Author + information
- Received September 10, 2018
- Revision received November 1, 2018
- Accepted November 8, 2018
- Published online December 26, 2018.
- Fehmi Keçe, MDa,
- Eline F. Bruggemans, MScb,
- Marta de Riva, MDa,
- Reza Alizadeh Dehnavi, MD, PhDa,
- Adrianus P. Wijnmaalen, MD, PhDa,
- Tamara J. Meulman, MDc,
- Julia A. Brugman, MScd,
- Anouk M. Rooijmans, MScd,
- Mark A. van Buchem, MD, PhDc,
- Huub A. Middelkoop, PhDd,
- Jeroen Eikenboom, MD, PhDe,
- Martin J. Schalij, MD, PhDa,
- Katja Zeppenfeld, MD, PhDa and
- Serge A. Trines, MD, PhDa,∗ ()
- aDepartment of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, the Netherlands
- bDepartment of Cardio-thoracic Surgery, Heart Lung Center, Leiden University Medical Center, Leiden, the Netherlands
- cDepartment of Radiology, Leiden University Medical Center, Leiden, the Netherlands
- dDepartment of Neurology & Clinical Neuropsychology, Leiden University Medical Center, Leiden, the Netherlands
- eDepartment of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
- ↵∗Address for correspondence:
Dr. Serge A. Trines, Department of Cardiology, Heart Lung Center, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
Objectives The purpose of this study was to randomly compare the incidence of asymptomatic cerebral embolism (ACE) between the second-generation pulmonary vein ablation catheter (PVAC Gold) and the irrigated Thermocool catheter.
Background Pulmonary vein isolation (PVI) with the pulmonary vein ablation catheter (PVAC) is associated with ACE. The PVAC Gold was designed to avoid this complication.
Methods Patients with paroxysmal atrial fibrillation were randomized 1:1 to PVI with the PVAC Gold or Thermocool catheter. Cerebral magnetic resonance imaging was performed in the days before and after ablation and repeated after 3 months in case of a new lesion. Monitoring for microembolic signals (MES) was performed by using transcranial Doppler ultrasonography. Parameters of coagulation were determined before, during, and after ablation. Neuropsychological tests and questionnaires were applied 10 days before and 3 months after ablation.
Results Seventy patients were included in the study (mean age 61 ± 9 years; 43 male subjects; CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category] score 1.6 ± 1.2; international normalized ratio 2.7 ± 0.5; activated clotting time 374 ± 24 s; p > 0.05 for all parameters). Procedural duration was shorter in the PVAC Gold group (140 ± 34 vs. 207 ± 44 min; p < 0.001). Eight (23%; 7 infarcts) patients in the PVAC Gold group exhibited a new ACE, compared with 2 (6%; no infarcts) patients in the Thermocool group (p = 0.042). Median number of MES was higher in the PVAC Gold group (1,111 [interquartile range, 715-2,234] vs. 787 [interquartile range, 532-1,053]; p < 0.001). There were no differences between groups regarding coagulation and neuropsychological outcomes.
Conclusion PVI with the new PVAC Gold was associated with a higher incidence of ACE/cerebral infarcts and number of MES. Both catheters induced a comparable procoagulant state. Because there were no measurable differences in neuropsychological status, the clinical significance of ACE remains unclear. (Cerebral Embolism (CE) in Catheter Ablation of Atrial Fibrillation (AF) (CE-AF); NCT01361295)
- asymptomatic cerebral embolism
- atrial fibrillation
- catheter ablation
- cooled radiofrequency ablation
- pulmonary vein isolation
- PVAC Gold
The pulmonary vein ablation catheter (PVAC; Medtronic, Minneapolis, Minnesota) is a multipolar, noncooled, duty-cycled radiofrequency (RF) device for pulmonary vein isolation (PVI). Although short procedure times with similar effectiveness compared with cooled point-by-point RF ablation have been described (1), the reported incidence of asymptomatic cerebral embolism (ACE) up to 42% on cerebral magnetic resonance imaging (MRI) raised significant concerns (2–4). Subsequent studies suggested temperature overshoot during intermittent tissue contact and electrical short-circuit between electrodes 1 and 10 as the main causes (5,6). Accordingly, the 9-electrode PVAC Gold was developed to prevent these issues, which led to a 2.1% incidence of ACE (7). This study lacked a control group, however, and the ACE definition did not comply with international consensus (3). Nonetheless, the clinical significance of ACE remains unclear (8,9).
