Human Atrial Fibrillation Research Articles

Incidence, prevalence, and trajectories of repetitive conduction patterns in human atrial fibrillation.

Repetitive conduction patterns in atrial fibrillation (AF) may reflect anatomical structures harbouring preferential conduction paths and indicate the presence of stationary sources for AF. Recently, we demonstrated a novel technique to detect repetitive patterns in high-density contact mapping of AF. As a first step towards repetitive pattern mapping to guide AF ablation, we determined the incidence, prevalence, and trajectories of repetitive conduction patterns in epicardial contact mapping of paroxysmal and persistent AF patients. A 256-channel mapping array was used to record epicardial left and right AF electrograms in persistent AF (persAF, n = 9) and paroxysmal AF (pAF, n = 11) patients. Intervals containing repetitive conduction patterns were detected using recurrence plots. Activation movies, preferential conduction direction, and average activation sequence were used to characterize and classify conduction patterns. Repetitive patterns were identified in 33/40 recordings. Repetitive patterns were more prevalent in pAF compared with persAF [pAF: median 59%, inter-quartile range (41-72) vs. persAF: 39% (0-51), P < 0.01], larger [pAF: = 1.54 (1.15-1.96) vs. persAF: 1.16 (0.74-1.56) cm2, P < 0.001), and more stable [normalized preferentiality (0-1) pAF: 0.38 (0.25-0.50) vs. persAF: 0.23 (0-0.33), P < 0.01]. Most repetitive patterns were peripheral waves (87%), often with conduction block (69%), while breakthroughs (9%) and re-entries (2%) occurred less frequently. High-density epicardial contact mapping in AF patients reveals frequent repetitive conduction patterns. In persistent AF patients, repetitive patterns were less frequent, smaller, and more variable than in paroxysmal AF patients. Future research should elucidate whether these patterns can help in finding AF ablation targets.

Cycle length statistics during human atrial fibrillation reveal refractory properties of the underlying substrate: a combined in silico and clinical test of concept study.

The treatment of atrial fibrillation beyond pulmonary vein isolation has remained an unsolved challenge. Targeting regions identified by different substrate mapping approaches for ablation resulted in ambiguous outcomes. With the effective refractory period being a fundamental prerequisite for the maintenance of fibrillatory conduction, this study aims at estimating the effective refractory period with clinically available measurements. A set of 240 simulations in a spherical model of the left atrium with varying model initialization, combination of cellular refractory properties, and size of a region of lowered effective refractory period was implemented to analyse the capabilities and limitations of cycle length mapping. The minimum observed cycle length and the 25% quantile were compared to the underlying effective refractory period. The density of phase singularities was used as a measure for the complexity of the excitation pattern. Finally, we employed the method in a clinical test of concept including five patients. Areas of lowered effective refractory period could be distinguished from their surroundings in simulated scenarios with successfully induced multi-wavelet re-entry. Larger areas and higher gradients in effective refractory period as well as complex activation patterns favour the method. The 25% quantile of cycle lengths in patients with persistent atrial fibrillation was found to range from 85 to 190 ms. Cycle length mapping is capable of highlighting regions of pathologic refractory properties. In combination with complementary substrate mapping approaches, the method fosters confidence to enhance the treatment of atrial fibrillation beyond pulmonary vein isolation particularly in patients with complex activation patterns.

Human Atrial Fibrillation Is Not Associated With Remodeling of Ryanodine Receptor Clusters

