Long-lasting Atrial Fibrillation Research Articles

Clonal haematopoiesis of indeterminate potential predicts recurrence of atrial arrhythmias after surgical ablation for atrial fibrillation

Abstract Background Clonal haematopoiesis of indeterminate potential (CHIP), characterized by the presence of somatic blood cell clone expanding without other haematological abnormalities, was recently shown to be significantly associated with the development and progression of atrial fibrillation (AF). However, the clinical relevance of CHIP in patients underwent surgical atrial ablation remained unexplored. Aims This study investigated the potential role of CHIP in the recurrence of atrial arrhythmias after surgical ablation in patients with AF. Methods Deep-target sequencing of 74 CHIP (a mean depth of coverage = 4051x) was performed in 132 patients with AF (mean age, 60 years; 75.8% male; mean left atrial diameter, 47mm) who underwent surgical ablation without previous atrial ablation between December 2014 and September 2021. Variant allele fraction (VAF) ≥ 2.0% of any targeted genes indicated the presence of CHIP mutations. The primary outcome is the recurrence of any atrial arrhythmias for >30s after a blanking period of 3 months within a year. The clinical significance of CHIP was determined by multivariable Cox proportional hazards regression. Results A total of 17.4% (23 of 132) patients with AF carried CHIP mutations (DNMT3A, 8.3% and TET2, 3.8%). CHIP prevalence varied among AF types, with paroxysmal, persistent, and long-lasting AF counting for 12.5%, 16.5%, and 36.4%, respectively. During one-year follow-up after blanking period, recurrent atrial arrhythmia was documented in 15 (65.2%) and 37 (33.4%) patients in the CHIP and non-CHIP groups, respectively (p = 0.005 for log-rank test). The association of CHIP with atrial arrhythmias recurrence remained significant after fully adjustment (hazard ratio, [95% confidence interval], 1.92 [1.02-3.63]). Conclusions CHIP mutations with a VAF ≥ 2.0% were identified in 17.4% AF patients undertaken surgical ablation and was associated with poor prognosis. CHIP assessment may be useful in the personalized management of patients who planned to perform surgical ablation for AF.

Roles of Major Chemokines in the Pathophysiology of Atrial Fibrillation

Chemokines are a subclass of cytokines, a large family of small secreted proteins that communicate via G protein-coupled heptahelical chemokine receptors on the cell surface. Atrial fibrillation (AF) is the most prevalent clinically relevant cardiac rhythm condition. Patients with persistent AF have higher levels of C-X-C motif chemokine ligand 8 (CXCL8) than those with paroxysmal AF, thus suggesting a link between long-lasting AF and a low-grade inflammatory response. A newly identified function of C-X-C motif chemokine receptor 2 (CXCR2) is promoting monocyte infiltration of the atria, thus accelerating atrial remodeling and AF after hypertension. Elevated expression of C-X-C motif chemokine ligand 12 (CXCL12) and C-X-C motif chemokine receptor 4 (CXCR4) in the plasma or atria in patients with AF has been linked to increased atrial remodeling, prolonged hospital stays, and elevated risk of death. The CXCL12/CXCR4 axis is highly upregulated in patients with AF which and is among the most effective targets for AF prevention. Upregulated CXCR4 in patients with chronic AF and mitral valve disease is associated with atrial remodeling. Thus, chemokines may be involved in AF development.

Performance of a multisensor implantable defibrillator algorithm for HF monitoring in the presence of atrial fibrillation