The main purpose of the current study was to randomly compare the incidence of ACE between the PVAC Gold and an irrigated RF catheter. A second goal was to expand the understanding of ACE by analysis of transcranial Doppler and coagulation parameters. The third aim was to evaluate the clinical significance of ACE by using neuropsychological tests.
Consecutive patients referred for a first ablation of paroxysmal, drug-refractory atrial fibrillation (AF) between March 2015 and December 2016 were included and randomized 1:1 to PVI using the PVAC Gold (n = 35) or the Thermocool catheter (Navistar Thermocool, Biosense Webster, Diamond Bar, California; n = 35). Twenty patients with AF (age and education matched) not undergoing ablation served as a reference group for neuropsychological testing (baseline and 3 months). Patients with previous AF ablation, persistent AF, contraindications for MRI, and/or the inability to perform neuropsychological testing were excluded. To avoid bias based on different anticoagulant drugs, we chose to start only vitamin K antagonists in all patients. Patients were maintained on vitamin K antagonists from at least 2 months before until 3 months after the procedure. For their anticoagulant control, all patients were monitored by the regional anticoagulation clinic. Because of the high expertise and structured protocols followed in these clinics, little deviation from the therapeutic international normalized ratio (INR) range is normally observed. All anticoagulation clinics in the Netherlands, in fact, follow the guidelines of the Dutch Federation of Anticoagulation Clinics, which are published in “Kunst van het doseren” (10) and are updated regularly. Data collection was performed by using our electronic patient information system (EPD-Vision). All patients provided written informed consent before study entry. The study was approved by the institutional ethical review board and registered at clinicaltrials.gov (NCT01361295).
Ablation was performed under continued vitamin K antagonist therapy with a targeted peri-procedural INR of 2.0 to 3.0. Patients were treated under deep sedation with propofol/remifentanil or conscious sedation with midazolam/fentanyl. After venous access, a dose of 5,000 IU of heparin was administered. Single (PVAC Gold) or double (Thermocool) transseptal access was obtained with the needle introduced by using the stylet and under intracardiac echocardiography guidance. Mapping of the left atrium (Thermocool) and pulmonary venography (both groups) was performed. Activated clotting time (ACT) was checked every 30 min after transseptal access and maintained >350 s. Energy delivery was not commenced before ACT was >350 s.
For ablation in the left atrium, only ablation lesions to achieve PVI were allowed. For the PVAC Gold, duty-cycled RF energy applications of 60 s (Genius Generator software version 15.1; Medtronic) were delivered in a bipolar:unipolar ratio of either 4:1 (10 W) or 2:1 (8 W) until PVI was achieved. PVI was mainly (99%) performed in the 2:1 energy mode. This method was common practice in our center already with the first-generation PVAC, as in general we often failed to isolate pulmonary veins with the 4:1 energy mode. No touch-ups with a single-tip catheter were performed. For the Thermocool catheter, a point-by-point ablation around both ipsilateral veins was performed until PVI was achieved. RF power was set at 30 to 35 W with a flow rate of 17 to 20 ml/min and a maximum temperature of 43°C for the post-ablation phase. Pulmonary vein isolation (PVI) was confirmed after a waiting period of 30 min, and 5,000 IU protamine was administered before sheath removal. In this study, no additional measures (e.g., adenosine testing) were taken to ensure lesion durability.
A cerebral MRI (1.5-T; Philips Medical Systems, Best, the Netherlands) was performed on the days before and after ablation. Hyperintensities on the diffusion-weighted image were identified, and the corresponding apparent diffusion coefficient maps were calculated. In addition, turbo fluid-attenuated inversion recovery (FLAIR) and T2 weighted turbo spin echo sequences were performed. Technical details of the MRI sequences are described in Online Table A. White matter lesions were categorized with the modified Fazekas scale (11). ACE was defined as a new diffusion abnormality on the diffusion-weighted image sequence with an apparent diffusion coefficient reduced map. Cerebral infarcts were defined as positive ACE with a positive FLAIR. Patients with ACE or cerebral infarcts underwent follow-up MRI using the same protocol 3 months later. MRI results were confirmed by 2 independent radiologists.
