Author + information
- Received March 20, 2000
- Revision received December 28, 2000
- Accepted January 24, 2001
- Published online May 1, 2001.
- Tse-Min Lu, MD†,
- Ching-Tai Tai, MD∗,†,
- Ming-Hsiung Hsieh, MD∗,
- Chin-Feng Tsai, MD∗,
- Yung-Kuo Lin, MD†,
- Wen-Chung Yu, MD∗,†,
- Hsuan-Ming Tsao, MD†,
- Shih-Huang Lee, MD∗,
- Yu-An Ding, MD∗,†,
- Mau-Song Chang, MD∗,† and
- Shih-Ann Chen, MD∗,†,* ()
- ↵*Reprint requests and correspondence: Dr. Shih-Ann Chen, Division of Cardiology, Veteran General Hospital-Taipei, 201 Sec 2, Shih-Pai Road, Taipei, Taiwan, Republic of China
We investigated the electrophysiologic characteristics in the initiation of paroxysmal atrial fibrillation (PAF) from a focal area.
The electrophysiologic characteristics in the initiation of PAF are still not clear.
The study group consisted of 77 patients (M/F = 65/12, age 66 ± 12 years) with frequent episodes of PAF; we analyzed: 1) 15 cycle lengths of electrical activity before the onset of atrial fibrillation (AF); 2) coupling interval (CI) of the first ectopic beat just before the initiation of AF; and 3) the prematurity of an ectopic beat (prematurity index [PI] = CI/mean of preceding 15 cycle lengths).
A total of 111 episodes of sustained AF were identified. Two patterns of AF initiation were observed: group I (59/111, 53%) included the episodes preceded by cycle length oscillation, and group II (52/111, 47%) included the episodes initiated by a single ectopic beat with preceding cycle length relatively constant. The PI of group I episodes was significantly greater than that of group II (0.41 ± 0.12 vs. 0.34 ± 0.10, p < 0.01). The CI (267 ± 54 ms vs. 217 ± 55 ms, p < 0.05), AF1 (194 ± 36 ms vs. 153 ± 37 ms, p < 0.05) and PI (0.49 ± 0.13 vs. 0.37 ± 0.11, p < 0.01) of the AF episodes from the superior vena cava (SVC) were significantly longer and greater than those of AF episodes from pulmonary veins (PVs).
In patients with PAF originating from PVs or the SVC, two major initiating patterns were found. Moreover, the electrophysiologic characteristics in the initiation of AF originating from the SVC were also different from those of AF initiating from the PVs.
Paroxysmal atrial fibrillation (PAF) is the most common arrhythmia encountered in clinical practice. However, how this troublesome arrhythmia occurs is still not clear. Previous and recent studies have shown, by analyzing surface electrocardiogram (ECG) and 24-h Holter recordings, that most PAF episodes were initiated by a single atrial ectopic beat without changes of preceding cycle length (1–3), in contrast to the findings at the onset of ventricular arrhythmia, in which most episodes were preceded by short-long cycle length sequences (4–6). Because P on T phenomenon is frequently seen at the onset of PAF, it is inadequate to analyze the initiation of PAF using surface ECG or 24-h Holter monitoring.
This laboratory and others have demonstrated that most PAF was initiated by ectopic beats originating from the pulmonary veins (PVs) (7–10). The purpose of this study was to evaluate how PAF episodes were initiated by ectopic atrial beats originating from PVs or other great vessels during the electrophysiologic study and to relate these observations to the possible mechanisms underlying this atrial arrhythmia.
The study consisted of 77 patients with frequent episodes of PAF (more than one episode/week, documented by ECG and 24-h Holter recording) referred to this institute for electrophysiologic study and catheter ablation. They were refractory to, or intolerant of, 3 ± 2 antiarrhythmic drugs. All of the patients underwent echocardiography, and the size of left atrium (LA) was measured. The LA was considered to be enlarged if its diameter measured from the aortic valve level in the parasternal short axis view was greater than 4 cm.
