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Characteristics of Fibrillatory Activities During Spontaneous Termination of Paroxysmal Atrial Fibrillation: New Insight From High-Density Right Atrium Frequency Mapping
Canadian Journal of Cardiology 28 (2012) 87–94
Clinical Research
Characteristics of Fibrillatory Activities During Spontaneous Termination of Paroxysmal Atrial Fibrillation: New Insight From High-Density Right Atrium Frequency Mapping Han-Wen Tso, MS,a Yenn-Jiang Lin, MD, PhD,b,c Ching-Tai Tai, MD,b Shin-Ann Chen, MD,b,c and Tsair Kao, PhDd a b
Institute of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan
Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan c d
Department of Medicine, National Yang-Ming University, Taipei, Taiwan
Department of Biomedical Engineering, Hungkuang University, Taichung City, Taiwan
ABSTRACT
RÉSUMÉ
Background: Sinus node (SN) activity is difficult to assess during atrial fibrillation (AF). The aim of the present study was to investigate SN activity by frequency analysis during AF. Methods: Thirteen patients with paroxysmal AF and atrial flutter in the right atrium (RA) underwent 3-dimensional noncontact mapping. The fibrillatory activity was recorded from a multielectrode array in the RA. A frequency analysis with 2- and 6-second time-segment lengths was performed. Spectral characteristics (dominant frequency and harmonic index) and isopotential activation maps were used to investigate the spatiotemporal activity of the SN region and the rest of the RA (crista terminalis, septum, and free wall) during the initiation, while ongoing, and before the termination of AF. Results: With duration of 6 seconds, the whole RA had similar trends of frequency distribution. With duration of 2 seconds prior to termination, the SN region exhibited a trend of low-frequency pattern and high-organization distribution, compared with the segments for the 2 to 4 and 4 to 6 seconds before termination. The isopotential activation
Introduction : L’activité du noeud sinusal (NS) est difficile à évaluer durant la fibrillation auriculaire (FA). Le but de la présente étude était d’examiner l’activité du NS par l’analyse de fréquence durant la FA. Méthodes : Treize patients ayant une FA paroxystique et un flutter auriculaire dans l’oreillette droite (OD) ont subi une cartographie tridimensionnelle sans contact. L’activité fibrillatoire a été enregistrée à partir d’un cathéter multiélectrode dans l’OD. Une analyse de fréquence ayant des intervalles de temps de deux (2) à six (6) secondes a été faite. Les caractéristiques spectrales (fréquence dominante et indice harmonique) et les cartes d’activation isopotentielle ont été utilisées pour explorer l’activité spatiotemporelle de la région du NS et le repos de l’OD (crista terminalis, cloison et paroi libre) au début, en cours et avant la fin de la FA. Résultats : Pour une durée de six (6) secondes, l’OD entière a eu des tendances similaires de distribution de fréquence. Dans les deux (2) secondes avant la fin, la région du NS a tendu vers un modèle de basse fréquence et une distribution très organisée, comparativement aux
Atrial fibrillation (AF) is the most common type of arrhythmia in clinical practice.1 In previous studies, the mechanism of AF spontaneous termination was mostly based on electric or drug-induced termination.2,3 The mechanism of spontaneous termination still remains unclear. Clinical observation demonstrated that the fibrillation rate decreases and
cycle length increases abruptly before spontaneous termination.3-5 Most studies have focused on surface ECG rather than the intracardiac recordings of each anatomic region.5-8 In Langendorff-perfused rabbit hearts, Kirchhof and Allessie showed that sinus node (SN) automaticity was preserved with a high degree of sinoatrial entrance block against rapid fibrillatory impulses during AF.9 However, beat-to-beat variation of time-domain electrogram is the universal limitation of AF mapping. Therefore, frequency analysis may provide an alternative tool to describe a longer duration of complex rhythm as AF.10,11 Furthermore, 3-dimensional noncontact mapping facilitates 1-beat analysis during initiation and termination of AF, which is almost impossible with previous conventional
Received for publication April 28, 2011. Accepted August 7, 2011. Corresponding author: Dr Tsair Kao, Department of Biomedical Engineering, Hungkuang University, 34, Chung-Chie Road, Shalu, Taichung City, 43302, Taiwan. E-mail: [email protected] See page 93 for disclosure information.
0828-282X/$ – see front matter © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.cjca.2011.08.119
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maps showed the spontaneous earliest activities had wave front propagation patterns similar to those during sinus rhythm (after termination). Conclusions: The fibrillatory activity of the SN region was organized, and slow activation was detected, by frequency analysis and isopotential mapping, within 2 seconds just prior to AF termination.
intervalles de temps de deux (2) à quatre (4) et de quatre (4) à six (6) secondes avant la fin. Les cartes d’activation isopotentielle ont montré que les activités spontanées les plus précoces avaient des modèles de propagation de front d’onde similaires à durant le rythme sinusal (après la fin). Conclusions : L’activité fibrillatoire de la région du NS a été organisée, et une activation lente a été détectée, par l’analyse de fréquence et la cartographie isopotentielle, dans les deux (2) dernières secondes avant la fin de la FA.
mapping techniques. Therefore, the purpose of this study was to investigate the spatiotemporal activity of the SN region by using noncontact mapping and frequency analysis.11,12 This study explored the fibrillatory activities of the SN region and outside SN region during different stages of AF, including spontaneous termination.
sented to the electrophysiology laboratory in sinus rhythm (SR), we first attempted to observe the spontaneous activation during baseline or after an isoproterenol infusion. The methods used to identify spontaneous AF were attempted at least twice to ensure reproducibility. In this study, all patients had spontaneous initiation and termination of AF.
Methods
Noncontact mapping system
Patient characteristics This study consisted of 13 patients (10 men, 3 women, aged 57 ⫾ 17 years) with paroxysmal AF (PAF) and atrial flutter (AFL), who underwent an electrophysiological study and catheter ablation (Table 1). The patients had suffered from frequent attacks of clinically documented paroxysmal AF and AFL for a mean duration of 4.2 ⫾ 2.7 years and were refractory to more than 1 antiarrhythmic drug. All antiarrhythmic drugs except for amiodarone were discontinued for at least 5 half-lives before the procedure. The patients underwent the RA electroanatomic mapping and catheter ablation with a noncontact mapping system. Informed written consent was obtained from all patients. We attempted to identify the initiation triggers in all AF patients who underwent catheter ablation.13,14 In brief, we attempted to find the spontaneous onset of atrial ectopic beats or repetitive episodes of short runs or sustained AF and predict the location of the initiating foci. When the AF patients preTable 1. Demographic data Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
The noncontact mapping system (NavX, St Jude Medical Inc, St Paul, MN) has been previously described.15-17 Briefly, the system consisted of a catheter (9F) with a multielectrode array (MEA) surrounding a 7.5-mL balloon mounted at the distal end. The system located any other catheters with respect to the MEA by using a navigation locator signal. It was used to construct a 3-dimensional computer model of the endocardium and to track the positions of the standard contact catheters within the RA relative to the anatomic structures or critical zones of conduction. Noncontact endocardial electrograms were mathematically reconstructed to produce isopotential or isochronal colour maps on the model.12 The accuracy of the electrogram morphology, activation time difference, and voltage between the contact and noncontact electrograms has been validated from the same endocardial locations during SR and atrial tachycardia.17 We have confirmed the accuracy of the noncontact MEA for reproducing the contact electrogram morphology, frequency measurements, and spectral morphology by coherence during human AF.18 Activation mapping
Gender
Age (years)
Underlying diseases
AF origin
Arrhythmia
M M M M M F M M M F M M F
76 31 68 77 78 53 72 56 34 35 50 58 65
HT, Thyroid Nil HT, CAD HT, COPD HT, CAD, COPD HT, Thyroid HT, DM HT Nil HT HT HT HT
SVC SVC PV SVC CT SVC CT PV PV PV PV PV PV
PAF PAF PAF, AFL PAF PAF PAF, AFL PAF, AFL PAF, AFL PAF PAF, CCWTAFL PAF, CWRTAFL PAF PAF
AF, atrial fibrillation; AFL, atrial flutter; CAD, coronary artery disease; CCWTAFL, counterclockwise typical AFL; COPD, chronic obstructive pulmonary disease; CT, crista terminalis; CWRTAFL, clockwise reverse typical AFL; DM, diabetes mellitus; F, female; HT, hypertension; M, male; Nil, no data available; PAF, paroxysmal atrial fibrillation; PV, pulmonary vein; SVC, superior vena cava.
