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Introduction

Atrial fibrillation (AF) is one of the most common types of cardiac arrhythmia, and incidence of AF is increasing with the aging of the global population (1,2). AF usually coexists with heart failure (HF) and can exacerbate adverse cardiovascular outcomes (3,4). AF can lead to HF decompensation or serve as the primary trigger for HF onset. Reciprocally, HF can promote AF through multiple mechanisms, including atrial pressure overload, impaired myocardial conduction, maladaptive genetic changes, and structural remodeling (5). Based on ejection fraction, HF is classified into two groups, including HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Previous studies have shown a higher risk of all-cause mortality in patients with HFpEF or HFrEF when combined with AF (6,7). Compared with antiarrhythmic drug therapy, catheter ablation achieves better outcomes with substantial reduction in AF burden (8). Increasing studies have shown that radiofrequency ablation is an effective treatment for patients with persistent AF and high-frequency HF (9,10). In recent years, multiple catheter ablation techniques have been explored in different medical centers to address recurrence after pulmonary vein isolation, with varying success rates in treating persistent AF (11).

Based on clinical observations, patients with AF and high-frequency HF predominantly present with persistent AF. The ligament of Marshall is initially characterized by Marshall in 1850(12). The vein of Marshall (VOM), an embryological remnant of the superior vena cava, serves as a potential source of AF triggers and contains both sympathetic and parasympathetic nerve fibers that contribute to AF pathogenesis and maintenance (13). Ethanol infusion into the VOM during AF ablation procedures can achieve dual therapeutic effects: elimination of AF triggers and facilitation of mitral isthmus block (14). This approach could potentially address a key limitation of conventional linear ablation techniques. A number of recent international studies, such as VENUS randomized trial (15), the Marshall-Plan (16), and the upgraded 2C3L approach (17), have indicated that VOM-ethanol infusion (VOM-EI) in combination with catheter ablation increase the rate of bi-directional mitral isthmus block and improve the maintenance of sinus rhythm in patients with persistent AF. However, these studies also showed that VOM-EI leads to increased cardiac volume loading and the risk of worsening HF. Therefore, the optimal strategy for the treatment of persistent AF and HF remains unclear.

In the present study, a single-center retrospective study of 85 patients with persistent AF and HFrEF in the First Affiliated Hospital of Shandong First Medical University was applied, of whom 40 patients were treated with catheter ablation plus VOM-EI, and the remaining 45 patients were treated with catheter ablation alone. The aim of the present study was to evaluate the efficacy and safety of VOM-EI in conjunction with catheter ablation for the treatment of patients with persistent AF and HFrEF.

Materials and methods

Participants and study design

The sample size of retrospective observational study was calculated as reported previously (18); 85 patients with persistent AF and HFrEF admitted between January 2018 and December 2023 at the First Affiliated Hospital of Shandong First Medical University (Jinan, China) were included in the present study. Persistent AF was defined as having a minimum duration of 1 week and a maximum duration of 1 year. HFrEF was defined as left ventricular ejection fraction (LVEF) ≤50% and patients have received improving HF therapy for at least 1 month. The inclusion criteria included 45-75 years of age, clinical diagnosis of persistent AF and HFrEF with poor pharmacologic outcomes, AF lasting for >1 month but <1 year, LVEF range from 29-50%, New York Heart Association (NYHA) classification II, III, or IV, complete clinical baseline and follow-up data. Exclusion criteria were as follows: (i) NYHA classification I; (ii) left atrium diameter (LAD) >60 mm; (iii) severe valvular heart disease, intraventricular conduction block or left bundle branch block; (iv) thyroid diseases; (v) contraindications to amiodarone; (vi) presence of atrial thrombosis; (vii) severe hypotension or bradycardia; (viii) history of ablation surgery within 1 year, (ix) severe hepatic, renal or pulmonary insufficiency and (x) pregnancy, breastfeeding, or mental illness.