The release of Ca2+ by ryanodine receptor (RyR2) channels is critical for cardiac function. However, abnormal RyR2 activity has been linked to the development of arrhythmias, including increased spontaneous Ca2+ release in human atrial fibrillation (AF). Clustering properties of RyR2 have been suggested to alter the activity of the channel, with remodeling of RyR2 clusters identified in pre-clinical models of AF and heart failure. Whether such remodeling occurs in human cardiac disease remains unclear. This study aimed to investigate the nanoscale organization of RyR2 clusters in AF patients – the first known study to examine this potential remodeling in diseased human cardiomyocytes. Right atrial appendage from cardiac surgery patients with paroxysmal or persistent AF, or without AF (non-AF) were examined using super-resolution (dSTORM) imaging. Significant atrial dilation and cardiomyocyte hypertrophy was observed in persistent AF patients compared to non-AF, with these two parameters significantly correlated. Interestingly, the clustering properties of RyR2 were remarkably unaltered in the AF patients. No significant differences were identified in cluster size (mean ∼18 RyR2 channels), density or channel packing within clusters between patient groups. The spatial organization of clusters throughout the cardiomyocyte was also unchanged across the groups. RyR2 clustering properties did not significantly correlate with patient characteristics. In this first study to examine nanoscale RyR2 organization in human cardiac disease, these findings indicate that RyR2 cluster remodeling is not an underlying mechanism contributing to altered channel function and subsequent arrhythmogenesis in human AF.

Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis

In addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues. Our results highlighted the unknown detrimental effects of KDs and provided insights into strategies for preventing cardiac fibrosis in patients for whom KDs are medically necessary.

M/M/Infinity Birth-Death Processes - A Quantitative Representational Framework to Summarize and Explain Phase Singularity and Wavelet Dynamics in Atrial Fibrillation.

RationaleA quantitative framework to summarize and explain the quasi-stationary population dynamics of unstable phase singularities (PS) and wavelets in human atrial fibrillation (AF) is at present lacking. Building on recent evidence showing that the formation and destruction of PS and wavelets in AF can be represented as renewal processes, we sought to establish such a quantitative framework, which could also potentially provide insight into the mechanisms of spontaneous AF termination.ObjectivesHere, we hypothesized that the observed number of PS or wavelets in AF could be governed by a common set of renewal rate constants λf (for PS or wavelet formation) and λd (PS or wavelet destruction), with steady-state population dynamics modeled as an M/M/∞ birth–death process. We further hypothesized that changes to the M/M/∞ birth–death matrix would explain spontaneous AF termination.Methods and ResultsAF was studied in in a multimodality, multispecies study in humans, animal experimental models (rats and sheep) and Ramirez-Nattel-Courtemanche model computer simulations. We demonstrated: (i) that λf and λd can be combined in a Markov M/M/∞ process to accurately model the observed average number and population distribution of PS and wavelets in all systems at different scales of mapping; and (ii) that slowing of the rate constants λf and λd is associated with slower mixing rates of the M/M/∞ birth–death matrix, providing an explanation for spontaneous AF termination.ConclusionM/M/∞ birth–death processes provide an accurate quantitative representational architecture to characterize PS and wavelet population dynamics in AF, by providing governing equations to understand the regeneration of PS and wavelets during sustained AF, as well as providing insight into the mechanism of spontaneous AF termination.

Signal Transduction Profiling of Angiotensin II Type 1 Receptor With Mutations Associated to Atrial Fibrillation in Humans.

The AT1 receptor (AT1R) has a major role in the Renin-Angiotensin System, being involved in several physiological events including blood pressure control and electrolyte balance. The AT1R is a member of the G protein coupled receptors (GPCR) family, classically known to couple Gαq and engage β-arrestin recruitment. Both G protein and arrestin signaling pathways are involved in modulation of different downstream kinases. A previous study reported that mutations in the AT1R (A244S and I103T-A244S) were positively correlated with higher risk of atrial fibrillation in men. Based on that report, we aimed to investigate if these mutations, including I103T only, could affect AT1R signal transduction profile, and consequently, implicate in atrial fibrillation outcome. To address that, we engineered an AT1R carrying the above-mentioned mutations, and functionally evaluated different signaling pathways. Phosphokinase profiler array to assess the mutations downstream effects on kinases and kinase substrates phosphorylation levels was used. Our results show that the I103T-A244S mutant receptor presents decreased β-arrestin 2 recruitment, which could lead to a harmful condition of sustained Gαq signaling. Moreover, the phosphokinase profiler array revealed that the same mutation led to downstream modulation of kinase pathways that are linked to physiological responses such as fibrous tissue formation, apoptosis and cell proliferation.

Focal and pseudo/rotational activations in human atrial fibrillation defined with automated periodicity mapping.

