Author + information
- Received October 15, 2008
- Revision received December 2, 2008
- Accepted January 8, 2009
- Published online August 25, 2009.
- Seiichiro Matsuo, MD⁎,⁎ (, )
- Nicolas Lellouche, MD⁎,
- Matthew Wright, MBBS, PhD⁎,
- Michela Bevilacqua, MD⁎,
- Sébastien Knecht, MD⁎,
- Isabelle Nault, MD⁎,
- Kang-Teng Lim, MD⁎,
- Leonardo Arantes, MD⁎,
- Mark D. O'Neill, MB, BCh, DPhil⁎,
- Pyotr G. Platonov, MD, PhD†,
- Jonas Carlson, MSC, PhD†,
- Frederic Sacher, MD⁎,
- Mélèze Hocini, MD⁎,
- Pierre Jaïs, MD⁎ and
- Michel Haïssaguerre, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Seiichiro Matsuo, Service de Rythmologie, Hôpital Cardiologique du Haut-Lévêque, Avenue de Magellan, 33604 Bordeaux-Pessac, France
Objectives This study evaluated the role of pre-procedural clinical variables to predict procedural and clinical outcomes of catheter ablation in patients with long-lasting persistent atrial fibrillation (AF).
Background Catheter ablation of persistent AF remains a challenging task.
Methods Catheter ablation was performed in 90 patients (76 men, age 57 ± 11 years) with long-lasting persistent AF. The history of AF, echocardiographic parameters, presence of structural heart disease, and surface electrocardiogram (ECG) AF cycle length (CL) were assessed before ablation and analyzed with respect to procedural termination and clinical outcome. Mean follow-up was 28 ± 4 months.
Results Persistent AF was terminated in 76 of 90 patients (84%) by ablation. The duration of continuous AF was shorter (p < 0.0001), the surface ECG AFCL was longer (p < 0.0001), and the left atrium was smaller (p < 0.01) in patients in whom AF was terminated by catheter ablation. The surface ECG AFCL was the only independent predictor of AF termination (p < 0.01). Maintenance of sinus rhythm was associated with a shorter duration of continuous AF (p < 0.0001), a longer surface ECG AFCL (p < 0.001), and a smaller left atrium (p < 0.05) compared with those with recurrent arrhythmia. In multivariate analysis, the surface ECG AFCL and the AF duration predicted clinical success of persistent AF ablation (p < 0.01 and p < 0.05, respectively).
Conclusions The surface ECG AFCL is a clinically useful pre-ablation tool for predicting patients in whom sinus rhythm can be restored by catheter ablation. The duration of continuous AF and the surface ECG AFCL are predictive of maintenance of sinus rhythm.
Atrial fibrillation (AF) accounts for almost one-third of all admissions to a hospital for a cardiac rhythm disturbance. Catheter ablation targeting isolation of the pulmonary veins (PVs) has evolved over the past decade and has become the treatment of choice for drug-resistant paroxysmal AF. The use of ablation for treatment of persistent AF has been expanding, with more centers now offering the procedure. Catheter ablation can terminate persistent AF and can result in maintenance of sinus rhythm, at least in the medium term (1–5). The AF cycle length (CL) measured from the left atrial appendage (LAA) has been used as a predictor of procedural termination of persistent AF (5); however, this can only be performed at the time of the procedure. The purpose of this study was to investigate which clinical variables, including a noninvasive measurement of AFCL from the surface electrocardiogram (ECG), are predictive of a successful procedural and medium-term clinical outcome using a sequential catheter ablation approach in patients with persistent AF.
Of a total of 92 consecutive patients, 90 patients who underwent first-time radiofrequency catheter ablation for long-lasting persistent AF were included in the present study, with 2 patients excluded because of low-amplitude fibrillatory waves (minimal voltage <0.01 mV) that precluded accurate measurement of AFCL from the surface ECG. Long-lasting persistent AF was defined as continuous AF lasting longer than 1 month, resistant to either electrical or pharmacological cardioversion. All patients gave written informed consent.
