Original Research

Chronic Effects of Vein of Marshall Ethanol Infusion on Pulmonary Vein and Mitral Isthmus Reconnection

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Abstract

Background: While combined vein of Marshall ethanol infusion (EIVOM) and radiofrequency ablation improves acute left pulmonary vein (LPV) isolation and posterior mitral isthmus block in nonparoxysmal AF (non-PAF) ablation, its long-term efficacy remains unclear. This multicentre cohort study aimed to evaluate the chronic effect of EIVOM on LPV and mitral isthmus conduction recovery beyond 3 months post-initial ablation. Methods: We retrospectively analysed consecutive non-PAF patients undergoing reablation across three tertiary centres, categorised by EIVOM use during initial ablation: the EIVOM cohort (n=41) versus the non-EIVOM cohort (n=50). Primary endpoints included the prevalence and anatomical distribution of conduction gaps at the LPV antrum and posterior mitral isthmus lines. Results: LPV reconnection rates were comparable (39% in the EIVOM cohort versus 28% in non-EIVOM cohort; p=0.27), with the EIVOM cohort showing more frequent conduction gaps at the inferior antrum of the LPV. Mitral isthmus conduction recovery was significantly reduced in the EIVOM cohort versus the non-EIVOM cohort (46.3% versus 80.8%; p=0.002). Absence of EIVOM use (OR 3.611; 95% CI [1.377–9.465]; p=0.009) and AF duration (OR 1.012; 95% CI [1.002–1.023]; p=0.021) were significant predictors for mitral isthmus conduction recovery. Mitral isthmus conduction gaps were commonly localised at the lateral ridge in both cohorts; endocardial mitral annulus conduction gaps were more frequent in the EIVOM cohort and epicardial vein of Marshall-related epicardial conduction gaps were predominant in the non-EIVOM cohort. Conclusion: The combined EIVOM-radiofrequency ablation strategy significantly improved chronic mitral isthmus block durability but did not enhance long-term durability of LPV isolation compared with radiofrequency ablation alone. Distinct anatomical patterns of LPV and mitral isthmus conduction recovery provide useful clues for refining ablation strategies in non-PAF ablation.

Received:

Accepted:

Published online:

Disclosure: The authors have no conflicts of interest to declare.

Funding: This study was supported by funding from Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2023ZD0513400), National Natural Science Foundation of China (No. 82400377) and Special Fund for Clinical Research of Shanghai Municipal Health Commission (20224Y0020).

Acknowledgements: LK and TS contributed equally to this work. WJ and XW are considered co-last authors.

Data availability: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions: Conceptualisation: XW; data curation: LK, TS; formal analysis: YS, JH, WJ; visualisation: LK; writing – original draft: XW, LK; writing – review & editing: XW, LK.

Ethics: This study was carried out in accordance with Declaration of Helsinki of the World Medical Association and approved by the Human Research Ethics Committee of Renji Hospital and three other centres (Shanghai Jing’an District Central Hospital, Fudan University; Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University; Dachang Hospital (Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University).

Consent: All patients have given written informed consent.

Correspondence: Xin-hua Wang, Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Rd, Shanghai, China 200127. E: wangxinhua@renji.com

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Despite significant advancements in radiofrequency ablation (RFA) tools, lesion durability remains a critical challenge and a major concern in catheter ablation for AF as it is closely linked to clinical effectiveness.1–6 Pulmonary vein reconnection and linear lesion conduction recovery are among the most common factors contributing to late recurrence post-ablation.7–10 Achieving mitral isthmus block is particularly challenging with RFA alone because of complex anatomical structures, the ‘heat sink’ effect associated with epicardial vessels and the presence of epicardial bypass connections.11–16

The vein of Marshall, one of the therapeutic neuromodulation targets of the autonomic nervous system for AF, has a significant role in the structures predisposing to the triggers, perpetuators and substrate for AF.17 Recent studies have demonstrated that vein of Marshall ethanol infusion (EIVOM) followed by RFA requires fewer RFA lesions and shorter time to achieve posterior mitral isthmus line block and left pulmonary vein (LPV) isolation, while also reducing acute conduction recovery compared with RFA alone.18–27 However, there is limited discrepant evidence to support whether this combined approach enhances the long-term durability of LPV isolation and posterior mitral isthmus line block.28,29

In this multicentre, retrospective cohort study, we aimed to evaluate the durability of LPV isolation and chronic posterior mitral isthmus block in patients undergoing reablation for recurrent AF or atrial flutter (AFL) following the index ablation.

