Time Interval From Right Atrium to Coronary Sinus Predicts Postablation Atrial Fibrillation Recurrence in Current Ablation Practice

Abstract

Background: Recurrence after ablation for atrial fibrillation (AF) may occur in patients in whom atrial remodeling progresses. Atrial conduction time is a marker of remodeling. This study investigated whether atrial conduction time is related to postoperative recurrence.

Methods and Results: This study enrolled 441 patients with AF (median age 69 years; 144 women; paroxysmal/non-paroxysmal AF=231/210) who underwent initial radiofrequency catheter ablation at Mie University Hospital between January 2018 and December 2022. The interval from the earliest potential in the right atrium (RA) to the latest potential in the coronary sinus (CS) was measured using a BeeAT catheter during sinus rhythm after ablation. The primary endpoint was AF recurrence or atrial tachycardia lasting >30 s in the 1 year after ablation. Recurrence was observed in 44 patients. Patients were categorized into 2 groups according to recurrence. The RA-CS interval was significantly longer in the recurrence group (122.5±17.7 vs. 98.5±17.7 ms; P<0.001). In Cox regression analysis, the RA-CS interval was independently associated with recurrence (hazard ratio 1.05; 95% confidence interval [CI] 1.03–1.07; P<0.001). The cut-off value for the RA-CS interval was 111 ms (area under the curve=0.845; 95% CI 0.785–0.905). The recurrence rate was significantly higher in patients with an RA-CS interval ≥111 vs. <111 ms.

Conclusions: The RA-CS interval time was an independent predictor of recurrence after AF ablation.

Atrial fibrillation (AF) can be treated effectively using catheter ablation, and the technology for this procedure is continually evolving. The Japanese Catheter Ablation Registry of Atrial Fibrillation reported that approximately 70% of paroxysmal AF (PAF) and 60% of non-PAF patients were free from AF recurrence 1 year after AF ablation.¹ Ablation failure after single or multiple ablation procedures has been correlated with the presence of hypertension,² larger left atrial (LA) size,^2,3 the presence of non-PAF,^2,3 coronary artery disease,³ prolonged AF duration,⁴ more antiarrhythmic drugs (AADs) before ablation,^5,6 higher CHADS₂ and CHA₂DS₂-VASc scores,^7–9 higher B-type natriuretic peptide levels,¹⁰ and untreated obstructive sleep apnea.¹¹ These factors have been linked to the anatomical and electrical remodeling of the atrium, resulting in AF.

It has been reported that slowed conduction contributes to the so-called “second factor” that is critical to the development of AF.¹² In addition, a systematic review and meta-analysis found that the P wave duration index on electrocardiography (ECG) predicts repeat catheter ablation for AF.¹³ Therefore, atrial conduction time may be an additional marker of atrial remodeling. However, there are few reports on the association between the atrial conduction time measured using only intracardiac potentials during an electrophysiological study (EPS) and AF recurrence. In this study, we investigated whether atrial conduction time, measured during an EPS using the interval from the earliest potential in the right atrium (RA) to the latest potential in the coronary sinus (CS; RA-CS interval time), is associated with AF recurrence in patients after ablation.

Methods

Study Population

Patients with AF who underwent initial radiofrequency (RF) catheter ablation between January 2018 and December 2022 were enrolled in the AF ablation registry database of Mie University Hospital. The 537 patients who met the following inclusion criteria were enrolled in the present study: age ≥20 years, PAF or non-PAF, and having undergone initial RF catheter ablation for AF. Patients were excluded from the study if they had undergone open-heart surgery (n=16) or hemodialysis (n=14), had cardiovascular implantable electronic devices (n=23), severe valvular disease (n=7), or difficult-to-record RA or CS potential during catheter ablation (n=29), or had been lost to follow-up (n=7). Consequently, the final analysis included 441 patients (median age 69.0 years [interquartile range 60.0–76.0 years]; 144 women; PAF/non-PAF=231/210; Figure 1). In this retrospective analysis of prospectively collected data, patients were classified into 2 groups according to postoperative recurrence.

Figure 1.

Flowchart showing recruitment to the present study. Overall, 441 patients were included in the final analysis. AF, atrial fibrillation; CS, coronary sinus; RA, right atrium; RF, radiofrequency.

This study complied with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Mie University Graduate School of Medicine (Reference no. 3038). All patients provided informed consent.

Study Protocol

Data Collection ECG and a chest radiograph were obtained for each patient; cardiovascular status was evaluated using echocardiography and laboratory data within 3 months of the initial visit. Information regarding patient sex and age, as well as coexisting cardiac and other diseases, was collected.

