Impact of Catheter Ablation for Paroxysmal Atrial Fibrillation in Patients With Sick Sinus Syndrome　– Important Role of Non-Pulmonary Vein Foci –

Abstract

Background: The clinical efficacy of catheter ablation (CA) for paroxysmal atrial fibrillation (PAF) in patients with sick sinus syndrome (SSS) and the mechanism and predictors of recurrence are not yet completely elucidated.

Methods and Results: Of 963 consecutive patients who underwent PAF ablation during the study period, a total of 108 patients with SSS (SSS group) and 108 matched controls without SSS (non-SSS group) were followed up. During the follow-up period (mean, 32.8±17.5 months), the SSS group had significantly higher AF recurrence rate since the last procedure than the non-SSS group (26.9% vs. 12.0%; P=0.02). The SSS group had significantly higher prevalence of non-pulmonary vein (non-PV) foci than the non-SSS group (25.9% vs. 13.9%; P=0.027). On multivariate analysis congestive heart failure (HR, 13.7; 95% CI: 1.57–119; P=0.02) and non-PV foci (HR, 5.75; 95% CI: 1.69–19.6; P=0.005) were independent predictors of recurrence following CA in the SSS group. In the SSS group, 88 patients had bradycardia-tachycardia syndrome without prior permanent pacemaker implantation. Of these, 6 required pacemaker implantation because of AF and sinus pause recurrence.

Conclusions: Patients with SSS are at higher risk of AF recurrence after CA. Non-PV foci are associated with AF recurrence following PAF with SSS. (Circ J 2016; 80: 887–894)

Patients with sick sinus syndrome (SSS) are more prone to developing atrial fibrillation (AF),¹ both of which are associated with electrical or structural remodeling.^2–5 Symptomatic SSS is an acceptable indication for pacemaker implantation (PMI), whereas radiofrequency catheter ablation (CA) targeting the pulmonary veins (PV) has become the treatment of choice for AF.^6,7 Previous studies of AF ablation in patients with SSS have demonstrated the feasibility of CA and that both paroxysmal AF (PAF) and prolonged sinus pauses could be successfully eliminated in the majority of patients with bradycardia-tachycardia syndrome (BTS) over mid- to long-term follow up.^8–11 Previous studies, however, included a relatively small number of patients, with several confounders such as high age and previous PMI, and also did not consider structural remodeling in patients with SSS. Therefore, the clinical efficacy of CA for PAF in SSS patients and the mechanism and predictors of AF recurrence in this population remain unknown. To address this issue, we conducted a case-control study of a larger number of patients to elucidate the clinical efficacy of CA for PAF in patients with or without SSS.

Methods

Subjects

Between January 2008 and March 2013, a total of 963 consecutive patients with symptomatic PAF refractory to at least 1 anti-arrhythmic drug (AAD) underwent first CA at Kokura Memorial Hospital, Kitakyushu, Japan. Of those, 108 (11.2%) had SSS (SSS group) and 855 (88.8%) did not. Of those without SSS, we selected a matched cohort according to gender, age by decade, hypertension, presence of congestive heart failure (CHF) or left ventricular dysfunction, diabetes mellitus, previous history of stroke or transient ischemic attack, vascular disease, dilated cardiomyopathy, ischemic cardiomyopathy, hypertrophic cardiomyopathy, and valvular heart disease (non-SSS group, n=108, on a 1:1 basis). In the case of absence of fully matched patients, a hierarchical approach with the matching variable list was used. SSS was defined as history of presyncope or syncope secondary to pause lasting ≥3 s on ambulatory monitoring studies. Severe bradycardia (heart rate <50 beats/min) resulting in weakness and fatigue was also considered a sign of SSS. All patients with SSS were diagnosed according to clinical manifestations prior to CA. The study was approved by the ethics committee of Kokura Memorial Hospital.

Electrophysiological Study and Mapping

AAD were discontinued at least 5 half-lives prior to CA, except for amiodarone, which was discontinued shortly before ablation. The presence of left atrium (LA) thrombi was excluded on transesophageal echocardiography. Each patient provided written informed consent to undergo electrophysiological study in the fasting state under conscious sedation.

