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Background: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. We hypothesize that patients with symptomatic AF but without overt clinical HF commonly exhibit subclinical HFpEF according to established hemodynamic criteria., Objectives: The authors sought to use invasive hemodynamics to investigate the prevalence and implications of subclinical HFpEF in AF ablation patients., Methods: Consecutive symptomatic AF ablation patients were prospectively recruited. Diagnosis of subclinical HFpEF was undertaken by invasive assessment of left atrial pressure (LAP). Participants had HFpEF if the baseline mean LAP was >15 mm Hg and early HFpEF if the mean LAP was >15 mm Hg after a 500-mL fluid challenge. LA compliance was assessed invasively by monitoring the LAP and LA diameter during direct LA infusion of 15 mL/kg normal saline. LA compliance was calculated as Δ LA diameter/ΔLAP. LA cardiomyopathy was further studied with exercise echocardiography and electrophysiology study. Functional impact was evaluated using cardiopulmonary exercise testing and the AF Symptom Severity questionnaire., Results: Of 120 participants, 57 (47.5%) had HFpEF, 31 (25.8%) had early HFpEF, and 32 (26.7%) had no HFpEF. Both HFpEF and early HFpEF were associated with lower LA compliance compared with those without HFpEF (P < 0.001). Participants with HFpEF and early HFpEF also displayed decreased LA emptying fraction (P = 0.004), decreased LA voltage (P = 0.001), decreased VO 2peak (P < 0.001), and increased AF symptom burden (P = 0.002) compared with those without HFpEF., Conclusions: Subclinical HFpEF is common in AF ablation patients and is characterized by a LA cardiomyopathy, decreased cardiopulmonary reserve and increased symptom burden. The diagnosis of HFpEF may identify patients with AF with the potential to benefit from novel HFpEF therapies. (Characterising Left Atrial Function and Compliance in Atrial Fibrillation; ACTRN12620000639921)., Competing Interests: Funding Support and Author Disclosures Drs Ariyaratnam, Mishima, Kadhim, Emami, Malik, and Fitzgerald are supported by Postgraduate Scholarships from the University of Adelaide. Dr Elliott is supported by a Future Leader Fellowship from the National Heart Foundation of Australia. Dr Gallagher is supported by a Postdoctoral Fellowship from the University of Adelaide. Dr Lau is supported by a Mid-career fellowship from The Hospital Research Foundation. Dr Sanders is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia. Dr Lau reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Biotronik, BMS Pfizer, Boehringer Ingelheim, Medtronic, and MicroPort CRM. Dr Sanders has served on the advisory board of Medtronic, Abbott Medical, Boston-Scientific, Pacemate, and CathRx. Dr Sanders reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Boston-Scientific, and Abbott Medical; and reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific, and Microport CRM. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background Adenosine shortens action potential duration and refractoriness and provokes atrial fibrillation. This study aimed to evaluate the effect of adenosine on mechanisms of wavefront propagation during atrial fibrillation. Methods and Results The study included 22 patients undergoing catheter ablation for persistent atrial fibrillation. Left atrial mapping was performed using the AcQMap charge density system before and after administration of intravenous adenosine at 1 or more of 3 time points during the procedure (before pulmonary vein isolation, after pulmonary vein isolation, and after nonpulmonary vein isolation ablation). Wave-front propagation patterns were evaluated allowing identification and quantification of localized rotational activation (LRA), localized irregular activation, and focal firing. Additional signal processing was performed to identify phase singularities and calculate global atrial fibrillation cycle length and dominant frequency. A total of 35 paired maps were analyzed. Adenosine shortened mean atrial fibrillation cycle length from 181.7±14.3 to 165.1±16.3, (mean difference 16.6 ms; 95% CI, 11.3-21.9, P <0.0005) and increased dominant frequency from 6.0±0.7 Hz to 6.6±0.8 Hz (95% CI, 0.4-0.9, P <0.0005). This was associated with a 50% increase in the number of LRA occurrences (16.1±7.6-24.2±8.1; mean difference 8.1, 95% CI, 4.1-12, P <0.0005) as well as a 20% increase in the number of phase singularities detected (30.1±7.8-36.6±9.3; mean difference 6.5; 95% CI, 2.6-10.0, P =0.002). The percentage of left atrial surface area with LRA increased with adenosine and 42 of 70 zones (60%) with highest density of LRA coincided with high density LRA zones at baseline with only 28% stable across multiple maps. Conclusions Adenosine accelerates atrial fibrillation and promotes rotational activation patterns with no impact on focal activation. There is little evidence that rotational activation seen with adenosine represents promising targets for ablation aimed at sites of stable arrhythmogenic sources in the left atrium.

Background: Charge density mapping of atrial fibrillation (AF) reveals dynamic localized rotational activation (LRA), irregular activation (LIA) and focal firing (FF). Their spatial stability, conduction characteristics and the optimal duration of mapping required to reveal these phenomena and has not been explored., Methods: Bi-atrial mapping of AF propagation was undertaken using AcQMap (Acutus Medical) and variability of activation patterns quantified up to a duration of 30 s. The frequency of each pattern was quantified at each unique point of the chamber over two separate 30-s recordings before ablation and R 2 calculated to quantify spatial stability. Regions with the highest frequency were identified at increasing time durations and compared to the result over 30 s using Cohen's kappa. Properties of regions with the most stable patterns were assessed during sinus rhythm and extrastimulus pacing., Results: In 21 patients, 62 paired LA and RA maps were obtained. LIA was highly spatially stable with R 2 between maps of 0.83 (0.71-0.88) compared to 0.39 (0.24-0.57), and 0.64 (0.54-0.73) for LRA and FF, respectively. LIA was most temporally stable with a kappa of >0.8 reached by 12 s. LRA showed greatest variability with kappa >0.8 only after 22 s. Regions of LIA were of normal voltage amplitude (1.09 mv) but showed increased conduction heterogeneity during extrastimulus pacing (p = .0480)., Conclusion: Irregular activation patterns characterized by changing wavefront direction are temporally and spatially stable in contrast with LRA that is transient with least spatial stability. Focal activation appears of intermediate stability. Regions of LIA show increased heterogeneity following extrastimulus pacing and may represent fixed anatomical substrate., (© 2021 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Aims: Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF., Methods and Results: Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed., Conclusions: Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age ( n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.

Background: 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., Methods: 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 (λ f /λ d ) determined. A systematic review was conducted to cross-validate with source data from literature., Results: In all systems, PS lifetime and interformation times were consistent with underlying Poisson renewal processes (human: λ f , 4.2%/ms±1.1 [95% CI, 4.0-5.0], λ d , 4.6%/ms±1.5 [95% CI, 4.3-4.9]; sheep: λ f , 4.4%/ms [95% CI, 4.1-4.7], λ d , 4.6%/ms±1.4 [95% CI, 4.3-4.8]; rat atrial fibrillation: λ f , 33%/ms±8.8 [95% CI, 11-55], λ d , 38%/ms [95% CI, 22-55]; rat ventricular fibrillation: λ f , 38%/ms±24 [95% CI, 22-55], λ f , 46%/ms±21 [95% CI, 31-60]; simulated fibrillation λ d , 6.6-8.97%/ms [95% CI, 4.1-6.7]; R 2 ≥0.90 in all cases). All PS distributions identified through systematic review were also consistent with an underlying Poisson renewal process., Conclusions: Poisson renewal theory provides an evolutionarily preserved universal framework to quantify formation and destruction of rotational events in cardiac fibrillation.