EPS and Catheter Ablation In principle, AADs were discontinued at least 5 half-lives prior to the procedure. All patients were effectively anticoagulated with oral anticoagulants for at least 1 month before the procedure. Cardiac computed tomography or transesophageal echocardiography was performed immediately before the ablation procedure to exclude LA appendage thrombosis.

Our ablation protocol for the catheter ablation procedure has been described elsewhere.¹⁴ Briefly, heparin was infused continuously to maintain an activated clotting time of >300 s. The sedation protocol started with the administration of hydroxyzine hydrochloride 25 mg, i.v., and pentazocine 15 mg, i.v., given 10–20 min before the patient entered the catheter laboratory. Subsequently, a dexmedetomidine infusion (0.3–0.5 µg/kg/h) was started inside the catheter laboratory. If sedation was inadequate, the dexmedetomidine infusion was uptitrated (to 0.7 µg/kg/h) and an i.v. thiopental bolus was administered. If sedation remained inadequate, patients were administered an i.v. midazolam bolus. A 6-Fr, 20-pole, 3-site mapping catheter (BeeAT; Japan Lifeline, Tokyo, Japan) inserted into the coronary sinus through the jugular vein. The BeeAT catheter has 4 proximal, 8 middle, and 8 distal electrodes. Four proximal and 8 middle electrodes were placed in the RA. Eight distal electrodes were placed in the CS proximal to the distal electrode throughout the procedure. Pulmonary vein isolations (PVIs) were performed using a 3-dimensional mapping system (CARTO3 system; Biosense Webster) and an EZ Steer Thermo Cool STSF (Thermo Cool SmartTouch; Biosense Webster), guided by the VISITAG module with recommended settings (i.e., location stability of 3 mm, minimum time of 3 s, and a force-over-time filter ≤50%). RF energy was delivered with a target temperature of 43℃ at a power setting of 25–35 W. Each target site was ablated for 20–30 s. The endpoints of catheter ablation were achieving PVI and the absence of induction of supraventricular arrhythmias other than AF. After the procedure, atrial arrhythmia was induced by rapid atrial stimulus pacing up to 300 beats/min from the CS, and non-pulmonary vein (PV) induction was performed with a high-dose (up to 30 µg/min) isoproterenol infusion. More than half the patients underwent posterior wall isolation (PWI) according to preoperative findings such as longer (>1 year) AF duration (i.e., long persistent AF) and enlarged LA volume (i.e., LA diameter >40 mm or LA volume index [LAVI] >34 mL/m²), as well as intraoperative findings, such as the existence of low-voltage areas and non-PV foci in the posterior wall in the LA based on EPS or high-density mapping findings. Sinus mapping was performed in most patients during the first AF ablation procedure. In patients with electrical potentials in the superior vena cava (SVC), SVC isolation was added. Cavotricuspid isthmus (CTI) linear ablation was also added for all types of atrial tachycardia or atrial flutter, not just common atrial flutter documented before or during the ablation procedure. If sustained atrial tachycardia such as a peri-mitral flutter was induced during the ablation procedure, an additional EPS and ablation were performed. In addition to these procedures, operator-dependent protocols were also considered.

Measurement of Atrial Conduction Time After the initial catheter ablation and sinus rhythm conversion, the RA-CS interval time (i.e., the interval from the earliest potential in the RA to the latest in the CS) was measured using the BeeAT catheter (Figure 2A,B). The duration of the P wave was also measured the day after catheter ablation as another index of atrial conduction time. The P wave duration on ECG was measured from the earliest onset to the latest offset in the inferior leads with reference to a previous study (Figure 2C).¹³

Figure 2.

(A) Fluoroscopic images of the catheter position. The BeeAT catheter has 4 proximal electrodes, and 8 middle and distal electrodes. The 4 proximal (p) and 8 middle electrodes were in the right atrium (RA) proximate to the sinus node. The 8 distal (d) electrodes were positioned in the coronary sinus (CS) proximal to distal throughout the procedure. (B) Intracardiac recordings during sinus rhythm in the same patient as in (A). The RA-CS interval during sinus rhythm was 102 ms. The red arrows indicate the earliest RA potential and the latest CS potential. (C) The electrocardiogram P wave duration measured in the inferior leads was 103 ms, as in (A).