After informed consent was obtained, electrophysiologic study was performed. All antiarrhythmic drugs were discontinued for at least five half-lives before the study, and the techniques for the electrophysiologic study have been established in this laboratory (9,11). In short, one 7F, deflectable, decapolar catheter (7F, Daig Co., Minnetonka, Minnesota) with 2-mm interelectrode distance and 5-mm space between each electrode pair was inserted into the coronary sinus via the internal jugular vein. Two quadripolar catheters (Mansfield, Boston Scientific Corp., Watertown, Massachusetts) with 2-mm interelectrode spacing and 5-mm spacing between bipolar electrodes were routinely placed in the anterolateral right atrium and His bundle area. If the ectopic focus was suspected to originate from PVs, two 6F, deflectable, decapolar catheters (same electrode space as coronary sinus catheter) were put into the right superior pulmonary vein (RSPV) and left superior pulmonary vein (LSPV) after successful trans-septal procedure, respectively, or the inferior PVs, if necessary (cannulation of PVs were guided by direct pulmonary venography, with the first pair of electrodes straddling the ostium of the PV). Intravenous heparin was administered in a loading dose of 5,000 U and followed by doses of 2,000 to 3,000 U at 30-min to 1-h intervals, if needed, to maintain activated clotting time >300 s.
A programmed digital stimulator (DTU 215, Bloom Associates Ltd., Reading, Pennsylvania) was used to deliver electrical impulses. Intracardiac bipolar electrograms were displayed simultaneously with 12-lead ECG on a multichannel recorder (Prucka Engineering, Inc., Houston, Texas). As described previously (9,11), we first tried to find onset of atrial fibrillation (AF) initiated by premature ectopic beats in the baseline or after infusion of isoproterenol (up to 4 μg/min). If AF did not appear, a short duration of atrial burst pacing at a cycle length of 250 to 300 ms from the right atrium or coronary sinus was used to facilitate spontaneous initiation of AF. If AF could not be provoked, atrial burst pacing was used to induce AF. After the episode of AF was sustained for longer than 5 min, external cardioversion was attempted to convert AF to sinus rhythm and facilitate the reinitiation of AF. The methods used to facilitate AF onset were tried at least twice to ensure reproducibility (9).
As described previously, if the initiating focus of AF was considered to originate from the right atrium, we put one duodecapolar catheter (electrode length, 1 mm; 2 mm of interelectrode spacing) along the crista terminalis into the superior vena cava (SVC) to the height indicated by a distal electrogram amplitude >0.05 mV for simultaneous mapping of the PVs and the SVC (12). The junction of the SVC and the right atrium was determined fluoroscopically using multiple projections of the SVC angiography (12).
Analysis of the initiation pattern
The spontaneous and provoked cases of AF were observed during the electrophysiologic studies. We analyzed: 1) 15 cycle lengths of electrical activity at the recording site of the earliest activation just before the onset of AF; 2) coupling interval (CI) of the first ectopic beat just before initiation of AF; and 3) CI of the ectopic beats that did not initiate AF. The first cycle length of AF episodes (AF1) were also analyzed. In the electrical activities before the initiation of AF, the short cycle was defined as a cycle length <80% of the mean of the preceding 15 cycle lengths, and the long cycle length was defined as a cycle length >120% of the mean cycle length (3). In AF episodes originating from superior PVs, the locations of initiating ectopic beats were further divided into proximal and distal parts of superior PVs (<2 cm and >2 cm inside the pulmonary ostium, respectively). The prematurity of an ectopic beat was expressed as the ratio of the CI to the mean of the preceding 15 cycle lengths (prematurity index [PI] = CI/mean of preceding 15 cycle lengths).