Atrial fibrillation (AF), the most common sustained heart rhythm disorder worldwide, is linked to dysfunction of the intrinsic cardiac autonomic nervous system (ICNS). The role of ICNS damage occurring during catheter-based treatment of AF, which is the therapy of choice for many patients, remains controversial. We show here that the neuronal injury marker S100B is expressed in cardiac glia throughout the ICNS and is released specifically upon catheter ablation of AF. Patients with higher S100B release were more likely to be AF free during follow-up. Subsequent in vitro studies revealed that murine intracardiac neurons react to S100B with diminished action potential firing and increased neurite growth. This suggests that release of S100B from cardiac glia upon catheter-based treatment of AF is a hallmark of acute neural damage that contributes to nerve sprouting and can be used to assess ICNS damage., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: The potential utility of entropy (En) for atrial fibrillation (AF) mapping has been demonstrated in previous studies by multiple groups, where an association between high bipolar electrogram (EGM) entropy and the pivot of rotors has been shown. Though En is potentially attractive new approach to ablation, no studies have examined its temporal stability and specificity, which are critical to the application of entropy to clinical ablation. In the current study, we sought to objectively measure the temporal stability and specificity of bipolar EGM entropy in medium to long term recordings using three studies: i) a human basket catheter AF study, ii) a tachypaced sheep AF study and iii) a computer simulation study., Objective: To characterize the temporal dynamics and specificity of Approximate, Sample and Shannon entropy (ApEn/SampEn/ShEn) in human (H), sheep (S), and computer simulated AF., Methods: 64-electrode basket bi-atria sustained AF recordings (H:15 min; S:40 min) were separated into 5 s segments. ShEn/ApEn/SampEn were computed, and co-registered with NavX 3D maps. Temporal stability was determined in terms of: (i) global pattern stability of En and (ii) the relative stability the top 10% of En regions. To provide mechanistic insights into underlying mechanisms, stability characteristics were compared to models depicting various propagation patterns. To verify these results, cross-validation was performed across multiple En algorithms, across species, and compared with dominant frequency (DF) temporal characteristics. The specificity of En was also determined by looking at the association of En to rotors and areas of wave cross propagation., Results: Episodes of AF were analysed (H:26 epochs, 6040 s; S:15 epochs, 14,160 s). The global pattern of En was temporally unstable (CV- H:13.42% ± 4.58%; S:14.13% ± 8.13%; Friedman- H: p > 0.001; S: p > 0.001). However, within this dynamic flux, the top 10% of ApEn/SampEn/ShEn regions were relatively temporally stable (Kappa >0.6) whilst the top 10% of DF regions were unstable (Kappa <0.06). In simulated AF scenarios, the experimental data were optimally reproduced in the context of an AF pattern with stable rotating waves surrounded by wavelet breakup (Kappa: 0.610; p < 0.0001)., Conclusion: En shows global temporal instability, however within this dynamic flux, the top 10% regions exhibited relative temporal stability. This suggests that high En regions may be an appealing ablation target. Despite this, high En was associated with not just the pivot of rotors but also with areas of cross propagation, which suggests the need for future work before clinical application is possible., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Several recent studies suggest rotors detected by phase mapping may act as main drivers of persistent atrial fibrillation. However, the electrophysiological nature of detected rotors remains unclear. We performed a direct, 1:1 comparison between phase and activation time mapping in high-density, epicardial, direct-contact mapping files of human atrial fibrillation., Methods: Thirty-eight unipolar electrogram files of 10 s duration were recorded in patients with atrial fibrillation (n=20 patients) using a 16×16 electrode array placed on the epicardial surface of the left atrial posterior wall or the right atrial free wall. Phase maps and isochrone wave maps were constructed for all recordings. For each detected phase singularity (PS) with a lifespan of >1 cycle length, the corresponding conduction pattern was investigated in the isochrone wave maps., Results: When using sinusoidal recomposition and Hilbert Transform, 138 PSs were detected. One hundred and four out of 138 PSs were detected within 1 electrode distance (1.5 mm) from a line of conduction block between nonrotating wavefronts detected by activation mapping. Far fewer rotating wavefronts were detected when rotating activity was identified based on wave mapping (18 out of 8219 detected waves). Fourteen out of these 18 cases were detected as PSs in phase mapping. Phase analysis of filtered electrograms produced by simulated wavefronts separated by conduction block also identified PSs on the line of conduction block., Conclusions: PSs identified by phase analysis of filtered epicardial electrograms colocalize with conduction block lines identified by activation mapping. Detection of PSs using phase analysis has a low specificity for identifying rotating wavefronts during human atrial fibrillation using activation mapping.

Aims: Contact force (CF) catheters provide catheter-tissue contact information to improve outcome of pulmonary vein isolation (PVI) in paroxysmal atrial fibrillation (PAF). We evaluated different target-CF values for achievement of the additional endpoint of an unexcitable ablation line., Methods: A total of 106 patients undergoing PVI were randomized into three groups (G) (G1: target-CF 15 g, G2: target-CF 10 g, G3: CF concealed from operator). The PVI encircling line was divided into predefined sections. Excitable tissue along the PVI-line identified by high output pacing (10 V, 2 ms) was targeted for further ablation., Results: Mean average CF was 17.4 ± 4.7 g (G1) vs. 12.3 ± 6.0 g (G2) vs. 11.1 ± 6.5 g (G 3) (p < 0.001). Primary unexcitable ablation lines were found in 38.6, 19.4 and 5.7% (G1, G2, G3 respectively; G1 vs. G2 p < 0.05, G1 vs. G3 p < 0.001, G2 vs. G3 ns). Additional radiofrequency (RF)-energy to achieve unexcitability was lowest in G1 (3.6 ± 3.1 kJ vs. 8.6 ± 7.2 kJ (G2) and 10.4 ± 6.7 (G3), p ≤ 0.001, G2 vs. G3 ns) with accordingly lowest additional RF applications in G1 (3.0 ± 2.6 vs. 7.0 ± 5.4 in G2 and 8.4 ± 4.0 in G3; G1 vs. G2 and G3, p < 0.001, G 2 vs. G 3 ns). Sections along ablation lines with low initial CF were most likely to reveal excitability. Single procedure success was 81.9 vs. 73.5 vs. 71.4% (G 1, 2 and 3, p = 0.6) during 437 ± 254 day follow-up., Conclusion: Higher tip-to-tissue CF during PVI facilitates the achievement of an unexcitable ablation line, requiring less additional RF-energy.

BACKGROUND Recent evidence indicates that sympathetic/parasympathetic coactivation (CoA) is causally linked to changes in heart rate (HR) dynamics. Whether this is relevant for patients with atrial fibrillation (AF) is unknown. MATERIAL AND METHODS In patients with paroxysmal AF (n=26) and age-matched controls, (n=10) we investigated basal autonomic outflow and HR dynamics during separate sympathetic (cold hand immersion) and parasympathetic activation (O2-inhalation), as well as during CoA (cold face test). In an additional cohort (n=7), HR response was assessed before and after catheter-based pulmonary vein isolation (PVI). Ultra-high-density endocardial mapping was performed in patients (n=6) before and after CoA. RESULTS Sympathetic activation increased (control: 74±3 vs. 77±3 bpm, p=0.0098; AF: 60±2 vs. 64±2 bpm, p=0.0076) and parasympathetic activation decreased HR (control: 71±3 vs. 69±3 bpm, p=0.0547; AF: 60±1 vs. 58±2 bpm, p<0.0009), while CoA induced a paradoxical HR increase in patients with AF (control: 73±3 vs. 71±3 bpm, p=0.084; AF: 59±2 vs. 61±2 bpm, p=0.0006), which was abolished after PVI. Non-linear parameters of HR variability (SD1) were impaired during coactivation in patients with AF (control: 61±7 vs. 69±6 ms, p=0.042, AF: 44±32 vs. 32±5 ms, p=0.3929). CoA was associated with a shift of the earliest activation site (18±4 mm) of the sinoatrial nodal region, as documented by ultra-high-density mapping (3442±343 points per map). CONCLUSIONS CoA perturbs HR dynamics and shifts the site of earliest endocardial activation in patients with paroxysmal AF. This effect is abolished by PVI, supporting the value of emerging methods targeting the intrinsic cardiac autonomic nervous system to treat AF. CoA might be a valuable tool to assess cardiac autonomic function in a clinical setting.

