JACC: Clinical Electrophysiology
Persistent Atrial Fibrillation From the OnsetA Specific Subgroup of Patients With Biatrial Substrate Involvement and Poorer Clinical Outcome
Author + information
- Received July 6, 2015
- Revision received November 30, 2015
- Accepted December 27, 2015
- Published online April 1, 2016.
Author Information
- Han S. Lim, MBBS, PhDa,
- Arnaud Denis, MDa,b,
- Melissa E. Middeldorpd,
- Dennis H. Lau, MBBS, PhDd,
- Rajiv Mahajan, MD, PhDd,
- Nicolas Derval, MDa,b,
- Jean-Paul Albenque, MDc,
- Serge Boveda, MDc,
- Stephan Zellerhoff, MDa,
- Seigo Yamashita, MDa,
- Benjamin Berte, MDa,
- Saagar Mahida, MBChBa,
- Yuki Komatsu, MDa,
- Matthew Daly, MBChBa,
- Laurence Jesel, MDa,
- Carole Pomier, PhDa,b,
- Valentin Meillet, MSca,b,
- Remi Dubois, PhDa,b,
- Sana Amraoui, MDa,b,
- Ashok Shah, MDa,
- Frédéric Sacher, MDa,b,
- Hubert Cochet, MDa,b,
- Mélèze Hocini, MDa,b,
- Pierre Jaïs, MDa,b,
- Prashanthan Sanders, MBBS, PhDd and
- Michel Haïssaguerre, MDa,b,∗ (michel.haissaguerre{at}chu-bordeaux.fr)
- aHôpital Cardiologique du Haut-Lévêque, CHU Bordeaux, Université Victor Segalen Bordeaux II, France
- bINSERM U1045 – L’Institut de Rythmologie et Modélisation Cardiaque LIRYC, Bordeaux, France
- cClinique Pasteur, Toulouse, France
- dCentre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia
- ↵∗Reprint requests and correspondence:
Dr. Michel Haïssaguerre, Hôpital Cardiologique du Haut-Lévêque, Avenue de Magellan, 33604 Bordeaux-Pessac, France.
Abstract
Objectives This study sought to characterize the clinical characteristics, atrial substrate, and prognosis in a subgroup of patients with persistent atrial fibrillation (AF) from the onset (PsAFonset).
Background Patients with AF frequently progress from trigger-driven paroxysmal arrhythmias to substrate-dependent persistent arrhythmias.
Methods Patients referred for persistent AF (PsAF) ablation were enrolled from 3 centers. Consecutive patients with PsAFonset (n = 129) were compared with patients with PsAF that progressed from paroxysmal AF (n = 231). In addition, 90 patients (30 patients with PsAFonset and 60 control subjects) were studied with noninvasive mapping to characterize the AF drivers. The degree of fractionation and endocardial voltages were assessed invasively.
Results Patients with PsAFonset were younger (p = 0.047) and more obese (p < 0.001); there were more men (p = 0.034), more patients with hypertension (p = 0.044), and these patients had larger left (p < 0.05) and right atria (p < 0.05). Baseline AF cycle length was shorter in the PsAFonset group (p < 0.01); the degree of fractionation was higher (p < 0.001 for both atria), and the endocardial voltage was lower (p < 0.05 for both atria). Patients with PsAFonset had higher a number of re-entrant driver regions (p < 0.001) and extrapulmonary vein regions that had re-entrant drivers (p < 0.05), whereas control subjects displayed more focal driver regions (p = 0.029). The acute AF termination rate was lower in the PsAFonset group (42% vs. 81%; p < 0.001). During a mean follow-up of 17 ± 11 months from the last procedure, patients with PsAFonset had significantly higher AF, atrial tachycardia (AT), and AF/AT recurrence rates (p < 0.01).
Conclusions Patients with PsAFonset represent a distinct subgroup defined by specific demographics, underlying diffuse biatrial substrate disease, and worse clinical outcome. The findings highlight the importance of defining criteria for early detection of atrial substrate disease.
