ABSTRACT
The clinical risk factors associated with late recurrence in patients with non-valvular atrial fibrillation (AF) (NVAF) undergoing radiofrequency catheter ablation (RFCA) remain unknown. Furthermore, the current prognostic risk score system is commonly used in such patients as a noninvasive method to assess late AF recurrence. According to recent research, the Age, creatinine, and ejection fraction (ACEF) score is a useful risk score for cardiovascular morbidity and mortality. As a result, we hypothesized that pre-ablation ACEF score could be used to assess late recurrence in patients with NVAF. We included 325 NVAF patients undergoing RFCA. During a median follow-up period of 12 months, patients with late AF recurrence had higher ACEF scores (P < .001). The pre-ablation ACEF score was a risk factor for late AF recurrence after RFCA (P = .027). The ACEF score was a predictor of late AF recurrence after RFCA, with an AUC of 0.624 (P = .001). Moreover, the AUC of left atrial diameter (LAD) was 0.7 (P < .001), which was higher than the ACEF score, but no significant difference was found (P = .104). The ACEF score was positively correlated with LAD, advanced age, and B-type natriuretic peptide. In patients with NVAF, the pre-ablation ACEF score is a valuable risk score for assessing late AF recurrence after RFCA, as with LAD.
Introduction
Atrial fibrillation (AF) is the most common persistent arrhythmia, affecting approximately 30 million people worldwide and resulting in a death rate twice that of patients with normal sinus rhythm (SR) (Citation1) (Citation2,Citation3). Thus, it is a serious and expensive public health issue worldwide (Citation4–6).
AF is associated with numerous adverse cardiovascular and non-cardiovascular outcomes, including recurrent hospitalization, stroke, dementia, and heart failure, seriously threatening the patients’ health (Citation7). Radiofrequency catheter ablation (RFCA), as one of the most effective methods to control AF rhythm and maintain SR, is currently considered the gold standard therapeutical approach for the treatment of AF and is widely implemented worldwide (Citation8,Citation9). Despite great technical and procedural advances, AF recurrence is still a significant problem, with a recurrence rate ranging from 30% to 50% (Citation10).
Previous studies have shown that age, left atrial diameter (LAD), and ejection fraction (EF) can predict AF recurrence after ablation therapy, facilitating the choice of an appropriate and individualized treatment option for these patients (Citation11–13). The decreased renal function causes hemodynamic and metabolic abnormalities, inducing atrial fibrosis and leading to AF (Citation14–16). Furthermore, a pilot study showed that concomitant chronic kidney disease increased the AF recurrence rate, suggesting that renal function may be a modifiable risk factor for AF (Citation17). Currently, serum creatinine is widely used as a marker of renal function in clinical practice (Citation18).
The age, creatinine, and ejection fraction (age, serum creatinine, and ejection fraction [ACEF]) score is a simple risk assessment tool that was initially proposed in patients undergoing elective cardiac surgery and validated in patients undergoing percutaneous coronary intervention (PCI) (Citation19,Citation20). Interestingly, previous research has demonstrated that the ACEF score correlates cardiovascular disease morbidity and mortality, which increases its value as a risk scoring system (Citation21).
Therefore, we hypothesized that pre-ablation ACEF scores are associated with post-ablation AF recurrence. To the best of our knowledge, this finding has not been previously reported in the literature. This study was designed to investigate whether pre-ablation ACEF scores are associated with AF recurrence after RFCA treatment or not and to evaluate their predictive power.
Materials and methods
Study participants
This retrospective study included 325 patients with non-valvular AF (NVAF) who underwent the first radiofrequency ablation in the Department of Cardiology of the Third People’s Hospital of Chengdu from January 2019 to August 2021.
The inclusion criteria were: 1) NVAF, paroxysmal or persistent AF, first RFCA, patients aged>18 years; 2) the diagnosis of NVAF met the diagnostic criteria of the European Society of Cardiology guidelines; 3): patients with regular electrocardiograms (ECGs), 24-hour Holter ECGs, or 7-day history of cardiovascular events; 4) the patient met the indications for radiofrequency ablation for AF; and 5) actively cooperative regarding the postoperative follow-up.