All patients had effective anticoagulation therapy (target international normalized ratio of 2 to 3) for more than 1 month, and atrial thrombus was excluded by transesophageal echocardiography before the procedure. All antiarrhythmic drugs, with the exception of amiodarone, were discontinued 5 half-lives before the procedure. The electrophysiological study was performed in the fasting state under mild sedation using midazolam and morphine. The following catheters were introduced via the right femoral vein: 1) a steerable decapolar catheter (Xtrem, Sorin Group, Le Plessis-Robinson, France) was positioned within the coronary sinus; 2) a circumferential mapping catheter (Lasso, Biosense Webster, Diamond Bar, California) was introduced after transseptal access; and 3) a 4-mm externally irrigated-tip ablation catheter (Thermocool, Biosense Webster) was used for mapping and ablation. After transseptal access, a single bolus of 50 IU/kg body weight of heparin was administrated and repeated only for procedures lasting more than 4 h. Surface ECG and endocardial electrograms were continuously monitored and recorded for off-line analysis (Bard Electrophysiology, Lowell, Massachusetts).
Measurement of the AFCL from surface ECG and intracardiac electrograms
The surface ECG AFCL was compared with the endocardial AFCL obtained simultaneously from the intracardiac recordings at both the LAA and the right atrial appendage (RAA) before ablation. In all patients, the surface ECG AFCL was manually measured from 10 unambiguous fibrillatory waves on lead V1(minimal voltage >0.01 mV) that were not fused with QRST segments (Fig. 1)at a paper speed of 50 mm/s and a gain setting of 20, 40, or 80 mm/mV. The mean LAA CL and RAA CL were calculated using custom software (Bard Electrophysiology) with manual verification (5).
In the first 30 patients, intraobserver and interobserver error of the surface ECG AFCL from 10 CL was assessed. The surface ECG AFCL from 10 CL was measured on 2 different days and using 2 independent experts, respectively. The mean surface ECG AFCL from 10 CL was compared with that from 30 CL (manually measured) and with the mean AFCL using automated time frequency analysis (TFA) of 60 s of simultaneous surface ECG recording as previously described (6,7). Digital measurement of fibrillatory rates using TFA was disqualified because of poor signal quality in 4 patients.
Ablation of long-lasting persistent AF
In all patients, sequential stepwise ablation was performed as previously described (5), involving PV isolation, electrogram-based ablation, and linear ablation. Ablation around the PVs was performed with the aid of a Lasso catheter. The end point of this step was the elimination or dissociation of the PV potentials as determined by a Lasso catheter in all veins. Isolation of the PVs was confirmed after restoration of sinus rhythm. After this, electrogram-based ablation was performed at sites in the left atrium (LA) showing any of the following electrogram features: continuous electrical activity, complex rapid and fractionated electrograms, and a gradient of activation (a temporal gradient of at least 70 ms between the distal and proximal bipoles on the roving distal ablation electrode, potentially representing a local circuit). Linear ablation in the LA was performed if AF persisted after electrogram-based ablation. A roof line was performed joining the right and left superior PVs, and if AF continued, a mitral isthmus line from the mitral annulus to the left inferior PV was performed as previously described (5). After restoration of sinus rhythm, assessment of conduction block across the lines was performed in all patients with supplementary ablation, if necessary, to achieve block (8). A cavotricuspid isthmus line was performed in all patients with an end point of bidirectional block.
Procedural end point of long-lasting persistent AF ablation
The procedural end point was termination of long-lasting persistent AF by catheter ablation, either by conversion directly to sinus rhythm or via one or more atrial tachycardias, which were subsequently mapped and ablated (5). When AF was not terminated by ablation, it was terminated by electrical cardioversion (procedural failure). After cardioversion, if necessary, supplemental radiofrequency energy was delivered to establish PV isolation and conduction block of any linear lesion.