Although the role of triggers in the initiation of paroxysmal atrial fibrillation (AF) is well-established, the underlying mechanisms sustaining persistent AF (PsAF) remain poorly understood (1). It is unclear why certain patients remain in paroxysmal AF (PAF) for an extended period of time, whereas others progress rapidly to a persistent form of AF (2–5). Atrial electrical remodeling demonstrates early reversal with restoration of sinus rhythm (SR) (6); however, structural remodeling has been suggested to persist in the long term (7,8). These underlying structural changes seem to be the major determinant for susceptibility to induction of AF (7–9). Atrial substrate remodeling has been demonstrated in multiple cardiovascular conditions that are predisposed to AF (10–14), and underlying substrate abnormalities have been demonstrated even in patients with “lone” AF (15–18). It has been proposed that “AF begets AF,” resulting in the progression of disease from paroxysmal to persistent to permanent AF, which occurs because of the progression of the substrate caused by the arrhythmia or the underlying conditions (19). However, why some patients present for the first time with PsAF is unknown, and the natural history of these patients has not been characterized.
In this multicenter cohort, we report on this unique subgroup of patients who presented with PsAF from the onset (PsAFonset). The aim of this study was to characterize the clinical characteristics, atrial substrate, arrhythmia characteristics, and clinical outcomes of this specific subset of patients compared with patients with PsAF who progressed from PAF.
Methods
A detailed description of the Methods is provided in the Online Appendix.
Study population
This multicenter cohort study involved patients with persistent and/or long-standing persistent AF who underwent catheter ablation at the following 3 institutions: CHU Bordeaux, France; Clinique Pasteur, Toulouse, France; and the Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia. Consecutive patients with PsAFonset (n = 129) were compared with a control group of patients with PsAF that progressed from PAF (n = 231). The last 90 consecutive patients at CHU Bordeaux (30 patients with PsAFonset and 60 control subjects) were prospectively studied noninvasively for AF drivers and invasively for fractionation and voltage.
PsAFonset was defined as: 1) PsAF from the time of first AF diagnosis, with a definite date of onset, clear perception of initial presentation, and documented duration of the first AF episode; 2) no previous documentation of PAF by clinical examination or by electrocardiography (ECG) and/or Holter monitoring; and 3) no history of palpitations before the initial diagnosis of AF. Patients were excluded if they had history of palpitations, irregular pulse, or ECG and/or Holter monitoring, or medical documentation of previous PAF. Online Table 1 lists the symptom profiles of both groups of patients. The use of patient information was approved by each institutional Clinical Research Ethics Committee. All patients provided written informed consent for their clinical procedures and additional informed consent for the mapping protocol, which was approved by the Research Ethics Committee.
Assessment of electrogram characteristics
In 30 consecutive patients with PsAFonset and 60 consecutive control subjects (PsAF duration 7 months [interquartile range: 3 to 12 months] vs. 7 months [interquartile range: 4 to 11 months]) at CHU Bordeaux, the characteristics of AF drivers were examined by noninvasive biatrial mapping, and fractionation levels were assessed invasively. Electrogram (EGM) characteristics (maximum EGM duration, maximum number of deflections crossing the isoelectric line, and maximum number of direction changes) from the LA and RA appendages were analyzed from a 5-s recorded window. In 25 consecutive patients from each group, endocardial peak-to-peak bipolar voltages were measured and averaged over a 10-s recording at 4 regions in the RA and at 6 regions in the LA (Online Appendix).