All parametric values were presented as mean ± standard deviation. Chi-square test with Yates’ correction and Mann-Whitney Utest were used to compare nonparametric data; paired ttest was used to analyze the parametric data. In order to adjust the within-patients effects (48 patients had one episode, 24 patients had two episodes, and the remaining 5 patients had three episodes), we used a mixed effect model (13). We treated the patient as a random effect and evaluated the contributions of initiation patterns of AF, locations of AF-initiating foci (RSPV vs. LSPV, proximal part vs. distal part of superior PVs, superior vs. inferior PVs and PVs vs. SVC), LA enlargement and other variables (including age and gender) to each of the dependent variables, including mean cycle length, AF1, CI and PI. The analyses were performed using the SAS PROC MIXED (SAS version 6.12, Cary, North Carolina). More precisely, for each dependent variable, we put all the dependent variables, including patient effect as a random effect and initiation patterns, locations of initiating foci, LA enlargement as fixed effects in the model. A p value < 0.05 was considered to be statistically significant.
This study population consisted of 77 patients (mean age: 66 ± 12 years, range: 35 to 86 years; 65 men, 12 women). Nearly half of these 77 patients (35/77, 45%) had concomitant cardiovascular disease, including hypertensive heart disease (24 patients), coronary artery disease (8 patients), and hypertrophic (1 patient) and dilated cardiomyopathy (1 patient). Left atrium enlargement was observed by echocardiography in 34 patients (44%) (Table 1).
Locations of ectopic foci and electrophysiologic characteristics in initiation of AF
Locations of ectopic foci
A total of 111 episodes of sustained AF were analyzed. Most of these episodes came from PVs (103 episodes, 93%); the remaining eight episodes came from the SVC (Table 1). The majority of patients had one AF-initiating focus, and 22 patients had more than two foci (29%). Among the AF episodes originating from PVs, 53 episodes (51%) were from the LSPV, 37 episodes (36%) from the RSPV and the remaining 13 episodes from inferior PVs (13%). Moreover, among the episodes from the superior PVs, most of these episodes originated from the proximal part of PVs (75/90, 83%), while only 16 episodes originated from the distal part (16/90, 17%).
Electrophysiologic characteristics in initiation of AF
The mean values of CI and AF1 of these AF episodes were 220 ± 56 ms and 157 ± 41 ms, respectively. The mean value of PI was 0.38 ± 0.12. Before the onset of AF episodes, 95 ectopic beats without triggering AF were also analyzed. In comparison, the mean CI of ectopic beats initiating AF was significantly shorter than that of ectopic beats without initiating AF (220 ± 56 ms vs. 299 ± 81 ms, p < 0.0001). Similarly, the mean PI of the AF-initiating ectopic beats was also significantly lower than that of ectopic beats without initiating AF (0.38 ± 0.11 vs. 0.54 ± 0.13, p < 0.0001).
Relationship between the location of the initiating foci and the electrophysiologic parameters
Among AF episodes originating from superior PVs, the CI (183 ± 50 ms vs. 225 ± 54 ms, p < 0.01) and PI (0.32 ± 0.12 vs. 0.41 ± 0.12, p < 0.01) were significantly shorter in the episodes originating from the distal part of PVs than those originating from the proximal part (Fig. 1A).
On the other hand, the AF1 (147 ± 30 ms vs. 162 ± 38 ms, p < 0.05) and CI (204 ± 47 ms vs. 227 ± 57 ms, p < 0.05) of AF episodes originating from the RSPV were significantly shorter than those arising from the LSPV. However, the PI of the ectopic beats that initiated AF from the RSPV and LSPV did not show significant difference (0.36 ± 0.11 vs. 0.40 ± 0.11, p = 0.09) (Fig. 1B).
Among the 13 episodes originating from inferior PVs, all the electrophysiologic parameters, including CI (207 ± 63 ms vs. 218 ± 54 ms, p > 0.05), PI (0.31 ± 0.09 vs. 0.38 ± 0.11, p > 0.05) and AF1 (137 ± 48 ms vs. 155 ± 35 ms, p > 0.05), were similar to those of AF episodes originating from superior PVs (Fig. 1C).