Defining atrial fibrillation (AF) wave propagation is challenging unless local signal features are discrete or periodic. Periodic focal or rotational activity may identify AF drivers. Our objective was to characterize AF propagation at sites with periodic activation to evaluate the prevalence and relationship between focal and rotational activation. We included 80 patients (61 ± 10 years, persistent AF 49%) from the FaST randomized trial that compared the efficacy of adjunctive focal site ablation versus pulmonary vein isolation. Patients underwent left atrial (LA) activation mapping with a 20-pole circular catheter during spontaneous or induced AF. Five-second bipolar and unipolar electrograms in AF were analyzed. Periodic sites were identified by spectral analysis of the bipolar electrogram. Activation maps of periodic sites were constructed using an automated, validated tracking algorithm, and classified into three patterns: focal sites (FS), rotation (RO), or pseudo-rotation (pRO). The most common propagation pattern at periodic sites was FS for 5-s in all patients (4.9 ± 1.9 per patient). RO and pRO were observed in two and seven patients, respectively, but were all transient (3-5 cycles). Activation from a FS evolved into transient RO/pRO in five patients. No patient had autonomous RO/pRO activations. Patients with RO/pRO had greater LA surface area with periodicity (78 ± 7 vs. 63 ± 16%, p = .0002) and shorter LA periodicity CL (166 ± 10 vs. 190±28 ms, p = .0001) than the rest. Using automated, regional AF periodicity mapping, FS is more prevalent and temporally stable than RO/pRO. Most RO/pRO evolve from neighboring FS. These findings and their implications for AF maintenance require verification with global, panoramic mapping.

Expression Profiles of Circular RNA in Human Atrial Fibrillation With Valvular Heart Diseases.

Circular RNAs (circRNA) are involved in a variety of human heart diseases, however, circRNA expression profiles and circRNA-miRNA-mRNA regulatory network in human atrial fibrillation (AF) especially with valvular heart diseases (VHD) remain poorly understood. A high-throughput RNA sequencing was used to investigate the differentially expressed circRNAs in left atrial appendage from VHD patients with or without persistent AF. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to predict the potential functions of the host genes of differentially expressed circRNA and their downstream targets. CircRNA–miRNA-mRNA regulatory network was constructed to identify mechanisms underlying circRNAs. qRT-PCR and sanger sequencing were further performed to validate the results. Compared with sinus rhythm (SR) patients, there were 3094 upregulated and 4472 downregulated circRNAs in AF patients respectively. The expression of 10 most differentially expressed circRNAs (circ 255-ITGA7, circ 418-KCNN2, circ 13913-MIB1, circ 44670-BARD1, circ 44782-LAMA2, circ 81906-RYR2, circ 35880-ANO5, circ 22249-TNNI3K, circ 3136-TNNI3K, circ 56186-TNNI3K) between SR and persistent AF patients were verified by qRT-PCR. In addition, specific back-splicing sites of these circRNAs was confirmed by sanger sequencing. GO and KEGG pathway analysis indicated that cAMP signal pathway and Wnt signal pathway might play important role in the development of AF in VHD patients, which might be affected by circRNAs. This study provided a preliminary landscape of circRNAs expression profiles which are involved in persistent AF due to VHD, and established the possibility for future related researches in this field.

Abstract 14897: Activation Dyssynchrony Between Contact Multielectrode Mapping and Subsurface Near-Infrared Optical Mapping During Human Atrial Fibrillation

