Prognostic Importance of B-Type Natriuretic Peptide Level in Patients Undergoing Catheter Ablation for Atrial Fibrillation

Tetsuma Kawaji; Satoshi Shizuta; Takanori Aizawa; Shushi Nishiwaki; Takashi Yoshizawa; Suguru Nishiuchi; Masashi Kato; Takafumi Yokomatsu; Shinji Miki; for the TRANQUILIZE AF Registry Investigators

doi:10.1253/circj.CJ-23-0263

Abstract

Background: This study assessed the prognostic importance of B-type natriuretic peptide (BNP) concentrations for clinical events after catheter ablation for atrial fibrillation (AF).

Methods and Results: We enrolled 1,750 consecutive patients undergoing initial AF ablation whose baseline BNP data were available from a large-scale multicenter observational cohort (TRANQUILIZE-AF Registry). The prognostic impact of BNP concentration on clinical outcomes, including recurrent tachyarrhythmias and a composite of heart failure (HF) hospitalization or cardiac death, was evaluated. Median baseline BNP was 94.2 pg/mL. During a median follow-up of 2.4 years, low BNP (<38.3 pg/mL) was associated with lower rates of recurrent atrial tachyarrhythmias than BNP concentrations ≥38.3 pg/mL (19.9% vs. 30.6% at 3 years; P<0.001) and HF (0.8% vs. 5.3% at 3 years; P<0.001). Multivariable Cox regression analyses revealed that low BNP was independently associated with lower risks of arrhythmia recurrence (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.47–0.82; P<0.001) and HF (HR 0.17; 95% CI 0.04–0.71; P=0.002). The favorable impact of low BNP on arrhythmia recurrence was prominent in patients with paroxysmal, but not non-paroxysmal, AF, particularly among those with long-standing AF.

Conclusions: Low BNP concentrations had a favorable impact on clinical outcomes after AF ablation. The heterogeneous impact of baseline BNP concentrations on arrhythmia recurrence for the subgroups of patients divided by AF type warrants future larger studies with longer follow-up periods.

Both atrial fibrillation (AF) and heart failure (HF) are common diseases that increase with age, with each disease predisposing to the other.¹^,² B-Type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are natriuretic peptide hormones secreted by cardiac myocytes in response to wall stress that are used as biomarkers of HF.³ High BNP and NT-proBNP concentrations are also associated with clinical adverse events in AF patients.⁴^–⁶

Catheter ablation is a popular treatment strategy for AF complicated by HF, which improves HF status and reduces BNP concentrations by eliminating AF.⁷^–⁹ However, there is a considerable risk of refractory AF to the ablation procedure.¹⁰ Several small studies have reported that high baseline BNP concentrations before ablation are associated with a higher rate of AF recurrence.¹¹^–¹⁴ However, the association between baseline BNP concentration and clinical outcomes after ablation has not been fully evaluated in large cohort studies. Furthermore, data regarding the clinical impact of follow-up BNP concentrations are scarce. Here, we investigated the significance of serum BNP concentrations as a prognostic risk factor for subsequent clinical events after the procedure, including AF recurrence and HF events, from a large-scale multicenter observational study.

Methods

Study Population

We conducted a large-scale multicenter retrospective observational study, named the Transcatheter Radiofrequency And ballooN ablation to improve QUalIty of Life in generaliZEd Atrial Fibrillation patients (TRANQUILIZE-AF) Registry. Patients were recruited from Kyoto University Hospital and its 3 affiliated hospitals between April 2017 and December 2020. In all, 1,780 consecutive patients undergoing first-time catheter ablation for AF were enrolled. In the present study, we analyzed 1,750 patients (98.3%) whose baseline serum BNP or NT-pro BNP concentrations before the index ablation procedure were available.

Ethical Considerations

Informed consent was obtained by the opt-out method. The study protocol was approved by the Institutional Review Board of Kyoto University Hospital, and each participating institution. The study protocol conformed to the guidelines of the 1975 Declaration of Helsinki.