A 20-pole catheter was inserted through the right jugular vein, with the proximal portion positioned along the superior vena cava (SVC) and crista terminalis (CT) and the distal portion placed in the coronary sinus (CS). A 10-pole catheter was then positioned in the region of the His bundle to record the His bundle potential and pace the right ventricle.

Following the standard Brockenbrough technique, two 10-pole circular mapping catheters and an ablation catheter were introduced into the LA. Furthermore, the location of the AF initiation foci were estimated using endocardial atrial activation sequences from the SVC, CT, His bundle, PV, and CS catheters (Figure 1). An electroanatomical mapping system (CARTO, Biosense-Webster, Diamond Bar, CA, USA or Ensite NavX, St. Jude Medical, St. Paul, MN, USA) was used to provide additional guidance and minimize fluoroscopy time.

Figure 1.

Catheter positions for the induction of non-pulmonary vein foci. CS, coronary sinus; CT, crista terminalis; LAPW, left atrial posterior wall; LSPV, left superior pulmonary vein; RSPV, right superior pulmonary vein; SVC, superior vena cava.

Induction of Ectopic Beats Initiating AF

We analyzed initiating foci using electrode catheters during the initiation of AF by spontaneous ectopic beats. When no spontaneous ectopic beats inducing AF were observed before the PV isolation (PVI) procedure, adenosine triphosphate (ATP, 20–40 mg) was injected i.v. to induce AF. After PVI, bolus injection of ATP during continuous infusion of isoproterenol (ISP, 1–5 µg/min) was used to facilitate the identification of non-PV foci. If AF was not initiated by the ATP and ISP injection, sustained AF was induced by rapid atrial pacing, which was terminated by intracardiac defibrillation. After the restoration of sinus rhythm, we investigated whether there had been any spontaneous re-initiation of AF. Non-PV foci were defined as the earliest ectopic sites where ectopic beats had initiated AF. Any solitary ectopic beat that did not initiate AF was excluded from analysis.

CA

The PVI was carried out using 2 circular lines encircling the ipsilateral PV in all patients. We aimed to ablate non-PV foci consecutively if induced during the procedure. Linear ablation or complex fractionated atrial electrogram (CFAE) ablation was performed, as appropriate. LA roof and floor linear lesions were created to prevent roof-dependent atrial tachycardia when 2 PVI circles were too close (within 1 cm). A 3.5-mm or 4-mm open-irrigated-tip ablation catheter (ThermoCool, Biosense-Webster or Cool Path, St. Jude Medical) were used in the present study. PVI was considered successful in the acute setting if both entrance and exit block were confirmed. When a non-PV focus was identified, limited-area ablation of the earliest ectopic sites was carried out, except for those of the LA posterior wall (LAPW) and SVC. For ectopy from the LAPW, box-shaped linear ablation was performed around the ectopy by creating roof and floor lines. For ectopy from the SVC, SVC isolation was done from a site proximal to the SVC ectopic focus. Linear ablation was carried out at the cavotricuspid isthmus in patients with documented or inducible cavotricuspid isthmus-dependent atrial flutter. Power delivery during radiofrequency ablation was adjusted according to the ablation site. The temperature at the ablation catheter and the impedance drop were recorded. Esophageal temperature probe was also inserted to monitor and titrate the power delivered to the LAPW.

Follow-up of AF Recurrence

Recurrence of atrial arrhythmia was defined as atrial arrhythmia lasting for >1 min and occurring ≥3 months after ablation. Patients were observed in the hospital for at least 3 days after the procedure. After discharge, patients were evaluated in the outpatient clinic at 1 month, 3 months, and every 1–3 months after the procedure. AAD were prescribed for 4–12 weeks if early AF recurrence occurred within 3 months or was suspected according to reported symptoms. When patients had clinical symptoms suggestive of AF recurrence, electrocardiography, 24-h Holter monitoring, 2-week cardiac event recording, or pacemaker interrogation was done. If ≥2 recurrence episodes were documented, patients were encouraged to undergo repeat CA.