Abstract Background Some implantable cardioverter defibrillators (ICD) are equipped with diagnostic algorithms that combine data from multiple sensors. The HeartLogic Index was shown to accurately stratify patients at risk of heart failure (HF) events. However, there are no data on its performance in the presence of atrial fibrillation (AF). We evaluated and compared the performance of the algorithm during sinus rhythm and during long-lasting AF episodes. Methods The feature was activated in 568 ICD patients from 26 centers. We analyzed stored data to identify periods of ≥30 consecutive days with atrial high-rate episode (AHRE) burden <1hour/day, and periods with AHRE burden ≥20hours/day. Then, we identified patients who met both conditions during their follow-up (AHRE group, N=53), to allow pairwise comparison of periods. For control purposes, we identified patients with AHRE burden <1h during the entire follow-up and we implemented a 2:1 propensity score matching versus the AHRE group (Matched non-AHRE group, N=106). Results In the AHRE group, the rate of HeartLogic alerts was 1.2 (95%CI:1.0-1.5) /patient-year during periods with AHRE burden <1hour/day and 2.0 (95%CI:1.5-2.6) /patient-year during AHRE burden ≥20hours/day periods (p=0.004). Significantly higher values of the combined index were recorded during periods with AHRE burden ≥20 hours/day (in Figure the average combined index – Day 0: alert day). The rate of HF hospitalizations was 0.34 (95%CI:0.15-0.69) /patient-year during IN-alert periods and 0.06 (95%CI:0.02-0.14) /patient-year during OUT-of-alert periods (p<0.001). The IN/OUT-of-alert state incidence rate ratio of HF hospitalizations was 8.59 (95%CI:1.67-55.31) during periods with AHRE burden <1hour/day and 2.70 (95%CI:1.01-28.33) during AHRE burden ≥20hours/day periods. In the Matched non-AHRE group, the rate of HF hospitalizations was 0.29 (95%CI:0.12-0.60) /patient-year during IN-alert periods, and 0.04 (95%CI:0.02-0.08) /patient-year during OUT-of-alert periods (p<0.001). The incidence rate ratio was 7.11 (95% CI: 2.19-22.44). Conclusions Patients seemed more exposed to alerts during periods of AF. The ability of the algorithm to identify increased risk of HF events was confirmed during AF, despite a lower IN/OUT-of-alert incidence rate ratio when compared to non-AF periods and non-AF patients.

In patients with atrial cardiomyopathy long-lasting atrial fibrillation is associated with unfavorable structural changes in right chambers and worse outcome

Abstract Background The main factor responsible for atrial cardiomyopathy (ACM) is atrial fibrillation (AF). It is known that AF causes remodeling of the left atrium but its effects on the right heart chambers and mortality are not well studied. Purpose To assess the echocardiographic characteristics of patients with atrial cardiomyopathy with long-standing and paroxysmal AF and their impact on survival. Methods From 624 consecutive patients with AF only 173 met the inclusion criteria for atrial cardiomyopathy, defined as severely dilated left atrium with indexed left atrial volume (LAVI) >48 ml/m2, preserved left ventricular systolic function, without significant valvular disease or left ventricular hypertrophy. The mean age of the studied population was 73,7 ± 9,5 years, 59% women. The patients were divided into two groups according to the presence of persistent or permanent AF (long-standing AF) - Group 1 (n = 87) or paroxysmal AF - Group 2 (n = 86). All patients underwent a comprehensive echocardiography with volumetric and speckle tracking analysis on enrollment and were followed for cardiovascular outcomes, including mortality 24 months. Results The group with long-standing AF had more dilated right atrium (indexed right atrial volume- RAVI 41.9 ± 24.4 vs. 33 ± 13.5 ml/m2; P=0.003), lower reservoir strain of the right atrium (13.1% ± 8.6 vs. 19.7% ± 10.6; P<0.001) and lower right ventricular free wall strain (18.1% ±7.3 vs. 21.2% ± 7.1; P=0.006). Over a median follow up of 18 months (7-29) 16 patients (18%) from Group 1 died compared to 6 patients (7%) from Group 2 (P=0.022). The presence of more than mild tricuspid regurgitation (OR 4.53; CI: 2.37-8.67; P<0.001), heart failure (OR 3.44; 95% CI: 1.83-6.48; P<0.001), and long-standing AF (OR 3.00, 95% CI: 1.41-8.09; P=0.028) were associated with worse mid-term survival. Conclusion Patients with ACM and long-standing AF have more advanced structural changes of the right atrium and the right ventricle and worse prognosis. The presence of more than mild tricuspid regurgitation, heart failure, and long-standing AF are predictors of poor outcome.

Electrocardiographic markers of subclinical atrial fibrillation detected by implantable loop recorder: insights from the LOOP Study.