Ablation Procedure and Postprocedural Management

Pulmonary vein isolation was performed by radiofrequency catheter or cryoballoon (Arctic Front; Medtronic, Minneapolis, MN, USA) under a 3-dimensional mapping system (CARTO [Biosense-Webster, Diamond Bar, CA, USA], Ensite NavX [Abbott, Chicago, IL, USA], Rhythmia [Boston Scientific, Natick, MA, USA]). Additional ablation strategies, such as cavotricuspid isthmus ablation, superior vena cava isolation, left atrial linear ablations, and other substrate ablation, were conducted at the discretion of the attending physician or the operator.

Antiarrhythmic drugs were discontinued before the ablation procedure, and were restarted only when recurrent atrial tachyarrhythmias were detected. A second procedure was recommended to patients who had recurrent atrial tachyarrhythmias after the blanking period of 3 months. A 12-lead electrocardiogram was routinely obtained at each clinic visit, and 24-h Holter monitoring was recommended at 3, 6, and 12 months, and yearly thereafter. It was recommended that BNP concentrations were reassessed 3 months after the ablation procedure. Follow-up information was obtained by review of hospital charts and/or contact with the patient, relatives, and/or referring physicians.

Definitions and Outcome Measures

AF was classified into paroxysmal (lasting <7 days), persistent (lasting between ≥7 days and <1 year), and long-standing (lasting ≥1 year). Recurrent atrial tachyarrhythmias were defined as documented AF and/or atrial tachycardia (AT) lasting for >30 s or those requiring repeat ablation procedures with a blanking period of 90 days after procedure.¹⁵ Early recurrence of AF (ERAF) was defined as documented AF/AT lasting for >30 s within the blanking period of 90 days. Serum BNP concentrations were measured just before the index ablation procedure. The decision to evaluate either or both serum BNP and NT-proBNP concentrations was left to the discretion of the attending physicians. In this study, NT-proBNP concentrations in patients whose BNP levels were not available were converted to BNP concentrations using the following conversion formula based on previous reports:¹⁶^,¹⁷

log₁₀(BNP) × 1.1 = log₁₀(NT-proBNP) − 0.570

Chronic kidney disease was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m².

The primary outcome measure was recurrent atrial tachyarrhythmias after the procedure. The secondary outcome measures were a composite HF endpoint, defined as a composite of HF hospitalization or cardiac death. In the main analysis, we evaluated the prognostic impact of baseline BNP concentrations on the cumulative incidences of the clinical outcomes during the follow-up period. In additional analyses, we also assessed the prognostic impact of follow-up BNP concentration at 3 months along with ERAF within the blanking period of 3 months, and improvement in BNP concentration of >50% from baseline to 3 months.

Statistical Analysis

Categorical variables are presented as numbers and percentages and were compared with the Chi-squared test or Fisher’s exact test. Continuous variables are presented as the mean ±SD or as the median with interquartile range (IQR), and were compared using Student’s t-test or the Wilcoxon rank-sum test based on their distribution. The cumulative incidence and event-free rates were estimated by the Kaplan-Meier method, and differences were assessed by the log-rank test.

Cox proportional hazard analysis was conducted to identify independent risk factors for clinical outcomes. Clinically relevant covariables included age, sex, body weight, AF duration, AF type, pre-existing HF, left ventricular ejection fraction, chronic kidney disease, and baseline and/or follow-up BNP concentrations. BNP concentrations were divided into quartiles (Q1–4) and all clinical outcomes were assessed between patients with low (Q1; <38.3 pg/mL) and high (Q2–4; ≥38.3 pg/mL) BNP concentrations. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented. We performed subgroup analyses stratified by clinical variables with P values for interaction in the Cox proportional hazard models to examine heterogeneity in the subgroups. Furthermore, we performed 2 sensitivity analyses to confirm the consistency of the study results. One sensitivity analysis excluded patients whose BNP concentration had been converted from a NT-proBNP concentration. The other divided patients using tertiles (T1–3) of baseline BNP concentrations, and compared T1 against T2 and T3.

