Integrating pre-ablation and post-ablation B-type natriuretic peptide to identify high-risk population for long-term adverse events and arrhythmic recurrence in persistent atrial fibrillation

Abstract

Background

Pre-procedural and post-procedural plasma B-type natriuretic peptide (BNP) levels can predict rhythm outcomes after catheter ablation for atrial fibrillation (AF). However, the significance of long-term events remains unclear. Therefore, this study aimed to investigate the significance of integrating pre-ablation and post-ablation BNP levels on major adverse cardiovascular events (MACE) and arrhythmic recurrence in patients with persistent AF undergoing catheter ablation.

Methods

We analysed 392 patients who underwent first catheter ablation. Patients were stratified into four subgroups based on pre-ablation plasma BNP level and its relative change after ablation (ΔBNP) using their respective median values (pre-ablation BNP: 148.0 pg/mL, ΔBNP: −52.6%): Low-Low (pre-ablation<148.0 pg/mL, ΔBNP<−52.6%), Low-High (pre-ablation<148.0 pg/mL, ΔBNP≥−52.6%), High-Low (pre-ablation≥148.0 pg/mL, ΔBNP<−52.6%) and High-High (pre-ablation≥148.0 pg/mL, ΔBNP≥−52.6%). The primary endpoint was MACE, which included all-cause death, heart failure hospitalisation and other cardiovascular hospitalisations. The secondary endpoint involved arrhythmic recurrence.

Results

Of the 392 patients, 101 were classified as Low-Low, 91 as Low-High, 97 as High-Low and 103 as High-High. During a median follow-up of 5.3 (IQR: 3.2–7.2) years, 63 patients (16%) experienced MACE. Heart failure hospitalisation accounted for the majority of events (63%). The High-High subgroup showed significantly higher MACE rates than others (cumulative incidence (95% CI): 26.3% (16.2% to 35.2%), p<0.001). Low-High and High-High subgroups demonstrated a higher arrhythmic recurrence (p<0.001). After multivariate adjustment, the High-Low and High-High subgroups demonstrated progressively higher risks of MACE incidence compared with the Low-Low and Low-High subgroups. Both Low-High and High-High subgroups showed an elevated arrhythmic recurrence risk (both p<0.001).

Conclusions

Integrating pre-ablation and post-ablation BNP levels can be useful for identifying patients with persistent AF at high risk of MACE and arrhythmic recurrence during long-term follow-up.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Plasma B-type natriuretic peptide (BNP) levels serve as established diagnostic and prognostic markers in heart failure (HF) management.

• In patients with atrial fibrillation (AF), BNP levels are elevated independently of HF status and remain valuable predictors of adverse outcomes.

• Pre-procedural BNP levels have demonstrated significant predictive value for rhythm outcomes following catheter ablation for AF.

• However, the significance of the pre-procedural and post-procedural BNP on long-term clinical events in patients with persistent AF, where plasma BNP levels can fluctuate markedly after the procedure due to rhythm changes, remains unclear.

WHAT THIS STUDY ADDS

• Integration of pre-ablation and post-ablation BNP measurements provides comprehensive risk stratification for both major adverse cardiovascular events (MACE) and arrhythmic recurrence during the long-term follow-up (over a median of 5.3 years) in persistent AF.

• Patients with persistently elevated BNP (High-High group; pre-ablation≥148.0 pg/mL or 908 pg/mL in NT-proBNP using the converting formula, and post-ablation change≥−52.6 %) face significantly higher risks of MACE over long-term follow-up.

• Lower pre-ablation BNP levels are associated with reduced MACE risk, independent of post-ablation values.

• Elevated post-ablation BNP levels correlate with increased risk of arrhythmic recurrence.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Measurement of pre-ablation and post-ablation BNP levels may help optimise risk stratification in patients with persistent AF.

• In patients with lower pre-ablation BNP levels, while MACE risk is not increased, smaller post-ablation BNP reduction may signal increased arrhythmic recurrence risk.

• Among patients with elevated pre-ablation BNP levels, a smaller post-ablation BNP reduction suggests high MACE risk, particularly for HF hospitalisation, while a greater post-ablation BNP reduction is associated with intermediate risk

• These results establish a foundation for personalised follow-up strategies based on BNP trajectory patterns.

