Atrial Fibrillation Dominant Frequency Research Articles

Spatiotemporal stability of digital twin-guided atrial fibrillation dominant frequency sites and the clinical outcome of catheter ablation

Abstract Background Although the dominant frequency (DF) may localize the reentrant drivers of atrial fibrillation (AF), its meandering nature makes it difficult to localize as an extra-pulmonary vein (extra-PV) target. Purpose We explored and quantified the spatiotemporal stability of DF by sophisticated digital-twin maps and the association with the rhythm outcome of clinical AF catheter ablation (AFCA). Methods We retrospectively examined the DF sites in the digital twin integrated by high-density electroanatomical maps (EAM) of 170 patients previously included in the CUVIA-AF2 trial (male 70.6%, 59.2±11.3 years old, 100% persistent AF). We monitored 34 seconds of virtual AF and analyzed DF sites in 10 different left atrial (LA) regions at 3 consecutive periods (6 seconds each after 16sec induction and blanking periods). The spatiotemporal stability index (STSI) was calculated to quantify mean DF's spatial and temporal variability. During protocol-based rhythm follow-up, we assessed the atrial arrhythmia recurrence rate by dividing patients into two groups based on STSI 0.75. Results During the simulation, 108 out of 170 (63.5%) patients obtained mean DF values in all three consecutive periods. There were 26 (24.1%) patients in the stable DF group (STSI ≥0.75, Stable group) and 82 (75.9%) patients in the unstable DF group (STSI <0.75, Unstable group). Although the proportion of patients with hypertension (73.1 vs. 47.6%, p=0.041) was higher and left ventricular end-diastole diameter (51.3±3.9 vs. 49.0±4.4 mm, p=0.020) was larger in the stable DF group than in the unstable DF group, other parameters, including LA size, LA voltage, or AF ablation targets, did not differ between two groups. During the median 19 [15-22] months follow-up, the atrial arrhythmia recurrence rate of the Stable group is higher than that of the Unstable group (log-rank p=0.031, HR = 2.06, CI [1.06-4.01]) Conclusions We found that the temporally stable DF in EAM-integrated virtual AF, the potential extra-PV AF drivers, is a surrogate marker of the adverse rhythm outcome of AFCA. A prospective clinical trial targeting the spatiotemporally stable DF will be warranted.

Abstract 17861: Separating Patients With Long-Term Success versus Acute Response From Atrial Fibrillation Ablation Using Explainable Machine Learning

Introduction: It is difficult to predict outcomes from atrial fibrillation (AF) ablation. In particular, it is unclear what physiology explains patients with long-term AF elimination yet no acute response, or vice versa. Hypothesis: We hypothesize that different combinations of electrophysiological and clinical features predict long-term outcome or acute response to AF ablation. We tested this hypothesis using machine learning of a large Registry. Methods: We studied N=561 patients at pulmonary vein isolation (65±10 years, 28% female) with rich clinical data (44 elements, ECGs), and 64 pole global electrograms (EGMs). We propensity matched the dataset 70/30 for training/testing (fig A). We extracted (i) 4 EGM features: dominant frequency (DF), similarity over time, rate (CL), and voltage; (ii) 6 ECG features; (iii) 44 clinical features. We compared 6 ML models including logistic regression to predict 1 year and acute outcomes in the test set, then used explainability (e.g. Shapley scores) to explain the top models and contributing features for each outcome. Results: Of 561 patients, N=390 (69.5%) had 1 year success and N=278 (49.6%) had AF termination by ablation. The best ML model predicted acute response (Random Forest), provided AUROC = 0.83 (fig B) with highest predictors of AF type, RR interval, CL, DF, and voltage. Conversely, the best model for long-term success provided AUC of 0.65 (accuracy of LT vs acute: p<0.001 McNemar test), but top features were PR interval, QRS axis, AF duration, and age (shapley Rsq = 0.11, fig C). Predictors for long term outcome poorly predicted acute outcome and vice versa (fig C). Conclusions: Clinical features for long-term and acute response to AF ablation were quite different, applying several classification methods to a well-characterized registry. Confirmation in other registries may reveal novel phenotypes to guide clinical decision making or procedural planning, and shed mechanistic insights.

