© 2004 by European Society of Cardiology
Computerized high-density mapping of the pulmonary veins: new insights into their electrical activation in patients with atrial fibrillation
aUniversity of Insubria, Department of Cardiovascular Sciences "Ospedale di Circolo e Fondazione Macchi" Varese, Italy; bDepartment of Cardiology "Mater Domini" Castellanza, Italy
Manuscript submitted 25 March 2003. Accepted after revision 9 November 2003.
*Corresponding author. Tel.: +39-0332-278394; fax: +39-0332-393309. E-mail address: rdponti{at}tin.it (R. De Ponti).
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AIM: To report the method and findings of computerized high-density mapping of pulmonary veins (PVs) in patients undergoing their electrical isolation for atrial fibrillation (AF).
METHODS AND RESULTS: In 17 consecutive patients (8 M, age 55±11 years), a 64 electrode basket catheter was placed in the target PVs and 56 bipolar electrograms were recorded, analyzed and isochronal maps were generated. PVs were mapped during sinus rhythm, left-sided pacing and ectopic activity. The sites of earliest activation at the veno-atrial junction were defined as the atrium to vein conduction breakthroughs. PV activation pattern was classified as predominantly longitudinal or transverse, according to the direction of the impulse from the breakthroughs. The ectopic pattern was defined as multifocal, when distant areas in the PV had activation times within 10 ms. Thirty-one PVs were mapped. The activation pattern was predominantly longitudinal in 13 PVs and transverse in 18 PVs. Two breakthroughs were identified in 22 PVs and three in nine. All the breakthroughs were evident simultaneously in sinus rhythm and left-sided pacing changed only the predominance of the breakthrough. Ectopies were mapped in 10 PVs: eight showed a multifocal and two a monofocal pattern; six ectopies originated from the proximal tract of the PV.
CONCLUSION: High-density mapping of PV identifies a typical activation pattern. Multiple and discrete breakthroughs are simultaneously identified in sinus rhythm. The majority of the mapped ectopies has a multifocal pattern and proximal origin.
Key Words: high-density mapping, pulmonary veins, atrial fibrillation
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Introduction |
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In patients with atrial fibrillation (AF), the pulmonary veins (PVs) are considered a critical area for arrhythmogenesis and therefore they represent a target for ablation [1,
2]. Over the last years, several reports [3–7] focussed on the anatomy and the histology of the myocardial extensions surrounding the PVs, in patients with or without AF, providing detailed description of their complex morphology, where fibrous and fatty tissue are interspersed among the myocardial fibres, forming a mesh-like arrangement [5,6]. On the other hand, little is known about the electrophysiological properties and electrical activation of the myocardial tissue surrounding the PVs. Both in the past [8,9] and recently [10,11], limited data have been gathered, which provide evidence of heterogeneous and decremental conduction properties [10] and of shorter effective refractory period [11] of these myocardial extensions, compared with the proper left atrial musculature. High-density mapping of the PVs may contribute to increase our knowledge of their functional aspects and electrical activation. This may be useful not only precisely to locate the breakthroughs of atrium to vein conduction, an essential prerequisite for their ablation in patients with AF [12], but also to identify patterns of electrical activation during different heart rhythms and, especially, during ectopic activity triggering AF. The aim of this study was to define by computerized high-density mapping the electrical activation of the PVs during sinus rhythm, pacing from different left atrial sites and ectopic beats, in patients with AF.
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Patient population
Seventeen consecutive patients (8 M, 9 F; mean age 55±11 years) with paroxysmal, frequently recurrent AF, undergoing an electrophysiological procedure for electrical isolation of the PVs, have been included. Patients who previously underwent a PV isolation procedure were excluded from the study. In all patients, repeated 12-lead Holter monitoring showed that the clinical palpitation episodes were related to AF, reproducibly initiated by atrial ectopies. All patients were refractory to 2.5±1.3 antiarrhythmic drugs, previously tested. No patient had structural heart disease, as assessed by echocardiogram. For at least 45 days before the electrophysiological procedure, all patients were on oral anticoagulants, which were withdrawn and substituted by heparin 24 h before the procedure. A preprocedure transoesophageal echocardiogram revealed no thrombus in the left atrium and normal blood flow velocity in the left atrial appendage. All antiarrhythmic drugs were discontinued one week before the procedure; no patient was receiving amiodarone.
