Ibutilide Increases the Variability and Complexity of Atrial Fibrillation Electrograms: Antiarrhythmic Insights Using Signal Analyses

Introduction Intravenous ibutilide is used to convert atrial fibrillation (AF) to sinus rhythm (SR) due to its Class III antiarrhythmic mechanisms. However, the effects of ibutilide on local electrograms (EGMs) during AF have not been elucidated. Methods and Results We used EGM analysis techniques to characterize how ibutilide administration changes the frequency, morphology, and repeatability of AF EGM signals, thereby providing insight into ibutilide's antiarrhythmic mechanism of action. AF recordings were collected from 21 patients with AF, both before and after ibutilide administration. The effects of ibutilide on the following AF EGM parameters were assessed: (1) dominant frequency (DF), (2) variations in EGM amplitude and overall morphology, (3) repetition of EGM patterns, and (4) complexity of the AF frequency spectra. When comparing pre- versus post-ibutilide administration EGMs, DF decreased from 5.45 Hz to 4.02 Hz (P < 0.0001). There was an increase in the variability of both AF EGM amplitudes (P = 0.003) and overall AF EGM morphologies (P = 0.003). AF EGM pattern repetitiveness decreased (P = 0.01), and the AF frequency spectral profile manifested greater complexity (P = 0.02). Conclusions Novel EGM signal analysis techniques reveal that ibutilide administration causes increased complexity in the atrial electrical activation pattern with decreasing rate. These findings may be explained by the progressive destabilization of higher frequency, more homogeneous primary drivers of AF over the course of ibutilide administration, and/or less uniform propagation of atrial activation, until AF maintenance becomes more difficult and either transforms to atrial tachycardia or terminates to SR

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

Practical Considerations for the Application of Nonlinear Indices Characterizing the Atrial Substrate in Atrial Fibrillation

[EN] Atrial fibrillation (AF) is the most common cardiac arrhythmia, and in response to increasing clinical demand, a variety of signals and indices have been utilized for its analysis, which include complex fractionated atrial electrograms (CFAEs). New methodologies have been developed to characterize the atrial substrate, along with straightforward classification models to discriminate between paroxysmal and persistent AF (ParAF vs. PerAF). Yet, most previous works have missed the mark for the assessment of CFAE signal quality, as well as for studying their stability over time and between different recording locations. As a consequence, an atrial substrate assessment may be unreliable or inaccurate. The objectives of this work are, on the one hand, to make use of a reduced set of nonlinear indices that have been applied to CFAEs recorded from ParAF and PerAF patients to assess intra-recording and intra-patient stability and, on the other hand, to generate a simple classification model to discriminate between them. The dominant frequency (DF), AF cycle length, sample entropy (SE), and determinism (DET) of the Recurrence Quantification Analysis are the analyzed indices, along with the coefficient of variation (CV) which is utilized to indicate the corresponding alterations. The analysis of the intra-recording stability revealed that discarding noisy or artifacted CFAE segments provoked a significant variation in the CV(%) in any segment length for the DET and SE, with deeper decreases for longer segments. The intra-patient stability provided large variations in the CV(%) for the DET and even larger for the SE at any segment length. To discern ParAF versus PerAF, correlation matrix filters and Random Forests were employed, respectively, to remove redundant information and to rank the variables by relevance, while coarse tree models were built, optimally combining high-ranked indices, and tested with leave-one-out cross-validation. The best classification performance combined the SE and DF, with an accuracy (Acc) of 88.3%, to discriminate ParAF versus PerAF, while the highest single Acc was provided by the DET, reaching 82.2%. This work has demonstrated that due to the high variability of CFAEs data averaging from one recording place or among different recording places, as is traditionally made, it may lead to an unfair oversimplification of the CFAE-based atrial substrate characterization. Furthermore, a careful selection of reduced sets of features input to simple classification models is helpful to accurately discern the CFAEs of ParAF versus PerAF.This research has received partial financial support from public national grants DPI2017-83952-C3, PID2021-00X128525-IV0, and PID2021-123804OB-I00 of the Spanish Government with DOI 10.13039/501100011033 jointly with the European Regional Development Fund (EU), and regional grants SBPLY/17/180501/000411 from Junta de Comunidades de Castilla-La Mancha and AICO/2021/286 from Generalitat Valenciana.Finotti, E.; Quesada, A.; Ciaccio, EJ.; Garan, H.; Hornero, F.; Alcaraz, R.; Rieta, JJ. (2022). Practical Considerations for the Application of Nonlinear Indices Characterizing the Atrial Substrate in Atrial Fibrillation. Entropy. 24(24):1-17. https://doi.org/10.3390/e24091261117242