Impact of Interatrial Epicardial Connections on the Dominant Frequency of Atrial Fibrillation.

An epicardial connection (EC) between the right-sided pulmonary venous (RtPV) carina and right atrium (RA) may preclude PV isolation, but its electrophysiological role during atrial fibrillation (AF) remains unknown.Methods and Results: This prospective observational study included 98 consecutive patients undergoing catheter ablation for AF, subdivided into the EC group (n=17) and non-EC group (n=80) based on observation of RA posterior wall breakthrough during RtPV pacing. Mean left atrial (LA) dominant frequency (mean DFLA) was defined as the averaged DFs at the right and left PVs and LA appendage. The regional DF was higher in the EC group vs. the non-EC group except at the left PV antrum. The DF at the RA appendage (RAA) and mean DFLAwere equivocal (6.5±0.7 vs. 6.6±0.7 Hz) in the EC group, but the mean DFLAwas significantly higher than that at the RAA (5.8±0.6 vs. 6.1±0.5 Hz, P=0.001) in the non-EC group, suggesting an LA-to-RA DF gradient. A significant correlation of DF between the RtPV antrum and RAA was observed in the EC group (P<0.001, r=0.84) but not in the non-EC group. An electrophysiological link via interatrial ECs might attenuate the hierarchical nature of activation frequencies of AF, leading to advanced electrical remodeling of the atria.

Fibrillatory Wave Amplitude Evolution during Persistent Atrial Fibrillation Ablation: Implications for Atrial Substrate and Fibrillation Complexity Assessment.

Background. Fibrillatory Wave Amplitude (FWA) has been described as a non-invasive marker of atrial fibrillation (AF) complexity, and it predicts catheter ablation outcome. However, the actual determinants of FWA remain incompletely understood. Objective. To assess the respective implications of anatomical atrial substrate and AF spectral characteristics for FWA. Methods. Persistent AF patients undergoing radiofrequency catheter ablation were included. FWA was measured on 1-min ECG by TQ concatenation in Lead I, V1, V2, and V5 at baseline and immediately before AF termination. FWA evolution during ablation was compared to that of AF dominant frequency (DF) measured by Independent Component Analysis on 12-lead ECG. FWA was compared to the extent of endocardial low-voltage areas (LVA I < 10%; II 10–20%; III 20–30%; IV > 30%), to the surface of healthy left atrial tissue, and to P-wave amplitude in sinus rhythm. The predictive value of FWA for AF recurrence during follow-up was assessed. Results. We included 29 patients. FWA remained stable along ablation procedure with comparable values at baseline and before AF termination (Lead I p = 0.54; V1 p = 0.858; V2 p = 0.215; V5 p = 0.14), whereas DF significantly decreased (5.67 ± 0.68 vs. 4.95 ± 0.58 Hz, p < 0.001). FWA was higher in LVA-I than in LVA-II, -III, and -IV in Lead I and V5 (p = 0.02 and p = 0.01). FWA in V5 was strongly correlated with the surface of healthy left atrial tissue (R = 0.786; p < 0.001). FWA showed moderate to strong correlation to P-wave amplitude in all leads. Finally, FWA did not predict AF recurrence after a follow-up of 23.3 ± 9.8 months. Conclusions. These findings suggest that FWA is unrelated to AF complexity but is mainly determined by the amount of viable atrial myocytes. Therefore, FWA should only be referred as a marker of atrial tissue pathology.

Higher F-wave frequency associates with poor procedural success rate after Maze procedure.

