Human Persistent Atrial Fibrillation Research Articles

Organized patterns of excitation during persistent atrial fibrillation in humans relate to tissue structure and activation rate

Abstract Background The contribution of organized patterns of excitation as mechanisms maintaining persistent atrial fibrillation (PAF) is questioned. Purpose We aim to analyze the relationship of focal and reentrant activities, identified with the CARTO-Finder system, with tissue structure and activation rate to explain potential link with mechanisms and outcomes. Methods 33 patients with PAF of at least 6 months (24±4 months) were admitted for right and left atrial (RA & LA) mapping with the CARTO-Finder system. The biatrial geometry, bipolar Penta-Ray`s signals (30 sec long) and activation patterns were exported for off-line analysis (MatLab environment). A fast-Fourier transform was computed on 30 sec bipolar signal length segments to compute dominant frequency (DF) and represented on atrial shells. Focal and reentrant patterns of activation were superimposed, and correlation with DF and bipolar voltage analyzed. Results Biatrial mapping was performed obtaining 15.3±5 Finder maps from the RA and 15.9±5 Finder maps from the LA. Focal activities (182±151 at the RA & 270±21 at the LA) were documented in all patients at both atria. Rotational activities (more than 2 consecutive) were documented in the left atria in 4 patients (22.5±16.8 rotations) and in the right atria in 9 patients (35.5±32 rotations). 30 sec long activation rate was higher at places with focal activities compared with areas without organized patterns (DF: 6.11±0.09 Hz vs 5.7±0.09 Hz; p<0.001). The higher the number of consecutive focal activities, the higher the tissue activation rate (DF no focal activities 5.7±0.09 Hz vs DF 1-5 focal activities 6.0±0.14 Hz vs DF>5 focal activities 6.2±0.14 Hz; p<0.001). In addition, DF at focal activities strongly correlates with DF at areas without organized patterns (Pearson 0.91; p<0.001). The bipolar voltage was higher at places with focal activities compared with areas without organized patterns (1.0±0.04 mV vs 0.5±0.04 mV; p<0.001). None of the previous were observed at places with rotational activities (DF: 5.9±0.16 Hz vs 5.7±0.09 Hz; p=0.204 & Volt: 0.6±0.08 mV vs 0.5±0.04 mV; p=0.364). During follow-up after ablation (24±7 months), a cox regression model including number of focal activities, number of rotations, mean tissue activation rate (mean DF) and bipolar voltage, identified bipolar voltage as a unique independent predictor of survival free of AF recurrence (p=0.04). Conclusions Focal activities identified with the CARTO Finder system during PAF in humans correlate with tissue structure and activation rate, suggesting a potential link with mechanisms.

PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation.

Electrical remodeling in human persistent atrial fibrillation is believed to result from rapid electrical activation of the atria, but underlying genetic causes may contribute. Indeed, common gene variants in an enhancer region close to PITX2 (paired-like homeodomain transcription factor 2) are strongly associated with atrial fibrillation, but the mechanism behind this association remains unknown. This study evaluated the consequences of PITX2 deletion (PITX2-/-) in human induced pluripotent stem cell-derived atrial cardiomyocytes. CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) was used to delete PITX2 in a healthy human iPSC line that served as isogenic control. Human induced pluripotent stem cell-derived atrial cardiomyocytes were differentiated with unfiltered retinoic acid and cultured in atrial engineered heart tissue. Force and action potential were measured in atrial engineered heart tissues. Single human induced pluripotent stem cell-derived atrial cardiomyocytes were isolated from atrial engineered heart tissue for ion current measurements. PITX2-/- atrial engineered heart tissue beats slightly slower than isogenic control without irregularity. Force was lower in PITX2-/- than in isogenic control (0.053±0.015 versus 0.131±0.017 mN, n=28/3 versus n=28/4, PITX2-/- versus isogenic control; P<0.0001), accompanied by lower expression of CACNA1C and lower L-type Ca2+ current density. Early repolarization was weaker (action potential duration at 20% repolarization; 45.5±13.2 versus 8.6±5.3 ms, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P<0.0001), and maximum diastolic potential was more negative (-78.3±3.1 versus -69.7±0.6 mV, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P=0.001), despite normal inward rectifier currents (both IK1 and IK,ACh) and carbachol-induced shortening of action potential duration. Complete PITX2 deficiency in human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulates some findings of electrical remodeling of atrial fibrillation in the absence of fast beating, indicating that these abnormalities could be primary consequences of lower PITX2 levels.