Insights into subclinical atrial fibrillation (AF) development are warranted to inform the strategies of screening and subsequent clinical management upon AF detection. Hence, this study sought to characterize the onset and progression of subclinical AF with respect to 12-lead electrocardiogram (ECG) parameters. We included AF-naïve individuals aged 70-90 years with additional stroke risk factors who underwent implantable loop recorder (ILR) monitoring in the LOOP Study. Using data from daily ILR recordings and the computerized analysis of baseline ECG, we studied empirically selected ECG parameters for AF detection (≥6 min), cumulative AF burden, long-lasting AF (≥24 h), and AF progression. Of 1370 individuals included, 419 (30.6%) developed AF during follow-up, with a mean cumulative AF burden of 1.5% [95% CI: 1.2-1.8]. Several P-wave-related and ventricular ECG parameters were associated with new-onset AF and with cumulative AF burden in AF patients. P-wave duration (PWD), P-wave terminal force in Lead V1, and interatrial block (IAB) further demonstrated significant associations with long-lasting AF. Among AF patients, we observed an overall reduction in cumulative AF burden over time (IRR 0.70 [95% CI: 0.51-0.96]), whereas IAB was related to an increased risk of progression to AF ≥24 h (HR 1.86 [95% CI: 1.02-3.39]). Further spline analysis also revealed longer PWD to be associated with this progression in AF duration. We identified several ECG parameters associated with new-onset subclinical AF detected by ILR. Especially PWD and IAB were robustly related to the onset and the burden of AF as well as progression over time.

PO-690-03 ATRIAL ELECTROMECHANICAL DISSOCIATION AS A NOVEL NON-INVASIVE PARAMETER OF EARLY REMODELING PROGRESSION DURING ATRIAL FIBRILLATION

Electromechanical assessment during atrial fibrillation (AF) remains a significant knowledge gap in patient-specific characterization of atrial remodeling. Study electromechanical remodeling progression in a long-term pig model of AF and establish the clinical prognostic value of the atrial electromechanical relationship. Experimental group of pigs with AF (N=15) and a prospective clinical cohort (N=95) of symptomatic AF patients (episode duration ≤6 months) undergoing atrial remodeling characterization. Atrial electromechanical remodeling was assessed using simultaneous surface ECG recordings and tissue Doppler imaging (TDI) signals during echocardiography studies in AF. Electromechanical dissociation (EMD) was defined as faster atrial electrical activation rates (EAR) than the simultaneous counterpart TDI-derived mechanical activation rates (MAR). In patients, the primary outcome was cardioversion within a 24-h window after flecainide. Secondary outcomes were cardioversion of persistent AF and recurrences at 1-year. Pigs developed progressive EMD during the first weeks of AF-related remodeling (5-to-21 weeks after protocol initiation). EMD reached 2.29±2.47 Hz (p=0.04) at 12 weeks after the first recorded AF episode lasting ≥6 seconds. In pigs with long-lasting AF (342.5±86.6 d of self-sustained AF), high-resolution electroanatomical mapping and transesophageal echocardiography imaging demonstrated overt EMD (EAR-MAR=3.49±0.67 Hz) between local EARs from unipolar electrograms and the corresponding spatially and temporally synchronized MARs. In patients (55.0±11.6 years old), regardless of AF classification (paroxysmal or persistent AF), EMD was associated with failure of pharmacological cardioversion within the 24-h window after flecainide. EMD provided the highest increase in certainty for the primary outcome when added to AF classification compared to the increase provided by clinical variables and EARs. EMD was also associated with long-term AF recurrences both in the overall AF population and in the patient subset with persistent AF. Figure 1 summarizes the main study results. Atrial EMD is an early indicator of AF remodeling progression with prognostic value in acute and long-term rhythm control.

Classification of De novo post-operative and persistent atrial fibrillation using multi-channel ECG recordings

Atrial fibrillation (AF) is the most sustained arrhythmia in the heart and also the most common complication developed after cardiac surgery. Due to its progressive nature, timely detection of AF is important. Currently, physicians use a surface electrocardiogram (ECG) for AF diagnosis. However, when the patient develops AF, its various development stages are not distinguishable for cardiologists based on visual inspection of the surface ECG signals. Therefore, severity detection of AF could start from differentiating between short-lasting AF and long-lasting AF. Here, de novo post-operative AF (POAF) is a good model for short-lasting AF while long-lasting AF can be represented by persistent AF. Therefore, we address in this paper a binary severity detection of AF for two specific types of AF. We focus on the differentiation of these two types as de novo POAF is the first time that a patient develops AF. Hence, comparing its development to a more severe stage of AF (e.g., persistent AF) could be beneficial in unveiling the electrical changes in the atrium. To the best of our knowledge, this is the first paper that aims to differentiate these different AF stages. We propose a method that consists of three sets of discriminative features based on fundamentally different aspects of the multi-channel ECG data, namely based on the analysis of RR intervals, a greyscale image representation of the vectorcardiogram, and the frequency domain representation of the ECG. Due to the nature of AF, these features are able to capture both morphological and rhythmic changes in the ECGs. Our classification system consists of a random forest classifier, after a feature selection stage using the ReliefF method. The detection efficiency is tested on 151 patients using 5-fold cross-validation. We achieved 89.07% accuracy in the classification of de novo POAF and persistent AF. The results show that the features are discriminative to reveal the severity of AF. Moreover, inspection of the most important features sheds light on the different characteristics of de novo post-operative and persistent AF.