Persistent atrial fibrillation (AF) causes atrial remodeling, which causes myocardial fibrosis and micro-reentry. Fibrosis may reduce wave voltage and micro-reentry may enhance the dominant frequency (DF) of the F-wave. We investigated whether the DF predicts procedural success by the Maze procedure. In 138 consecutive patients who underwent mitral valve surgery and a modified Cox-Maze III procedure for persistent AF in Nagoya University in 2002-2018, 96 (70%) were successfully cardioverted (group S); 42 had persistent or relapsed AF after surgery (group F). Patient data were compared between the groups. Cut-off values were determined by an ROC analysis and predictors of procedural success were evaluated. The DF was obtained from the F-wave of V1 by a high-speed Fourier analysis using the CEPAS software program. Group F showed a significantly larger LA diameter, better LVEF, lower F-wave voltage, higher DF, and longer duration of AF. The cut-off values were as follows: LA diameter, 56mm; EF, 64.5%; F-wave voltage, 0.13mV; DF, 7.3Hz; and duration of AF, 44months. Each factor showed statistical significance in a univariate analysis; DF lost significance in the multivariate analysis. The higher (DF ≥ 7.3Hz) and lower voltage group (≤ 0.13mV) showed the worst procedural success rate (36%), while the lower DF (< 7.3Hz) and higher voltage group (> 0.13mV) showed a good rate (86%). The DF of the F-wave is a useful predictor of procedural success after the Maze procedure in addition to the voltage of F-wave.

The selective late sodium current inhibitor eleclazine reduces atrial fibrillation dominant frequency and facilitates the suppression of arrhythmia in HL-1 cells

Abstract Background The cardiac late sodium current (INaL) has been increasingly implicated in the initiation of atrial fibrillation (AF). In fact, it has been reported that the augmentation of INaL in pathophysiological conditions prolongs repolarization and facilitates the appearance of afterdepolarizations, which can act as triggers of arrhythmic activity. Eleclazine is a novel selective inhibitor of INaL and is undergoing clinical testing for the treatment of cardiac arrhythmias. Purpose The aim of this study was to investigate the effects of eleclazine on spectral characteristics of atrial fibrillation in cultured atrial myocyte monolayer in order to assess whether this inhibitor could protect against cardiac arrhythmias. Methods Confluent HL-1 murine atrial myocyte monolayer with spontaneous fibrillatory activity was cultured in 1.5 cm diameter petri dishes (n=10). A high-resolution optical mapping system was used to record fibrillatory activity under basal conditions (without drug), and under eleclazine at increasing concentrations (1, 3 and 5 μM). Power spectra of optical signals were estimated by using Welch periodogram and dominant frequency (frequency with the largest peak in the spectrum between 0.05 and 30 Hz) was determined. The incidence of spontaneous defibrillation was analyzed under control and drug conditions. An ANOVA and a chi-squared test were used. Significance was reached when p&amp;lt;0.05. Results Eleclazine at 1, 3 and 5 μM significantly decreased dominant frequency with respect to basal conditions (basal: 4.74±1.31 Hz; 1μM: 3.59±1.17 Hz, p&amp;lt;0.001; 3μM: 3.19±0.64 Hz, p&amp;lt;0.01; 5μM: 2.58±0.40 Hz, p&amp;lt;0.01). The magnitude of drug-induced decrease in AF activation frequency was enhanced by increasing concentrations (1μM: 27%, 3μM: 42%; 5μM: 46%; p&amp;lt;0.05). After the analysis of optical signals, we observed that the incidence of spontaneous defibrillation in atrial monolayers was significantly greater under eleclazine 5μM action than under control conditions (chi-square=5.00, p=0.025). In fact, under the action of eleclazine 5μM, fibrillatory activity was suppressed in 4 of the 10 monolayers, phenomenon that did not occur in any case of control situation. Conclusions Selective late INa inhibition with eleclazine reduced dominant frequency of atrial fibrillation and facilitates the termination of arrhythmia in cultured atrial myocyte monolayer. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Ministerio de Innovaciόn y Ciencia, Spain; Generalitat Valenciana, Spain

Pulmonary Delivery of Metoprolol Reduces Ventricular Rate During Atrial Fibrillation and Accelerates Conversion to Sinus Rhythm.