Background: 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., Objective: 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., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: 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)., Background: Currently available systems display phase as simplified 2-dimensional maps. We developed a novel 3D phase mapping system that uses the 3D location of basket catheter electrodes and the patient's 3D left atrial surface geometry to interpolate phase and create a 3D representation of phase progression., Methods: 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 then visualized 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 activation in the same 1-min segment; and 3) determining the distribution of dominant propagation patterns in 6-min recordings using 3D phase., Results: There was strong agreement of beat-to-beat AF cycle length between activation analysis and phase inversion (R 2  = 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%). A total of 34 rotors were seen in 9 of 14 patients. All rotors were transient with mean duration of 1.0 ± 0.6 s. Rotors were only observed 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)., Conclusions: 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 detection of rotors., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie conduction disturbances predisposing to atrial fibrillation (AF). Putatively, disruption of electrical connections occurs not only within the epicardial layer but also between the epicardial layer and the endocardial bundle network, thus impeding transmural conductions (‘breakthroughs’). However, both clinical and experimental studies have shown an enhancement of breakthroughs during later stages of AF. We tested the hypothesis that endo-epicardial uncoupling enhances endo-epicardial electrical dyssynchrony, breakthrough rate (BTR), and AF stability., Methods and Results: In a novel dual-layer computer model of the human atria, 100% connectivity between the two layers served as healthy control. Atrial structural remodelling was simulated by reducing the number of connections between the layers from 96 to 6 randomly chosen locations. With progressive elimination of connections, AF stability increased. Reduction in the number of connections from 96 to 24 resulted in an increase in endo-epicardial dyssynchrony from 6.6 ± 1.9 to 24.6 ± 1.3%, with a concomitant increase in BTR. A further reduction to 12 and 6 resulted in more pronounced endo-epicardial dyssynchrony of 34.4 ± 1.15 and 40.2 ± 0.52% but with BTR reduction. This biphasic relationship between endo-epicardial coupling and BTR was found independently from whether AF was maintained by re-entry or by ectopic focal discharges., Conclusion: Loss of endo-epicardial coupling increases AF stability. There is a biphasic relation between endo-epicardial coupling and BTR. While at high degrees of endo-epicardial connectivity, the BTR is limited by the endo-epicardial synchronicity, at low degrees of connectivity, it is limited by the number of endo-epicardial connections.

Objective: To explore technical challenges of phase singularity (PS) mapping during atrial fibrillation (AF) using direct contact electrograms., Methods: AF mapping was performed in high-density epicardial recordings of human paroxysmal (PAF) or persistent (PersAF) (N = 20 pts) AF with an array of 16 × 16 electrodes placed on atrial epicardium. PS points were detected using subsets of electrodes forming rings of varying sizes., Results: PS detection using a 2 × 2 electrode ring identified 0.88 ± 1.00 PS/s in PAF group and 3.91 ± 2.51 per s in PersAF group (p < 0.001) in 2.4 × 2.4 cm mapping area. All detected PS had a short lifespan with the longest being 1100 ms (6.8 rotations). Exploration of the PS detection in a numerical model demonstrated that at least eight electrodes are required to avoid frequent false positive PS detection due to chance. Application of a detection grid consisting a double ring of electrodes (2 × 2 and 4 × 4 rings) decreased the number of false positive detections. The double ring was more resilient to electrode swapping (with just three instances of false positives versus 4380 false positives using 2 × 2 ring)., Conclusions: The number of detected rotors critically depends upon the parameters of the detection algorithm, especially the number of electrodes used to detect PS. Based on our results, we recommend double ring comprised of 2 × 2 and 4 × 4 grid of electrodes for robust rotor detection., Significance: Great methodological care has to be taken before equating detected PS with rotating waves and using PS detection algorithms to guide catheter ablation of AF.

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis., Competing Interests: The authors declare no competing financial interests.

Background: Electrogram-based identification of the regions maintaining persistent Atrial Fibrillation (AF) is a subject of ongoing debate. Here, we explore the concept of local electrical dyssynchrony to identify AF drivers., Methods and Results: Local electrical dyssynchrony was calculated using mean phase coherence. High-density epicardial mapping along with mathematical model were used to explore the link between local dyssynchrony and properties of wave conduction. High-density mapping showed a positive correlation between the dyssynchrony and number of fibrillatory waves (R2 = 0.68, p<0.001). In the mathematical model, virtual ablation at high dyssynchrony regions resulted in conduction regularization. The clinical study consisted of eighteen patients undergoing catheter ablation of persistent AF. High-density maps of left atrial (LA) were constructed using a circular mapping catheter. After pulmonary vein isolation, regions with the top 10% of the highest dyssynchrony in LA were targeted during ablation and followed with ablation of complex atrial electrograms. Catheter ablation resulted in termination during ablation at high dyssynchrony regions in 7 (41%) patients. In another 4 (24%) patients, transient organization was observed. In 6 (35%) there was no clear effect. Long-term follow-up showed 65% AF freedom at 1 year and 22% at 2 years., Conclusions: Local electrical dyssynchrony provides a reasonable estimator of regional AF complexity defined as the number of fibrillatory waves. Additionally, it points to regions of dynamical instability related with action potential alternans. However, despite those characteristics, its utility in guiding catheter ablation of AF is limited suggesting other factors are responsible for AF persistence., Competing Interests: The authors have declared that no competing interests exist.

Background: The success rate of catheter ablation for persistent atrial fibrillation (AF) is still far from satisfactory. Identification of patients who will benefit from ablation is highly desirable. We investigated the predictive value of noninvasive AF complexity parameters derived from standard 12-lead ECGs for AF termination and long-term success of catheter ablation and compared them with clinical predictors., Methods and Results: The study included a training (93 patients) and a validation set (81 patients) of patients with persistent AF undergoing stepwise radiofrequency ablation. In the training set AF terminated in 81% during catheter ablation, 77% were in sinus rhythm after 6 years and multiple ablations. ECG-derived complexity parameters were determined from a baseline 10-s 12-lead ECG. Prediction of AF termination was similar using only ECG (cross-validated mean area under the curve [AUC], 0.76±0.15) or only clinical parameters (mean AUC, 0.75±0.16). The combination improved prediction to a mean AUC of 0.79±0.13. Using a combined model of ECG and clinical parameters, sinus rhythm at long-term follow-up could be predicted with a mean AUC of 0.71±0.12. In the validation set AF terminated in 57%, 61% were in sinus rhythm after 4.6 years. The combined models predicted termination with an AUC of 0.70 and sinus rhythm at long-term follow-up with an AUC of 0.61. Overall, fibrillation-wave amplitude provided the best rhythm prediction., Conclusions: The predictive performance of ECG-derived AF complexity parameters for AF termination and long-term success of catheter ablation in patients with persistent AF is at least as good as known clinical predictive parameters, with fibrillation-wave amplitude as the best predictor., (© 2016 American Heart Association, Inc.)

Background: Temporal dynamics of electrical wave propagation during AF is unknown. There are reports of transient linking of atrial activation. We aim to characterize temporal dynamics of wave propagation patterns during AF in an established chronically remodeled substrate., Methods: Bi-atrial epicardial mapping of AF (mean duration 62±61s) was performed in 13 sheep with induced hypertension using custom-designed plaques. Wave propagation patterns were classified into periods of repetitive activity termed modes., Results: In total, we identified 9241 distinct depolarization events which were classified as: passing wave (69% occurrence, 68.6% of total time), point source (20.4%, 13.1%), wave collision (4%, 2.8%), re-entrant wave (0.7%, 6.3%), half-rotation (2.9%, 4.4%), wave splitting (2.7%, 4.3%), conduction block (0.05%, 0.03%) and figure of eight reentry (0.05%, 0.05%). Episodes of re-entrant activity had mean length 701±1012ms. A total of 435 modes of distinct periods of repetitive activity were detected (121 in LA and 314 in RA). Looking at temporal changes between modes, we found a preferential transition: change between train of waves propagating from direction of coronary sinus and reentrant activity. High density mapping of the hypertensive fibrillating atria observed 20% point sources and 0.7% of reentrant activation which may have served as drivers of AF. Remaining activations were peripheral waves. Majority of the activation was organized into events of transient linking with existence of preferential types of transitions., Conclusions: These findings support the importance of substrate based regions of anatomically or functionally determined preferential conduction in the maintenance of AF., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Permanent pulmonary vein isolation (PVI) remains an essential goal of ablation therapy in patients with atrial fibrillation. Aim of this study was the intraindividual comparison of unexcitability to pacing along the ablation line versus dormant conduction (DC) as additional procedural endpoints., Methods: A total of 58 patients with paroxysmal atrial fibrillation (PAF) underwent PVI by circumferential ablation of ipsilateral pulmonary veins (PVs), followed by testing for DC by adenosine administration. Irrespective of the presence of DC, pacing along the ablation line for left atrium capture was performed and additional radio frequency energy applied if necessary. PVs with initial DC were retested after achieving unexcitability., Results: PVI was achieved in 224 of 224 PVs. In 33 of 224 PVs (15%) DC was revealed. At 92 of 112 ablation lines (82%) sites of excitability were found. Three (9%) of the initial 33 PVs with DC showed further DC after achieving unexcitability at repeated testing. Thirty-two of 33 assumed areas of unmasked PV-LA reconduction as revealed by DC-testing showed a corresponding site of excitability on the ablation line. After a follow-up of 11.6 ± 3.4 months 79% of patients were free of arrhythmia., Conclusions: Pacing for unexcitability can safely identify potential sites of DC and even sites that would have not been detected by testing for DC. Unexcitability, therefore, serves as a suitable and safe procedural endpoint not only for patients with contraindications to adenosine administration. Our data suggest that adenosine may be expendable when achieving unexcitability along the ablation line., (© 2015 Wiley Periodicals, Inc.)