The 85 patients with persistent AF and HFrEF were divided into two groups including group A (n=40) and group B (n=45). The patients in the group A (male/female: 29/11, average age: 62.33±11.50 years) received VOM-EI combined with catheter ablation treatment, and the patients in group B (male/female: 34/11, average age: 59.36±10.91 years) received catheter ablation treatment only. The flowchart for the present study is demonstrated in Fig. 1. The present study was approved (approval no. 2018-094) by the Ethics Committee of the First Affiliated Hospital of Shandong First Medical University (Jinan, China) and complied strictly with the 2008 Declaration of Helsinki Principle. Written informed consent was obtained from all participants.

Figure 1 Flow of study design in patients with persistent AF and HFrEF for VOM-EI combined with catheter ablation vs. conventional catheter ablation. AF, atrial fibrillation; HFrEF, heart failure with reduced ejection fraction; VOM-EI, vein of Marshall ethanol infusion.

Baseline data collection

The baseline characteristics of each patient in the two groups were reviewed from electronic medical records system, including age, sex, body mass index (BMI), smoking, drinking, past medical history (hypertension, type 2 diabetes, chronic kidney disease, stroke, hyperthyroidism, hypothyroidism), AF course, HF etiology (non-ischemic cardiomyopathy and ischemic cardiomyopathy), heart rate, NYHA classification (II, III and IV), echocardiographic parameters [LVEF, LAD and left ventricular end diastolic volume (LVEDV)], biochemical indicators [hemoglobin, glomerular filtration rate (GFR), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), total cholesterol (TC), B-type natriuretic peptide (BNP)], and medication history [beta-blocker, angiotensin converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (ACEI/ARB/ANRI) and sodium-glucose cotransporter 2 (SGLT2) inhibitor].

Based on the clinical information, patients were subsequently scored on congestive HF, hypertension, age, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age, sex category (CHA2DS2-VASc) (19), and hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile International Normalized Ratio, elderly, drugs/alcohol concomitantly (HAS-BLED) (20).

Catheter ablation

Prior to catheter ablation, group B patients received enhanced HF management and at least 3 weeks of oral anticoagulation. Antiarrhythmic drugs were discontinued for at least five half-lives. A total of 3 days before surgery, oral anticoagulants were replaced with subcutaneous low molecular weight heparin sodium, considering the patient's renal function, thrombosis risk and clinical experience. Transesophageal echocardiography was used to rule out atrial thrombus pre-procedure.

Catheter ablation was performed using the traditional bilateral femoral vein approach. A SmartTouch pressure ablation catheter was used to quantify the Ablation Index (AI) of the anterior, apical, and posterior walls of the pulmonary veins, and the AIs of the anterior, apical, and posterior walls of the pulmonary veins were 450, 400, and 350, respectively. Then linear ablation of the left atrial roof, mitral isthmus, and tricuspid isthmus. If the pulmonary veins remained in an AF rhythm after complete electrical isolation of the pulmonary veins, midazolam was given intravenously to sedate the patient and then synchronized with direct-current electrical rewarming. Pentaray electrodes were used to determine the degree of left atrial fibrosis by left atrial stromal specimens. Fibrosis or scarring was defined as a local potential of 0.5 MV, and homogenization ablation was performed if there was significant scarring and folded back matrix.

When AF persisted or reverted to atrial tachycardia (AT), cardioversion was performed to determine the efficacy of catheter ablation. The duration of the procedure is the time interval between the start of venipuncture and the removal of the sheath. Ablation endpoints were defined by successful pulmonary vein isolation and bidirectional block. After ablation, oral anticoagulants were mandated for a minimum of three months, Amiodarone was routinely administered for 3 months to prevent arrhythmias. In addition, the proton pump inhibitor rabeprazole should be administered for 3 months.