Noninvasive panoramic mapping of AF drivers
The methodology has been previously described (20,21). A commercially available noninvasive mapping system (ECVue, Cardioinsight Technologies Inc., Cleveland, Ohio) was used to provide panoramic mapping. A 252-electrode vest was applied to the patient’s torso. A noncontrast thoracic computed tomography scan was performed to obtain high-resolution, 3-dimensional images of the individual biatrial geometry. Cardiac surface potentials (unipolar EGMs) from torso potentials were reconstructed during each beat and/or cycle using mathematical algorithms and projected on the epicardial biatrial shell. Maps of AF were generated using phase-mapping algorithms (20,21). Localized AF drivers were classified into focal (with ≥2 repetitive focal activities) or re-entrant (with ≥2 rotations), and verified by unipolar EGMs. The biatrial geometry was divided into 7 anatomical regions for aggregated driver-density maps: 1) left pulmonary veins (PVs)/LA appendage; 2) right PV/posterior-septum; 3) posterior and inferior LA and the coronary sinus; 4) superior RA; 5) inferior RA; 6) anterior LA/roof; and 7) anterior LA/anteroseptal region (Online Figure 1). The electrophysiological study and ablation technique are described further in the Online Appendix.
Statistical analysis
Continuous variables were compared using the unpaired t-test for normally distributed data and Mann-Whitney test for non-normally distributed data. Categorical variables were compared using Fisher’s exact or Pearson’s chi-square tests as appropriate. Cumulative event rates for recurrence of atrial arrhythmias were calculated according to the Kaplan-Meier method. Statistical significance was established at p < 0.05. All data were analyzed using PASW Statistics 18 (version 18.0.0, SPSS, Chicago, Illinois).
Results
Clinical and echocardiographic characteristics
Patients with PsAFonset were younger (54.9 ± 11.1 years vs. 57.2 ± 10.1 years; p = 0.047), more likely to be men (89.1% vs. 80.5%; p = 0.034), had a higher proportion of hypertension (50.4% vs. 39.4%; p = 0.044), and were significantly more obese (body mass index: 29.4 ± 4.8 kg/m2 vs. 27.3 ± 3.9 kg/m2; p < 0.001). The duration of the AF diagnosis was significantly longer in control subjects due to the preceding duration of the PAF. However, distribution and median duration of PsAF were similar between the 2 groups (12 months [interquartile range: 4 to 24 months] vs. 12 months [interquartile range: 6 to 20 months]; p = 0.8). LA (p = 0.026) and RA sizes (p = 0.012) were significantly larger in patients with PsAFonset compared with the control subjects. However, left ventricular ejection fractions were similar. Clinical characteristics are listed in Table 1.
Clinical Characteristics of Patients With Persistent AF From the Onset
Baseline atrial fibrillation cycle length, fractionation, and endocardial voltage
Baseline atrial fibrillation cycle length (AFCL) was significantly shorter in patients with PsAFonset compared with control subjects (LA AFCL: 153.0 ms [interquartile range: 138.5 to 161.5 ms] vs. 172.0 ms [interquartile range: 151.0 to 201.0 ms]; p = 0.0011; RA AFCL: 153.0 ms [interquartile range: 137.8 to 166.5 ms] vs. 180.5 ms [interquartile range: 154.5 to 211.8 ms]; p < 0.001). Patients with PsAFonset manifested a higher degree of fractionation measured by several indexes in the left and right atria: 1) increased maximum duration of continuous EGM fractionation (LA: 86.0 ms [interquartile range: 74.0 to 91.5 ms] vs. 54.0 ms [interquartile range: 42.0 to 68.0 ms]; p < 0.001; RA: 76.0 ms [interquartile range: 62.0 to 80.0 ms] vs. 53.0 ms [interquartile range: 39.5 to 61.0 ms]; p < 0.001); 2) increased maximal number of EGM deflections across the isoelectric line (LA: 6 [interquartile range: 4 to 7] vs. 2 [interquartile range: 1 to 4]; p < 0.001; RA: 5 [interquartile range: 4 to 6] vs. 3 [interquartile range: 2 to 3.25]; p < 0.001); and 3) increased maximal number of EGM direction changes (LA: 8 [interquartile range: 6 to 10] vs. 4 [interquartile range: 3 to 6]; p < 0.001; RA: 7 [interquartile range: 6 to 9] vs. 4 [interquartile range: 4 to 5]; p < 0.001) (Figure 1). Endocardial voltage was lower in the patients with PsAFonset in both the LA (p < 0.05) and RA (p < 0.01) compared with control subjects (Figure 2).