Unipolar electrogram can detect local as well as remote electrical activity of the heart. Information on how the amplitude and morphology of the recorded signal changes with the distance from the source tissue undergoing depolarization can help to better understand unipolar electrograms fractionation and provide insights into the passive conduction properties of the atrial tissue. Ten second unipolar atrial fibrillation (AF) electrograms were recorded using high-density electrode array from the posterior left atrium (LA) and right atrium (RA) of 19 (8 persistent - PERS & 11 paroxysmal - PAF) AF patients undergoing cardiac surgery. Conduction along lines of conduction block was detected in the recorded activation patterns by a proposed automated algorithm. Changes of the amplitude of the unipolar electrogram with increasing distance from the conduction blocks were assessed and compared to predictions of a theoretical model. For each recording, the median far-field decay space constant (FF0.5) was calculated. Overall, we found a significant difference between FF0.5 for patients with paroxysmal and persistent AF. Estimation of maximum FF0.5 from both RA and LA resulted in a mean FF0.5 of 1.5±0.2 mm for PERS patients and 2.1±0.6 mm for PAF patients (p=0.03). Moreover, detected conduction blocks demonstrated high spatial organization and appeared in distinctive areas of the mapped area in all patients, regardless of the type of AF, while the total number of detected block lines was higher in PERS patients.

Introduction: Recently, a new image integration module (IIM, CartoUnivu™ Module) has been introduced to combine and merge fluoroscopy images with 3-dimensional-(3D)-electroanatomical maps (Carto® 3 System) into an accurate 3D view. The aim of the study was to investigate the influence of IIM on the fluoroscopy exposure during pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) in a prospective randomized trial., Methods and Results: Between June and November 2014, a total of 60 patients with PAF (73.3% male, 64.0 ± 9.2 years), who underwent PVI with the endpoint of unexcitability of the ablation line, were randomized to either a conventional 3D mapping system (Carto® 3 System) or to an additional IIM on the basis of an assumed reduction of fluoroscopy exposure by the use of IIM. There were no significant differences in baseline characteristics. The median ablation procedure time was identical in both groups (140.7 ± 27.8 minutes vs. 140.8 ± 39.5 minutes; P = 0.851). A significant decrease of mean fluoroscopy time from 11.9 ± 2.1 to 7.4 ± 2.6 minutes (P < 0.0006) and median fluoroscopy dose from 882.9 to 476.5 cGycm(2) (P < 0.001) was achieved. The main reduction of radiation could be realized during creation of the 3D-map. No major complications occurred during the procedures. After a median follow-up of 125.7 ± 45.6 days 80% of the patients were free from any atrial arrhythmias., Conclusion: CartoUnivu™ module easily integrates into the workflow of PVI with the endpoint of unexcitability of the ablation line without prolonging the procedure time. It is associated with a marked reduction in fluoroscopic dose when compared to a conventional 3D mapping system., (© 2015 Wiley Periodicals, Inc.)

Background: The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood., Objective: The aim of this study was to comprehensively investigate how bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF., Methods: Ten-second unipolar AF electrograms were recorded using a high-density electrode from the left atrium of 20 patients with AF (10 with persistent AF and 10 with paroxysmal AF) undergoing cardiac surgery. Semiautomated bipolar CFAE algorithms: complex fractionated electrogram-mean, interval confidence interval, continuous electrical activity, average complex interval, and shortest complex interval were evaluated against AF substrate complexity measures following fibrillation wave reconstruction derived from local unipolar activation time. The effect of interelectrode spacing and electrode orientation on bipolar CFAE was also examined., Results: All 5 semiautomated bipolar CFAE algorithms showed poor correlation with each other and AF substrate complexity measures (conduction velocity, number of waves or breakthroughs per AF cycle, and electrical dissociation). Bipolar CFAE also correlated poorly with fractionation index derived from unipolar electrograms. Increased interelectrode spacing resulted in an increase in bipolar CFAE detected except for the interval confidence interval algorithm. CFAE appears unaffected by bipolar electrode orientation (vertical vs horizontal). By contrast, unipolar fractionation index correlated well with AF substrate complexity measures and can be regarded as a marker for conduction block., Conclusion: The lack of pathophysiological relevance of bipolar CFAE analysis may in part contribute to the divergent and limited success rates of catheter ablation strategies targeting CFAE., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The Hilbert transform has been used to characterize wave propagation and detect phase singularities during cardiac fibrillation. Two mapping modalities have been used: optical mapping (used to map atria and ventricles) and contact electrode mapping (used only to map ventricles). Due to specific morphology of atrial electrograms, phase reconstruction of contact electrograms in the atria is challenging and has not been investigated in detail. Here, we explore the properties of Hilbert transform applied to unipolar epicardial electrograms and devise a method for robust phase reconstruction using the Hilbert transform. We applied the Hilbert transform to idealized unipolar signals obtained from analytical approach and to electrograms recorded in humans. We investigated effects of deflection morphology on instantaneous phase. Application of the Hilbert transform to unipolar electrograms demonstrated sensitivity of reconstructed phase to the type of deflection morphology (uni- or biphasic), the ratio of R and S waves and presence of the noise. In order to perform a robust phase reconstruction, we propose a signal transformation based on the recomposition of the electrogram from sinusoidal wavelets with amplitudes proportional to the negative slope of the electrogram. Application of the sinusoidal recomposition transformation prior to application of the Hilbert transform alleviates the effect of confounding features on reconstructed phase.

Aims: Mapping and interpretation of wave conduction patterns recorded during simultaneous mapping of the electrical activity on both endocardial and epicardial surfaces are challenging because of the difficulty of reconstruction of reciprocal alignment of electrodes in space. Here, we suggest a method to overcome this difficulty using a concept of maximized endo-epicardial phase coherence., Methods and Results: Endo-epicardial mapping was performed in six humans during induced atrial fibrillation (AF) in right atria using two sets of 8 × 8 electrode plaques. For each electrode, mean phase coherence (MPC) with all electrodes on the opposite side of the atrial wall was calculated. Localization error was defined as a distance between the directly opposing electrode and the electrode with the maximal MPC. Overall, there was a linear correlation between MPC and distance between electrodes with R(2) = 0.34. Localization error obtained for electrodes of the plaque in six patients resulted in a mean 2.3 ± 1.9 mm for 25 s electrogram segment length. Eighty-four per cent of the measurements resulted in error smaller than 3.4 mm. The duration of the recording used to compute MPC was negatively correlated with localization error; however, the effect reached plateau for segment durations longer than 15 s., Conclusion: Application of the concept of maximized endo-epicardial phase coherence to electrograms during AF allows reconstruction of reciprocal alignment of the electrodes on the opposite side of the atrial wall. This approach may be especially useful in settings where the spatial position of endo- and epicardial electrodes for intracardiac mapping cannot otherwise be determined., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Both ageing and hypertension are known risk factors for atrial fibrillation (AF) although the pathophysiological contribution or interaction of the individual factors remains poorly understood. Here we aim to delineate the arrhythmogenic atrial substrate in mature spontaneously hypertensive rats (SHR)., Methods: SHR were studied at 12 and 15 months of age (n = 8 per group) together with equal numbers of age-matched normotensive Wistar-Kyoto control rats (WKY). Electrophysiologic study was performed on superfused isolated right and left atrial preparations using a custom built high-density multiple-electrode array to determine effective refractory periods (ERP), atrial conduction and atrial arrhythmia inducibility. Tissue specimens were harvested for structural analysis., Results: COMPARED TO WKY CONTROLS, THE SHR DEMONSTRATED: Higher systolic blood pressure (p<0.0001), bi-atrial enlargement (p<0.05), bi-ventricular hypertrophy (p<0.05), lower atrial ERP (p = 0.008), increased atrial conduction heterogeneity (p = 0.001) and increased atrial interstitial fibrosis (p = 0.006) & CD68-positive macrophages infiltration (p<0.0001). These changes resulted in higher atrial arrhythmia inducibility (p = 0.01) and longer induced AF episodes (p = 0.02) in 15-month old SHR. Ageing contributed to incremental bi-atrial hypertrophy (p<0.01) and atrial conduction heterogeneity (p<0.01) without affecting atrial ERP, fibrosis and arrhythmia inducibility. The limited effect of ageing on the atrial substrate may be secondary to the reduction in CD68-positive macrophages., Conclusions: Significant atrial electrical and structural remodeling is evident in the ageing spontaneously hypertensive rat atria. Concomitant hypertension appears to play a greater pathophysiological role than ageing despite their compounding effect on the atrial substrate. Inflammation is pathophysiologically linked to the pro-fibrotic changes in the hypertensive atria.