The colour settings were adjusted so that the colour range matched 1:1 with the milli-volt range of the electrogram deflection. We also interactively placed virtual electrodes on the colour contours to analyze the corresponding unipolar noncontact electrograms. The SN region was identified as the earliest activation of the isopotential map, with a QS pattern as earliest activation site (EAS) during the analysis of the unipolar electrograms during SR.19 Through the 3-dimensional coordination of the noncontact mapping system’s built-in electrodes, the location of the SN was labelled on the 3-dimensional reconstructed geometry of the RA, and the activation pattern during SR was observed (Fig. 1A, left panel). Centrifugal activation away from the SN region was observed from the colour-coded isopotential maps during SR. An example of electrograms of the SN is shown in Figure 1A (right panel). Figure 1B shows the propagation of wave fronts away from the SN in a centrifugal activation pattern to the rest of the RA. The anatomic locations of the RA free wall (FW), RA septum (SEP), and crista terminalis (CT) were also determined on the 3-dimensional endocardium by fluoroscopy, as marked in Figure 1A
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Figure 1. The isopotential map of the sinus node (SN), earliest activation site (A, left panel). The anatomic locations of the free wall (FW), septum (SEP), and crista terminalis (CT) of the right atrium are marked on the map. The corresponding unipolar electrograms of the SN and its 4 nearby sites are also shown (A, right panel). (B) Shows the propagation of wave fronts away from the SN in an activation pattern centrifugal to the rest of the right atrium. ECG, electrocardiogram.
(left panel). At least 10 virtual electrograms were analyzed in each region. Identification of the SN activities Ten consecutive sinus activities, both before spontaneous initiation and after termination of AF, were recorded. The spatial variations of the EASs were calculated. For each sinus activity, the Cartesian coordinates (x, y, z) of the EAS on the 3-dimensional geometry could be obtained in order to assess the reproducibility of the SN location. The centre points of 10 EASs before and after AF were represented by Cb and Ca, respectively. The distance
between each EAS and the centre point was calculated. If the distance was limited and the SN region also covered the EAS distribution, we assumed the stability of the SN location detected by the noncontact mapping system to have been confirmed. Signal acquisition and preprocessing The unipolar endocardial electrograms from the noncontact mapping system were sampled at 1.2 kHz and filtered with a second-order Butterworth filter bandwidth between 2 and 300 Hz. Six-second intervals after the (spontaneous) AF onset and before the (spontaneous) offset of AF were defined as the
Figure 2. Noncontact unipolar electrograms of patient 11 simultaneously recorded from surface electrocardiogram (ECG) lead I and 4 anatomic sites, sinus node (SN), crista terminalis (CT), septum (SEP), and free wall (FW). Each electrogram with QRS-T complex cancellation includes 4 periods: initiation of atrial fibrillation (AF), ongoing AF, termination of AF, and resumed sinus rhythm (SR).
90
initiation and termination stages, respectively. The timing of spontaneous initiation and termination were defined by surface electrograms. The data of the first 6 seconds of AF (initiation), ongoing AF (after 50 seconds of initiation), and the last 6 seconds of AF (termination) were exported for off-line analysis. The raw data with simultaneously recorded surface 12-lead electrograms and unipolar electrograms reconstructed from the electrodes on the endocardial surface were obtained from the noncontact mapping system. The electrograms of the defined regions in the RA were exported to an external Matlab (MathWorks, Inc, Natick, MA) software program for frequency analysis. The ventricular component (QRS-T complex) in the endocardial electrogram was eliminated by use of the adaptive cancellation technique.20 Each R wave in the electrogram was identified by using a peak detection algorithm, based on the surface ECG lead V1 aligned. The QRS-T segments were aligned on this fiducial point and averaged to create the template. The template was positioned at the location of each QRS complex in the electrogram. Because of variations in the amplitude of the QRS complex, the template was adjusted accordingly for every beat to form the QRS-T parts of a reference. With the reference signal, each QRS-T complex was adaptively cancelled from the original endocardial electrogram by the use of a recursive least-squares algorithm, resulting in a remainder electrogram. The QRS-T complex was cancelled in all electrograms in this study. Frequency analysis of the AF electrograms A fast Fourier transform was calculated on the remainder electrogram, which was zero-padded to keep a frequency resolution of 0.143 Hz for each 2-second and 6-second segment.5,10 The frequency of the spectra was limited to 1 to 20 Hz, which covered the physiological range of practical interest. The largest peak frequency of the spectrum was defined as the dominant frequency (DF).11 The total power of the spectrum was calculated from 1 to 20 Hz. The power under the DF and its 3 harmonic peaks were calculated over a 1-Hz window for each. The ratio of the power under these 4 peaks to the total power was defined as the harmonic index (HI).21 The HI represents the degree of organization of the AF during the time of the signal. We described the regional frequency distribution of the spectral characteristics at the SN and other regions in the RA, including FW, SEP, and CT regions. Statistical analysis Data were presented as the mean value ⫾ standard deviation (SD). A chi-square test with a Fisher exact test was used for the categorical data. Normally distributed continuous variables were compared by means of 1-way ANOVA and post hoc analyses, whereas not normally distributed variables were compared by means of the Kruskal-Wallis H test. A P value ⬍ 0.05 was considered statistically significant. Results Patient characteristics In these 13 patients, AF originated from the superior vena cava (SVC, N ⫽ 4), CT (N ⫽ 2), and pulmonary vein (N ⫽ 7). Sustained AF was observed in 13 patients, with duration of
Canadian Journal of Cardiology Volume 28 2012 Table 2. Summary of frequency analysis of 6-second segments during different stages of atrial fibrillation DF (Hz)
HI
Region
Initiation
Ongoing
Termination
SN CT SEP FW RRA SN CT SEP FW RRA
4.96 ⫾ 0.95 5.13 ⫾ 0.72 4.97 ⫾ 0.86 5.17 ⫾ 0.82 5.12 ⫾ 0.87* 0.55 ⫾ 0.09 0.55 ⫾ 0.14 0.54 ⫾ 0.15 0.54 ⫾ 0.15 0.54 ⫾ 0.14
5.31 ⫾ 1.01 5.39 ⫾ 1.00 5.45 ⫾ 1.03 5.55 ⫾ 1.21 5.46 ⫾ 1.00 0.50 ⫾ 0.09† 0.49 ⫾ 0.10 0.47 ⫾ 0.08 0.45 ⫾ 0.09 0.46 ⫾ 0.09
4.91 ⫾ 0.69* 5.23 ⫾ 0.71 5.02 ⫾ 0.70 5.12 ⫾ 0.75 5.09 ⫾ 0.90* 0.56 ⫾ 0.09* 0.50 ⫾ 0.08 0.48 ⫾ 0.10 0.49 ⫾ 0.12 0.51 ⫾ 0.10
Values are expressed as mean ⫾ SD. CT, crista terminalis; DF, dominant frequency; FW, free wall; HI, harmonic index; SEP, septum; SN, sinus node; RRA, the rest of the RA outside the SN. * P ⬍ 0.05 vs ongoing. † P ⬍ 0.05 vs FW.