Safe, effective pulmonary delivery of cardioactive agents in humans is under development. We examined whether intratracheal delivery of metoprolol can reduce ventricular rate during atrial fibrillation (AF) and accelerate conversion to sinus rhythm. In 7 closed-chest, anesthetized Yorkshire pigs, AF was induced by intrapericardial infusion of acetylcholine (1 mL of 102.5-mM solution) followed by atrial burst pacing and was allowed to continue for 2 minutes before intratracheal instillation of sterile water or metoprolol (0.2-mg/kg bolus) using a catheter positioned at the bifurcation of the main bronchi. High-resolution electrograms were obtained from catheters fluoroscopically positioned in the right atrium and left ventricle. Rapid intratracheal instillation of metoprolol caused a 32-beat/min reduction in ventricular rate during AF (from 272 ± 13.7 to 240 ± 12.6 beats/min, P = 0.008) and a 2.3-minute reduction in AF duration (from 10.3 ± 2.0 to 8.0 ± 1.4 minutes, P = 0.018) compared with sterile water control. Conversion of AF to sinus rhythm was associated with rapid restoration (5-6 minutes) of heart rate and arterial blood pressure toward control values. Intratracheal metoprolol reduced AF dominant frequency by 31% (from 8.7 ± 0.9 to 6.0 ± 1.1 Hz, P = 0.04) compared with control and resulted in a trend toward a 5% increase in PR interval (from 174 ± 11.2 to 182 ± 11.4 ms, P = 0.07). Intratracheal delivery of metoprolol effectively reduces ventricular rate during AF and accelerates conversion to normal sinus rhythm in a pig model of acetylcholine-induced AF.

Role of atrial wall thickness in wave-dynamics of atrial fibrillation.

Background/AimsAtrial anatomy and thickness may affect the electrical wave-dynamics of atrial fibrillation (AF). We explored the relationship between left atrial (LA) wall thickness (LAWT) or LA geometry and AF wave-dynamics.MethodsWe included 15 patients with persistent AF (age, 62.3 ± 11.9 years) who underwent AF catheter ablation. We measured the LAWT, LA endocardial curvature, and SD-curvature (surface bumpiness) from preprocedural computed tomography images. We compared those anatomical characteristics with electrophysiologic parameters such as dominant frequency (DF), Shannon entropy (ShEn), or complex fractionated atrial electrogram (CFAE)-cycle length (CL), calculated from intracardiac bipolar electrograms (300–500 points, 5 s), acquired during ablation procedures.Results1. LAWT (excluding fat) varied widely among patients, locations, and types of AF. LAWT was inversely correlated with LA volume (r = -0.565, p = 0.028) and positively correlated with SD-curvature (r = 0.272, p < 0.001). 2. LAWT was positively correlated with ShEn (r = 0.233, p < 0.001) and negatively correlated with CFAE-CL (r = -0.107, p = 0.038). 3. In the multivariate linear regression analyses for AF wave-dynamics parameters, DF (β = -0.29 [95% CI -0.44–-0.14], p < 0.001), ShEn (β = 0.19 [95% CI 0.12–0.25], p < 0.001), and CFAE-CL (β = 7.49 [95% CI 0.65–14.34], p = 0.032) were independently associated with LAWT.ConclusionRegional LAWT is associated with LA structural features, and has significant correlations with the wave-dynamics parameters associated with electrical wavebreaks or rotors in patients with persistent AF.

Spectral and spatiotemporal variability ECG parameters linked to catheter ablation outcome in persistent atrial fibrillation

With the increasing prevalence of atrial fibrillation (AF), there is a strong clinical interest in determining whether a patient suffering from persistent AF will benefit from catheter ablation (CA) therapy at long term. This work presents several regression models based on noninvasive measures automatically computed from the standard 12-lead electrocardiogram (ECG) such as AF dominant frequency (DF), spectral concentration and spatiotemporal variability (STV). Sixty-two AF patients referred to CA were enrolled in this study. Forty-seven of them had no recurrence after CA during an average follow-up of 14 ± 8 months. The ECG features were extracted from an ECG recorded before the CA intervention and they were combined by means of logistic regression. The combination of DF and STV values from different precordial leads reached AUC = 0.939, outperforming the best results by using only one kind of features, such as DF (AUC = 0.801), and yielding a global accuracy of 93.5% for discriminating the best long-term responders to CA. These results point out the need to take into consideration the spatial variation of spectral ECG parameters to build predictive models dealing with AF.

