Author + information
- Received January 29, 2004
- Revision received April 22, 2004
- Accepted April 27, 2004
- Published online August 18, 2004.
- Hans Kottkamp, MD* (, )
- Hildegard Tanner, MD,
- Richard Kobza, MD,
- Petra Schirdewahn, MD,
- Anja Dorszewski, MD,
- Jin-Hong Gerds-Li, MD,
- Corrado Carbucicchio, MD,
- Christopher Piorkowski, MD and
- Gerhard Hindricks, MD
- ↵*Reprint requests and correspondence:
Prof. Dr. Hans Kottkamp, University of Leipzig, Heart Center, Cardiology, Department of Electrophysiology, Struempellstrasse 39, D-04289 Leipzig, Germany
Objectives We sought to analyze the time course of atrial fibrillation (AF) episodes before and after circular plus linear left atrial ablation and the percentage of patients with complete freedom from AF after ablation by using serial seven-day electrocardiograms (ECGs).
Background The curative treatment of AF targets the pathophysiological corner stones of AF (i.e., the initiating triggers and/or the perpetuation of AF). The pathophysiological complexity of both may not result in an “all-or-nothing” response but may modify number and duration of AF episodes.
Methods In patients with highly symptomatic AF, circular plus linear ablation lesions were placed around the left and right pulmonary veins, between the two circles, and from the left circle to the mitral annulus using the electroanatomic mapping system. Repetitive continuous 7-day ECGs administered before and after catheter ablation were used for rhythm follow-up.
Results In 100 patients with paroxysmal (n = 80) and persistent (n = 20) AF, relative duration of time spent in AF significantly decreased over time (35 ± 37% before ablation, 26 ± 41% directly after ablation, and 10 ± 22% after 12 months). Freedom from AF stepwise increased in patients with paroxysmal AF and after 12 months measured at 88% or 74% depending on whether 24-h ECG or 7-day ECG was used. Complete pulmonary vein isolation was demonstrated in <20% of the circular lesions.
Conclusions The results obtained in patients with AF treated with circular plus linear left atrial lesions strongly indicate that substrate modification is the main underlying pathophysiologic mechanism and that it results in a delayed cure instead of an immediate cure.
Atrial fibrillation (AF) is an arrhythmic manifestation of a complex, chronic, and progressive disease of the atria with electrical, contractile, and structural remodeling that often gradually worsens over time (1,2). The curative treatment of AF involves targeting the pathophysiological cornerstones of AF (i.e., the initiating triggers and/or the perpetuation of the arrhythmia) (3–8). The pathophysiological complexity of both the initiation as well as the perpetuation is likely to result in a clinical outcome after ablation that differs from results that have been obtained in arrhythmias like atrial flutter or accessory atrioventricular pathways, which have well-defined reentrant circuits. Therefore, ablation strategies for the treatment of AF may not necessarily result in a “all-or-nothing” response (i.e., AF is unchanged after ablation or completely prevented), but ablation may rather quantitatively modify the number and/or duration of individual AF episodes and, in addition, may result in a gradual improvement over time as the result of atrial “reverse remodeling.”
In the present study, radiofrequency energy-induced circular plus linear lesions were percutaneously placed in the left atrium around the left and right pulmonary veins (PVs), between the encircling lines, and from the left circle to the mitral annulus. This approach was chosen to principally target both the initiation as well as the perpetuation of AF. Using repetitive continuous 7-day electrocardiogram (ECG) recordings with an overall analysis of >54,000 h of ECG, we sought to analyze the time course of total time spent in AF before and after ablation, the percentage of patients with complete freedom from AF after ablation by comparing classic 24-h ECG versus 7-day ECG, as well as the time course of the number and duration of recurrent individual AF episodes after ablation.
In this prospective study, 100 consecutive patients with paroxysmal (n = 80) or persistent (n = 20) AF were included (Table 1).In all patients, AF was documented on ECG/Holter-ECG at least three times before ablation. Persistent AF was defined as AF lasting at least for 7 days according to the Consensus Paper (9). As an inclusion criterion, all patients were highly symptomatic despite multiple antiarrhythmic drug treatment regimens (Table 1). Left heart catheterization and transthoracic/transesophageal echocardiography were performed before ablation. All patients gave written informed consent on the investigational nature of the procedure that was approved by the institutional review committee.