Eight AF episodes originated from the SVC. The mean values of the 15 cycle lengths before onset of AF originating from PVs and SVC showed no significant difference (607 ± 146 ms vs. 562 ± 106 ms, p > 0.05). However, the CI and AF1 of AF episodes from the SVC were significantly longer (CI: 267 ± 54 ms vs. 217 ± 55 ms, p < 0.05; AF1: 194 ± 36 ms vs. 153 ± 37 ms, p < 0.05) than those in AF episodes from PVs. Moreover, the PI of AF originating from SVC was also greater than that of AF originating from PVs (0.49 ± 0.13 vs. 0.37 ± 0.11, p < 0.01) (Fig. 1D).
Initiation patterns at the onset of AF
Two patterns of AF initiation from PVs were observed (Fig. 2). Group I (59/111, 53%) included the episodes that were preceded by cycle length oscillation (the cycle length was prolonged or shortened by 20% or more than that of the preceding beat). Group II (52/111, 47%) included episodes that were initiated by a single ectopic beat, with preceding cycle length relatively constant. Most AF-initiating foci only demonstrated one initiation pattern, and only nine foci demonstrated two different initiation patterns (8%). The mean cycle lengths before the onset of group I AF episodes were similar to those of group II episodes (577 ± 135 ms vs. 634 ± 148 ms, p = 0.10). On the other hand, the CI of group I patients was marginally longer than those in group II patients (230 ± 57 ms vs. 209 ± 53 ms, p = 0.06), while the PI of group I patients was significantly greater than those in group II patients (0.41 ± 0.12 vs. 0.34 ± 0.10, p < 0.01) (Table 2). However, the AF1 values were similar between group I and group II patients, and there was no significant relationship between the pattern of AF initiation and the location of AF-initiating foci at the right, left PVs or inferior PVs (p > 0.05).
Two patterns of AF initiation from the SVC were also observed. Five of the eight AF episodes originating from the SVC were preceded by cycle length oscillation, while the initiation of the remaining three episodes was not preceded by changes in cycle length.
Relationship with LA enlargement
Fifty-two AF episodes originating from PVs occurred in patients with LA enlargement (52/103, 50%). Comparisons between the patients with and without LA enlargement did not show significant differences in the CI or PI of the AF episodes, while the AF1 of AF episodes in patients with LA enlargement were slightly longer that those in patients with normal LA size (160 ± 37 ms vs. 146 ± 36 ms, p < 0.05). On the other hand, the presence or absence of the LA enlargement was not related to the patterns of AF initiation (Table 3).
In this study, all AF episodes were initiated by ectopic beats originating either from PVs or the SVC, with a significantly shorter CI and lower PI than those of ectopic beats without initiating AF. Two major patterns of AF initiation were observed in patients with PAF originating from the great vessels. More than half of the AF episodes were preceded by cycle length oscillation. The PI of ectopic beat preceding AF initiation in these episodes was significantly greater than those in the episodes without preceding cycle length oscillation. Furthermore, ectopic beats from the distal part of superior PVs could trigger AF with a significantly shorter CI and lower PI. On the other hand, the CI, AF1 and PI were significantly longer and greater in the AF episodes originating from the SVC than from those initiating from PVs.
Preceding cycle length oscillation and initiation of AF
The importance of short-long sequences preceding ectopic beats initiating ventricular arrhythmia has been addressed before. These findings have been consistently observed by analyzing 24-h Holter recordings in about 30% to 45% of episodes of ventricular tachycardia/ventricular fibrillation reported in patients with coronary artery disease (4–6)and in more than 90% of episodes of torsade de pointes (14–16). On the contrary, the initiating pattern of PAF is not clear. Hnatkova et al. (3)reported that in 231 episodes of PAF from 24-h Holter recordings in 19 patients, short-long sequence occurred before the AF initiation in only about 10% of AF episodes. However, by identifying the foci originating from PVs and the SVC, we found that, in over half of AF episodes, the initiation of AF was preceded by oscillation of the cycle lengths. Moreover, the PI was significantly greater in the AF episodes with preceding cycle length oscillation. Because the changes of short-long cycle length could further shorten the refractory period of the atrium and cause a nonuniform distribution of refractoriness, a relatively less premature ectopic beat could also trigger the initiation of AF after a preceding cycle length change. According to this finding that preceding cycle length change may be important to the initiation of AF, atrial pacing may be beneficial in preventing the frequency of PAF by shortening the long cycle length.