Complex fractionated atrial electrograms, high dominant frequency regions, and left atrial voltages during sinus rhythm and atrial fibrillation

BackgroundAblation targeting complex fractionated atrial electrograms (CFAEs) or high dominant frequency (DF) sites is generally effective for persistent atrial fibrillation (AF). CFAEs and/or high DF sites may exist in low-voltage regions, which theoretically represent abnormal substrates. However, whether CFAEs or high DF sites reflect low voltage substrates during sinus rhythm (SR) is unknown. MethodsSixteen patients with AF (8 with paroxysmal AF; 8, persistent AF) underwent high-density mapping of the left atrium (LA) with a 3-dimensional electroanatomic mapping system before ablation. The LA was divided into 7 segments and the mean bipolar voltage recorded during AF and SR, CFAEs (cycle lengths of 50–120ms), and DF sites were assessed in each segment with either a duo-decapolar ring catheter (n=10) or a 64-pole basket catheter (n=6). Low-voltage areas were defined as those of <0.5mV during AF and <1.0mV during SR. ResultsRegional mean voltage recorded from the basket catheter showed good correlation between AF and SR (r=0.60, p<0.01); however, the % low-voltage area in the LA recorded from the ring catheter showed weak correlation (r=0.34, p=0.05). Mean voltage was lower during AF than during SR (1.0mV [IQR, 0.5–1.4] vs. 2.6mV [IQR, 1.8–3.6], p<0.01). The regional and overall % low-voltage area of the LA was greater during AF than during SR (20% vs. 11%, p=0.05). CFAEs and high DF sites (>8Hz) did not correlate with % low-voltage sites during SR; however, CFAEs sites were located in high-voltage regions during AF and high DF sites were located in low voltage regions during AF. ConclusionsCFAEs and high DF areas during AF do not reflect damaged atrial myocardium as shown by the SR voltage. However, CFAEs and high DF sites may demonstrate different electrophysiologic properties because of different voltage amplitude during AF.

Ranolazine reduces atrial fibrillatory wave frequency.

Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF. Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04). Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazine's potential as a novel antiarrhythmic drug for AF.

Ability of magnetocardiography to detect regional dominant frequencies of atrial fibrillation

BackgroundLead V1 on electrocardiography (ECG) can detect the dominant frequency (DF) of atrial fibrillation (AF) in the right atrium (RA). Paroxysmal AF is characterized by a frequency gradient from the left atrium (LA) to the right atrium (RA). We examined the ability of magnetocardiography (MCG) to detect regional DFs in both the atria. MethodsStudy subjects comprised 18 consecutive patients referred for catheter ablation of persistent AF. An MCG system with 64 magnetic sensors was used to perform MCG in the frontal, lateral, and back planes prior to the ablation procedure in each patient. DFMCG and organization index (OIMCG) were calculated using fast Fourier transformation. Intracardiac electrograms (ICEs) in both the atria and the coronary sinus (CS) were mapped at 17 sites. Regional DFsICE were also determined. ResultsMean LA DFICE was higher than mean RA DFICE (6.40±0.66 versus 6.16±0.80Hz, P=0.03). DFMCG in the channel having the highest OIMCG was 6.61±0.88Hz in the frontal plane, 6.52±0.64Hz in the lateral plane, and 6.42±0.62Hz in the back plane (P=0.3). In each plane, DFMCG correlated with DFICE at the RA appendage (R=0.95, P<0.0001), the LA appendage (R=0.91, P<0.0001), and the CS (R=0.93, P<0.0001). DFECG in V5 modestly correlated with DFICE at the LA appendage (R=0.82, P<0.0001). ConclusionsMCG could more precisely detect the DFs in the LA and the CS than ECG. However, the usefulness of pre-procedural detection of the AF frequency gradient for ablation therapy needs to be evaluated in future prospective studies.

Atrial electrogram discordance during baseline vs reinduced atrial fibrillation: Potential ramifications for ablation procedures.