6.61 ⫾ 5.56 minutes. Overall, the PAF periods included the 11 episodes of spontaneous initiation, 25 episodes of ongoing AF, and 22 episodes of spontaneous termination analyzed in this study. The detailed information is shown in Table 1. A representative noncontact unipolar electrogram is shown in Figure 2. Identification of SN activities The isopotential map of the EAS sites showed a centrifugal pattern, as in Figure 1A. The average distance between each EAS to the centre point inside the SN region was 1.14 ⫾ 0.33 mm (with respect to Cb) before spontaneous initiation of AF and 1.43 ⫾ 0.44 mm (with respect to Ca) after termination of AF. The difference between Cb and Ca was 2.40 ⫾ 1.90 mm (P ⬎ 0.05). The isopotential maps of the sinus activity during SR, before spontaneous initiation of AF, and after AF termination were similar in all patients. Fibrillatory activity in the RA Table 2 shows the spectral analysis for 6-second signal segments. The frequency characteristics (DF and HI) in the SN region were similar to those of the rest of the RA outside the SN during the initiation of AF. During the termination of AF, the SN region was characterized by a lower DF and higher HI compared with the ongoing AF (all P ⬍ 0.05). There was no significant difference in DF among different regions during AF. However, a significant difference in HI between SN and FW regions was observed. Table 3 shows the spectral analysis for 2-second signal segments in the termination stage. The fibrillatory activity of the RA other than the SN region was similar for 0 to 2, 2 to 4, and 4 to 6 seconds before termination. However, the SN region during 0 to 2 seconds before termination was characterized by a lower DF (all P ⬍ 0.05) and higher HI (all P ⬍ 0.05) than the DFs and HIs for 2 to 4 and for 4 to 6 seconds before termination, respectively. For the frequency characteristics (DF and HI) in the specific regions, only the SN region represented significant differences compared with other regions (all P ⬍ 0.05) during the 2 seconds before termination. In the present study, the activities that resembled activity during SR were detected before the termination by using the 2-second time segment of the frequency analysis (19/22, 86%). In the other 3 patients, only organized AFL was observed. The
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Table 3. Summary of frequency analysis of 2-second segments during termination stages of atrial fibrillation
DF (Hz)
HI
Region
4-6 s before termination
2-4 s before termination
0-2 s before termination
SN CT SEP FW RRA SN CT SEP FW RRA
4.64 ⫾ 1.21 4.67 ⫾ 0.99 4.94 ⫾ 1.05 4.97 ⫾ 1.29 4.74 ⫾ 1.16 0.47 ⫾ 0.11 0.46 ⫾ 0.08 0.46 ⫾ 0.11 0.50 ⫾ 0.13 0.51 ⫾ 0.10
4.87 ⫾ 1.21 4.73 ⫾ 0.99 4.23 ⫾ 1.05 4.93 ⫾ 1.29 4.89 ⫾ 1.16 0.50 ⫾ 0.09 0.47 ⫾ 0.11 0.46 ⫾ 0.10 0.44 ⫾ 0.06 0.46 ⫾ 0.08
3.78 ⫾ 1.02*† 4.53 ⫾ 1.47 4.82 ⫾ 0.86 4.63 ⫾ 1.45 4.89 ⫾ 1.32 0.57 ⫾ 0.08*† 0.50 ⫾ 0.08 0.47 ⫾ 0.11 0.50 ⫾ 0.10 0.47 ⫾ 0.10
Values are expressed as mean ⫾ SD. CT, crista terminalis; DF, dominant frequency; FW, free wall; HI, harmonic index; SEP, septum; SN, sinus node; RRA, the rest of the RA outside the SN. * P ⬍ 0.05 vs 4-6 s before termination and 2-4 s before termination, respectively. † P ⬍ 0.05 vs CT, SEP, FW, and RRA, respectively.
frequency disparities were found between the SN and outside SN regions (CT, FW, SEP), and the different morphologies between SN and CT before termination were also observed. Figure 3 illustrates the irregular wave fronts’ splitting and collision during 0 to 2 seconds before termination in isopotential maps. The isopotential maps before AF termination were compared with the activation pattern during SR. Activity from the SN region on the isopotential map that resembled activity during SR (Fig. 3, panels 3 and 10) coexisted with fibrillatory waves. During the last 2 seconds before spontaneous termination, activity patterns with local unipolar QS patterns were observed at the SN region in 22 of 22 termination episodes. Discussion Main findings The activities around the SN had special frequency patterns through the 2-second frequency analysis during the last 2 seconds just before spontaneous termination. The SN regions were characterized by a slow and organized activity when compared with the rest of the RA (CT, SEP, and FW), as indicated by a lower DF and higher HI before spontaneous termination of AF. These phenomena were similar with the wave front propagation patterns between AF termination and SR around the SN. Meanwhile, the frequency gradient existed from the SN outward to FW at spontaneous termination. Comparison with previous studies A previous animal study demonstrated that automatic sinus activity was observed in the SN region during AF.9 However, the electrogram signal properties of the SN region during AF were difficult to assess. The fibrillatory activity of the region around the SN, as well as the other regions of the RA, were acquired for analysis based on the accuracy of the mapping system.17 Furthermore, with the simultaneous frequency analysis and isopotential maps obtained from the reconstructed noncontact electrograms in the RA, we were able to investigate the spatiotemporal electrical activity of the different regions during each stage of AF. In a study conducted by Stiles et al.,19
the SN region was identified as the earliest activation of the isopotential map with a QS pattern as EAS in the analysis of the unipolar electrograms during SR. After rapid pacing, the SN had dynamic changes, which resulted in causal shift along between EAS and sinus breakout site. In this study, we confirmed the EAS was not variable before and after AF, with a distance of 2.40 ⫾ 1.90 mm (P ⬎ 0.05). The distance between the origin and the breakout sites was 8.3 ⫾ 2.9 mm before AF initiation and 11.7 ⫾ 4.9 mm after termination of AF (P ⬍ 0.05). In the present study, we found the electrophysiological behaviour of the SN region differed during the 3 stages of paroxysmal AF (ie, initiation, ongoing, and termination). During initiation of AF and ongoing AF, the DF gradient was not observed between the SN region and the rest of the RA. An RA-to-SN DF gradient was observed from the nearby RA substrate to the SN region before termination, indicating that the AF sources of the maintainers were outside the SN region and exhibited entrance conduction block into the SN region. The activity that resembled activity during SR could be detected before termination by using the 2-second time segment of the frequency analysis (19/22) and isopotential map (22/22) in termination episodes. The present study showed that lowering of DF in the SN region occurred with activity patterns of the SN region resembling those in SR, and these phenomena were associated with spontaneous termination in particular AF patients. SN and AF termination Functional and/or structural abnormalities of the SN commonly occur in contexts associated with predisposition to the initiation or maintenance of atrial fibrillation.22,23 AF-induced remodelling can cause changes in SN function, impairing SN effectiveness in both animal and human studies.24 The mechanism of spontaneous termination of AF remains an unsolved issue.25 It is well known that the specialized structure of the SN is an important factor in the atrial activity of the RA. The SN is an inhomogeneous tissue, with regional differences in electrical activity from the periphery to the centre. These properties are physiologically important for the response to abnormal conditions,26 such as those caused by premature impulses or fibrillatory waves. This specialized structure of the SN helps it to continue to manifest driver capacity with pacemaker shifting that protects it from suppression by atrial activity, and also contributes to the tendency for conduction block of SN activity toward the atrial septum.27 The SN has electrical communication with the atria through specialized atrial conduction pathways.26-28 This study demonstrated that SN activity patterns similar to those in SR were observed during the last 2 seconds before spontaneous AF termination. This SN activity showed the similarity of the EAS before the spontaneous AF termination, compared with the pattern of SR.27 There are several possible explanations for this observation. First, this type of SN-region activity might represent spontaneous SN activity that is overshadowed by rapid fibrillatory waves during the initiation and maintenance of AF.29-31 Underlying SN activity could be visible only when global RA activity is slower and more organized within 2 seconds just before termination, when the RA-to-SN frequency gradient becomes evident. SN activity may interfere with AF maintainers in the CT and posterior wall area in AF
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Figure 3. Isopotential maps showing right atrial fibrillatory activities during spontaneous termination of atrial fibrillation. The wave fronts are propagated in the free wall and low septum in panels 1 and 2 (yellow arrows). In panel 3, activity that resembled activity during sinus rhythm from the sinus node region (green star) fused with the free wall wave fronts (green arrow) and propagated though the posterior wall (panels 4 and 5) and split again into multiple wavelets (yellow arrows). In panel 10, activity that resembled activity during sinus rhythm occurred again, fused with the free wall wave fronts, and propagated through the posterior wall before termination. The location of the activity (green star) was compatible with the location of the sinus node during sinus rhythm.