Clinical outcome of long-lasting persistent AF ablation
Success was defined as maintenance of sinus rhythm without antiarrhythmic drug treatment more than 12 months after the final procedure. Failure was defined as documented recurrence of AF or atrial tachycardia lasting for more than 3 min.
Patients were hospitalized for between 3 and 5 days post-procedure and seen at 1, 3, 6, and 12 months for clinical interview, echocardiography, and 24-h ambulatory monitoring in addition to routine follow-up by the referring cardiologist. One year from the last procedure, patients were seen every 6 months by their referring cardiologist. All patients underwent 24-h Holter monitoring within the last 3 months of follow-up. Antiarrhythmic medication was continued for 1 to 3 months after the index procedure, and anticoagulation treatment was continued for at least 6 months. A repeat ablation procedure was undertaken in the event of a recurrence of AF or atrial tachycardia lasting more than 3 min.
Linear regression analysis was used to test the association between the surface ECG AFCL from 10 CL and 30 CL, TFA of a 60-s sample window, LAA AFCL, RAA AFCL, and procedure time. A Bland-Altman plot was generated to examine the precision between the RAA CL and the surface ECG AFCL from 10 CL, 30 CL, and TFA. To evaluate intraobserver and interobserver variability, the Pearson correlation coefficient (r) was calculated for the surface ECG AFCL from 10 CL.
Continuous variables are expressed as mean ± SD or median with interquartile range where indicated. Statistical significance was assessed using the unpaired Student ttest or Mann-Whitney Utest if necessary. Categorical variables, expressed as numbers or percentages, were analyzed using the chi-square test or Fisher exact test. To analyze independent predictive factors of termination of AF during ablation and independent factors of clinical success, univariate factors presenting p < 0.1 were analyzed using logistic regression (multivariate analysis). The receiver-operator characteristic (ROC) curve was determined to evaluate the performance of the best independent predictor of AF termination by catheter ablation. The optimal cutoff point was chosen as the combination with the highest sensitivity and specificity. All tests were 2-tailed, and p < 0.05 was considered significant. Cumulative event rates (recurrence of arrhythmia) were calculated according to the Kaplan-Meier method.
The baseline characteristics of the overall study population are shown in Table 1.The mean age was 57 ± 11 years (median 56 years, interquartile range 50 to 64 years); 84% (76) were male. The mean duration of continuous AF was 28 ± 31 months (median 19 months, interquartile range 9 to 36 months), and 28% (25 of 90) of patients took amiodarone within 3 months of the procedure. Patients were followed up for a mean of 28 ± 4 months (median 27 months, interquartile range 24 to 30 months) after the first ablation procedure. Patients were later categorized according to whether or not persistent AF was terminated by catheter ablation and whether or not atrial arrhythmia recurred after the final ablation procedure.
Validation of surface ECG AFCL from 10 fibrillatory waves
Intraobserver and interobserver correlations were high in the measurement of the AFCL from the surface ECG using 10 CL (R = 0.97 and R = 0.98, respectively). In first 30 patients, surface ECG AFCL was calculated using manual measurement of 10 and 30 CL and the use of TFA analysis of a 60-s simultaneous recording window. There was a strong correlation between the AFCL from the surface ECG measured with 10 and 30 CL (R = 0.984, p < 0.0001) (Fig. 2A)and between the surface ECG AFCL calculated manually using 10 CL and digital measurement using TFA (R = 0.941, p < 0.0001) (Fig. 2B).
Correlation of surface AFCL and intracardiac AFCL
The mean surface ECG AFCL from 10 CL and LAA and RAA AFCL of the total population were 150 ± 19 ms, 153 ± 20 ms, and 157 ± 20 ms, respectively. The mean surface ECG AFCL was longer in patients taking amiodarone (163 ± 18 ms vs. 146 ± 16 ms, p < 0.0001). The mean differences between the surface ECG AFCL from 10 CL and the endocardial AFCL in the LAA and RAA were 7 ± 6 ms and 8 ± 8 ms, respectively. The surface ECG AFCL from 10 CL was strongly correlated with both the LAA CL (R = 0.893, p < 0.0001) and the RAA CL (R = 0.876, p < 0.0001) (Figs. 2C and 2D).