Exclusion criteria were defined as follows: 1) the patient had left atrial thrombosis or other absolute contraindications for catheter ablation surgery; 2) history of left intra-atrial catheter ablation and left atrial surgery; 3) AF caused by reversible and pathological factors, including hyperthyroidism, drugs, or alcoholism; 4) left ventricular dysfunction<30% or severe cardiac valvular disease, including severe aortic stenosis or aortic insufficiency, severe mitral valve stenosis or incomplete closure, and mitral valve replacement surgery; 5) patients with serious liver disease (i.e., three times the normal value of transaminase), malignant tumors, autoimmune tumors, and other diseases; 6) acute coronary syndrome requiring interventional treatment; 7) active presence of hemorrhagic disease, systemic infection, organ failure, or any other factor precluding surgery; 8) patients with cognitive impairment, central nervous system disease, or severe peripheral nerve disease; 9) patients with incomplete clinical records; and 10) life expectancy less than 1 year. A total of 325 eligible patients with baseline blood creatinine levels, age, and EF values, together with complete clinical data availability, were included and considered suitable for post analysis.
This is a sub-study of the larger study of the individualized localization method of the AF maintenance matrix (2020YJ0483). The study was approved by the Chinese Ethics Committee for Registered Clinical Trials under ECRCT-20170082 and was conducted in accordance with the Declaration of Helsinki and institutional guidelines. All patients signed the informed consent form for radiofrequency ablation. Due to the retrospective nature of the study, the institutional review board waived the need for a written informed consent from the patients. All subjects’ privacy was adequately protected and the patients’ private information was encrypted before publication of the data.
Data collection and processing
Clinical and echocardiographic data, serological indicators, and discharge medication of the included patients were collected from the electronic information system of the Chengdu Third People’s Hospital. These data included: 1) clinical data: age, sex, type of AF, height, weight, smoking history, alcohol consumption history, hypertension, coronary atherosclerotic heart disease, diabetes, and dyslipidemia; 2) echocardiography data (preoperative): LAD, left ventricular EF, and left ventricular internal diameter; 3) serology index (preoperative): B-type natriuretic peptide (BNP), blood creatinine, cystatin C (CysC), endogenous creatinine clearance, uric acid, albumin, and fasting venous blood glucose; and 4) discharge medication.
Risk scoring system
The congestive heart failure, hypertension, age≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 and sex category (female) (CHA2DS2-VASc) score was assessed in those patients aged between 65–74 years, female sex, congestive heart failure, hypertension, diabetes, and vascular lesions, receiving two points if they were 75 years-old or had stroke, TIA, or history of thrombosis. The ACEF score considers age, blood creatinine, and ejection fraction. The formula for this score is as follows: age/left ventricular ejection fraction (%)+blood creatinine score (blood creatinine 2 mg/dL=score 1; blood creatinine<2 mg/dL=score 0) (Citation20). The value for each patient was calculated using the data before the surgery.
Preoperative preparation
All patients with AF were treated with warfarin or novel oral anticoagulants, such as rivaroxaban or dabigatran, for at least 2 months before undergoing RFCA (Citation22). Echocardiography was performed within 48 hours before the procedure to assess the structure and function of cardiac tissue. Moreover, transesophageal echocardiography, cardiac computed tomography angiography (CTA), or left atrial magnetic resonance imaging were performed in order to exclude left atrial thrombus.
Electrophysiological examination and catheter ablation
AF was confirmed by ECG, 24-hour Holter ECG, or 7-day long-course cardiovascular events. All patients underwent a cardiac CTA before ablation to assess the size and structure of the left atrium and the shape of the pulmonary vein. RFCA was performed under general anesthesia in all patients, with their vital signs continuously monitored intraoperatively. A coronary sinus electrode was inserted into the left subclavian vein and a ventricular electrode was inserted into the right femoral vein. The electrophysiological examination suggested persistent AF or paroxysmal AF.