Statistical analyses were performed using JMP Pro 14 (SAS Institute Inc., Cary, NC, USA) software. All analyses were 2-tailed, and P<0.05 was considered statistically significant.

Results

Baseline Characteristics

The distribution of baseline BNP and NT-proBNP concentrations, as well as BNP concentrations estimated by converting from NT-proBNP using the conversion formula, are shown in Supplementary Figure 1. The patterns of distribution were similar across the groups. The median for the combined BNP concentrations was 94.2 pg/mL (IQR 38.3–194.6 pg/mL). The quartile ranges for BNP were as follows: Q1, <38.3 pg/mL; Q2, ≥38.3 and <94.2 pg/mL; Q3, ≥94.2 and <194.6 pg/mL; and Q4, ≥194.6 pg/mL. Patients with the lowest BNP concentrations (Q1; <38.3 pg/mL) were significantly older and had a higher prevalence of paroxysmal AF, a lower prevalence of pre-existing HF, a lower CHA₂DS₂-VASc score, and more preserved cardiac function than patients with high BNP levels (Q2–4; ≥38.3 pg/mL; Table 1). Baseline BNP concentration was weakly inversely correlated with AF duration after perpetuation before procedure (R=0.10; P=0.009; Supplementary Figure 2).

Table 1. Baseline Characteristics in Patients With Low and High BNP Concentrations at Baseline

	Low BNP (Q1; <38.3 pg/mL; n=439)	High BNP (Q2–4; ≥38.3 pg/mL; n=1,311)	P value
Age (years)	64.1±11.6	71.3±9.0	<0.001
Age ≥75 years	77 (17.5)	518 (39.5)	<0.001
Female sex	120 (27.3)	445 (33.9)	0.01
Body weight (kg)	66.6±13.3	63.5±12.9	<0.001
<60 kg	143 (32.6)	520 (39.7)	0.008
Paroxysmal AF	401 (91.3)	616 (47.0)	<0.001
AF duration (years)	0.6 [0.2–3.2]	0.8 [0.3–3.2]	0.10
≥3 years	111 (26.9)	321 (26.1)	0.75
Hypertension	218 (50.0)	805 (61.4)	<0.001
Diabetes	58 (13.2)	220 (16.8)	0.07
Pre-existing heart failure	12 (2.7)	201 (15.3)	<0.001
Previous ischemic stroke	22 (5.0)	104 (7.9)	0.03
Chronic kidney disease	100 (22.8)	714 (54.5)	<0.001
CHA₂DS₂-VASc score	1.6±1.3	2.5±1.3	<0.001
Echocardiographic findings
LV diastolic diameter	45.3±4.9	45.8±6.5	0.18
LVEF	67.4±7.3	63.0±12.0	<0.001
LVEF <50%	7 (1.6)	169 (13.2)	<0.001
Left atrial diameter	37.1±6.0	41.1±7.5	<0.001
E/e′	9.5±3.9	12.2±7.3	<0.001
Medication
Oral anticoagulants	439 (100)	1,311 (100)	1.00
Warfarin	7 (1.6)	83 (6.3)	<0.001
Direct oral anticoagulants	432 (98.4)	1,228 (93.7)	<0.001
Antiplatelet agents	36 (8.2)	131 (10.0)	0.26
β-blockers	76 (17.3)	289 (22.0)	0.03
Digitalis	1 (0.2)	26 (2.0)	0.002
Non-dihydropyridine CCBs	32 (7.3)	103 (7.9)	0.70
Dihydropyridine CCBs	144 (32.8)	448 (34.2)	0.60
ACEI/ARB/ARNI	115 (26.2)	365 (27.8)	0.50
MRA	17 (3.9)	147 (11.2)	<0.001
Diuretic agents	25 (5.7)	278 (21.2)	<0.001
SGLT2 inhibitors	20 (4.6)	60 (4.6)	0.99
Statins	146 (33.3)	410 (31.3)	0.44

Categorical variables are presented as n (%). Continuous variables are presented as the mean±SD or median [interquartile range]. ACEI, angiotensin covering enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BNP, B-type natriuretic peptide; CCBs, calcium channel blockers; LV, left ventricle; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2, sodium-glucose cotransporter 2.