Additionally, Bland-Altman plots show good agreement between the RAA CL versus the AFCL from TFA (Fig. 3A),the RAA CL versus the manual measurement surface ECG AFCL from 30 CL (Fig. 3B), and the RAA CL versus the manual measurement surface ECG AFCL from 10 CL (Fig. 3C).
Clinical variables and procedural termination of persistent AF
Long-lasting persistent AF was terminated by ablation in 76 of 90 patients (84%), with a mean procedure time of 245 ± 70 min. Pre-procedural clinical variables were compared in patients in whom AF was terminated by ablation versus in those who were not (Table 2).Compared with patients in whom AF was not terminated, patients with AF termination had a significantly shorter duration of continuous AF (22 ± 24 months vs. 60 ± 44 months, p < 0.0001), a longer surface ECG AFCL (154 ± 17 ms vs. 132 ± 10 ms, p < 0.0001), and a smaller LA dimension (47 ± 7 mm vs. 54 ± 11 mm, p < 0.01). Using multivariate analysis (Table 3),the surface ECG AFCL was the only independent predictor of AF termination by catheter ablation (p = 0.005). There was a trend toward duration of continuous AF predicting AF termination (p = 0.08), but LA dimension was not an independent predictor.
The ROC curve for the surface ECG AFCL as a predictor of termination of long-lasting persistent AF showed an area under the curve of 0.880 (95% confidence interval [CI]: 0.795 to 0.939, p < 0.0001) (Fig. 4).A cutoff point of 142 ms of the AFCL (Fig. 4, arrow) had a specificity of 92.9% and a sensitivity of 69.7% in predicting procedural termination of persistent AF. The positive and negative predictive value of the AFCL >142 ms were 98.1% and 36.1%, respectively, for procedural termination of persistent AF. There was an inverse relationship between procedural time and the surface ECG AFCL (R = −0.55, p < 0.0001).
For the association between the duration of continuous AF and procedural termination, the area under the ROC curve was calculated to be 0.844 (95% CI: 0.752 to 0.912, p < 0.0001) (Fig. 4). The optimal cutoff point for the duration of continuous AF was 21 months for AF termination (specificity 92.9%, sensitivity 61.8%). The combined cutoff using a surface ECG AFCL >142 ms and a duration of continuous AF <21 months had 100.0% specificity in predicting procedural termination of persistent AF (sensitivity 39.5%, positive predictive value 100.0%, negative predictive value 23.3%).
Clinical variables and clinical outcome
After the final procedure (mean number of procedures 1.8 ± 0.8 [1 to 4]), 84% (76 of 90) of patients were in sinus rhythm without antiarrhythmic drug treatment during follow-up of 18 ± 6 months (median 18 months, interquartile range 12 to 24 months). The clinical characteristics are shown in Table 4.There was no difference in total number of procedures between patients with and without recurrence (1.8 ± 0.8 vs. 1.9 ± 0.9, p = NS). The duration of continuous AF (57 ± 54 months vs. 23 ± 21 months, p < 0.0001) and the surface ECG AFCL were longer (154 ± 18 ms vs. 136 ± 11 ms, p < 0.001) in patients with recurrence of arrhythmia than in those who maintained sinus rhythm without antiarrhythmic drugs. The dimension of the LA was smaller (48 ± 8 mm vs. 53 ± 8 mm, p < 0.05) in patients with a successful medium-term outcome. There was a trend toward lower left ventricular ejection fraction in patients with arrhythmia recurrence after the final ablation (53 ± 10% vs. 60 ± 14%, p = 0.08). In multivariate analysis, the surface ECG AFCL and the duration of continuous AF independently predicted clinical outcome of persistent AF ablation (p < 0.01 and p < 0.05, respectively) (Table 5).Patients with a surface ECG AFCL <142 ms had a significantly higher rate of recurrent arrhythmia (p = 0.001, hazard ratio: 6.0, 95% CI: 2.0 to 18.5) (Fig. 5A).Additionally, arrhythmia recurrence after the final ablation was frequently observed in patients with duration of continuous AF >21 months compared with those with persistent AF lasting <21 months (p = 0.002, hazard ratio: 0.13, 95% CI: 0.06 to 0.51) (Fig. 5B).
