for AF ablation.This work was supported in part by Generalitat-Valenciana Grants [ACIF/2013/021]; Instituto de SaludCarlos III, Ministerio de Ciencia e Innovacion [PI13/00903, PI13-01882, PI14/00857, PI16/01123, TEC2013-46067-R, DTS16/0160 and IJCI-2014-22178] cofound by FEDER.; Spanish Society of Cardiology [Clinical research Grants 2015]; Ministerio de Ciencia e Innovacion [Red RICRD12.0042.0001]; and the National Heart, Lung, and Blood Institute [P01-HL039707, P01-HL087226 and R01-HL118304].Rodrigo Bort, M.; Climent Martínez, BA.; Liberos Mascarell, A.; Fernández-Avilés, F.; Atienza, F.; Guillem Sánchez, MS.; Berenfeld, O. (2017). Minimal configuration of body surface potential mapping for discrimination of left versus right dominant frequencies during atrial fibrillation. Pacing and Clinical Electrophysiology. 40(8):940-946. https://doi.org/10.1111/pace.13133S940946408Atienza, F., Almendral, J., Ormaetxe, J. M., Moya, Á., Martínez-Alday, J. D., Hernández-Madrid, A., … Jalife, J. (2014). Comparison of Radiofrequency Catheter Ablation of Drivers and Circumferential Pulmonary Vein Isolation in Atrial Fibrillation. Journal of the American College of Cardiology, 64(23), 2455-2467. doi:10.1016/j.jacc.2014.09.053Narayan, 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.2013.03.021Haissaguerre, 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.113.005421Atienza, F., Almendral, J., Jalife, J., Zlochiver, S., Ploutz-Snyder, R., Torrecilla, E. G., … Berenfeld, O. (2009). Real-time dominant frequency mapping and ablation of dominant frequency sites in atrial fibrillation with left-to-right frequency gradients predicts long-term maintenance of sinus rhythm. Heart Rhythm, 6(1), 33-40. doi:10.1016/j.hrthm.2008.10.024Lim, H. S., Zellerhoff, S., Derval, N., Denis, A., Yamashita, S., Berte, B., … Haissaguerre, M. (2015). Noninvasive Mapping to Guide Atrial Fibrillation Ablation. Cardiac Electrophysiology Clinics, 7(1), 89-98. doi:10.1016/j.ccep.2014.11.004Rodrigo, 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.2014.05.013Guillem, 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.112.000167Lux, R. L., Smith, C. R., Wyatt, R. F., & Abildskov, J. A. (1978). Limited Lead Selection for Estimation of Body Surface Potential Maps in Electrocardiography. IEEE Transactions on Biomedical Engineering, BME-25(3), 270-276. doi:10.1109/tbme.1978.326332Finlay, D. D., Nugent, C. D., Donnelly, M. P., & Black, N. D. (2008). Selection of optimal recording sites for limited lead body surface potential mapping in myocardial infarction and left ventricular hypertrophy. Journal of Electrocardiology, 41(3), 264-271. doi:10.1016/j.jelectrocard.2008.02.009Guillem, M. S., Castells, F., Climent, A. M., Bodí, V., Chorro, F. J., & Millet, J. (2008). Evaluation of lead selection methods for optimal reconstruction of body surface potentials. Journal of Electrocardiology, 41(1), 26-34. doi:10.1016/j.jelectrocard.2007.07.001De la Salud Guillem, M., Bollmann, A., Climent, A. M., Husser, D., Millet-Roig, J., & Castells, F. (2009). How Many Leads Are Necessary for a Reliable Reconstruction of Surface Potentials During Atrial Fibrillation? IEEE Transactions on Information Technology in Biomedicine, 13(3), 330-340. doi:10.1109/titb.2008.2011894Castells, F., Mora, C., Rieta, J. J., Moratal-Pérez, D., & Millet, J. (2005). Estimation of atrial fibrillatory wave from single-lead atrial fibrillation electrocardiograms using principal component analysis concepts. Medical & Biological Engineering & Computing, 43(5), 557-560. doi:10.1007/bf02351028Narayan, S. M., & Jalife, J. (2014). CrossTalk proposal: Rotors have been demonstrated to drive human atrial fibrillation. The Journal of Physiology, 592(15), 3163-3166. doi:10.1113/jphysiol.2014.271031Allessie, 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.2014.271809Berenfeld, O., & Oral, H. (2012). The quest for rotors in atrial fibrillation: Different nets catch different fishes. Heart Rhythm, 9(9), 1440-1441. doi:10.1016/j.hrthm.2012.04.029PEDRÓN-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.12931Uijen, G., van Oosterom, A., & Hoekema, R. (1999). The Number of Independent Signals in Body Surface Maps. Methods of Information in Medicine, 38(02), 119-124. doi:10.1055/s-0038-1634176Ihara, Z., van Oosterom, A., Jacquemet, V., & Hoekema, R. (2007). Adaptation of the standard 12-lead electrocardiogram system dedicated to the analysis of atrial fibrillation. Journal of Electrocardiology, 40(1), 68.e1-68.e8. doi:10.1016/j.jelectrocard.2006.04.006Gerstenfeld, E. P., SippensGroenewegen, A., Lux, R. L., & Lesh, M. D. (2000). Derivation of an optimal lead set for measuring ectopic atrial activation from the pulmonary veins by using body surface mapping. Journal of Electrocardiology, 33, 179-185. doi:10.1054/jelc.2000.20307SippensGroenewegen, A., Peeters, H. A. P., Jessurun, E. R., Linnenbank, A. C., Robles de Medina, E. O., Lesh, M. D., & van Hemel, N. M. (1998). Body Surface Mapping During Pacing at Multiple Sites in the Human Atrium. Circulation, 97(4), 369-380. doi:10.1161/01.cir.97.4.369SALINET, J. L., TUAN, J. H., SANDILANDS, A. J., STAFFORD, P. J., SCHLINDWEIN, F. S., & NG, G. A. (2013). Distinctive Patterns of Dominant Frequency Trajectory Behavior in Drug-Refractory Persistent Atrial Fibrillation: Preliminary Characterization of Spatiotemporal Instability. Journal of Cardiovascular Electrophysiology, 25(4), 371-379. doi:10.1111/jce.12331Sanders, P., Berenfeld, O., Hocini, M., Jaïs, P., Vaidyanathan, R., Hsu, L.-F., … Haïssaguerre, M. (2005). Spectral Analysis Identifies Sites of High-Frequency Activity Maintaining Atrial Fibrillation in Humans. Circulation, 112(6), 789-797. doi:10.1161/circulationaha.104.517011Atienza, F., Almendral, J., Moreno, J., Vaidyanathan, R., Talkachou, A., Kalifa, J., … Berenfeld, O. (2006). Activation of Inward Rectifier Potassium Channels Accelerates Atrial Fibrillation in Humans. Circulation, 114(23), 2434-2442. doi:10.1161/circulationaha.106.63373