Rationale for the lesion line concept
A linear lesion line concept confined to the left atrium targeting specifically the elimination of anatomically defined left atrial “anchor” reentrant circuits eliminated AF in >90% of the patients with paroxysmal and persistent AF who were treated with intraoperative radiofrequency ablation using minimally invasive surgical techniques (7). On the other hand, circumferential catheter ablation around each PV at the atrial level has been demonstrated by Pappone et al. (4) to be highly effective in patients with paroxysmal and persistent AF. In the present study, radiofrequency energy-induced circular plus linear lesions were combined and percutaneously placed in the left atrium around the left and right PVs, between the encircling lines, and from the left circle to the mitral annulus (Fig. 1). This approach was chosen to principally target both the initiation as well as the perpetuation of AF.
Mapping and ablation procedure
Standard multielectrode catheters were placed in the coronary sinus and right ventricular apex. After transseptal catheterization, systemic anticoagulation with intravenous heparin was achieved (target activated clotting time of 200 to 250 s). The electromagnetic mapping system (Carto, Biosense Webster Inc., Diamond Bar, California) was used for reconstruction of the left atrium and navigation of the ablation catheter (Navistar, Biosense Webster Inc.). All PVs were visited with the mapping/ablation catheter and tagged. The vein-atrium transition was determined combining information from the fluoroscopic cardiac silhouette, impedance changes, and PV-atrium electrogram characteristics (i.e., fusion of the atrial electrogram component and the PV potential component). In addition, the mitral annulus was tagged. Ablation was performed during sinus rhythm. In patients with sustained AF at the beginning of the procedure, sinus rhythm was achieved with electrical cardioversion and stabilized, if necessary, with intravenous amiodarone or ajmalin.
Radiofrequency alternating current was delivered in a unipolar mode between the 8-mm tip electrode of the ablation catheter and an external backplate electrode. Temperature-guided energy applications were performed (preselected catheter tip temperature of 60°C, maximum power of 60 W). The circumferential lines were placed at a distance of >5 mm from the PV-atrium transition zone. Based on catheter stability, reduction in electrogram amplitude/occurrence of split potentials, and achievement of the preselected catheter tip temperature, the ablation catheter was stepwise dragged after 20 to 30 s, and the individual ablation sites were tagged on the map. No cutoff point of electrogram amplitude reduction was preselected. The end point of the procedure was the completion of the proposed circular and linear lesions, whereas neither definite isolation of the PV nor complete left atrial isthmus block was a required prerequisite of the procedure. However, the investigators clearly tried to place the lines as continuously and transmurally as possible. After placement of the circular lesions, pacing maneuvers were performed inside the circles to check for complete isolation of the PVs indicated by conduction from the PVs across the circles to the left atrium. After completion of ablation, selective angiography of all PVs was performed.
Pre- and post-ablation monitoring and management
All patients underwent continuous 7-day ECG recordings (DelmarReynolds Medical, Irvine, California) before ablation, within 1 h after ablation, and during outpatient clinic visits 3, 6, and 12 months after ablation (see the following text).
From a maximum of 168 h per 7-day ECG, 148 ± 32 h could be analyzed (88% of maximum recording time) and were evaluated. With respect to complete freedom from AF, the 7-day ECG results were compared with the first respective 24-h period. Individual AF episodes documented on the 7-day ECG recordings were separated in three groups: 30 s to 2 h, >2 h to 24 h, and >24 h.
In all patients, antiarrhythmic drug treatment was advised using amiodarone or the class Ic drug flecainide for the first three months after ablation. Oral anticoagulation was required in all patients four weeks before ablation and was continued for at least three months. Especially in patients with persistent AF and in patients with paroxysmal AF and underlying structural heart disease, further continuation of oral anticoagulation was advised.
Results are expressed as mean values ± 1 SD, or numbers and percentages, as appropriate. Continuous variables as number of AF episodes and duration per AF episode were compared by a one-way analysis of variance (ANOVA), post-hoc analysis with Bonferroni correction for multiple comparisons for parametric data, and Mann-Whitney Utest if normal distribution was not given. Categorical variables as freedom from AF in 24-h ECG and 7-day ECG were compared using the Fisher exact test. Duration of AF before and after ablation and after 3, 6, and 12 months was compared using the general linear model for repeated measures. A p value of <0.05 was considered statistically significant.
Procedure data, second procedures, and complications.