Indexes of Fractionation in Patients With PsAFonset and Control Subjects
(A) Maximum duration of fractionation. (B) Ratio of maximum duration of fractionation over baseline atrial fibrillation cycle length (AFCL). (C) Maximum number of direction changes. (D) Maximum number of deflections across isoelectric line. Median (interquartile range) shown. LA = left atrium; PsAFonset = persistent atrial fibrillation from the onset; RA = right atrium.
Mean Bipolar Voltages of RA and LA Regions
The difference in mean log bipolar voltage between the PsAFonset group and control group was significant for both the RA (group effect p < 0.01, region effect p < 0.01) (A) and the LA (group effect p = 0.015, region-effect p < 0.01) (B). Abbreviations as in Figure 1.
Characteristics of AF drivers
Distribution
Both groups had similarly high proportions of patients with re-entrant drivers in the PV regions (regions 1 and 2). However, patients with PsAFonset had a significantly higher proportion of extra-PV regions with re-entrant drivers: inferoposterior LA (region 3: 93.3% vs. 70.0%; p = 0.015), superior RA (region 4: 86.7% vs. 58.3%; p = 0.008), inferior RA (region 5: 40.0% vs. 16.7%; p = 0.015), and anterior LA (region 6: 46.7% vs. 16.7%; p = 0.002) compared with control subjects (Figures 3 and 4). Overall, there was a significantly greater involvement of the RA (re-entrant drivers in regions 4 or 5) in these patients (96.7% vs. 61.7%; p < 0.001).
Distribution of Re-Entrant and Focal AF Drivers in PsAFonset Versus Control Subjects
(A) Proportion of patients (left) with re-entrant drivers and number of rotor rotations per second (right, median [interquartile range (IQR)]) in each region. (B) Proportion of patients (left) with focal drivers and number of focal events per second (right, median [IQR]) in each region.*p < 0.05 between groups. See text and Online Figure 1 for details. PV = pulmonary vein; other abbreviation as in Figure 1.
Driver-Aggregated Maps of Re-Entrant AF Drivers in PsAFonset Versus Control Subject
(A) A 30-year-old woman with 10 months of PsAFonset. Re-entrant drivers were situated diffusely throughout both atria. (B) A 76-year-old woman with similar 10-month duration of PsAF, which was preceded by PAF. Re-entrant drivers were localized at the inferoposterior-wall, left superior PV, and anterior to the right PVs. Anteroposterior and posteroanterior views shown. LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; MA = mitral annulus; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein; TA = tricuspid annulus; other abbreviations as in Figures 1 and 3.
Nature and extent
In the PsAFonset group, the median number of regions with re-entrant drivers (5 [interquartile range: 4 to 6] vs. 4 [interquartile range: 2.25 to 5]; p = 0.0002) and total number of rotor rotations per second (5.72 [interquartile range: 3.92 to 6.79] vs. 4.42 [interquartile range: 3.41 to 5.75]; p = 0.044) were higher compared with those in the control subjects, which was indicative of more widespread substrate disease (Figure 5).
Number of Regions With Re-Entrant and Focal Drivers
(A) Number of regions with re-entrant drivers and total number of rotor rotations in all regions between groups. (B) Number of regions with focal drivers and total number of focal discharges in all regions between groups. Median [IQR] and 10th to 90th percentiles shown. Abbreviation as in Figure 1.
In contrast, the control group of PsAF patients with progression from PAF demonstrated more focal drivers, reflected by: 1) the higher total number of focal discharges per second (1.05 [interquartile range: 0.56 to 1.51] vs. 0.56 [interquartile range: 0.26 to 0.96]; p = 0.013); 2) the higher number of regions with focal drivers (2 [interquartile range: 1 to 3] vs. 2 [interquartile range: 1 to 2]; p = 0.029); and 3) the higher proportion of patients with focal drivers from the right PV region (38.3% vs. 16.7%; p = 0.036).