The primary endpoint of the present study was the recurrence of AF after the last CA, defined as the occurrence of any symptomatic or asymptomatic atrial tachyarrhythmias including atrial flutter and procedure-related atrial tachycardia.

Statistical Analysis

Continuous variables are expressed as mean±SD or median. The demographic and clinical characteristics of the 2 groups were compared using Student’s t-test or Mann-Whitney test for continuous variables and with chi-squared test for categorical variables. Kaplan-Meier survival analysis with log-rank test was used to assess AF recurrence. Cox proportional hazard model was used to identify independent predictors of AF recurrence. All clinically relevant variables (age, gender, presence of hypertension, diabetes mellitus, CHF, vascular disease, LA dimension, left ventricular ejection fraction, SSS type, and presence of PV or non-PV foci) were included in the full model. For sensitivity analyses, we selected a model incorporating minimum Akaike information criterion (AIC) using backward stepwise analysis. All statistical analysis was 2-tailed, and P<0.05 was considered statistically significant. Analysis was conducted using Stat-View 5.0 (SAS Institute, Cary, NC, USA) and R version 3.2.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Clinical Characteristics

Patient clinical characteristics vs. presence of SSS are listed in Table 1. Patients with SSS were often older, and female, and had a higher prevalence of hypertension. CHADS₂ and CHA₂DS₂-VASc scores were significantly higher in patients with SSS than without SSS in the entire cohort. After 1:1 matching, no significant differences in demographic or echocardiographic profiles were observed between the SSS and non-SSS groups. In the SSS group, 97 patients were categorized as having BTS. The mean maximum symptomatic prolonged sinus pause on termination of AF at baseline was 5.9±2.1 s (range, 3.0–14.0 s).

Table 1. Baseline Patient Characteristics

	SSS (n=108)	Non-SSS		P-value (SSS vs. entire cohort)	P-value (SSS vs. matched cohort)
		Entire cohort (n=855)	Matched cohort (n=108)
Clinical characteristics
Female†	48 (44)	233 (27)	48 (44)	<0.001	1.00
Age (years)†	67.9±6.8	61.3±10.8	67.9±7.1	<0.001	1.00
CHADS2 score	1.2±1.0	0.9±1.0	1.2±1.0	0.002	0.78
≥2	38 (35)	194 (23)	36 (33)	0.004	0.77
CHA2DS2-VASc score	2.4±1.4	1.6±1.5	2.4±1.4	<0.001	0.74
≥3	53 (49)	223 (26)	51 (47)	<0.001	0.79
Hypertension†	65 (60)	396 (46)	64 (59)	0.007	0.89
Diabetes mellitus†	19 (18)	116 (14)	14 (13)	0.26	0.34
Prior stroke or TIA†	9 (8.3)	67 (7.8)	10 (9.3)	0.86	0.81
CHF†	6 (5.6)	49 (5.7)	5 (4.6)	0.94	0.76
DCM†	0 (0.0)	9 (1.1)	1 (0.9)	0.59	1.00
HCM†	2 (1.9)	32 (3.7)	4 (3.7)	0.32	0.41
Valvular heart disease†	6 (5.6)	29 (3.4)	6 (5.6)	0.26	0.77
CAD†	11 (10)	68 (8.0)	10 (9.3)	0.43	0.82
Vascular disease†	13 (12)	85 (9.9)	11 (10)	0.50	0.67
PMI before procedure	16 (15)	3 (0.4)	0 (0.0)	<0.001	<0.001
Echocardiographic parameters
LAD (mm)	40.7±5.3	39.5±6.0	39.4±5.6	0.06	0.08
LVEF (%)	64.2±9.5	64.5±7.6	66.5±5.9	0.76	0.08

Data given as mean±SD or n (%). ^†Variables used for matching. CAD, coronary artery disease; CHADS₂, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke, transient ischemic attack [doubled]; CHA₂DS₂-VASc , congestive heart failure, hypertension, age ≥75 years [doubled], diabetes mellitus, prior stroke, transient ischemic attack [doubled], vascular disease, age 65 to 74 years, sex category; CHF, congestive heart failure; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LAD, left atrial dimension; LVEF, left ventricular ejection fraction; PMI, pacemaker implantation; SSS, sick sinus syndrome; TIA, transient ischemic attack.