Postprocedural Management and Follow-up Patients were followed for 1 year after the first procedure. After discharge from hospital, all patients underwent clinical review, ECG monitoring, and 24-h ambulatory monitoring to check for asymptomatic arrhythmias. These assessments were conducted at 1, 3, and 6 months at Mie University Hospital, and up to 12 months at either Mie University Hospital or referral centers to communicate with the patient’s primary physician. Patients underwent 24-h ambulatory monitoring at least once within the first 6 months after ablation at Mie University Hospital, and up to 12 months if clinically necessary. If patients had subjective symptoms, such as palpitations, a portable ECG-recording device was encouraged to check for arrhythmias. AADs, such as amiodarone or bepridil, were prescribed for 3 months after the ablation (blanking period) if necessary, and, in principle, were discontinued after the blanking period. Patients with reduced cardiac function were treated with amiodarone; otherwise, bepridil was chosen.

The primary outcome of this study was freedom from any documented episode of AF or atrial tachycardia lasting longer than 30 s during the 1-year follow-up, starting 3 months after the first ablation procedure.

Statistical Analysis

Normally distributed continuous variables are presented as the mean±SD, whereas those with a skewed distribution are presented as the median and interquartile range (IQR). Categorical variables were presented as numbers and percentages. To assess the significance of differences between 2 subgroups, Student’s t-test was used for normally distributed continuous variables and the Mann-Whitney U test was used for variables with a skewed distribution; categorical data were compared using Pearson’s Chi-squared test. For descriptive statistics, categorical data were analyzed using Fisher’s exact or Pearson’s Chi-squared test. Correlations were analyzed using Spearman’s correlation coefficient test. Hazard ratios (HRs) were calculated using simple and multivariate Cox regression analyses. The mean AF-free survival was determined by Kaplan-Meier estimation and compared between groups using the log-rank test. The area under the receiver operating characteristic (ROC) curve was used to define the thresholds for these predictors. This analysis provided the optimal sensitivity and specificity for predicting recurrence. Two correlated ROC curves were analyzed using DeLong’s test.

Statistical significance was set at two-tailed P<0.05. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria), which is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.¹⁵

Results

Patient Characteristics

Patient characteristics are presented in Table 1 presents. The median age was 69.0 years (IQR 60.0–76.0 years), with 231 patients having PAF and 210 patients without PAF. All patients successfully underwent PVI. Approximately 60% of patients underwent PWI due to preoperative findings, such as longer AF duration and enlarged LA volume, as well as intraoperative findings, such as low-voltage areas and non-PV foci in the posterior wall in the LA. Overall, 232 patients underwent SVC isolation, and 223 patients underwent CTI linear ablation.

Table 1.

Patient Characteristics

	All patients (n=441)	AF recurrence		P value
		No (n=397)	Yes (n=44)
Clinical characteristics
Age (years)	69.0 [60.0–76.0]	69.0 [60.0–75.0]	70.5 [62.8–77.0]	0.386
Female sex	144 (32.7)	128 (32.2)	16 (36.4)	0.701
BMI (kg/m2)	24.0 [21.9–26.4]	24.0 [21.9–26.5]	24.1 [21.9–25.9]	0.856
Non-PAF	210 (47.6)	180 (45.3)	30 (68.2)	0.007
Medical history
Hypertension	283 (64.2)	259 (65.2)	24 (54.5)	0.216
Diabetes	85 (19.3)	77 (19.4)	8 (18.2)	1.000
Chronic heart failure	143 (32.4)	125 (31.5)	18 (40.9)	0.273
Previous stroke/TIA	38 (8.6)	34 (8.6)	4 (9.1)	1.000
Vascular disease	44 (10.0)	41 (10.3)	3 (6.8)	0.634
SAS	203 (46.0)	184 (46.3)	19 (43.2)	0.810
CHADS2 score	1.6±1.2	1.6±1.2	1.6±1.1	0.910
CHADS2DS2-VASc score	2.8±2.2	2.7±1.7	3.5±4.8	0.028
Medication (at discharge)
ACEi/ARB	213 (48.3)	195 (49.1)	18 (40.9)	0.382
ARNI	9 (2.0)	8 (2.0)	1 (2.3)	1.000
Loop diuretics	81 (18.4)	74 (17.6)	7 (15.9)	0.811
MRA	45 (10.2)	42 (10.6)	3 (6.8)	0.603
β-blocker	219 (49.7)	199 (50.1)	20 (45.5)	0.668
AADs	236 (53.5)	203 (51.1)	33 (75.0)	0.004
SGLT2 inhibitor	17 (3.9)	15 (3.8)	2 (4.5)	1.000
Echocardiography data
LA diameter (mm)	42.0 [37.0–46.0]	41.5 [37.0–46.0]	43.0 [39.5–48.0]	0.077
LAVI (mL/m2)	41.0 [32.0–53.0]	40.0 [31.0–51.0]	45.0 [36.5–57.0]	0.037
LVEF (%)	66.0 [60.0–71.0]	66.0 [60.8–71.0]	64.5 [57.8–72.5]	0.792
Laboratory data
eGFR (mL/min/1.73 m2)	66.9 [54.6–74.5]	67.0 [55.0–76.5]	64.1 [51.7–75.2]	0.493
Hemoglobin (g/dL)	14.0 [12.7–15.2]	13.9 [12.6–15.2]	14.1 [13.4–15.1]	0.402
BNP (pg/mL)	65.7 [30.4–132.0]	63.9 [29.7–132.0]	84.4 [46.1–130.2]	0.216
ECG data
P-wave duration (ms)	104.5±14.8	103.0±13.1	118.5±20.8	<0.001

