Multiple Arrhythmogenic Foci Associated With the Development of Perpetuation of Atrial Fibrillation

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1 Multiple Arrhythmogenic Foci Associated With the Development of Perpetuation of Atrial Fibrillation Toshiya Kurotobi, MD, PhD; Katsuomi Iwakura, MD, PhD; Koichi Inoue, MD, PhD; Ryusuke Kimura, MD; Atsunori Okamura, MD, PhD; Yasushi Koyama, MD; Yuko Tosyoshima, MD; Norihisa Ito, MD, PhD; Kenshi Fujii, MD, PhD Background The presence of multiple arrhythmogenic sources may be associated with the perpetuation of atrial fibrillation (AF). In this study, we investigated the hypothesis that multiple foci might be involved in the development of AF persistency. Methods and Results Two hundred fourteen consecutive patients with AF undergoing catheter ablation were enrolled in this study. The location of the arrhythmogenic foci was determined using simultaneous recordings from multipolar catheters before and after pulmonary vein isolation during an isoproterenol administration. We detected 500 arrhythmogenic foci (263 foci as AF initiators, and 237 foci as non-af initiators). High-dose isoproterenol infusions (ranging from 2 to 20 g/min) revealed potential arrhythmogenic foci, especially non pulmonary vein foci (55%). Persistent AF was more highly associated with an incidence of multiple ( 2) foci than paroxysmal AF (88% versus 65%, P 0.002), and a multivariate analysis demonstrated that multiple foci ( 2) were an independent contributing factor for persistent AF (odds ratio; 95% confidence interval, 4.69; 1.82 to 12.09, P 0.001). In paroxysmal AF, the number of foci was higher in patients with long-term AF ( 24 hours) than in those with short-lasting AF ( versus , P 0.001). In the persistent AF group, the patients with short-lasting AF ( 12 months) had a greater number of foci than did those with long-term AF ( 12 months) ( versus , P 0.04). Conclusions Multiple foci were likely to be involved in the development of persistent AF. However, if AF persisted for 12 months, they may not have had a significant effect on the AF perpetuation. (Circ Arrhythm Electrophysiol. 2010; 3:39-45.) Key Words: ablation arrhythmia cardioversion catheter ablation nervous system sympathetic In patients with atrial fibrillation (AF), some cases remain in a paroxysmal state long-term, whereas other cases easily develop persistent AF. Electric and structural changes due to AF perpetuation could help to promote its persistency; however, the mechanism of how AF transforms from paroxysmal to persistent AF remains unknown. It is possible that other unknown factors may also be associated with the development of AF persistency. Editorial see page 7 Clinical Perspective on p 45 AF may be triggered by ectopy from the pulmonary veins (PVs) and/or non-pv foci. 1,2 The mechanisms underlying the rapid activity from the PVs and non-pv foci may include enhanced automaticity, triggered activity, and localized microreentry, which may be involved in both the initiation and maintenance of AF. 3 5 The presence of multiple triggers may facilitate the development of AF persistency because their presence may provide a greater chance of reinitiating AF after spontaneous termination in patients with paroxysmal AF. Further, the site of the arrhythmogenic foci could also exhibit a more frequent activation during AF, 6 and its triggered activity may become exaggerated under conditions of tachycardia remodeling due to rapid activation, 7 which may imply the possibility of multiple arrhythmogenic foci as promoters of AF perpetuation. In this study, we investigated the hypothesis that the presence of latent multiple foci were associated with the development of AF persistency. Methods Study Population The study population consisted of 214 consecutive patients with drug-refractory AF episodes who underwent radiofrequency catheter ablation (CA). The patients mean age was 61 years, 152 (71%) were male, and 44 (21%) had persistent AF. Persistent AF was defined as that lasting longer than 7 days, not self-terminating, and usually requiring medical intervention. 8 Permanent AF, which was refractory to cardioversion or persisted for greater than 1 year, was also included in the persistent AF group. The patients were considered for ablation based on the presence of symptomatic AF resistant to 1 antiarrhythmic agents (AAAs). All AAAs were generally discontin- Received June 5, 2009; accepted November 27, From the Cardiovascular Division, Sakurabashi Watanabe Hospital, Osaka, Japan. Correspondence to Toshiya Kurotobi, MD, PhD, Division of Cardiology, Sakurabashi Watanabe Hospital, , Kita-ku, Osaka City, Osaka, , Japan. kurotobi-circ@umin.ac.jp 2010 American Heart Association, Inc. Circ Arrhythm Electrophysiol is available at DOI: /CIRCEP

2 40 Circ Arrhythm Electrophysiol February 2010 ued for at least 3 days before the CA. Amiodarone was withdrawn at least 2 months before the procedure. The AF duration was defined as the longest-lasting AF episode assessed from the medical records, Holter ECG, and patient complaints if the episodes were symptomatic in the clinical setting. All patients provided written informed consent for the electrophysiological study and CA. This study was approved by our institutional review board. Electrophysiological Study and Catheter Ablation Transesophageal echocardiography was performed to exclude any left atrial (LA) thrombi. A 10-pole or 20-pole diagnostic catheter was positioned in the CS for pacing and recording. A 20-pole catheter was placed in the right atrium to cover the area along the crista terminalis or superior vena cava (SVC). The LA and PVs were accessed by a transseptal approach. We introduced 3 steerable catheters, including 2 spiral curve catheters, into the left atrium through a single transseptal puncture site. The PVs were mapped with a circumferential 10-pole or 20-pole catheter (IBI, Irvine, Calif). The surface ECG and intracardiac electrograms filtered between 30 to 500 Hz were recorded simultaneously with a polygraph (DUO EP Laboratory; Bard Electrophysiology, Lowell, Mass). A single 150 IU/kg bolus of heparin was administered after the transseptal puncture and repeated to maintain an activated clotting time of 300 seconds. After the initial AF induction protocol, a PV isolation procedure was performed using a double circular mapping catheter technique. We confirmed the success of the electric PV isolation by monitoring the circumferential electric isolation at the antrum level: approximately 1 cm from the ostium of both the right and left PVs. The complete disappearance of the potentials from all 4 PVs was confirmed in all patients. In the case of burst-inducible AF after the PV isolation procedure, an additional roof line was created. Then, additional radiofrequency (RF) energy applications were appropriately applied for any mitral isthmus induced atrial tachycardia circuits and complex fractionated electric activity. RF energy was delivered for 30 to 60 seconds at each site using an 8-mm tip catheter. The RF energy was delivered with the power limited to 35 W. The temperature was limited to 55 C (Japan Life Line Co, Ltd, Fantasista, Tokyo, Japan). Protocol for Induction and Detection of the Arrhythmogenic Foci At first, spontaneous arrhythmogenic foci in both atria were carefully mapped before the PV isolation procedure during an intravenous infusion of isoproterenol (ISP) without sedation. In the case of sinus rhythm, ISP was initially administered at 1 to 2 g/min for at least 5 minutes, and then the dose was gradually increased to 20 g/min while blood pressure was carefully monitored. If the blood pressure fell below 70 mm Hg, the increased dose of ISP was reversed to the 1to2 g/min basal level. If AF persisted or spontaneously occurred under ISP, we attempted to cardiovert the AF up to 3 times. The DC energy was delivered with an external biphasic waveform up to 270 J, and hence sinus rhythm was temporarily or successfully restored in all patients including permanent AF. During the ablation procedure, the ISP administration was maintained at 1 to 2 g/min. At the end of the procedure, the same induction maneuvers as in the initial protocol (up to 20 g/min) were repeated. To detect the location of the arrhythmogenic foci, we simultaneously used 5 multipolar catheters to record the electrograms from the PVs and outside the PVs to search for any arrhythmogenic foci. A 20-pole catheter (2-mm interelectrode spacing) covered the area from the SVC to the crista terminalis, coronary sinus, and ostium of the left PVs. A roving catheter was located at the right superior PV ostium (Figure 1). If the arrhythmogenic foci were suspected to have originated from a non-pv area uncovered by the catheters, we attempted to search the location with a roving catheter followed by the previous mapping technique. 2 Arrhythmogenic foci were defined as direct AF triggers or spontaneous reproducible atrial premature Figure 1. Catheter locations for detecting arrhythmogenic foci. Twenty-pole circular catheters were positioned at the left superior pulmonary vein (LSPV) and left inferior pulmonary vein (LIPV). A 10-pole catheter was positioned in the coronary sinus (CS), and the SVC and crista terminalis were covered with a 20 pole catheter. The roving catheter was initially positioned at the right superior pulmonary vein (RSPV). When arrhythmogenic foci were suspected to arise from the RIPV or a non-pv area, the site was searched by using a roving catheter. The location of the arrhythmogenic foci representing the earliest atrial activity was determined by a reference to the local electrogram or onset of the ectopic P wave. Further, the direction of the earliest activation site of the foci also could be estimated by the sequence of the activation recorder from multipolar catheters, which could help detect the location of the non-pv sites in the left atrium. Mechanically produced beats were prevented by avoiding any manipulation of the catheters during the recordings, and such beats were excluded from the analysis. beats with coupling intervals of 350 ms or frequent repetitive firings (Figure 2). Follow-Up All patients were discharged home 3 days after the CA procedure and were seen in our hospital at 1- to 2-month intervals. The AF episodes after discharge were adequately assessed by the patients complaints, 12-lead ECG, and 24-hour Holter ECG recordings. AF recurrence was defined as the occurrence of atrial tachyarrhythmias after a 2-month blanking period after the CA procedure. After the CA, AAAs were given for 3 to 6 months to patients with long-lasting persistent AF or to those with paroxysmal AF and easily inducible residual AF. The mean follow-up period after the CA was 563 days (355 to 1052 days). Statistical Analysis The continuous variables with a normal distribution are expressed as mean SD; data were compared by a Student t test. The number of foci are expressed as mean SEM; percentage of the variables or the distribution was compared by a 2 test. The variables without a normal distribution are expressed as the median (25th percentile, 75th percentile); data were compared by a Mann-Whitney U test, which was used for the nonparametric analysis. A logistic multivariate analysis was used to assess the relationship between the predictor variables and persistent AF, and backward selection using P 0.05 (Wald test) to stay was used to detect significant independent factors related to persistent AF. The possible confounding clinical factors (age, male sex, structural heart disease, hypertension, AF duration, atrial flutter, number of AAAs used, left ventricular ejection fraction, and left atrial diameter) related to the development of persistent AF and multiple ( 2) foci were incorporated into the multivariate model. The relationship between multiple ( 2) foci and AF recurrence was assessed by a log-rank analysis. A Cox proportional hazards analysis was used to assess the relationship between multiple ( 2) foci and AF recurrence as multivariate analysis. P 0.05 was considered statistically significant. All

3 Kurotobi et al Multiple Foci and Atrial Fibrillation 41 Table 1. Clinical Characteristics Paroxysma (n 170) Persistent (n 44) P Value Age, y Male, % SHD, % AF period, min 38 (15, 88) 40 (14, 93) 0.68 AFL, % No. of AAAs, count LAD, mm LVEF, % AF duration is expressed as the median (25%, 75%). SHD indicates structural heart disease; AFL, clinical coexistent atrial flutter; LAD, left atrial diameter; LVEF, left ventricular ejection fraction. Data of age, number of AAAs, LAD, and LVEF are expressed as mean SD. Figure 2. Multiple arrhythmogenic foci from the right superior pulmonary vein (RSPV) and left superior pulmonary vein (LSPV). The electrogram exhibiting the PV spike is the terminal part of a 2-component electrogram obtained during sinus rhythm. PAC 1 originated from the RSPV (A). The electrogram of the ectopic beat exhibits a temporal reversal, with a rapid deflection spike preceding a lower-amplitude, slower far-field atrial activity with a coupling interval of 269 ms and apparently precedes the onset of the P wave recorded in the 12-lead ECG. Just after 1 sinus rhythm beat, the following PAC 2, which originated from the LSPV, occurred with a coupling interval of 195 ms. The frequency of PAC 1 and PAC 2 gradually increased and then PAC 2 shifted to AF (B). RA indicates right atrium; SR, sinus rhythm; PAC, premature atrial contraction. d, Distal site of the electrode; p, proximal site of the electrode. analyses were performed using SPSS 10.0 statistical software (SPSS, Inc, Chicago, Ill). Results Patient Characteristics Patient characteristics are shown in Table 1. There were no significant differences in the mean age, structural heart disease, mean AF duration, clinical coexistence of atrial flutter, or number of prior AAAs between the paroxysmal and persistent AF groups. Male sex was significantly higher for persistent AF than paroxysmal AF. The left atrial diameter was significantly larger and left ventricular ejection fraction significantly lower for persistent AF than paroxysmal AF. Features of the Arrhythmogenic Foci Table 2 demonstrates the clinical and electrophysiological characteristics of the arrhythmogenic foci. Five hundred arrhythmogenic foci were found. PV and/or non-pv foci were revealed in 201 of 217 (93.9%) patients, 263 foci (52.6%) in 174 patients (81.3%) were confirmed as direct AF triggers, and 237 foci (47.4%) in 150 patients (70.1%) exhibited reproducible premature atrial contractions with an interval of 350 ms or frequent repetitive firings. PV foci were detected in 195 of 214 patients (91.1%) and non-pv foci in 107 of 214 (50%), which accounted for one third of all the arrhythmogenic foci (164 of 500 foci). Foci from only PVs were detected in 95 of 214 patients (44.4%), both PVs and non-pv origins in 98 of 214 (45.8%), and only non-pv origins in 8 of 214 (3.7%). The locations of 142 non-pv foci included the left atrial posterior wall (31, 14%), superior vena cava (41, 21%), crista terminalis (16, 7.4%), lateral mitral area (15, 6.9%), left atrial roof (12, 4.6%), interatrial septum (7, 3.7%), coronary sinus (16, 7.4%), and other sites (4, 1.5%). Non-PV foci were documented before the PV isolation in 55 of 109 foci (50%) [left atrial posterior wall (13%), left atrial roof (24%), superior vena cava (77%), crista terminalis (38%), lateral mitral area (20%), interatrial septum (39%), and coronary sinus (38%)], and hence the roving catheter had to be relocated to search for the foci uncovered by the catheters in 58 of 214 patients (27%). The coupling interval of the PV foci was shorter than that of the non-pv foci ( versus ms, P 0.001). The PV foci were significantly more associated with the occurrence of AF than non-pv foci (PV foci, 61% versus non-pv foci, 28%, P 0.001). The total number of induced foci was higher in patients with non-pv foci than in those without ( versus , P 0.001). Table 3 shows a comparison of the clinical characteristics between the patients with and without direct AF triggers. The AF patients with structural heart disease included a significantly lower incidence of foci related to the AF initiation than those without structural heart disease (22% versus 38%, P 0.039). There was no significant impact of the mean age, male sex, mean AF duration, number of prior AAAs, left atrial diameter, or left ventricular ejection fraction on direct AF triggers. Figure 3 demonstrates the association between the inducibility of PV/non-PV foci and the ISP dose. Non-PV foci were induced 15% of the time with no ISP, 30% with 1 to 2 g/min, and 55% with 2 to 20 g/min. PV foci were revealed 25% of the time with no ISP, 43% with 1 to 2 g/min, and 32% with 2 to 20 g/min. The distribution of the inducibility according to the ISP dose significantly differed between PV foci and non-pv foci (P 0.001).

4 42 Circ Arrhythm Electrophysiol February 2010 Table 2. Relations Among Arrhythmogenic Foci, Clinical Characteristics, and Procedural Outcomes Document Before PVI, % Successful Delineation, % Recurrence, % Patients, n (%) Age, y LAD, mm AF Shift, % Multifoci, % PV foci LSPV 118 (54) N/A LIPV 71 (36) N/A RSPV 91 (42) N/A RIPV 46 (21) N/A (Non-PV foci) L-LPW 20 (9.2) R-LPW 11 (5.1) Roof 12 (4.6) SVC 41 (21) CT 16 (7.4) MIA 15 (6.9) IAS 7 (3.4) CS 16 (7.4) LSPV indicates left superior pulmonary vein; LIPV, left inferior pulmonary vein; RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein; L-LPW, left-sided left atrial posterior wall; R-LPW, right-sided left atrial posterior wall; Roof, left atrial roof; CT, crista terminalis; MIA, surrounding mitral isthmus area; IAS, interatrial septum; CS, coronary sinus. Comparison of the Arrhythmogenic Foci Between Paroxysmal and Persistent AF Table 4 shows the comparison of the arrhythmogenic foci features between paroxysmal and persistent AF. The incidence of PV foci and foci from the left atrium did not significantly differ between paroxysmal and persistent AF. The incidence of non-pv foci, total number of foci, number of non-pv foci, incidence of foci in the right atrium, and incidence of multiple foci was significantly higher in the persistent AF than paroxysmal AF patients. A multivariate analysis demonstrated that multiple foci were one of the independent factors to persistent AF as well as the left atrial diameter (Table 5). Number of Foci and AF Duration Figure 4 shows the comparison of the number of induced foci between paroxysmal and persistent AF. The number of induced foci was significantly higher after 24 hours than 24 hours ( versus , P 0.001) in the patients with paroxysmal AF and significantly higher after Table 3. Comparison of Characteristics Between Patients With and Without Direct AF Triggers Shifted to AF ( ) (n 174) Shifted to AF ( ) (n 40) P Value Age, y Male, % SHD, % AF period, mo No. of AAAs, count LAD, mm LVEF, % Data of age, LAD, and LVEF are expressed as mean SD. SHD indicates structural heart disease; AAAs, antiarrhythmic agents; LAD, left atrial diameter; LVEF, left ventricular ejection fraction. 1 year than 1 year ( versus , P 0.038) in those with persistent AF. As a result of comparing the incidence of AF arising from PVs and non-pv foci between paroxysmal and persistent AF, PV foci were observed in 86% after 24 hours, in 94% within 24 hours in the patients with paroxysmal AF, in 96% within 1 year, and in 86% after 1 year in the patients with persistent AF. Non-PV foci were observed in 32% after 24 hours, in 58% within 24 hours in the paroxysmal AF patients, in 66% after 1 year, and in 59% after 1 year in the persistent AF patients. Procedural Outcome All foci from the PVs were successfully delineated by the PV electric isolation procedure, and 109 of 146 (75%) non-pv foci could be delineated at the end of the CA (Table 2). AAAs Figure 3. Effect of the dose of the isoproterenol administration on the inducibility of PV and non-pv foci. Non-PV foci were revealed 15% of the time with no ISP, 30% with 1 to 2 g/min, and 55% with 2 to 20 g/min. PV foci were revealed 25% of the time with no ISP, 43% with 1 to 2 g/min, and 32% with 2 to 20 g/min. The distribution of the inducibility according to the ISP dose significantly differed between paroxysmal and persistent AF (P 0.001). Compared with PV foci, a high-dose ISP administration was required to reveal non-pv foci.

5 Kurotobi et al Multiple Foci and Atrial Fibrillation 43 Table 4. Comparison of Characteristics of Arrhythmogenic Foci Between Paroxysmal and Persistent AF Paroxysmal (n 170) Persistent (n 44) P Value PV foci, % Non-PV foci, % Total No. of foci, counts No. of non-pv foci, counts Foci in the left atrium, % Foci in the right atrium, % Multiple foci ( 2) 65% 88% No. of foci are expressed as mean SEM. were administered in 32% of the patients after the CA. The use of AAAs was significantly higher in patients with non-pv foci than in those without (42% versus 26%, P 0.001). AF recurrence was observed in 22% of the patients with PV foci and in 28% with non-pv foci. AF recurrence was significantly higher in patients with multiple ( 2) foci than in those without (total; 26% versus 11%, P 0.024, [22% versus 14%, P in paroxysmal AF, 26% versus 19%, P in persistent AF]). After adjusting for persistent AF and the duration of the AF episodes, the hazard ratio of multiple foci being related to AF recurrence revealed that those foci were not a significant related factor for AF recurrence (2.03 [0.92 to 3.76], P 0.106). Discussion In this study, we examined the features of the induced arrhythmogenic foci and assessed the implications of multiple foci in AF persistency. We detected PV foci in 195 of 214 patients (91.1%), and non-pv foci were highly revealed in 107 of 214 patients (50%); which accounted for one third of all the inducible foci. The number of foci was significantly higher in the persistent than paroxysmal AF patients, and multiple foci were an independent related factor for persistent Table 5. Results of Multivariate Analysis of Persistent AF Individual Variable Odds Ratio (95% CI) P Value Multivariable Odds Ratio (95% CI) P Value Multiple foci, 4.15 ( ) ( ) yes/no LAD, mm 1.17 ( ) ( ) LVEF, % 1.03 ( ) Male sex, 2.52 ( ) yes/no Age, y 0.98 ( ) Hypertension, 1.13 ( ) 0.65 yes/no SHD, yes/no 1.27 ( ) 0.67 AF duration, mo 1.00 ( ) 0.68 No. of AAAs, counts 0.84 ( ) 0.50 LAD indicates left anterior descending coronary artery; LVEF, left ventricular ejection fraction; SHD, structural heart disease. Figure 4. Comparison of the number of induced foci between paroxysmal and persistent AF. Left panel represents the comparison of the number of inducible foci between those with a maximal duration of AF episodes of 24 hours (n 70) and those 24 hours (n 82) in patients with paroxysmal AF. Right panel represents that between AF episodes of less than 1 year (n 19) and those more than 1 year (n 21) in patients with persistent AF. The duration of the longest AF episodes was determined by the patient statements or medical records. The number of foci was significantly higher after 24 hours than within 24 hours ( vs , P 0.001) in the patients with paroxysmal AF and significantly higher within 1 year than after 1 year ( vs , P 0.038) in the patients with persistent AF. These findings may suggest that the presence of multiple foci may facilitate the progression from paroxysmal to persistent AF, and long-lasting AF might reduce the significance of the arrhythmogenic foci in the perpetuation of AF. Number of foci is expressed as mean SEM. AF. Increased foci were associated with foci from non-pv lesions, which could be revealed by using a high dose ISP administration. An increased number of foci was significantly associated with a longer AF duration in the patients with paroxysmal AF, whereas it was significantly associated with a shorter AF duration in the patients with persistent AF. Thus, these findings may suggest the possibility that transient increased foci may facilitate the development of a transition from paroxysmal to persistent AF; however, the significance of that may gradually become reduced as long-lasting AF develops. Multiple Triggers and AF Persistency The presence of multiple triggers may provide a greater chance of reinitiating AF after the spontaneous termination and may help the AF persistency progress from a paroxysmal to persistent state. Meanwhile, the increased triggered activity from multiple sites as the cause of AF persistency may beget AF perpetuation by creating new wavelets and decreasing the likelihood of AF termination. Dispersion of the atrial refractoriness is also an essential element for AF persistency. The increased atrial dispersion is likely to be associated with the progression from paroxysmal to persistent AF, 9 and a reversal of the atrial dispersion by biatrial resynchronized pacing may prevent the development of AF persistency. Ventricular premature beats could promote an increased dispersion of the ventricular refractoriness, 10 and polymorphic premature beats exhibiting multiple origins may increase the risk of ventricular fibrillation with remodeled heart disease. 11 These observations may provide a clue as to why multiple triggers are associated with the development of the fibrillatory process in AF persistency. PV/Non-PV Foci as AF Triggers and Involvement in the Perpetuation of AF AF is mainly initiated by PV triggers, 1 and a rapidly firing source located within the PVs could be responsible for