Due to complex 3D human atrial structure, atrial fibrillation (AF) mapping with multielectrode arrays (MEA) mostly represents surface activation. Therefore, MEA may not properly visualize patient specific AF mechanisms, which impairs ablation outcomes. Conversely, near-infrared optical mapping (NIOM) visualizes subsurface intramural activation and can efficiently reveal reentrant drivers responsible for AF maintenance. Delay between surface activation seen by MEA electrograms (EGMs) vs subsurface activation seen by NIOM optical action potentials (OAPs) occurs due to dyssynchrony between myocardium layers, especially during AF. Coronary perfused explanted human atria (n=7) were mapped with NIOM (0.3-0.9mm 2 resolution) and 64-electrode MEA (3mm 2 resolution). Unipolar EGMs were analyzed for the steepest negative deflection. The delay between [-dV/dtmax] of unipolar EGMs and corresponding optical action potentials (OAPs) was compared in 500ms and 300ms pacing and AF. Subsequent structural analysis was done by 9.4T MRI (154-180μm 3 resolution) with gadolinium enhancement and histology. Delay between EGM and OAP local activation times rate-dependently and heterogeneously increased from 6±3 ms and 10±4 ms during 500ms and 300ms pacing to 15±11 ms (with maximum delay 47±18 ms) during pacing induced AF (average cycle length 124±65ms). Large local OAP-EGM delay, seen during AF, correlates with higher fibrosis percentage and fiber twist (p&lt;0.05). NIOM identified reentrant drivers maintaining AF, which were incorrectly visualized as multiple breakthroughs in 68% of MEA maps (n=22). Higher frequency leads to an increased activation discrepancy between EGM and NIOM caused by increased dyssynchrony in regions of higher fibrosis percentage and fiber twist, which may prevent MEA from proper identification of AF drivers in diseased fibrotic human atria. Reannotation of EGM activation based on NIOM may be required for correct AF mechanisms visualization.

Abstract 14900: Human Atrial Fibrillation Drivers Revealed by Machine Learning Using Multicomponent Electrograms and 3D CE-MRI Structural Features

Introduction: Conventional multielectrode mapping is not sufficient to reveal subsurface intramural activation. Thus, atrial fibrillation (AF) driver identification remains challenging. To overcome these limitations we utilized machine learning (ML) to identify AF drivers based on the combination of electrogram (EGM) and 3D structural magnetic resonance imaging (MRI) features. Hypothesis: Detailed electrogram features analysis, including minor deflections, combined with local structural features, can be used to define AF driver. Methods: Sustained AF was mapped in coronary perfused explanted human atria (n=7) with near-infrared optical mapping (NIOM) (0.3-0.9mm 2 resolution) and 64-electrode mapping catheter (3mm 2 resolution). Unipolar EGMs were analyzed for multiple features of the steepest negative deflection and the 2nd-4th steepest deflections in multicomponent EGMs. Atria underwent 9.4T MRI (154-180μm 3 resolution) with gadolinium enhancement and histology validation of fibrosis. Both 3D structural and EGM data from NIOM defined driver and non-driver regions were processed by ML algorithms (LR; PLSDA; GBM; CRF; PSVM; RSVM) using double cross-validation. Results: AF drivers’ reentrant tracks were defined by NIOM activation mapping, the gold-standard, and confirmed by targeted ablation. The best performing ML algorithm (PLSDA) correctly classified mapped driver region with 76.1% accuracy on the testing data. The most important features included sub-endocardial fibrosis, sub-epicardial fiber orientation, local wall thickness, beat-to-beat variability of multicomponent EGM deflections. Conclusions: The ML models pre-trained on combined EGM and structural features allow efficient classification of AF driver vs non-driver regions defined by the NIOM gold-standard. The results suggest that AF driver substrates formed by the combination of 3D fibrotic structural features, which correlate with local EGM characteristics.

Atrial fibrillation modelling at physiologically relevant scales enabled by massive expansion of native human atrial cardiomyocytes through immortogenetics