Introduction

Atrial fibrillation (AF) frequently coexists with heart failure (HF).¹ The clinical management of HF with concurrent AF represents a critical therapeutic target due to its direct impact on patient prognosis.2,4 In contemporary clinical practice, catheter ablation has emerged as an effective therapeutic strategy for AF, yielding significant improvements in both exercise capacity and quality of life across the HF spectrum.⁵ Moreover, catheter ablation may potentially offer mortality benefits, particularly in patients with HF with a reduced ejection fraction.^{5 6}

B-type natriuretic peptide (BNP) is a cardiac neurohormone primarily secreted in response to myocardial wall stretch.⁷ BNP and N-terminal pro-BNP, which are derived from the same precursor molecule, accurately reflect the pathophysiological state of HF and their elevated plasma levels have been incorporated into guideline-recommended diagnostic algorithms for HF.⁸ In patients with AF, plasma levels of these peptides are elevated independent of HF status.⁹ These elevated levels mirror various complex pathophysiological factors, including arrhythmic burden and underlying cardiac pathology, serving as important surrogate markers for adverse clinical outcomes such as HF and stroke.¹⁰

In patients undergoing catheter ablation for AF, baseline plasma BNP levels are reportedly a predictor of rhythm outcomes.^{11 12} However, previous studies primarily examined mixed populations of paroxysmal and persistent AF, with limited data on persistent AF, a form characterised by substantial rhythm changes following ablation. As plasma BNP levels can change dynamically after the procedure, reflecting both rhythm alterations and the reversal of underlying cardiac conditions, single-point BNP measurements may insufficiently capture the complex pathophysiological changes during the post-ablation period. Given plasma BNP levels before and after ablation reflect the corresponding cardiac status at each time point, integrating these pre-procedural and post-procedural measurements may provide novel insights into risk stratification for both adverse events and rhythm outcomes following ablation procedures.

To address these knowledge gaps, we investigated the effect of integrating both pre-ablation and post-ablation plasma BNP levels on major adverse cardiovascular events (MACEs) and arrhythmic recurrence following catheter ablation in patients with persistent AF.

Methods

Study design

Patient-level data from this study were not publicly accessible because of institutional review board restrictions. We conducted a historical cohort study of patients who underwent an initial catheter ablation for persistent AF at our institution between January 2010 and June 2023. This study adhered to both the principles of the Declaration of Helsinki and the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for observational cohort studies.¹³

We selected patients with complete plasma BNP measurements obtained before and 3 months after the procedure. Persistent AF was characterised as continuous episodes exceeding 7 days as per current guidelines.²

Patients were stratified into four groups based on pre-ablation BNP and relative BNP change (delta(Δ)BNP). Using the median values of pre-ablation BNP and ΔBNP as cut-off points, patients were classified as: Low-Low (pre-ablation<median, ΔBNP<median), Low-High (pre-ablation<median, ΔBNP≥median), High-Low (pre-ablation≥median, ΔBNP<median) and High-High (pre-ablation≥median, ΔBNP≥median). We compared the cumulative incidence of MACEs and arrhythmic recurrence after the procedure across these subgroups.

Study endpoints

The primary endpoint was the incidence of MACE following the ablation procedures. According to our previous studies,^{14 15} MACE was defined as a composite endpoint encompassing three components: all-cause death, HF hospitalisation and other cardiovascular hospitalisations. HF hospitalisation was defined as any unscheduled hospital admission required to manage decompensated HF. Other cardiovascular hospitalisations included any unplanned admissions necessary for the treatment of cardiovascular disorders excluding HF. We excluded any events that occurred during the blanking period within 3 months of the procedure.

Secondary endpoints included the assessment of cumulative arrhythmic recurrence rates across BNP subgroups and analysis of the risk of MACE and arrhythmic recurrence across subgroups, adjusted for potential confounding factors.

Ablation procedure

Our initial procedural approach for persistent AF generally focused on a trigger-targeted strategy, incorporating pulmonary vein isolation with either radiofrequency energy or cryoballoon energy, along with superior vena cava isolation.¹⁴ For patients with clinically diagnosed or induced atrial flutters, we added specific ablations. Atrial substrate modifications have not been empirically conducted.