patients, originating from RA and SVC.32,33 Second, recent studies have showed that the ion channel expression of the SN is altered during atrial tachyarrhythmias,34,35 and activation from the EAS and the breakout site in the atrial endocardial surface is slower.19 Those features may explain RA-to-SN DF gradient in a rate-dependent manner.27 According to previous studies, the structures around the SN act as filters for atrial waves to prevent the re-entry of waves from the atrium.26,27 This may explain partly the slowing of the SN and CT region before termination of AF in these patients. Thirdly, disturbances in the autonomic nervous system may enhance the entrance and exit block of the SN region.27,28 The sinus rate increased from 69.4 ⫾ 17.9 beats per minute at baseline to 89.6 ⫾ 22.3 beats per minute (P ⬍ 0.001) after AF termination, which may be related to changes in autonomic tone before vs after episodes of AF. Finally, the activity in the SN region may represent mechanisms different from spontaneous SR, such as local triggered activity that slows immediately before
AF termination or re-entry through pathways that break through to the endocardium at sites close to the spontaneous SN pacemaker. Clinical implications During the termination stage, the activity of the region outside the SN was slower and more organized. SN entrance block occurred along with SN activity patterns similar to those of SR observed immediately before AF termination. These data suggested (1) complex interactions between the SN region and RA during the different stages of AF and (2) the possibility that SN-region entrance block could develop in a rate-dependent manner. Limitations First, the SN is a complex structure and it could originate from the subepicardial position with the wave front exit to the endocar-
Tso et al. Fibrillatory Activities During AF Termination
dial surface. It is possible that the location of the endocardium with earliest activation may not completely correspond to the SN. However, it is the universal limitation of human studies. Second, a distance to the array of more than 38 mm may decrease the accuracy of activation timing and electrogram morphology. In addition, the 3-dimensional mapping had a spatial resolution of 2 to 3 mm. In spite of the high-density mapping in the RA, the resolution of the mapping may not have been sufficient to appreciate SN activity during pretermination phases of AF. Thirdly, the proportion of SVC-AF and RA-AF patients in this study was higher compared with historical controls. In the present study, 46% of the AF patients were from the right side (SVC and CT). This may relate to the mechanism of spontaneous termination, because the maintainers of the SVC-AF and CT-AF were near the SN region. Therefore, the data may not be extrapolated to all types of AF patients. In this study, we did not observe any patient with a long pause after restoration to SR, possibly because of the limited number of patients and/or the rate-dependent manner of exit block during SR and AF. Conclusions The spectral characteristics of the SN region differed from the rest of the RA during spontaneous termination of AF. The spatiotemporal activity of the SN region was characterized by a more organized and slower activity, with conduction block prior to AF termination. Using frequency analysis and activation mapping, we observed lowering of the DF in the SN region, within 2 seconds just before AF termination, occurring with activity patterns of the SN region similar to those of SR. The SN preservation and SN conduction block are important factors before AF termination. A frequency analysis could help us to describe the detailed process of the fibrillatory waves around the SN region. Funding Sources This study was supported by grants NSC90-2213-E-010007 and NSC92-2218-E-010- 002 from the National Science Council, Taiwan.
93 mal and persistent atrial fibrillation using the Holter ECG. Cardiovasc Res 1999;44:60-6. 7. Nilsson F, Stridh M, Bollmann A, Sornmo L. Predicting spontaneous termination of atrial fibrillation using the surface ECG. Med Eng Phys 2006;28:802-8. 8. Chiarugi F, Varanini M, Cantini F, Conforti F, Vrouchos G. Noninvasive ECG as a tool for predicting termination of paroxysmal atrial fibrillation. IEEE Trans Biomed Eng 2007;54:1399-406. 9. Kirchhof CJ, Allessie MA. Sinus node automaticity during atrial fibrillation in isolated rabbit hearts. Circulation 1992;86:263-71. 10. Everett TH, Kok LC, Vaughn RH, Moorman JR, Haines DE. Frequency domain algorithm for quantifying atrial fibrillation organization to increase defibrillation efficacy. IEEE Trans Biomed Eng 2001; 48:969-78. 11. Lin YJ, Tai CT, Kao T, et al. Frequency analysis in different types of paroxysmal atrial fibrillation. J Am Coll Cardiol 2006;47:1401-7. 12. Schilling RJ, Kadish AH, Peters NS, Goldberger J, Davies DW. Endocardial mapping of atrial fibrillation in the human right atrium using a non-contact catheter. Eur Heart J 2000;21:550-64. 13. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999;100:1879-86. 14. Lin WS, Tai CT, Hsieh MH, et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation 2003; 107:3176-83. 15. Lin YJ, Tai CT, Kao T, et al. Electrophysiological characteristics and catheter ablation in patients with paroxysmal right atrial fibrillation. Circulation 2005;112:1692-700. 16. Lin YJ, Tai CT, Huang JL, et al. Characteristics of virtual unipolar electrograms for detecting isthmus block during radiofrequency ablation of typical atrial flutter. J Am Coll Cardiol 2004;43:2300-4. 17. Kadish A, Hauck J, Pederson B, Beatty G, Gornick C. Mapping of atrial activation with a noncontact, multielectrode catheter in dogs. Circulation 1999;99:1906-13.
Disclosures The authors have no conflicts of interest to disclose.
18. Lin YJ, Higa S, Kao T, et al. Validation of the frequency spectra obtained from the noncontact unipolar electrograms during atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:1147-53.
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20. Tai CT, Chen SA, Liu AS, et al. Spectral analysis of chronic atrial fibrillation and its relation to minimal defibrillation energy. Pacing Clin Electrophysiol 2002;25:1747-51. 21. Everett TH, Moorman JR, Kok LC, Akar JG, Haines DE. Assessment of global atrial fibrillation organization to optimize timing of atrial defibrillation. Circulation 2001;103:2857-61. 22. Sano T, Suzuki F, Sato S. Sinus node impulses and atrial fibrillation. Circ Res 1967;21:507-13.
