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

Catheter ablation in patients with atrial fibrillation : mapping refinements, outcome prediction and effect on quality of life

PhD ThesisChapter 1 presents a literature review, focused primarily on the pathophysiology and management of atrial fibrillation (AF). Chapter 2 examines correlations between the dominant frequency of AF - calculated using principal component analysis from a modified surface 12-lead ECG (which included posterior leads), a standard 12-lead ECG and intracardiac recordings from both atria. The inclusion of posterior leads did not improve correlation with left atrial activity because of the dominance of lead V1 in both ECG configurations. Chapter 3 explores whether acute and 12-month outcome following catheter ablation for AF can be predicted beforehand from clinical and surface AF waveform parameters. Multivariate risk scores combining these parameters can predict arrhythmia outcome following ablation, and could therefore be used to identify those most likely to benefit from this therapy. Chapter 4 examines the effect of catheter ablation on AF symptoms and quality of life (QoL). AF symptom and QoL scores improved significantly in patients who maintained sinus rhythm after ablation but did not change in those with recurrent AF. AF-specific QoL scales are more responsive to change and correlate better with ablation outcome. Chapter 5 examines inter-atrial frequency gradients in patients with persistent AF using multipolar contact mapping. A right-to-left atrial frequency gradient was found in a quarter of the patients studied, implying that their arrhythmia was being maintained by high frequency sources in the right rather than the left atrium. Chapter 6 examines whether targeting high frequency and highly repetitive complex fractionated atrial electrogram sites, identified using multipolar contact mapping during persistent AF, resulted in arrhythmia termination and maintenance of sinus rhythm long-term. The utility of administering flecainide to distinguish critical from bystander AF sites was also investigated. Flecainide did not help refine ablation targets and 12-month outcome after targeting these sites was not superior to other ablation strategies

Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies

[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI

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). Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovascular Research, 54(2), 230-246. doi:10.1016/s0008-6363(02)00258-4Allessie, 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.109.910125Atienza, 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.2008.10.024Atienza, 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.2014.09.053Bikou, O., Thomas, D., Trappe, K., Lugenbiel, P., Kelemen, K., Koch, M., … Bauer, A. (2011). Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovascular Research, 92(2), 218-225. doi:10.1093/cvr/cvr209Bollmann, A., Sonne, K., Esperer, H.-D., Toepffer, I., & Klein, H. U. (2002). Patients with Persistent Atrial Fibrillation Taking Oral Verapamil Exhibit a Lower Atrial Frequency on the ECG. Annals of Noninvasive Electrocardiology, 7(2), 92-97. doi:10.1111/j.1542-474x.2002.tb00148.xBRUNDEL, B. (2004). Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation. Cardiovascular Research, 62(3), 521-528. doi:10.1016/j.cardiores.2004.02.007Calkins, H., Kuck, K. H., Cappato, R., Brugada, J., Camm, A. J., Chen, S.-A., … Wilber, D. (2012). 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design. Heart Rhythm, 9(4), 632-696.e21. doi:10.1016/j.hrthm.2011.12.016Claycomb, W. C., Lanson, N. A., Stallworth, B. S., Egeland, D. B., Delcarpio, J. B., Bahinski, A., & Izzo, N. J. (1998). HL-1 cells: A cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proceedings of the National Academy of Sciences, 95(6), 2979-2984. doi:10.1073/pnas.95.6.2979Filgueiras-Rama, D., Price, N. F., Martins, R. P., Yamazaki, M., Avula, U. M. R., Kaur, K., … Berenfeld, O. (2012). Long-Term Frequency Gradients During Persistent Atrial Fibrillation in Sheep Are Associated With Stable Sources in the Left Atrium. Circulation: Arrhythmia and Electrophysiology, 5(6), 1160-1167. doi:10.1161/circep.111.969519Haïssaguerre, M., Jaïs, P., Shah, D. C., Takahashi, A., Hocini, M., Quiniou, G., … Clémenty, J. (1998). Spontaneous Initiation of Atrial Fibrillation by Ectopic Beats Originating in the Pulmonary Veins. New England Journal of Medicine, 339(10), 659-666. doi:10.1056/nejm199809033391003Haralick, R. M., Shanmugam, K., & Dinstein, I. (1973). Textural Features for Image Classification. IEEE Transactions on Systems, Man, and Cybernetics, SMC-3(6), 610-621. doi:10.1109/tsmc.1973.4309314Jalife, J. (2010). Deja vu in the theories of atrial fibrillation dynamics. Cardiovascular Research, 89(4), 766-775. doi:10.1093/cvr/cvq364Koivumäki, 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.1003620Lee, P., Klos, M., Bollensdorff, C., Hou, L., Ewart, P., Kamp, T. J., … Herron, T. J. (2012). Simultaneous Voltage and Calcium Mapping of Genetically Purified Human Induced Pluripotent Stem Cell–Derived Cardiac Myocyte Monolayers. Circulation Research, 110(12), 1556-1563. doi:10.1161/circresaha.111.262535Lieu, D. K., Fu, J.-D., Chiamvimonvat, N., Tung, K. C., McNerney, G. P., Huser, T., … Li, R. A. (2013). Mechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes. Circulation: Arrhythmia and Electrophysiology, 6(1), 191-201. doi:10.1161/circep.111.973420Liu, X., Shi, H., Tan, H., Wang, X., Zhou, L., & Gu, J. (2009). Decreased Connexin 43 and Increased Fibrosis in Atrial Regions Susceptible to Complex Fractionated Atrial Electrograms. Cardiology, 114(1), 22-29. doi:10.1159/000210398Mansour, M., Mandapati, R., Berenfeld, O., Chen, J., Samie, F. H., & Jalife, J. (2001). Left-to-Right Gradient of Atrial Frequencies During Acute Atrial Fibrillation in the Isolated Sheep Heart. Circulation, 103(21), 2631-2636. doi:10.1161/01.cir.103.21.2631Martins, R. P., Kaur, K., Hwang, E., Ramirez, R. J., Willis, B. C., Filgueiras-Rama, D., … Jalife, J. (2014). Dominant Frequency Increase Rate Predicts Transition from Paroxysmal to Long-Term Persistent Atrial Fibrillation. Circulation, 129(14), 1472-1482. doi:10.1161/circulationaha.113.004742McDowell, K. S., Vadakkumpadan, F., Blake, R., Blauer, J., Plank, G., MacLeod, R. S., & Trayanova, N. A. (2013). Mechanistic Inquiry into the Role of Tissue Remodeling in Fibrotic Lesions in Human Atrial Fibrillation. Biophysical Journal, 104(12), 2764-2773. doi:10.1016/j.bpj.2013.05.025Narayan, 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.2012.05.022Noguchi, K., Masumiya, H., Takahashi, K., Kaneko, K., Higuchi, S., Tanaka, H., & Shigenobu, K. (1997). Comparative effects of gallopamil and verapamil on the mechanical and electrophysiological parameters of isolated guinea-pig myocardium. Canadian Journal of Physiology and Pharmacology, 75(12), 1316-1321. doi:10.1139/y97-161Pandit, S. V., Berenfeld, O., Anumonwo, J. M. B., Zaritski, R. M., Kneller, J., Nattel, S., & Jalife, J. (2005). Ionic Determinants of Functional Reentry in a 2-D Model of Human Atrial Cells During Simulated Chronic Atrial Fibrillation. Biophysical Journal, 88(6), 3806-3821. doi:10.1529/biophysj.105.060459Pandit, S. V., & Jalife, J. (2013). Rotors and the Dynamics of Cardiac Fibrillation. Circulation Research, 112(5), 849-862. doi:10.1161/circresaha.111.300158Riccio, M. L., Koller, M. L., & Gilmour, R. F. (1999). Electrical Restitution and Spatiotemporal Organization During Ventricular Fibrillation. Circulation Research, 84(8), 955-963. doi:10.1161/01.res.84.8.955Samie, F. H., Mandapati, R., Gray, R. A., Watanabe, Y., Zuur, C., Beaumont, J., & Jalife, J. (2000). A Mechanism of Transition From Ventricular Fibrillation to Tachycardia. Circulation Research, 86(6), 684-691. doi:10.1161/01.res.86.6.684Samie, F. H., Berenfeld, O., Anumonwo, J., Mironov, S. F., Udassi, S., Beaumont, J., … Jalife, J. (2001). Rectification of the Background Potassium Current. Circulation Research, 89(12), 1216-1223. doi:10.1161/hh2401.100818Smith, A. W., Segar, C. E., Nguyen, P. K., MacEwan, M. R., Efimov, I. R., & Elbert, D. L. (2012). Long-term culture of HL-1 cardiomyocytes in modular poly(ethylene glycol) microsphere-based scaffolds crosslinked in the phase-separated state. Acta Biomaterialia, 8(1), 31-40. doi:10.1016/j.actbio.2011.08.021Tsai, C.-T., Chiang, F.-T., Chen, W.-P., Hwang, J.-J., Tseng, C.-D., Wu, C.-K., … Lin, J.-L. (2011). Angiotensin II induces complex fractionated electrogram in a cultured atrial myocyte monolayer mediated by calcium and sodium-calcium exchanger. Cell Calcium, 49(1), 1-11. doi:10.1016/j.ceca.2010.10.005Tsai, C.-T., Chiang, F.-T., Tseng, C.-D., Yu, C.-C., Wang, Y.-C., Lai, L.-P., … Lin, J.-L. (2011). Mechanical Stretch of Atrial Myocyte Monolayer Decreases Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Expression and Increases Susceptibility to Repolarization Alternans. Journal of the American College of Cardiology, 58(20), 2106-2115. doi:10.1016/j.jacc.2011.07.039Tuomi, J. M., Tyml, K., & Jones, D. L. (2011). Atrial tachycardia/fibrillation in the connexin 43 G60S mutant (Oculodentodigital dysplasia) mouse. American Journal of Physiology-Heart and Circulatory Physiology, 300(4), H1402-H1411. doi:10.1152/ajpheart.01094.2010White, S. M., Constantin, P. E., & Claycomb, W. C. (2004). Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. American Journal of Physiology-Heart and Circulatory Physiology, 286(3), H823-H829. doi:10.1152/ajpheart.00986.2003Wijffels, M. C. E. F., Kirchhof, C. J. H. J., Dorland, R., & Allessie, M. A. (1995). Atrial Fibrillation Begets Atrial Fibrillation. Circulation, 92(7), 1954-1968. doi:10.1161/01.cir.92.7.1954Zlochiver, S., Muñoz, V., Vikstrom, K. L., Taffet, S. M., Berenfeld, O., & Jalife, J. (2008). Electrotonic Myofibroblast-to-Myocyte Coupling Increases Propensity to Reentrant Arrhythmias in Two-Dimensional Cardiac Monolayers. Biophysical Journal, 95(9), 4469-4480. doi:10.1529/biophysj.108.13647