Recurrent Atrial Tachyarrhythmias

The median follow-up duration was 2.4 years (IQR 1.5–3.4 years). The cumulative incidence of recurrent atrial tachyarrhythmias after the procedure was 27.9% at 3 years (Figure 1A). The incidence was significantly lower in patients with low BNP (Q1) than in those with high BNP (Q2–4; 19.9% vs. 30.6% at 3 years; log-rank, P<0.001; Figure 1B). Even after adjusting for clinical confounders on multivariable analysis, low BNP level independently associated with lower rate of recurrent atrial tachyarrhythmias (HR 0.63; 95% CI 0.47–0.82; P<0.001; Table 2A). Adjusted HRs (95% CI) of Q2, Q3, and Q4 relative to Q1 in BNP level for recurrent atrial tachyarrhythmias were 1.46 (1.07–1.99), 1.80 (1.31–2.48), and 1.59 (1.12–2.26), respectively (Table 2C). Other independent risk factors for recurrent atrial tachyarrhythmias were AF duration ≥3 years and pre-existing HF. Lower risk for arrhythmia recurrence in patients with low BNP was consistent in all subgroups except for AF type (Figures 1C–E,2A).

Figure 1.

Cumulative incidence of clinical outcomes after ablation procedure according to B-type natriuretic peptide (BNP) concentration. (A) Recurrent atrial tachyarrhythmia and the composite heart failure endpoint in all study patients. (B) Recurrent atrial tachyarrhythmia according to BNP concentration. (C–E) Recurrent atrial tachyarrhythmia according to BNP concentration in patients with paroxysmal atrial fibrillation (AF; C), persistent AF (D), and long-standing AF (E). (F) Composite heart failure endpoint according to BNP concentration.

Table 2. Risk Factors for Clinical Outcomes After Ablation Procedure

(A) Recurrent atrial tachyarrhythmia
Variable	Univariate analysis			Multivariable analysis
Variable	HR	95% CI	P value	HR	95% CI	P value
Age ≥75 years	1.21	0.99–1.47	0.06	1.07	0.86–1.33	0.51
Female sex	1.10	0.90–1.33	0.37	1.06	0.84–1.34	0.61
Body weight <60 kg	1.08	0.89–1.31	0.46	1.00	0.80–1.26	0.99
AF duration ≥3 years	1.49	1.21–1.81	<0.001	1.50	1.22–1.85	<0.001
Paroxysmal AF	0.76	0.63–0.92	0.004	0.94	0.75–1.16	0.54
Diabetes	1.07	0.82–1.36	0.61	1.00	0.76–1.30	0.98
Pre-existing heart failure	1.51	1.16–1.93	0.003	1.36	1.01–1.82	0.046
Chronic kidney disease	1.12	0.93–1.35	0.24	0.94	0.76–1.16	0.54
LVEF <50%	1.09	0.79–1.46	0.60	0.83	0.58–1.15	0.27
Low baseline BNP^A	0.60	0.47–0.76	<0.001	0.63	0.47–0.82	<0.001
(B) Composite heart failure endpoint
Variable	Univariate analysis			Multivariable analysis
Variable	HR	95% CI	P value	HR	95% CI	P value
Age ≥75 years	2.49	1.49–4.18	<0.001	1.79	1.03–3.11	0.04
Female sex	0.93	0.52–1.60	0.80	0.87	0.46–1.66	0.67
Body weight <60 kg	1.08	0.89–1.31	0.39	1.06	0.58–1.91	0.85
AF duration ≥3 years	0.83	0.44–1.48	0.54	0.86	0.47–1.59	0.63
Paroxysmal AF	1.15	0.68–1.98	0.61	2.09	1.20–3.66	0.009
Diabetes	2.76	1.58–4.69	<0.001	1.81	1.02–3.19	0.048
Pre-existing heart failure	5.44	3.19–9.14	<0.001	2.20	1.18–4.09	0.014
Chronic kidney disease	2.66	1.53–4.65	<0.001	1.37	0.75–2.48	0.30
LVEF <50%	6.33	3.68–10.7	<0.001	3.67	1.97–6.84	<0.001
Low baseline BNP^A	0.10	0.02–0.33	<0.001	0.17	0.04–0.71	0.002
(C) Adjusted risks of baseline BNP levels for clinical outcomes
Variable	Recurrent atrial tachyarrhythmia			Composite heart failure endpoint
Variable	HR	95% CI	P value	HR	95% CI	P value
Q1 (<38.3 pg/mL; reference)	1.00	–	–	1.00	–	–
Q2 (≥38.3, <94.2 pg/mL)	1.46	1.07–1.99	0.02	5.10	1.12–23.2	0.01
Q3 (≥94.2, <194.6 pg/mL)	1.80	1.31–2.48	<0.001	5.13	1.10–23.8	0.02
Q4 (≥194.6 pg/mL)	1.59	1.12–2.26	0.009	10.3	2.26–47.0	<0.001