CA and Distribution of AF Foci

Electrical PVI was completed in all patients. PV foci were identified in 41.7% of SSS patients (n=45) and in 40.7% of non-SSS patients (n=44; P=0.89) through all procedures. When LA–PV reconnection was present, PVI was accomplished during repeat procedures. Non-PV foci were detected in 25.9% of SSS patients (n=28) and in 13.9% of non-SSS patients (n=15; P=0.027) through all procedures. The distribution of AF foci is shown in Table 2. Ten patients in the SSS group and 3 in the non-SSS group had ≥2 non-PV foci. In 7 patients in the SSS group and 5 in the non-SSS group, indefinite non-PV foci remained despite aggressive search for non-PV foci, because of the difficulty in identifying the precise foci owing to low inducibility or chaotic multiple non-PV foci under induction protocols. The ablation of non-PV foci was carried out primarily via limited focal area ablation, segmental SVC isolation, LA-roof line creation, and additional LA-floor line creation (Table 3). Mitral isthmus lines and CFAE ablation were rarely performed. Two patients in each group developed pericardial effusions during CA, which were resolved by pericardiocentesis, with no procedures aborted as a result. No other major complications related to CA were observed.

Table 2. AF Foci Distribution

	SSS (n=108)	Non-SSS (n=108)
PV	45 (42)	44 (41)
SVC	12 (11)	3 (2.8)
CT	2 (1.9)	2 (1.9)
CSO	1 (0.9)	–
RIAS	5 (4.6)	3 (2.8)
RAFW	3 (2.8)	–
LIAS	1 (0.9)	1 (0.9)
LAPW	4 (3.7)	2 (1.9)
PLSVC	–	2 (1.9)
LOM	1 (0.9)	–
LAFW	2 (1.9)	1 (0.9)
LAA	1 (0.9)	–
Unknown	7 (6.5)	5 (4.6)

Data given as n (%). AF, atrial fibrillation; CSO, coronary sinus ostium; CT, crista terminalis; LAA, left atrial appendage; LAFW, left atrial free wall; LAPW, left atrial posterior wall; LIAS, left interatrial septum; LOM, ligament of Marshall; PLSVC, persistent left superior vena cava; PV, pulmonary veins; RAFW, right atrial free wall; RIAS, right interatrial septum; SVC, superior vena cava. Other abbreviation as in Table 1.

Table 3. Ablation Procedure Characteristics

	SSS group (n=108)	Non-SSS group (n=108)	P-value
No. sessions			0.02
1	75 (69)	89 (82)
2	27 (25)	16 (15)
3	5 (4.6)	3 (2.8)
4	1 (0.9)	0 (0.0)
PV foci	45 (42)	44 (41)	0.89
Non-PV foci	28 (26)	15 (14)	0.03
SVC isolation	13 (12)	5 (4.6)	0.05
Limited area ablation for non-PV foci	14 (13)	5 (4.6)	0.03
LA roof line	28 (26)	12 (11)	0.005
LA floor line	21 (19)	11 (10)	0.06
Mitral isthmus line	3 (2.8)	2 (1.9)	0.65
CFAE ablation	3 (2.8)	0 (0.0)	0.08
CTI block line	83 (77)	73 (68)	0.13
Major complications	2 (1.9)	2 (1.9)	1.00
Follow-up (months)	35.1±18.7	31.3±15.7	0.11

Data given as mean±SD or n (%). CFAE, complex fractionated atrial electrogram; CTI, cavotricuspid isthmus; LA, left atrium. Other abbreviations as in Tables 1,2.