Restitution Slope Affects the Outcome of Dominant Frequency Ablation in Persistent Atrial Fibrillation: CUVIA-AF2 Post-Hoc Analysis Based on Computational Modeling Study.

IntroductionAlthough the dominant frequency (DF) localizes the reentrant drivers and the maximal slope of the action potential duration (APD) restitution curve (Smax) reflects the tendency of the wave-break, their interaction has never been studied. We hypothesized that DF ablation has different effects on atrial fibrillation (AF) depending on Smax.MethodsWe studied the DF and Smax in 25 realistic human persistent AF model samples (68% male, 60 ± 10 years old). Virtual AF was induced by ramp pacing measuring Smax, followed by spatiotemporal DF evaluation for 34 s. We assessed the DF ablation effect depending on Smax in both computational modeling and a previous clinical trial, CUVIA-AF (170 patients with persistent AF, 70.6% male, 60 ± 11 years old).ResultsMean DF had an inverse relationship with Smax regardless of AF acquisition timing (p < 0.001). Virtual DF ablations increased the defragmentation rate compared to pulmonary vein isolation (PVI) alone (p = 0.015), especially at Smax <1 (61.5 vs. 7.7%, p = 0.011). In post-DF ablation defragmentation episodes, DF was significantly higher (p = 0.002), and Smax was lower (p = 0.003) than in episodes without defragmentation. In the post-hoc analysis of CUVIA-AF2, we replicated the inverse relationship between Smax and DF (r = −0.47, p < 0.001), and we observed better rhythm outcomes of clinical DF ablations in addition to a PVI than of empirical PVI at Smax <1 [hazard ratio 0.45, 95% CI (0.22–0.89), p = 0.022; log-rank p = 0.021] but not at ≥ 1 (log-rank p = 0.177).ConclusionWe found an inverse relationship between DF and Smax and the outcome of DF ablation after PVI was superior at the condition with Smax <1 in both in-silico and clinical trials.

Characterization of persistent atrial fibrillation with non-contact charge density mapping and relationship to voltage.

BackgroundDespite studies using localized high density contact mapping and lower resolution panoramic approaches, the mechanisms that sustain human persistent atrial fibrillation (AF) remain unresolved. Voltage mapping is commonly employed as a surrogate of atrial substrate to guide ablation procedures.ObjectiveTo study the distribution and temporal stability of activation during persistent AF using a global non‐contact charge density approach and compare the findings with bipolar contact mapping.MethodsPatients undergoing either redo or de novo ablation for persistent AF underwent charge density and voltage mapping to guide the ablation procedure. Offline analysis was performed to measure the temporal stability of three specific charge density activation (CDA) patterns, and the degree of spatial overlap between CDA patterns and low voltage regions.ResultsCDA was observed in patient‐specific locations that partially overlapped, comprising local rotational activity (18% of LA), local irregular activity (41% of LA), and focal activity (39% of LA). Local irregular activity had the highest temporal stability. LA voltage was similar in regions with and without CDA.ConclusionIn persistent AF, CDA patterns appear unrelated to low voltage areas but occur in varying locations with high temporal stability.

Abstract 12053: Age is a Predictor of Right Atrial Drivers in Human Persistent Atrial Fibrillation