Transcranial Doppler ultrasonography
Transcranial Doppler ultrasonography (2 MHz; DWL Multidop-P, DWL, Sipplingen, Germany) of the right middle cerebral artery was continuously performed from venous access to catheter removal. Raw Doppler signals were recorded as MP3 (Eridol R-09, Roland Corporation, Nakagawa, Japan) for off-line analysis. Microembolic signals (MES) were automatically detected and discriminated from artifacts by using a locally developed MATLAB algorithm (MATLAB R2007b, The MathWorks, Inc., Natick, Massachusetts) (12). Number and concentration of MES (MES per unit of time) were calculated for the entire procedure and according to ablation phase: pre-ablation, ablation (10 s before first RF until 60 s after last RF), and post-ablation.
Citrated blood samples (2 × 5 ml) were collected the day before ablation (T1), during the procedure before the first RF application (T2), before sheath removal (T3), and the day after ablation (T4). Samples were centrifuged at 2,700 g for 10 min at 18°C. Markers of intrinsic and extrinsic coagulation (activated partial thromboplastin time, prothrombin time/INR), fibrin turnover (D-dimer), acute phase markers, and coagulant potential (fibrinogen) were measured directly. Other coagulation parameters were analyzed on frozen –70°C aliquots: von Willebrand factor antigen as a marker of endothelial damage, prothrombin fragment 1 + 2 as a marker of thrombin generation, tissue plasminogen activator as a marker of fibrinolysis, and soluble P-selectin as a marker of platelet activation. Measurements are described in the Online Methods.
Two weeks before and 3 months after the ablation, patients underwent neuropsychological testing for global cognitive functioning and intelligence level, memory function, attention and concentration, executive functioning, psychomotor speed, and mood. The age and education matched (based on Verhage) (13) reference group underwent the same tests. The tests are described in the Online Methods.
Power analysis was based on the outcome of 3 previous studies (2,4,14) and the results of our pilot study (15). Combining the outcomes of these studies, 56 (39.4%) of the 142 patients reported ACE after PVAC ablation, and 8 (9.8%) of 82 patients reported ACE after cooled-tip ablation. The rate difference was therefore 29.6%, with a required sample size of 64 to detect a difference in ACE with 80% power at a 0.05% probability level (SPSS Sample Power 2.0; IBM SPSS Statistics, IBM Corporation, Armonk, New York). Accordingly, the group size was set to 35. All continuous data were checked for normality with the Shapiro-Wilk or Kolmogorov-Smirnov test and are expressed as mean ± SD or median and interquartile range (IQR), when appropriate. Data were compared by using an unpaired t-test or Mann-Whitney U test. For categorical data, numbers and frequencies were provided and compared by using a chi-square test or Fisher exact test for low expected count. A mixed linear model with between-subject (group) and within-subject (time) factors was used for the laboratory values and neuropsychological measures. Kaplan-Meier survival curves were constructed (log-rank test) to compare the AF-free survival between the 2 groups. Values of p < 0.05 (2-sided) were considered statistically significant. Data were analyzed by using SPSS version 23.
Patients’ mean age was 59 ± 9 years in the PVAC Gold group and 62 ± 9 years in the Thermocool group. The groups were predominantly male (66% and 57%, respectively). There were no significant differences in any of the baseline characteristics between the 2 groups (Table 1).
Procedure time and RF duration with PVAC Gold were shorter compared with the Thermocool group (Table 2). During the ablation, 99% of the applications were performed in 2:1 bipolar:unipolar mode. The ACT values before electrical cardioversion were always >350 s, except in 1 patient in the PVAC Gold group (327 s).
All patients underwent pre- and post-procedural MRI, and no patients were excluded because of missing data. At pre-procedural MRI, 42 (60%) patients had white matter lesions (25 PVAC Gold–treated patients and 17 Thermocool-treated patients; p = 0.087) with modified Fazekas scores of 0.7 ± 0.6 and 0.7 ± 0.8 (p = 0.725), respectively. Ten patients (5 in each group) had a previous infarction. In 8 patients, the previous infarction was asymptomatic. MRI at a median of 21 h (IQR, 18 to 25 h) after ablation showed 16 new cerebral lesions in 8 (23%) patients (7 patients with cerebral infarction) of the PVAC Gold group compared with 2 ACE in 2 (6%) patients (no cerebral infarction) of the Thermocool group (p = 0.042) (Figure 1). One patient in the PVAC Gold group experienced symptomatic diplopia with corresponding embolism in the nucleus of the oculomotor nerve. The symptoms resolved a few hours after ablation. At follow-up MRI, 6 (38%) of 16 ACE in 4 (11%) patients in the PVAC Gold group but none in the Thermocool group persisted as cerebral infarcts.