Background: Myocardial infarction (MI) is associated with the development of atrial fibrillation (AF). We aimed to characterize the atrial abnormalities because of MI and determine the role of ischemia to the AF substrate., Methods and Results: Forty-four sheep were studied. MI was induced by occlusion of the left circumflex artery (LCX) or left anterior descending artery (LAD). Excluding 11 with fatal arrhythmias, equal groups of animals (LCX; LAD; and sham-operated) underwent sequential electrophysiology study for 45 minutes to determine atrial effective refractory periods, conduction velocity, conduction heterogeneity index, and AF inducibility. Postmortem evaluation was performed with 2,3,5 triphenyl tetrazolium chloride staining. MI resulted in greater left ventricular dysfunction (P<0.05), LA pressure (P<0.0003), and reduction in atrial effective refractory periods (P<0.0001) compared with control. 2,3,5 triphenyl tetrazolium chloride staining demonstrated that the left circumflex artery, and not the LAD, group had atrial infarction. The left circumflex artery group demonstrated the following compared with the LAD or control groups: greater slowing in atrial conduction velocity (P<0.0001 and P<0.001); increased absolute range of conduction phase delay (P<0.001 and P<0.001); increased conduction heterogeneity index (P<0.0001 and P<0.001); greater AF vulnerability (P<0.05 for both); and longer AF duration (P<0.05 for both). LAD group had modest but significant slowing in conduction velocity (P<0.01) but no change in conduction heterogeneity index or AF duration compared with control., Conclusions: Left ventricular infarction, which is known to result in atrial stretch, hemodynamic change, and neurohumoral activation, contributes partially to the atrial abnormalities in MI. Atrial ischemia/infarction results in greater atrial electrophysiological changes and propensity for AF forming the dominant substrate for AF in MI.

Background: In the past decade, catheter ablation has become an established therapy for symptomatic atrial fibrillation (AF). Until very recently, few data have been available to guide the clinical community on the outcomes of AF ablation at ≥3 years of follow-up. We aimed to systematically review the medical literature to evaluate the long-term outcomes of AF ablation., Methods and Results: A structured electronic database search (PubMed, Embase, Web of Science, Cochrane) of the scientific literature was performed for studies describing outcomes at ≥3 years after AF ablation, with a mean follow-up of ≥24 months after the index procedure. The following data were extracted: (1) single-procedure success, (2) multiple-procedure success, and (3) requirement for repeat procedures. Data were extracted from 19 studies, including 6167 patients undergoing AF ablation. Single-procedure freedom from atrial arrhythmia at long-term follow-up was 53.1% (95% CI 46.2% to 60.0%) overall, 54.1% (95% CI 44.4% to 63.4%) in paroxysmal AF, and 41.8% (95% CI 25.2% to 60.5%) in nonparoxysmal AF. Substantial heterogeneity (I(2)>50%) was noted for single-procedure outcomes. With multiple procedures, the long-term success rate was 79.8% (95% CI 75.0% to 83.8%) overall, with significant heterogeneity (I(2)>50%).The average number of procedures per patient was 1.51 (95% CI 1.36 to 1.67)., Conclusions: Catheter ablation is an effective and durable long-term therapeutic strategy for some AF patients. Although significant heterogeneity is seen with single procedures, long-term freedom from atrial arrhythmia can be achieved in some patients, but multiple procedures may be required.

Background: The pivot is critical to rotors postulated to maintain atrial fibrillation (AF). We reasoned that wavefronts circling the pivot should broaden the amplitude distribution of bipolar electrograms because of directional information encoded in these signals. We aimed to determine whether Shannon entropy (ShEn), a measure of signal amplitude distribution, could differentiate the pivot from surrounding peripheral regions and thereby assist clinical rotor mapping., Methods and Results: Bipolar electrogram recordings were studied in 4 systems: (1) computer simulations of rotors in a 2-dimensional atrial sheet; (2) isolated rat atria recorded with a multi-electrode array (n=12); (3) epicardial plaque recordings of induced AF in hypertensive sheep (n=11); and (4) persistent AF patients (n=10). In the model systems, rotation episodes were identified, and ShEn calculated as an index of amplitude distribution. In humans, ShEn distribution was analyzed at AF termination sites and with respect to complex fractionated electrogram mean. We analyzed rotation episodes in simulations (4 cycles) and animals (rats: 14 rotors, duration 80±81 cycles; sheep: 13 rotors, 4.2±1.5 cycles). The maximum ShEn bipole was consistently colocated with the pivot zone. ShEn was negatively associated with distance from the pivot zone in simulated spiral waves, rats, and sheep. ShEn was modestly inversely associated with complex fractionated electrogram; however, there was no relationship at the sites of highest ShEn., Conclusions: ShEn is a mechanistically based tool that may assist AF rotor mapping.