Structural remodeling and rotational activity in persistent/long-lasting atrial fibrillation: gender-effect differences and impact on post-ablation outcome

Background: Structural and post-ablation gender differences are reported in atrial fibrillation (AF). We analyzed the gender differences in structural remodeling and AF mechanisms in patients with persistent/long-lasting AF who underwent wide area circumferential pulmonary vein isolation (WACPVI). Materials and Methods: Ultra-high-density mapping was used to study atrial remodeling and AF drivers in 85 consecutive patients. Focal and rotational activity (RAc) were identified with the CartoFinder system and activation sequence analysis. The impact of RAc location on post-ablation outcomes was analyzed. Results: This study included 64 men and 21 women. RAc was detected in 73.4% of men and 38.1% of women (p = 0.003). RAc patients had higher left atrium (LA) voltage (0.64 ± 0.3 vs. 0.50 ± 0.2 mV; p = 0.01), RAc sites had higher voltage than non-RAc sites 0.77 ± 0.46 vs. 0.53 ± 0.37 mV (p < 0.001). Women had lower LA voltage than men (0.42 vs. 0.64 mV; p < 0.001), including pulmonary vein (PV) antra (0.16 vs. 0.30 mV; p < 0.001) and posterior wall (0.34 vs. 0.51 mV; p < 0.001). RAc in the posterior atrium was recorded in few women (23.8 vs. 54.7% in men; p = 0.014). AF recurrence rate was higher in patients with RAc outside WACPVI than those with all RAc inside WACPVI or no RAc (63.4 vs. 11.1 and 31.0%; p = 0.008 and p = 0.01). Comparison of selected patients using propensity score matching confirmed lower atrial voltage (0.4 ± 0.2 vs. 0.7 ± 0.3 mV; p = 0.007) and less RAc (38 vs. 75%; p = 0.02) in women. Conclusion: Women have shown more advanced structural remodeling at ablation, which is associated with a lower incidence of RAc (usually located outside the WACPVI). These findings could explain post-ablation gender differences.This study was supported by the Instituto de Salud Carlos III, Madrid, Spain (PI18/01895 and DTS21/00064), Red de Terapia Celular from the Instituto de Salud Carlos III, Madrid, Spain (RD16/0011/0029), Ricors "Red de Investigación Cooperativa Orientada a Resultados en Salud" RICORS TERAV (RD21/0017/0002), and the Sección del Ritmo de la Sociedad Española de Cardiología (Grant: Beca de la Asociacion del Ritmo para formación en investigacion post-residencia en centros españoles de la Sección del Ritmo de la Sociedad Española de Cardiología), Madrid, Spain

