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.

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).

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.

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.

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.

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 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.

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).

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.

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.

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.

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).

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.