Figure 2 shows an example of a patient with 4 cerebral lesions. Details about lesion size and location are described in Online Table B. In the PVAC Gold group, there was no significant difference in the median number of MES between patients with and without cerebral lesions. There was no relation between peri-procedural electrical cardioversion and ACE. The patient who underwent electrical cardioversion with an ACT of 327 s had no cerebral lesion after ablation. There were 9 patients (4 patients in the PVAC Gold group vs. 5 patients in the Thermocool group) with an INR of 1.8 to 1.9 before ablation. However, none of these patients experienced cerebral embolism.
The median number and concentration of MES during the total procedure were higher with the PVAC Gold compared with the Thermocool catheter (1,111 [IQR, 715 to 2,234] vs. 787 [IQR, 532 to 1,053], p < 0.001, respectively, and 8 [IQR, 5 to 17] MES/min vs. 4 [IQR, 3 to 5] MES/min, p < 0.001) (Figure 3). Figure 4 provides an example of procedural MES detection. In the pre-ablation phase, median number but not median concentration of MES was higher in the Thermocool group. In contrast, in the ablation phase, median MES number and concentration were significantly higher in the PVAC Gold group (819 [IQR, 509 to 1,608] vs. 354 [IQR, 181 to 593], p < 0.001 and 13 [IQR, 7 to 24] MES/min vs. 3 [IQR, 2 to 5] MES/min, p < 0.001).
Parameters of coagulation
Ablation with both catheters induced a procoagulant state. This outcome was observed by an increase in D-dimer with no significant difference between the groups (Online Table C). In addition, fibrinogen and prothrombin fragment 1 + 2 were slightly lower during the procedure, whereas von Willebrand factor was elevated post-ablation. No differences in activation of coagulation were observed between the 2 catheters.
No significant differences in test performance were observed between the PVAC Gold and the Thermocool groups for all cognitive domains (Online Table D). For both groups, an increase in the Groninger Intelligence Test-2 results and an increase in memory functioning, executive functioning and psychomotor speed as measured with several subtests was observed 3 months after the ablation. Both groups reported significantly better results on the Hospital Anxiety and Depression Scale after 3 months. No significant differences in neuropsychological test results were observed 3 months after the procedure between patients with and without cerebral infarcts.
The mean age (60 ± 8 years), sex (70% male), and education level (5.6 ± 1.5, equivalent to Higher Professional Education) in the reference group were not significantly different compared with the combined study groups. No significant differences in neuropsychological test results were found between the reference group and the combined study group (Online Table E).
Outcome and complications
One-year antiarrhythmic drug-free AF survival was 49% in the PVAC Gold group and 63% in the Thermocool group (p = 0.229). In the PVAC Gold group, 1 patient had asymptomatic severe (>70%) pulmonary vein stenosis, and 1 patient had a urinary tract infection. In the Thermocool group, there was 1 tamponade and 1 groin hematoma.
To the best of our knowledge, this analysis is the first randomized controlled trial comparing cerebral embolism with the new nonirrigated PVAC Gold catheter and with the irrigated Thermocool catheter. The main findings are that: 1) ablation with the PVAC Gold catheter is associated with a higher incidence of cerebral lesions (23% vs. 6%) and in addition, in the PVAC Gold group, the majority of these lesions were cerebral infarcts compared with none in the Thermocool group; 2) there was a significantly higher number of MES on transcranial Doppler in the PVAC Gold group; and 3) coagulation activity and cognitive functioning did not differ between the groups.