Introduction: Persistent atrial fibrillation (perAF) may be maintained by localized extra-pulmonary vein (PV) drivers. Most clinical studies have focused on left atrial (LA) sources ablation, but right atrial (RA) arrhythmogenic substrate, due to certain comorbidities, may also maintain perAF. Hypothesis: Patient (Pt)-specific characteristics and comorbidities may predict occurrence of RA AF drivers. Methods: Consecutive Pts (n=105) underwent driver ablation in addition to PV isolation for perAF after panoramic multi-electrode mapping (MEM) at a single medical center. Logistic regression (LR) models were used to characterize the relationship between Pt characteristics and presence of AF drivers in each atrium. LR was used to predict 12-month AF-free survival. Results: Pts were 63.1±9.9 years old, 24.8% female, 21.9% in HF, 76.2% had HTN, 24.8% had DM, 22.9% had CAD and 59.0% had OSA. MEM identified a mean of 1.6±1.2 LA drivers and 1.4±1.2 RA drivers per Pt. Forty two Pts had drivers in both LA and RA, 19 in RA only, and 26 in LA only. Older age was a predictor of RA drivers presence (p=0.06), factors that predicted presence of LA drivers were female gender (p=0.19), HTN (p=0.03), and comorbidity score (p = 0.07). CHADS 2 -VASc score and LVEF predicted both LA and RA drivers. Following ablation, 75% of the Pts sustained sinus rhythm after 6 months, 70% after 12 months and 72% after 18 months. AF recurrence within 12 months of ablation was associated with DM (p=0.03), BMI (p=0.03) and RV systolic pressure (p=0.07). Presence of RA drivers was not associated with the 12 and 18-months freedom from AF. Conclusions: In this cohort of perAF patients, older age and higher CHADS 2 -VASc score predicted RA driver occurrence. These preliminary findings suggest that patient-specific clinical characteristics may uniquely impact LA vs RA myocardium by promoting development of chamber-specific arrhythmogenic structural and functional substrates of AF drivers.

Automatic Extraction of Recurrent Patterns of High Dominant Frequency Mapping During Human Persistent Atrial Fibrillation.

Purpose: Identifying targets for catheter ablation remains challenging in persistent atrial fibrillation (persAF). The dominant frequency (DF) of atrial electrograms during atrial fibrillation (AF) is believed to primarily reflect local activation. Highest DF (HDF) might be responsible for the initiation and perpetuation of persAF. However, the spatiotemporal behavior of DF remains not fully understood. Some DFs during persAF were shown to lack spatiotemporal stability, while others exhibit recurrent behavior. We sought to develop a tool to automatically detect recurrent DF patterns in persAF patients.Methods: Non-contact mapping of the left atrium (LA) was performed in 10 patients undergoing persAF HDF ablation. 2,048 virtual electrograms (vEGMs, EnSite Array, Abbott Laboratories, USA) were collected for up to 5 min before and after ablation. Frequency spectrum was estimated using fast Fourier transform and DF was identified as the peak between 4 and 10 Hz and organization index (OI) was calculated. The HDF maps were identified per 4-s window and an automated pattern recognition algorithm was used to find recurring HDF spatial patterns. Dominant patterns (DPs) were defined as the HDF pattern with the highest recurrence.Results: DPs were found in all patients. Patients in atrial flutter after ablation had a single DP over the recorded time period. The time interval (median [IQR]) of DP recurrence for the patients in AF after ablation (7 patients) decreased from 21.1 s [11.8 49.7 s] to 15.7 s [6.5 18.2 s]. The DF inside the DPs presented lower temporal standard deviation (0.18 ± 0.06 Hz vs. 0.29 ± 0.12 Hz, p < 0.05) and higher OI (0.35 ± 0.03 vs. 0.31 ± 0.04, p < 0.05). The atrial regions with the highest proportion of HDF region were the septum and the left upper pulmonary vein.Conclusion: Multiple recurrent spatiotemporal HDF patterns exist during persAF. The proposed method can identify and quantify the spatiotemporal repetition of the HDFs, where the high recurrences of DP may suggest a more organized rhythm. DPs presented a more consistent DF and higher organization compared with non-DPs, suggesting that DF with higher OI might be more likely to recur. Recurring patterns offer a more comprehensive dynamic insight of persAF behavior, and ablation targeting such regions may be beneficial.

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.

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.

Granger Causality-Based Analysis for Classification of Fibrillation Mechanisms and Localization of Rotational Drivers.