VOM-EI combined with catheter ablation

Group A patients underwent VOM-EI combined with catheter ablation after receiving enhanced HF therapy, discontinuation of antiarrhythmics and anticoagulation treatment. The procedure followed the typical VOM-EI protocol as previously described (21). A long sheath of SL1 was inserted through the right femoral vein into the coronary sinus (CS) opening, and then the right coronary guide tube JR4 was delivered to the CS opening. JR4 was rotated clockwise, and the head of the guide tube was pointed in a posterior-superior direction under right anterior oblique 30-degree fluoroscopy to find the VOM chamber. After selective VOM venography, a BMW guidewire was guided proximal to the VOM and supported by an OTW balloon (1.5-2.5 mm in diameter, Boston Scientific), which was placed at the middle and distal to the VOM. The balloon was inflated to a maximum of 6-8 atm, then the BMW guidewire was removed and VOM angiography was performed. Selective venography of the VOM was repeated by slowly injecting 2-4 ml of 95% ethanol through the OTW balloon into the middle/distal VOM. The total amount of continuous injection was 9 ml and the maximum amount of ethanol allowed was 12 ml. A 6F decapolar catheter was then introduced into the CS, and an 8-long sheath was introduced into the LA after successful puncture of the interatrial septum.

After left pulmonary venography, the left atrium was reconstructed under the guidance of a three-dimensional mapping system (Carto®3 system, Biosense Webster Inc.). A cold saline infusion catheter was first used to perform bilateral pulmonary vein vestibular loop ablation. Subsequently, ablation of the left atrial roof line, mitral isthmus line, and tricuspid isthmus line was performed with the goal of achieving bidirectional obstruction as per the protocol. Ablation of the mitral isthmus began ~1 cm from the junction of the VOM and coronary veins and continued into the low voltage zone. Afterward, ablation procedure was performed at the corresponding epicardial sites within the coronary veins. Finally, the tricuspid isthmus was ablated, starting at 6 a.m. in the tricuspid annulus and continuing to the inferior vena cava. The pulmonary veins were then examined for isolation and linear bidirectional obstruction. Ablation endpoints were defined by successful pulmonary vein isolation and bidirectional block. Postoperative patients' medications were the same as in group B.

Follow-up after surgery

As referenced in previous studies (22,23), the patients who returned to sinus rhythm in both groups underwent follow up for 1, 3, and 6 months. Follow-up was predominantly carried out via outpatient review and telephone communication. It involved detailed inquiries into symptoms such as palpitations, chest tightness, shortness of breath, dizziness and fatigue, along with their frequency, duration and severity. Physical examinations for heart murmurs and pulmonary crackles were also part of this process. The telephone communication lasted 10-20 min at each measurement point and was conducted by a single researcher. Follow-up examinations included 12-lead electrocardiogram (ECG) and 24-h Holter ECG Monitoring to detect the occurrence of AF/AT, and echocardiography to evaluate LVEF, LAD and LVEDV parameters. AF recurrence was defined as a postoperative episode of atrial arrhythmia including AF/AT lasting >30 sec after surgery.

Observation indicators

The study compared the two groups in terms of primary endpoint events and secondary endpoint events. The primary endpoint events comprised the rate of restoration of sinus rhythm after surgery and the rate of postoperative AF recurrence at follow-up. The secondary endpoint events comprised cardiac function parameters (LVEF, LAD and LVEDV), NYHA classification, BNP levels and the rate of postoperative rehospitalization at follow-up. Surgery duration and perioperative adverse events (pericardial effusion, inguinal hematoma, acute left HF, cardiac perforation, pericardial tamponade, CS rupture, massive bleeding and atrial-esophageal fistula) were compared between the two groups.

Statistical analysis

Statistical analysis was performed using SPSS 27.0 software (IBM Corp.). Statistical graphs were created using GraphPad Prism 9 (Dotmatics For normally distributed variables, quantitative data were expressed as the mean ± standard deviation (SD), and assessed statistical difference through the two-tailed unpaired Student's t-test (two groups) or the one-way ANOVA followed by Tukey's test (≥ three groups), as appropriate. Categorical data were expressed as frequencies and percentages. Statistical difference was assessed through the chi-square test or Fisher's exact test, as appropriate. The Kaplan-Meier method and log-rank test were used to estimate differences in cumulative rate of free AF recurrence between two groups. A two-tailed P<0.05 was considered to indicate a statistically significant difference.