Atrial fibrillation dynamics and ionic block effects in six heterogeneous human 3D virtual atria with distinct repolarization dynamics

Atrial fibrillation (AF) usually manifests as reentrant circuits propagating through the whole atria creating chaotic activation patterns. Little is yet known about how differences in electrophysiological and ionic properties between patients modulate reentrant patterns in AF. The goal of this study is to quantify how variability in action potential duration (APD) at different stages of repolarization determines AF dynamics and their modulation by ionic block using a set of virtual whole-atria human models. Six human whole-atria models are constructed based on the same anatomical structure and fiber orientation, but with different electrophysiological phenotypes. Membrane kinetics for each whole-atria model are selected with distinct APD characteristics at 20, 50, and 90% repolarization, from an experimentally calibrated population of human atrial action potential models, including AF remodeling and acetylcholine parasympathetic effects. Our simulations show that in all whole-atria models, reentrant circuits tend to organize around the pulmonary veins and the right atrial appendage, thus leading to higher dominant frequency (DF) and more organized activation in the left atrium than in the right atrium. Differences in APD in all phases of repolarization (not only APD90) yielded quantitative differences in fibrillation patterns with long APD associated with slower and more regular dynamics. Long APD50 and APD20 were associated with increased interatrial conduction block and interatrial differences in DF and organization index, creating reentry instability and self-termination in some cases. Specific inhibitions of IK1, INaK, or INa reduce DF and organization of the arrhythmia by enlarging wave meandering, reducing the number of secondary wavelets, and promoting interatrial block in all six virtual patients, especially for the phenotypes with short APD at 20, 50, and/or 90% repolarization. This suggests that therapies aiming at prolonging the early phase of repolarization might constitute effective antiarrhythmic strategies for the pharmacological management of AF. In summary, simulations report significant differences in atrial fibrillatory dynamics resulting from differences in APD at all phases of repolarization

New insights in atrial fibrillation mechanisms, electrogram analysis and alternative therapeutic approaches