5. Petrutiu S, Sahakian AV, Swiryn S. Abrupt changes in fibrillatory wave characteristics at the termination of paroxysmal atrial fibrillation in humans. Europace 2007;9:466-70.
23. Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs: electrophysiological remodeling. Circulation 1996;94:2953-60.
6. Bollmann A, Sonne K, Esperer HD, Toepffer I, Langberg JJ, Klein HU. Non-invasive assessment of fibrillatory activity in patients with paroxys-
24. Sanders P, Kistler PM, Morton JB, Spence SJ, Kalman JM. Remodeling of sinus node function in patients with congestive heart
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30. Krishnaswami V, Geraci AR. Permanent pacing in disorders of sinus node function. Am Heart J 1975;89:579-85.
25. Nattel S. From guidelines to bench: implications of unresolved clinical issues for basic investigations of atrial fibrillation mechanisms. Can J Cardiol 2011;27:19-26.
31. Steinbeck G, Allessie MA, Bonke FI, Lammers WJ. Sinus node response to premature atrial stimulation in the rabbit studied with multiple microelectrode impalements. Circ Res 1978;43:695-704.
26. Boyett MR, Honjo H, Yamamoto M, Nikmaram MR, Niwa R, Kodama I. Downward gradient in action potential duration along conduction path in and around the sinoatrial node. Am J Physiol 1999;276:H686-98.
32. Lin YJ, Tai CT, Liu TY, et al. Electrophysiological mechanisms and catheter ablation of complex atrial arrhythmias from crista terminalis. Pacing Clin Electrophysiol 2004;27:1231-9.
27. Fedorov VV, Chang R, Glukhov AV, et al. Complex interactions between the sinoatrial node and atrium during reentrant arrhythmias in the canine heart. Circulation 2010;122:782-9.
33. Liu TY, Tai CT, Lee PC, et al. Novel concept of atrial tachyarrhythmias originating from the superior vena cava: insight from noncontact mapping. J Cardiovasc Electrophysiol 2003;14:533-9.
28. Sharifov OF, Fedorov VV, Beloshapko GG, Glukhov AV, Yushmanova AV, Rosenshtraukh LV. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J Am Coll Cardiol 2004;43:483-90.
34. Yeh YH, Burstein B, Qi XY, et al. Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome. Circulation 2009; 119:1576-85.
29. Gomes JA, Kang PS, Matheson M, Gough WB Jr, El-Sherif N. Coexistence of sick sinus rhythm and atrial flutter-fibrillation. Circulation 1981;63:80-6.
35. Joung B, Lin SF, Chen Z, et al. Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation. Heart Rhythm 2010;7:88-95.
Clinical Research
Characteristics of Fibrillatory Activities During Spontaneous Termination of Paroxysmal Atrial Fibrillation: New Insight From High-Density Right Atrium Frequency Mapping Han-Wen Tso, MS,a Yenn-Jiang Lin, MD, PhD,b,c Ching-Tai Tai, MD,b Shin-Ann Chen, MD,b,c and Tsair Kao, PhDd a b
Institute of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan
Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan c d
Department of Medicine, National Yang-Ming University, Taipei, Taiwan
Department of Biomedical Engineering, Hungkuang University, Taichung City, Taiwan
ABSTRACT
RÉSUMÉ
Background: Sinus node (SN) activity is difficult to assess during atrial fibrillation (AF). The aim of the present study was to investigate SN activity by frequency analysis during AF. Methods: Thirteen patients with paroxysmal AF and atrial flutter in the right atrium (RA) underwent 3-dimensional noncontact mapping. The fibrillatory activity was recorded from a multielectrode array in the RA. A frequency analysis with 2- and 6-second time-segment lengths was performed. Spectral characteristics (dominant frequency and harmonic index) and isopotential activation maps were used to investigate the spatiotemporal activity of the SN region and the rest of the RA (crista terminalis, septum, and free wall) during the initiation, while ongoing, and before the termination of AF. Results: With duration of 6 seconds, the whole RA had similar trends of frequency distribution. With duration of 2 seconds prior to termination, the SN region exhibited a trend of low-frequency pattern and high-organization distribution, compared with the segments for the 2 to 4 and 4 to 6 seconds before termination. The isopotential activation
Introduction : L’activité du noeud sinusal (NS) est difficile à évaluer durant la fibrillation auriculaire (FA). Le but de la présente étude était d’examiner l’activité du NS par l’analyse de fréquence durant la FA. Méthodes : Treize patients ayant une FA paroxystique et un flutter auriculaire dans l’oreillette droite (OD) ont subi une cartographie tridimensionnelle sans contact. L’activité fibrillatoire a été enregistrée à partir d’un cathéter multiélectrode dans l’OD. Une analyse de fréquence ayant des intervalles de temps de deux (2) à six (6) secondes a été faite. Les caractéristiques spectrales (fréquence dominante et indice harmonique) et les cartes d’activation isopotentielle ont été utilisées pour explorer l’activité spatiotemporelle de la région du NS et le repos de l’OD (crista terminalis, cloison et paroi libre) au début, en cours et avant la fin de la FA. Résultats : Pour une durée de six (6) secondes, l’OD entière a eu des tendances similaires de distribution de fréquence. Dans les deux (2) secondes avant la fin, la région du NS a tendu vers un modèle de basse fréquence et une distribution très organisée, comparativement aux
Atrial fibrillation (AF) is the most common type of arrhythmia in clinical practice.1 In previous studies, the mechanism of AF spontaneous termination was mostly based on electric or drug-induced termination.2,3 The mechanism of spontaneous termination still remains unclear. Clinical observation demonstrated that the fibrillation rate decreases and
cycle length increases abruptly before spontaneous termination.3-5 Most studies have focused on surface ECG rather than the intracardiac recordings of each anatomic region.5-8 In Langendorff-perfused rabbit hearts, Kirchhof and Allessie showed that sinus node (SN) automaticity was preserved with a high degree of sinoatrial entrance block against rapid fibrillatory impulses during AF.9 However, beat-to-beat variation of time-domain electrogram is the universal limitation of AF mapping. Therefore, frequency analysis may provide an alternative tool to describe a longer duration of complex rhythm as AF.10,11 Furthermore, 3-dimensional noncontact mapping facilitates 1-beat analysis during initiation and termination of AF, which is almost impossible with previous conventional
Received for publication April 28, 2011. Accepted August 7, 2011. Corresponding author: Dr Tsair Kao, Department of Biomedical Engineering, Hungkuang University, 34, Chung-Chie Road, Shalu, Taichung City, 43302, Taiwan. E-mail: [email protected] See page 93 for disclosure information.
0828-282X/$ – see front matter © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.cjca.2011.08.119
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maps showed the spontaneous earliest activities had wave front propagation patterns similar to those during sinus rhythm (after termination). Conclusions: The fibrillatory activity of the SN region was organized, and slow activation was detected, by frequency analysis and isopotential mapping, within 2 seconds just prior to AF termination.
intervalles de temps de deux (2) à quatre (4) et de quatre (4) à six (6) secondes avant la fin. Les cartes d’activation isopotentielle ont montré que les activités spontanées les plus précoces avaient des modèles de propagation de front d’onde similaires à durant le rythme sinusal (après la fin). Conclusions : L’activité fibrillatoire de la région du NS a été organisée, et une activation lente a été détectée, par l’analyse de fréquence et la cartographie isopotentielle, dans les deux (2) dernières secondes avant la fin de la FA.
mapping techniques. Therefore, the purpose of this study was to investigate the spatiotemporal activity of the SN region by using noncontact mapping and frequency analysis.11,12 This study explored the fibrillatory activities of the SN region and outside SN region during different stages of AF, including spontaneous termination.
sented to the electrophysiology laboratory in sinus rhythm (SR), we first attempted to observe the spontaneous activation during baseline or after an isoproterenol infusion. The methods used to identify spontaneous AF were attempted at least twice to ensure reproducibility. In this study, all patients had spontaneous initiation and termination of AF.