Results

Comparison of baseline data

The baseline data of the patients between the two groups were shown in Table I. Statistical analysis showed that there were no statistically significant differences between the two groups in terms of baseline data including age, sex, BMI, smoking, drinking, past medical history, AF course, HF etiology, heart rate, NYHA classification, echocardiographic parameters, biochemical indicators, and medication history (all P>0.05). The CHA2DS2-VASc score in the group A and group B was 3.48±1.58 and 3.13±1.63, respectively, with no statistical difference (P>0.05). Additionally, there was no statistical difference in HAS-BLED score between the two groups (0.90±0.87 vs. 0.76±0.80, P>0.05).

Table I Comparison of baseline data between group A and group B.

Table I

Comparison of baseline data between group A and group B.

Characteristics	Group A (n=40)	Group B (n=45)	P-value
Age, years	62.33±11.50	59.36±10.91	0.226
Sex, male/female	29/11	34/11	0.748
Body mass index (kg/m2)	25.72±5.55	26.07±5.10	0.762
Smoking [n, (%)]	7 (17.50)	4 (8.89)	0.238
Drinking [n, (%)]	11 (27.50)	7 (15.56)	0.179
Past medical history [n, (%)]
Hypertension	28 (70.00)	23 (51.11)	0.076
Type 2 diabetes	7 (17.50)	14 (31.11)	0.146
Chronic kidney disease	2 (5.00)	3 (6.67)	1.000
Stroke	9 (22.50)	6 (13.33)	0.268
Hyperthyroidism	2 (5.00)	2 (4.44)	1.000
Hypothyroidism	0 (0.00)	1 (2.22)	1.000
Atrial fibrillation course, months	30.15±42.55	21.70±38.79	0.341
Heart failure etiology [n, (%)]			0.395
Non-ischemic cardiomyopathy	34 (85.00)	35 (77.78)
Ischemic cardiomyopathy	6 (15.00)	10 (22.22)
Heart rate (beats/min)	101.12±19.27	101.93±25.96	0.872
New York Heart Association classification, [n, (%)]			0.529
II	11 (27.50)	8 (17.78)
III	23 (57.50)	28 (62.22)
IV	6 (15.00)	9 (20.00)
Echocardiographic parameters
Left ventricular ejection fraction (%)	41.95±5.42	39.80±6.60	0.107
Left atrium diameter, mm	47.23±4.32	46.58±4.59	0.507
Left ventricular end diastolic volume, mm	53.58±5.35	54.07±6.87	0.716
CHA2DS2-VASc score	3.48±1.58	3.13±1.63	0.332
HAS-BLED score	0.90±0.87	0.76±0.80	0.428
Hemoglobin, g/l	149.12±18.63	146.18±18.20	0.463
Glomerular filtration rate, ml/min	82.86±18.07	82.93±21.19	0.987
Creatinine, µmol/l	86.44±21.07	90.43±25.08	0.433
Alanine aminotransferase, U/l	28.65±16.77	35.08±32.09	0.259
Aspartate aminotransferase, U/l	25.52±11.48	28.22±16.51	0.389
Low-density lipoprotein, mmol/l	2.33±0.87	2.33±0.66	0.994
High-density lipoprotein, mmol/l	0.91±0.45	0.98±0.28	0.430
Triglycerides, mmol/l	1.31±0.75	1.34±0.53	0.794
Total cholesterol, mmol/l	3.91±1.13	3.96±0.91	0.824
B-type natriuretic peptide, pg/ml	580.89±524.60	515.08±425.05	0.525
Medication history [n (%)]
Beta-blocker	18 (45.00)	29 (64.44)	0.072
ACEI/ARB/ANRI	26 (65.00)	28 (62.22)	0.791
Sodium-glucose cotransporter 2 inhibitor	12 (30.00)	8 (17.78)	0.185

Evaluation of restoration of sinus rhythm after surgery

Postoperatively, 36 patients in group A and 38 patients in group B immediately restored sinus rhythm, respectively. No significant differences were observed between the two groups in the rate of sinus rhythm restoration (90.0 vs. 84.44%) (P>0.05). These data revealed that VOM-EI combined with catheter ablation is as effective as catheter ablation alone in restoration of sinus rhythm.