Procedural characteristics
There were no significant differences in total radiofrequency ablation time and total procedural time for the 2 groups. However, the procedural AF termination rate was strikingly low in patients with PsAFonset compared with control subjects (41.9% vs. 80.5%; p < 0.001) (Figure 6). When analyzed according to the ablation strategy, the AF termination rate was 40.4% versus 82.5% (p < 0.001) in the stepwise ablation group and 46.7% versus 75.0% (p = 0.008) in the driver ablation group. The number of driver regions ablated was significantly higher in the PsAFonset group compared with the control subjects (5 [interquartile range: 4 to 6] vs. 4 [interquartile range: 2 to 6]; p = 0.049).
Procedural AF Termination Rates in the Entire Cohort, and Stepwise and Driver Ablation Subgroups
AF = atrial fibrillation; other abbreviation as in Figure 1.
Follow-up
The average follow-up was 20.1 ± 11.7 months from the first procedure and 16.9 ± 10.7 months from the last procedure. The mean number of procedures was 1.4 ± 0.5 during the follow-up period. There were no significant differences in arrhythmia recurrences after a single procedure (Online Figure 2). However, patients with PsAFonset had a significantly lower freedom from recurrent AF (p < 0.001 log-rank), recurrent AT (p < 0.01 log-rank), and recurrent atrial arrhythmias (AF/AT) (p < 0.001 log-rank) during follow-up from the last procedure (Figure 7).
Kaplan-Meier Estimates of Cumulative Long-Term Freedom
Kaplan-Meier estimates of cumulative long-term freedom from (A) atrial fibrillation (AF), (B) atrial tachycardia (AT), and (C) AF/AT following multiple procedures. Abbreviation as in Figure 1.
Discussion
Patients with AF frequently progress from paroxysmal, trigger-driven arrhythmias to persistent and more substrate-dependent arrhythmias. However, a small group of patients evolve to PsAF without previous paroxysmal episodes. In this less common entity, substrate disease may progress in a rapid or concealed fashion, such that the first presentation of AF is persistent. In this multicenter cohort study, we characterized, for the first time, this unique subset of patients who presented with PsAFonset. This specific subgroup of patients was characterized by the following:
1. A unique set of demographics:
a. Younger;
b. A higher proportion of men;
c. Obese;
d. Presence of cardiovascular disease (e.g., hypertension); and
e. Larger LA and RA size
2. Electrophysiological properties and AF drivers:
a. Shorter AF cycle length;
b. Higher degree of fractionation;
c. Lower biatrial endocardial voltage;
d. Increased number and widespread distribution of re-entrant AF drivers; and
e. Less focal drivers
3. Poorer prognosis:
a. Low acute AF termination rate; and
b. Higher AF and AT recurrence after ablation.
These findings indicate that the underlying substrate disease was the dominant pathophysiological determinant in this group of patients.
Substrate predisposing to the development of persistent AF
The importance of structural remodeling in the pathogenesis of AF has been outlined in numerous animal and human studies (7,8,11,15,18). Although electrical remodeling may reverse with restoration of SR, ultrastructural changes persist in the long term and determine the vulnerability of AF induction despite reverse electrical remodeling (7–9). Indicators of atrial structural remodeling (e.g., increased prevalence of complex signals, conduction slowing, and reduction in voltage) have been described in various cardiovascular conditions that are predisposed to AF, such as hypertension (10,11), valvular heart disease (12), heart failure (14), and sinus node disease. Stiles et al. reported that even when remote from an arrhythmic episode, patients with lone AF demonstrated biatrial voltage reduction, conduction slowing, and increased fractionated signals (15). These structural changes were posited as the predominant contributors to the substrate that underlay AF. Furthermore, abnormal atrial histology consisting of patchy fibrosis and inflammatory infiltrates have been demonstrated in patients with lone AF in a surgical series (18). In patients with PsAF compared with PAF, a higher extent of substrate abnormality was demonstrated with endocardial voltage mapping and fibrosis on autopsy (22,23). The biatrial involvement shown in this subset of patients from echocardiographic and electrophysiological assessments also indicated a more global process that affected the biatrial substrate.