Background: Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown., Objective: To examine the effect of progressive weight gain on the substrate for AF., Methods: Thirty sheep were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor., Results: Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels., Conclusions: Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background: Atrial premature contractions (APCs) are well described to precede the initiation of paroxysmal atrial fibrillation (pAF). However, whether APC characteristics alter with progression of the arrhythmia is unknown., Objective: To determine the APC characteristics in terms of burden and relative coupling interval with progression of the AF disease process., Methods: Fifty consecutive patients with pAF, 50 consecutive patients with persistent AF (perAF), and 25 age-matched controls underwent clinical review, transthoracic echocardiography, and ambulatory electrocardiogram monitoring. After excluding 29 patients who had AF for the entire recording (n = 24) or unreliable recordings (n = 5), we analyzed data from 49 patients with pAF, 24 patients with perAF, and 23 healthy controls. All normal morphology R-R intervals with a >25% decrease in R-R coupling compared with the previous R-R interval (coupling interval index) were deemed APCs (n = 95,873)., Results: The median APC burden was higher in patients with pAF (2 [1-22] APCs/h; P = .004) and perAF (3 [1-6] APCs/h; P = .04) than in controls (1 [0-1] APCs/h) but was not different (P = .66) between the AF subgroups. Patients with pAF had a distinct increase in ectopy burden after 7 PM and elevation throughout the night (P = .002) in comparison with a blunted and complementary temporal response in the perAF cohort (P = .01). Patients with pAF demonstrated a greater proportion of shortly coupled APCs (29% [13-45]; P = .04) compared with persistent arrhythmia (17% [5-29])., Conclusions: "Real-life" atrial trigger statistics of APC burden, timing, and diurnal rhythms track the transition from a trigger-based, autonomically sensitive paroxysmal arrhythmia to a more substrate-based persistent disease., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Background: There is a known association between obstructive sleep apnea (OSA) and atrial fibrillation (AF); however, how OSA affects the atrial myocardium is not well described., Objective: To determine whether patients with OSA have an abnormal atrial substrate., Methods: Forty patients undergoing ablation of paroxysmal AF and in sinus rhythm (20 with OSA [apnea-hypopnea index ≥ 15] and 20 reference patients with no OSA [apnea-hypopnea index < 15] by polysomnography) were studied. Multipolar catheters were positioned at the lateral right atrium (RA), coronary sinus, crista terminalis, and RA septum to determine the effective refractory period at 5 sites, conduction time along linear catheters at the RA and the coronary sinus, conduction at the crista terminalis, and sinus node function (corrected sinus node recovery time). Biatrial electroanatomic maps were created to determine the voltage, conduction, and distribution of complex electrograms (duration ≥ 50 ms)., Results: The groups had no differences in the prevalence of established risk factors for AF. Patients with OSA had the following compared with those without OSA: no difference in effective refractory period (P = .9), prolonged conduction times along the coronary sinus and RA (P = .02), greater number (P = .003) and duration (P = .03) of complex electrograms along the crista terminalis, longer P-wave duration (P = .01), longer corrected sinus node recovery time (P = .02), lower atrial voltage (RA, P <.001; left atrium, P <.001), slower atrial conduction velocity (RA, P = .001; left atrium, P = .02), and more widespread complex electrograms in both atria (RA, P = .02; left atrium, P = .01)., Conclusion: OSA is associated with significant atrial remodeling characterized by atrial enlargement, reduction in voltage, site-specific and widespread conduction abnormalities, and longer sinus node recovery. These features may in part explain the association between OSA and AF., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Background: Hypertension accounts for more atrial fibrillation (AF) than any other predisposing factor., Objective: The purpose of this study was to characterize the time course, extent, and electrostructural correlation of atrial remodeling in chronic hypertension., Methods: Thirty-two sheep were studied: 21 with induced "one-kidney, one-clip" hypertension and 11 controls. Sequential closed-chest electrophysiologic studies were performed in 12 conscious animals (6 hypertensive, 6 controls) to evaluate progressive remodeling over 15 weeks. Additional atrial structural/functional analyses were performed in 5 controls and at 5, 10, and 15 weeks of hypertension (five per time point) via histology/cardiac magnetic resonance imaging to correlate with open-chest electrophysiologic parameters., Results: The hypertensive group developed a progressive increase in mean arterial pressure (P <.001). Mean effective refractory periods were uniformly higher at all time points (P <.001). Progressive biatrial hypertrophy (P = .003), left atrial dysfunction (P <.05) and greater AF inducibility were seen early with increased inflammation from 5 weeks of hypertension. In contrast, significant conduction slowing (P <.001) with increased heterogeneity (P <.001) along with increased interstitial fibrosis resulted in longer and more fractionated AF episodes only from 10 weeks of hypertension. Significant electrostructural correlation was seen in conduction abnormalities and AF inducibility with both atrial inflammation and fibrosis., Conclusion: Hypertension is associated with early and progressive changes in atrial remodeling. Atrial remodeling occurs at different time domains in chronic hypertension with significant electrostructural correlation of the remodeling cascade. Early institution of antihypertensive treatment may prevent formation of substrate capable of maintaining AF., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients with lone atrial fibrillation (AF) have an abnormal atrial substrate., Objective: The purpose of this study was to determine the role of direction-dependent conduction in patients with lone AF., Methods: Twenty-four patients with paroxysmal lone AF and 24 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium, crista terminalis, coronary sinus (CS), and left atrial roof were used to determine direction-dependent conduction characteristics. Biatrial electroanatomic maps were created during sinus rhythm and with distal CS pacing to characterize direction-dependent differences in conduction velocities, electrogram complexity, and voltage., Results: Differing wavefront directions caused changes in conduction velocity (P <.001), biatrial activation times (P <.001), electrogram fragmentation (P <.001), site-specific conduction delays (P <.001), and voltage (P <.001) in both lone AF and reference patients. These direction-dependent abnormalities were amplified in lone AF patients compared to reference patients, who exhibited greater slowing in conduction velocities (P = .02), prolongation of biatrial activation time (P = .04), increase in number (P <.001) and length (P <.001) of lines of conduction block, increase in proportion of fractionated electrograms (P <.001), and decrease in voltage (P = .03) during distal CS pacing compared to sinus rhythm., Conclusion: This study demonstrates the marked direction-dependent conduction abnormalities present in patients with lone AF. These results provide further insights into the critical interplay between the underlying abnormal substrate and differing wavefront directions. The study suggests that direction-dependent conduction abnormalities may explain in part the greater arrhythmogenicity of ectopic triggers from the left atrium rather than the right atrium., (Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.)