Follow-up

All patients underwent comprehensive postprocedural assessment at 3 months, including 24-hour Holter ECG monitoring and echocardiography. Follow-up visits were scheduled at 6 and 12 months, and we subsequently performed annual evaluations for up to 5 years. Arrhythmic recurrence was defined as atrial tachyarrhythmia persisting for >30 s beyond the blanking period. When atrial tachyarrhythmia recurred, a repeat procedure was scheduled unless the patient declined. Clinical event data were obtained from primary care physicians in August 2024.

BNP measurement

Pre-ablation plasma BNP levels were measured within 3 days before the procedure. Post-ablation plasma BNP levels were measured 3 months after the procedure, concurrent with echocardiographic and Holter monitoring assessments. ΔBNP was calculated as ((post-ablation BNP − pre-ablation BNP) / pre-ablation BNP × 100).

Statistical analysis

Continuous variables with a normal distribution are expressed as mean±SD, whereas those with a non-normal distribution are presented as medians with IQR (25–75th percentiles). Continuous variables across subgroups were compared using a one-way analysis of variance. Categorical variables were compared using the χ² test.

The cumulative incidence of MACE, their individual components and arrhythmic recurrence are calculated at the median follow-up time using Kaplan-Meier analysis and reported with 95% CIs. Differences in cumulative incidence among the BNP subgroups were evaluated using log-rank tests. Given that some patients had arrhythmic recurrence at the time of post-ablation BNP measurement, a sensitivity analysis was performed limited to patients who maintained sinus rhythm at 3 months after ablation (sensitivity analysis #1). To enhance the generalisability of our findings, another sensitivity analysis was performed using 240 pg/mL as the cut-off value for pre-ablation BNP instead of our cohort-specific median value (sensitivity analysis #2), as this threshold represents the established cut-off for BNP elevation in patients with AF according to the HFA-PEFF score.¹⁶ In both sensitivity analysis cohorts, the incidence of MACE and arrhythmic recurrence was evaluated, and multivariate analysis was performed. In evaluating arrhythmic recurrence, a landmark analysis designating 4 months post-procedure as the starting point (day 0) was also conducted to exclude patients with arrhythmic recurrence at the time of post-ablation BNP measurement.

For the multivariate analysis, factors relevant to MACE development, particularly those associated with HF hospitalisation and all-cause mortality were included as covariates. The covariates included age, sex, AF duration, comorbid structural heart disease, history of hospitalisation for HF, pre-ablation left ventricular ejection fraction (LVEF), left atrial volume index, estimated glomerular filtration rate and recurrence at 3 months. To compare the risks between subgroups, a stratified analysis was performed using the Low-Low subgroup as the reference. The results are presented as adjusted HRs with 95% CIs.

All statistical analyses were performed using R software V.4.3.2, with statistical significance set at p<0.05. Missing values were imputed using Multivariate Imputation by the Chained Equations package in R when performing multivariate analysis.

Results

Study population

Figure 1 illustrates a flow chart of the study protocol. Among 418 patients with persistent AF who underwent their first catheter ablation during the study period, we analysed the data of 392 patients who met the inclusion criteria. Approximately 80% of the patients underwent the procedure after 2016. The median pre-ablation plasma BNP value and ΔBNP were 148.0 pg/mL and −52.6%, respectively. Based on these values, 101 patients were classified as Low-Low, 91 as Low-High, 97 as High-Low and 103 as High-High.

Figure 1. Study diagram. AF, atrial fibrillation; BNP, B-type natriuretic peptide; MACE, major adverse cardiovascular events.

Table 1 shows the baseline characteristics of patients in each subgroup. The Low-Low subgroup was characterised by younger age, lower prevalence of structural heart disease and smaller left atrial volume index, whereas opposite trends were observed in the High-High subgroup (online supplemental figure 1). In the subgroups with low pre-ablation plasma BNP levels (Low-Low and Low-High), patients had lower CHA₂DS₂-VASc scores and elevated estimated glomerular filtration rates than those with high pre-ablation plasma BNP levels. In the High-Low subgroup, the left atrial volume index markedly decreased from 53±14 mL/m² to 41±10 mL/m² and the proportion of patients with LVEF≤50% substantially decreased from 37% to 8%. Other subgroups except Low-Low did not demonstrate this change.

