Dynamical mechanism of atrial fibrillation: a topological approach

While spiral wave breakup has been implicated in the emergence of atrial fibrillation, its role in maintaining this complex type of cardiac arrhythmia is less clear. We used the Karma model of cardiac excitation to investigate the dynamical mechanisms that sustain atrial fibrillation once it has been established. The results of our numerical study show that spatiotemporally chaotic dynamics in this regime can be described as a dynamical equilibrium between topologically distinct types of transitions that increase or decrease the number of wavelets, in general agreement with the multiple wavelets hypothesis. Surprisingly, we found that the process of continuous excitation waves breaking up into discontinuous pieces plays no role whatsoever in maintaining spatiotemporal complexity. Instead this complexity is maintained as a dynamical balance between wave coalescence -- a unique, previously unidentified, topological process that increases the number of wavelets -- and wave collapse -- a different topological process that decreases their number.Comment: 15 pages, 14 figure

Nonlinear physics of electrical wave propagation in the heart: a review

The beating of the heart is a synchronized contraction of muscle cells (myocytes) that are triggered by a periodic sequence of electrical waves (action potentials) originating in the sino-atrial node and propagating over the atria and the ventricles. Cardiac arrhythmias like atrial and ventricular fibrillation (AF,VF) or ventricular tachycardia (VT) are caused by disruptions and instabilities of these electrical excitations, that lead to the emergence of rotating waves (VT) and turbulent wave patterns (AF,VF). Numerous simulation and experimental studies during the last 20 years have addressed these topics. In this review we focus on the nonlinear dynamics of wave propagation in the heart with an emphasis on the theory of pulses, spirals and scroll waves and their instabilities in excitable media and their application to cardiac modeling. After an introduction into electrophysiological models for action potential propagation, the modeling and analysis of spatiotemporal alternans, spiral and scroll meandering, spiral breakup and scroll wave instabilities like negative line tension and sproing are reviewed in depth and discussed with emphasis on their impact in cardiac arrhythmias.Peer ReviewedPreprin

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

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

Three dimensional reconstruction to visualize atrial fibrillation activation patterns on curved atrial geometry

Background: The rotational activation created by spiral waves may be a mechanism for atrial fibrillation (AF), yet it is unclear how activation patterns obtained from endocardial baskets are influenced by the 3D geometric curvature of the atrium or 'unfolding' into 2D maps. We develop algorithms that can visualize spiral waves and their tip locations on curved atrial geometries. We use these algorithms to quantify differences in AF maps and spiral tip locations between 3D basket reconstructions, projection onto 3D anatomical shells and unfolded 2D surfaces. Methods: We tested our algorithms in N = 20 patients in whom AF was recorded from 64-pole baskets (Abbott, CA). Phase maps were generated by non-proprietary software to identify the tips of spiral waves, indicated by phase singularities. The number and density of spiral tips were compared in patient-specific 3D shells constructed from the basket, as well as 3D maps from clinical electroanatomic mapping systems and 2D maps. Results: Patients (59.4±12.7 yrs, 60% M) showed 1.7±0.8 phase singularities/patient, in whom ablation terminated AF in 11/20 patients (55%). There was no difference in the location of phase singularities, between 3D curved surfaces and 2D unfolded surfaces, with a median correlation coefficient between phase singularity density maps of 0.985 (0.978-0.990). No significant impact was noted by phase singularities location in more curved regions or relative to the basket location (p>0.1). Conclusions: AF maps and phase singularities mapped by endocardial baskets are qualitatively and quantitatively similar whether calculated by 3D phase maps on patient-specific curved atrial geometries or in 2D. Phase maps on patient-specific geometries may be easier to interpret relative to critical structures for ablation planning

Presence and stability of rotors in atrial fibrillation: evidence and therapeutic implications