In cases of paroxysmal AF, the adjustable curved sheath was directed to the left atrium. A pressure-sensing ablation catheter was infused with 50 w, 15 mL/min cold saline. Thereafter, the bilateral pulmonary vein was electrochemically isolated after ablation, marking the completion of the procedure. If AF persisted, a Swarts long sheath was placed via the right femoral vein puncture by the Swarts long sheath puncture chamber interval. The adjustable sheath was placed into the pentary electrode in the left chamber. The CARTO3 navigation system was used to guide the descending left atrial anatomy modeling, collecting the contact bipolar cavity electrical graph signal throughout the left chamber. After that, the left atrial matrix was mapped for SR and AF. The ablation circuit was designed according to these mapping results.
Ablation was performed by pressure sensing with the catheter and cold saline, (50 w, 15 mL/min) leading to left atrial matrix improvement (e.g., anterior and posterior pulmonary vein, BOX). If the AF changed to atrial flutter or auricular tachycardia during ablation, the ablation area was electroisolated. If AF changed to SR during ablation, the operation was completed. A temporary pacemaker was implanted in the postoperative period, if needed. The operation was performed under X-ray fluoroscopy, computed radiography digital photography, continuous invasive blood pressure monitoring, postoperative sterile dressing, and wound dressing. The patient’s consciousness and vital signs were monitored intraoperatively and recorded. Heparin sodium and contrast agent were used intraoperatively.
Postoperative sinus rhythm maintenance and anticoagulation methods
Patients were continuously monitored for SR maintenance during hospitalization. After the procedure, all patients were given oral anticoagulation for at least 3 months, in accordance with the European Guidelines for Cardiology (Citation4). If the patients had no contraindications for amiodarone (such as those with thyroid dysfunction or pulmonary fibrosis), they were started on oral treatment with this drug on the second day in order to maintain the SR. Amiodarone side effects were monitored under the guidance of a doctor. This drug was administered as follows: 100 mg/dose in the first week, three times a day; 100 mg/dose in the second week, twice a day; and 100 mg/dose in the third week, once a day.
If oral amiodarone was contraindicated, it was replaced with dronedarone at 400 mg/dose twice a day. In the absence of contraindications and other side effects, antiarrhythmic drugs were taken orally until the end of the 3-month postoperative blank period. During this period, when oral amiodarone could not maintain SR, electrocardioversion was performed.
End points and follow-up
After discharge from the hospital, follow-up visits were performed at 3, 6, and 12 months. All patients were recommended to have 7-day long-course ECG at regular follow-ups. Follow-up methods included outpatient follow-up with an AF specialist, readmission, and telephonic follow-up. Follow-up visits included AF-related symptoms, specialist physical examination, ECG, 24-hour or 7-day long-course ECG, and cardiac color Doppler examination. Telephonic follow-up mainly screened for palpitations, dizziness, fatigue, and other symptoms related to AF. Specific data from ECG and 24-hour or 7-day long-course ECG could be obtained from the electronic recording system of our hospital.
Amiodarone and anticoagulant drugs were withdrawn based on ECG at 3 months, 24-h, or seven-day Holter results for patients with recovered SR. Electrocardioversion was performed when oral amiodarone failed to maintain SR. After 3 months post-surgery, the 7-day long-course Holter ECG was reviewed in order to evaluate the SR recovery. The 7-day long-course ECG and the cardiac color ultrasound were reviewed to monitor and verify the SR maintenance, cardiac morphology, and functional status. After 12 months, the postoperative follow-up examination was the same as that performed in June. The blank period was considered when any atrial arrhythmia (AF, atrial flutter, or atrial tachycardia) occurred 90 days after RFCA and was not considered as AF recurrence. Late AF recurrence was defined as all 30-sec AF events (atrial arrhythmia) continuously recorded by any ECG or Holter monitoring device after the 90-day gap period (Citation2).
In this study, there was only one endpoint event: late recurrence of AF during the follow-up period after the blank period. Patients were divided into recurrence and non-recurrence groups, according to late AF recurrence after RFCA.
Statistical analysis
All data were analyzed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 9.0 (GraphPad Software, San Diego, CA, USA). Data distribution was first tested for normality using the Kolmogorov – Smirnov test. If data were normally distributed, continuous variables were expressed as mean ± standard deviation. Otherwise, categorical variables were expressed as frequency and percentage. T-test or non-parametric (Mann – Whitney U) rank sum tests were used for continuous variables. Categorical variables were compared between groups using the Chi-square test or Fisher’s exact test. Univariate and multivariate Cox regression analyses were performed using posterior likelihood ratio methods to identify risk predictors of postoperative AF recurrence. The selection of covariates in multivariate Cox regression analysis mainly had two aspects: variables that were statistically significant in univariate analysis and variables considered clinically meaningful.
Correlation analysis between the ACEF score and the other baseline characteristics was performed using the Spearman’s rank test. Receiver operating characteristic (ROC) curve analysis was used to investigate the diagnostic value of the ACEF score as a predictor of postoperative recurrence of AF and was determined with the Youden Index. A Kaplan – Meier survival curve was constructed to evaluate the incidence of postoperative AF recurrence in each group according to the ACEF score. The difference was considered statistically significant if two-tailed P < .05.
Results
Baseline characteristics and demographical features
We included 380 patients with AF who first underwent RFCA. Of these, 55 patients were excluded according to the exclusion criteria. Finally, a total of 325 patients with AF were included in this study. Of these, persistent AF accounted for 35.4% and paroxysmal AF for 64.6%. Additionally, 52.3% were male and 47.7%, female, with a mean age of 65.36 ± 10.73 years. A total of 74 patients (22.8%) had late AF recurrence during the average follow-up period of 12 months. According to late AF recurrence after RFCA, patients were divided into AF late recurrence and non-recurrence groups. summarizes the baseline demographic characteristics, laboratory data, and discharge data from both groups.
Table 1. Baseline characteristics of study population.
Statistically significant differences between the two groups were observed in age, sex, AF type, BMI, obesity, BNP, urea, endogenous creatinine clearance (Ccr), CysC, LAD, total operation time, ACEF score, and CHA2DS2-VASc score (all P < .05). In addition, patients were divided into the low ACEF group (<1.037) and the high ACEF group (≥1.037) by dichotomy. The subgroup analysis revealed a statistically significant increase in ACEF in the late AF recurrence group (86.5 vs. 13.5, P < .001) (). Additionally, compared with the low ACEF group, patients in the high ACEF group were significantly older (70.94 ± 6.25 vs. 54.15 ± 8.94; P < .001), most were female (55.3% vs. 32.4%; P < .001), with persistent AF (39.2% vs. 27.8%; P = .043), history of hypertension (54.8% vs. 26.9%; P < .001), higher BNP (182.46 ± 253.28 vs. 99.16 ± 119.67; P < .001), higher CCR (77.23 ± 17.80 vs. 85.53 ± 15.75; P < .001), higher CysC (1.12 ± 0.32 vs. 0.99 ± 0.19; P < .001), higher hemoglobin (134.69 ± 15.04 vs. 142.35 ± 17.63; P < .001), higher LAD (41.09 ± 5.45 vs. .39.26 ± 5.36; P = .004), higher EF (59.09 ± 5.91 vs. 60.93 ± 4.54; P = .005), and higher CHA 2 DS2-VASc (P < .001) ().
Figure 1. Percentage of the patients developing late AF recurrence post-ablation divided into the low group and the high group by the cutoff of pre-ablation ACEF score.
Table 2. Clinical characteristics of AF patients according to the ACEF score.
Comparison of the ACEF score
As shown in , patients with late AF recurrence had significantly higher ACEF scores than those without late recurrence (median: 1.13 vs. 1.09; P < .0001). The ACEF score was higher in the LAD>40 mm group than in the LAD<40 mm group (median: 1.11 vs. 1.08, P = .0156). ACEF scores were higher in female patients (median: 1.15 vs. 1.06; P = .0223) as well as in older AF patients (median: 1.17 vs. 0.96; P < .0001).
Figure 2. Comparison of ACEF score. Box plots represent median levels with 25th and 75th percentiles of the value of ACEF score.
Predictors of late AF recurrence using clinical variables
According to univariate Cox proportional hazards regression analysis, advanced age (≥65 years), female sex, AF type (persistent AF), BNP, Ccr, LAD (≥40 mm), ACEF score, and total operation time were significantly associated with late AF recurrence (P < .05). However, history of hypertension, diabetes mellitus, and dyslipidemia were not statistically different between the two groups (). Furthermore, we performed multivariate Cox proportional hazards regression analysis, which revealed that the ACEF score (hazard ratio [HR]: 3.073; 95% confidence interval [CI]: 1.134–8.326; P = .027), LAD (HR: 2.851; 95% CI: 1.326–6.131; P = .007), AF type (persistent AF) (HR: 1.944; 95% CI: 1–3.799; P = .05), and BNP (HR: 3.046; 95% CI: 1.544–6.012; P = .001) were independent risk factors predicting the recurrence of AF after radiofrequency ablation ().
Table 3. Univariate and multivariate Cox proportional hazards regression analysis of late AF recurrence.
Predictive value of the ACEF score
The predictive value of the risk factors for late AF recurrence after RFCA was evaluated by ROC analysis. The area under the curve (AUC) of the ACEF score and LAD was 0.624 (95% CI: 0.556–0.692; P = .0012) and 0.7 (95% CI: 0.634–0.767; P < .0001), respectively (). Furthermore, the Z-test showed no statistically significant differences between the ACEF score and LAD in terms of AUC (Z = 1.624; P = .104). The AUC value of ACEF and LAD was 0.731 (95% CI: 0.667–0.795; P < .0001) (). The cutoff value for the ACEF score was 1.037, according to the ROC analysis. The corresponding sensitivity and specificity were 86.5% and 39%, respectively. Kaplan – Meier analyses revealed that patients in the high ACEF group presented lower event-free survival, compared to those in the low ACEF group (P < .0001 by log-rank test, ).
Figure 3. A Receiver operating characteristic curve (ROC) of ACEF score for predictor of late recurrence of atrial Fibrillation(AF) after RFCA; b ROC of LAD for predictor of late recurrence of AF after RFCA; c ROC of ACEF score for predictor of late recurrence of AF after RFCA; d Event-free survival analyses according to the low grouping and high grouping of pre-ablation ACEF score.
Additionally, the correlation analysis revealed a positive correlation between the ACEF score, advanced age (r = 748; P < .0001), LAD (r = 0.201; P = .0003), and BNP (r = 0.381; P < .0001) (). However, the correlation coefficient was not very high. Studies with a larger sample size are needed to validate our results.
Figure 4. Correlation between age, LAD, BNP and pre-ablation ACEF score. a ACEF score is positively correlated with age (r = 0.748, p < .0001); b ACEF score is positively correlated with LAD (r = 0.201, p = .0003); c ACEF score is positively correlated with BNP level (r = 0.381, p < .0001).
Discussion
In our retrospective study, clinical data from 325 patients with NVAF were systematically reviewed, with a mean follow-up time of 12 months. We also investigated the relationship between the pre-ablation ACEF score and LAD, prognostic risk scores, and other crucial biomarkers. Our results revealed that the pre-ablation LAD and ACEF score were reliable and independent predictive factors of late AF recurrence.
In addition, we specifically focused on the predictive ability of the ACEF score to estimate late AF recurrence after RFCA, showing an AUC of 0.624 (95% CI, 0.556–0.692; P = .0012) in patients with NVAF. The AUC value was not ideal, but Ding et al. (Citation22) previously reported an AUC for LAD of 0.658 (95% CI, 0.585–0.732; P < .0001), which is similar to our result. It is known that LAD is a valuable predictor of late AF recurrence after RFCA (Citation22,Citation23). Furthermore, correlation analysis in this study indicated a positive correlation between ACEF and LAD(r = 0.201; P = .0003). Therefore, the ACEF score of our study may also be a valuable predictor of late AF recurrence after RFCA. Moreover, the AUC of LAD was 0.7 (95%CI: 0.634–0.767; P < .0001), which was higher than the ACEF score, but the Z test showed no significant difference between ACEF score and LAD (Z = 1.624; P = .104). Therefore, it can be considered that the ACEF score in this study has the same predictive value of LAD for late AF recurrence after RFCA.
We also further investigated the predictive value of the ACEF score and LAD, showing an AUC value of 0.731 (95%CI, 0.667–0.795; P < .0001), revealing that the ACEF score improves the predictive value of LAD. Therefore, the ACEF score has some predictive value for late AF recurrence and is worth applying, along with LAD. The ACEF score has the potential to serve as a simple, comprehensive, and noninvasive tool to assess the risk of late NVAF recurrence.