The mechanisms sustaining myocardial fibrillation remain disputed, partly due to a lack of mapping tools that can accurately identify the mechanism with low spatial resolution clinical recordings. Granger causality (GC) analysis, an econometric tool for quantifying causal relationships between complex time-series, was developed as a novel fibrillation mapping tool and adapted to low spatial resolution sequentially acquired data. Ventricular fibrillation (VF) optical mapping was performed in Langendorff-perfused Sprague-Dawley rat hearts (n=18), where novel algorithms were developed using GC-based analysis to (1) quantify causal dependence of neighboring signals and plot GC vectors, (2) quantify global organization with the causality pairing index, a measure of neighboring causal signal pairs, and (3) localize rotational drivers (RDs) by quantifying the circular interdependence of neighboring signals with the circular interdependence value. GC-based mapping tools were optimized for low spatial resolution from downsampled optical mapping data, validated against high-resolution phase analysis and further tested in previous VF optical mapping recordings of coronary perfused donor heart left ventricular wedge preparations (n=12), and adapted for sequentially acquired intracardiac electrograms during human persistent atrial fibrillation mapping (n=16). Global VF organization quantified by causality pairing index showed a negative correlation at progressively lower resolutions (50% resolution: P=0.006, R2=0.38, 12.5% resolution, P=0.004, R2=0.41) with a phase analysis derived measure of disorganization, locations occupied by phase singularities. In organized VF with high causality pairing index values, GC vector mapping characterized dominant propagating patterns and localized stable RDs, with the circular interdependence value showing a significant difference in driver versus nondriver regions (0.91±0.05 versus 0.35±0.06, P=0.0002). These findings were further confirmed in human VF. In persistent atrial fibrillation, a positive correlation was found between the causality pairing index and presence of stable RDs (P=0.0005,R2=0.56). Fifty percent of patients had RDs, with a low incidence of 0.9±0.3 RDs per patient. GC-based fibrillation analysis can measure global fibrillation organization, characterize dominant propagating patterns, and map RDs using low spatial resolution sequentially acquired data.

Renewal Theory as a Universal Quantitative Framework to Characterize Phase Singularity Regeneration in Mammalian Cardiac Fibrillation.

Despite a century of research, no clear quantitative framework exists to model the fundamental processes responsible for the continuous formation and destruction of phase singularities (PS) in cardiac fibrillation. We hypothesized PS formation/destruction in fibrillation could be modeled as self-regenerating Poisson renewal processes, producing exponential distributions of interevent times governed by constant rate parameters defined by the prevailing properties of each system. PS formation/destruction were studied in 5 systems: (1) human persistent atrial fibrillation (n=20), (2) tachypaced sheep atrial fibrillation (n=5), (3) rat atrial fibrillation (n=4), (5) rat ventricular fibrillation (n=11), and (5) computer-simulated fibrillation. PS time-to-event data were fitted by exponential probability distribution functions computed using maximum entropy theory, and rates of PS formation and destruction (λf/λd) determined. A systematic review was conducted to cross-validate with source data from literature. In all systems, PS lifetime and interformation times were consistent with underlying Poisson renewal processes (human: λf, 4.2%/ms±1.1 [95% CI, 4.0-5.0], λd, 4.6%/ms±1.5 [95% CI, 4.3-4.9]; sheep: λf, 4.4%/ms [95% CI, 4.1-4.7], λd, 4.6%/ms±1.4 [95% CI, 4.3-4.8]; rat atrial fibrillation: λf, 33%/ms±8.8 [95% CI, 11-55], λd, 38%/ms [95% CI, 22-55]; rat ventricular fibrillation: λf, 38%/ms±24 [95% CI, 22-55], λf, 46%/ms±21 [95% CI, 31-60]; simulated fibrillation λd, 6.6-8.97%/ms [95% CI, 4.1-6.7]; R2≥0.90 in all cases). All PS distributions identified through systematic review were also consistent with an underlying Poisson renewal process. Poisson renewal theory provides an evolutionarily preserved universal framework to quantify formation and destruction of rotational events in cardiac fibrillation.

Characterization and significance of localized sources identified by a novel automated algorithm during mapping of human persistent atrial fibrillation.