[EN] Rotor-guided ablation has opened new perspectives into the therapy of atrial fibrillation (AF). Analysis of the spatio-temporal cardiac excitation patterns in the frequency and phase domains has demonstrated the importance of rotors in research models of AF, however, the dynamics and role of rotors in human AF are still controversial. In this review, the current knowledge gained through research models and patient data that support the notion that rotors are key players in AF maintenance is summarized. We report and discuss discrepancies regarding rotor prevalence and stability in various studies, which can be attributed in part to methodological differences among mapping systems. Future research for validation and improvement of current clinical electrophysiology mapping technologies will be crucial for developing mechanistic-based selection and application of the best therapeutic strategy for individual AF patient, being it, pharmaceutical, ablative, or other approach.This work was supported in part by grants from the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882, PI13-00903, and PI14/00857), Spanish Society of Cardiology (Clinical Research Grant 2015), Generalitat Valenciana (ACIF/2013/021), Innovation (Red RIC, PLE2009-0152), and NHLBI (P01-HL039707, P01-HL087226, and R01-HL118304).Guillem Sánchez, MS.; Climent, AM.; Rodrigo Bort, M.; Fernandez-Aviles, F.; Atienza, F.; Berenfeld, O. (2016). Presence and stability of rotors in atrial fibrillation: evidence and therapeutic implications. Cardiovascular Research. 109(4):480-492. https://doi.org/10.1093/cvr/cvw011S480492109

Investigation of pattern generating mechanisms during atrial fibrillation based on the FitzHugh Nagumo equations

Die häufigste Arrhythmie des Herzens im klinischen Alltag ist Vorhofflimmern. Sie ist die Ursache von einem Drittel aller Behandlungen von Herzrhythmusstörungen. Obwohl das Phänomen des Vorhofflimmerns seit Anfang des letzten Jahrhunderts bekannt ist, sind die zugrunde liegenden Mechanismen noch nicht ausreichend verstanden. Als mögliche generierende Mechanismen werden in dieser Arbeit ektopische Zentren und Spiralwellen auf der Grundlage der FitzHugh-Nagumo- Gleichungen untersucht. Zur Darstellung von lokalen Gewebeveränderungen und der mit ihnen verbundenen Entstehung von ektopischen Zentren und Spiralwellen werden Zelleigenschaften wie die Anregbarkeit und die Stabilität des Ruhezustandes in räumlich begrenzten Gebieten variiert. Das Auftreten von Aktivitätsmustern in Abhängigkeit der linearen Ausdehnung der modifizierten Zellbereiche und der Stärke der Modifikation wird in dynamischen Phasendiagrammen erfasst und die mit den verschiedenen Mustern verbundenen Eigenschaften werden analysiert. Der abschließende Teil betrifft die Untersuchung von Mustern, welche durch Interferenz von regelmässigen, periodisch angeregten Wellen im rechten Vorhof mit Wellen ausgehend von einer stabilen Spiralwelle im linken Vorhof entstehen. Es wird gezeigt, dass diese Interferenz Ursache eines Flimmerzustandes im rechten Vorhof sein kann. Dabei führt insbesondere eine hohe Anregungsrate zu einem irregulären, flimmerähnlichen Zustand im rechten Vorhof. Sie erweist sich als Schlüsselfaktor für das Auftreten von Flimmerepisoden.Atrial fibrillation is the most important arrhythmia in clinical practice, accounting for one third of hospitalisations for cardiac disrhythms. Although it is known since the beginning of the last century, the underlying mechanisms are still under disucssion. In this work two proposed mechanisms are investigated, ectopic activity and spiral waves, with focus on their generating conditions, characteristic properties and wether they can be a possible cause of atrial fibrillation. Thereby, the cell properties like excitability and resting state stability are spatially varied to model possible generating conditions. The calculations are carried out on the basis of the FitzHugh Nagumo model. Dynamical phase diagrams are constructed for the ectopic activity as well as for the spiral waves, which classify the behaviour of the system in dependence on the properties of the spatial variation of the cell properties. The fibrillation rate is analysed and a transition from anatomical to functional reentry is observed for the spiral waves. Moreover, interference patterns of waves are studied in comparison to patterns found in recent experiments. The interference of waves from a stable spiral wave in the left atrium with regular paced waves in the right atrium, as a model of the sinus node, is shown to be a possible cause of fibrillation in the right atrium. A high pacing rate can yield an irregular, fibrillatory state, which describes the generation of fibrillation episodes and is seen as a key factor for the occurrence of fibrillation episodes.Ilmenau, Techn. Univ., Diplomarbeit, 200