Table 1. Patient demographics.

	Low-Low(n=101)	Low-High(n=91)	High-Low(n=97)	High-High(n=103)	P value
Fundamental demographics
**Age (years), mean±SD [0]	60±10	64±9	69±8	70±7	<0.001
*Female sex, n (%) [0]	11 (11)	16 (18)	28 (29)	32 (31)	0.001
BMI (kg/m2), mean±SD [1]	25±3	25±4	25±4	24±4	0.774
**CHA2DS2-VASc, mean±SD [0]	1.5±1.2	1.9±1.2	2.9±1.7	2.9±1.5	<0.001
*AF duration (months), median (IQR) [2]	8 (4–22)	9 (4–29)	6 (3–12)	6 (3–19)	0.048
*History of HF hospitalisation, n (%) [0]	14 (14)	16 (18)	30 (31)	19 (18)	0.018
Systolic BP (mm Hg), mean±SD [0]	128±16	131±20	127±17	128±19	0.477
Diastolic BP (mm Hg), mean±SD [0]	83±12	81±11	80±12	80±13	0.195
*HR (/min), mean±SD [0]	79±17	74±14	82±17	78±15	0.002
**eGFR (mL/min/1.73 m2), mean±SD [0]	66±16	63±16	58±16	57±18	<0.001
**Pre-BNP level (pg/mL), median (IQR) [0]	89 (64–114)	83 (57–113)	227 (186–336)	215 (174–289)	<0.001
**Post-BNP level (pg/mL), median (IQR) [0]	16 (10–26)	77 (43–132)	53 (31–83)	196 (51–298)	<0.001
Therapeutic agents
*ACEI/ARB, n (%) [0]	39 (39)	46 (51)	57 (59)	55 (54)	0.033
ARNI, n (%) [0]	1 (1)	2 (2)	4 (4)	7 (7)	0.130
**Beta-blocker, n (%) [0]	52 (51)	51 (56)	72 (74)	85 (82)	<0.001
SGLT2i, n (%) [0]	5 (5)	7 (8)	11 (11)	13 (13)	0.220
*MRA, n (%), n (%) [0]	10 (10)	15 (16)	27 (28)	19 (18)	0.012
**Diuretics, n (%), n (%) [0]	14 (14)	22 (24)	35 (36)	43 (42)	<0.001
Digitalis, n (%), n (%) [0]	6 (6)	4 (4)	1 (1)	1 (1)	0.101
*Class I or III AADs, n (%), n (%) [0]	5 (5)	8 (9)	13 (13)	23 (22)	0.013
**Amiodarone, n (%) [0]	1 (1)	5 (5)	9 (9)	17 (17)	<0.001
**Any structural heart diseases, n (%)	13 (13)	23 (25)	24 (25)	45 (44)	<0.001
CAD, n (%) [0]	6 (6)	13 (14)	12 (12)	15 (15)
HCM, n (%) [0]	1 (1)	2 (2)	5 (5)	14 (14)
DCM/DHCM, n (%) [0]	5 (5)	2 (2)	2 (2)	3 (3)
VHD, n (%) [0]	0	3 (3)	3 (3)	5 (5)
Congenital heart diseases, n (%) [0]	1 (1)	1 (1)	0	2 (2)
Other cardiomyopathies, n (%) [0]	0	3 (3)	2 (2)	6 (6)
Ablation-related parameters
Radiofrequency-PVI, n (%) [0]	101 (100)	90 (99)	97 (100)	102 (99)	0.558
Cryo-PVI, n (%) [0]	0	1 (1)	0	1 (1)	0.558
CTI-ablation, n (%) [0]	10 (10)	18 (20)	13 (13)	21 (20)	0.123
Posterior wall isolation, n (%) [0]	0	0	0	0	>0.999
Left isthmus ablation, n (%) [0]	0	1 (1)	0	0	0.345
SVC isolation, n (%) [0]	80 (79)	75 (82)	74 (76)	72 (70)	0.194
Pre-ablation echocardiographic parameters
LVDd (mm), mean±SD [0]	49±5	49±6	49±6	49±6	0.758
LVEF (%), mean±SD [0]	58±11	60±12	56±13	56±14	0.083
LVEF≤50%, n (%) [0]	21 (21)	21 (23)	34 (35)	34 (33)	0.061
**LAVI (mL/m2), mean±SD [4]	47±12	50±13	56±16	63±22	<0.001
**E/e’ ratio, mean±SD [6]	9±3	9±4	10±3	11±5	<0.001
**ePASP (mm Hg), mean±SD [4]	24±4	26±5	27±5	29±6	<0.001
Post-ablation echocardiographic parameters
LVDd (mm), mean±SD [0]	48±5	49±8	49±6	49±6	0.729
*LVEF (%), mean±SD [0]	62±9	60±11	61±10	56±14	0.001
**LVEF≤50%, n (%) [0]	11 (11)	18 (20)	12 (12)	34 (33)	<0.001
**LAVI (mL/m2), mean±SD [5]	37±9	48±13	45±16	60±20	<0.001
**E/e’ ratio, mean±SD [5]	8±3	9±4	10±6	12±7	<0.001
**ePASP (mm Hg), mean±SD [10]	24±4	26±5	28±6	30±7	<0.001