Automated algorithms may identify focal (FA) and rotational (RoA) activations during persistent atrial fibrillation (PeAF). To evaluate an automated algorithm for characterizing and assessing significance of FA/RoA. Eighty-six PeAF ablation patients (1411 maps) were analyzed. Maps were obtained with a 64-electrode basket using CARTOFINDER, which filters/annotates atrial unipolar electrograms over 30 seconds. Operators ablated FA/RoA followed by pulmonary vein isolation (PVI). The automated algorithm was retrospectively applied using QS patterns to identify FA and sequential activation gradients for RoA without phase mapping. Algorithm-identified FA and RoA were validated against blinded adjudicators. Ablation of algorithm-identified FA/RoA was related to procedural AF termination. 73% ± 18% of electrodes (65% ± 11% atrial surface area) were adequate for analysis. Compared with adjudicators, the algorithm had a sensitivity of 84% for FA and 86% for RoA. There were 4 ± 2 FA and 2 ± 2 RoA per patient. FA occurred 8 ± 6 times during the 30-second window (cumulative duration 8 ± 6 seconds). RoA occurred 5 ± 3 times (median 2, consecutive rotations) with a cumulative duration of 3 ± 2 seconds. Compared to patients without procedural AF termination, patients with termination had more FA ablated (75% vs 38%, P = 0.006). AF termination was not predicted by percentage of RoA ablated although there was a trend towards a higher percentage of left atrial RoA ablated ( P = 0.06). An automated algorithm had high sensitivity for FA and RoA. Acute AF termination was associated with FA ablation but not RoA ablation. Future studies need to define the significance of FA and RoA and whether they are overlapping or separate mechanisms.

Characterizing Electrogram Signal Fidelity and the Effects of Signal Contamination on Mapping Human Persistent Atrial Fibrillation.

Objective: Determining accurate intracardiac maps of atrial fibrillation (AF) in humans can be difficult, owing primarily to various sources of contamination in electrogram signals. The goal of this study is to develop a measure for signal fidelity and to develop methods to quantify robustness of observed rotational activity in phase maps subject to signal contamination.Methods: We identified rotational activity in phase maps of human persistent AF using the Hilbert transform of sinusoidally recomposed signals, where localized ablation at rotational sites terminated fibrillation. A novel measure of signal fidelity was developed to quantify signal quality. Contamination is then introduced to the underlying electrograms by removing signals at random, adding noise to computations of cycle length, and adding realistic far-field signals. Mean tip number N and tip density δ, defined as the proportion of time a region contains a tip, at the termination site are computed to compare the effects of contamination.Results: Domains of low signal fidelity correspond to the location of rotational cores. Removing signals and altering cycle length accounted for minor changes in tip density, while targeted removal of low fidelity electrograms can result in a significant increase in tip density and stability. Far-field contamination was found to obscure rotation at the termination site.Conclusion: Rotational activity in clinical AF can produce domains of low fidelity electrogram recordings at rotational cores. Observed rotational patterns in phase maps appear most sensitive to far-field activation. These results may inform novel methods to map AF in humans which can be tested directly in patients at electrophysiological study and ablation.

Characterization of human persistent atrial fibrillation electrograms using recurrence quantification analysis.

Atrial fibrillation (AF) is regarded as a complex arrhythmia, with one or more co-existing mechanisms, resulting in an intricate structure of atrial activations. Fractionated atrial electrograms (AEGs) were thought to represent arrhythmogenic tissue and hence have been suggested as targets for radiofrequency ablation. However, current methods for ablation target identification have resulted in suboptimal outcomes for persistent AF (persAF) treatment, possibly due to the complex spatiotemporal dynamics of these mechanisms. In the present work, we sought to characterize the dynamics of atrial tissue activations from AEGs collected during persAF using recurrence plots (RPs) and recurrence quantification analysis (RQA). 797 bipolar AEGs were collected from 18 persAF patients undergoing pulmonary vein isolation (PVI). Automated AEG classification (normal vs. fractionated) was performed using the CARTO criteria (Biosense Webster). For each AEG, RPs were evaluated in a phase space estimated following Takens' theorem. Seven RQA variables were obtained from the RPs: recurrence rate; determinism; average diagonal line length; Shannon entropy of diagonal length distribution; laminarity; trapping time; and Shannon entropy of vertical length distribution. The results show that the RQA variables were significantly affected by PVI, and that the variables were effective in discriminating normal vs. fractionated AEGs. Additionally, diagonal structures associated with deterministic behavior were still present in the RPs from fractionated AEGs, leading to a high residual determinism, which could be related to unstable periodic orbits and suggesting a possible chaotic behavior. Therefore, these results contribute to a nonlinear perspective of the spatiotemporal dynamics of persAF.