Unless indicated otherwise, data are presented as the mean±SD, median [interquartile range], or n (%). AADs, antiarrhythmic drugs; ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BMI, body mass index; BNP, B-type natriuretic peptide; CHADS₂DS₂-VASc, congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65–74 years, and female sex; CHADS₂, congestive heart failure, hypertension, age ≥75, diabetes, stroke (doubled); ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; LA, left atrium; LAVI, left atrial volume index; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; PAF, paroxysmal atrial fibrillation; SAS, sleep apnea syndrome; TIA, transit ischemic attack.

Patients were categorized into 2 groups according to postablation AF recurrence over the course of a 1-year follow-up; the clinical characteristics of these 2 groups are summarized in Table 1. There were no significant differences between the group without AF recurrence and the group with AF recurrence in terms of age (69.0 [IQR 60.0–75.0] vs. 70.5 [IQR 62.8–77.0] years, respectively; P=0.386), sex (P=0.701), or CHADS₂ score (P=0.910). There were also no differences between the 2 groups in B-type natriuretic peptide (P=0.216), hemoglobin (P=0.402), and eGFR levels (P=0.493). Compared with the non-recurrence group, the recurrence group had more non-PAF patients, a higher proportion of patients prescribed AADs at discharge, higher CHADS₂-VASc scores, a higher LAVI, and longer P wave duration on ECG (118.5±20.8 vs. 103.0±13.1 ms; P<0.001).

Comparison of EPS in Patients With and Without AF Recurrence

There were 44 cases of AF recurrence during the 1-year follow-up period (Table 2). The RA-CS interval time was significantly longer in recurrence than non-recurrence group (122.5±17.7 vs. 98.5±17.7 ms; P<0.001). Compared with the non-recurrence group, more patients in the recurrence group underwent PVI plus PWI and mitral isthmus block, whereas fewer patients underwent only PVI. There was no significant difference between the 2 groups in the number of patients with SVC isolation and CTI block; however, more patients in the recurrence group underwent a CTI block ablation procedure (P=0.177).

Table 2.

Data From the Electrophysiological Study and the First Ablation Procedure

	All patients (n=441)	AF recurrence		P value
		No (n=397)	Yes (n=44)
Electrophysiological study
RA-CS interval time (ms)	100.9±19.1	98.5±17.7	122.5±17.7	<0.001
Ablation procedure
PVI only	173 (39.2)	168 (42.3)	5 (11.4)	<0.001
PVI plus PWI	268 (60.8)	229 (57.7)	39 (88.6)	<0.001
SVC isolation	232 (52.6)	210 (52.9)	22 (50.0)	0.837
CTI block	223 (50.6)	196 (49.4)	27 (61.4)	0.177
Mitral isthmus block	10 (2.3)	6 (1.5)	4 (9.1)	0.008

Unless indicated otherwise, data are presented as the mean±SD or n (%). AF, atrial fibrillation; CS, coronary sinus; CTI, cavotricuspid isthmus; PVI, pulmonary vein isolation; PWI, posterior wall isolation; RA, right atrium; SVC, superior vena cava.

Second Ablation Procedure

Of the 44 patients with postablation AF recurrence, 33 (75%) underwent a second ablation procedure. During the second ablation procedure, reconnection of the PV was found in 26 patients (reconnection rate 79%), reconnection of the posterior wall was found in 22 patients (reconnection rate 79%), reconnection of the SVC was found in 6 patients (reconnection rate 40%), reconnection of the CTI was found in 6 patients (reconnection rate 38%), and reconnection of the mitral isthmus in was found 2 patients (reconnection rate 50%). In these all cases, the reconnection was successfully re-isolated. After the second ablation procedure, 11 (33%) patients experienced AF recurrence.