^ALow baseline BNP refers to the first quartile (Q1; <38.3 pg/mL). CI, confidence interval; HR, hazard ratio; Q, quartile. Other abbreviations as in Table 1.

Figure 2.

Subgroup analysis for clinical outcomes. AF, atrial fibrillation; BNP, B-type natriuretic peptide; CI, confidence interval; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction.

Composite HF Endpoint

The cumulative incidence of the composite HF endpoint after the procedure was only 4.2% at 3 years (Figure 1A). The incidence of the composite HF endpoint was significantly lower in patients with low BNP (Q1) than in those with high BNP (Q2–4; 0.8% vs. 5.3% at 3 years; log-rank, P<0.001; Figure 1F). Even after adjusting for clinical confounders in the multivariable analysis, low BNP was independently associated with lower risk for the composite HF endpoint (HR 0.17; 95% CI 0.04–0.71; P=0.002; Table 2B). Across BNP quartiles, adjusted HRs (95% CI) for Q2, Q3, and Q4 relative to Q1 for the composite HF endpoint were 5.10 (1.12–23.2), 5.13 (1.10–23.8), and 1.59 (2.26–47.0), respectively (Table 2C). Other independent risk factors for the composite HF endpoint were age ≥75 years, paroxysmal AF, diabetes, pre-existing HF, and left ventricular ejection fraction <50%. The results were consistent in all subgroups, except for AF duration (Figure 2B).

Sensitivity Analyses

Among 1,750 study patients, baseline BNP data was available for 1,375 (78.6%). For the remaining 375 patients, only NT-pro BNP was available, which was converted to BNP using the calculation formula. The cumulative incidence of recurrent atrial tachyarrhythmias after the procedure was comparable between patients with and without baseline BNP data (27.5% vs. 28.9% at 3 years, respectively; P=0.72), although the cumulative incidence of the composite HF endpoint was significantly lower in patients with than without baseline BNP data (3.0% vs. 7.5% at 3 years; P<0.001; Supplementary Figure 3). Even after excluding the 375 patients with NT-proBNP data only from the analysis, the results were consistent with the original results (Supplementary Figure 4). The cumulative incidence of recurrent atrial tachyarrhythmias was significantly lower in patients with low BNP (Q1) than in those with high BNP (Q2–4). In addition, the favorable impact of low BNP on arrhythmia recurrence was attenuated in patients with non-paroxysmal AF, particularly those with long-standing AF.