Abstract Background Current in vitro models of atrial fibrillation have limited translational potential due to a lack of relevant human physiology or the inability to reach the high activation frequencies present in human atrial fibrillation. Absence of relevant models is the result of a general deficit of readily available and standardized sources of well-differentiated human atrial cardiomyocytes. Therefore, we aimed to immortalize native human atrial cardiomyocytes to produce natural and standardized lines of these cells. Methods Human fetal atrial cardiomyocytes were transduced with a lentiviral vector directing myocyte-specific and doxycycline-inducible expression of simian virus 40 large T antigen (here defined as immortogenetics). Addition of doxycycline to the culture medium pushed cardiomyocytes towards a highly proliferative phenotype (proliferation up to 1012 cells). These cells were labelled hiAMs (human immortalised Atrial Myocytes). After differentiation upon doxycycline removal, hiAM cells were characterized using various molecular, biological and electrophysiological assays. Results Following cardiomyogenic differentiation, hiAMs no longer expressed the proliferation marker Ki67, revealed striated α-actinin and troponin T staining patterns and displayed synchronous contractions. Optical voltage mapping of hiAM monolayers revealed excitable cells showing homogeneous spreading of action potentials at 22.5±3.1 cm/s with a mean APD80 of 139±22 ms. Addition of flecainide (10 μM) to hiAM monolayers decreased the conduction velocity by 35% and increased the APD80 by 107%. Dofetilide (10 nM) addition had no effect on the conduction velocity, but did increase the APD80 by 81%. Due to their scalability, monolayers of hiAMs as big as 10 cm2 showing homogenous action potential propagation could easily be created. Following high-frequency electrical pacing, rotors could be induced with an average activation frequency of 7.5±0.9 Hz. Infusion of flecainide during arrhythmic activity resulted in termination of the rotor in 18 of 24 attempts (75%), whereas addition of 0.1% DMSO (vehicle control) did not result in termination in any of the attempts. Dofetilide infusion did not result in termination. However, it did lower the average activation frequency to 2.1±0.7 Hz. Conclusion We have generated first-of-a-kind lines of human atrial cardiomyocytes, allowing massive cell expansion under proliferation conditions and robust formation of cross-striated, contractile and excitable cardiomyocytes after differentiation. These characteristics allow, for the first time, the modelling, at a large-scale, of human atrial arrhythmias with frequencies similar to human atrial fibrillation. With the generation of hiAMs, a user-friendly, clinically-relevant and much-anticipated human atrial research model has been produced. Large-scale AF model using hiAMs Funding Acknowledgement Type of funding source: None

Acute and chronic cholinergic activity in the inflammatory and lipid regulation of epicardial stromal cells from patients with and without atrial fibrillation

Abstract Aims Acetylcholine (ACh) released modulation by botulinum toxin injection into epicardial fat diminish atrial fibrillation (AF) recurrence. These results suggest an interaction between autonomic imbalance and epicardial fat as risk factors of AF. Our aim was to study the inflammatory and lipid profile of epicardial stroma from AF patients and their regulation by high cholinergic activity. Methods and results We performed in vitro assays with primary cultures from paired subcutaneous and epicardial stromal cells from 33 patients. We analysed ACh effect on gene expression, intracellular calcium mobilization and neutrophil migration. Plasma protein regulation by parasympathetic denervation was performed in vagotomised rats. Acute ACh treatment up-regulated MCP1 levels on epicardial stromal cells and suggested a neutrophil infiltration enhancement. Patients with AF had a greater FABP4 gene expression (1.54±0.01 vs 1.47±0.01, p=0.005). Its plasma levels were pronouncedly declined on vagotomised rats (2.02±0.21 ng/mL vs 0.65±0.23 ng/mL, p&amp;lt;0.001). Additionally, chronic ACh treatment improved lipid accumulation within epicardial stromal cells (60.50% [22.82–85.13] vs 13.85% [6.17–23.16], p&amp;lt;0.001). Conclusions Acute ACh activity up-regulates MCP1 and calcium mobilization on epicardial stromal cells. Longer ACh treatment enhanced lipid accumulation. In this line, epicardial stroma from patients with permanent AF contains higher FABP4 expression levels. Thus, modulate cholinergic activity might reduce FABP4 since vagus nerve denervation is associated with a sharply decrease in FABP4 plasma levels. FABP4 in human AF and vagotomised rats Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Carlos III Health Institute; Health Research Institute of Santiago de Compostela

Impaired Mitophagy: A New Potential Mechanism of Human Chronic Atrial Fibrillation.