Electrophysiological procedure and data acquisition
All patients underwent the electrophysiological procedure after having signed the consent form for the study, approved by the Institutional Ethical Committee. Double transseptal puncture was performed in all cases. Two long sheaths were, then, positioned in the left atrium: an 8F 62 cm long sheath (Preface, Biosense Webster, Inc., USA) was used to introduce the angiographic catheter or, alternatively, the ablation catheter in the left atrium, whereas a 9F 60 cm long sheath (Boston Scientific Corporation, USA) with different curves (55, 90 or 120°) was used to position the mapping catheter. After transseptal puncture, intravenous heparin was administered to maintain the activated clotting time between 250 and 300 s. A 64 electrode 31 mm diameter basket catheter (Constellation, Boston Scientific Corporation, USA) was used to map the PVs; in this catheter eight electrodes are uniformly distributed on each of the eight splines. In every patient, after venography of all PVs, every effort was made to identify the arrhythmogenic PV(s). For this purpose, if the patient was in AF, repeated cardioversions during temporary sedation with propofol were performed. If the patient was in sinus rhythm, prolonged observation and provocative manoeuvers were used to detect spontaneous ectopic activity. Once the arrhythmogenic PVs were identified, they were targeted for electrical isolation. In case no ectopic activity was observed, the superior PVs were isolated. In every case, the basket catheter was deployed in the target vein (Fig. 1A) by withdrawing the long sheath, previously advanced in the PV over a 0.035 in. guidewire. After deployment, minimal rotations of the basket helped to distribute uniformly the splines of the basket inside the vein and optimize the electrode/tissue contact. A second venography (Fig. 1B) was then performed to assess the position of the proximal electrodes at or very close to the os of the vein. By using two fluoroscopic projections (Fig. 2), the position of the "A" and "B" splines (identified by radiopaque markers) in the vein was recorded and classified according to the clock quadrant, where 12 and 3 h are superior and anterior, respectively, for the left PVs, while they are superior and posterior, respectively, for the right PVs. Through a junction box, the bipolar signals from the basket catheter were simultaneously recorded on a computerized mapping system (QMS2 System, Boston Scientific Corporation, USA) for data analysis and on the conventional electrophysiology system for on-line continuous monitoring. In the QMS2 system, 56 bipolar electrograms were recorded from seven contiguous longitudinal bipoles on each spline. Signals were processed with filter and gain settings of 30–290 Hz and 8–64, respectively. For each mapped PV, 30 s recordings were made in three different rhythms: sinus rhythm, pacing from distal coronary sinus and left atrial appendage for the left PVs and sinus rhythm, pacing from proximal coronary sinus and roof of the left atrium for the right PVs. For the evaluation of the ectopic activity, only cases, in whom at least three recordings of the ectopic activity in the same vein were acquired, were considered. In all cases, recordings of the ectopic activity were performed when no catheter other than the basket was inside the vein.
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Data analysis and definitions
Each segment acquired by the QMS2 system was analyzed in order to (1) define the pattern of electrical activation in the PV, (2) identify the sites of the breakthroughs of atrium to vein conduction, and (3) evaluate the pattern and site of earliest activation during the ectopic activity. On the system, each electrogram was manually annotated to determine the local activation time, according to the following criteria.