Currently, the increasing number of patients with AF cannot be ignored (Citation1,Citation2). Understanding which patients will benefit from RFCA still remains a considerable challenge. However, late AF recurrence, as well as the first AF diagnosis, is often asymptomatic and difficult to notice. Thus, determining the predictors of late AF recurrence after RFCA is important for selecting appropriate individualized treatment options. This study revealed that the ACEF score may be a new scoring system for predicting late recurrence of AF. As far as we know, this is the first study to apply the ACEF score to an AF cohort. Moreover, this study also showed that late AF recurrence was closely related to the clinical characteristics, AF type, cardiac function, and LAD, which is similar to findings previously reported (Citation22–24).
The precise mechanisms of late AF recurrence have not been fully elucidated (Citation25). It is well established that inflammation, oxidative stress, and atrial structural remodeling are involved in the recurrence of AF (Citation26–28). Previous studies have shown that chronic kidney disease (CKD) causes these pathophysiological changes in AF recurrence and maintenance, thereby increasing the risk of late AF recurrence (Citation29,Citation30). Moreover, some studies have shown that AF and CKD share common cardiovascular risk factors (Citation31). Therefore, renal function may be a modifiable AF risk factor (Citation17).
Currently, serum creatinine is widely used as a marker of renal function in clinical practice (Citation18). Therefore, it is worthwhile to study the recurrence AF potential after RFCA with serum creatinine. Given that late recurrence of AF is significant (Citation32), it is crucial to select appropriate patients for RFCA. However, there are few scoring models in the literature for predicting late AF recurrence and building more manageable scoring models remains the goal of researchers and clinicians (Citation33–35).
In 2009, Ranucci et al (Citation20), established the ACEF score following the law of simplicity. The ACEF score contains only the three objective and important prognostic indicators of age, and renal and cardiac functions. Previous studies have shown that the ACEF score is a valuable clinical score in multiple clinical situations and populations in multiple centers, due to its strong predictive ability (Citation19,Citation21). Currently, the prognosis value of ACEF score for coronary heart disease cohorts has been recommended by guidelines and applied worldwide (Citation36), but it has not been applied to AF cohorts. This study included all post-RFCA patients with NVAF from January 2019 to 20 August 2021. Our dataset was derived from all the RFCA patients with NVAF from our hospital and has data on long-term follow-up, aiming to provide more useful information for current clinical practice. Furthermore, to our knowledge, this is the first validation of the ACEF score for RFCA in AF patients on a Chinese population.
In addition, our study showed a higher late AF recurrence rate after RFCA with increasing age, similar to the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial (Citation37). Sex differences were present, as female patients with AF were prone to late recurrence, consistent with the data reported in the CABANA trial, where the findings support catheter ablation as an effective strategy for both males and females (Citation38).
This study focused on the ability of the pre-ablation ACEF score to predict the late recurrence of AF after RFCA in patients with NVAF, providing evidence-based insights for the scoring system in order to predict the risk of late AF recurrence after RFCA. Our findings showed that the preoperative ACEF score may be useful for assessing the risk of late AF recurrence after RFCA, selecting appropriate patients for surgery, reducing unnecessary intervention, facilitating early detection of high-risk relapse patients, and providing corresponding intensive intervention to improve the long-term outcomes of patients.
Limitations
The predictive value of the ACEF score in predicting late recurrence of NVAF is relatively low. This study was a single-center retrospective study. Therefore, the conclusions need to be further explored in multiple centers before generalization. And, the study had a small sample size and the postoperative follow-up time was limited. Moreover, the recurrence of asymptomatic AF may have been overlooked during the follow-up process, leading to some bias in the detection of postoperative late recurrence of AF.
Conclusion
In our study, we observed that an elevated pre-ablation ACEF score was associated with an increased risk of late AF recurrence after RFCA. Furthermore, the ACEF score independently predicted late AF recurrence after RFCA with a predictive value comparable to LAD.
Acknowledgments
We would like to thank Editage (www.editage.cn) for English language editing.
Disclosure statement
No potential conflict of interest was reported by the authors.
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.
Additional information
Funding
References
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