Numerical data are expressed as mean±SD or median (IQR; first quartile, third quartile); categorical data are expressed as percentages and numbers; [] indicates a missing rate; Aasterisks indicate statistical significance (*p<0.05, **p<0.001).

AADs, antiarrhythmic drugs; ACEI, ACE inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BMI, body mass index; BNP, B-type natriuretic peptide; BP, blood pressure; CAD, coronary artery disease; CTI, cavotricuspid isthmus; DCM, dilated cardiomyopathy; DHCM, dilated phase of hypertrophic cardiomyopathy; eGFR, estimated glomerular filtration rate; ePASP, estimated pulmonary artery systolic pressure; HCM, hypertrophic cardiomyopathy; HF, heart failure; HR, heart rate; LAVI, left atrial volume index; LVDd, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; PVI, pulmonary vein isolation; SGLT2i, sodium-glucose transport protein 2 inhibitors; SVC, superior vena cava; VHD, valvular heart disease

The BNP change across subgroups

Figure 2 compares pre-ablation and post-ablation plasma BNP levels across subgroups. Overall, BNP levels decreased after ablation. The median ΔBNP (IQR) was −81.7% (−87.5% to −68.0%) in the Low-Low subgroup, −9.1% (−33.7% to 34.5%) in the Low-High subgroup, −78.2% (−87.1% to −68.5%) in the High-Low subgroup and −6.7% (−31.3% to 10.5%) in the High-High subgroup.

Figure 2. Comparison of pre-ablation and post-ablation BNP level across the BNP subgroup. Each boxplot represents BNP levels at pre-ablation and post-ablation timepoints (left and right boxes for each subgroup, respectively). Dashed line indicates the median pre-ablation BNP level (148.0 pg/mL). BNP, B-type natriuretic peptide.

MACE incidence across subgroups

Over the median follow-up period of 5.3 years (IQR, 3.2–7.2), 63 (16%) patients experienced at least one adverse event, with a total of 114 documented events. HF hospitalisation accounted for most events (72/114, 63%), followed by all-cause death (23/114, 20%) and other cardiovascular hospitalisations (19/114, 17%). Among all-cause mortalities, malignancy was the predominant cause (48%), followed by cardiovascular causes (17%). Among other cardiovascular hospitalisations, stroke was the most frequent cause (53%), with acute coronary syndrome and bradyarrhythmias accounting for 18% of the cases.