AF Recurrence in the Matched Cohort

The mean clinical follow-up duration after the last procedure was 35.1±18.7 months in the SSS group and 31.3±15.7 months in the non-SSS group (P=0.11). At 36 months, crude recurrence rate was 46.3% in the SSS group and 27.8% in the non-SSS group after a single procedure. In total, 40 and 22 repeat ablation procedures were performed for 33 patients (30.6%) in the SSS group and for 19 patients (17.6%) in the non-SSS group (P=0.02), respectively, over the entire follow-up period. LA–PV reconnection was observed in 32 patients (97.0%) in the SSS group and in 18 patients (94.7%) in the non-SSS group in repeated procedures. Nineteen patients (57.6%) in the SSS group and 6 patients (31.6%) in the non-SSS group who underwent repeat procedure had non-PV foci. Cumulative recurrence rate at 36 months after the last procedure was 23.1% in the SSS group and 12.0% in the non-SSS group (Figure 2A; log-rank, P=0.02). No cases of procedure-related atrial tachycardia were observed during the follow-up period.

Figure 2.

Kaplan-Meier curves of freedom from recurrence of atrial fibrillation after the last procedure vs. (A) presence of sick sinus syndrome (SSS) and (B) presence of non-pulmonary vein (non-PV) foci in SSS.

In the SSS group, the cumulative recurrence rate after the last procedure was significantly higher in patients with non-PV foci than in patients without non-PV foci (Figure 2B; log-rank, P=0.02). CHF and prevalence of non-PV foci were independent predictors of AF recurrence after the last procedure in the SSS group (CHF: HR, 13.7; 95% CI: 1.57–119; P=0.02; prevalence of non-PV foci: HR, 5.75; 95% CI: 1.69–19.6; P=0.005; Table 4). The independent predictors identified in the minimum AIC model were the same as those in the full model.

Table 4. Indicators of AF Recurrence After the Last Procedure

	Univariate		Multivariate
	HR (95% CI)	P-value	HR (95% CI)	P-value
Age (≥75 years)	0.62 (0.21–1.83)	0.38	0.59 (0.15–2.33)	0.45
Female	0.81 (0.35–1.90)	0.63	1.86 (0.58–6.01)	0.30
Hypertension	0.51 (0.21–1.21)	0.13	0.57 (0.18–1.78)	0.33
Diabetes	0.45 (0.12–1.69)	0.24	0.60 (0.11–3.13)	0.54
CHF	6.16 (1.06–35.7)	0.04	13.7 (1.57–11.9)	0.02
Vascular disease	0.80 (0.20–3.12)	0.74	1.00 (0.17–5.87)	1.00
LAD (mm)	0.98 (0.91–1.07)	0.70	0.98 (0.88–1.09)	0.70
LVEF (%)	1.00 (0.95–1.05)	0.93	0.99 (0.91–1.07)	0.76
SSS type I/II	2.54 (0.71–9.06)	0.15	4.22 (0.63–28.3)	0.14
PV foci	0.85 (0.36–2.04)	0.72	0.47 (0.13–1.64)	0.24
Non-PV foci	2.78 (1.11–6.98)	0.03	5.75 (1.69–19.6)	0.005

Abbreviations as in Tables 1,2.

Clinical Outcome of CA in SSS Patients

Baseline and electrophysiological characteristics of patients with SSS type I/II and BTS are listed in Table 5. No significant differences were observed between the groups, except for the prevalence of PMI before CA. The cumulative recurrence rate at 36 months was 36.4% in patients with SSS type I/II and 21.6% in those with BTS (log-rank, P=0.40). In patients with SSS type I/II without PMI before the procedure, all 4 patients required PMI regardless of AF recurrence, and 6 of the 19 patients with BTS who had AF recurrence required PMI because of sinus pause recurrence. No patients with BTS without AF recurrence required PMI during the follow-up period, except 1 who required PMI because of atrioventricular block (Figure 3).

Table 5. Patient Characteristics vs. SSS Type I/II and BTS

	SSS type I/II (n=11)	BTS (n=97)	P-value
Age (years)	70.6±6.6	67.6±6.7	0.16
Female	4 (36)	44 (45)	0.57
CHA2DS2-VASc score	2.7±1.2	2.4±1.5	0.48
LAD (mm)	41.7±7.2	40.6±5.1	0.57
LVEF (%)	65.7±7.8	64.1±9.7	0.64
PV foci	5 (46)	40 (41)	0.79
Non-PV foci	1 (9.1)	27 (28)	0.18
AF recurrence	5 (46)	24 (25)	0.14
PMI before procedure	7 (64)	9 (9.3)	<0.001

Data given as mean±SD or n (%). BTS, bradycardia-tachycardia syndrome. Other abbreviations as in Tables 1,2.

Figure 3.

Flow diagram of patient selection. AF, atrial fibrillation; AVB, atrioventricular block; BTS, bradycardia-tachycardia syndrome; CA, catheter ablation; PMI, pacemaker implantation; SSS, sick sinus syndrome.

Discussion

The main findings of the current 1:1 matched case-control study were as follows: first, the cumulative incidence of AF recurrence was significantly higher in patients with SSS than in patients without SSS; and second, the prevalence of non-PV foci was significantly higher in patients with SSS than that in patients without SSS. In patients with SSS, the cumulative recurrence rate after the last procedure was significantly higher in patients with non-PV foci than that in patients without non-PV foci, and non-PV foci was identified as an independent predictor of AF recurrence. To the best of our knowledge, this is the first report to describe the importance of non-PV foci in PAF with SSS. And third, despite the high AF recurrence rate in patients with SSS, few patients required PMI after CA.

Impact of Non-PV Foci on AF Recurrence in SSS Patients

The rates of mid to long-term freedom from AF recurrence after CA for PAF with SSS range between 56% and 87%.^8–10,12 We enrolled a larger number of patients with a relatively longer follow-up duration and found that 73.1% of SSS patients were free from AF recurrence after the last procedure, corroborating previous reports. We used matched non-SSS controls to evaluate AF recurrence in SSS patients, because the characteristics of these patients, such as high age, hypertension, and cardiovascular disease, could be associated with AF recurrence.^13–15 The AF recurrence rate was significantly higher in the SSS group than in the matched non-SSS controls, indicating that other factors may underlie the recurrence of AF in patients with SSS.

A previous report posited the reconnection of isolated PV and recovery from previously ablated PV foci as the major causes of AF recurrence.^8,16 We found, however, no significant difference in the incidence of PV foci (SSS group, 41.7% vs. non-SSS group, 40.7%, P=0.87) or LA–PV reconnection observed on second ablation (SSS group, 97.0% vs. non-SSS group, 94.7%, P=0.69) between the 2 groups. Thus, PV foci appear to have less impact on the discrepancy in recurrence rate between the 2 groups. The low incidence of PV foci (41.2%) may be attributable in part to the induction of AF solely with ATP prior to PVI in order to proceed with CA efficiently.

In the SSS group there was a tendency toward increased prevalence of non-PV foci on repeat procedures compared with the non-SSS group (SSS group, 57.6% vs. non-SSS group, 31.6%; P=0.07). Moreover, the prevalence of non-PV foci was significantly higher than in the non-SSS group for all procedures, and was identified as an independent predictor of AF recurrence on multivariate analysis. Several previous studies have highlighted the importance of non-PV foci in the initiation of AF, with non-PV foci reportedly accounting for 16–32% of PAF.^17–20 Chang et al and Lin et al noted that AF originating from non-PV foci was associated with worse outcome compared with AF originating from the PV alone.^17,19 We previously reported that the success rate of PAF ablation can be improved if all non-PV foci are detected and eliminated, although the mapping of all non-PV foci is technically challenging, even with the use of multiple procedures.¹⁸ In the present study, at least 9.3% of patients had multiple non-PV foci in the SSS group, indicating that efforts to identify and ablate non-PV foci in patients with SSS, despite the presence of multiple non-PV foci or low reproducibility, may reduce the risk of subsequent AF recurrence.

On another front, both AF and SSS are associated with electrical or structural remodeling.^2–5 Ejima et al reported that LA volume index and estimated total atrial conduction time measured using tissue Doppler imaging were associated with AF recurrence.²¹ In the present study, there was a tendency for patients with SSS to have larger LA dimension than patients without SSS (40.7±5.3 mm vs. 39.4±5.6 mm, P=0.08). Although LA dimension did not predict AF recurrence on univariate and multivariate analysis, and we did not have precise information on atrial voltage or scarring, the damaged atrial substrate itself in SSS patients may influence the difference in AF recurrence rate between the SSS and non-SSS groups.