6 44 Circ Arrhythm Electrophysiol February 2010 initiating, and in some cases, maintaining arrhythmias in patients with AF. The mechanism underlying such rapid discharges from PVs, including enhanced automaticity or triggered activity mechanisms may be involved in the initiation of AF 3. 4 Further, the PV circumference is also most likely important for sustaining the reentry for maintaining AF 12 and may also provide a substrate that is suitable for a possible reentrant mechanism, which could potentially promote a condition for persistent AF. Non-PV foci could arise from the superior vena cava, left atrial posterior free wall, crista terminalis, ostium of the coronary sinus, inter atrial septum, or Marshall bundle 13,14 with an incidence of those ranging from 3.2% to 47%. 2,15,16 The predominant non-pv triggering sites have a slow diastolic depolarization that enhances spontaneous depolarization, 5 and the triggered activity of the non-pv triggers could also be involved in the onset and perpetuation of AF. Previous studies have reported that triggered activity with delayed afterdepolarizations has been documented in the superior vena cava, 5 coronary sinus, 17 ligament of Marshall continuous with the muscular sleeve around the coronary sinus, 18 atrial muscle that extends into the mitral valve, 19 and working muscle. 20 Because triggered activity is likely to occur in the presence of underlying disease such as cardiomyopathy, 21 the development of the atrial remodeling process may enhance the triggered activity of PV/non-PV lesions. A previous study reported that multiple PV arrhythmogenic foci may be associated with an older age, longer AF duration and larger atrial dimensions. 22 LA enlargement predisposes the atrium to LA posterior wall triggers, 23 and persistent AF is more frequently triggered by foci from the LA side of the LA-PV junction than is paroxysmal AF. 24 Induction of Arrhythmogenic Foci The incidence of PV/non-PV foci may be influenced by the induction maneuvers. PV arrhythmogenicity is enhanced by neurohumoral stimulation with acetylcholine or isoproterenol. 3,25 The relationship between the precise ISP dose and arrhythmogenic inducibility remains unknown; however, the majority of PV/non-PV foci may be revealed during a high dose isoproterenol administration of up to 20 g/min or after cardioversion of AF. 2,26 High-dose ISP often invokes vagally mediated nerve reflex bradycardia, which appears to cause an increased arrhythmogenicity due to autonomic nerve competition. In this study, non-pv foci could be induced in 55% of the patients and PV foci in 32% when the ISP dose ranged from 2 to 20 g/min. Non-PV foci were detected in half the patients and accounted for one third of all arrhythmogenic foci. Although high-dose ISP could increase the ratio of the detection of both PV and non-pv foci, the dose of the ISP was significantly higher for the non-pv foci than the PV foci. The predominant non-pv trigger sites appeared to be associated with anatomic structures such as the crista terminalis or ligament of Marshall, which are known to be catecholamine sensitive structures, 13 which may explain why the a relatively high dose of ISP was required to induce non-pv foci. Comparison of the Pathogenesis Between Paroxysmal and Persistent AF Because PVs are major sites of AF initiation and maintenance in patients with paroxysmal AF, 1 PV isolation is the cornerstone of the treatment of paroxysmal AF, with a 65% to 85% success rate. 27 Compared with paroxysmal AF, the mechanisms underlying persistent AF are more complex and multifactorial. Although PVs remain as the dominant source of the maintenance of persistent AF, macroreentrant and microreentrant mechanisms are involved in AF perpetuation. The development of a remodeled atrium due to AF perpetuation could promote the multifactorial evidence for maintaining AF. A recent study demonstrated that rapid focal activity in the LA and PVs, demonstrated by epicardial mapping, implied the potential role of focal atrial activity in the maintenance of AF, 28,29 and the localized fibrillating sources that demonstrated an identical pattern of centrifugal activation were successful targets for catheter ablation. 