En la presente tesis se intentan evaluar aspectos importantes referentes al manejo integral de los pacientes con fibrilación auricular, desde aspectos mecanísticos (en concreto el papel del la apnea del sueño en el desarrollo y mantenimiento de la FA) hasta técnicos, relativos a la hora de mapeo de la FA durante el procedimiento de ablación (rentabilidad de los algoritmos automáticos de detección de actividad rotacional y focal además del análisis detallado de los mapas de voltaje en función del ritmo subyacente). Finalmente se presenta el primer atlas del sistema venoso auricular imprescindible con "estrategias de rescate" tales como la ablación alcohólica de la fibrilación auricular

Studies on the dynamics of chaotic multi-wavelet reentrant propagation using a hybrid cellular automaton model of excitable tissue

There is a compelling body of evidence implicating continuous propagation (reentry) sustained by multiple meandering wavelets in the pathology of advanced human atrial fibrillation (AF). This forms the basis for many current therapies such as the Cox MAZE procedure and its derivatives, which aim to create non-conducting lesions in order to "transect" these circuits before they form. Nevertheless, our ability to successfully treat persistent and permanent AF using catheter ablation remains inadequate due to current limitations of clinical mapping technology as well as an incomplete understanding of how to place lesions in order to maximize circuit transection and, more importantly, minimize AF burden. Here, we used a hybrid cellular automaton model to study the dynamics of chaotic, multi-wavelet reentry (MWR) in excitable tissue. First, we used reentry as an exemplar to investigate a hysteretic disease mechanism in a multistable nonlinear system. We found that certain interactions with the environment can cause persistent changes to system behavior without altering its structure or properties, thus leading to a disconnect between clinical symptoms and the underlying state of disease. Second, we developed a novel analytical method to characterize the spatiotemporal dynamics of MWR. We identified a heterogeneous spatial distribution of reentrant pathways that correlated with the spatial distribution of cell activation frequencies. Third, we investigated the impact of topological and geometrical substrate alterations on the dynamics of MWR. We demonstrated a multi-phasic relationship between obstacle size and the fate of individual episodes. Notably, for a narrow range of sizes, obstacles appeared to play an active role in rapidly converting MWR to stable structural reentry. Our studies indicate that reentrant-pathway distributions are non-uniform in heterogeneous media (such as the atrial myocardium) and suggest a clinically measurable correlate for identifying regions of high circuit density, supporting the feasibility of patient-specific targeted ablation. Moreover, we have elucidated the key mechanisms of interaction between focal obstacles and MWR, which has implications for the use of spot ablation to treat AF as some recent studies have suggested

A Mechanistically Guided Approach to Treatment of Multi-Wavelet Reentry: Experiments in a Computational Model of Cardiac Propagation

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States today. However, treatment options remain limited despite the enormous magnitude of both AF prevalence and the associated economic cost. Of those treatment options that are available, ablation-based interventional methods have demonstrated the highest rates of long-term cure. Unfortunately, these methods have substantially lower efficacy in patients with heavier burdens of disease, thus leaving the most affected individuals with the least hope for successful treatment. The focus of this research is to develop a mechanistically guided approach towards the treatment of multi-wavelet reentry (MWR), one of the primary drivers of AF. For this purpose, we use a computational model of electrical propagation in cardiac tissue to simulate both episodes of fibrillatory activity and the ablative treatment thereof. We demonstrate that the probability of forming the reentrant circuits necessary for continuous electrical activity is a function of the shape and size of a tissue as well as its underlying cellular properties. Ablation at tissue sites with high probability of circuit formation more efficiently reduces the overall duration of fibrillatory episodes than ablation at sites with low probability. We then propose and validate in silico a parameter-based metric for predicting the propensity of an individual tissue to support fibrillation, which we term the fibrillogenicity index. Using this metric, we develop an algorithm for prospectively determining optimized, tissue-specific ablation patterns. Finally, we examine the relationship between multi-wavelet reentry and focal drivers, and demonstrate that MWR and fibrillatory conduction exist along a continuum. We examine the complex interplay between functional and structural substrates within fibrillating tissue and define the mechanisms by which they promote the perpetuation of AF. These findings present a novel theoretical framework for understanding treatment of multi-wavelet reentry driven AF and provide a set of testable predictions that can serve to guide the design of future experimental studies aimed at advancing the rational design of patient-specific ablation sets for treating AF

Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely