A predictive model using left atrial function and B‐type natriuretic peptide level in predicting the recurrence of early persistent atrial fibrillation after radiofrequency ablation

Abstract Aim A predictive model using left atrial function indexes obtained by real‐time three‐dimensional echocardiography (RT‐3DE) and the blood B‐type natriuretic peptide (BNP) level was constructed, and its value in predicting recurrence in patients with early persistent atrial fibrillation (AF) after radiofrequency ablation was explored. Methods A total of 228 patients with early persistent AF who were scheduled to receive the first circular pulmonary vein ablation (CPVA) were enrolled. Clinical data of patients were collected: (1) The blood BNP level was measured before radiofrequency ablation; (2) RT‐3DE was used to obtain the left atrial (LA) time‐volume curve; (3) The clinical characteristics, BNP level and LA function parameters were compared, and logistic regression was used to construct a prediction model with combined parameters; (4) The receiver operating characteristic (ROC) curve was used to examine the diagnostic efficacy of the model. Results (1) 215 patients with early persistent AF completed CPVA and the follow‐up. After 3–6 months of follow‐up, the patients were divided into sinus rhythm group (160 cases) and recurrence group (55 cases); (2) The recurrence group showed higher minimum LA volume index, diastolic ejection index, and preoperative BNP (all p ≤ .001), while the sinus rhythm group exhibited higher expansion index (PI) and left atrial appendage peak emptying velocity (p ≤ .001); (3) In univariate analysis, BNP level had the best diagnostic performance in predicting the recurrence of AF(AUC = 0.703). We constructed a model based on LA function and BNP level to predict the recurrence of persistent AF after CPVA. This combined model was better than BNP alone in predicting the recurrence of persistent AF after CPVA (AUC: 0.814 vs. 0.703, z = 2.224, p = .026). Conclusion The combined model of LA function and blood BNP level has good predictive value for the recurrence of early persistent AF after CPVA.

Conclusion: The combined model of LA function and blood BNP level has good predictive value for the recurrence of early persistent AF after CPVA.

K E Y W O R D S
atrial fibrillation, B-type natriuretic peptide, circular pulmonary vein ablation, echocardiography, prediction model, recurrence

| INTRODUCTION
Atrial fibrillation (AF) is one of the most common clinical tachyarrhythmias, and its incidence is relatively high. AF can result in a series of severe public health problems, including increased thromboembolic events, cardiogenic sudden death, and low quality of life. 1 Early persistent AF is a newly defined term; it refers to the continuous AF that lasts for more than 7 days but less than 3 months. 2 Circular pulmonary vein isolation (CPVI) is the cornerstone of catheter ablation (CA) therapy for AF. 3 Many studies have shown that circular pulmonary vein ablation (CPVA) is superior to anti-arrhythmic drug treatment in terms of maintaining sinus rhythm and improving life quality of AF patients. 4 European Society of Cardiology (ESC) 2020 recommend that:AF catheter ablation for CPVI should/may be considered as first-line rhythm control therapy to improve symptoms in selected AF patients. 5 The role of CPVA in the treatment of persistent AF has been recognized. 6 The clinical characteristics, such as age, CHA 2 DS 2 -Vasc score, and the pattern of AF, can help formulate the treatment plan, because they are related to adverse outcomes and recurrence of AF. However, despite these predictive factors, the recurrence rate is still relatively high. Thus, it is necessary to search for candidate markers that can accurately predict the outcome of CPVA.
During the progression of AF, AF patients may have atrial structural remodeling, which is mainly manifested as atrial muscle degeneration, increased fibrosis of atrial muscle and extracellular matrix, etc., which will cause atrial enlargement; moreover, atrial structural remodeling is also the structural basis for AF recurrence after CPVA. 7 The functions of left atrium mainly include atrial storage, passage, and active contraction. Real-time three-dimensional echocardiography (RT-3DE) is a new method to evaluate left atrial (LA) remodeling. The quantification of atrio-ventricle by RT-3DE is highly correlated with the gold standard of cardiac magnetic resonance (CMR) imaging and computed tomography. 8,9 B-type natriuretic peptide (BNP) is a structurally related peptide hormone secreted by heart cells. The BNP in AF patients is mainly produced by LA cells. The increase in blood BNP level is related to atrium overload and remodeling. Meta-analys shows that the increased baseline level of BNP is associated with an increased risk of AF recurrence after CPVA, and it is believed that BNP may be a marker for predicting AF recurrence after CPVA. 10 It is notable that many of the risk factors that are associated with AF also contribute to AF progression, AF recurrence following ablation, and complications associated with AF. Therefore, the studies that focus on both atrial structural and functional changes can help to evaluate the development, maintenance and progression of AF. In this study, we used RT-3DE to evaluate the structural remodeling of LA, and constructed a predictive model combining LA function and BNP. We explored the efficacy of the combined model based on ultrasound structural function parameters and blood marker in predicting the recurrence of early persistent AF after CPVA.

| Object
A total of 228 patients with early persistent AF who were admitted to The First People's Hospital of Changzhou City, China, from January 2017 to December 2019 and scheduled to receive the first CPVA operation were enrolled in this study, including 188 males and 40 females. Inclusion criteria: (1) Patients with AF recorded by electrocardiogram (ECG) and Holter, and the AF lasted for more than 7 days but less than 3 months; (2) Patients of age 18 to 75 years old; (3) The cardiac function of patients with heart failure returned to cardiac function I (NYHA classification) after treatment; (4) Patients had the ability to understand and sign the informed consent. Exclusion criteria: (1) History of heart disease such as coronary heart disease, valvular disease, and congenital heart disease; (2) Symptoms and signs of cardiac insufficiency did not improve after treatment, and no evidence of cardiac insufficiency in preoperative echocardiography (left ventricular ejection fraction≥50%); This study complied with the principles of Declaration of Helsinki.
All patients signed the written informed consent. The study was approved by the Scientific Ethics Committee. The patient selection process is shown in Figure 1. Informed consents of all patients were obtained from the patients themselves.

| Blood sample collection and measurement
According to the standard recommendations from the ESC, on the day before surgery, 2 ml of cubital venous blood was collected from each patient in supine position in the morning while fasting. The blood was put into an anticoagulation test tube with ethylenediamine tetraacetic acid. Within 2 h after collection, the blood sample was centrifuged at 3000 r/min for 10 min, and the supernatant serum was F I G U R E

| Postoperative treatment, follow-up, and grouping
All patients took new anticoagulants (non-vitamin K antagonist oral anticoagulants) orally for at least 2 months after the operation, and the electrocardiogram was followed up every day for 3 days after the operation.
All patients continued to use an antiarrhythmic drug treatment for 3 months after surgery (amiodarone, 200 mg, Qd; propafenone 150 mg, Tid or morerazine 150 mg, Tid; sotalol 80 mg, Bid). After discharge, patients were followed up for ECG every month, and a 24-h Holter examination was performed at least once a month. Phone calls and faxes were also used for follow-up and receiving ECG data. All patients were followed up for at least 3 months and up to 6 months (healing period).
AF recurrence that occurred in the first 3 months after the ablation (blanking period) was not included in the present analysis. AF recurrence was defined as a documented episode of any atrial arrhythmias (AF, atrial tachycardia and atrial flutter) lasting ≥30s during the follow-up period after the3-month blanking period. 2 Patient's follow-up was terminated at the first AF recurrence recorded after the blanking period. Normally distributed data were expressed as x AE s, and non-normally distributed data were expressed as M (P25, P75). The comparisons between groups were performed by independent sample t test or

| Statistical analysis
Mann-Whitney U nonparametric test. Classification data were expressed by frequency or rate (%), and comparison between groups was performed by Pearson chi-square test or Fisher exact probability method.
Multi-factor logistic regression was used to establish the prediction model, and the optimal model parameters were selected based on minimum Akaike's information criterion. The Bootstrap resampling (times = 500) method recommended by the TRIPOD report was used to internally verify the model. 13 Figure 2(A)).
Next, we performed multivariate logistic regression analysis, and used all the influential factors in Table 1 as independent variables to construct a predictive model for predicting the recurrence of early persistent 3.1 | Comparison of the predictive performance of optimal single factor and combined prediction models ROC curve analysis was used to compare the diagnostic performance of the optimal single-factor index BNP and the combined prediction model ( Table 2 and Figure 2

| Comparison of the prediction model in different subgroups
After adjusting for age and gender, the multi-factor predictive model showed consistent trends in subgroups with different left ventricular ejection fraction, smoking, drinking, hyperlipidemia, hypertension, and diabetes history, all of which were risk factors (Figure 3).

| CONCLUSION
In this study, we constructed a combined prediction model based on LA function and blood BNP level for predicting the recurrence of AF in early persistent AF patients after CPVA combined with linear ablation. SARA study demonstrated that CA was significantly more effective than antiarrhythmic drug therapy in maintaining sinus rhythm for patients with persistent AF, and it reduced the recurrence of sustained episodes (24 h) of AF by 47.4%. 6 Furthermore, CA had a good safety profile according to the latest international registries. 15 However, the energy from CA can aggravate the fibrosis of the LA muscle, and the scar after ablation can exacerbate the structural remodeling of left atrium and lead to the recurrence of AF. The efficiency of ablation is often offset by the recurrence of AF. Therefore, identifying non-invasive indicators of LA remodeling to predict patients with high risk of recurrence after CPVA can help clinicians make more optimal treatment plans. 16 Most studies on the risk factors of recurrence in persistent AF consider both persistent AF and long-term persistent AF. Among trials that included patients with persistent AF or combined paroxysmal and persistent AF, the success rates after ablation ranged from 59 to 80% at 6 or 12 months. 17,18 The stratified studies on patients with persistent AF may be more accurate in predicting success rates. The patient selection in this study based on the concept of early persistent AF These indicators are easy to detect and can provide us with valuable information. 16,17,20,21 In patients with persistent AF and normal left ventricular function, BNP is mainly produced by LA myocytes. Metaanalysis showed that the AF recurrence group had a higher preablation baseline level of BNP than sinus rhythm group, but the heterogeneity was also significant (I2 = 89%, p < .0001). 22  This study still has some limitations. Due to the influence of heart rate during the examination and the various ventricular filling time, the data measured from patients with continuous AF may still be limited and biased, even though the data were measured and averaged from multiple cardiac cycles; Patients in this study were followed up for 3-6 months, and the recurrence of atrial fibrillation after 6 months was not included in this study. In addition, longterm continuous record of patients' cardiac rhythm after ablation has not been carried out, and occasional atrial fibrillation may not be recorded, so it cannot reflect the long-term specific results of patients with atrial fibrillation after ablation. Due to the small sample size, we used the Bootstrap internal verification method to verify the statistical effectiveness, and did not divide patients into modeling and verification groups or perform external verification.
Therefore, it is necessary to further increase the sample size to optimize the prediction model parameters.
In summary, the prediction model of LA function combined with BNP level can be used to predict the recurrence of early persistent AF after CPVA, and the prediction efficiency, accuracy and specificity are better than a single factor model based on BNP. Therefore, the multifactor combination model can identify high-risk patients for AF recurrence, help doctors optimize patient selection, inform patients about the risk-benefit ratio, guide operators to choose the best ablation strategy, and help apply personalized treatment plan. Bureau has no role in this study.

CONFLICT OF INTEREST
All authors declare that: (1) they have not received any support from any organization having an interest in the submitted works, whether financial or otherwise; (2) there are no other relationships or activities that may affect the submitted works.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.