Substrate versus trigger-based disease
Patients with PsAFonset had a significantly higher number and widespread distribution of re-entrant drivers, but they also had a significantly less number of focal drivers and regions that had foci compared with control subjects. This signifies an underlying pathology that is more substrate-based rather than trigger-dependent. Studies on patients with implantable devices, Holter monitoring, and invasive mapping have uniformly demonstrated a reduction in atrial premature beats or focal activity from paroxysmal to PsAF, indicating the transition from a trigger-based paroxysmal disease to a more substrate-based persistent arrhythmia (24,25).
Several studies have examined factors that determine progression from PAF to PsAF (3,5). Conditions that affect the atrial substrate, such as hypertension, structural heart disease, age, and LA enlargement, have consistently been associated with progression to PsAF (3,5). In a recent study, the increase in the dominant frequency rate and atrial fibrosis were also associated with transition to PsAF, corroborating the shorter AFCL recorded in patients with PsAFonset (4). A first presentation with PsAF described in this study is not implausible based on previous reports. Israel et al. described the occurrence of sustained episodes of atrial tachyarrhythmia lasting >48 h in patients with bradycardia despite previous sustained periods of SR lasting >3 months (26). Saksena et al. described the sudden transition from PAF to PsAF in patients monitored with a pacemaker device (24). Most patients transitioning to PsAF were in SR (median atrial tachyarrhythmia burden of 0 or close to 0 h) in the days preceding onset of PsAF, and most patients at risk of developing PsAF had a progressive decrease in atrial tachyarrhythmia burden over time, suggesting that the inception of PsAF was due to substrate remodeling rather than trigger-based events (24).
Despite higher use of amiodarone, AFCL remained shorter, and procedural AF termination rates were remarkably lower in this subset of patients during ablation (27). Furthermore, AF, AT, and AF/AT recurrences were significantly higher after multiple procedures (27). These findings are consistent with previous reports of pre-existent atrial scarring in patients who underwent catheter ablation as an independent predictor of procedural failure, and that it is associated with recurrence of arrhythmias (28,29).
Potential underlying etiologies
Patients with PsAFonset had a higher proportion of hypertension, larger LA and RA sizes, were younger, and more obese. These findings likely reflect several underlying etiologies in this specific subset of patients (underlying structural heart disease, obesity, and genetics). It has been well-established that cardiovascular conditions such as hypertension, structural heart disease, and enlarged atria predispose to the development of AF (10–12,14). Even in patients with lone AF, left ventricular diastolic dysfunction has been demonstrated invasively (16). Interestingly, in another large multicenter study, the only statistically significant factor associated with the degree of atrial fibrosis on magnetic resonance imaging was a history of hypertension (29). Obesity is a known risk factor for AF development, and is associated with diastolic dysfunction and atrial enlargement (30). Increased body mass index is more strongly associated with the development of PsAF compared with PAF (31). Atrial structural and electrical remodeling, including histologic changes and increased expression of profibrotic mediators, have been demonstrated as a direct result of obesity and have been associated with more PsAF (13). Findings of a younger cohort of patients with PsAFonset implicate the contribution of genetics in this specific subgroup (32). Certain genetic AF variants are known to modulate structural remodeling and atrial fibrosis (33). The poor prognosis of these patients emphasizes the need to further characterize AF susceptibility loci and the biological pathways underlying familial AF.
Clinical implications
The present study highlights the critical role of substrate disease in the specific subgroup of patients with PsAFonset, which is associated with a worse prognosis. These findings call for methods to detect subclinical constituents of atrial substrate disease, an emphasis on upstream therapies that modulate the atrial substrate (34), and intensive cardiovascular risk factor management (30,35). Finally, further studies are required to delineate atrial structural remodeling in patients with obesity, underlying cardiovascular comorbidities, and genetic causes of AF, to develop new molecular strategies to modulate the atrial substrate in these patients (30,32).