Univariate and Multivariate Cox Regression Analyses for Predictors of AF Recurrence

As indicated in Table 3, univariate and stepwise multivariate Cox regression analyses revealed that the RA-CS interval time was independently associated with AF recurrence after catheter ablation (HR 1.06; 95% CI 1.04–1.07; P<0.001; Model 1, Table 3). Prescription of AADs at discharge was also independently associated with AF recurrence. When P wave duration was added to the model (Model 2, Table 3), the RA-CS interval time, P wave duration, and the prescription of AADs at discharge remained independent variables associated with AF recurrence, with HRs of 1.05, 1.03, and 2.56, respectively (P<0.001 for all).

Table 3.

Cox Regression Analysis for Predictors of AF Recurrence 1-Year After Catheter Ablation

	Univariate		Multivariate
	HR (95% CI)	P value	HR (95% CI)	P value
Model 1
RA-CS interval time (per 1-ms increase)	1.05 (1.04–1.06)	<0.001	1.06 (1.04–1.07)	<0.001
Age	1.02 (0.99–1.04)	0.27
Female sex	1.19 (0.64–2.19)	0.59
BMI	0.99 (0.92–1.07)	0.78
Non-PAF	2.42 (1.28–4.57)	0.006	–	0.116
Hypertension	0.66 (0.36–1.19)	0.17
Diabetes	0.93 (0.43–2.00)	0.85
Chronic heart failure	1.49 (0.81–2.71)	0.20
Previous stroke/TIA	1.08 (0.39–3.01)	0.89
Vascular disease	0.65 (0.20–2.10)	0.47
CHADS2 score	1.02 (0.80–1.30)	0.88
CHADS2DS2-VASc score	1.10 (1.02–1.18)	0.01	–	0.643
AADs	2.70 (1.36–5.33)	0.004	3.12 (1.53–6.35)	<0.001
LA diameter (per 1-mm increase)	1.03 (0.99–1.08)	0.13
LAVI (per 1-mL/m2 increase)	1.01 (1.00–1.03)	0.13
LVEF (per 1% increase)	1.00 (0.97–1.03)	0.85
eGFR	1.00 (0.98–1.01)	0.64
Hemoglobin	1.07 (0.91–1.27)	0.42
BNP	1.00 (1.00–1.00)	0.97
Ablation procedure (PVI plus PWI)	5.25 (2.07–13.33)	<0.001	–	0.172
Model 2
RA-CS interval time (per 1-ms increase)	1.05 (1.04–1.06)	<0.001	1.05 (1.03–1.07)	<0.001
P wave duration (per 1-ms increase)	1.06 (1.04–1.72)	<0.001	1.03 (1.02–1.05)	<0.001
Age	1.02 (0.99–1.04)	0.27
Female sex	1.19 (0.64–2.19)	0.59
BMI	0.99 (0.92–1.07)	0.78
Non-PAF	2.42 (1.28–4.57)	0.006	–	0.071
Hypertension	0.66 (0.36–1.19)	0.17
Diabetes	0.93 (0.43–2.00)	0.85
Chronic heart failure	1.49 (0.81–2.71)	0.20
Previous stroke/TIA	1.08 (0.39–3.01)	0.89
Vascular disease	0.65 (0.20–2.10)	0.47
CHADS2 score	1.02 (0.80–1.30)	0.88
CHADS2DS2-VASc score	1.10 (1.02–1.18)	0.01	–	0.637
AADs	2.70 (1.36–5.33)	0.004	2.56 (1.27–5.18)	<0.001
LA diameter (per 1-mm increase)	1.03 (0.99–1.08)	0.13
LAVI (per 1-mL/m2 increase)	1.01(1.00–1.03)	0.13
LVEF (per 1% increase)	1.00 (0.97–1.03)	0.85
eGFR	1.00 (0.98–1.01)	0.64
Hemoglobin	1.07 (0.91–1.27)	0.42
BNP	1.00 (1.00–1.00)	0.97
Ablation procedure (PVI plus PWI)	5.25 (2.07–13.33)	<0.001	–	0.172

Univariate Cox regression and stepwise multivariate Cox regression analyses were performed. CI, confidence interval; HR, hazard ratio. Other abbreviations as in Tables 1,2.