Effects of Geometry in Atrial Fibrillation Markers Obtained With Electrocardiographic Imaging

[EN] Electrocardiographic imaging (ECGI) can characterise cardiac pathologies such as atrial fibrillation (AF) through specific markers based on frequency or phase analysis. In this study, the effect of the geometry of patients torso and atria in the ECGI resolution is studied. A realistic 3D atrial geometry was located on 30 patient torsos and ECGI signals were calculated for 30 different AF simulations in each torso. Dominant frequency (DF) and reentrant activity analysis were calculated for each scenario. Anatomical and geometrical measurements of each torso (30-80% of variability between patients) and atria were calculated and compared with the errors in the ECGI estimation versus the departing EGM maps. Results show evidences that big chest dimensions worsen the non-invasive calculation of AF markers (p<0.05). Also, higher number of visible electrodes from each atrial region improves ECGI characterization measured as lower DF deviations (0.64±0.26 Hz vs 0.72±0.27 Hz, p<0.05) and higher reentrant activity coincidence (10.1±12.2% vs 3.4±3.4%, p<0.05). Torso and atrial geometry affect the quality of the non-invasive reconstruction of AF markers such as DF or reentrant activity. Knowing the geometrical parameters that worsen non-invasive AF maps may help to measure each detected AF driver reliability.Supported in part by: Instituto de Salud Carlos III FEDER (Fondo Europeo de Desarrollo Regional; IJCI2014-22178, DTS16/00160; PI14/00857, PI16/01123; PI17/01059; PI17/01106), Generalitat Valenciana Grants (APOSTD/2017 and APOSTD/2018) and projects (GVA/2018/103) and EIT-Health 19600 AFFINE.Molero-Alabau, R.; Climent, AM.; Hernández-Romero, I.; Liberos, A.; Fernández-Avilés, F.; Atienza, F.; Guillem Sánchez, MS.... (2019). Effects of Geometry in Atrial Fibrillation Markers Obtained With Electrocardiographic Imaging. IEEE. 1-4. https://doi.org/10.22489/CinC.2019.3081

Electrophysiological effects of extracellular vesicles secreted by cardiosphere-derived cells: Unraveling the antiarrhythmic properties of cell therapies

This article belongs to the Special Issue Advances in Regenerative Medicine and Tissue Engineering.Although cell-based therapies show potential antiarrhythmic effects that could be mediated by their paracrine action, the mechanisms and the extent of these effects were not deeply explored. We investigated the antiarrhythmic mechanisms of extracellular vesicles secreted by cardiosphere-derived cell extracellular vesicles (CDC-EVs) on the electrophysiological properties and gene expression profile of HL1 cardiomyocytes. HL-1 cultures were primed with CDC-EVs or serum-free medium alone for 48 h, followed by optical mapping and gene expression analysis. In optical mapping recordings, CDC-EVs reduced the activation complexity of the cardiomyocytes by 40%, increased rotor meandering, and reduced rotor curvature, as well as induced an 80% increase in conduction velocity. HL-1 cells primed with CDC-EVs presented higher expression of SCN5A, CACNA1C, and GJA1, coding for proteins involved in INa, ICaL, and Cx43, respectively. Our results suggest that CDC-EVs reduce activation complexity by increasing conduction velocity and modifying rotor dynamics, which could be driven by an increase in expression of SCN5A and CACNA1C genes, respectively. Our results provide new insights into the antiarrhythmic mechanisms of cell therapies, which should be further validated using other models.This research was funded by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain: PI16/01123, PI17/01059, Red de Terapia Celular-Tercel-RD16.0011.0029 and CIBERCV-CB16.11.00292

Solving Inaccuracies in Anatomical Models for Electrocardiographic Inverse Problem Resolution by Maximizing Reconstruction Quality