A new transform for the analysis of complex fractionated atrial electrograms

Representation of independent biophysical sources using Fourier analysis can be inefficient because the basis is sinusoidal and general. When complex fractionated atrial electrograms (CFAE) are acquired during atrial fibrillation (AF), the electrogram morphology depends on the mix of distinct nonsinusoidal generators. Identification of these generators using efficient methods of representation and comparison would be useful for targeting catheter ablation sites to prevent arrhythmia reinduction. A data-driven basis and transform is described which utilizes the ensemble average of signal segments to identify and distinguish CFAE morphologic components and frequencies. Calculation of the dominant frequency (DF) of actual CFAE, and identification of simulated independent generator frequencies and morphologies embedded in CFAE, is done using a total of 216 recordings from 10 paroxysmal and 10 persistent AF patients. The transform is tested versus Fourier analysis to detect spectral components in the presence of phase noise and interference. Correspondence is shown between ensemble basis vectors of highest power and corresponding synthetic drivers embedded in CFAE. Results: The ensemble basis is orthogonal, and efficient for representation of CFAE components as compared with Fourier analysis (p ≤ 0.002). When three synthetic drivers with additive phase noise and interference were decomposed, the top three peaks in the ensemble power spectrum corresponded to the driver frequencies more closely as compared with top Fourier power spectrum peaks (p ≤ 0.005). The synthesized drivers with phase noise and interference were extractable from their corresponding ensemble basis with a mean error of less than 10%. Conclusions: The new transform is able to efficiently identify CFAE features using DF calculation and by discerning morphologic differences. Unlike the Fourier transform method, it does not distort CFAE signals prior to analysis, and is relatively robust to jitter in periodic events. Thus the ensemble method can provide a useful alternative for quantitative characterization of CFAE during clinical study

Differences in atrial fibrillation properties under vagal nerve stimulation versus atrial tachycardia remodeling

Fond : Le substrat de fibrillation auriculaire (FA) vagale et celui secondaire à remodelage par tachycardie auriculaire (RTA) partagent beaucoup des caractéristiques : période réfractaire efficace (PRE) réduite, hétérogénéité accrue de PRE et quelques mécanismes moléculaires communs. Cette étude a comparé les 2 substrats à une abréviation comparable de PRE. Méthodes : Chez chacun de 6 chiens de groupe de stimulation vagal (SV), les paramètres de stimulation cervicale bilatérale de nerves vagaux ont été ajustés pour produire la même PRE moyenne (calculé à 8 sites des oreillettes gauche et droite) avec 6 chiens de groupe de RTA assorti à sexe et poids. Des paramètres électrophysiologiques, la durée moyenne de la fibrillation auriculaire (DAF) et les fréquences dominantes (FD) locales ont étés calculés. Résultats : En dépit des PREs assorties (SV: 80±12msec contre RTA: 79±12msec) la DAF était plus longue (*), l’hétérogénéité de conduction était plus élevée (*), la FD était plus rapide (*) et la variabilité de FD plus grande (*) chez les chiens SV. Les zones de maximum FD qui reflètent les zones d’origine de FA étaient à côté de ganglions autonomes chez les chiens SV. Conclusions : Pour un PRE atriale comparable, la FA secondaire à SV est plus rapide et plus persistante que la FA avec un substrat de RTA. Ces résultats sont consistants avec des modèles de travail suggérant que l'hyperpolarisation SV-induite contribue de façon important à la stabilisation et à l'accélération des rotors qui maintiennent la FA. La similitude de la distribution de FD du groupe vagal avec la distribution des lésions d’ablation après cartographie des électrogrammes atriales fragmentés suggère des nouvelles techniques d’ablation. La distribution des FD entre le SV et le RTA fournit de nouvelles idées au sujet de possible rémodelage neuroreceptorial et indique des différences importantes entre ces substrats de FA superficiellement semblables.Background: Vagal nerve stimulation (VS) and atrial tachycardia remodeled (ATR) atrial fibrillation (AF) substrates share many features: reduced effective refractory period (ERP), increased ERP heterogeneity and some common molecular mechanisms. This study compared VS and ATR substrates at comparable ERP abbreviation. Methods: In each of 6 VS dogs, bilateral cervical VS parameters were adjusted to produce the same mean ERP as a sex and weight matched ATR dog. Electrophysiological parameters, mean duration of AF (DAF) and local dominant frequencies (DF) were determined (before (CTL) and after VS in VS dogs). Results: Despite matched ERPs (VG: 80±12msec vs ATR: 79±12msec) DAF was greater (*), conduction heterogeneity was greater (*), DF was faster (*) and DF variability greater (*) in VS dogs. AF drivers reflected by maximum DF zones were adjacent to autonomic ganglia in VS dogs; there was a tendency (p<0.07) to faster driver zones in the left atrium comparing to the right in ATR dogs. Conclusions: For a comparable atrial ERP, VS AF is faster and more persistent than AF with an ATR substrate. These results are consistent with modeling work suggesting that VS-induced hyperpolarization is an important contributor to AF-maintaining rotor stabilization and acceleration. Similarities in DF distribution in VS dogs with distribution of ablation lesions performed after Complex Fractionated Atrial Electrograms mapping suggests new curative ablation methods. DF distribution differences between VS and ATR provides new ideas about possible neuroreceptorial remodeling and indicates important differences between these superficially similar AF substrates