Figure 3 illustrates the comparison of cumulative MACE incidence across the subgroups. The High-High subgroup demonstrated significantly higher event rates than the other subgroups (figure 3, online supplemental table 1a p<0.001). The cumulative incidence of events at 5.3 years following the procedure was 5.8% (95% CI: 0.6% to 10.6%) in the Low-Low subgroup, 5.5% (95% CI: 0.1% to 10.5%) in the Low-High subgroup, 16.0% (95% CI: 7.5% to 23.6%) in the High-Low subgroup, and 26.3% (95% CI: 16.2% to 35.2%) in the High-High subgroup. Both sensitivity analyses showed consistent trends: sensitivity analysis #1 demonstrated event rates of 6.2% (95% CI: 0.7% to 11.5%), 5.5% (95% CI: 0% to 12.5%), 14.9% (95% CI: 6.3% to 22.7%) and 34.2% (95% CI: 17.7% to 47.4%), while sensitivity analysis #2 showed rates of 6.0% (95% CI: 1.8% to 10.1%), 9.3% (95% CI: 4.1% to 14.3%), 28.1% (95% CI: 11.4% to 41.6%) and 41.6% (95% CI: 22.2% to 56.2%) in the respective subgroups.

Figure 3. Kaplan-Meier curves comparing the cumulative Incidence of MACE Across the BNP subgroups. Each plot is expressed as the cumulative incidence of the event with a 95% CI (red: High-High, purple: High-Low, green: Low-High, blue: Low-Low). Asterisks indicate statistical significance (**p<0.001). BNP, B-type natriuretic peptide; MACE, major adverse cardiovascular events.

Analysis of individual MACEs revealed significantly higher rates of all-cause death in both the High-Low and High-High subgroups (p<0.001, online supplemental table 1a). The High-High subgroup also demonstrated a significantly higher HF hospitalisation incidence, consistent with the overall MACE pattern (p<0.001).

Arrhythmic recurrence across subgroups

Figure 4 illustrates the comparison of cumulative arrhythmic recurrence across subgroups (figure 4a, online supplemental table 1b). The Low-High and High-High subgroups demonstrated significantly higher incidence rates than the other subgroups (p<0.001). This pattern generally persisted in the landmark analysis (figure 4b), with the High-Low subgroup showing a trend toward higher recurrence rates than the Low-Low subgroup. Both sensitivity analyses demonstrated consistent patterns of arrhythmic recurrence across the subgroups.

Figure 4. Kaplan-Meier curves comparing the cumulative incidence of freedom from arrhythmic recurrence across the BNP subgroups. (a) Whole cohort (b) landmark cohort. Each plot is expressed as the cumulative incidence of the event with a 95% CI (red: High-High, purple: High-Low, green: Low-High, blue: Low-Low). Asterisks indicate statistical significance (**p<0.001). BNP, B-type natriuretic peptide.

Multivariate analysis

Figure 5 and online supplemental table 2 present the risks of MACE and arrhythmic recurrence across the subgroups after multivariate adjustment. Compared with the Low-Low and Low-High subgroups, both the High-Low and High-High subgroups demonstrated progressively higher risks of MACE incidence (figure 5a). For arrhythmic recurrence, both Low-High and High-High subgroups showed substantially higher risks (figure 5b, adjusted HR: 4.57 (95% CI: 2.90 to 7.21), p<0.001 and 7.17 (95% CI: 4.35 to 11.80), p<0.001, respectively). The sensitivity analyses demonstrated the highest risk for MACE incidence in the High-High subgroup in both sensitivity analyses #1 and #2 (online supplemental table 2b,C). Similarly, the Low-High and High-High subgroups showed the highest risk for arrhythmic recurrence. All results were consistent with the initial analysis.

Figure 5. Risk of MACE and arrhythmic recurrence across the BNP subgroup. (a) Risk of MACE across BNP subgroups. (b) The risk of arrhythmic recurrence across BNP subgroups. Each plot is expressed as an adjusted HR with a 95% CI. HR was adjusted for age, sex, atrial fibrillation duration, structural heart disease, history of heart failure hospitalisation, pre-ablation left ventricular ejection fraction, left atrial volume index, estimated glomerular filtration rate and recurrence at 3 months. Asterisks indicate statistical significance (*p<0.05, **p<0.001). BNP, B-type natriuretic peptide; MACE, major adverse cardiovascular event.