Relationship Between Fibrosis Detected on Late Gadolinium-Enhanced Cardiac Magnetic Resonance and Re-Entrant Activity Assessed With Electrocardiographic Imaging in Human Persistent Atrial Fibrillation.

This study sought to assess the relationship between fibrosis and re-entrant activity in persistent atrial fibrillation (AF). The mechanisms involved in sustaining re-entrant activity during AF are poorly understood. Forty-one patients with persistent AF (age 56 ± 12 years; 6 women) were evaluated. High-resolution electrocardiographic imaging (ECGI) was performed during AF by using a 252-chest electrode array, and phase mapping was applied to locate re-entrant activity. Sites of high re-entrant activity were defined as re-entrant regions. Late gadolinium-enhanced (LGE) cardiac magnetic resonance (CMR) was performed at 1.25 × 1.25 × 2.5 mm resolution to characterize atrial fibrosis and measure atrial volumes. The relationship between LGE burden and the number of re-entrant regions was analyzed. Local LGE density was computed and characterized at re-entrant sites. All patients underwent catheter ablation targeting re-entrant regions, the procedural endpoint being AF termination. Clinical, CMR, and ECGI predictors of acute procedural success were then analyzed. Left atrial (LA) LGE burden was 22.1 ± 5.9% of the wall, and LA volume was 74 ± 21 ml/m2. The number of re-entrant regions was 4.3 ± 1.7 per patient. LA LGE imaging was significantly associated with the number of re-entrant regions (R = 0.52, p = 0.001), LA volume (R = 0.62, p < 0.0001), and AF duration (R = 0.54, p = 0.0007). Regional analysis demonstrated a clustering of re-entrant activity at LGE borders. Areas with high re-entrant activity showed higher local LGE density as compared with the remaining atrial areas (p < 0.0001). Failure to achieve AF termination during ablation was associated with higher LA LGE burden (p < 0.001), higher number of re-entrant regions (p < 0.001), and longer AF duration (p = 0.008). The number of re-entrant regions during AF relates to the extent of LGE on CMR, with the location of these regions clustering to LGE areas. These characteristics affect procedural outcomes of ablation.

Absence of rotational activity detected using 2-dimensional phase mapping in the corresponding 3-dimensional phase maps in human persistent atrial fibrillation

Current phase mapping systems for atrial fibrillation create 2-dimensional (2D) maps. This process may affect the accurate detection of rotors. We developed a 3-dimensional (3D) phase mapping technique that uses the 3D locations of basket electrodes to project phase onto patient-specific left atrial 3D surface anatomy. We sought to determine whether rotors detected in 2D phase maps were present at the corresponding time segments and anatomical locations in 3D phase maps. One-minute left atrial atrial fibrillation recordings were obtained in 14 patients using the basket catheter and analyzed off-line. Using the same phase values, 2D and 3D phase maps were created. Analysis involved determining the dominant propagation patterns in 2D phase maps and evaluating the presence of rotors detected in 2D phase maps in the corresponding 3D phase maps. Using 2D phase mapping, the dominant propagation pattern was single wavefront (36.6%) followed by focal activation (34.0%), disorganized activity (23.7%), rotors (3.3%), and multiple wavefronts (2.4%). Ten transient rotors were observed in 9 of 14 patients (64%). The mean rotor duration was 1.1 ± 0.7 seconds. None of the 10 rotors observed in 2D phase maps were seen at the corresponding time segments and anatomical locations in 3D phase maps; 4 of 10 corresponded with single wavefronts in 3D phase maps, 2 of 10 with 2 simultaneous wavefronts, 1 of 10 with disorganized activity, and in 3 of 10 there was no coverage by the basket catheter at the corresponding 3D anatomical location. Rotors detected in 2D phase maps were not observed in the corresponding 3D phase maps. These findings may have implications for current systems that use 2D phase mapping.

Transient Rotor Activity During Prolonged3-Dimensional PhaseMapping in Human Persistent AtrialFibrillation.