[EN] Electrocardiographic Imaging has become an increasingly used technique for non-invasive diagnosis of cardiac arrhythmias, although the need for medical imaging technology to determine the anatomy hinders its introduction in the clinical practice. This paper explores the ability of a new metric based on the inverse reconstruction quality for the location and orientation of the atrial surface inside the torso. Body surface electrical signals from 31 realistic mathematical models and four AF patients were used to estimate the optimal position of the atria inside the torso. The curvature of the L-curve from the Tikhonov method, which was found to be related to the inverse reconstruction quality, was measured after application of deviations in atrial position and orientation. Independent deviations in the atrial position were solved by finding the maximal L-curve curvature with an error of 1.7 +/- 2.4 mm in mathematical models and 9.1 +/- 11.5 mm in patients. For the case of independent angular deviations, the error in location by using the L-curve was 5.8 +/- 7.1 degrees in mathematical models and 12.4 degrees +/- 13.2 degrees in patients. The ability of the L-curve curvature was tested also under superimposed uncertainties in the three axis of translation and in the three axis of rotation, and the error in location was of 2.3 +/- 3.2 mm and 6.4 degrees +/- 7.1 degrees in mathematical models, and 7.9 +/- 10.7 mm and 12.1 degrees +/- 15.5 degrees in patients. The curvature of L-curve is a useful marker for the atrial position and would allow emending the inaccuracies in its location.This work was supported in part by Generalitat Valenciana under Grant ACIF/2013/021, in part by the Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Spain, under Grant PI13-01882, Grant PI13-00903, Grant PI14/00857, Grant TEC2013-46067-R, and Grant DTS16/00160, in part by the Spanish Society of Cardiology (Grant for Clinical Research in Cardiology 2015), and in part by the Spanish Ministry of Science and Innovation (Red RIC) under Grant PLE2009-0152.Rodrigo Bort, M.; Climent, AM.; Liberos Mascarell, A.; Hernández-Romero, I.; Arenal, A.; Bermejo, J.; Fernández-Avilés, F.... (2018). Solving Inaccuracies in Anatomical Models for Electrocardiographic Inverse Problem Resolution by Maximizing Reconstruction Quality. IEEE Transactions on Medical Imaging. 37(3):733-740. https://doi.org/10.1109/TMI.2017.2707413S73374037

Role of atrial tissue remodeling on rotor dynamics an in vitro study

The objective of this article is to present an in vitro model of atrial cardiac tissue that could serve to study the mechanisms of remodeling related to atrial fibrillation (AF). We analyze the modification on gene expression and modifications on rotor dynamics following tissue remodeling. Atrial murine cells (HL-1 myocytes) were maintained in culture after the spontaneous initiation of AF and analyzed at two time points: 3.1 +/- 1.3 and 9.7 +/- 0.5 days after AF initiation. The degree of electrophysiological remodeling (i.e., relative gene expression of key ion channels) and structural inhomogeneity was compared between early and late cell culture times both in nonfibrillating and fibrillating cell cultures. In addition, the electrophysiological characteristics of in vitro fibrillation [e.g., density of phase singularities (PS/cm2), dominant frequency, and rotor meandering] analyzed by means of optical mapping were compared with the degree of electrophysiological remodeling. Fibrillating cell cultures showed a differential ion channel gene expression associated with atrial tissue remodeling (i.e., decreased SCN5A, CACN1C, KCND3, and GJA1 and increased KCNJ2) not present in nonfibrillating cell cultures. Also, fibrillatory complexity was increased in late- vs. early stage cultures (1.12 +/- 0.14 vs. 0.43 +/- 0.19 PS/cm(2), P < 0.01), which was associated with changes in the electrical reentrant patterns (i.e., decrease in rotor tip meandering and increase in wavefront curvature). HL-1 cells can reproduce AF features such as electrophysiological remodeling and an increased complexity of the electrophysiological behavior associated with the fibrillation time that resembles those occurring in patients with chronic AF.This work was supported in part by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882, PI13-00903, and TEC2013-50391-EXP), and the Red de Investigacion Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain).Climent, A.; Guillem Sánchez, MS.; Fuentes, L.; Lee, P.; Bollensdorff, C.; Fernandez-Santos, M.; Suarez-Sancho, S.... (2015). Role of atrial tissue remodeling on rotor dynamics an in vitro study. AJP - Heart and Circulatory Physiology. 309(11):H1964-H1973. doi:10.1152/ajpheart.00055.2015SH1964H197330911Allessie, M. (2002). 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Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling

[EN] Atrial fibrillation (AF) results in a remodeling of the electrical and structural characteristics of the cardiac tissue which dramatically reduces the efficacy of pharmacological and catheter-based ablation therapies. Recent experimental and clinical results have demonstrated that the complexity of the fibrillatory process significantly differs in paroxysmal versus persistent AF; however, the lack of appropriate research models of remodeled atrial tissue precludes the elucidation of the underlying AF mechanisms and the identification of appropriated therapeutic targets. Here, we summarize the different research models used to date, highlighting the lessons learned from them and pointing to the new doors that should be open for the development of innovative treatments for AF.The authors were supported by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882 and PI13-00903) the Red de Investigacion Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain). F Atienza served on the advisory board of Medtronic and has received research funding from St. Jude Medical Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Climent, A.; Guillem Sánchez, MS.; Atienza Fernández, F.; Fernandez-Aviles, F. (2014). Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling. Expert Review of Cardiovascular Therapy. 13(1):1-3. https://doi.org/10.1586/14779072.2015.986465S1313