**2. The feature and clinical implication of arrhythmogenic foci of atrial fibrillation**

### **2.1. The method of induction and detection of PV/non-PV arrhythmogenic foci**

We used five multipolar catheters recording the electrograms to search for the location of the arrhythmogenic foci (AMF). A 20-pole catheter covered the SVC to the crista terminalis, CS, and the left PVs. A mapping catheter was located at the right superior PV (Figure 1). When the AMF have originated from a non-PV area uncovered by the catheters, we searched the location with a mapping catheter. The 12-lead ECG and intracardiac electrograms were filtered between 30 to 500 Hz (DUO EP Laboratory; Bard Electrophysiology, Lowell, MA, USA).

The occurrence of PV/non-PV foci could be influenced by the induction methods, and PV arrhythmogenicity may be enhanced by the stimulation with acetylcholine or isoproterenol (ISP) [2, 18]. The relationship between the ISP dose and arrhythmogenicity remains unclear; however, the PV/non-PV foci are likely to be revealed with a high-dose isoproterenol up to 20 g/min or subsequent cardioversion of AF [19, 20]. High-dose ISP can cause the vagally mediated nerve reflex bradycardia, which seems to increase arrhythmogenicity after auto‐ nomic nerve competition.

Both atrial spontaneous AMF were carefully searched before the PV isolation procedure under an intravenous infusion of isoproterenol (ISP) without sedation. During sinus rhythm, ISP was Clinical Significance of Arrhythmogenic Foci in Atrial Fibrillation http://dx.doi.org/10.5772/60646 57

LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein; CS, coronary sinus; RSPV, right superior pul‐ monary vein; SVC, superior vena cava.

**Figure 1.** Catheter locations for detecting AMF. Twenty-pole circular catheters were positioned at the left superior and inferior PV. A 10- or 20-pole catheter was located in the CS, and then terminal crest and the SVC were covered with a 20-pole catheter. The mapping catheter was located at the RSPV. When arrhythmogenic foci arise from the RIPV or a non-PV area, the suspected area was confirmed by a mapping catheter. The location of the PV/non-PV foci showing the earliest atrial focus was referred to the local electrogram or onset of the ectopic P wave. In addition, the direction of the earliest activated site of the PV/non-PV foci could be also determined by the sequence of the activation recorded from multipolar catheters allowing to detect the non-PV sites in both atria.

initially delivered at 1–2 g/min for 5 min, and then the dose was gradually increased up to 20 g/min with careful monitoring of the blood pressure. When the blood pressure dropped under 70 mm Hg, the dose of ISP was reversed to the basal level. When AF persisted and/or sponta‐ neously occurred, direct cardioversion (DC) was attempted up to three times. The DC energy was delivered by using an external biphasic wave up to 270 J, and sinus rhythm was tempo‐ rarily or successfully restored in all enrolled patients.

The ISP administration was maintained at basal level (1–2 g/min) during the ablation. At the end of the session, the increased dose of ISP was administered up to 20 g/min. AMF were confirmed as direct AF triggers and/or reproducible atrial premature beats with coupling intervals of <350 ms or frequent firings (Figure 2).

#### **2.2. The location of PV/non-PV arrhythmogenic foci**

AF. The enhanced automaticity or triggered activity mechanisms could be involved in the initiation of AF [2, 3]. In addition, the PV's circumference is also most likely crucial for sustaining the reentry of maintaining AF [4], which can enhance a condition for persistent AF. Non-PV foci can also arise from the crista terminalis, ostium of the coronary sinus, interatrial septum, superior vena cava, left atrial posterior free wall, and Marshall bundle [5, 6] with the incidence ranging from 3.2 to 47 % [7, 8, 9]. The dominant triggering sites of non-PV have a slow diastolic depolarization, increasing the chance of the spontaneous depolarization [10], and the triggered activity from the non-PV sites could also be involved in the initiation and perpetuation of AF. Previous studies have reported that the increased delay after depolariza‐ tions has been documented from the superior vena cava [10], coronary sinus (CS) [11], Marshall bundle and the coronary sinus [12], atrial muscle that extends into the mitral valve [13], and working muscle [14]. Especially, the Marshall bundle may be a crucial structure to initiate

The development of the remodeling process and preexistent anatomical structures seems to be related to the structural and electrophysiological remodeling in the PVs and atrium, which can increase the local abnormal conduction and develop an increased PV/non-PV arrhythmo‐

In this section, we assessed the features and relating factors of PV/non-PV arrhythmogenicity in patients with AF and evaluated their clinical implication during catheter ablation procedure.

**2. The feature and clinical implication of arrhythmogenic foci of atrial**

We used five multipolar catheters recording the electrograms to search for the location of the arrhythmogenic foci (AMF). A 20-pole catheter covered the SVC to the crista terminalis, CS, and the left PVs. A mapping catheter was located at the right superior PV (Figure 1). When the AMF have originated from a non-PV area uncovered by the catheters, we searched the location with a mapping catheter. The 12-lead ECG and intracardiac electrograms were filtered between 30 to 500 Hz (DUO EP Laboratory; Bard Electrophysiology, Lowell, MA, USA).

The occurrence of PV/non-PV foci could be influenced by the induction methods, and PV arrhythmogenicity may be enhanced by the stimulation with acetylcholine or isoproterenol (ISP) [2, 18]. The relationship between the ISP dose and arrhythmogenicity remains unclear; however, the PV/non-PV foci are likely to be revealed with a high-dose isoproterenol up to 20 g/min or subsequent cardioversion of AF [19, 20]. High-dose ISP can cause the vagally mediated nerve reflex bradycardia, which seems to increase arrhythmogenicity after auto‐

Both atrial spontaneous AMF were carefully searched before the PV isolation procedure under an intravenous infusion of isoproterenol (ISP) without sedation. During sinus rhythm, ISP was

**2.1. The method of induction and detection of PV/non-PV arrhythmogenic foci**

catecholamine-sensitive AF.

56 Abnormal Heart Rhythms

**fibrillation**

nomic nerve competition.

genicity leading to AF persistency [15, 16, 17, 10, 11].

Two hundred fourteen consecutive patients with drug-refractory AF episodes were enrolled in this study (mean age of 61 years, male, 71 %; persistent AF, 21%). The clinical and electro‐ physiologic characteristics of the AMF were demonstrated in Figure 3. Five hundred AMF were observed. PV and/or non-PV foci were detected in 201 of 214 (93.9 %). Two hundred sixtythree foci (52.6 %) in 174 patients (81.3 %) were confirmed as the triggers directly shifted to AF, and 237 foci (47.4 %) in 150 patients (70.1 %) showed reproducible premature atrial beats with an interval of <350 ms or repetitive firings. PV foci were confirmed in 195 of 214 patients (91 %) and non-PV foci in 107 of 214 (50 %), accounting for one third of all the AMF. Foci originating from only PVs were detected in 95 of 214 patients (44 %), both PV and non-PV origins in 98 of 214 (46 %), and only non-PV origins in 8 of 214 (3.7 %). Non-PV foci are located

**Figure 2.** Multiple foci from the right and left PVs. The electrogram exhibiting the PV foci is a two-component electro‐ gram during sinus rhythm. Premature atrial beats one from the right superior PV (a). The electrogram of the ectopic beat exhibits a reversal polarity and a rapid deflection with a coupling interval of 269 ms and apparently precedes the P-wave onset recorded in the 12 ECG. The following PAC 2 originating from the left superior PV spontaneously occur‐ red with a coupling interval of 195 ms. The frequency of PAC 1 and PAC 2 gradually developed, and then PAC 2 was finally shifted to AF (b).

in the superior vena cava (21 %), LA posterior wall (14 %), terminal crest (7.4 %), coronary sinus (7.4 %), left lateral area (6.9 %), LA roof (4.6 %), atrial septum (3.7 %), and other sites (1. 5%). Non-PV foci were detected before the PV isolation procedure in 55 of 109 foci (50 %) (superior vena cava (77 %), atrial septum (39 %), terminal crest (38 %), coronary sinus (38 %), LA roof (24 %), left lateral area (20 %), LA posterior wall (13 %)). The roving catheter had to be relocated to search for the foci uncovered by the catheters in 58 of 214 patients (27 %). PV foci were significantly more related to AF occurrence than non-PV foci (PV foci 61 % vs. non-PV foci 28 %, p<0.001]. The mean coupling interval of PV foci was significantly shorter than that of non-PV foci (196±68 vs. 255±90ms, p<0.001]. The number of inducible foci was signifi‐ cantly higher in patients with non-PV foci than without those (3.1±1.7 vs. 1.5±1.4, p<0.001].

Non-PV foci were induced 15 % of the time with no ISP, 30 % with 1–2 g/min, and 55 % with 2–20 g/min. PV foci were revealed 25 % of the time with no ISP, 43 % with 1–2 g/min, and 32 % with 2–20 g/min. The distribution of the inducibility according to the ISP dose significantly differed between PV foci and non-PV foci (p<0.001).

In half of the enrolled patients, non-PV foci were confirmed and accounted for one third of all AMF. High-dose ISP could improve the ratio of the detection of both PV and non-PV foci;

**Figure 3.** The location of induced AMF. AMF were determined as direct AF triggers or spontaneous reproductive pre‐ mature atrial premature contraction (PAC) with the coupling interval less than 350 ms or repetitive firing in arrhyth‐ mogenic foci. Black circle represents foci which directly shifted to AF; white circle represents reproductive PAC and repetitive firing. To detect the location of foci, we simultaneously used five multipolar catheters to record the electro‐ grams outside the PVs, coronary sinus, SVC, and crista terminalis to search for the AMF during isoproterenol adminis‐ tration.

however, the dose of the ISP was significantly higher for the non-PV foci than the PV foci. The predominant non-PV trigger sites seemed to be related to anatomical structures such as the terminal crest or ligament/vein of Marshall, known to be catecholamine-sensitive structures [5]. These evidences may explain why a high dose of ISP was needed to reveal non-PV foci.

#### **2.3. The PV/non-PV arrhythmogenic foci between paroxysmal and persistent AF**

in the superior vena cava (21 %), LA posterior wall (14 %), terminal crest (7.4 %), coronary sinus (7.4 %), left lateral area (6.9 %), LA roof (4.6 %), atrial septum (3.7 %), and other sites (1. 5%). Non-PV foci were detected before the PV isolation procedure in 55 of 109 foci (50 %) (superior vena cava (77 %), atrial septum (39 %), terminal crest (38 %), coronary sinus (38 %), LA roof (24 %), left lateral area (20 %), LA posterior wall (13 %)). The roving catheter had to be relocated to search for the foci uncovered by the catheters in 58 of 214 patients (27 %). PV foci were significantly more related to AF occurrence than non-PV foci (PV foci 61 % vs. non-PV foci 28 %, p<0.001]. The mean coupling interval of PV foci was significantly shorter than that of non-PV foci (196±68 vs. 255±90ms, p<0.001]. The number of inducible foci was signifi‐ cantly higher in patients with non-PV foci than without those (3.1±1.7 vs. 1.5±1.4, p<0.001].

**Figure 2.** Multiple foci from the right and left PVs. The electrogram exhibiting the PV foci is a two-component electro‐ gram during sinus rhythm. Premature atrial beats one from the right superior PV (a). The electrogram of the ectopic beat exhibits a reversal polarity and a rapid deflection with a coupling interval of 269 ms and apparently precedes the P-wave onset recorded in the 12 ECG. The following PAC 2 originating from the left superior PV spontaneously occur‐ red with a coupling interval of 195 ms. The frequency of PAC 1 and PAC 2 gradually developed, and then PAC 2 was

Non-PV foci were induced 15 % of the time with no ISP, 30 % with 1–2 g/min, and 55 % with 2–20 g/min. PV foci were revealed 25 % of the time with no ISP, 43 % with 1–2 g/min, and 32 % with 2–20 g/min. The distribution of the inducibility according to the ISP dose significantly

In half of the enrolled patients, non-PV foci were confirmed and accounted for one third of all AMF. High-dose ISP could improve the ratio of the detection of both PV and non-PV foci;

differed between PV foci and non-PV foci (p<0.001).

finally shifted to AF (b).

58 Abnormal Heart Rhythms

. The incidence of PV foci and non-PV foci from the left atrium was not significantly different between paroxysmal and persistent AF patients. The incidence of non-PV foci, the sum number of foci, the number of non-PV foci, the incidence of right atrial foci, and the occurrence of multiple foci were significantly higher in the persistent than paroxysmal AF. In a multivariate analysis, multiple foci were one of the independent contributing factors to persistent AF as well as the left atrial dimension.

Furthermore, Figure 4 demonstrated that the number of foci was significantly higher in >24 h than < 24 h (1.77±0.16 vs. 2.64±0.14, p<0.001) in the paroxysmal AF patients and also signifi‐ cantly higher <1 year than >1 year (3.62±0.15 vs. 1.92±0.16, p=0.038) in persistent AF patients. In the data of comparing the AF incidence from PV/non-PV foci between paroxysmal and persistent AF, PV foci were confirmed in 86 % >24 h and in 94 % < 24 h in paroxysmal AF patients and in 96 % <1 year and in 86 % >1 year in persistent AF patients. Non-PV foci were confirmed in 32 % >24 h and in 58 % < 24 h in the paroxysmal AF and in 66 % <1 year and in 59 % >1 year in the persistent AF. The number of foci was significantly increased with a longer AF period in paroxysmal AF, whereas it had significant association on a short AF period in persistent AF. Therefore, these findings may imply that the presence of increased foci may possibly facilitate the development of a shift from paroxysmal to persistent AF, although that may gradually become less significant as long-lasting AF develops.

**Figure 4.** The number of induced foci between paroxysmal and persistent AF. The left graph demonstrates the compar‐ ison of the number of foci between those with episodes of < 24 h (n=70) and > 24 h (n=82) in patients with paroxysmal AF. The right graph shows the comparison between AF episodes < 1 year (n=19) and those > 1 year (n=21) in persisted AF patients. The number of foci was significantly higher in >24 h than < 24 h (1.77±0.16 vs. 2.64±0.14, p<0.001) in the paroxysmal AF patients and significantly higher <1 year than >1 year (3.62±0.15 vs. 1.92±0.16, p=0.038) in the persistent AF patients. These evidences may imply that the presence of multiple foci may help the promotion from paroxysmal to persistent AF state, and long-lasting AF might reduce the significance of the multiple foci in the perpetuation of AF.

AF occurrence after ablation was significantly higher in patients with multiple foci than without it (sum; 26 % vs. 11 %, p=0.024, paroxysmal; 22 % vs. 14 %, p=0.087, persistent; 26 % vs. 19 %, p=0.630). The hazard ratio of multiple foci being associated with recurrent AF demonstrated that those foci were not a significant relating factor for recurrent AF (2.03 (0.92– 3.76), p=0.106).

The multiple triggers may allow a greater chance of reinitiating AF even after the AF selftermination and may facilitate the progression to the persistency from a paroxysmal to persistent AF. In the meantime, the enhanced triggered activity of multiple sites as the cause of AF persistency could also beget AF perpetuation by making new wavelets and less likeli‐ hood of AF self-termination. Furthermore, the enhanced dispersion of the atrial refractoriness may also be a crucial factor for AF persistency. The presence of increased atrial dispersion might promote the progression from paroxysmal to persistent AF state [21]. These observations may provide a clue as to why multiple triggers are associated with the development of the fibrillatory process in AF persistency.

#### **2.4. Mutual linkage of left PV AMF**

PV myocardial sleeves with complex muscle bundle orientations or specific autonomic nervous system may have the same interactions between each PV. Thus, we determined the mutual linkage of AMF around PVs. AFC from the left superior PV were significantly associated with AFC of the left inferior PV (42 % vs. 23 %, p<0.05), left-sided left posterior wall (20 % vs. 5 %, p<0.05), and roof area (8 % vs. 2 %, p<0.05) (Figure 5). In case of foci from LSPV, the occur‐ rence of AMF was 68 % in LIPV, 85 % in the left side LA posterior wall, and 75 % in the roof. Right PVs had no significant mutual association for AFC between each other (Figure 6).

persistent AF. Therefore, these findings may imply that the presence of increased foci may possibly facilitate the development of a shift from paroxysmal to persistent AF, although that

**Figure 4.** The number of induced foci between paroxysmal and persistent AF. The left graph demonstrates the compar‐ ison of the number of foci between those with episodes of < 24 h (n=70) and > 24 h (n=82) in patients with paroxysmal AF. The right graph shows the comparison between AF episodes < 1 year (n=19) and those > 1 year (n=21) in persisted AF patients. The number of foci was significantly higher in >24 h than < 24 h (1.77±0.16 vs. 2.64±0.14, p<0.001) in the paroxysmal AF patients and significantly higher <1 year than >1 year (3.62±0.15 vs. 1.92±0.16, p=0.038) in the persistent AF patients. These evidences may imply that the presence of multiple foci may help the promotion from paroxysmal to persistent AF state, and long-lasting AF might reduce the significance of the multiple foci in the perpetuation of AF.

AF occurrence after ablation was significantly higher in patients with multiple foci than without it (sum; 26 % vs. 11 %, p=0.024, paroxysmal; 22 % vs. 14 %, p=0.087, persistent; 26 % vs. 19 %, p=0.630). The hazard ratio of multiple foci being associated with recurrent AF demonstrated that those foci were not a significant relating factor for recurrent AF (2.03 (0.92–

The multiple triggers may allow a greater chance of reinitiating AF even after the AF selftermination and may facilitate the progression to the persistency from a paroxysmal to persistent AF. In the meantime, the enhanced triggered activity of multiple sites as the cause of AF persistency could also beget AF perpetuation by making new wavelets and less likeli‐ hood of AF self-termination. Furthermore, the enhanced dispersion of the atrial refractoriness may also be a crucial factor for AF persistency. The presence of increased atrial dispersion might promote the progression from paroxysmal to persistent AF state [21]. These observations may provide a clue as to why multiple triggers are associated with the development of the

PV myocardial sleeves with complex muscle bundle orientations or specific autonomic nervous system may have the same interactions between each PV. Thus, we determined the mutual linkage of AMF around PVs. AFC from the left superior PV were significantly associated with AFC of the left inferior PV (42 % vs. 23 %, p<0.05), left-sided left posterior wall (20 % vs. 5 %, p<0.05), and roof area (8 % vs. 2 %, p<0.05) (Figure 5). In case of foci from LSPV, the occur‐

may gradually become less significant as long-lasting AF develops.

3.76), p=0.106).

60 Abnormal Heart Rhythms

fibrillatory process in AF persistency.

**2.4. Mutual linkage of left PV AMF**

**Figure 5.** The relation between left PV foci and other foci. The incidence of foci from LIPV (42 % vs. 23, p<0.05), leftside left atrial posterior wall (20 % vs. 5 %, p<0.05) and left atrial roof (8 % vs. 2 %, p<0.05) was highly detected in patients with LSPV than without LSPV foci.

**Figure 6.** The relation between right PV foci and other foci. There is no significant relation between right PV foci and other foci.

Left lateral ridge as the anterior wall of left PVs facilitating to connect both superior and inferior PV may contribute the mutual arrhythmogenic linkage of them. Thus, we examined the relation between the shape of left lateral ridge and LPV's arrhythmogenicity in 120 AF patients.

Morphology of the left lateral ridge was determined by the endoscopic view of 64-MDCT. From the relation to superior and inferior PVs, the characteristics of the ridge was classified into 3 groups: long (connecting both PVs, n=44), intermediate (half of PV distance, n=53), and poor (only around PV, n=23) (Figure 7). The incidence of AF foci from the left inferior PV (29 % vs. 9 %, p<0.05) and spontaneous AF occurrence from both PVs (23 % vs. 5 %, p<0.05) were significantly higher in the long type than in the intermediate and short types. The number of AF foci around the ridge was significantly greater in patients with long type than those without it (1.2±0.9 vs. 0.6±0.7, p<0.01).

**Figure 7.** Endoscopic view of left PVs ostium. LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein; LAA, left atrial appendage.