Study limitations
This study was a nonrandomized multicenter cohort study from prospective databases, with its inherent limitations. Furthermore, the study population consisted only of patients referred for catheter ablation. Although this study was the first to characterize this specific subgroup of patients, further studies are required to demarcate the different underlying etiologies for this presentation. Although younger patients identified in this specific subgroup implicate an underlying genetic component for AF, this could not be confirmed, because genetic studies were not systematically performed. Despite ensuring that patients with PsAFonset included in the study had clear medical documentation of the duration of PsAF upon initial diagnosis, absence of previous ECG and Holter monitor findings of PAF, absence of previous symptoms of palpitations, and clear initiation of their first AF episode, it was possible that some of these patients might have had previous episodes of undocumented and/or asymptomatic PAF. However, the significant findings despite the possibility of misclassification bias and “dilution effect” highlight the importance of this subgroup with rapid development to PsAF.
Conclusions
Patients with PsAFonset represent a distinct subgroup that are younger, more obese, and have a higher proportion of hypertension. The underlying biatrial substrate is diffusely diseased with increased fractionation, decreased endocardial voltage, and more re-entrant and less focal drivers. The ability to maintain SR is worse in these patients. These findings highlight the importance of defining early detection criteria for atrial substrate disease that predispose patients to AF.
COMPETENCY IN MEDICAL KNOWLEDGE: Patients with PsAFonset represent a specific subgroup of patients with underlying diffuse atrial substrate disease and worse clinical outcome. Upon identifying these patients, early therapy and intensive cardiovascular risk factor management should be considered.
TRANSLATIONAL OUTLOOK: The study findings highlight the need to develop methods to detect subclinical constituents of atrial-specific substrate disease.
Appendix
Appendix
For an expanded Methods section as well as supplemental figures and tables, please see the online version of this article.
Footnotes
This work was supported by the Agence Nationale de la Recherche (ANR) under grant ANR-10-IAHU-04, ANR Tempo, Leducq Foundation and European Frame Programme 7. Dr. Lim is supported by the Neil Hamilton Fairley Early Career Fellowship from the National Health and Medical Research Council of Australia. Dr. Lau is supported by a Postdoctoral Fellowship from the National Health and Medical Research Council of Australia. Dr. Mahajan is supported by the Leo J. Mahar Lectureship from the University of Adelaide. Dr. Sanders is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia; is the Knapman Chair of Cardiology Research from the National Heart Foundation of Australia; is on the advisory board of and receives consulting fees from Biosense-Webster, Medtronic, and St. Jude Medical; and has received research funding from Medtronic, St. Jude Medical, Boston Scientific, Biotronik, and Sorin.
Dr. Boveda has consulted for Medtronic and Boston Scientific. Dr. Pomier is an employee of CardioInsight. Dr. Dubois is a consultant for CardioInsight. Dr. Sacher has received lecture honoraria from Biosense-Webster; and is a consultant for St. Jude Medical and Sorin. Dr. Jais is a stockholder in CardioInsight. Dr. Hocini is a stockholder in CardioInsight. Dr. Sanders is a member of the advisory board for Biosense-Webster, Medtronic, St. Jude Medical, Sanofi-Aventis, and Merck, Sharpe, and Dohme; has received consulting fees from Biosense-Webster, Medtronic, and St. Jude Medical; has received lecture fees from Biosense-Webster, Medtronic, St. Jude Medical, Boston Scientific, Merck, Sharpe, and Dohme, Biotronik, and Sanofi-Aventis; and has received research funding from Medtronic, St. Jude Medical, Boston Scientific, Biotronik, and Sorin. Dr. Haissaguerre is a stockholder in CardioInsight. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- AF
- atrial fibrillation
- AFCL
- atrial fibrillation cycle length
- AT
- atrial tachycardia
- ECG
- electrocardiography
- EGM
- electrogram
- LA
- left atrium
- PAF
- paroxysmal AF
- PsAF
- persistent atrial fibrillation
- PsAFonset
- persistent atrial fibrillation from the onset
- PV
- pulmonary vein
- RA
- right atrium
- SR
- sinus rhythm
- Received July 6, 2015.
- Revision received November 30, 2015.
- Accepted December 27, 2015.
- 2016 American College of Cardiology Foundation
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