ROC curve analyses were performed to evaluate the discriminative performance of these variables in predicting postablation AF recurrence after catheter ablation (Figure 3). The areas under the ROC curve for the RA-CS interval time and P wave duration were 0.845 (95% CI 0.785–0.905) and 0.741 (95% CI 0.649–0.832), respectively. Although the RA-CS interval time showed higher diagnostic accuracy than P wave duration for postablation AF recurrence, the difference was not statistically significant (P=0.067) when examined by DeLong’s test. An RA-CS interval of 111 ms exhibited the best combined sensitivity and specificity (78.8% and 79.5%, respectively). Patient characteristics according to an RA-CS interval time <111 and ≥111 ms are presented in the Supplementary Table. The best combined sensitivity and specificity was seen for a P wave duration of 116 ms (81.4% and 62.8%, respectively). To further illustrate the impact of the RA-CS interval on AF recurrence, Kaplan-Meier curves were constructed for freedom from recurrence after catheter ablation according to the RA-CS interval (Figure 4). Kaplan-Meier analysis demonstrated a lower rate of freedom from AF recurrence in patients with an RA-CS interval <111 ms compared with those with an RA-CS interval ≥111 ms (log-rank P<0.001).

Figure 3.

Receiver operating characteristic (ROC) curve analyses of the right atrium (RA)-coronary sinus (CS) interval time and P wave duration according to postablation recurrence of atrial fibrillation during follow-up. AUC, area under the curve; CI, confidence interval.

Figure 4.

Kaplan-Meier curves for freedom from postablation recurrence of atrial fibrillation after catheter ablation according to a cut-off value of 111 ms for the right atrium (RA)-coronary sinus (CS) interval time.

Correlation Between RA-CS Interval Time, LA Diameter, and P Wave Duration

As shown in Figure 5A, there were weak positive correlations between RA-CS interval time and LA diameter (r=0.31; P<0.001) or LAVI (r=0.284; P<0.001), indicating a weak positive correlation between electrical and structural remodeling of the atrium. Figure 5B shows weak positive correlations between the RA-CS interval time and P wave duration on ECG (r=0.258; P<0.001).

Figure 5.

(A) Correlation between the right atrium (RA)-coronary sinus (CS) interval time and left atrial (LA) diameter, and LA volume index (LAVI). (B) Correlation between the RA-CS interval time and P wave duration. The box plots adjacent to the x- and y-axes show the interquartile range, with median values indicated by the horizontal/vertical lines in the boxes; whiskers show the range.

We divided patients into different groups based on ablation procedure, namely PVI alone (42 cases), PVI plus PWI (51 cases), PVI plus SVC isolation (47 cases), PVI plus CTI linear ablation (44 cases), PVI plus mitral isthmus linear ablation (0 cases), and PVI plus ≥2 additional ablation procedures (257 cases). In most cases, PVI plus ≥2 additional ablation procedures was performed. As shown in the Supplementary Figure, there was a significant difference in the RA-CS interval time among groups (ANOVA P<0.001; PVI alone, 92.9±16.7 ms; PVI plus PWI, 102.7±20.2 ms; PVI plus SVC isolation, 94.4±15.1 ms; PVI plus CTI linear ablation, 93.2±19.5 ms; PVI plus ≥2 additional ablation procedures, 104.4±18.9 ms). Patients who underwent PVI plus ≥2 additional ablation procedures had a longer RA-CS interval time than those who underwent PVI alone, PVI plus SVC isolation, or PVI plus CTI linear ablation (P<0.05; Supplementary Figure).

Discussion

In this large cohort of patients, in whom conduction time and procedural outcomes were tracked and analyzed in detail, we found that the RA-CS interval time was significantly longer in the group with than without AF recurrence within the first year after catheter ablation. Patients with an RA-CS interval ≥111 ms had a higher risk of postablation AF recurrence. This study is the first to demonstrate that atrial conduction time, measured using unique EPS findings (i.e., “earliest” RA potential and “latest” CS potential) is associated with the recurrence of AF after ablation.

Association Between Atrial Conduction Time and AF Recurrence

Intzes et al. reported that P wave duration predicted AF recurrence.¹³ Interatrial block was defined as a P wave duration ≥120 ms on ECG. Atrial conduction delay leads to atrial remodeling and can manifest without LA enlargement as AF substrate. In the present study, multivariate Cox regression analysis showed that both the RA-CS interval time and P wave duration were significantly associated with AF recurrence after catheter ablation (HR 1.05 [95% CI 1.04–1.07; P<0.001] and 1.04 [95% CI 1.02–1.05; P<0.001], respectively). In ROC curve analysis, the areas under the ROC curves for the RA-CS interval time and P wave duration were 0.845 (95% CI 0.785–0.905) and 0.741 (95% CI 0.649–0.832), respectively. Therefore, the RA-CS interval time exhibited higher diagnostic accuracy for AF recurrence than P wave duration. In addition, there were only weak positive correlations between the RA-CS interval time and P wave duration (r=0.258; P<0.001).