Even when patients were divided into BNP tertiles, patients with low BNP (T1) had lower incidence rates of arrhythmia recurrence and HF than those with high BNP (T2 and T3; Supplementary Figure 5). Similar to the original analysis, the favorable impact of low BNP on arrhythmia recurrence was attenuated in patients with non-paroxysmal AF, especially those with long-standing AF.

Follow-up BNP Concentration 3 Months After the Ablation Procedure

The follow-up BNP concentration at 3 months after procedure was available for 1,258 (71.9%) patients. Among these patients, BNP decreased significantly at 3 months (from a median of 103.4 [IQR 41.8–207.9] to 48.9 [IQR 21.3–108.1] pg/mL; P<0.001; Figure 3A). The improvement in BNP concentration was consistently observed in all subgroups (Supplementary Figure 6). The cumulative incidence of subsequent recurrent atrial tachyarrhythmias was significantly lower in patients with low follow-up BNP (Q1; <21.3 pg/mL) than in those with high follow-up BNP (Q2–4; ≥21.3 pg/mL; 17.0% vs. 35.1%, respectively, at 3 years; log-rank, P<0.001; Figure 3B). Less arrhythmia recurrence in patients with a low follow-up BNP concentration was consistent in all subgroups (Supplementary Figure 7). Even after adjusting for clinical confounders in the multivariable analysis, both low baseline and follow-up BNP concentrations were associated with lower risk for arrhythmia recurrence (HR 0.64 [95% CI 0.46–0.90; P=0.009] and 0.68 [95% CI 0.47–0.96; P=0.02], respectively; Table 3A). Adjusted HRs (95% CIs) for follow-up BNP Q2 (≥21.3 and <49.2 pg/mL), Q3 (≥49.2 and <108.1 pg/mL), and Q4 (≥108.1 pg/mL) relative to Q1 for arrhythmia recurrence were 1.34 (0.91–0.13), 1.65 (1.09–2.52), and 2.71 (1.72–4.27), respectively (Table 3C). Other independent risk factors were AF duration ≥3 years, paroxysmal AF, improvement in BNP concentration ≥50%, and ERAF within the blanking period of 3 months.

Figure 3.

Follow-up B-type natriuretic peptide (BNP) concentrations and clinical outcomes after the procedure. (A) Changes in BNP concentrations 3 months after the ablation procedure. (B,C) Incidence of recurrent atrial tachyarrhythmias (B) and the composite heart failure endpoint (C) according to follow-up BNP concentrations.

Table 3. Risk Factors for Clinical Outcomes After Ablation Procedure Including Clinical Parameters at 3 Months