There are scant data comparing the electrogram (EGM) signal characteristics of atrial fibrillation (AF) at baseline vs electrically induced states during ablation procedures. The purpose of this study was to use novel intracardiac signal analysis techniques to gain insights into the effects of catheter ablation and AF reinduction on AF EGMs in patients with persistent AF. We collected left atrial EGMs in patients undergoing first ablation for persistent AF at 3 time intervals: (1) AF at baseline; (2) AF after pulmonary vein isolation (PVI); and (3) AF after post-PVI cardioversion and subsequent reinduction. We analyzed 2 EGM spectral characteristics: (1) dominant frequency and (2) spectral complexity; and 2 EGM morphologic characteristics: (1) morphology variation and (2) pattern repetitiveness. There were no differences in AF dominant frequency, dominant amplitude, spectral complexity, or metrics of EGM morphology or repetitiveness at baseline vs after PVI. However, dominant frequency, dominant amplitude, and spectral complexity differed significantly after direct current cardioversion and reinduction of AF. The frequency, spectral complexity, and local EGM morphologies of AF do not significantly change over the course of a PVI procedure in patients with persistent AF. However, reinduction of AF after direct current cardioversion results in different dominant frequency and spectral complexity, consistent with a change in the characteristics of the perpetuating source(s) of the newly induced AF. These data suggest that AF properties can vary significantly between baseline and reinduced AF, with potential clinical ramifications for outcomes of catheter ablation procedures.

Combined actions of ivabradine and ranolazine reduce ventricular rate during atrial fibrillation.

Ventricular rate during atrial fibrillation (AF) can be reduced by slowing atrioventricular (AV) node conduction and/or by decreasing dominant frequency of AF. We investigated whether combined administration of ivabradine and ranolazine reduces ventricular rate during AF. Ivabradine (maximum clinical dose, 0.25 mg/kg, and 0.10 mg/kg, i.v.) and ranolazine (2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min) were studied in an anesthetized pig (N = 16) model of AF. Combined administration of 0.25 mg/kg ivabradine with ranolazine reduced ventricular rate during AF by 51.9 ± 9.7 beats/min (23%, P = 0.017) and dominant frequency of AF by 2.8 ± 0.5 Hz (32%, P = 0.005). It increased PR (P = 0.0002, P = 0.0007) and A-H intervals (P = 0.047, P = 0.002) during pacing at 130 and 180 beats/min, respectively, to a greater degree than additive effects of single agents. Combined administration of 0.1 mg/kg ivabradine with ranolazine exceeded additive effects of single agents on A-H intervals and dominant frequency of AF. Moreover, ranolazine potentiated low-dose ivabradine's reduction in ventricular rate, as combined administration more than doubled effects of the higher ivabradine dose alone and was similar to the combination with the higher dose. Neither drug nor their combination affected contractility (left ventricular [LV] dP/dt), QT or His-ventricular (H-V) intervals, or mean arterial pressure during sinus rhythm or AF. Combined administration of ivabradine and ranolazine at clinically safe levels decreases ventricular rate during AF by reducing AV node conduction and AF dominant frequency without QT prolongation or depression in contractility. Targeting these actions offers intrinsic advantages over conventional nodal agents, which can reduce contractility.