High Morbidity of Non-PV Foci and Remodeling in SSS AF Patients

The mechanisms underlying the high prevalence of non-PV foci in SSS patients have yet to be fully elucidated. It is known that non-PV foci are associated with a large atrium and worse atrial substrate.^20,22 In the present study, there was a tendency toward larger LA dimension in SSS patients than in those without SSS. Although we did not evaluate atrial voltage or scarring, Akoum et al reported that significant atrial fibrosis in the right atrium (RA) and LA quantified using late gadolinium enhancement-magnetic resonance imaging (LGE-MRI) is associated with clinically significant SSS.⁵ They also showed that RA fibrosis was correlated with LA fibrosis. Previous studies have reported that increased automaticity and triggered activity may occur in diseased human atrial fibers.^23,24 This indicates that prevalence of non-PV foci may be associated with diseased atrial substrate in PAF patients with SSS.

Zhao et al reported that the prevalence of non-PV foci was higher in patients with PAF and left ventricular systolic dysfunction than in patients with normal systolic function, and that the ablation of non-PV foci in addition to PVI significantly improved long-term outcome. They suggested that the presence of non-PV foci was associated with LA enlargement and atrial scarring.²⁵ These atrial abnormalities are common characteristics in PAF patients with SSS. Moreover, 2 previous studies reported similar ionic remodeling in sinoatrial node tissues between AF patients with SSS and with CHF, such as decreasing funny current (I_f), slow delayed-rectifier (I_Ks), and a lack of change in L-type Ca²⁺ current (I_CaL).^4,26 These specific ionic remodeling characteristics may affect the triggered activity mechanism and the prevalence of non-PV foci in PAF patients with SSS.

Influence of Reverse Remodeling on AF Course in SSS Patients

Clinical and experimental studies have indicated the development of electrical reverse remodeling of SSS in AF patients after the restoration of sinus rhythm.^8,9,11,27 Hocini et al noted a significant improvement of sinus node function, with an increase in mean heart rate and a decrease in corrected sinus node recovery time, in patients with BTS after CA of AF.¹¹ While SSS type I/II may be associated with severe sinus node structural remodeling and fibrosis, regional atrial remodeling near the sinus node area has been reported.^2,5 Akoum et al reported that significant atrial fibrosis detected on LGE-MRI is associated with clinically significant SSS requiring PMI.⁵

In BTS patients without PMI prior to CA, 19 patients (21.6%) had AF recurrence after the last procedure, but only 6 (31.6%) of the 19 patients had symptoms caused by sinus pauses requiring PMI. This is consistent with a previous study.⁹ All 4 patients with SSS type I/II without PMI before CA, however, required PMI regardless of AF recurrence. Furthermore, in the present study, there was a tendency toward a higher AF recurrence rate in patients with SSS type I/II (36.4%) than in patients with BTS (21.6%). This indicates that electrical reverse remodeling or autonomic modulation after CA may affect sinus node dysfunction in patients with BTS,¹¹ and that both AF and SSS may be improved in patients with BTS. SSS type I/II, however, may be associated with relatively severe structural atrial remodeling.

Study Limitations

The clinical diagnosis of SSS was not confirmed using invasive measures, such as sinus node recovery or sinoatrial conduction times. The observed AF recurrence rate may have been underestimated in patients without PMI compared with patients with PMI because of pacemaker interrogation. Only one patient diagnosed with AF recurrence with pacemaker interrogation before other modalities was included in the follow-up study; moreover, the patient was subsequently found to have AF recurrence on 12-lead electrocardiogram. Because we did not perform voltage mapping of the atrium during CA, we were unable to obtain precise information regarding the condition of the atrial muscle.

Conclusions

A significantly higher AF recurrence rate was observed in patients with SSS than in patients without SSS after CA. The prevalence of non-PV foci was found to be an independent predictor of AF recurrence and was associated with the success rate of treatment for PAF with SSS.

Acknowledgments

We are indebted to Harushi Niu, Koji Katayama, and Tomoaki Ito for assistance in electrophysiological assessment.

Conflicts of Interest

None.

References

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