Unlike the measurement of QRS duration, accurately measuring P wave duration can sometimes be challenging because the waveform exhibits gradual rises and falls, and the height of the P wave is sometimes low. Previous studies often used a cut-off value of ≥120 ms for P wave duration, suggesting the progression of an interatrial block.¹³ However, the optimal cut-off values for predicting AF recurrence may differ. Therefore, we propose that the RA-CS interval time is a more sensitive and accurate marker for predicting AF recurrence; furthermore, the procedure for measuring the RA-CS interval time is simple.

Higuchi et al. previously reported that, in EPS, the atrial conduction time, defined as the interval from the earliest onset of the P wave on the ECG to the latest activation in the CS, was significantly associated with AF recurrence in 113 patients with persistent AF.¹⁶ The present study confirms the results of Higuchi et al. and extends the findings to include not only non-PAF patients but also PAF patients, incorporating a larger patient population and ablation procedures such as PWI and CTI linear ablation. We used only EPS findings, not ECG findings, for the new index of atrial conduction time, which improved simplicity and strengthened accuracy.

In our study, the CS activation sequence pattern among 441 patients was found to be proximal to distal in 245 patients, distal to proximal in 38 patients, and for the latest CS activation to occur in the middle of the CS in 158 patients. The 158 cases with the latest CS activation in the middle of the CS appear to reflect more accurate total atrial conduction times. The RA-CS interval time did not appear to be significantly affected by the position of the BeeAT catheter in our small sample.

Intriguingly, our multivariate analysis revealed that the RA-CS interval time and P wave duration were both independent factors associated with AF recurrence. There are other ways of measuring atrial conduction time by mapping both atria. Mapping the LA and RA during sinus rhythm provides a more accurate assessment of the total atrial conduction time, although it is time-consuming. CS potentials, which are easily obtained from the catheter in the CS during ablation, are often used as indicators of the endocardial potentials of the LA; however, the RA-CS time and P wave duration may not always coincide because the CS is anatomically located on the epicardial side. This discrepancy between the RA-CS interval time and P wave duration is supported by the results of our statistical analyses.

Effect of Atrial Size on Clinical Outcomes

Previous studies have reported that LA size is an important predictor of AF recurrence.^2,3 We speculate that LA size may be a useful predictor of AF recurrence in patients with atrial enlargement. In our study, a statistically significant association was observed between LA size and recurrence. Kranert et al. reported that an LAVI >36 mL/m² could be an independent predictor of AF recurrence.¹⁷ The LAVI in our study was 41.0 mL/m², larger than that in the previous study. We speculate that the LAVI may also be a useful predictor of AF recurrence in patients with progressive LA enlargement.

Association Between Electrical and Structural Remodeling in AF

The LA remodeling process is associated with electrical remodeling. Delayed conduction is a requirement for the initiation of re-entry and the development of AF.¹⁸ den Uijl et al. reported that assessing total atrial conduction time using tissue Doppler imaging can predict AF recurrence after RF catheter ablation with greater accuracy than using maximum LAVI.¹⁹ In addition, the low-voltage zone is not sufficiently associated with LA dimensions or LA surface area.^20,21

We observed weak positive correlations between the RA-CS interval time and parameters of LA volume, such as LA diameter (r=0.31; P<0.001) and LAVI (r=0.284; P<0.001). Our results showed that atrial conduction time is not necessarily related to atrial volume. Therefore, we speculate that electrical and structural remodeling may not be correlated in patients with AF.

Ablation Procedure in AF

PVI is an established strategy for AF ablation. Additional benefits of PVI plus PWI in non-PAF have been reported.²² Song et al. reported that PVI plus PWI significantly increased atrial tachyarrhythmia-free survival compared with PVI alone in patients with persistent AF.²³ Matsunaga-Lee et al. reported that patients with AF and no PV-specific AF trigger benefited from substrate ablation.²⁴ At Mie University Hospital, PVI plus PWI is often performed, especially in patients with non-PAF. However, in the present study, PVI plus PWI was performed more frequently in the recurrence group, suggesting that this combined approach is unlikely to have contributed to a reduction in AF recurrence.