The analysis of the activation pattern of the PV during sinus rhythm or pacing was performed at a sweep speed of 200 mm/s. The local activation time was measured at the onset of each PV potential and the activation time of the earliest activated PV potential was considered as time 0. The following two criteria were used to discriminate PV potentials from atrial electrograms, which may be recorded as a far field activity even in the distal electrode pairs. The first criterion was the chronology of the PV potential from the surface P wave onset: no signal was considered as a PV potential if earlier than 75 and 35 ms in sinus rhythm and left atrial pacing, respectively, for the left PVs and 40 and 60 ms, in sinus rhythm/left atrial roof pacing and proximal coronary sinus pacing, respectively, for the right PVs. These time intervals were determined on the basis of a previous activation study [13]. Second, for each spline, the discrimination of the atrial from PV potentials was done first in the proximal electrograms, where the onset of the PV potentials was annotated. Each subsequent annotation in a more distal dipole was made at the onset of the first deflection later than the previous annotation in the proximal dipole on the same spline. Examples may be seen in Figs. 3 and 4. In case satisfactory discrimination between atrial and vein potentials was not possible, the recording was not considered for analysis.
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During the ectopic activity, in order to evaluate the site of earliest activation, each electrogram visualized at the maximum gain value was annotated at the onset of the first sharp deflection. To avoid the bias of artefact and misinterpretation of the signals, the analysis was repeated for three ectopic beats from each vein and comparison with the electrograms of a sinus beat not followed by concealed or manifest ectopy was made.
After the annotation process was complete, a polar isochronal map was generated by the system, where red and blue indicate early and late activation, respectively, and the distal electrodes are visualized in the centre of the map, whereas the proximal electrodes are along the outer perimeter. The position of spline "A" is identified on the map by larger dots and the other splines are distributed in a counter-clockwise fashion. For each map, the position of the spline "A" was adjusted according to its position on the clock quadrant as assessed by fluoroscopy. On each map, during sinus rhythm or pacing a breakthrough of atrium to vein conduction was defined as the site of earliest activation along the outer perimeter of the map. Comparison between the site of the breakthrough and the site where ablation modified and abolished PV activity was made for each breakthrough in every patient. The pattern of electrical activation inside the vein was defined as predominantly longitudinal, if fast propagation was observed from the breakthrough to the distal part of the vein with a direction longitudinal to the long axis of the vein. On the isochronal map, red to yellow colours are distributed on the same spline. Conversely, the propagation pattern inside the vein was defined as predominantly transverse, when the propagation proceeds from the breakthrough with a direction perpendicular to the long axis of the vein. In this case, the red to yellow colours are distributed in the proximal electrodes of adjacent splines. In the analysis of the site of earliest activation during ectopies, the pattern was defined as multifocal if activation times of different sites in non-adjacent splines were within 10 ms. All the recordings and maps were independently evaluated by two electrophysiologists.
Statistical analysis
Continuous variables are expressed as mean ± 1 SD. Considering the limited value of finding statistically significant differences in such a restricted number of patients and veins as those of the present study, statistical analysis was not performed for the activation times and the distribution of activation patterns.
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Data acquisition and analysis
A total of 123 acquisitions was made by the QMS2 system in 31 PVs, whose location is shown in Table 1. The number of PVs mapped per patient was 2±0.7. In two patients the left PVs were mapped and isolated at their common os and, for the purpose of this study, they have been considered as a single vein. In no case, was ectopy arising from the right inferior PV documented and, according to the protocol, this vein was not considered for ablation. Ninety-three acquisitions were made during sinus rhythm, coronary sinus and left atrial stimulation, whereas the remaining 30 acquisitions (three repeated acquisitions in 10 different veins) were performed during ectopies. Sixty-seven of 93 (72%) acquisitions during sinus rhythm or pacing could be analyzed and an isochronal map generated; the remaining 26 (28%) acquisitions performed during pacing were not considered for analysis, because the atrial and PV potentials could not be clearly discriminated. Anyhow, it is important to highlight that all the 31 veins could be evaluated in sinus rhythm. Table 1 reports the percent of the recordings that could be analyzed in different rhythms out of the overall number of acquisitions made for each vein. As also shown in Table 1, 7/31 (22.5%) veins were evaluated in a single (sinus) rhythm, the vast majority of them (5/7 veins) being right superior PVs. In only two cases, the basket catheter displaced minimally during the procedure, with a clockwise rotation of 15 and 30°, respectively, which, in no case, rendered the evaluation of the map impossible. Overall, in the 97 analyzed acquisitions a total of 5328 electrograms (96.4%) were free from technical artefacts and have been annotated. Concordance between the two independent observers was obtained in 97% of the maps. Thirty of 31 PVs were completely isolated by low power radiofrequency energy (14 patients) or cryothermal energy (three patients) delivery, whereas in one vein a 90% reduction of the amplitude of the PV potentials was obtained. No complication was observed during or after the procedure.