Methods
Noncontact mapping system
Patient characteristics This study consisted of 13 patients (10 men, 3 women, aged 57 ⫾ 17 years) with paroxysmal AF (PAF) and atrial flutter (AFL), who underwent an electrophysiological study and catheter ablation (Table 1). The patients had suffered from frequent attacks of clinically documented paroxysmal AF and AFL for a mean duration of 4.2 ⫾ 2.7 years and were refractory to more than 1 antiarrhythmic drug. All antiarrhythmic drugs except for amiodarone were discontinued for at least 5 half-lives before the procedure. The patients underwent the RA electroanatomic mapping and catheter ablation with a noncontact mapping system. Informed written consent was obtained from all patients. We attempted to identify the initiation triggers in all AF patients who underwent catheter ablation.13,14 In brief, we attempted to find the spontaneous onset of atrial ectopic beats or repetitive episodes of short runs or sustained AF and predict the location of the initiating foci. When the AF patients preTable 1. Demographic data Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
The noncontact mapping system (NavX, St Jude Medical Inc, St Paul, MN) has been previously described.15-17 Briefly, the system consisted of a catheter (9F) with a multielectrode array (MEA) surrounding a 7.5-mL balloon mounted at the distal end. The system located any other catheters with respect to the MEA by using a navigation locator signal. It was used to construct a 3-dimensional computer model of the endocardium and to track the positions of the standard contact catheters within the RA relative to the anatomic structures or critical zones of conduction. Noncontact endocardial electrograms were mathematically reconstructed to produce isopotential or isochronal colour maps on the model.12 The accuracy of the electrogram morphology, activation time difference, and voltage between the contact and noncontact electrograms has been validated from the same endocardial locations during SR and atrial tachycardia.17 We have confirmed the accuracy of the noncontact MEA for reproducing the contact electrogram morphology, frequency measurements, and spectral morphology by coherence during human AF.18 Activation mapping
Gender
Age (years)
Underlying diseases
AF origin
Arrhythmia
M M M M M F M M M F M M F
76 31 68 77 78 53 72 56 34 35 50 58 65
HT, Thyroid Nil HT, CAD HT, COPD HT, CAD, COPD HT, Thyroid HT, DM HT Nil HT HT HT HT
SVC SVC PV SVC CT SVC CT PV PV PV PV PV PV
PAF PAF PAF, AFL PAF PAF PAF, AFL PAF, AFL PAF, AFL PAF PAF, CCWTAFL PAF, CWRTAFL PAF PAF
AF, atrial fibrillation; AFL, atrial flutter; CAD, coronary artery disease; CCWTAFL, counterclockwise typical AFL; COPD, chronic obstructive pulmonary disease; CT, crista terminalis; CWRTAFL, clockwise reverse typical AFL; DM, diabetes mellitus; F, female; HT, hypertension; M, male; Nil, no data available; PAF, paroxysmal atrial fibrillation; PV, pulmonary vein; SVC, superior vena cava.
The colour settings were adjusted so that the colour range matched 1:1 with the milli-volt range of the electrogram deflection. We also interactively placed virtual electrodes on the colour contours to analyze the corresponding unipolar noncontact electrograms. The SN region was identified as the earliest activation of the isopotential map, with a QS pattern as earliest activation site (EAS) during the analysis of the unipolar electrograms during SR.19 Through the 3-dimensional coordination of the noncontact mapping system’s built-in electrodes, the location of the SN was labelled on the 3-dimensional reconstructed geometry of the RA, and the activation pattern during SR was observed (Fig. 1A, left panel). Centrifugal activation away from the SN region was observed from the colour-coded isopotential maps during SR. An example of electrograms of the SN is shown in Figure 1A (right panel). Figure 1B shows the propagation of wave fronts away from the SN in a centrifugal activation pattern to the rest of the RA. The anatomic locations of the RA free wall (FW), RA septum (SEP), and crista terminalis (CT) were also determined on the 3-dimensional endocardium by fluoroscopy, as marked in Figure 1A
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Figure 1. The isopotential map of the sinus node (SN), earliest activation site (A, left panel). The anatomic locations of the free wall (FW), septum (SEP), and crista terminalis (CT) of the right atrium are marked on the map. The corresponding unipolar electrograms of the SN and its 4 nearby sites are also shown (A, right panel). (B) Shows the propagation of wave fronts away from the SN in an activation pattern centrifugal to the rest of the right atrium. ECG, electrocardiogram.
(left panel). At least 10 virtual electrograms were analyzed in each region. Identification of the SN activities Ten consecutive sinus activities, both before spontaneous initiation and after termination of AF, were recorded. The spatial variations of the EASs were calculated. For each sinus activity, the Cartesian coordinates (x, y, z) of the EAS on the 3-dimensional geometry could be obtained in order to assess the reproducibility of the SN location. The centre points of 10 EASs before and after AF were represented by Cb and Ca, respectively. The distance
between each EAS and the centre point was calculated. If the distance was limited and the SN region also covered the EAS distribution, we assumed the stability of the SN location detected by the noncontact mapping system to have been confirmed. Signal acquisition and preprocessing The unipolar endocardial electrograms from the noncontact mapping system were sampled at 1.2 kHz and filtered with a second-order Butterworth filter bandwidth between 2 and 300 Hz. Six-second intervals after the (spontaneous) AF onset and before the (spontaneous) offset of AF were defined as the
Figure 2. Noncontact unipolar electrograms of patient 11 simultaneously recorded from surface electrocardiogram (ECG) lead I and 4 anatomic sites, sinus node (SN), crista terminalis (CT), septum (SEP), and free wall (FW). Each electrogram with QRS-T complex cancellation includes 4 periods: initiation of atrial fibrillation (AF), ongoing AF, termination of AF, and resumed sinus rhythm (SR).