Long-Term Recurrence-Free Outcome

Previous studies have identified some predictors of the long-term outcomes of RF catheter ablation for AF, such as LA size and AF duration. However, the preoperative predictors of recurrence have been inconsistent across studies. In the present study, the rate of sinus rhythm maintenance was approximately 90%, showing a lower recurrence rate of 10% compared with previous studies. This lower recurrence rate may be related to our exclusion of patient groups with presumably higher recurrence rates (e.g., those with open-heart surgery, hemodialysis, cardiovascular implantable electronic devices, severe valvular disease, difficult-to-record intracardiac potential due to low voltage area). The shorter follow-up period of 1 year, fewer outpatient follow-ups, and the inclusion of PAF patients, who comprised approximately half our study population, could be also related to discrepancies in results between the present study and a previous study.¹⁵ In the present study, the prescription of AADs at discharge during the blanking period may not have reduced AF recurrence after the blanking period.

Clinical Relevance

We propose new RA-CS interval-guided approaches to ablation strategies, in which the induction of tachycardia using high doses of isoproterenol or adenosine and additional ablation procedures such as PWI, SVC isolation, CTI linear ablation, mitral isthmus linear ablation, and non-PV foci ablation are warranted if the RA-CS interval time exceeds 111 ms. Moreover, we propose new postoperative AF management strategies, in which longer use of AADs beyond the blanking period, shorter intervals between outpatient clinic visits, extension of the follow-up period, and incorporation of continuous monitoring (detailed follow-up) are necessary if the RA-CS interval time exceeds 111 ms.

Study Limitations

This study has some limitations. First, this was a retrospective single-center study. Further studies, including larger multicenter studies with longer follow-up periods, are needed to strengthen external validity and clarify the impact of variations in ablation strategy. Second, the relatively short follow-up period of 1 year in this study, coupled with a reliance on systematic ECG and intermittent 24-h Holter monitoring, raises the possibility that some asymptomatic recurrences could have been missed. Therefore, extending the follow-up period or incorporating continuous monitoring may capture more robust data on late recurrence. Third, the exclusion criteria (e.g., excluding patients with open-heart surgery, dialysis, or implantable devices) may limit the generalizability of the findings. Further studies are needed to verify the generalizability of the results, either by reducing the exclusion criteria or by including a more diverse patient population. Fourth, the atrial conduction time may be slightly affected by heart rate and sedation. We measured the RA-CS interval without isoproterenol or adenosine; however, all patients were deeply sedated. Fifth, although 3-dimensional mapping of the LA and RA during sinus rhythm provides a more accurate assessment of the total atrial conduction time, this procedure is time-consuming and is not generally performed during the first AF ablation procedure. Sixth, the distance from RA sites to the CS varied between patients. Atrial size or catheter position may have affected RA and CS sequence patterns. Therefore, we used the “earliest” RA potential and “latest” CS potential to simplify the measurement of atrial conduction time and minimize biases, because these potentials are largely unaffected by atrial size and catheter position. Seventh, the complex ablation procedure itself may prolong the RA-CS interval and postablation AF recurrence. In this retrospective study, non-PAF patients underwent ablation procedures such as PVI or PVI plus PWI during AF rhythm, followed by cardioversion. Therefore, it was impossible to measure the RA-CS interval before the ablation procedure in all patients. Eighth, this new parameter, the RA-CS interval, is highly dependent on the RA-CS catheter (e.g., BeeAT catheter). The BeeAT catheter is used mainly in Japan, and not in the US or Europe. Ninth, atrial reverse remodeling in patients who underwent ablation may influence AF recurrence despite the long RA-CS interval times measured immediately after AF ablation. Moreover, atrial reverse remodeling may also shorten the RA-CS interval time, but the RA-CS interval time was only measured during the ablation procedure.

Conclusions

The RA-CS interval time is an independent predictor of postablation AF recurrence within the first year following catheter ablation. It may serve as a useful and straightforward predictor for identifying patients at risk of AF recurrence even in the era of high-density 3-dimensional mapping.

Sources of Funding

This study did not receive any specific funding. These funders played no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the article.

Disclosures

K.D. reports research grants from Bristol-Myers Squibb, MSD K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo Pharmaceutical Co., Ltd., Genzyme Japan, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Corporation, Otsuka Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., AstraZeneca K.K., and Boehringer Ingelheim Co., Ltd. The remaining authors have no disclosures to report. These grants did not contribute to the present study.

IRB Information

This study complied with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Mie University Graduate School of Medicine (Reference no. 3038).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-1009

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