Incidence of ACE
In the first-generation PVAC, a high incidence of ACE (up to 42%) was reported in several studies (2,3). Investigations revealed a suboptimal ACT, air entrapment during catheter introduction, peri-procedural cardioversion, temperature overshoot during intermittent catheter–tissue contact (6), and electrical interaction between electrodes 1 and 10 as possible causes (16). After implementation of procedural modifications (ACT >350 s, catheter submersion before introduction, and deactivating of electrode 10), ACE incidence was reduced to 1.7% (17). Subsequently, the 9-polar PVAC Gold was developed to prevent temperature overshoot and electrode interaction, which yielded an ACE incidence of 2.1% (7). However, discussions were raised about MRI timing and ACE definition in these studies (3). A positive FLAIR sequence was required for ACE diagnosis although scans were performed 16 to 72 hours’ post-ablation (7,17). Because the FLAIR sequence usually becomes positive after 2 to 7 days, underestimation of the real ACE incidence may have occurred (3). In the current trial, ACE incidence with PVAC Gold was 23%, >10-fold compared with the previous studies. In the PVAC Gold group, in 7 of 8 patients, the lesions were cerebral infarctions, compared to none in the Thermocool group. Although we performed the MRI 21 h (IQR, 18 to 25 h) after ablation, FLAIR positivity was seen in 83% of all lesions. Therefore, MRI timing cannot fully explain the differences found in ACE.
In addition, the total duration of RF delivery was similar to other studies (7,17). However, in this study, 99% of the applications were performed in the 2:1 mode. In previous studies (7, 17), respectively 57% and 67% of the ablations were performed in 2:1 mode, 7% in 1:1 mode, and 36% and 26% in 4:1 mode. Accordingly, the mixture in energy mode may have influenced the results.
At 3 months’ follow-up, a lower incidence of cerebral lesions was detected compared with directly post-ablation. In a study with 3-T MRI instead of 1.5-T MRI, the incidence of ACE was doubled to tripled due to the higher spatial resolution, a slice thickness of 2.5 mm instead of 5 mm, and an improved signal-to-noise ratio (18). Because the lesion size of ACE in the current trial was between 3 and 6 mm, and lesions tend to decrease in size during follow-up (14), lesions may have been missed on follow-up MRI.
Across the entire procedure, the number and concentration of MES were much higher in the PVAC Gold group. In the pre-ablation phase, however, the Thermocool catheter showed a higher number of MES. In addition to energy delivery, catheter manipulation contributes to the generation of MES (6). The additional mapping procedure before ablation may therefore explain this finding. During ablation, a higher number and concentration of MES were detected with PVAC Gold. In our pilot with the first-generation PVAC and ACT >300 s, we detected a mean MES number of 2,324 ± 1,406 (15), comparable to other reports with relatively high MES numbers with this catheter (8,19). In the current study with ACT >350 s, we still detected a higher number of MES with PVAC Gold compared with the Thermocool catheter. We therefore believe that several factors (energy mode, temperature overshoot, anticoagulation protocol, and aspect of nonirrigation) may contribute to the incidence of ACE in the PVAC Gold catheter.
Parameters of coagulation activity
There are no other studies comparing coagulation activity between cooled RF ablation and PVAC. During and after the procedure, we observed a progressive increase in D-dimer levels that reflects fibrin formation and subsequent breakdown of fibrin, suggesting activation of coagulation during the procedure. In addition, a progressive increase of von Willebrand factor antigen was observed, reflecting endothelial damage and/or acute phase response. These observations may indicate that the ablation procedure in itself is prothrombotic. However, no significant differences were observed between the 2 groups. Accordingly, the difference in ACE cannot solely be attributed to the observed changes in the pro-coagulant state. One study comparing PVAC with the cryoballoon catheter also found no significant differences in coagulation activity (20), similar to our results.
Clinical significance of ACE
In the current study, 42 (60%) patients had pre-existent white matter lesions and 14% exhibited a previous lacunar infarction. It is known that preexistent white matter lesions can cause cognitive decline (21). However, the additive cognitive effect of new ACE in AF-ablation patients is still a matter of debate. In previous studies, both the presence (9) and absence (8) of negative cognitive effects of ACE have been described. In our study, we detected no decline in cognitive function in patients with and without ACE. It is difficult to determine which numerical decline (whether statistically significant) is also clinically meaningful. There are limited data about cognitive functioning after AF ablation (22). In several studies on other procedures (e.g., after coronary artery bypass grafting), statistical techniques have been implemented to determine “true” (i.e., statistically significant) cognitive decline at the individual level (23). In addition, for major neurocognitive disorder as defined by using international diagnostic guidelines for mental disorders (24), a meaningful decrease in test performance is typically ≥2 SDs below appropriate norms or reference groups (third percentile or below). However, because we did not observe any significant difference but also not a trend toward impaired test results in patients with ACE, we believe that a clinically relevant decline in cognitive function is unlikely. Cerebral location of the lesions between studies may explain the differences in cognitive effects of ACE. Lesion symptom mapping studies have shown that the impact on cognition depends on lesion volume but also on location (25). Lesions in strategic brain regions cause more cognitive impairment. It is more difficult to detect lesions in cortical regions with mechanisms compensating for the affected neuropsychological function. In our study, most of the lesions were located in the cortical regions of the brain.