Evaluation of surgery duration and perioperative adverse events

As summarized in Table II, the surgery duration in group A was significantly shorter than that in group B (156.78±39.36 min vs. 181.73±52.39 min, P<0.05). Perioperatively, one patient in group A developed pericardial effusion, while two patients in group B also developed pericardial effusion. None of these patients required pericardiocentesis or drainage, and the effusions subsided after conservative management. In each group, there were two patients who developed inguinal hematoma, and these were effectively controlled using pressure dressing. In addition, no cases of acute left HF, cardiac perforation, pericardial tamponade, CS rupture, massive hemorrhage and atrial-esophageal fistula were observed in either group. Results showed that no statistically significant difference was observed in the overall incidence of perioperative adverse events between the two groups (7.5% vs. 8.89%, P>0.05). The findings indicated that the combination of VOM-EI and catheter ablation provides comparable safety to catheter ablation and helped shorten the surgical duration.

Table II Comparison of surgery duration and perioperative adverse events between group A and group B.

Table II

Comparison of surgery duration and perioperative adverse events between group A and group B.

Variables	Group A (n=40)	Group B (n=45)	P-value
Surgery duration (min)	156.78±39.36	181.73±52.39	0.016
Perioperative adverse events [n (%)]
Pericardial effusion	1 (2.50)	2 (4.44)
Inguinal hematoma	2 (5.0)	2 (4.44)
Acute left heart failure	0	0
Cardiac perforation	0	0
Pericardial tamponade	0	0
Coronary sinus rupture	0	0
Massive bleeding	0	0
Atrial-esophageal fistula	0	0
Total	3 (7.5%)	4 (8.89%)	1.0

Evaluation of cardiovascular outcomes at follow-up

The cardiovascular outcomes of patients who returned to sinus rhythm were presented in Table III. One in group A and eight in group B had AF recurrence during the 6-month follow-up, with a statistical difference observed (2.78 vs. 21.05%; P<0.05). In group A, one patient was re-hospitalized due to worsening cardiac function, while six patients in group B were re-hospitalized for the same reason. However, the difference was not statistically significant (2.78 vs. 15.79%, P>0.05). No patient deaths occurred in either group. Kaplan-Meier survival analysis showed that patients returned to sinus rhythm in group A had a significantly lower cumulative rate of free AF recurrence than those patients in group B (Fig. 2; P<0.05). These results suggested that combining VOM-EI with catheter ablation decreases the risk of postoperative AF recurrence relative to catheter ablation alone.

Figure 2 Kaplan-Meier curves analysis of free AF recurrence. Patients returned to sinus rhythm in group A had a significantly lower cumulative rate of free AF recurrence than those patients in group B. AF, atrial fibrillation.

Table III Comparison of cardiovascular outcomes and cardiac function restoration between group A and group B at follow-up.

Table III

Comparison of cardiovascular outcomes and cardiac function restoration between group A and group B at follow-up.

Variables	Group A (n=36)	Group B (n=38)	P-value
Atrial fibrillation recurrence, [n, (%)]	1 (2.78)	8 (21.05)	0.029a
Rehospitalization, [n, (%)]	1 (2.78)	6 (15.79)	0.108
New York Heart Association classification, [n, (%)]			0.033a
II	18 (50.0)	9 (23.68)
III	17 (47.22)	24 (63.16)
IV	1 (2.78)	5 (13.16)
B-type natriuretic peptide, pg/ml	429.21±407.25	491.60±458.34	0.038a
Left ventricular ejection fraction (%)			<0.001a
1 month	53.93±8.56b	49.78±8.99
3 months	57.51±7.93b	53.11±9.91
6 months	59.22±9.01b	53.47±9.88
Left atrium diameter, mm			0.740
1 month	42.80±5.89	42.91±4.39
3 months	42.82±5.98	41.62±4.07
6 months	42.31±4.70	41.04±4.25
Left ventricular end diastolic volume, mm			0.529
1 month	51.23±5.92	53.87±5.81
3 months	50.87±4.69	52.76±5.60
6 months	49.97±5.69	51.91±5.98

[i] Categorical data were expressed as frequencies and percentages, and quantitative data were expressed as the mean ± standard deviation.

[ii] ^aP<0.05. Compared with Group B,

[iii] ^bP<0.05.