Prevention of long-lasting atrial fibrillation through antitachycardia pacing in DDDR pacemakers.

The MINERVA trial showed that in pacemaker patients with atrial fibrillation (AF) history, DDDRP pacing combining three algorithms - (a) atrial antitachycardia pacing with Reactive ATP enabled, (b) atrial preventive pacing and (c) managed ventricular pacing (MVP)-may effectively delay progression to persistent/permanent AF compared with standard DDDR pacing. We performed a comparative non-randomised evaluation to evaluate if Reactive ATP can be the main driver of persistent/permanent AF reduction independently on preventive pacing. Thirty-one centres included consecutive dual-chamber pacemaker patients with AF history. Reactive ATP was programmed in all patients while preventive atrial pacing was not enabled. These patients were compared with the three groups of MINERVA randomised trial (Control DDDR, MVP, and DDDRP). The main endpoint was the incidence of AF longer than 7 consecutive days. A total of 146 patients (73years old, 54% male) were included and followed for a median observation period of 31months. The 2-year incidence of AF>7days was 12% in the Reactive ATP group, very similar to that found in the DDDRP arm of the MINERVA trial (13.8%, P=.732) and significantly lower than AF incidence found in the MINERVA Control DDDR arm (25.8%, P=.012) and in the MINERVA MVP arm (25.9%, P=.025). In a real-world population of dual-chamber pacemaker patients with AF history, the use of Reactive ATP is associated with a low incidence of persistent AF, highlighting that the positive results of the MINERVA trial were related to the effectiveness of Reactive ATP rather than to preventive pacing.

Prevention of long-lasting atrial fibrillation through antitachycardia pacing in 584 dual-chamber pacemaker patients

Abstract Background Atrial fibrillation (AF) is a frequent arrhythmia in pacemaker patients and is associated with poor quality of life and increased risks of heart failure, dementia, stroke, and death. The MINERVA trial has shown that the combination of 3 pacing algorithms – 1) atrial antitachycardia pacing (aATP), 2) atrial preventive pacing and 3) managed ventricular pacing (MVP) - delays progression to persistent and permanent AF, compared with standard DDDR pacing mode and with MVP mode, in pacemaker patients with AF history. Purpose We performed a comparative non randomized evaluation to confirm the hypothesis that aATP is the main driver of persistent/permanent AF reduction independently on the effect of preventive atrial pacing. Methods Thirty-one Italian and Japanese Cardiology centers included consecutive dual-chamber pacemaker patients with AF history. aATP was programmed in all patients while preventive atrial pacing was not enabled. Comparison was made with all the 3 groups in MINERVA randomized trial. The main endpoint was incidence of AF longer than 7 consecutive days, as detected by device diagnostics. Results A total of 146 patients (73 years old, 54% male) were included and followed for a median observation period of 31 months. The 2-year incidence of AF>7 days was 12% in the aATP group, very similar to that found in the arm of the MINERVA trial with aATP enabled (13.8%, p=0.732) and significantly lower than AF incidence found in the MINERVA Control DDDR arm (25.8%, p=0.012) and in the MINERVA MVP arm (25.9%, p=0.025). Conclusions In a real-world population of dual-chamber pacemaker patients with AF history, use of aATP was associated with low incidence of persistent AF during follow up, highlighting that the positive results of the MINERVA trial are related to the effectiveness of aATP rather than to the effects of preventive atrial pacing. Funding Acknowledgement Type of funding source: None

Assessment of Left Atrial Function in Patients with Paroxysmal, Persistent, and Permanent Atrial Fibrillation using Two-Dimensional Strain.