This study sought to validate a 3-dimensional (3D) phase mapping system and determine the distribution of dominant propagation patterns in persistent atrial fibrillation (AF). Currently available systems display phase as simplified 2-dimensional maps. We developed a novel 3Dphase mapping system that uses the 3D location of basket catheter electrodes and the patient's 3D left atrial surfacegeometry to interpolate phase and create a 3D representation of phase progression. Six-min AF recordings from the left atrium were obtained in 14 patients using the Constellation basket catheter and analyzed offline. Exported signals underwent both phase and traditional activation analysis and were thenvisualized using a novel 3D mapping system. Analysis involved: 1) validation of phase analysis by comparing beat-to-beat AF cycle length calculated using phase inversion with that determined from activation timing in the same 20-s segment; 2) validation of 3D phase by comparing propagation patterns observed using 3D phase with 3D activationin the same 1-min segment; and 3) determining the distribution of dominant propagation patterns in 6-min recordings using 3D phase. There was strong agreement of beat-to-beat AF cycle length between activation analysis and phase inversion (R2= 0.91). There was no significant difference between 3D activation and 3D phase in mean percentage of propagation patterns classified as single wavefronts (p= 0.99), focal activations (p= 0.26), disorganized activity (p= 0.76), or multiple wavefronts (p= 0.70). During prolonged 3D phase, single wavefronts were the most common propagation pattern (50.2%). Atotal of 34 rotors were seen in 9 of 14 patients. All rotors were transient with mean duration of1.0±0.6 s. Rotors were onlyobserved in areas of high electrode density where the interelectrode distance was significantly shorter than nonrotor sites (7.4 [interquartile range: 6.3 to 14.6] vs. 15.3 mm [interquartile range: 10.1 to 22.2]; p< 0.001). During prolonged 3D phase mapping, transient rotors were observed in 64% of patients and reformed at the same anatomic location in 44% of patients. The electrode density of the basket catheter may limit the detectionofrotors.

Atrial Electrogram Fractionation Distribution before and after Pulmonary Vein Isolation in Human Persistent Atrial Fibrillation-A Retrospective Multivariate Statistical Analysis.

Purpose: Complex fractionated atrial electrograms (CFAE)-guided ablation after pulmonary vein isolation (PVI) has been used for persistent atrial fibrillation (persAF) therapy. This strategy has shown suboptimal outcomes due to, among other factors, undetected changes in the atrial tissue following PVI. In the present work, we investigate CFAE distribution before and after PVI in patients with persAF using a multivariate statistical model.Methods: 207 pairs of atrial electrograms (AEGs) were collected before and after PVI respectively, from corresponding LA regions in 18 persAF patients. Twelve attributes were measured from the AEGs, before and after PVI. Statistical models based on multivariate analysis of variance (MANOVA) and linear discriminant analysis (LDA) have been used to characterize the atrial regions and AEGs.Results: PVI significantly reduced CFAEs in the LA (70 vs. 40%; P < 0.0001). Four types of LA regions were identified, based on the AEGs characteristics: (i) fractionated before PVI that remained fractionated after PVI (31% of the collected points); (ii) fractionated that converted to normal (39%); (iii) normal prior to PVI that became fractionated (9%) and; (iv) normal that remained normal (21%). Individually, the attributes failed to distinguish these LA regions, but multivariate statistical models were effective in their discrimination (P < 0.0001).Conclusion: Our results have unveiled that there are LA regions resistant to PVI, while others are affected by it. Although, traditional methods were unable to identify these different regions, the proposed multivariate statistical model discriminated LA regions resistant to PVI from those affected by it without prior ablation information.

The temporal behavior and consistency of bipolar atrial electrograms in human persistent atrial fibrillation