The total procedure time as measured from the first femoral puncture to removal of all sheaths was 139 ± 31 min (Table 2).Complete pulmonary vein isolation was achieved in <20% of the circular lesions and did not predict freedom from AF over time (Table 2). In seven patients (7%) with additional documented typical atrial flutter, the right atrial isthmus was successfully ablated during the same ablation procedure. In 22 patients (22%) with documented symptomatic recurrences of AF, the ablation procedure was repeated after 7 ± 3 months. One patient had a third procedure. Circular plus linear ablation lines were repeated as in the initial procedure, with special attention to areas with present atrial electrograms on the original lines to close gaps. In five additional patients (5%), stable gap-related left atrial flutter occurred. The gap was successfully ablated in two patients, and circular plus linear ablation lines were repeated in the remaining three patients. In eight patients (8%) with documented typical atrial flutter, right atrial isthmus ablation was performed during follow-up. No PV stenosis and no other procedure-related complications were observed.
Before ablation, the overall study population experienced AF for 35 ± 37% of the complete 7-day ECG recording time, the patients with paroxysmal AF for 17 ± 18%, and the patients with persistent AF for 93 ± 22% (Figs. 2 and 3).⇓⇓The relative duration of AF during seven-day ECG monitoring significantly decreased stepwise after ablation in patients with paroxysmal and persistent AF (Figs. 2 and 3) (repeated measures).
In patients with paroxysmal AF, the freedom from AF stepwise increased, over time although the percentage of patients on antiarrhythmic drugs decreased over time substantially, from 86% (70% flecainide, 16% amiodarone) directly after ablation to 42% after 12 months (29% flecainide, 13% amiodarone) (Fig. 4).In patients with paroxysmal AF, significantly more AF recurrences were detected using 7-day ECG recording compared with classic 24-h ECG directly after ablation as well as 3 and 6 months after ablation (Fig. 4) (Fisher exact test). In contrast, the freedom from AF after 12 months did not differ significantly and measured 88% when 24-h ECG was used compared with 74% when 7-day ECG was used (Fisher exact test).
The time course of number of AF episodes in patients with recurrences after ablation did not show a significant trend after ablation over time in patients with paroxysmal AF and significantly increased in patients with persistent AF (Fig. 5)(ANOVA). In contrast, the duration of individual AF episodes in patients with recurrences after ablation decreased significantly after ablation in patients with persistent AF (Fig. 6)(ANOVA, Bonferroni test).
The relative distribution of the lengths of individual AF episodes in patients with recurrences after ablation changed substantially: The relative occurrence of short episodes (0.5 min to 2 h) increased to 90% whereas the relative occurrence of middle (>2 h to 24 h) and long episodes (>24 h) decreased (Fig. 7).Overall, only 1 of 33 patients (3%) with paroxysmal AF who completed the 12-month follow-up experienced AF episodes lasting longer than 24 h compared with 13 of 61 patients (21%) with paroxysmal AF before ablation (p = 0.017; chi-square test), although antiarrhythmic drug use declined substantially over time.
Antiarrhythmic drug use after ablation
Overall, 90% of all patients received previously failed antiarrhythmic drug treatment directly after ablation: 68% flecainide and 22% amiodarone. After 12 months, antiarrhythmic drugs were significantly reduced to 40% of the patients: 27% were on flecainide and 13% on amiodarone. Standard doses were used: flecainide 100 mg twice a day and amiodarone 200 mg once a day after a loading dose of 12 g. Antiarrhythmic drugs were stopped after three months if no other than early AF recurrences—within the first week after ablation—occurred. In the other patients, antiarrhythmic drugs were stopped if they had no further AF recurrences.
Anticoagulation after ablation
In the group of patients with paroxysmal AF, oral anticoagulation was administered in 96% after 3 months, 84% after 6 months, and 74% after 12 months ablation. In the group of patients with persistent AF, anticoagulation was continued in 66% after 6 and 12 months. No thromboembolic complications or major bleedings were observed in the entire study population during a mean follow-up of 12 ± 5 months.
In the present study, results of catheter ablation of AF are described for the first time with time courses of relative time spent in AF and time courses of freedom from AF plus quantitative analysis of individual AF episode number and duration during follow-up using serial continuous 7-day ECG recordings. Freedom from AF increased stepwise over time in patients with paroxysmal AF and, 12 months after ablation, complete freedom from AF was measured in 88% or 74% of the patients, depending on whether classic 24-h ECG or 7-day ECG results were analyzed. Complete pulmonary vein isolation was demonstrated in <20% of patients. The results obtained in patients with AF treated with circular plus linear left atrial lesions using the electromagnetic mapping system strongly indicate that substrate modification is the main underlying pathophysiologic mechanism and that it results in a delayed cure instead of an immediate cure.