Central Illustration: Chronic Vein of Marshall Ethanol Infusion Effects on Pulmonary Vein Isolation and Mitral Isthmus

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Methods

Study Population

Between January 2023 and October 2024, a consecutive cohort of patients with nonparoxysmal AF (non-PAF) underwent catheter ablation at three tertiary medical centres. Patients experiencing recurrence of AF or AFL beyond the 3-month blanking period post-initial ablation were eligible for inclusion.

The inclusion criteria required that patients had achieved procedural endpoints (including complete pulmonary vein isolation [PVI] and posterior mitral isthmus line conduction block) during the index ablation, were willing to undergo a repeat ablation procedure and provided informed consent to participate. Participants were categorised into either the EIVOM or the non-EIVOM cohorts based on whether adjunctive EIVOM was used during the index ablation.

The exclusion criteria comprised decompensated heart failure, prior history of surgical AF ablation, significant valve stenosis or regurgitation and left atrial thrombus detected by echocardiography. The study protocol was approved by the institutional review board at each medical centre and conducted in accordance with the Declaration of Helsinki.

Ablation Procedure Flow

During the index ablation, PVI and posterior mitral isthmus ablation were performed following the completion of the EIVOM procedure, reflecting an ‘EIVOM first followed by RFA’ strategy (Supplementary Figure 1A).

For reablation procedures, the sequence of steps varied depending on clinical circumstances, as detailed in the study flowchart (Supplementary Figure 1B).

Common Pathway of the Index and Redo Procedure

The procedure was performed under conscious sedation and analgesia, achieved through continuous infusion of midazolam and fentanyl. A deflectable decapolar mapping catheter (Abbott Laboratories) was positioned in the coronary sinus (CS) via the left femoral vein. Under the guidance of intracardiac echocardiography (CARTOSOUND, Biosense Webster), two Swartz sheaths (L1 type, Abbott Laboratories) were guided into the left atrium (LA) via two transseptal punctures. A multipolar mapping catheter (PENTARAY or LassoNav, Biosense Webster) was used for 3D geometry reconstruction and electrophysiological mapping and LA volume was recorded. To reduce the risk of oesophagus injury, the contour of the oesophagus behind the posterior LA was reconstructed by intracardiac echocardiogram (ICE) imaging. A porous contact force-sensing ablation catheter (STSF, Biosense Webster) was employed for both mapping and ablation procedures.

Protocol for the Vein of Marshall Ethanol Infusion Procedure

The EIVOM procedure was conducted as previously detailed in our earlier studies.30 In brief, the vein of Marshall was identified by retrograde CS venography, then a 0.014-inch guidewire (Runthrough, Terumo Corporation) was advanced to the distal end of the vein of Marshall via the guiding catheter positioned at the vein of Marshall ostium. A 1.5~2.0 × 8 mm over-the-wire balloon catheter (Voyage, Boston Scientific) was used for vein of Marshall occlusion and ethanol injection. After balloon inflation to 6–8 atm, 7–9 ml of absolute ethanol was injected manually in three 2–3 ml aliquots. The effect of ethanol ablation was assessed and visualised using vein of Marshall angiography and electroanatomic substrate mapping.30,31 Newly occurring low voltage areas (LVAs; bipolar amplitude <0.05 mV during AF on substrate mapping) were deemed EIVOM-related.32

In redo cases, if mitral isthmus block was not achieved during evaluation, CS venography was performed to rule out vein of Marshall occlusion due to previous ethanol infusion or ablation inside the CS.