Mitophagy is an autophagic response and plays essential roles in survival, development, and homeostasis of cells. It has been reported that mitophagic dysfunction is involved in several cardiovascular diseases. However, the effect of mitophagy on atrial fibrillation (AF) is still unknown. Therefore, we investigated the exact role of mitophagy in human chronic AF. Western blot was used to detect the protein abundance. The mitochondrial morphology and structure were observed by transmission electron microscopy. Immunofluorescent stainings were performed to analyze colocalization of mitochondria with autophagosomes or lysosomes. Totally, 43 patients with valvular heart disease undergoing cardiac surgery were selected, including 21 patients with chronic AF. Comparing with the sinus rhythm (SR) group, we found the size and number of mitochondria in atrial myocytes of patients with AF increased significantly. In addition, expression of LC3B II and LC3B II/LC3B I ratio was significantly decreased in the AF group. Moreover, the expression of p62 was markedly elevated in the AF group compared with that in the SR group. The results of immunofluorescence staining and western blot showed an enhanced expression of Cox IV in the AF group. Dual immunofluorescent stainings revealed that mitophagy defect in atrial myocytes of patients with AF resulted from dysfunction in the process of delivery of mitochondria into autophagosomes. For the first time, impaired mitophagy, during the phagocytosis of mitochondria, is associated with human chronic AF. Mitophagy could be a potential therapeutic target for AF.

Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation

Atrial fibrillation (AF)–associated remodeling includes contractile dysfunction whose reasons are only partially resolved. Serotonin (5-HT) increases contractile force and causes arrhythmias in atrial trabeculae from patients in sinus rhythm (SR). In persistent atrial fibrillation (peAF), the force responses to 5-HT are blunted and arrhythmic effects are abolished. Since force but not arrhythmic responses to 5-HT in peAF could be restored by PDE3 + PDE4 inhibition, we sought to perform real-time measurements of cAMP to understand whether peAF alters PDE3 + PDE4-mediated compartmentation of 5-HT4 receptor-cAMP responses. Isolated human atrial myocytes from patients in SR, with paroxysmal AF (paAF) or peAF, were adenovirally transduced to express the FRET-based cAMP sensor Epac1-camps. Forty-eight hours later, cAMP responses to 5-HT (100 μM) were measured in the absence or concomitant presence of the PDE3 inhibitor cilostamide (0.3 μM) and the PDE4 inhibitor rolipram (1 μM). We successfully established real-time cAMP imaging in AF myocytes. 5-HT increased cAMP in SR, paAF, and peAF, but in line with previous findings on contractility, this increase was considerably smaller in peAF than in SR or paAF. The maximal cAMP response to forskolin (10 μM) was preserved in all groups. The diminished cAMP response to 5-HT in peAF was recovered by preincubation with cilostamide + rolipram. We uncovered a significantly diminished cAMP response to 5-HT4 receptor stimulation which may explain the blunted 5-HT inotropic responses observed in peAF. Since both cAMP and force responses but not arrhythmic responses were recovered after concomitant inhibition of PDE3 + PDE4, they might be regulated in different subcellular microdomains.

Unsupervised Classification of Atrial Electrograms for Electroanatomic Mapping of Human Persistent Atrial Fibrillation.

Ablation treatment for persistent atrial fibrillation (persAF) remains challenging due to the absence of a 'ground truth' for atrial substrate characterization and the presence of multiple mechanisms driving the arrhythmia. We implemented an unsupervised classification to identify clusters of atrial electrograms (AEGs) with similar patterns, which were then validated by AEG-derived markers. 956 bipolar AEGs were collected from 11 persAF patients. CARTO variables (Biosense Webster; ICL, ACI and SCI) were used to create a 3D space, and subsequently used to perform an unsupervised classification with k-means. The characteristics of the identified groups were investigated using nine AEG-derived markers: sample entropy (SampEn), dominant frequency, organization index (OI), determinism, laminarity, recurrence rate (RR), peak-to-peak (PP) amplitude, cycle length (CL), and wave similarity (WS). Five AEG classes with distinct characteristics were identified (F = 582, P<0.0001). The presence of fractionation increased from class 1 to 5, as reflected by the nine markers. Class 1 (25%) included organized AEGs with high WS, determinism, laminarity, and RR, and low SampEn. Class 5 (20%) comprised fractionated AEGs with in low WS, OI, determinism, laminarity, and RR, and in high SampEn. Classes 2 (12%), 3 (13%) and 4 (30%) suggested different degrees of AEG organization. Our results expand and reinterpret the criteria used for automated AEG classification. The nine markers highlighted electrophysiological differences among the five classes found by the k-means, which could provide a more complete characterization of persAF substrate during ablation target identification in future clinical studies.