Mapping Technologies for Catheter Ablation of Atrial Fibrillation Beyond Pulmonary Vein Isolation

Catheter ablation remains the most effective and relatively minimally invasive therapy for rhythm control in patients with AF. Ablation has consistently shown a reduction of arrhythmia-related symptoms and significant improvement in patients’ quality of life compared with medical treatment. The ablation strategy relies on a well-established anatomical approach of effective pulmonary vein isolation. Additional anatomical targets have been reported with the aim of increasing procedure success in complex substrates. However, larger ablated areas with uncertainty of targeting relevant regions for AF initiation or maintenance are not exempt from the potential risk of complications and pro-arrhythmia. Recent developments in mapping tools and computational methods for advanced signal processing during AF have reported novel strategies to identify atrial regions associated with AF maintenance. These novel tools – although mainly limited to research series – represent a significant step forward towards the understanding of complex patterns of propagation during AF and the potential achievement of patient-tailored AF ablation strategies for the near future

Factors Affecting Catheter Contact in the Human Left Atrium, its Impact on the Electrogram and Radiofrequency Ablation.

PhDThe interaction between the mapping/ablation catheter and left atrial (LA) myocardium potentially affects the LA electrical and mechanical properties and impacts on ablation efficacy. Using catheters able to provide real-time contact force (CF) measurement, it has become possible to explore these relationships in vivo. In 60 persistent atrial fibrillation (AF) patients, ablation CF was higher in the right than left wide area circumferential (WACA) lines and where steerable transseptal sheaths were used. Differences were also apparent in the burden of WACA segment reconnection but did not just reflect differences in ablation CFs, suggesting factors other than CF contribute to ablation efficacy. Relationships between ablation force time integral (FTI), impedance drop and electrogram attenuation were assessed in 15 persistent AF patients. FTI significantly correlated with electrogram attenuation and impedance drop from ablation. The relationship was stronger for the former but in both cases plateaued at 500g.s, suggesting no ablation efficacy gains beyond this. Factors further affecting CF and ablation efficacy, the latter judged by impedance drop, were assessed in 30 patients. The variability of the CF waveform and catheter locational stability were both affected by factors including atrial rhythm and catheter delivery mode. Greater CF variability, catheter drift and perpendicular catheter contact were associated with reduced ablation efficacy. The relationship between CF and the electrogram was assessed in 30 patients. The size of the electrogram complexes was affected by CF increases but only where initial CF was <10g. This was also the case for electrogram fractionation measurements. Increasing CF was associated with an increasing incidence of atrial ~ 3 ~ ectopics during sinus rhythm. Spectral parameters (dominant frequency and organisation index) were unaffected by CF. Various factors affect the contact between the catheter and LA myocardium. In turn, catheter contact significantly affects the electrogram during LA mapping and the efficacy of clinical radiofrequency ablation

The contact electrogram and its architectural determinants in atrial fibrillation

The electrogram is the sine qua non of excitable tissues, yet classification in atrial fibrillation (AF) remains poorly related to substrate factors. The objective of this thesis was to establish the relationship between electrograms and two commonly implicated substrate factors, connexin 43 and fibrosis in AF. The substrates and methods chosen to achieve this ranged from human acutely induced AF using open chest surgical mapping (Chapter 6), ex vivo whole heart Langendorff (Chapter 7) with in vivo telemetry confirming spontaneous AF in a new species of rat, the Brown Norway and finally isolated atrial preparations from an older cohort of rats using orthogonal pacing and novel co-localisation methods at sub-millimetre resolution and in some atria, optical mapping (Chapter 8). In rodents, electrode size and spacing was varied (Chapters 5, 10) to study its effects on structure function correlations (Chapter 9). Novel indices of AF organisation and automated electrogram morphology were used to quantify function (Chapter 4). Key results include the discoveries that humans without any history of prior AF have sinus rhythm electrograms with high spectral frequency content, that wavefront propagation velocities correlated with fibrosis and connexin phosphorylation ratios, that AF heterogeneity of conduction correlates to fibrosis and that orthogonal pacing in heavily fibrosed atria causes anisotropy in electrogram-fibrosis correlations. Furthermore, fibrosis and connexin 43 have differing and distinct spatial resolutions in their relationship with AF organisational indices. In conclusion a new model of AF has been found, and structure function correlations shown on an unprecedented scale, but with caveats of electrode size and direction dependence. These findings impact structure function methods and prove the effect of substrate on AF organisation.Open Acces