Atrial fibrillation (AF) has a progressive nature, leading to structural, functional, and electrical changes in the left atrium (LA). Enhanced response to treatment in patients with AF can be achieved through improved knowledge of atrial structure and a better understanding of its function. The aim of this study was to assess LA strain and its determinants in patients with paroxysmal (PAF), persistent (PsAF), and permanent AF (PmAF). Fifty-eight patients with registered non-valvular AF were divided into 3 groups depending on the type of AF. The participants underwent transthoracic echocardiography to assess the anatomy and function of heart chambers. Left atrial longitudinal strain (LALS) was measured in four-chamber projections using two-dimensional speckle tracking echocardiography. Patients with PAF had higher LALS (15.7±12.0) when compared to those with PsAF (4.3±7.9) and PmAF (5.8±7.8, all P=0.003). Multiple linear regression showed that the independent predictors of LALS were diastolic blood pressure (β=0.95, R2=0.88) in the PAF group; left atrial area (β=-0.56) and creatinine (β=-0.63, R2=0.58) in the PsAF group; AF duration (β=0.89) in the PmAF group (R2=0.72). LA strain has different determinants depending on AF type. LA size, renal function, and AF duration determine LALS in long-lasting AF. LA strain is a simple and accurate technique to estimate LA dysfunction in patients with long-lasting AF.

P6556Prevention of long-lasting atrial fibrillation through device therapy in dual-chamber pacemakers: analysis on 1384 patients of the role of Reactive ATP and atrial preventive pacing

Abstract Background Atrial fibrillation (AF) is the most prevalent heart rhythm disorder in clinical practice and it is associated with poor quality of life and increased risks of heart failure, dementia, stroke, and death. Moreover AF management is a huge cost for healthcare systems. AF is irregular, typically originates from the pulmonary veins, and as such, requires cardioversion to terminate persistent episodes. AF is not susceptible to pace-termination, however, the MINERVA trial has shown that AF may transform in slower organized rhythms such as atrial flutter or atrial tachycardia, which can often be terminated by atrial anticahycardia pacing (ATP); in particular by Reactive ATP, a specific ATP feature which can be re-armed when atrial arrhythmias get slower or more regular. The MINERVA trial showed that the combination of ATP, preventive atrial pacing algorithms and minimal ventricular pacing (MVP) was associated with lower progression to persistent and permanent AF, compared with standard DDD pacing mode and to MVP mode, in pacemaker patients with clinical history of AF. Purpose We aimed to confirm MINERVA trial results in real-world clinical practice and to evaluate whether AF prevention was associated with preventive atrial pacing or solely with ATP. Indeed in our project atrial preventive pacing algorithms were not enabled and the pacing mode (DDD or MVP) was chosen according to patients' AV conduction characteristics. Methods Consecutive dual-chamber pacemaker patients with sinus node disease and device detected AT/AF were prospectively followed by 30 Italian cardiologic centers in an observational research. Clinical and device data were collected and reviewed by expert cardiologists to assess AT/AF occurrence through in clinic visit and/or remote transmissions of device data. Results A total of 239 patients (73 years old, 56% male) wearing a dual-chamber pacemaker with Reactive ATP were included in the project, followed for a median observation period of 13 months and compared with 1145 patients included in the MINERVA trial followed for a median observation period of 34 months and programmed with DDD pacing mode (383 patients), MVP (389 patients) and MVP+Reactive ATP+preventive algorithms (373 patients). As shown in the following figure incidence of 7 consecutive days of AF in the patients treated by DDD/MVP+Reactive ATP in real-world clinical practice was very similar to that found in the MINERVA trial arm programmed with MVP+Reactive ATP+preventive algorithms. Incidence of AF longer than 7 days Conclusions Our analysis performed in a population of sinus node disease patients with dual-chamber pacemakers confirmed MINERVA trial results in terms of prevention of long-lasting AF episodes. In particular these results confirm the benefit associated with the use of Reactive ATP, rather than preventive atrial pacing algorithms.

HDAC (Histone Deacetylase) Inhibitor Valproic Acid Attenuates Atrial Remodeling and Delays the Onset of Atrial Fibrillation in Mice.