STRUCTURAL AND MOLECULAR BASES FOR THE CONSTITUTIVE ACTIVITY OF IKACH IN CHRONIC ATRIAL FIBRILLATION

Background: A hallmark of remodeling in chronic atrial fibrillation (AF) is action potential duration (APD) shortening. It has been suggested that in chronic AF: (1) the acetylcholine-sensitive inward rectifier potassium current is constitutively active (ca-IKACh); (2) ca-IKACh is due to interaction between Kir3.1 (a molecular correlate of IKACh) and protein kinase C epsilon (PKCe); and (3) oxidative stress (OS) is increased. However, the structural and molecular bases of ca-IKACh and its possible role in APD shortening and AF maintenance remain poorly understood. We hypothesized that OS phosphorylates Kir3.1 at residue S185 via PKCe, leading to ca-IKACh and contributing to APD shortening and AF perpetuation. Methods and Results: We tested our hypothesis using molecular, electrophysiologic, and numerical approaches. We induced OS with 100 μM H2O2 for 1 hour. In HEK cells transfected with Kir3.1/4, OS increased reactive oxygen species as assayed by dihydroethidium fluorescence. In addition, PKCe translocated to the membrane, Kir3.1 showed phosphorylation at S185, and IKACh increased from –16.1 5.1 pA/pF (n 1⁄4 3) to –34.2 3.8 pA/pF (n 1⁄4 6, Po.01). PKCe silencing prevented OS-induced phosphorylation of Kir3.1 and IKACh increase. In mouse atrial myocytes, OS shortened APD90 from 98 13 ms (n 1⁄4 6) to 37.9 5.3 ms (n 1⁄4 13, Po.01). Tertiapin Q, a selective IKACh blocker, significantly prolonged APD90 in stressed but not unstressed myocytes. In sheep atria with tachypacing-induced chronic AF, phospho-Kir3.1 increased 2.45-fold in chronic AF (n 1⁄4 4) vs sham (n 1⁄4 4, Po.05). Optical maps showed that tertiapin Q progressively reduced chronic AF dominant frequency until sinus rhythm resumed. Molecular dynamics simulations using the chimeric Kir3.1 crystal structure suggested that the region containing S185 was a switch that initiated conformational changes resulting in channel opening upon phosphorylation. Finally, purified chimeric Kir3.1 was phosphorylated in vitro by recombinant activated PKCe. Conclusions: Arrhythmogenic ca-IKACh is due in part to OS-mediated PKCe activation and Kir3.1 phosphorylation at residue S185. These results shed new light on the complex ionic mechanisms of AF and may help in the development of new anti-AF agents.

Inhibition of If in the atrioventricular node as a mechanism for dronedarone’s reduction in ventricular rate during atrial fibrillation

In clinical trials, dronedarone lowers ventricular rate during atrial fibrillation (AF). This agent was recently demonstrated to inhibit If in the sinoatrial node. The purpose of this study was to examine whether dronedarone inhibits If at the atrioventricular (AV) node to reduce ventricular rate during AF by slowing conduction at the AV node. We studied the effects of dronedarone (1.0 mg/kg IV bolus) before and after administration of the If inhibitor ivabradine (0.5 mg/kg IV). Ventricular rate, mean arterial pressure, dominant frequency of AF, PR and QT intervals, and atrial (AERP) and ventricular effective refractory periods (VERP) were measured during atrial pacing at 150 bpm in an anesthetized pig model of AF induced by intrapericardial acetylcholine and burst pacing. Dronedarone reduced ventricular rate during AF by 22.1% (from 213 ± 11.1 bpm to 166 ± 8.3 bpm, P = .01) and increased PR interval by 8.7% (from 173 ± 5.6 ms to 188 ± 5.2 ms, P = .001), QT interval by 3.3% (from 272 ± 6.2 ms to 281 ± 4.9 ms, P = .05), and AERP and VERP by 6.2% and 11.7%, respectively. All other parameters remained unchanged. Dronedarone plasma levels were low (29 ± 4 nM), and concentration in tissue was 15- to 21-fold higher than in plasma. Ivabradine reduced ventricular rate during AF by 39.5% (from 200 ± 14.6 bpm to 121 ± 20.1 bpm, P = .005) and increased PR interval by 20.4% (from 157 ± 9.5 ms to 189 ± 7.4 ms, P <.05). Administration of dronedarone after ivabradine did not further alter these endpoints. Dronedarone, which is concentrated in myocardial tissue, reduces ventricular rate during AF by slowing AV conduction. Absence of this effect after ivabradine administration implicates If inhibition as a mechanism.

An Echo State Neural Network for QRST Cancellation During Atrial Fibrillation

A novel method for QRST cancellation during atrial fibrillation (AF) is introduced for use in recordings with two or more leads. The method is based on an echo state neural network which estimates the time-varying, nonlinear transfer function between two leads, one lead with atrial activity and another lead without, for the purpose of canceling ventricular activity. The network has different sets of weights that define the input, hidden, and output layers, of which only the output set is adapted for every new sample to be processed. The performance is evaluated on ECG signals, with simulated f-waves added, by determining the root mean square error between the true f-wave signal and the estimated signal, as well as by evaluating the dominant AF frequency. When compared to average beat subtraction (ABS), being the most widely used method for QRST cancellation, the performance is found to be significantly better with an error reduction factor of 0.24-0.43, depending on f-wave amplitude. The estimates of dominant AF frequency are considerably more accurate for all f-wave amplitudes than the AF estimates based on ABS. The novel method is particularly well suited for implementation in mobile health systems where monitoring of AF during extended time periods is of interest.