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Activation patterns in the pulmonary veins
As shown in Table 1, a predominant longitudinal activation pattern (Fig. 3) was observed in 13 veins, while in the remaining 18 veins it was transverse (Fig. 4), with a trend towards a more frequent transverse pattern in the right superior PV. Also in veins classified as having a predominant longitudinal activation pattern, limited areas of transverse conduction were present, as shown in Fig. 3. In no case, in whom the PV was evaluated in more than one rhythm, was a rhythm-dependent change in the activation pattern observed. Interestingly, among the 13 patients, in whom more than one vein was mapped, nine showed the same activation pattern in all mapped veins, which was transverse in five and longitudinal in four. During sinus rhythm, the time interval between the earliest and latest activated PV potential was 40±19 ms in the left superior PV, 36±19 ms in the right superior, 31±8 ms in the left inferior and 49±27 ms in the common os of left PVs. In sinus rhythm, the activation time of veins with a predominantly longitudinal pattern was very similar to one of the veins with a predominantly transverse pattern (37±9 ms vs 35±8 ms).
Localization of atrium to vein conduction breakthroughs
In all the 31 veins, more than one breakthrough of atrium to vein conduction was observed and in no case were more than three breakthroughs identified. The number of breakthroughs in the different PVs is shown in Table 1. The location of the breakthroughs was ubiquitous in the clock quadrants in mapped veins. In 24 PVs analyzed in more than one rhythm, the position of the breakthrough was not rhythm-dependent and, importantly, no additional breakthrough became evident by pacing at different sites. Nevertheless, a change in the predominance of a breakthrough depending on the change of the rhythm was observed in every case, the breakthrough closer to the site of origin of the rhythm becoming predominant. Fig. 5 shows an example of this finding. In all cases, in whom both the left superior and left inferior PVs were separately mapped, a strict anatomical relationship was observed between the inferior breakthrough of the superior vein (identified at 6–7 o'clock) and the superior breakthrough of the inferior vein, localized between 11 and 1 o'clock (Fig. 6). Finally, in 29 out of 31 veins there was coincidence of the location of the splines identifying the atrium to vein conduction breakthroughs and the site where energy application resulted in modification and abolition of the PV potentials. In two PVs, this validation was rendered impossible by a rotation of the basket catheter after the mapping phase.
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Evaluation of ectopic activity
Recordings of the ectopic activity were repeatedly acquired in 10 veins in seven patients. Data are shown in Table 2. In all cases, the ectopy in a given vein showed a reproducible activation pattern with no significant change among the three subsequent acquisitions. In eight veins, ectopies showed a multifocal activation pattern with areas of early simultaneous activation widely distributed in the vein, as paradigmatically shown in Fig. 7. Only in two veins in the same patient, ectopies had a monofocal pattern, with a wide longitudinal area of early activation, corresponding to the area of a breakthrough of atrium to vein conduction (Fig. 8). In seven veins, at least one site of earliest activation during the ectopy corresponded or was very close to a breakthrough; in these veins the activation pattern was longitudinal in four veins and transverse in three. In the remaining three veins, the ectopy was not spatially related to a breakthrough. Of the 10 ectopies mapped, six showed at least one area of earliest activation recorded in the two proximal dipoles of the basket catheter, and, therefore, in the area corresponding to veno-atrial junction. Seven ectopies occurred in a vein with a longitudinal activation pattern, whereas in the remaining three the activation pattern of the vein was transverse.