A structural, electrical and metabolic atrial remodeling is central in the development of atrial fibrillation (AF) contributing to its initiation and perpetuation. In the heart, HDACs (histone deacetylases) control remodeling associated processes like hypertrophy, fibrosis, and energy metabolism. Here, we analyzed, whether the HDAC class I/IIa inhibitor valproic acid (VPA) is able to attenuate atrial remodeling in CREM-IbΔC-X (cAMP responsive element modulator isoform IbΔC-X) transgenic mice, a mouse model of extensive atrial remodeling with age-dependent progression from spontaneous atrial ectopy to paroxysmal and finally long-lasting AF. VPA was administered for 7 or 25 weeks to transgenic and control mice. Atria were analyzed macroscopically and using widefield and electron microscopy. Action potentials were recorded from atrial cardiomyocytes using patch-clamp technique. ECG recordings documented the onset of AF. A proteome analysis with consecutive pathway mapping identified VPA-mediated proteomic changes and related pathways. VPA attenuated many components of atrial remodeling that are present in transgenic mice, animal AF models, and human AF. VPA significantly ( P<0.05) reduced atrial dilatation, cardiomyocyte enlargement, atrial fibrosis, and the disorganization of myocyte's ultrastructure. It significantly reduced the occurrence of atrial thrombi, reversed action potential alterations, and finally delayed the onset of AF by 4 to 8 weeks. Increased histone H4-acetylation in atria from VPA-treated transgenic mice verified effective in vivo HDAC inhibition. Cardiomyocyte-specific genetic inactivation of HDAC2 in transgenic mice attenuated the ultrastructural disorganization of myocytes comparable to VPA. Finally, VPA restrained dysregulation of proteins in transgenic mice that are involved in a multitude of AF relevant pathways like oxidative phosphorylation or RhoA (Ras homolog gene family, member A) signaling and disease functions like cardiac fibrosis and apoptosis of muscle cells. Our results suggest that VPA, clinically available, well-tolerated, and prescribed to many patients for years, has the therapeutic potential to delay the development of atrial remodeling and the onset of AF in patients at risk.

Efficacy of Antiarrhythmic Drugs Short-Term Use After Catheter Ablation for Atrial Fibrillation (EAST-AF) trial.

Substantial portion of early arrhythmia recurrence after catheter ablation for atrial fibrillation (AF) is considered to be due to irritability in left atrium (LA) from the ablation procedure. We sought to evaluate whether 90-day use of antiarrhythmic drug (AAD) following AF ablation could reduce the incidence of early arrhythmia recurrence and thereby promote reverse remodelling of LA, leading to improved long-term clinical outcomes. A total of 2038 patients who had undergone radiofrequency catheter ablation for paroxysmal, persistent, or long-lasting AF were randomly assigned to either 90-day use of Vaughan Williams class I or III AAD (1016 patients) or control (1022 patients) group. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of class I or III AAD at 1 year, following the treatment period of 90 days post ablation. Patients assigned to AAD were associated with significantly higher event-free rate from recurrent atrial tachyarrhythmias when compared with the control group during the treatment period of 90 days [59.0 and 52.1%, respectively; adjusted hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.73-0.96; P = 0.01]. However, there was no significant difference in the 1-year event-free rates from the primary endpoint between the groups (69.5 and 67.8%, respectively; adjusted HR 0.93; 95% CI 0.79-1.09; P = 0.38). Short-term use of AAD for 90 days following AF ablation reduced the incidence of recurrent atrial tachyarrhythmias during the treatment period, but it did not lead to improved clinical outcomes at the later phase.

Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial.

Most of recurrent atrial tachyarrhythmias after pulmonary vein isolation (PVI) for atrial fibrillation (AF) are due to reconnection of PVs. The aim of the present study was to evaluate whether elimination of adenosine triphosphate (ATP)-induced dormant PV conduction by additional energy applications during the first ablation procedure could reduce the incidence of recurrent atrial tachyarrhythmias. We randomly assigned 2113 patients with paroxysmal, persistent, or long-lasting AF to either ATP-guided PVI (1112 patients) or conventional PVI (1001 patients). The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at 1 year with the blanking period of 90 days post ablation. Among patients assigned to ATP-guided PVI, 0.4 mg/kg body weight of ATP provoked dormant PV conduction in 307 patients (27.6%). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4%). At 1 year, 68.7% of patients in the ATP-guided PVI group and 67.1% of patients in the conventional PVI group were free from the primary endpoint, with no significant difference (adjusted hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.74-1.09; P = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the 1-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; P = 0.16). In the catheter ablation for AF, we found no significant reduction in the 1-year incidence of recurrent atrial tachyarrhythmias by ATP-guided PVI compared with conventional PVI.

Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice.

BackgroundAtrial fibrillation (AF) is the most common arrhythmias among old people. It causes serious long-term health problems affecting the quality of life. It has been suggested that the autonomic nervous system is involved in the onset and maintenance of AF in human. However, investigation of its pathogenesis and potential treatment has been hampered by the lack of suitable AF models in experimental animals.ObjectivesOur aim was to establish a long-lasting AF model in mice. We also investigated the role of adrenergic receptor (AR) subtypes, which may be involved in the onset and duration of AF.Methods and ResultsTrans-esophageal atrial burst pacing in mice could induce AF, as previously shown, but with only a short duration (29.0±8.1 sec). We found that adrenergic activation by intraperitoneal norepinephrine (NE) injection strikingly increased the AF duration. It increased the duration to more than 10 minutes, i.e., by more than 20-fold (656.2±104.8 sec; P<0.001). In this model, a prior injection of a specific β1-AR blocker metoprolol and an α1-AR blocker prazosin both significantly attenuated NE-induced elongation of AF. To further explore the mechanisms underlying these receptors’ effects on AF, we assessed the SR Ca2+ leak, a major trigger of AF, and consequent spontaneous SR Ca2+ release (SCR) in atrial myocytes. Consistent with the results of our in-vivo experiments, both metoprolol and prazosin significantly inhibited the NE-induced SR Ca2+ leak and SCR. These findings suggest that both β1-AR and α1-AR may play important roles in the development of AF.ConclusionsWe have established a long-lasting AF model in mice induced by adrenergic activation, which will be valuable in future AF study using experimental animals, such as transgenic mice. We also revealed the important role of β1- and α1-AR-mediated signaling in the development of AF through in-vivo and in-vitro experiments.

EP News: Clinical

Haissaguerre et al (Circulation 2014;130:530, PMID 2502839) applied noninvasive signal processing to identify drivers of persistent atrial fibrillation (AF). In 103 consecutive patients with persistent AF, accurate biatrial geometry relative to an array of 252 body surface electrodes was obtained from a computed tomographic scan. The driver domains were catheter ablated by using AF termination as the procedural end point in comparison with the stepwise-ablation control group. In total, 4720 drivers were identified in 103 patients: 3802 (80.5%) reentries and 918 (19.5%) focal breakthroughs. Driver ablation alone terminated 75% and 15% of persistent and long-lasting AF, respectively. The mean radiofrequency delivery to AF termination was 28 ± 17 minutes vs 65 ± 33 minutes in the control group (P < .0001). At 12 months, 85% of patients with AF termination were free from AF, which was similar to the control population (87%; P = NS). The authors conclude that persistent AF in early months after ablation is maintained predominantly by drivers clustered in a few regions, most of them being unstable reentries.

Driver domains in persistent atrial fibrillation.

Specific noninvasive signal processing was applied to identify drivers in distinct categories of persistent atrial fibrillation (AF). In 103 consecutive patients with persistent AF, accurate biatrial geometry relative to an array of 252 body surface electrodes was obtained from a noncontrast computed tomography scan. The reconstructed unipolar AF electrograms acquired at bedside from multiple windows (duration, 9±1 s) were signal processed to identify the drivers (focal or reentrant activity) and their cumulative density map. The driver domains were catheter ablated by using AF termination as the procedural end point in comparison with the stepwise-ablation control group. The maps showed incessantly changing beat-to-beat wave fronts and varying spatiotemporal behavior of driver activities. Reentries were not sustained (median, 2.6 rotations lasting 449±89 ms), meandered substantially but recurred repetitively in the same region. In total, 4720 drivers were identified in 103 patients: 3802 (80.5%) reentries and 918 (19.5%) focal breakthroughs; most of them colocalized. Of these, 69% reentries and 71% foci were in the left atrium. Driver ablation alone terminated 75% and 15% of persistent and long-lasting AF, respectively. The number of targeted driver regions increased with the duration of continuous AF: 2 in patients presenting in sinus rhythm, 3 in AF lasting 1 to 3 months, 4 in AF lasting 4 to 6 months, and 6 in AF lasting longer. The termination rate sharply declined after 6 months. The mean radiofrequency delivery to AF termination was 28±17 minutes versus 65±33 minutes in the control group (P<0.0001). At 12 months, 85% patients with AF termination were free from AF, similar to the control population (87%,); P=not significant. Persistent AF in early months is maintained predominantly by drivers clustered in a few regions, most of them being unstable reentries.