Discussion

The key findings of this study are summarised as follows (online supplemental graphical abstract): first, the incidence of MACE was predominantly higher in the High-High subgroup, with lower rates in the remaining subgroups, particularly in Low-Low and Low-High. Second, regarding MACE components, all-cause death and HF hospitalisation rates were markedly elevated in the High-High subgroup compared with other subgroups. Third, the incidence of arrhythmic recurrence was significantly higher in both the Low-High and High-High subgroups. This finding generally remained consistent in the landmark cohort analysis after excluding patients with arrhythmic recurrence at the time of the post-ablation BNP measurement. Fourth, compared with the Low-Low and Low-High subgroups, both the High-Low and High-High subgroups demonstrated progressively higher risks of MACE incidence after multivariate adjustment. The subgroups with elevated post-ablation BNP levels (Low-High and High-High) exhibited a significantly higher risk of arrhythmic recurrence than the other groups.

Clinical significance of BNP levels in pre-ablation and post-ablation

Multiple pathophysiological mechanisms involving both cardiac and non-cardiac factors contribute to elevated BNP levels in patients with AF. For example, haemodynamic alterations in AF, including atrial wall stretch due to pressure overload, impaired left ventricular filling and increased/irregular ventricular rates, promote both atrial and ventricular BNP production.¹⁷ Furthermore, degenerative changes in the atrial myocardium, manifesting as increased fibrosis and altered collagen turnover, drive BNP elevation; these pathological changes in atrial tissue are collectively known as atrial cardiomyopathy.^{18 19} Furthermore, systemic inflammatory signals, which are commonly elevated in patients with AF, have been shown to enhance BNP production.²⁰

Catheter ablation potentially reduces BNP levels by mitigating the arrhythmic burden and achieving haemodynamic stabilisation through the restoration of normal sinus rhythm. Supporting these mechanistic effects, previous studies have demonstrated that post-ablation BNP reduction serves as a marker of favourable rhythm outcomes and cardiac functional recovery.^{11 21 22} Although the literature examining the relationship between BNP levels and clinical events in patients undergoing ablation remains limited, a few investigations have suggested that a greater reduction in BNP levels or lower post-procedural BNP levels is associated with fewer adverse events during follow-up, including hospitalisation for HF.^{23 24}

MACE incidence in the subgroups with high pre-ablation BNP levels

Consistent with these findings, we demonstrated that the High-Low subgroup (high baseline but greater reduction of post-ablation BNP levels) exhibited a lower risk of MACE than the High-High subgroup (consistently high BNP levels). Beyond the higher rate of successful sinus rhythm maintenance in the High-Low subgroup, disparities in the underlying cardiac condition between these subgroups may account for this differential outcome. The High-Low subgroup likely encompasses a greater proportion of patients with arrhythmia-induced cardiomyopathy, who derive substantial benefit from sinus rhythm restoration.²⁵ Supporting this speculation, only the High-Low subgroup experienced marked improvements in cardiac function, with mean LVEF increasing from 56±12% to 62±8% and fewer patients showing LVEF≤50%, whereas the High-High subgroup showed minimal changes despite similar baseline characteristics (online supplemental figure 1d). Conversely, the High-High subgroup may involve a higher proportion of patients with atrial cardiomyopathy, where AF development can represent a consequence of underlying atrial myocardial impairment.¹⁹ This inference is supported by the distinctive finding of persistently enlarged left atrial volume index in this subgroup, showing only minimal reduction after ablation (62±21 mL/m² to 58±20 mL/m²) in contrast to other subgroups (online supplemental figure 1c). Moreover, this subgroup demonstrated a higher incidence of MACEs in the sensitivity analysis cohort, where patients demonstrated and maintained sinus rhythm at the time of post-ablation BNP measurement. These findings suggest that the elevated MACE risk in this subgroup derives not only from lower rates of sinus rhythm maintenance but also from a substantial proportion of patients who derive limited benefit from rhythm control.