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Discussion |
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PVs have been identified as structures playing a major role in the genesis of AF in humans [1,
2]. Nevertheless, comprehensive understanding of the arrhythmogenesis of AF and particularly of the underlying mechanism and role of ectopic activity arising from the left atrium and PVs has not yet been gathered [14,15]. Apparently, precise anatomical and histological analysis of the PVs in humans has found no major difference in subjects with and without AF, since in both cases the substrate for non-uniform anisotropic conduction related to fibrosis and complex fibre alignment was observed [3,5,6]. On the other hand, it is possible that the major difference between patients with and those without AF concerns functional aspects of the myocardial fibres surrounding the PVs. Recent reports provided evidence of a higher degree of decremental conduction [10] and a shorter effective refractory period [11] of these fibres compared with left atrial myocardium in patients suffering from AF. To our knowledge, this is the first study of computerized high-density mapping of the PVs during sinus rhythm, pacing and ectopic activity originating from the PVs, in patients with paroxysmal AF. Although preliminary, these data may contribute to increase our understanding of functional aspects of the veno-atrial junction and myocardial extensions of the PVs.
Pulmonary vein activation patterns
In the present study, the evaluation of activation inside the PVs led to identification of different patterns, which can be grouped into two fundamental forms: a predominantly longitudinal activation pattern (observed in 13 veins) and a predominantly transverse activation pattern (observed in 18 veins). In the first pattern, the impulse proceeds from the breakthrough distally in the vein, following a direction parallel to the long vein axis. Conversely, in the transverse pattern, the impulse propagates from the breakthrough in a circular fashion with a direction perpendicular to the long vein axis. Although the type of activation pattern in each vein appears very clear in a qualitative analysis, limited areas of transverse activation were observed even in patients with a predominantly longitudinal pattern, reflecting a complex electrical activation of the vein. However, the different activation patterns apparently have no impact on the duration of PV electrical activation and, in fact, the time interval between the earliest and the latest PV potential is very similar for both patterns. This suggests that the two activation patterns are an expression of different propagation directions into the PVs, with no significant effect on duration, since later activated areas, although differently distributed, can be observed in both patterns. These findings may be well correlated with histological data of PVs, reporting the presence of loops of fibres leaving the atrium and returning to it after covering the venous wall [3] and of a mesh-like arrangement with a combination of spirally and longitudinally oriented bundles of myocytes [6]. In the present study a trend towards a higher prevalence of the transverse activation pattern has been noted in the right superior PVs. This may reflect a more complex fibre orientation in the right PVs, as they are close to interatrial connections observed in this area [4]. Interestingly, in the majority of patients in whom more than one vein was mapped, the same activation pattern (longitudinal or transverse) was observed in all the veins, suggesting in some cases a patient specific activation pattern of PVs.
High-density mapping and identification of atrium to vein conduction breakthroughs
High-density mapping of the PVs identifies multiple discrete areas of earliest activation along the perimeter of the vein os, which reflect the location of the atrium to vein conduction breakthroughs. According to the data presented in this study, all the sites of breakthrough can be localized simultaneously and precisely on the high-density map. This ability can be explained by the high resolution provided by 56 bipolar recordings distributed along the perimeter of the vein os, which allow detailed analysis of the activation at the veno-atrial junction. In the present study, no less than two and no more than three discrete breakthroughs were found in the mapped veins. In a previous study [12], in 34 out of 162 (20%) of the considered PVs a single breakthrough of atrium to vein conduction was found. Conversely, a study of PV anatomy [7] reported the presence of myocardial tissue along the entire perimeter of the PV ostium, suggesting that ablation should be frequently extended to the complete circumference of the ostium to obtain electrical vein isolation. The discrepancy between the first and our study could be explained both by the relevantly smaller number of patients considered in this paper and by the fact that in the present study the breakthroughs were evaluated at the very proximal veno-atrial junction, where the longitudinal myocardial fibres tend to be broader and thicker, whereas they become thinner in a more distal position in the vein [6]. This might have led to identification of a higher number of breakthroughs. As to the other study [7], the presence of muscular fibres all along the perimeter of the vein ostium does not necessarily imply that they have a functional relevance to the atrium to vein conduction and, moreover, the definition of the ostium position may be different in anatomical specimens compared with