(A) Recurrent atrial tachyarrhythmia
Variables	Univariate analysis			Multivariable analysis
Variables	HR	95% CI	P value	HR	95% CI	P value
Age ≥75 years	1.20	0.97–1.49	0.10	0.97	0.77–1.22	0.79
Female sex	1.14	0.92–1.42	0.24	0.99	0.78–1.28	0.99
Body weight <60 kg	1.03	0.83–1.28	0.77	0.89	0.70–1.14	0.35
AF duration ≥3 years	1.65	1.32–2.05	<0.001	1.49	1.19–1.87	<0.001
Paroxysmal AF	0.74	0.60–0.91	0.005	0.76	0.60–0.97	0.03
Diabetes	1.04	0.78–1.38	0.78	0.94	0.70–1.27	0.70
Pre-existing heart failure	1.49	1.13–1.94	0.006	1.35	0.97–1.86	0.08
Chronic kidney disease	1.19	0.97–1.47	0.10	0.92	0.72–1.16	0.47
LVEF <50%	1.06	0.75–1.45	0.74	0.71	0.59–1.04	0.07
Low baseline BNP^A	0.58	0.44–0.77	<0.001	0.64	0.46–0.90	0.009
Low follow-up BNP^B	0.42	0.31–0.56	<0.001	0.68	0.47–0.96	0.02
Improvement in BNP >50%	0.55	0.44–0.69	0.03	0.49	0.37–0.65	<0.001
Early recurrence	4.27	3.46–5.27	<0.001	3.79	3.04–4.72	<0.001
(B) Composite heart failure endpoint
Variables	Univariate analysis			Multivariable analysis
Variables	HR	95% CI	P value	HR	95% CI	P value
Age ≥75 years	2.66	1.52–4.67	<0.001	1.81	0.99–3.32	0.05
Female sex	1.03	0.56–1.82	0.92	0.98	0.48–1.96	0.95
Body weight <60 kg	1.25	0.71–2.19	0.43	0.99	0.52–1.91	0.98
AF duration ≥3 years	0.86	0.44–1.58	0.64	0.90	0.47–1.72	0.75
Paroxysmal AF	1.26	0.72–2.27	0.42	1.76	0.95–3.28	0.07
Diabetes	2.78	1.52–4.93	0.001	1.56	0.83–2.92	0.18
Pre-existing heart failure	5.75	3.27–10.0	<0.001	2.56	1.27–5.15	0.009
Chronic kidney disease	2.73	1.51–5.23	<0.001	1.24	0.63–2.44	0.53
LVEF <50%	5.46	3.02–9.63	<0.001	2.68	1.31–5.46	0.008
Low baseline BNP^A	0.60	0.47–0.76	<0.001	0.17	0.04–0.80	0.007
Low follow-up BNP^B	0.28	0.11–0.71	0.007	1.24	0.40–3.96	0.70
Improvement in BNP >50%	0.43	0.22–0.79	0.006	0.46	0.21–1.00	0.04
Early recurrence	1.57	0.85–2.78	0.14	1.44	0.79–2.62	0.24
(C) Adjusted risks of BNP levels for clinical outcomes
Variables	Recurrent atrial tachyarrhythmia			Composite heart failure endpoint
Variables	HR	95% CI	P value	HR	95% CI	P value
Q1 (<21.3 pg/mL; reference)	1.00	–	–	1.00	–	–
Q2 (≥21.3, <49.2 pg/mL)	1.34	0.91–1.96	0.13	–	–	0.007
Q3 (≥49.2, <108.0 pg/mL)	1.65	1.09–2.52	0.02	0.70	0.17–2.85	0.62
Q4 (≥108.1 pg/mL)	2.71	1.72–4.27	<0.001	3.52	0.96–12.9	0.048

^ALow baseline BNP refers to the first quartile (Q1; <38.3 pg/mL). ^BLow follow-up BNP refers to Q1 (<21.3 pg/mL). Other abbreviations as in Tables 1,2.

The cumulative incidence of the composite HF endpoint was significantly lower in patients with low (Q1) vs. high (Q2–4) follow-up BNP (1.9% vs. 5.7%, respectively, at 3 years; log-rank, P=0.004; Figure 3C). Fewer HF events in patients with low follow-up BNP was consistent in all subgroups, except for AF duration (Supplementary Figure 8). After adjusting for clinical confounders in the multivariable analysis, only baseline, and not follow-up, BNP concentration was associated with fewer composite HF endpoints (adjusted HR 0.17; 95% CI 0.04–0.80; P=0.007; Table 3B).

Discussion

The main findings of the present study were as follows: (1) a low baseline BNP concentration was independently associated with lower risks for recurrent tachyarrhythmias and the composite HF endpoint; (2) the favorable impact of low BNP on arrhythmia recurrence was prominent in patients with paroxysmal AF, but was attenuated in those with non-paroxysmal AF, especially long-standing AF; (3) BNP was significantly decreased 3 months after the procedure; and (4) a low follow-up BNP concentration was also independently associated with a lower risk for arrhythmia recurrence, but not with a lower risk of the composite HF endpoint.