Procedural termination and clinical outcome
Recurrence of arrhythmia after the index procedure was observed in 69% (62 of 90) of patients. Recurrence of AF after the index procedure was observed more frequently in patients with clinical failure compared with those with clinical success (93% [13 of 14] vs. 4% [3 of 76], p < 0.0001). In the remaining patients with recurrent arrhythmia, atrial tachycardia was observed and was terminated during the repeat ablation procedure. Additionally, procedural AF termination during the index procedure was associated with clinical success (92% [70 of 76] vs. 43% [6 of 14], p < 0.0001).
The present study evaluated the relationship between clinical variables and the procedural and clinical outcomes of catheter ablation for long-lasting persistent AF. Multivariate analysis showed that the surface ECG AFCL independently predicts procedural termination using the sequential stepwise approach. Furthermore, patients with a longer surface ECG AFCL and a shorter duration of continuous AF have a better outcome of catheter ablation.
Validation of AFCL from surface ECG
The surface ECG AFCL manually assessed from 10 CL correlated well with the AFCL recorded by intracardiac catheters in the LAA and RAA, and using TFA, confirming previous studies that have shown that AFCL can reliably be assessed from lead V1on the surface ECG (Fig. 2) (6,7). The absolute difference between the surface AFCL and the intracardiac CL (both LAA CL and RAA CL) was similar to that of a previous study using digital signal processing (6).
Clinical variables and ablation results
The procedural end point in this study was termination of persistent AF, and this was achieved in the majority of patients. This study shows that a longer surface ECG AFCL, a shorter duration of continuous AF, and a smaller LA dimension are predictive of procedural AF termination. A shorter surface ECG AFCL was associated with longer procedural times, suggesting that the results are not caused by operator bias, but by an increased complexity of AF. The complexity of AF and its association with the AFCL has been suggested by previous studies (9). In a canine model of AF, a shorter AFCL was observed in chronic AF compared with acute AF and there was a significant reduction in the endocardial atrial effective refractory period (10). In that study, the mean AFCL was correlated with the local epicardial refractory period and the marked changes in atrial architecture, such as fiber disarray and early hypertrophy, which could contribute to the maintenance of AF. Cryoablation directed to sites of the shortest local AFCL resulted in termination of sustained AF after prolongation of AFCL in that study (11). Although AFCL measured from the LAA is correlated with procedural outcome (5), AFCL calculated from the surface ECG is noninvasive and can be performed at the initial consultation.
Pre-procedural clinical variables and clinical outcome
In patients with persistent AF, restoration and maintenance of sinus rhythm can be attempted by drug treatment and/or electrical cardioversion. Previous studies have shown that the energy requirements, rate of AF recurrence, and long-term efficacy of antiarrhythmic treatment can be predicted from the surface ECG AFCL (12–14). The present study shows that an AFCL <142 ms predicts the outcome of catheter ablation. The agreement between these studies suggests that surface ECG AFCL is a powerful predictor of clinical outcome.