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initiation and termination stages, respectively. The timing of spontaneous initiation and termination were defined by surface electrograms. The data of the first 6 seconds of AF (initiation), ongoing AF (after 50 seconds of initiation), and the last 6 seconds of AF (termination) were exported for off-line analysis. The raw data with simultaneously recorded surface 12-lead electrograms and unipolar electrograms reconstructed from the electrodes on the endocardial surface were obtained from the noncontact mapping system. The electrograms of the defined regions in the RA were exported to an external Matlab (MathWorks, Inc, Natick, MA) software program for frequency analysis. The ventricular component (QRS-T complex) in the endocardial electrogram was eliminated by use of the adaptive cancellation technique.20 Each R wave in the electrogram was identified by using a peak detection algorithm, based on the surface ECG lead V1 aligned. The QRS-T segments were aligned on this fiducial point and averaged to create the template. The template was positioned at the location of each QRS complex in the electrogram. Because of variations in the amplitude of the QRS complex, the template was adjusted accordingly for every beat to form the QRS-T parts of a reference. With the reference signal, each QRS-T complex was adaptively cancelled from the original endocardial electrogram by the use of a recursive least-squares algorithm, resulting in a remainder electrogram. The QRS-T complex was cancelled in all electrograms in this study. Frequency analysis of the AF electrograms A fast Fourier transform was calculated on the remainder electrogram, which was zero-padded to keep a frequency resolution of 0.143 Hz for each 2-second and 6-second segment.5,10 The frequency of the spectra was limited to 1 to 20 Hz, which covered the physiological range of practical interest. The largest peak frequency of the spectrum was defined as the dominant frequency (DF).11 The total power of the spectrum was calculated from 1 to 20 Hz. The power under the DF and its 3 harmonic peaks were calculated over a 1-Hz window for each. The ratio of the power under these 4 peaks to the total power was defined as the harmonic index (HI).21 The HI represents the degree of organization of the AF during the time of the signal. We described the regional frequency distribution of the spectral characteristics at the SN and other regions in the RA, including FW, SEP, and CT regions. Statistical analysis Data were presented as the mean value ⫾ standard deviation (SD). A chi-square test with a Fisher exact test was used for the categorical data. Normally distributed continuous variables were compared by means of 1-way ANOVA and post hoc analyses, whereas not normally distributed variables were compared by means of the Kruskal-Wallis H test. A P value ⬍ 0.05 was considered statistically significant. Results Patient characteristics In these 13 patients, AF originated from the superior vena cava (SVC, N ⫽ 4), CT (N ⫽ 2), and pulmonary vein (N ⫽ 7). Sustained AF was observed in 13 patients, with duration of
Canadian Journal of Cardiology Volume 28 2012 Table 2. Summary of frequency analysis of 6-second segments during different stages of atrial fibrillation DF (Hz)
HI
Region
Initiation
Ongoing
Termination
SN CT SEP FW RRA SN CT SEP FW RRA
4.96 ⫾ 0.95 5.13 ⫾ 0.72 4.97 ⫾ 0.86 5.17 ⫾ 0.82 5.12 ⫾ 0.87* 0.55 ⫾ 0.09 0.55 ⫾ 0.14 0.54 ⫾ 0.15 0.54 ⫾ 0.15 0.54 ⫾ 0.14
5.31 ⫾ 1.01 5.39 ⫾ 1.00 5.45 ⫾ 1.03 5.55 ⫾ 1.21 5.46 ⫾ 1.00 0.50 ⫾ 0.09† 0.49 ⫾ 0.10 0.47 ⫾ 0.08 0.45 ⫾ 0.09 0.46 ⫾ 0.09
4.91 ⫾ 0.69* 5.23 ⫾ 0.71 5.02 ⫾ 0.70 5.12 ⫾ 0.75 5.09 ⫾ 0.90* 0.56 ⫾ 0.09* 0.50 ⫾ 0.08 0.48 ⫾ 0.10 0.49 ⫾ 0.12 0.51 ⫾ 0.10
Values are expressed as mean ⫾ SD. CT, crista terminalis; DF, dominant frequency; FW, free wall; HI, harmonic index; SEP, septum; SN, sinus node; RRA, the rest of the RA outside the SN. * P ⬍ 0.05 vs ongoing. † P ⬍ 0.05 vs FW.
6.61 ⫾ 5.56 minutes. Overall, the PAF periods included the 11 episodes of spontaneous initiation, 25 episodes of ongoing AF, and 22 episodes of spontaneous termination analyzed in this study. The detailed information is shown in Table 1. A representative noncontact unipolar electrogram is shown in Figure 2. Identification of SN activities The isopotential map of the EAS sites showed a centrifugal pattern, as in Figure 1A. The average distance between each EAS to the centre point inside the SN region was 1.14 ⫾ 0.33 mm (with respect to Cb) before spontaneous initiation of AF and 1.43 ⫾ 0.44 mm (with respect to Ca) after termination of AF. The difference between Cb and Ca was 2.40 ⫾ 1.90 mm (P ⬎ 0.05). The isopotential maps of the sinus activity during SR, before spontaneous initiation of AF, and after AF termination were similar in all patients. Fibrillatory activity in the RA Table 2 shows the spectral analysis for 6-second signal segments. The frequency characteristics (DF and HI) in the SN region were similar to those of the rest of the RA outside the SN during the initiation of AF. During the termination of AF, the SN region was characterized by a lower DF and higher HI compared with the ongoing AF (all P ⬍ 0.05). There was no significant difference in DF among different regions during AF. However, a significant difference in HI between SN and FW regions was observed. Table 3 shows the spectral analysis for 2-second signal segments in the termination stage. The fibrillatory activity of the RA other than the SN region was similar for 0 to 2, 2 to 4, and 4 to 6 seconds before termination. However, the SN region during 0 to 2 seconds before termination was characterized by a lower DF (all P ⬍ 0.05) and higher HI (all P ⬍ 0.05) than the DFs and HIs for 2 to 4 and for 4 to 6 seconds before termination, respectively. For the frequency characteristics (DF and HI) in the specific regions, only the SN region represented significant differences compared with other regions (all P ⬍ 0.05) during the 2 seconds before termination. In the present study, the activities that resembled activity during SR were detected before the termination by using the 2-second time segment of the frequency analysis (19/22, 86%). In the other 3 patients, only organized AFL was observed. The
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Table 3. Summary of frequency analysis of 2-second segments during termination stages of atrial fibrillation
DF (Hz)
HI
Region
4-6 s before termination
2-4 s before termination
0-2 s before termination
SN CT SEP FW RRA SN CT SEP FW RRA
4.64 ⫾ 1.21 4.67 ⫾ 0.99 4.94 ⫾ 1.05 4.97 ⫾ 1.29 4.74 ⫾ 1.16 0.47 ⫾ 0.11 0.46 ⫾ 0.08 0.46 ⫾ 0.11 0.50 ⫾ 0.13 0.51 ⫾ 0.10
4.87 ⫾ 1.21 4.73 ⫾ 0.99 4.23 ⫾ 1.05 4.93 ⫾ 1.29 4.89 ⫾ 1.16 0.50 ⫾ 0.09 0.47 ⫾ 0.11 0.46 ⫾ 0.10 0.44 ⫾ 0.06 0.46 ⫾ 0.08
3.78 ⫾ 1.02*† 4.53 ⫾ 1.47 4.82 ⫾ 0.86 4.63 ⫾ 1.45 4.89 ⫾ 1.32 0.57 ⫾ 0.08*† 0.50 ⫾ 0.08 0.47 ⫾ 0.11 0.50 ⫾ 0.10 0.47 ⫾ 0.10
Values are expressed as mean ⫾ SD. CT, crista terminalis; DF, dominant frequency; FW, free wall; HI, harmonic index; SEP, septum; SN, sinus node; RRA, the rest of the RA outside the SN. * P ⬍ 0.05 vs 4-6 s before termination and 2-4 s before termination, respectively. † P ⬍ 0.05 vs CT, SEP, FW, and RRA, respectively.