Left atrial volume and dominant frequency of atrial fibrillation in patients undergoing catheter ablation of persistent atrial fibrillation

Prior studies have suggested that left atrial (LA) volume and frequency of atrial fibrillation (AF) are associated with suboptimal outcomes in patients undergoing catheter ablation of AF. However, the interaction of these factors and their relative impact on outcome are not clear. Seventy-nine consecutive patients underwent catheter ablation of persistent AF. LA volume was determined by echocardiography. Electrograms from the LA appendage (LAA), coronary sinus (CS), and lead V(1) were obtained before ablation, and the dominant frequency (DF) was determined by fast Fourier transformation. The ablation strategy consisted of pulmonary vein isolation, electrogram-guided, and linear ablation. The mean LA volume indexed, LA voltage, and DF in the LAA were 48 ± 16 mL/m(2), 0.58 ± 0.20 mV, and 6.3 ± 0.8 Hz, respectively. There was a significant inverse correlation between LA volume and DF in the CS (P < 0.0001, R = -0.51). The mean LA amplitude also correlated with DF in the LAA (P = 0.0008, R = 0.37). In 38 patients (48%), AF terminated during catheter ablation. Sixty-six of the 79 patients (84%) are arrhythmia-free without antiarrhythmic drugs at a mean follow-up of 14 ± 7 months after the last procedure. Advancing age was associated with recurrence (odds ratio (OR), 1.2; 95% confidence interval (CI), 1.02 to 1.42; P = 0.02), and duration of radiofrequency energy delivery was associated with a favorable outcome (OR, 0.93; 95% CI, 0.86 to 0.99; P = 0.04). Atrial enlargement is associated with a lower AF frequency. Age and RF duration seem to be better predictors of outcome than LA volume or AF frequency.

Autonomic Remodeling in the Left Atrium and Pulmonary Veins in Heart Failure

Background— Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF. Methods and Results— Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular–paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, β-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and β-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in β 1 -adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. β-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration. Conclusions— In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.

Left atrial pressure and dominant frequency of atrial fibrillation in humans

Atrial stretch is thought to play a role in the development of atrial fibrillation (AF). However, the precise mechanism by which stretch contributes to AF maintenance in humans is unknown. The purpose of this study was to determine the impact of left atrial (LA) pressure on AF frequency in patients undergoing catheter ablation of AF. The subjects of this study were 58 consecutive patients with persistent AF (n = 40) or paroxysmal AF (n = 18) undergoing LA ablation. LA pressure was measured before ablation. Both atria and the coronary sinus were mapped, and regional dominant frequency (DF) was determined. Mean LA pressure in the persistent AF group was significantly higher than in the paroxysmal AF group (18 ± 5 vs 10 ± 4 mmHg, P <.0001). Mean DF in the persistent AF group was also higher than in the paroxysmal AF group (6.36 ± 0.51 Hz and 5.83 ± 0.54 Hz, P = .0006). In patients with persistent AF, there was a significant correlation between LA pressure and DF at the LA appendage (r = 0.55, P = .0002). DF(max) was found at the LA appendage region in 24 (60%) of the 40 patients with persistent AF (P = .0006). In multivariate analysis, LA pressure was the only independent predictor of DF(max) in the LA appendage (P = .04, odds ratio 1.41, 95% confidence interval 1.02-1.94). Higher LA pressure in patients with persistent AF implies that these patients are more vulnerable to stretch-related remodeling than are patients with paroxysmal AF. The DF of AF was directly related to LA pressure in patients with persistent AF. This finding suggests that atrial stretch may contribute to the maintenance of AF in humans by stabilizing high-frequency sources.