MACE incidence in the subgroups with low pre-ablation BNP levels

In the subgroups with low pre-ablation BNP levels (Low-Low and Low-High), both demonstrated a lower incidence of MACE than those with high pre-ablation BNP levels despite the higher arrhythmic recurrence rate observed in the Low-High subgroup. This disparity may be due to the relatively fewer comorbidities in these subgroups, as evidenced by younger age, lower CHA₂DS₂-VASc scores, lower prevalence of prior hospitalisation for HF and a higher estimated glomerular filtration rate. Previous studies aimed at characterising the heterogeneous nature of AF populations through cluster analysis commonly demonstrated that profiles with fewer comorbidities, typically characterised by younger age and lower CHA₂DS₂-VASc scores, tend to have a lower risk of adverse events, including all-cause death and HF hospitalisation.^{26 27} In our population, subgroups with low pre-ablation BNP levels likely consisted of this low-comorbidity profile. Our observation suggests that patients with low pre-ablation BNP levels may not have as poor clinical outcomes as those with high pre-ablation BNP levels, even if they experience arrhythmic recurrence, likely due to these phenotypic differences.

Clinical implications

The major strength of our study lies in its evaluation of MACE and arrhythmic recurrence risk over a median follow-up period exceeding 5 years, based on pre-ablation and post-ablation BNP levels in patients with persistent AF. Our data provide risk stratification for both MACE and arrhythmic recurrence according to pre-ablation and post-ablation BNP levels (online supplemental figure 2). Among patients with elevated pre-ablation BNP levels (≥148.0 pg/mL, or 908 pg/mL in NT-proBNP using the converting formula,²⁸ those experiencing poor post-ablation BNP reduction (ΔBNP≥−52.6 %) demonstrated an increased risk for both MACE and arrhythmic recurrence. Conversely, patients with greater BNP reduction exhibited an intermediate risk of both events. In patients with lower pre-ablation BNP levels, the MACE risk remained low regardless of post-ablation BNP reductions. However, within this group, the risk of arrhythmic recurrence was elevated in patients with smaller BNP reductions. These risk stratification patterns remained consistent even when using the established cut-off value of 240 pg/mL for pre-ablation BNP, which represents the standardised threshold for BNP elevation in patients with AF. This consistency may suggest that our risk stratification approach based on pre-ablation BNP levels and their post-ablation changes could be applicable across general clinical settings.

Limitations

This study has several limitations. First, we retrospectively collected data from a historical cohort with a relatively modest sample size at a single centre, which restricts the generalisability of our findings. Pre-ablation BNP thresholds may differ across institutions because of variations in primary patient populations. Therefore, external validation through multicentre prospective studies is crucial to establish broader applicability and reproducibility of our results. Second, post-ablation BNP levels can be influenced by arrhythmic recurrence, and a substantial proportion of patients in the Low-High subgroup experienced recurrence at 3 months. Although we conducted a sensitivity analysis and a landmark analysis to address this issue, the small sample size of the Low-High subgroup limited our analysis, warranting further validation in larger cohorts. Third, our study included patients over a broad period of 13 years. While approximately 80% of procedures were performed in the latter 7 years, catheter ablation practices evolved considerably during this time frame, with sinus rhythm maintenance rates improving through technological advancement.²⁹ Although our findings generally remained consistent in the sensitivity analysis, validation studies using contemporary cohorts are warranted to confirm the applicability of our results in current clinical practice.²⁹ Fourth, we acknowledge that our use of 24-hour Holter monitoring at 3 months post-ablation, rather than extended ECG monitoring systems (eg, 7-day or 14-day monitors), may have underestimated the true recurrence rate. Although the majority of our cohort (>90%) experienced recurrence in the form of persistent AF, which is more likely to be detected even with shorter monitoring periods, we cannot exclude the possibility of missing paroxysmal recurrences. Fifth, our population demonstrated significant differences in baseline characteristics across BNP-based subgroups, including a notably higher prevalence of hypertrophic cardiomyopathy in the High-High group. Although multivariate analysis incorporating any structural heart disease demonstrated persistently elevated event risk in the High-High subgroup, this baseline imbalance remains a potential limitation of our study.

Conclusions

We demonstrated that integrating pre-ablation and post-ablation BNP levels could be useful for stratifying the risk of both MACE and arrhythmic recurrence during long-term follow-up in patients with persistent AF. Patients with elevated pre-ablation BNP (≥148.0 pg/mL) who showed a poor reduction in BNP after ablation demonstrated increased risks of both events.

Data availability statement

No data are available.