frequency disparities were found between the SN and outside SN regions (CT, FW, SEP), and the different morphologies between SN and CT before termination were also observed. Figure 3 illustrates the irregular wave fronts’ splitting and collision during 0 to 2 seconds before termination in isopotential maps. The isopotential maps before AF termination were compared with the activation pattern during SR. Activity from the SN region on the isopotential map that resembled activity during SR (Fig. 3, panels 3 and 10) coexisted with fibrillatory waves. During the last 2 seconds before spontaneous termination, activity patterns with local unipolar QS patterns were observed at the SN region in 22 of 22 termination episodes. Discussion Main findings The activities around the SN had special frequency patterns through the 2-second frequency analysis during the last 2 seconds just before spontaneous termination. The SN regions were characterized by a slow and organized activity when compared with the rest of the RA (CT, SEP, and FW), as indicated by a lower DF and higher HI before spontaneous termination of AF. These phenomena were similar with the wave front propagation patterns between AF termination and SR around the SN. Meanwhile, the frequency gradient existed from the SN outward to FW at spontaneous termination. Comparison with previous studies A previous animal study demonstrated that automatic sinus activity was observed in the SN region during AF.9 However, the electrogram signal properties of the SN region during AF were difficult to assess. The fibrillatory activity of the region around the SN, as well as the other regions of the RA, were acquired for analysis based on the accuracy of the mapping system.17 Furthermore, with the simultaneous frequency analysis and isopotential maps obtained from the reconstructed noncontact electrograms in the RA, we were able to investigate the spatiotemporal electrical activity of the different regions during each stage of AF. In a study conducted by Stiles et al.,19
the SN region was identified as the earliest activation of the isopotential map with a QS pattern as EAS in the analysis of the unipolar electrograms during SR. After rapid pacing, the SN had dynamic changes, which resulted in causal shift along between EAS and sinus breakout site. In this study, we confirmed the EAS was not variable before and after AF, with a distance of 2.40 ⫾ 1.90 mm (P ⬎ 0.05). The distance between the origin and the breakout sites was 8.3 ⫾ 2.9 mm before AF initiation and 11.7 ⫾ 4.9 mm after termination of AF (P ⬍ 0.05). In the present study, we found the electrophysiological behaviour of the SN region differed during the 3 stages of paroxysmal AF (ie, initiation, ongoing, and termination). During initiation of AF and ongoing AF, the DF gradient was not observed between the SN region and the rest of the RA. An RA-to-SN DF gradient was observed from the nearby RA substrate to the SN region before termination, indicating that the AF sources of the maintainers were outside the SN region and exhibited entrance conduction block into the SN region. The activity that resembled activity during SR could be detected before termination by using the 2-second time segment of the frequency analysis (19/22) and isopotential map (22/22) in termination episodes. The present study showed that lowering of DF in the SN region occurred with activity patterns of the SN region resembling those in SR, and these phenomena were associated with spontaneous termination in particular AF patients. SN and AF termination Functional and/or structural abnormalities of the SN commonly occur in contexts associated with predisposition to the initiation or maintenance of atrial fibrillation.22,23 AF-induced remodelling can cause changes in SN function, impairing SN effectiveness in both animal and human studies.24 The mechanism of spontaneous termination of AF remains an unsolved issue.25 It is well known that the specialized structure of the SN is an important factor in the atrial activity of the RA. The SN is an inhomogeneous tissue, with regional differences in electrical activity from the periphery to the centre. These properties are physiologically important for the response to abnormal conditions,26 such as those caused by premature impulses or fibrillatory waves. This specialized structure of the SN helps it to continue to manifest driver capacity with pacemaker shifting that protects it from suppression by atrial activity, and also contributes to the tendency for conduction block of SN activity toward the atrial septum.27 The SN has electrical communication with the atria through specialized atrial conduction pathways.26-28 This study demonstrated that SN activity patterns similar to those in SR were observed during the last 2 seconds before spontaneous AF termination. This SN activity showed the similarity of the EAS before the spontaneous AF termination, compared with the pattern of SR.27 There are several possible explanations for this observation. First, this type of SN-region activity might represent spontaneous SN activity that is overshadowed by rapid fibrillatory waves during the initiation and maintenance of AF.29-31 Underlying SN activity could be visible only when global RA activity is slower and more organized within 2 seconds just before termination, when the RA-to-SN frequency gradient becomes evident. SN activity may interfere with AF maintainers in the CT and posterior wall area in AF
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Figure 3. Isopotential maps showing right atrial fibrillatory activities during spontaneous termination of atrial fibrillation. The wave fronts are propagated in the free wall and low septum in panels 1 and 2 (yellow arrows). In panel 3, activity that resembled activity during sinus rhythm from the sinus node region (green star) fused with the free wall wave fronts (green arrow) and propagated though the posterior wall (panels 4 and 5) and split again into multiple wavelets (yellow arrows). In panel 10, activity that resembled activity during sinus rhythm occurred again, fused with the free wall wave fronts, and propagated through the posterior wall before termination. The location of the activity (green star) was compatible with the location of the sinus node during sinus rhythm.
patients, originating from RA and SVC.32,33 Second, recent studies have showed that the ion channel expression of the SN is altered during atrial tachyarrhythmias,34,35 and activation from the EAS and the breakout site in the atrial endocardial surface is slower.19 Those features may explain RA-to-SN DF gradient in a rate-dependent manner.27 According to previous studies, the structures around the SN act as filters for atrial waves to prevent the re-entry of waves from the atrium.26,27 This may explain partly the slowing of the SN and CT region before termination of AF in these patients. Thirdly, disturbances in the autonomic nervous system may enhance the entrance and exit block of the SN region.27,28 The sinus rate increased from 69.4 ⫾ 17.9 beats per minute at baseline to 89.6 ⫾ 22.3 beats per minute (P ⬍ 0.001) after AF termination, which may be related to changes in autonomic tone before vs after episodes of AF. Finally, the activity in the SN region may represent mechanisms different from spontaneous SR, such as local triggered activity that slows immediately before
AF termination or re-entry through pathways that break through to the endocardium at sites close to the spontaneous SN pacemaker. Clinical implications During the termination stage, the activity of the region outside the SN was slower and more organized. SN entrance block occurred along with SN activity patterns similar to those of SR observed immediately before AF termination. These data suggested (1) complex interactions between the SN region and RA during the different stages of AF and (2) the possibility that SN-region entrance block could develop in a rate-dependent manner. Limitations First, the SN is a complex structure and it could originate from the subepicardial position with the wave front exit to the endocar-
Tso et al. Fibrillatory Activities During AF Termination
dial surface. It is possible that the location of the endocardium with earliest activation may not completely correspond to the SN. However, it is the universal limitation of human studies. Second, a distance to the array of more than 38 mm may decrease the accuracy of activation timing and electrogram morphology. In addition, the 3-dimensional mapping had a spatial resolution of 2 to 3 mm. In spite of the high-density mapping in the RA, the resolution of the mapping may not have been sufficient to appreciate SN activity during pretermination phases of AF. Thirdly, the proportion of SVC-AF and RA-AF patients in this study was higher compared with historical controls. In the present study, 46% of the AF patients were from the right side (SVC and CT). This may relate to the mechanism of spontaneous termination, because the maintainers of the SVC-AF and CT-AF were near the SN region. Therefore, the data may not be extrapolated to all types of AF patients. In this study, we did not observe any patient with a long pause after restoration to SR, possibly because of the limited number of patients and/or the rate-dependent manner of exit block during SR and AF. Conclusions The spectral characteristics of the SN region differed from the rest of the RA during spontaneous termination of AF. The spatiotemporal activity of the SN region was characterized by a more organized and slower activity, with conduction block prior to AF termination. Using frequency analysis and activation mapping, we observed lowering of the DF in the SN region, within 2 seconds just before AF termination, occurring with activity patterns of the SN region similar to those of SR. The SN preservation and SN conduction block are important factors before AF termination. A frequency analysis could help us to describe the detailed process of the fibrillatory waves around the SN region. Funding Sources This study was supported by grants NSC90-2213-E-010007 and NSC92-2218-E-010- 002 from the National Science Council, Taiwan.
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Disclosures The authors have no conflicts of interest to disclose.
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