Patient description and AF characterization
Atrial fibrillation is classified as paroxysmal, persistent, or permanent (9). Pathophysiologically, however, AF is an arrhythmic manifestation of a complex, chronic, and progressive disease of the atria with electrical, contractile, and structural remodeling that often gradually worsens over time (1,2). Thus, a more gradual transition of arrhythmia length often occurs clinically, with short bursts of atrial tachycardia at the beginning followed by first short episodes of paroxysmal AF, then longer and even longer episodes of paroxysmal AF with time, until finally many patients end with persistent AF. The different type of paroxysmal AF with respect to arrhythmia length may have an impact on ablation efficacy depending on the ablation strategy used. In the present study, pre-ablation seven-day ECG monitoring was helpful in characterizing our patients with AF in a more quantitative way, i.e., our patients with paroxysmal AF actually were in AF for 17% of the time before ablation. Such a quantitative description of the pre-ablation arrhythmia characteristics may not only be helpful for the analysis of the individual study results but may also allow a better analysis of divergent results in comparison with other studies.
Interestingly, patients with persistent AF in this study were in the state of arrhythmia for only 93% of the time during pre-ablation, although persistent AF was defined as AF lasting at least seven days, according to the Consensus Paper (9), which described seven days as the lower limit for persistent AF. In two patients with confirmed persistent AF, one episode each of sinus rhythm was present during the pre-ablation 7-day ECG. However, repetitive Holter-ECG before study entry had shown persistent AF. Thus, even seemingly long-standing persistent AF may occasionally terminate for limited time periods over time.
Interventional treatment strategies for AF
Interventional strategies for a curative treatment of AF target the pathophysiological corner stones of AF (i.e., the initiating triggers and/or the perpetuation of the arrhythmia) (3–8). In a milestone article, in 1998 Haïssaguerre et al. (3) described the spontaneous initiation of AF by ectopic beats originating in the PVs. The initiation of the foci during the electrophysiologic study, however, is not reproducible and, therefore, the local distribution of the foci can only be estimated. Elimination of the initiating triggers for curative treatment of AF may be difficult for several reasons. Although many of the foci are located within the PVs, other locations within either atrium are not uncommon and recently have been described to occur in up to 30% of patients with paroxysmal AF (10,11). Furthermore, studies using biatrial basket electrode mapping demonstrated that the earliest activation sites of atrial ectopic beats emerging after successful electrical cardioversion of persistent AF were scattered rather than concentrated over both atria (12). In addition, application of the technique of mapping of specific breakthroughs from the left atrium to the PVs and the use of partial perimetric ablation allowing ostial PV disconnection (13) will miss foci that are related to the PVs but are located proximal to the disconnection sites in the funnel shaped transition zone. So far, ablation results using the technique of PV disconnection in persistent AF have been disappointing (8). Furthermore, partial perimetric ostial PV ablation always carries a risk of PV stenosis.
The Maze operation as introduced and further developed by Cox et al. (14) often is referred to as a therapy of substrate modification. However, a detailed look at the Maze procedure indicates that this highly effective procedure is a hybrid approach from a pathophysiologic point of view: First, a substantial mass reduction is achieved with left and right atrial appendage amputation; second, a biatrial substrate modification is accomplished with multiple left and right atrial incisions; and third, a relevant trigger elimination is achieved by the excision of the PV area. Therefore, the relative contribution of biatrial mass reduction, biatrial substrate modification, and PV isolation cannot be determined.
In contrast to the Maze procedure, a specific left atrial linear lesion line concept for the treatment of AF targeting at the perpetuation of AF (i.e., modification of the substrate) was tested using intraoperative ablation with minimal invasive surgical techniques (the Intraoperative Radiofrequency Ablation of Atrial Fibrillation [IRAAF] study) (7). In that study, a linear lesion line concept confined to the left atrium targeting specifically at elimination of anatomically defined left atrial “anchor” reentrant circuits eliminated atrial fibrillation in >90% of the patients without isolation of the PVs. The potentiality of left atrial substrate modification (without trigger elimination and without mass reduction) as a curative treatment strategy for patients with paroxysmal and persistent AF was highlighted in that intraoperative ablation study.