Toward Mechanism-Directed Electrophenotype-Based Treatments for Atrial Fibrillation.

Current treatment approaches for persistent atrial fibrillation (AF) have a ceiling of success of around 50%. This is despite 15 years of developing adjunctive ablation strategies in addition to pulmonary vein isolation to target the underlying arrhythmogenic substrate in AF. A major shortcoming of our current approach to AF treatment is its predominantly empirical nature. This has in part been due to a lack of consensus on the mechanisms that sustain human AF. In this article, we review evidence suggesting that the previous debates on AF being either an organized arrhythmia with a focal driver or a disorganized rhythm sustained by multiple wavelets, may prove to be a false dichotomy. Instead, a range of fibrillation electrophenotypes exists along a continuous spectrum, and the predominant mechanism in an individual case is determined by the nature and extent of remodeling of the underlying substrate. We propose moving beyond the current empirical approach to AF treatment, highlight the need to prescribe AF treatments based on the underlying AF electrophenotype, and review several possible novel mapping algorithms that may be useful in discerning the AF electrophenotype to guide tailored treatments, including Granger Causality mapping.

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

PurposeRecent investigations failed to reproduce the positive rotor-guided ablation outcomes shown by initial studies for treating persistent atrial fibrillation (persAF). Phase singularity (PS) is an important feature for AF driver detection, but algorithms for automated PS identification differ. We aim to investigate the performance of four different techniques for automated PS detection.Methods2048-channel virtual electrogram (VEGM) and electrocardiogram signals were collected for 30 s from 10 patients undergoing persAF ablation. QRST-subtraction was performed and VEGMs were processed using sinusoidal wavelet reconstruction. The phase was obtained using Hilbert transform. PSs were detected using four algorithms: (1) 2D image processing based and neighbor-indexing algorithm; (2) 3D neighbor-indexing algorithm; (3) 2D kernel convolutional algorithm estimating topological charge; (4) topological charge estimation on 3D mesh. PS annotations were compared using the structural similarity index (SSIM) and Pearson’s correlation coefficient (CORR). Optimized parameters to improve detection accuracy were found for all four algorithms using Fβ score and 10-fold cross-validation compared with manual annotation. Local clustering with density-based spatial clustering of applications with noise (DBSCAN) was proposed to improve algorithms 3 and 4.ResultsThe PS density maps created by each algorithm with default parameters were poorly correlated. Phase gradient threshold and search radius (or kernels) were shown to affect PS detections. The processing times for the algorithms were significantly different (p < 0.0001). The Fβ scores for algorithms 1, 2, 3, 3 + DBSCAN, 4 and 4 + DBSCAN were 0.547, 0.645, 0.742, 0.828, 0.656, and 0.831. Algorithm 4 + DBSCAN achieved the best classification performance with acceptable processing time (2.0 ± 0.3 s).ConclusionAF driver identification is dependent on the PS detection algorithms and their parameters, which could explain some of the inconsistencies in rotor-guided ablation outcomes in different studies. For 3D triangulated meshes, algorithm 4 + DBSCAN with optimal parameters was the best solution for real-time, automated PS detection due to accuracy and speed. Similarly, algorithm 3 + DBSCAN with optimal parameters is preferred for uniform 2D meshes. Such algorithms – and parameters – should be preferred in future clinical studies for identifying AF drivers and minimizing methodological heterogeneities. This would facilitate comparisons in rotor-guided ablation outcomes in future works.

Endocardial-Epicardial Phase Mapping of Prolonged Persistent Atrial Fibrillation Recordings: High Prevalence of Dissociated Activation Patterns.