#### **2.5. Left atrial roof shape and PV/non-PV foci**

The remodeling process is associated with the structural and electrophysiological abnormality in the PVs and atrium, which could promote local conduction delay and lead to an increased PV/non-PV arrhythmogenicity developing to AF persistency [15, 16, 17, 10, 11]. These eviden‐ ces might imply that the morphological features of the PVs and atrium can contain a crucial role to detect their preexisting arrhythmogenicity, although the evaluation of the morpholog‐ ical features is limited in a quantitative manner because of their variable and unique structure.

The left atrial (LA) roof consisting of the upper wall of the left atrium and upper PVs was demonstrated as the silhouette of LA roof and could simply be visualized by PV angiography or left atrial CT imaging. In addition, the dominancy of morphological PVs/LA and the features of the LA roof silhouette could be easily determined in patients with AF. Thus, the relation between PV/non-PV arrhythmogenicity and LA roof silhouette was examined in this study.

Based on the PVs and LA dominancy, The LA roof shape was classified into a deep V shape (possible PV dominancy), shallow V shape, and flat-coved shape (possible LA dominancy) by cine angiography (Figure 8]. Angiography was conducted by both contrast media from the long sheath locating at the right and left superior PVs. The LA roof shape was assessed by A– P projection and was determined by the angle of the LA roof silhouette between the right and left LA wall. The deep V shape was defined as <140° , shallow V shape was 140° to180° , and flatcoved shape was > 180° .

Table 2 shows the relation between AMF and roof-shape group. In results, 335 AMF were detected. PV/ non-PV foci were observed in 136 of 152 (89 %) AF patients. AF triggers imme‐ diately shifting to AF were found in 114/152 (75 %) AF patients, and AF from PV foci was in 84 of 152 (55 %) AF patients. PV foci containing reproducible atrial premature contractions were observed in 135 of 152 AF patients (89 %) and non-PV foci in 77 of 152 (44 %). The location of non-PV foci was in the superior vena cava (25, 28 %), left atrial posterior wall (19, 21 %), terminal crest (10, 11 %), CS (10, 11 %), left lateral area (9, 10 %), LA roof (7, 8 %), atrial septum (4, 4 %), and other areas (6, 7 %).

#### Clinical Significance of Arrhythmogenic Foci in Atrial Fibrillation http://dx.doi.org/10.5772/60646 63

**Figure 8.** According to the PV and LA dominant level, the LA roof shapes into a deep V shape, shallow V shape, and flat-coved shape which were classified by using cineangiography and 64-slice MDCT. The upper figure is the cinean‐ giography, and the lower is the 3D-constructed image of the MDCT. The deep V shape seemed to be dominated by the segment of both trunks of the upper PVs, whereas the flat-coved LA roof shape shows less incorporation into the LA.

As the silhouette of LA roof got to flat, the incidence of AF from the PVs (deep V 70 % vs. shallow V 57 % vs. flat 40 %, p=0.003), AF of the upper PVs (deep V 63 % vs. shallow V 41 % vs. flat 38 %, p=0.046), and PV foci including reproducible premature contractions (deep V 94 % vs. shallow V 84 % vs. flat 76 %, p=0.033) significantly decreased. The incidence of AF from non-PV sites (sharp V 6 % vs. shallow V 13 % vs. flat 22 %, p=0.041) and non-PV foci including atrial premature contractions (sharp V 26 % vs. shallow V 46 % vs. flat 54 %, p=0.016) were significantly increased as the LA roof silhouette got to flat. In a multivariate analysis, the deep V was an independent relating factor to PV AF triggers (OR 2.94 (1.27–6.80), p=0.012). These findings may include the novelty of the LA roof silhouette as an index of the PV's arrhythmo‐ genicity.

AF is likely to originate from larger PVs [22], and the enlarged PVs may often be associated with the arrhythmogenic PVs [23]. Enlarged PV by the atrial stretch can enhance the PV's automaticity and triggered activity for AF initiation [24]. In addition, the atrial remodeling process may promote the increased triggered activity of non-PV lesions. The presence of multiple PV/non-PV foci could be related to longer AF duration, an older age, and larger atrial dimensions [25]. And also, LA enlargement could predispose LA posterior wall triggers [15].