Background: Ablation of long-standing persistent atrial fibrillation (AF) is highly variable, with differing techniques and outcomes., Objective: The purpose of this study was to undertake a systematic review of the literature with regard to the impact of ablation technique on the outcomes of long-standing persistent AF ablation., Methods: A systematic search of the contemporary English scientific literature (from January 1, 1990 to June 1, 2009) in the PubMed database identified 32 studies on persistent/long-standing persistent or long-standing persistent AF ablation (including four randomized controlled trials). Data on single-procedure, drug-free success, multiple procedure success, and pharmaceutically assisted success at longest follow-up were collated., Results: Four studies performed pulmonary vein isolation alone (21%-22% success). Four studies performed pulmonary vein antrum ablation with isolation (PVAI; n = 2; 38%-40% success) or without confirmed isolation (PVA; n = 2; 37%-56% success). Ten studies performed linear ablation in addition to PVA (n = 5; 11%-74% success) or PVAI (n = 5; 38%-57% success). Three studies performed posterior wall box isolation (n = 3; 44%-50% success). Five studies performed complex fractionated atrial electrogram ablation (n = 5; 24%-63% success). Six studies performed complex fractionated atrial electrogram ablation as an adjunct to PVA (n = 2; 50%-51% success), PVAI (n = 3; 36%-61% success), or PVAI and linear (n = 1; 68% success) ablation. Five studies performed the stepwise ablation approach (38%-62% success)., Conclusion: The variation in success within and between techniques suggests that the optimal ablation technique for long-standing persistent AF is unclear. Nevertheless, long-standing persistent AF can be effectively treated with a composite of extensive index catheter ablation, repeat procedures, and/or pharmaceuticals., (Copyright (c) 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this report was to study the effect of chronic stretch reversal on the electrophysiological characteristics of the atria in humans., Background: Atrial stretch is an important determinant for atrial fibrillation. Whether relief of stretch reverses the substrate predisposed to atrial fibrillation is unknown., Methods: Twenty-one patients with mitral stenosis undergoing mitral commissurotomy (MC) were studied before and after intervention. Catheters were placed at multiple sites in the right atrium (RA) and sequentially within the left atrium (LA) to determine: effective refractory period (ERP) at 10 sites (600 and 450 ms) and P-wave duration (PWD). Bi-atrial electroanatomic maps determined conduction velocity (CV) and voltage. In 14 patients, RA studies were repeated >or=6 months after MC., Results: Immediately after MC, there was significant increase in mitral valve area (2.1 +/- 0.2 cm(2), p < 0.0001) with decrease in LA (23 +/- 7 mm Hg to 10 +/- 4 mm Hg, p < 0.0001) and pulmonary arterial pressures (38 +/- 16 mm Hg to 27 +/- 12 mm Hg, p < 0.0001) and LA volume (75 +/- 20 ml to 52 +/- 18 ml, p < 0.0001). This was associated with reduction in PWD (139 +/- 19 ms to 135 +/- 20 ms, p = 0.047), increase in CV (LA: 1.3 +/- 0.3 mm/ms to 1.7 +/- 0.2 mm/ms, p = 0.006; and RA: 1.0 +/- 0.1 mm/ms to 1.3 +/- 0.3 mm/ms, p = 0.002) and voltage (LA: 1.7 +/- 0.6 mV to 2.5 +/- 1.0 mV, p = 0.005; and RA: 1.8 +/- 0.6 mV to 2.2 +/- 0.7 mV, p = 0.09), and no change in ERP. Late after MC, mitral valve area remained at 2.1 +/- 0.3 cm(2) (p = 0.7) but with further decrease in PWD (113 +/- 19 ms, p = 0.04) and RA ERP (at 600 ms, p < 0.0001), with increase in CV (1.0 +/- 0.1 mm/ms to 1.3 +/- 0.2 mm/ms, p = 0.006) and voltage (1.8 +/- 0.7 mV to 2.8 +/- 0.6 mV, p = 0.002)., Conclusions: The atrial electrophysiologic and electroanatomic abnormalities that result from chronic stretch due to MS reverses after MC. These observations suggest that the substrate predisposing to atrial arrhythmias might be reversed., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation is the most common type of arrhythmia to affect humans. One of the treatment modalities for atrial fibrillation is an electrical cardioversion. Electrical cardioversion can result in one of three outcomes: an immediate termination of arrhythmic activity, a delayed termination or unsuccessful termination. The mechanism of delayed termination is unknown. Here we present a model of an atrial fibrillation as a coexistence of several spiral waves pinned to the inhomogeneities in active media. We show that in inhomogeneous system delayed termination can be explained as the unpinning of a spiral wave from inhomogeneities and its termination after collision with the edge of the system., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Background: Hypertension is frequently complicated by the development of atrial fibrillation (AF). However, the mechanisms of this link remain poorly understood. In addition, whether short-term hypertension can result in a substrate for AF is not known., Objective: The purpose of this study was to characterize the atrial substrate predisposing to AF due to short-duration hypertension., Methods: Sixteen sheep were studied: 10 had induced hypertension for 7 +/- 4 weeks via the "one-kidney, one-clip" model, and six were controls. Cardiac magnetic resonance imaging was used to assess functional changes. Open-chest electrophysiological study was performed using a custom-made 128-electrode epicardial plaque applied to both right (RA) and left atria (LA), including the Bachmann's bundle, to determine effective refractory periods (ERPs) and conduction velocity at four pacing cycle lengths from six sites. Tissue specimens were harvested for structural analysis., Results: The hypertensive group demonstrated the following compared with controls: higher blood pressure (P <.0001), enlarged LA (P <.05), reduced LA ejection fraction (P <.05), uniformly higher mean ERP (P <.001), slower mean conduction velocity (P <.001), higher conduction heterogeneity index (P <.0001), greater AF inducibility (P = .03), and increased AF durations (P = .04). Picrosirius red staining of atrial tissues revealed increased interstitial fibrosis (P <.0001). There was also evidence of increased inflammatory cell infiltrates (P <.0001)., Conclusion: Short-duration hypertension is associated with significant atrial remodeling characterized by atrial enlargement/dysfunction, interstitial fibrosis, inflammation, slowed/heterogeneous conduction, increased ERP, and greater propensity for AF., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to determine whether patients with paroxysmal "lone" atrial fibrillation (AF) have an abnormal atrial substrate., Background: While "AF begets AF," prompt termination to prevent electrical remodeling does not prevent disease progression., Methods: Twenty-five patients with paroxysmal lone AF, without arrhythmia in the week prior, and 25 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium (RA), crista terminalis, coronary sinus, septal RA, and sequentially within the left atrium (LA) determined the effective refractory period (ERP) at 10 sites, conduction time along linear catheters, and conduction characteristics at the crista terminalis. Bi-atrial electroanatomic maps were created to determine regional differences in conduction velocity and voltage., Results: Patients with AF demonstrated the following compared with reference patients: larger atrial volumes (RA: 94 +/- 18 ml vs. 69 +/- 9 ml, p = 0.003; LA: 99 +/- 19 ml vs. 77 +/- 17 ml, p = 0.006); longer ERP (at 600 ms: 255 +/- 25 ms vs. 222 +/- 16 ms, p < 0.001; at 450 ms: 234 +/- 20 ms vs. 212 +/- 14 ms, p = 0.004); longer conduction time along linear catheters (57 +/- 18 ms vs. 47 +/- 10 ms, p = 0.01); longer bi-atrial activation time (128 +/- 17 ms vs. 89 +/- 10 ms, p < 0.001); slower conduction velocity (RA: 1.3 +/- 0.3 mm/ms vs. 2.1 +/- 0.5 mm/ms; LA: 1.2 +/- 0.2 mm/ms vs. 2.2 +/- 0.4 mm/ms, p < 0.001); greater proportion of fractionated electrograms (27 +/- 8% vs. 8 +/- 5%, p < 0.001); longer corrected sinus node recovery time (265 +/- 57 ms vs. 185 +/- 60 ms, p = 0.002); and lower voltage (RA: 1.7 +/- 0.4 mV vs. 2.9 +/- 0.4 mV; LA: 1.7 +/- 0.7 mV vs. 3.3 +/- 0.7 mV, p < 0.001)., Conclusions: Patients with paroxysmal lone AF, remote from arrhythmia, demonstrate bi-atrial abnormalities characterized by structural change, conduction abnormalities, and sinus node dysfunction. These factors are likely contributors to the "second factor" that predisposes to the development and progression of AF.

Introduction: Sites of complex fractionated atrial electrograms (CFAE) and dominant frequency (DF) have been implicated in maintaining atrial fibrillation (AF); however, their relationship is poorly understood., Methods and Results: Twenty patients underwent biatrial high-density contact mapping (507 +/- 150 points/patient) during AF. CFAE were characterized using software to quantify electrogram complexity (CFE-mean). Spectral analysis determined the frequency with greatest power and sites of high DF with a frequency gradient. CFE-mean was higher (less fractionated) for right compared with left atria (P < 0.001) and in paroxysmal compared with persistent AF (P < 0.001). DF was lower for right compared with left atria (P = 0.02) and in paroxysmal compared with persistent AF (P < 0.001). There was significant regional variation in DF in paroxysmal (P < 0.001) but not persistent AF. Highest DF points clustered together with 5.2 +/- 1.7 clusters/patient. Correlation between CFE-mean and DF was poor on a point-by-point basis (r =-0.17, P < 0.001), but moderate on an individual basis (r =-0.50, P = 0.03). Exploration of their spatial relationship demonstrated CFAE areas in close proximity (median 5 mm, IQR 2-10) to high DF sites; within 10 mm in 80% and 10-20 mm in 10%. Simultaneous activation mapping at these sites further supports this observation., Conclusion: Greater fractionation and higher DF are seen in persistent AF and left atria during AF. Preferential areas of high DF are observed in paroxysmal but not persistent AF. CFAE and DF correlate within an individual but not point-by-point. Exploration of their spatial relationship demonstrates CFAE in areas adjacent to high DF, and this is supported by activation mapping at these sites.

Aims: To characterize the atrial remodelling in mitral stenosis (MS)., Methods and Results: Twenty-four patients with severe MS undergoing commissurotomy and 24 controls were studied. Electrophysiological evaluation was performed in 12 patients in each group by positioning multi-electrode catheters in both atria to determine the following: effective refractory period (ERP) at 10 sites at 600 and 450 ms; conduction time; conduction delay at the crista terminalis (CT); and vulnerability for atrial fibrillation (AF). P-wave duration (PWD) was determined on the surface ECG. In the remaining 12 patients in each group, electroanatomic maps of both atria were created to determine conduction velocity and identify regions of low voltage and electrical silence. Patients with MS had larger left atria (LA) (P < 0.0001); prolonged PWD (P = 0.0007); prolonged ERP in both LA (P < 0.0001) and right atria (RA) (P < 0.0001); reduced conduction velocity in the LA (P = 0.009) and RA (P < 0.0001); greater number (P < 0.0001) and duration (P< 0.0001) of bipoles along the CT with delayed conduction; lower atrial voltage in the LA (P < 0.0001) and RA (P < 0.0001); and more frequent electrical scar (P = 0.001) compared with controls. Five of twelve with MS and none of the controls developed AF with extra-stimulus (P = 0.02)., Conclusion: Atrial remodelling in MS is characterized by LA enlargement, loss of myocardium, and scarring associated with widespread and site-specific conduction abnormalities and no change or an increase in ERP. These abnormalities were associated with a heightened inducibility of AF.