Evaluation of cardiac function restoration at follow-up

Compared with preoperative levels, LVEF values were significantly higher in both groups at follow-up, whereas both LAD and LVEDV values were significantly lower (Fig. 3; all P<0.05). Furthermore, during 1, 3, and 6 months of follow-up, LVEF values gradually increased in group A; in contrast, there were no significant differences in LVEF values in group B at the 3 and 6 months of follow-up (P>0.05). No significant differences were found in LAD and LVEDV values in group A at 1, 3, and 6 months follow-up, and similar results were presented for LAD and LVEDV values in group B (all P>0.05).

Figure 3 Evaluation of cardiac function restoration in patients returned to sinus rhythm between group A and group B at follow-up. (A) LVEF, (B) LAD and (C) LVEDV parameters were detected in patients preoperatively and at 1, 3, and 6 months of postoperative follow-up, respectively. LVEF, left ventricular ejection fraction; LAD, left atrium diameter; LVEDV, left ventricular end diastolic volume. ns, not significant (P>0.05).

Moreover, compared with group B, LVEF values were significantly higher in group A at 1, 3, and 6 months of follow-up (Table III, all P<0.05). However, there was no statistically significant difference in LAD and LVEDV values between the two groups (all P>0.05). In addition, compared with group B, NYHA classification and BNP levels showed significant improvement in group A at 6 months of follow-up (all P<0.05). Collectively, the evidence demonstrated that VOM-EI in conjunction with catheter ablation results in improved restoration of cardiac function than catheter ablation alone.

Discussion

The innovative aspect of the present retrospective study was the comparative analysis of the therapeutic efficacy and safety of VOM-EI combined with catheter ablation vs. conventional catheter ablation in patients with persistent AF and HFrEF, thereby providing valuable insights into optimizing treatment strategies for these complex clinical conditions. The findings of the present study indicated that VOM-EI combined with catheter ablation provides significant benefits over catheter ablation alone, including improved cardiac function restoration, a lower postoperative AF recurrence rate, and shorter procedure time, without increasing perioperative complications or adverse clinical events.

A previous study by Valderrábano et al (24) found that VOM-EI significantly reduces the time required for catheter ablation to achieve isolation of the left inferior pulmonary vein. Takigawa et al (25) also reported that VOM-EI reduces the time required for catheter ablation to achieve bi-directional mitral isthmus block and perimitral atrial flutter. Recently, Kamakura et al (26) indicated that after VOM-EI, the low voltage is predominantly distributed on the pulmonary vein side of the mitral isthmus as well as on the anterior border and base of the left inferior pulmonary vein, thus reducing the time requirement for catheter ablation procedures. Consistent with these aforementioned studies, it was found that the surgery duration for VOM-EI combined catheter ablation was significantly shorter than catheter ablation alone.

Concurrently, the present findings indicated that combining VOM-EI with catheter ablation achieves comparable efficacy in restoring sinus rhythm to catheter ablation alone, which aligns with prior research (15-17). Increasingly, acute tissue edema has been found to be a key factor limiting effective lesion formation (27). Radiofrequency ablation can be precisely localized to residual conduction based on voltage mapping after VOM-EI, thereby minimizing tissue edema and reducing perioperative complications. Previous studies have shown that longer duration of mitral isthmus catheter ablation is associated with a higher incidence of pericardial effusion (28,29). Combining VOM-EI with catheter ablation may reduce the duration and intensity of catheter ablation, thereby reducing the risk of pericardial effusion and cardiac tamponade. VOM-EI-associated pericardial effusion is primarily the result of perforation of the vein of Marshall, a complication that can be prevented with careful wire manipulation and appropriate balloon selection to minimize the risk of stop vessel injury and contrast leakage into the CS (30). In the present study, 3 patients developed pericardial effusion, which resolved spontaneously after receiving conservative diuretic therapy. These results suggested that VOM-EI in combination with catheter ablation provides comparable safety to catheter ablation and helps shorten the surgical duration.