Ryanodine Receptor–Mediated Calcium Leak Drives Progressive Development of an Atrial Fibrillation Substrate in a Transgenic Mouse Model

The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca(2+) leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca(2+) release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca(2+) release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca(2+)/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca(2+) release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca(2+)-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. RyR2-mediated SR Ca(2+) leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca(2+) release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.

Prevalence, Characteristics, Mapping, and Catheter Ablation of Potential Rotors in Nonparoxysmal Atrial Fibrillation

Identification of critical atrial substrates in patients with nonparoxysmal atrial fibrillation (AF) failing to respond to pulmonary vein isolation is important. This study investigated the signal characteristics, substrate nature, and ablation results of rotors during AF. In total, 53 patients (age=55±8), 31 with persistent AF and 22 with long-lasting AF, underwent pulmonary vein isolation and substrate modification of complex fractionated atrial electrograms. Small-radius-reentrant rotors were identified from signal analyses of the dominant frequency and fractionation interval and nonlinear analyses (newly developed, beat-to-beat nonlinear measurement of the repetitiveness of the electrogram morphology>6 seconds). In 15% of the patients, activation maps demonstrated occurrences of rotor-like small-radius reentrant circuits (n=9; 1.1 per patient; cycle length=110±21 ms; diameter=11±6 mm) with fibrillation occurring outside these areas. Rotors were identified by conventional point-by-point mapping and signal analyses and were subsequently eradicated by catheter ablation in these patients. Persistent AF for <1 year, a smaller left atrial size, substrates with higher mean voltages and shorter total activation durations predicted a higher incidence of rotors (all P<0.05). In the multivariable model, areas of reentrant circuits exhibited a higher dominant frequency, kurtosis, and higher degree of a beat-to-beat electrogram similarity than areas without or outside the rotors (all P<0.05). Rotor-like re-entry with fibrillatory conduction was found in a limited number of patients with nonparoxysmal AF after pulmonary vein isolation. Those areas were characterized by rapid repetitive activity with a high degree of electrogram similarity.

Conduction characteristics in atrial fibrillation

Atrial fibrillation (AF) is one of the most common arrhythmias observed in clinical practice. The frequency of AF is increased in patients with impaired interatrial conduction. We aimed to investigate whether tissue Doppler echocardiography could be used for the evaluation of atrial conduction characteristics instead of an electrophysiological study, and to examine the predictive accuracy of tissue Doppler echocardiography for the inducibility of sustained AF. We enrolled 86 consecutive patients who underwent an electrophysiological study. We performed electrocardiographic P wave dispersion, M-mode, two-dimensional, Doppler, and tissue Doppler echocardiography as well as an electrophysiological study (EPS) to evaluate the intra- and interatrial conduction times. We tried to induce AF, and the patients were categorized according to the inducibility of sustained (> 120s) AF. We found a good correlation between intra-left atrial conduction time detected by tissue Doppler echocardiography (ILCT-echo) and by EPS (ILCT-eps; r = 0.744, p < 0.001), and a weak correlation between interatrial conduction times (IACT-echo and IACT-eps, r = 0.396, p < 0.001). In patients with inducible sustained AF, P wave dispersion (46 ± 19ms vs. 27 ± 18, p < 0.001), ILCT-echo (29 ± 10ms vs. 17 ± 7ms, p < 0.001), and IACT-eps (47 ± 11ms vs. 36 ± 13ms, p < 0.001) were found to be higher than those of the noninducible/nonsustained AF group. These three parameters were independent predictors of the inducibility of sustained AF. We demonstrated that ILCT-echo could be used instead of ILCT-eps for the evaluation of left atrial conduction characteristics. We also showed that ILCT-eps could be a valuable parameter for predicting the development of long-lasting AF.