BNP is known as a prognostic biomarker for cardiovascular events in AF patients. Regarding the association between baseline BNP concentration and arrhythmia recurrence after AF ablation, in a single-center study with 53 patients, Date et al reported that baseline BNP was significantly higher in those with than without AF recurrence.¹¹ Although the difference in baseline BNP concentrations among patients with and without AF recurrence was heterogeneous in previous small studies,¹¹^,¹²^,¹⁸^,¹⁹ meta-analyses of those studies showed significantly higher baseline BNP concentrations in patients with AF recurrence.²⁰^,²¹ Furthermore, Miake et al reported that baseline BNP was independently associated with AF recurrence even after adjustment for clinical confounders in 245 patients undergoing AF ablation.¹⁴ In the present study, we demonstrated that low baseline BNP is independently associated with less recurrence of atrial tachyarrhythmias after AF ablation in a large-scale multicenter cohort. The favorable impact of low baseline BNP on arrhythmia recurrence was consistent in most subgroups, except for those divided by AF type. It was significant in patients with paroxysmal AF, and a similar trend was observed in patients with persistent AF. However, in patients with long-standing AF, low baseline BNP was associated with a numerically higher rate of arrhythmia recurrence. Possible explanations for this heterogeneity include different baseline characteristics among the groups and the relatively small number of patients in long-standing AF group.

In the present study, significant improvement in BNP concentrations was observed 3 months after the ablation procedure. Low follow-up BNP and an improvement in the BNP concentration of >50% were significantly associated with a lower risk for subsequent arrhythmia recurrence, which is in accordance with previous studies.²² The favorable impact of low follow-up BNP on arrhythmia recurrence was consistent in all subgroups. Unlike baseline BNP, there was no significant attenuation of the favorable impact of low follow-up BNP in patients with non-paroxysmal AF. Although baseline and follow-up BNP concentrations are both independent risk factors for recurrent atrial tachyarrhythmias, baseline BNP is likely to be more useful for simply assessing the prognosis of patients before the ablation procedure. Furthermore, baseline BNP, but not follow-up BNP, was an independent predictor of the composite HF endpoint.

Study Limitations

This study has several limitations. First, there may have been some selection bias in the study, although baseline BNP or NT-proBNP concentration was available for 1,750 of 1,780 consecutive patients (98.3%). Second, in 375 patients (21.4%), the BNP concentration was obtained by converting the NT-proBNP concentration using the conversion formula. However, the sensitivity analysis excluding those with NT-proBNP data only showed consistent results with the original analysis (Supplementary Figure 4). Third, we did not set the best cut-off values for BNP using receiver operating characteristic curves because the areas under curves were low and varied in patient subgroups (data not shown). However, the sensitivity analysis dividing patients using BNP tertiles showed consistent results with the original analysis (Supplementary Figure 5). Fourth, follow-up BNP concentrations after the procedure were not available for all patients. Finally, the multivariable analyses may not have sufficiently eliminated the influence of unmeasured confounders on determining the independent predictors of clinical outcomes after AF ablation.

Conclusions

Baseline BNP was an independent prognostic marker for both recurrent atrial tachyarrhythmias and HF events after AF ablation. The BNP concentration improved significantly 3 months after the procedure. The follow-up BNP concentration was also an independent risk factor for arrhythmia recurrence, but not for HF events. The heterogeneous effect of baseline BNP on arrhythmia recurrence in subgroups of patients divided by AF type should be evaluated in future larger studies with a longer follow-up period.

Acknowledgment

The authors thank the TRANQUILIZE-AF Registry Investigators for their contribution to this study.

Conflicts of Interest

None.

Sources of Funding

The TRANQUILIZE-AF Registry is supported by research funding from Boston Scientific, Biosense Webster Inc., Medtronic, and Japan Lifeline. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Disclosures

All authors report that they have no relationships relevant to the content of this paper to disclose.

IRB Information

This study was approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee (Reference no. R2618).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0263

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