30 These continuous or intermittent focal activities were commonly demonstrated in patients with paroxysmal and persistent AF, and, although the mechanisms of these focal activities could not be specified, triggered activity or abnormal automaticity may be the cause of the mechanism. 31 Whether or not the location of the arrhythymogenic foci is related to those sites with focal activity remains unknown; however, there is the possibility that the mechanism of enhanced triggered activity due to AF persistency may promote the sustainability of AF. Long-lasting AF perpetuation eventually leads to structural changes within the atria, and the structural changes, including left atrial dilation, further increase the fibrotic process with the deposition of increased amounts of connective tissue that promote the inconsistency and prolongation of the atrial conduction, which maintains macroreentrant AF. The data from our study support that process as a result of long-lasting AF perpetuation, because the significance of the arrhythmogenic foci on the AF perpetuation was less in the patients with long-lasting AF ( 1 year) than in those without ( 1 year). Study Limitations The AF duration was determined according to the patient s symptoms. Therefore, we could not evaluate the asymptomatic AF episodes in this study. Acknowledgments We thank John Martin (B.A.C., Inc) for his linguistic assistance with this manuscript. We also thank the medical engineers, Masaki Maekawa, Akimasa Abe, and Ryoko Muroi, for their help in operating the EP laboratory system and recording the data for this study. None. Disclosures References 1. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339: Lin WS, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, Huang JL, Yu WC, Yang SP, Ding YA, Chang MS, Chen SA. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation. 2003;107:

7 Kurotobi et al Multiple Foci and Atrial Fibrillation Po SS, Li Y, Tang D, Liu H, Geng N, Jackman WM, Scherlag B, Lazzara R, Patterson E. Rapid and stable re-entry within the pulmonary vein as a mechanism initiating paroxysmal atrial fibrillation. J Am Coll Cardiol. 2005;45: Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm. 2005;2: Chen YJ, Chen YC, Yeh HI, Lin CI, Chen SA. Electrophysiology and arrhythmogenic activity of single cardiomyocytes from canine superior vena cava. Circulation. 2002;105: Lin YJ, Tai CT, Kao T, Tso HW, Higa S, Tsao HM, Chang SL, Hsieh MH, Chen SA. Frequency analysis in different types of paroxysmal atrial fibrillation. J Am Coll Cardiol. 2006;47: Chen YJ, Chen SA, Chen YC, Yeh HI, Chan P, Chang MS, Lin CI. Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: implication in initiation of atrial fibrillation. Circulation. 2001;104: Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Zamorano JL. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257 e Koide Y, Yotsukura M, Ando H, Aoki S, Suzuki T, Sakata K, Ootomo E, Yoshino H. Usefulness of P-wave dispersion in standard twelve-lead electrocardiography to predict transition from paroxysmal to persistent atrial fibrillation. Am J Cardiol. 2008;102: Dabrowski A, Kramarz E, Piotrowicz R, Kubik L. Predictive power of increased QT dispersion in ventricular extrasystoles and in sinus beats for risk stratification after myocardial infarction. Circulation. 2000;101: Goldstein S, Brooks MM, Ledingham R, Kennedy HL, Epstein AE, Pawitan Y, Bigger JT. Association between ease of suppression of ventricular arrhythmia and survival. Circulation. 1995;91: Cherry EM, Ehrlich JR, Nattel S, Fenton FH. Pulmonary vein reentry: properties and size matter: insights from a computational analysis. Heart Rhythm. 2007;4: Hwang C, Wu TJ, Doshi RN, Peter CT, Chen PS. Vein of marshall cannulation for the analysis of electrical activity in patients with focal atrial fibrillation. Circulation. 2000;101: Chen SA, Tai CT, Yu WC, Chen YJ, Tsai CF, Hsieh MH, Chen CC, Prakash VS, Ding YA, Chang MS. Right atrial focal atrial fibrillation: electrophysiologic characteristics and radiofrequency catheter ablation. J Cardiovasc Electrophysiol. 1999;10: Mangrum JM, Mounsey JP, Kok LC, DiMarco JP, Haines DE. Intracardiac echocardiography-guided, anatomically based radiofrequency ablation of focal atrial fibrillation originating from pulmonary veins. JAm Coll Cardiol. 