Endocardial-epicardial dissociation and focal breakthroughs in humans with atrial fibrillation (AF) have been recently demonstrated using activation mapping of short 10-second AF segments. In the current study, we used simultaneous endo-epi phase mapping to characterize endo-epi activation patterns on long segments of human persistent AF. Simultaneous intraoperative mapping of endo- and epicardial lateral right atrium wall was performed in patients with persistent AF using 2 high-density grid catheters (16 electrodes, 3 mm spacing). Filtered unipolar and bipolar electrograms of continuous 2-minute AF recordings and electrodes locations were exported for phase analyses. We defined endocardial-epicardial dissociation as phase difference of ≥20 ms between paired endo-epi electrodes. Wavefronts were classified as rotations, single wavefronts, focal waves, or disorganized activity as per standard criteria. Endo-Epi wavefront patterns were simultaneously compared on dynamic phase maps. Complex fractionated electrograms were defined as bipolar electrograms with ≥5 directional changes occupying at least 70% of sample duration. Fourteen patients with persistent AF undergoing cardiac surgery were included. Endocardial-epicardial dissociation was seen in 50.3% of phase maps with significant temporal heterogeneity. Disorganized activity (Endo: 41.3% versus Epi: 46.8%, P=0.0194) and single wavefronts (Endo: 31.3% versus Epi: 28.1%, P=0.129) were the dominant patterns. Transient rotations (Endo: 22% versus Epi: 19.2%, P=0.169; mean duration: 590±140 ms) and nonsustained focal waves (Endo: 1.2% versus Epi: 1.6%, P=0.669) were also observed. Apparent transmural migration of rotational activations (n=6) from the epi- to the endocardium was seen in 2 patients. Electrogram fractionation was significantly higher in the epicardium than endocardium (61.2% versus 51.6%, P<0.0001). Simultaneous endo-epi phase mapping of prolonged human persistent AF recordings shows significant Endocardial-epicardial dissociation marked temporal heterogeneity, discordant and transitioning wavefronts patterns and complex fractionations. No sustained focal activity was observed. Such complex 3-dimensional interactions provide insight into why endocardial mapping alone may not fully characterize the AF mechanism and why endocardial ablation may not be sufficient. Graphic Abstract: A graphic abstract is available for this article.

Large animals as models of atrial fibrillation.

In clinical practice, atrial fibrillation (AF) is the most common cardiac arrhythmia in humans and it may lead to numerous complications, including central nervous system embolism. The electrical activity of the heart in AF is rapid and chaotic, while the atrioventricular conduction leads to irregular ventricular contraction. Consequently, the stroke volume is reduced, which may lead to symptoms of heart failure. Heart failure is one of the causes of AF as well. Numerous in vivo and in vitro models are used to study the pathophysiology of AF. Animal models play a key role in understanding the mechanisms of arrhythmias as well as in developing treatment regimens. The models of AF include large animals (goats, sheep, pigs, dogs) as well as small laboratory animals. This study reviews the large animal models of AF, which enhance our understanding of numerous mechanisms responsible for the development of AF, but we must be aware that the pathomechanism of AF in humans is complex and is affected by numerous factors, including environmental and congenital ones.

Animal Models of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in humans and is a significant source of morbidity and mortality. Despite its prevalence, our mechanistic understanding is incomplete, the therapeutic options have limited efficacy, and are often fraught with risks. A better biological understanding of AF is needed to spearhead novel therapeutic avenues. Although "natural" AF is nearly nonexistent in most species, animal models have contributed significantly to our understanding of AF and some therapeutic options. However, the impediments of animal models are also apparent and stem largely from the differences in basic physiology as well as the complexities underlying human AF; these preclude the creation of a "perfect" animal model and have obviated the translation of animal findings. Herein, we review the vast array of AF models available, spanning the mouse heart (weighing 1/1000th of a human heart) to the horse heart (10× heavier than the human heart). We attempt to highlight the features of each model that bring value to our understanding of AF but also the shortcomings and pitfalls. Finally, we borrowed the concept of a SWOT analysis from the business community (which stands for strengths, weaknesses, opportunities, and threats) and applied this introspective type of analysis to animal models for AF. We identify unmet needs and stress that is in the context of rapidly advancing technologies, these present opportunities for the future use of animal models.