In the PVAC Gold group, 1 patient experienced an asymptomatic pulmonary vein stenosis, which was detected during a second procedure. Because this patient underwent re-ablation of both left pulmonary veins, it is possible that the second ablation contributed to the progression of the stenosis. Importantly, it is well known that pulmonary vein stenosis might be underdiagnosed due to the lack of a specific clinical presentation (26) and the absence of systematic screening after ablation. In a cohort of 62 patients using the first-generation PVAC, we also observed mild (25% to 50%) narrowing in 37% of the PVs, a moderate (50% to 70%) narrowing in 9%, and severe narrowing (>70%) in 3% (27). Von Bary et al. (28) reported a detectable narrowing of the pulmonary vein diameter after first-generation PVAC ablation in 23% of the patients.
This analysis was a single-center study with a relatively small number of patients in each arm. The size of the study sample was calculated based on the estimates of differences in ACE. Strong conclusions regarding the neuropsychological effects of ACE cannot be drawn, and larger trials are required to confirm the results. We have no detailed information available on the INR values and time in therapeutic range for individual patients in the weeks before and after the procedure. Impedance data could have revealed possible interaction between PVAC Gold electrodes; however, impedance data were not available. The final blood sample was taken 1 day after the ablation. Delayed coagulation effects 3 days after the ablation could not be detected. We did not correct ACE and MES for total RF duration or energy because total RF energy data were not available. Differentiation between solid and gaseous MES would widen the scope of transcranial Doppler MES detection. Dual-frequency insonation during transcranial Doppler could have aided in this differentiation. However, despite developments in both signal acquisition techniques and MES classification algorithms, it remains difficult to reliably determine MES composition, especially in clinical settings in which periods with numerous MES may occur. A complete neurological evaluation by a neurologist according to the National Institutes of Health Stroke Scale could have provided more information on the neuropsychological status of patients with ACE. Only 20 patients were included in the reference group for neuropsychological testing. Neuropsychological tests may not have been sensitive enough to detect changes in complex cognitive functions. Long-term effects on cognitive functioning of the new ACE were not studied.
PVI with the new PVAC Gold is associated with a higher incidence of ACE/cerebral infarctions and a higher number of MES on transcranial Doppler compared with ablation with an irrigated tip catheter. Both ablation technologies induced a similar increase in the procoagulant state. We detected no cognitive decline in patients according to the available test results. Because the purpose of the redesign of the PVAC catheter was to reduce the high incidence of ACE, it can be stated that the improvement of this device was unsuccessful. Therefore, the manufacturer of the PVAC Gold should continue to improve the device.
COMPETENCY IN MEDICAL KNOWLEDGE: ACE is an important complication of AF ablation. The embolic load of noncooled ablation catheters is higher than cooled-RF catheters. In this trial, 23% of the patients undergoing ablation with the PVAC Gold exhibited one or more lesion on MRI, compared with 6% in the Thermocool group. Cognitive functioning was unimpaired, however.
TRANSLATIONAL OUTLOOK: When counseling patients for AF ablation, the risk of cerebral emboli for different catheters should be discussed, and neurological examination should be considered after ablation. The long-term effects of asymptomatic cerebral embolism need to be further evaluated in well-designed studies.
The Department of Cardiology Leiden receives unrestricted research and fellowship grants from Abbott, Boston Scientific, Medtronic, and Biotronik. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- asymptomatic cerebral embolism
- activated clotting time
- atrial fibrillation
- fluid-attenuated inversion recovery
- international normalized ratio
- interquartile range
- microembolic signals
- magnetic resonance imaging
- pulmonary vein ablation catheter
- pulmonary vein isolation
- Received September 10, 2018.
- Revision received November 1, 2018.
- Accepted November 8, 2018.
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