In 2000, Pappone et al. (4,15) introduced an anatomic approach using circumferential ablation of the PV ostia guided by the electromagnetic mapping system and later reported on the outcome in a larger patient population. Circular lesions were deployed around each PV ostium at the atrial level and isolation was defined by the achievement of low bipolar potentials (<0.1 mV) inside the circular lesions and local activation time delays of >30 ms between contiguous points across the line (15). Using these criteria, isolation was achieved in 75% of the patients. Interestingly, Pappone et al. (15) clearly pointed out that no significant relationship between lesion completeness and clinical outcome was observed and discussed that PV foci isolation might not have been the sole mechanism responsible for the cure of AF. Instead, the therapeutic efficacy was discussed as being related in part to an alteration of the substrate, changes in autonomic innervation, or atrial debulking (4,15). Furthermore and in contrast to the classic PV disconnection (8), high success rates could be achieved in both subgroups (i.e., in patients with paroxysmal as well as persistent AF) (15). In comparison to the data reported by Pappone et al., the patients in our series needed more antiarrhythmic drugs and second procedures, which might be related to the learning curve of our group.
In the present study, circular and linear left atrial lesions were combined and placed with guidance of the electromagnetic mapping system, thereby combining elements of the intraoperative IRAAF study (7) and the Pappone et al. (4) approach. Instead of encircling each PV, one big circle was placed around the PVs of each side, and linear lesions connected the two circles and also connected the left circle to the mitral annulus. Thereby, our approach theoretically targeted both the initiation as well as the perpetuation of AF. From a practical point of view, one big circle around the veins of each side protects from ablation in the transition zone between the upper and lower PVs, which often are separated only by a small fold instead of a linear atrial wall intersection. Furthermore, the addition of the linear lesions may have contributed to the very low incidence of stable left atrial flutter after ablation.
Analysis of rhythm outcome after interventional therapy of AF
The analysis of the rhythm outcome after intraoperative ablation of AF already has indicated that early relapses of AF after ablation for substrate modification did not predict long-term treatment failure (7). In the IRAAF study, two-thirds of patients with persistent and one third of patients with paroxysmal AF were treated transiently with antiarrhythmic drugs because of early recurrences; however, stable sinus rhythm was achieved during follow-up in 90% of both patient subgroups (7). To analyze the short- and long-term rhythm response after catheter ablation of AF, we used repetitive 7-day ECG recordings in the present study. Our results clearly indicate that the arrhythmia response after catheter ablation of AF using the current technique is far from being “all or nothing.” In many patients, early AF recurrences were observed but stepwise passed away over time, indicating toward a reverse remodeling of the atria, although the percentage of patients on antiarrhythmic drugs decreased over time substantially from 90% directly after ablation to 40% after 12 months. The significant stepwise reduction of the relative time spent in AF after ablation, the unchanged or even increased number of AF episodes in patients with recurrences, as well as the significant reduction of the duration of the individual AF episodes in patients with persistent AF all argue in favor of a substrate modification instead of a trigger elimination. Interestingly, the relative time spent in AF in patients with paroxysmal AF measured 17% before ablation and even transiently increased directly after ablation to 23%, thereby also indicating against a substantial trigger elimination. In addition, a complete isolation of the PVs as indicated by pacing maneuvers was achieved in <20% of the circular lesions in the present study and did not predict freedom from AF over time. However, the statistical power of that nonsignificant correlation is limited by the small number of patients with completely isolated PVs. Moreover, the clinical success might have been even significantly higher when more continuous and transmural lesion lines would have been accomplished resulting in complete PV isolation plus gap-free linear lesions.
The comparison of the “classic” 24-h ECG with the 7-day ECG indicated that the rhythm outcome is overestimated directly after ablation and during the first 12 months after ablation when 24-h ECGs are used.
Interestingly, only 1 of 33 patients (3%) with paroxysmal AF who completed the 12-month follow-up experienced AF episodes lasting longer than 24 h compared with 13 of 61 patients (21%) with paroxysmal AF before ablation (p = 0.017). On the one hand, this finding also argues in favor of substrate modification and, on the other hand, these results may have implications on the necessity of oral anticoagulation after ablation of AF. However, results with larger patient cohorts and longer follow-up are necessary to answer this question.
Drs. Kottkamp and Hindricks have received funding from Biosense Webster Inc., which supported this study in part by an unrestricted educational grant. Dr. Tanner was supported by a grant from the Swiss National Research Foundation.
- Abbreviations and acronyms
- atrial fibrillation
- analysis of variance
- Intraoperative Radiofrequency Ablation of Atrial Fibrillation study
- pulmonary vein
- Received January 29, 2004.
- Revision received April 22, 2004.
- Accepted April 27, 2004.
- American College of Cardiology Foundation
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