2002;39: Schmitt C, Ndrepepa G, Weber S, Schmieder S, Weyerbrock S, Schneider M, Karch MR, Deisenhofer I, Schreieck J, Zrenner B, Schomig A. Biatrial multisite mapping of atrial premature complexes triggering onset of atrial fibrillation. Am J Cardiol. 2002;89: Johnson N, Danilo P Jr, Wit AL, Rosen MR. Characteristics of initiation and termination of catecholamine-induced triggered activity in atrial fibers of the coronary sinus. Circulation. 1986;74: Scherlag BJ, Yeh BK, Robinson MJ. Inferior interatrial pathway in the dog. Circ Res. 1972;31: Wit AL, Cranefield PF. Triggered activity in cardiac muscle fibers of the simian mitral valve. Circ Res. 1976;38: Saito T, Otoguro M, Matsubara T. Electrophysiological studies on the mechanism of electrically induced sustained rhythmic activity in the rabbit right atrium. Circ Res. 1978;42: Boyden PA, Tilley LP, Albala A, Liu SK, Fenoglio JJ Jr, Wit AL. Mechanisms for atrial arrhythmias associated with cardiomyopathy: a study of feline hearts with primary myocardial disease. Circulation. 1984;69: Haissaguerre M, Jais P, Shah DC, Garrigue S, Takahashi A, Lavergne T, Hocini M, Peng JT, Roudaut R, Clementy J. Electrophysiological end point for catheter ablation of atrial fibrillation initiated from multiple pulmonary venous foci. Circulation. 2000;101: Lee SH, Tai CT, Hsieh MH, Tsao HM, Lin YJ, Chang SL, Huang JL, Lee KT, Chen YJ, Cheng JJ, Chen SA. Predictors of non-pulmonary vein ectopic beats initiating paroxysmal atrial fibrillation: implication for catheter ablation. J Am Coll Cardiol. 2005;46: Pak HN, Hwang C, Lim HE, Kim JW, Lee HS, Kim YH. Electroanatomic characteristics of atrial premature beats triggering atrial fibrillation in patients with persistent versus paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17: Arora R, Verheule S, Scott L, Navarrete A, Katari V, Wilson E, Vaz D, Olgin JE. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping. Circulation. 2003;107: Kurotobi T, Ito H, Inoue K, Iwakura K, Kawano S, Okamura A, Date M, Fujii K. Marshall vein as arrhythmogenic source in patients with atrial fibrillation: correlation between its anatomy and electrophysiological findings. J Cardiovasc Electrophysiol. 2006;17: Mainigi SK, Sauer WH, Cooper JM, Dixit S, Gerstenfeld EP, Callans DJ, Russo AM, Verdino RJ, Lin D, Zado ES, Marchlinski FE. Incidence and predictors of very late recurrence of atrial fibrillation after ablation. J Cardiovasc Electrophysiol. 2007;18: Wu TJ, Doshi RN, Huang HL, Blanche C, Kass RM, Trento A, Cheng W, Karagueuzian HS, Peter CT, Chen PS. Simultaneous biatrial computerized mapping during permanent atrial fibrillation in patients with organic heart disease. J Cardiovasc Electrophysiol. 2002;13: Nitta T, Ishii Y, Miyagi Y, Ohmori H, Sakamoto S, Tanaka S. Concurrent multiple left atrial focal activations with fibrillatory conduction and right atrial focal or reentrant activation as the mechanism in atrial fibrillation. J Thorac Cardiovasc Surg. 2004;127: Sanders P, Hocini M, Jais P, Hsu LF, Takahashi Y, Rotter M, Scavee C, Pasquie JL, Sacher F, Rostock T, Nalliah CJ, Clementy J, Haissaguerre M. Characterization of focal atrial tachycardia using high-density mapping. J Am Coll Cardiol. 2005;46: Takahashi Y, Hocini M, O Neill MD, Sanders P, Rotter M, Rostock T, Jonsson A, Sacher F, Clementy J, Jais P, Haissaguerre M. Sites of focal atrial activity characterized by endocardial mapping during atrial fibrillation. J Am Coll Cardiol. 2006;47: CLINICAL PERSPECTIVE In this study, we clarified the significance of multiple foci in the development of atrial fibrillation (AF) persistency. Two hundred fourteen consecutive patients with AF undergoing catheter ablation were enrolled in this study. We detected 500 arrhythmogenic foci. High-dose isoproterenol infusions revealed potential arrhythmogenic foci, especially non pulmonary vein foci. Persistent AF was more highly associated with an incidence of multiple ( 2) foci than paroxysmal AF, and a multivariate analysis demonstrated that multiple foci ( 2) were an independent contributing factor for persistent AF. In paroxysmal AF, the number of foci was higher in patients with long-term AF ( 24 hours) than in those with short-lasting AF. In the persistent AF, the patients with short-lasting AF ( 12 months) had a greater number of foci than did those with long-term AF ( 12 months). Thus, we concluded that multiple foci were likely to be involved in the development of persistent AF. However, if AF persisted for 12 months, they may not have had a significant effect on the AF perpetuation.