A study of multivariate analysis by Liu et al (31) suggested that VOM-EI is an independent predictor for free AF recurrence. Gillis et al (32) demonstrated that when VOM-EI combined with catheter ablation, the success rate of mitral isthmus block is almost 100%. This may be due to the fact that VOM-EI causes sufficient left pulmonary vein injury to enhance the durability of pulmonary vein isolation and effectively block residual electrical conduction due to epicardial connections. Also, VOM-EI facilitates mitral isthmus conduction block and improves the success rate of this block (33). According to our follow-up data on cardiovascular outcomes, patients who received VOM-EI in combination with catheter ablation had a lower incidence of AF recurrence than those who underwent catheter ablation alone. Similar results have been reported in the VENUS trial (15). Therefore, it was concluded that VOM-EI, as an adjunctive technique, improves the efficacy of pulmonary vein isolation and bidirectional block in patients with persistent AF and HFrEF, prevents residual postoperative epicardial electrical conduction connections, and thus reduces the recurrence rate of AF.

Previous studies have shown that the main feature of AF is elevated atrial and ventricular filling pressures, leading to left atrial dilatation, scar formation and fibrosis (34,35). These changes shorten the atrial refractory period, creating a favorable environment for the onset and persistence of AF. Atrial enlargement leads to mitral and tricuspid regurgitation, which worsens cardiac output and filling pressures, leading to the development of high-incidence AF (3,36). Follow-up of our study revealed a significant increase in LVEF and a significant decrease in LVEDV and LAD in both groups. Notably, the group treated with VOM-EI plus catheter ablation exhibited more pronounced improvements in LVEF at 1, 3, and 6 months of follow-up, as well as significantly greater enhancements in NYHA classification and BNP levels compared with the catheter ablation alone group. Accordingly, combining VOM-EI with catheter ablation is effective in restoring cardiac function in patients with persistent AF and HFrEF. This enhanced recovery of cardiac function may be due to the higher long-term maintenance of sinus rhythm in the VOM-EI combined catheter ablation group, which resulted in more effective reversal of severe ventricular systolic dysfunction.

There are some limitations that need attention. First, as a single-center retrospective study, it was susceptible to selection bias and information inaccuracy. Furthermore, unmeasurable confounders, such as patients' adherence to anticoagulation or management of comorbidities, may affect the results of the study. To strengthen the evidence base, future studies should use multicenter, prospective, randomized controlled trials. Second, the small sample size of the present study limited the generalizability of the findings, thus a larger cohort is needed to validate these observations. Furthermore, only 6 months of follow-up limited the understanding of long-term efficacy of VOM-EI combined with catheter ablation. Thus, extended follow-up (at least one year) is needed to assess the sinus rhythm maintenance, AF recurrence rate and cardiac function improvement. In addition, use of periprocedural heparin bridging is inconsistent with the 2024 ESC recommend guidelines for AF antithrombotic therapy, and this empirical medication use could potentially affect outcomes. Finally, the present study relied primarily on echocardiographic parameters to assess cardiac function, and more comprehensive assessment tools such as cardiac magnetic resonance imaging are needed to further assess cardiac function in future studies.

In conclusion, the present study demonstrated that VOM-EI combined with catheter ablation is highly effective and safe approach to treat patients with persistent AF and HFrEF. This combination significantly shortens procedure time, improves restoration of cardiac function, and reduces postoperative AF recurrence during follow-up. Nevertheless, large-scale, long-term prospective studies are needed to further validate our findings. Additionally, more research on the long-term efficacy and potential mechanisms of VOM-EI is needed to optimize its clinical application.

Acknowledgements

Not applicable.

Funding

Funding: The present study was supported by the Shandong Natural Science Foundation Project (grant no. ZR2020MH024) and the Clinical Research Fund of Shandong Medical Association-Qilu Special Project (grant no. YXH2022ZX02138).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

SC and HH were involved in the conception and design. SC, JY, XL and YW were involved in data collection and statistical analysis. SC was involved in the drafting of the manuscript. HH made critically revision for intellectual content of the manuscript. SC and JY confirm the authenticity of all the raw data. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

The present study was approved by the Ethics Committee of the First Affiliated Hospital of Shandong First Medical University (approval no. 2018-094). Written informed consent was obtained from all participants and controls in accordance with the Declaration of Helsinki.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References