Electrophysiologic characteristics of ectopic beats initiating AF
The finding that AF is induced by short-coupling ectopic beats has been reported in previous studies that analyzed the surface electrocardiography and 24-h Holter monitoring, intra-atrial recording or atrial monophasic action potential (1–3,17). The findings in our study noting that the AF episodes were triggered by ectopic beats when shorter CI and lower PI were achieved, were consistent with recent reports of the initiation of AF in patients with heart disease (18)and with chronic AF after successful internal cardioversion (19). The mean value of CI (220 ± 56 ms) was much less than that obtained from surface electrocardiography and was comparable to that observed in AF episodes produced by atrial stimulation (20). Previous studies have demonstrated that ectopic beats originating from PVs are important in the initiation of focal AF, and this study has, for the first time, reported the electrophysiologic properties of initiation of AF episodes (7–10).
In this study, we found that the CI was shorter and PI was lower in AF episodes induced by ectopic beats from the distal PVs. This finding might be related to the shorter effective refractory periods in the distal PVs (10,21,22). Because the length of the myocardial sleeve in the inferior PVs is less than 2 cm, the analysis of proximal and distal portions of inferior PVs was not performed.
Recently, the Prakash group (23)(using the noncontact mapping techniques to identify AF initiating focus), and the Natale group (24)found a high incidence of AF ectopic focus in the right atrium. This laboratory also found AF episodes originating from crista terminalis, coronary sinus and the SVC (11,12). In this study, despite the relatively small number of cases, statistically significant differences were still found in CI, AF1 and PI in these AF episodes originating from the SVC, suggesting that the electrophysiologic properties of the SVC may be different from those of PVs. Nevertheless, two distinct initiating patterns of AF were observed in episodes originating from the SVC, as in those from the PVs.
This study also showed that LA enlargement did not influence the CI or PI of AF episodes, while the AF1 interval was longer in AF episodes occurring in patients with LA enlargement. These findings suggest that the structural change of the atrium may be related to the sustenance of AF; however, the true relationship and mechanism of AF initiation needs further study.
The patients included in this study were multi-drug resistant and apparently unselected. All of their AF that was induced in our electrophysiologic laboratory originated from PVs and SVC, and the actual modes of spontaneous initiation of clinical episodes of AF may be different.
In patients with PAF originating from PVs or the SVC, two major initiating patterns were found. The electrophysiologic characteristics are different between the two patterns. Moreover, the electrophysiologic properties of the initiation of AF originating from the SVC are also different from those of AF initiating from PVs.
The authors are indebted to Ming-Wei Lin, PhD, Hsiu-Hsi Chen, PhD, and Benjamin Ing-Tiau Kuo, MD, DrPH, for their elegant statistical work.
☆ Supported, in part, by grants from the National Science Council (NSC 88-2314-B-010-094, NSC 89-2314-B-010-094 and VGH-89-68), Taipei, Taiwan, Republic of China. Part of the content has been presented as abstract form in the 71st and 72nd AHA Annual Scientific Meeting.
- atrial fibrillation
- first cycle length of AF
- coupling interval
- left atrium
- left superior pulmonary veins
- paroxysmal atrial fibrillation
- prematurity index
- pulmonary vein
- right superior pulmonary veins
- superior vena cava
- Received March 20, 2000.
- Revision received December 28, 2000.
- Accepted January 24, 2001.
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