The unstable temporal behavior of atrial electrical activity during persistent atrial fibrillation (persAF) might influence ablation target identification, which could explain the conflicting persAF ablation outcomes in previous studies. We sought to investigate the temporal behavior and consistency of atrial electrogram (AEG) fractionation using different segment lengths. Seven hundred ninety-seven bipolar AEGs were collected with three segment lengths (2.5, 5,and 8 s) from 18 patients undergoing persAF ablation. The AEGs with 8-s duration were divided into three 2.5-s consecutive segments. AEG fractionation classification was applied off-line to all cases following the CARTO criteria; 43% of the AEGs remained fractionated for the three consecutive AEG segments, while nearly 30% were temporally unstable. AEG classification within the consecutive segments had moderate correlation (segment 1 vs 2: Spearman’s correlation ρ = 0.74, kappa score κ = 0.62; segment 1 vs 3: ρ = 0.726, κ = 0.62; segment 2 vs 3: ρ = 0.75, κ = 0.68). AEG classifications were more similar between AEGs with 5 and 8 s (ρ = 0.96, κ = 0.87) than 2.5 versus 5 s (ρ = 0.93, κ = 0.84) and 2.5 versus 8 s (ρ = 0.90, κ = 0.78). Our results show that the CARTO criteria should be revisited and consider recording duration longer than 2.5 s for consistent ablation target identification in persAF.

Complexity and Distribution of Drivers in Relation to Duration of Persistent Atrial Fibrillation

BackgroundThe underlying mechanisms sustaining human persistent atrial fibrillation (PsAF) is poorly understood. ObjectivesThis study sought to investigate the complexity and distribution of AF drivers in PsAF of varying durations. MethodsOf 135 consecutive patients with PsAF, 105 patients referred for de novo ablation of PsAF were prospectively recruited. Patients were divided into 3 groups according to AF duration: PsAF presenting in sinus rhythm (AF induced), PsAF <12 months, and PsAF >12 months. Patients wore a 252-electrode vest for body surface mapping. Localized drivers (re-entrant or focal) were identified using phase-mapping algorithms. ResultsIn this patient cohort, the most prominent re-entrant driver regions included the pulmonary vein (PV) regions and inferoposterior left atrial wall. Focal drivers were observed in 1 or both PV regions in 75% of patients. Comparing between the 3 groups, with longer AF duration AF complexity increased, reflected by increased number of re-entrant rotations (p < 0.05), number of re-entrant rotations and focal events (p < 0.05), and number of regions harboring re-entrant (p < 0.01) and focal (p < 0.05) drivers. With increased AF duration, a higher proportion of patients had multiple extra-PV driver regions, specifically in the inferoposterior left atrium (p < 0.01), superior right atrium (p < 0.05), and inferior right atrium (p < 0.05). Procedural AF termination was achieved in 70% of patients, but decreased with longer AF duration. ConclusionsThe complexity of AF drivers increases with prolonged AF duration. Re-entrant and focal drivers are predominantly located in the PV antral and adjacent regions. However, with longer AF duration, multiple drivers are distributed at extra-PV sites. AF termination rate declines as patients progress to longstanding PsAF, underscoring the importance of early intervention.

An interactive platform to guide catheter ablation in human persistent atrial fibrillation using dominant frequency, organization and phase mapping

Background and ObjectiveOptimal targets for persistent atrial fibrillation (persAF) ablation are still debated. Atrial regions hosting high dominant frequency (HDF) are believed to participate in the initiation and maintenance of persAF and hence are potential targets for ablation, while rotor ablation has shown promising initial results. Currently, no commercially available system offers the capability to automatically identify both these phenomena. This paper describes an integrated 3D software platform combining the mapping of both frequency spectrum and phase from atrial electrograms (AEGs) to help guide persAF ablation in clinical cardiac electrophysiological studies. Methods30s of 2048 non-contact AEGs (EnSite Array, St. Jude Medical) were collected and analyzed per patient. After QRST removal, the AEGs were divided into 4s windows with a 50% overlap. Fast Fourier transform was used for DF identification. HDF areas were identified as the maximum DF to 0.25Hz below that, and their centers of gravity (CGs) were used to track their spatiotemporal movement. Spectral organization measurements were estimated. Hilbert transform was used to calculate instantaneous phase. ResultsThe system was successfully used to guide catheter ablation for 10 persAF patients. The mean processing time was 10.4 ± 1.5min, which is adequate comparing to the normal electrophysiological (EP) procedure time (120∼180min). ConclusionsA customized software platform capable of measuring different forms of spatiotemporal AEG analysis was implemented and used in clinical environment to guide persAF ablation. The modular nature of the platform will help electrophysiological studies in understanding of the underlying AF mechanisms.