The durations of continuous AF and LA dimensions are predictive of maintenance of sinus rhythm after DC cardioversion (15–17). Although it has previously been reported that atrial electrical remodeling can develop quickly (18), anatomical remodeling resulting in enlargement of the LA continues for a long period (19). The importance of LA size in the development of AF and in determining the long-term result of cardioversion has long been known (20). In the present study, the duration of continuous AF was independently predictive of arrhythmia recurrence after catheter ablation, whereas LA dimension and the presence of hypertension were not, in contrast to a previous study (21). This may be attributable to patient selection and the definition of success. In this study all patients had persistent AF lasting for more than 1 month, compared with 39% in the earlier study. Additionally, atrial tachycardia as well as AF was included as a recurrent arrhythmia in the present study. Finally, the success rate of catheter ablation to treat persistent AF ranges from 60% to 90%, depending on the patient's series and ablation strategies (3–5,22,23). The different success rate according to strategy to treat persistent AF patients may result in different predictors of arrhythmia recurrence after catheter ablation.
Effects of amiodarone on the surface ECG AFCL and ablation results
In the present study, although the surface ECG AFCL was longer in patients taking amiodarone compared with those not, the ablation results (procedural termination and maintenance of sinus rhythm after ablation) did not differ between the 2 groups. Atrial fibrillation has been shown to shorten the action potential duration and the atrial effective refractory period (electrical remodeling) while administration of antiarrhythmic agents such as amiodarone lengthen the atrial effective refractory period (24). A previous study has shown that the degree of complexity of endocardial atrial activation during AF was reflected on the surface ECG (25). A longer surface ECG AFCL in patients taking amiodarone could be led by prolongation of the atrial refractory period, resulting in organization of AF. However, the underlying progression of the electrical remodeling in patients with amiodarone may be masked and underestimated.
Currently there is an inability to offer AF ablation for all patients with persistent AF, and the optimal selection for catheter ablation has yet to be determined. This study suggests that it may be prudent to refer patients with persistent AF of <2 years' duration. However, when the duration of continuous AF is more than 2 years or the duration is unclear, the surface ECG AFCL can help the physician decide whether or not to recommend ablation therapy in the outpatient clinic.
This was a retrospective study, and the data may only apply to patients in whom a stepwise ablation approach is performed. Repeat procedures were performed in these patients with the aim of returning the patient to sinus rhythm without the need for antiarrhythmic medication. We measured the surface ECG AFCL using a computer-based system that allows modification of gain and sweep speed. It is sometimes difficult to assess the AFCL on the surface ECG using conventional settings, and therefore we recommend that multiple settings are used to get unequivocal f waves on the surface ECG. There were only 2 patients in whom the AFCL was unable to be calculated from the surface ECG, and the findings are only relevant when the AFCL can be calculated.
We did not analyze other potential predictors for AF recurrence after ablation, especially intraoperative parameters including procedural termination of long-lasting persistent AF, because we were aware that it would have been difficult to examine all possible risk factors, and we focused on clinical factors that can be assessed before ablation. Another limitation was the small sample size and the multiple variables entered into the multivariate model. Therefore, the findings might be influenced by the confounding effects of measured or unmeasured clinical variables. Additionally, in the present study the patients were followed up for only a midterm period; further research is required to evaluate our results for long-term clinical outcome.
Finally, we did not assess quality of life in this study. Although this study shows that sinus rhythm can be restored and maintained by ablation, further studies are required to determine whether this results in an improved quality of life in this population.
This study confirms that long-lasting persistent AF can be terminated and potentially cured by catheter ablation. The surface ECG AFCL independently predicts procedural termination of persistent AF, and both the surface ECG AFCL and the duration of continuous AF are predictive of clinical outcome. The measurement of the surface ECG AFCL and the duration of continuous AF could help with patient selection for catheter ablation of long-lasting persistent AF.
Dr. Knecht is supported by the Belgian Foundation for Cardiac Surgery. Dr. Platonov is supported by governmental funding of clinical research within the Swedish National Healthcare System and The Crafoord Foundation.
- Abbreviations and Acronyms
- atrial fibrillation
- confidence interval
- cycle length(s)
- left atrium
- left atrial appendage
- pulmonary vein
- right atrial appendage
- receiver-operator characteristic
- time frequency analysis
- Received October 15, 2008.
- Revision received December 2, 2008.
- Accepted January 8, 2009.
- American College of Cardiology Foundation
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