angiographic images during an electrophysiological procedure. Another interesting finding of the present study has to be highlighted. In all the 24/31 veins evaluated in more than one rhythm, the use of left atrial pacing had only the ability to render more evident the breakthrough closer to the site of origin of the rhythm and in no case did left-sided pacing reveal a latent breakthrough. This suggests that, when high-density mapping is used, analysis in a single rhythm could be enough to identify all the atrium to vein conduction breakthroughs. Some other considerations of the use of pacing to discriminate atrial to vein potentials have to be made. In this study acquisitions were made during sinus rhythm and pacing from different left sites, but 28% of them were not analyzed because of poor discrimination between atrial and venous potentials and five right and two left PVs were evaluated in a single rhythm. Nevertheless, sinus rhythm turned out to be the "golden" rhythm for high-density mapping, since it allowed satisfactory discrimination between the atrial and venous potentials in all cases. Coronary sinus pacing can be alternatively and successfully used in the vast majority of the left PVs, whereas the usefulness of pacing from the roof and appendage of the left atrium seems in doubt, since it allowed differentiation of the potentials only in approximately half of the cases, both in the right superior and left PVs. This could be in partial contrast to previous data [16], reporting the need for distal coronary sinus pacing to avoid the superimposition of atrial to PV potentials in the left PVs. Nevertheless, in the present study, the adaptability of the basket catheter favoured an orientation of the dipoles parallel to the long pulmonary vein axis, virtually concordant with the direction of atrium to vein propagation and this may have contributed to a better discrimination of potentials even in sinus rhythm.
Evaluation of ectopic activity
In the present study, spontaneous ectopic activity was repeatedly observed and recorded in approximately one third of the considered veins. Although this is very early experience, it is important to underline that in the majority of the cases the ectopy showed multiple sites of earliest activation in different areas of the veins, a close spatial relationship with the site of breakthrough and a proximal position in the vein. Of course, further data are required to confirm these observations and subclassify the ectopic pattern. Nevertheless, the finding of multiple foci in the same vein is in accordance with a prior report by Ha
̈ssaguerre et al. [1], who observed during ectopy, a synchronous local activation in a large sector of the venous perimeter or different activation times during ectopy, suggesting various ectopy sources or activation courses. Although less probable, it cannot be excluded "a priori" that a multifocal pattern is the result of simultaneous propagation in a distant part of the vein from a remote site, deep in the venous branch. It is also remarkable that in the present study high-density mapping showed an identical pattern of the earliest ectopic activation in the three subsequent recordings, which were performed in each vein, according to the protocol. This suggests that, regardless of the subsequent course from the vein to the atrium, each ectopic activity in each vein may have a precise and fixed "site of origin".
Clinical implications
The ability to locate simultaneously by high-density mapping all the atrium to vein connections in a single sinus beat may have an important practical role, especially in cases showing AF recurrences early after DC cardioversion. In these as well as in the other AF cases, this method allows a precise electrophysiologically guided approach to produce discrete lesions aimed at electrical disconnection of the PV. Moreover, localization of ectopic activity in the proximal part of the vein may have a direct implication on the ablation strategy, since the operator has consistent data to decide how proximal the ablation lesion should be to neutralize also the proximal PV foci. In so doing it may be hoped that the most clinically useful approach is obtained when an electrophysiologically guided method is used.
Limitations
These are preliminary data on a limited number of PVs and patients, which allow evaluation of the feasibility and the potential of high-density mapping of the PVs. There are two major limitations in this study. First, every electrogram was manually annotated to define the local activation time according to the method described, since the current version of the QMS2 system software has no algorithm for the discrimination between atrial and PV potentials and for the subsequent evaluation of activation times. Even if an algorithm for automatic analysis is developed, such a complex annotation of the signals will require further evaluation by the electrophysiologist to generate a correct map and this, as well as the manual annotation used in this study, is time consuming and may limit, in some cases, the use of this method. Second, although the deployment of the basket catheter in the PV was very accurate, in the majority of the cases it is not possible to distribute in a geometrically homogeneous way the splines along the circumference of the vein, as they are represented on the map. Consequently, the actual position and the width of each breakthrough is better defined referring to the position of the spline in the vein rather than to the clock quadrant on the map.
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