Background: Three-dimensional virtual anatomic navigation is increasingly used during mapping and ablation of complex arrhythmias. NavX Fusion software aims to mold the virtual anatomy to the patient's computed tomography (CT) image; however, the accuracy and clinical usefulness of this system have not been reported., Objective: The purpose of this study was to assess the accuracy and describe the initial experience of CT image integration using NavX Fusion for atrial fibrillation ablation., Methods: This study consisted of 55 consecutive patients undergoing atrial fibrillation ablation using NavX Fusion navigation. Left atrial NavX geometries were compared to a corresponding CT for geometric match. Geometric match, expressed as the difference in millimeters between CT and NavX geometry, was calculated for the original geometry (GEO-1), field scaled and primary fused geometry (GEO-2), and final secondary fused geometry (GEO-3). Navigational accuracy was assessed by moving the catheter to 10 discrete anatomic sites and determining the distance between the catheter tip and the closest GEO-2, GEO-3, and CT surface. Fusion integration time and procedural and fluoroscopic durations were recorded to assess clinical usefulness., Results: GEO-1, GEO-2 and GEO-3 were associated with CT-GEO errors of 6.6+/-2.8 mm, 4.1+/-0.7 mm, 1.9+/-0.4 mm, respectively. Navigational accuracy was not significantly different for GEO-2, GEO-3, and CT at 3.4+/-1.6 mm to any surface. A significant (P < or =.001) inverse curvilinear relationship was present between case number and the time required for image integration (r(2) = 0.35) and the fluoroscopic time normalized for procedural duration (r(2) = 0.18)., Conclusion: Image integration using the NavX Fusion software is highly accurate and is associated with a progressive reduction in fluoroscopic time relative to procedural duration.

Introduction: Sites of complex fractionated atrial electrograms (CFAEs) and highest dominant frequency (DF) have been proposed as critical regions maintaining atrial fibrillation (AF). This study aimed to determine the minimum electrogram recording duration that accurately characterizes CFAE or DF sites for ablation without unduly lengthening the procedure., Methods and Results: Fourteen patients with AF undergoing catheter ablation had high-density (498 +/- 174 points) biatrial mapping performed during AF before ablation. At each point, 8-second electrograms were recorded. CFAE characterization using the NavX software provided a representation of electrogram complexity (CFE-mean). CFE-mean for each point from 7-, 6-, 5-, 4-, 3-, 2-, and 1-second subsamples were compared with the index 8-second CFE-mean. Offline spectral analysis defined DF as the frequency with greatest power, and DF of subsamples were compared with index DF. Index 8-second electrogram CFE-mean was 114 +/- 20 ms for right atria and 102 +/- 17 ms for left atria (P = 0.01); DF was 5.7 +/- 0.8 Hz for right atria and 6.0 +/- 0.8 Hz for left atria (P = 0.02). Means from shorter electrograms were nonsignificantly decreased for CFE-mean and overestimated for DF (P < 0.001). Mean absolute differences between subsampled and index values ranged from 3.3 to 20.1 ms for CFE-mean and 0.11 to 1.18 Hz for DF. Subsampled electrograms deviating >10% from index values ranged from 2.5 to 56% for CFE-mean and 3.5 to 41% for DF. Intraclass correlation coefficients ranged from 0.992 to 0.788 for CFE-mean and 0.897 to 0.233 for DF. Unacceptable differences from index values were found with CFE-mean and DF from electrograms <5 seconds., Conclusion: Electrograms of >or=5-second duration are required to accurately characterize CFAE and DF sites for ablation.

Background: Atrial fibrillation (AF) is characterized by the repetitive regeneration of unstable rotational events, the pivot of which are known as phase singularities (PSs). The spatial concentration and distribution of PSs have not been systematically investigated using quantitative statistical approaches. Objectives: We utilized a geospatial statistical approach to determine the presence of local spatial concentration and global clustering of PSs in biatrial human AF recordings. Methods: 64‐electrode conventional basket (~5 min, n = 18 patients, persistent AF) recordings were studied. Phase maps were produced using a Hilbert‐transform based approach. PSs were characterized spatially using the following approaches: (i) local "hotspots" of high phase singularity (PS) concentration using Getis‐Ord Gi* (Z ≥ 1.96, P ≤.05) and (ii) global spatial clustering using Moran's I (inverse distance matrix). Results: Episodes of AF were analyzed from basket catheter recordings (H: 41 epochs, 120 000 s, n = 18 patients). The Getis‐Ord Gi* statistic showed local PS hotspots in 12/41 basket recordings. As a metric of spatial clustering, Moran's I showed an overall mean of 0.033 (95% CI: 0.0003‐0.065), consistent with the notion of complete spatial randomness. Conclusion: Using a systematic, quantitative geospatial statistical approach, evidence for the existence of spatial concentrations ("hotspots") of PSs were detectable in human AF, along with evidence of spatial clustering. Geospatial statistical approaches offer a new approach to map and ablate PS clusters using substrate‐based approaches. [ABSTRACT FROM AUTHOR]

Aims: Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF.Methods and Results: Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed.Conclusions: Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs. [ABSTRACT FROM AUTHOR]

Rationale: A 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. Objectives: Here, we hypothesized that the observed number of PS or wavelets in AF could be governed by a common set of renewal rate constants λ f (for PS or wavelet formation) and λ d (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 Results: AF 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 λ f and λ d 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 λ f and λ d is associated with slower mixing rates of the M/M/∞ birth–death matrix, providing an explanation for spontaneous AF termination. Conclusion: M/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. [ABSTRACT FROM AUTHOR]

Introduction: Respiratory sinus arrhythmia (RSA) describes heart rate (HR) changes in synchrony with respiration. It is relevant for exercise capacity and mechanistically linked with the cardiac autonomic nervous system. After pulmonary vein isolation (PVI), the current therapy of choice for patients with paroxysmal atrial fibrillation (AF), the cardiac vagal tone is often diminished. We hypothesized that RSA is modulated by PVI in patients with paroxysmal AF.Material and Methods: Respiratory sinus arrhythmia, measured by using a deep breathing test and heart rate variability parameters, was studied in 10 patients (64 ±3 years) with paroxysmal AF presenting in stable sinus rhythm for their first catheter-based PVI. Additionally, heart rate dynamics before and after PVI were studied during sympathetic/parasympathetic coactivation by using a cold-face test. All tests were performed within 24 h before and 48 h after PVI.Results: After PVI RSA (E/I difference: 7.9 ±1.0 vs. 3.5 ±0.6 bpm, p = 0.006; E/I ratio: 1.14 ±0.02 vs. 1.05 ±0.01, p = 0.003), heart rate variability (SDNN: 31 ±3 vs. 14 ±3 ms, p = 0.006; RMSSD: 17 ±2 vs. 8 ±2 ms, p = 0.002) and the HR response to sympathetic/parasympathetic coactivation (10.2 ±0.7% vs. 5.7 ±1.1%, p = 0.014) were diminished. The PVI-related changes in RSA correlated with the heart rate change during sympathetic/parasympathetic coactivation before vs. after PVI (E/I difference: r = 0.849, p = 0.002; E/I ratio: r = 0.786, p = 0.007). One patient with vagal driven arrhythmia experienced AF recurrence during follow-up (mean: 6.5 ±0.6 months).Conclusions: Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined. [ABSTRACT FROM AUTHOR]

Atrial Fibrillation (AF) is the most common cardiac rhythm disorder seen in hospitals and in general practice, accounting for up to a third of arrhythmia related hospitalizations. Unfortunately, AF treatment is in practice complicated by the lack of understanding of the fundamental mechanisms underlying the arrhythmia, which makes detection of effective ablation targets particularly difficult. Various approaches to AF mapping have been explored in the hopes of better pinpointing these effective targets, such as Dominant Frequency (DF) analysis, complex fractionated electrograms (CFAE) and unipolar reconstruction (FIRM), but many of these methods have produced conflicting results or require further investigation. Exploration of AF using information theoretic-based approaches may have the potential to provide new insights into the complex system dynamics of AF, whilst also providing the benefit of being less reliant on empirically derived definitions in comparison to alternate mapping approaches. This work provides an overview of information theory and reviews its applications in AF analysis, with particular focus on AF mapping. The works discussed in this review demonstrate how understanding AF from a signal property perspective can provide new insights into the arrhythmic phenomena, which may have valuable clinical implications for AF mapping and ablation in the future. [ABSTRACT FROM AUTHOR]