Ablation Approach at the Index Procedure

The initial ablation approach was standardised to include PVI as the foundational strategy for all patients, and additional linear ablation for substrate modification, including linear ablation at posterior mitral isthmus line and left atrial roof. Cavo-tricuspid isthmus (CTI) linear ablation was used in cases of typical AFL. For posterior mitral isthmus ablation, the use of adjunctive EIVOM was at the discretion of the operating physicians. However, when adopted, EIVOM was routinely performed before initiating PVI and posterior mitral isthmus ablation.18,30,31

The procedural endpoints were rigorously defined and included: successful PVI, confirmed by pulmonary vein potentials abolishment or dissociation with atrial electrograms in all pulmonary veins; and the achievement of bidirectional conduction block across any applied linear ablation lines, verified through pacing manoeuvres following the restoration of sinus rhythm.30,33

Radiofrequency Power Settings in the Combined Vein of Marshall Ethanol Infusion-Radiofrequency Ablation Approach

For anterior pulmonary vein antrum and posterior mitral isthmus line region ablation, saline-irrigated radiofrequency (RF) energy was delivered at a power of 40–50 watts, with an ablation index (AI) target of 450–550. For the posterior wall, the power was reduced to 40 watts, with an AI value of 380–400.34 RFA inside the CS was performed at 25 watts with a saline irrigation rate of 30 ml/minute and AI target of 350.26 To minimise the risk of cardiac perforation or oesophagus injury, no RF energy was delivered at the EIVOM-related LVAs close to the oesophagus (typically identified by ICE at inferior or the posterior-inferior antrum of LPVs), or delivered with an AI value of ≈350 at the other LVAs at the lateral ridge and upper mitral isthmus. The same RF power settings were applied during reablation as in the index ablation.

Identification and Localisation of Conduction Gaps

Mitral isthmus conduction recovery was deemed at the presence of either peri-mitral flutter (PMF) or the distal to proximal CS conduction sequence during left atrial appendage (LAA) pacing in sinus rhythm (SR). To localise the conduction gap (CG), the posterior mitral isthmus line region was divided into seven distinct segments: three endocardial RF-related segments (lateral ridge, medium and mitral annulus [MA]) and four epicardial segments, defined as RF-related CS medium, CS distal, CS proximal to posterior mitral isthmus line and vein of Marshall-related epicardial connections (Figure 1 ).

Figure 1: Mitral Isthmus Region Segmentation (Seven Zones) and Conduction Gap Distribution

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A mitral isthmus CG was defined as an RF lesion that led to significant changes in the activation sequence, cycle length prolongation, AFL termination (Supplementary Figure 2) or an increased time interval from LAA pacing to the distal CS electrode. A vein of Marshall-related epicardial connection was confirmed when such electrophysiological changes were observed during EIVOM.

To describe pulmonary vein reconnection in reablation, the pulmonary vein antrum was divided into six segments: anterosuperior, anteroinferior, posterosuperior, posteroinferior, top and bottom. A pulmonary vein CG was identified as an RF lesion causing activation change or reisolation of pulmonary vein potential during ablation, marked by a small red dot in Figure 2.

Figure 2: Pulmonary Vein Antrum Segmentation (Six Zones) and Conduction Gap Distribution

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Ablation Approaches for Recurrent AF and Atrial Flutter

In cases of recurrent AF, the ablation strategy was systematically implemented using the following steps (Supplementary Figure 1B). First, residual pulmonary vein potentials were eliminated by closing pulmonary vein CGs. Second, LA posterior wall ‘BOX’ isolation was performed by combining a previously ablated LA roof line with a new floor line to connect the circular lesions of the left and right pulmonary veins.35 Mitral isthmus conduction recovery evaluation and ablation was not performed until restoration of SR; additional ablation was applied to close the CGs once mitral isthmus conduction recovery was confirmed. EIVOM was performed only when endocardial mitral isthmus CGs were closed, followed by epicardial CG ablation inside the CS if necessary. Additional substrate modification approaches, such as ablation at the LA anterior wall, right atrium or superior vena cava (SVC) isolation, were performed at the operator’s discretion.

For recurrent AFL, a comprehensive mapping approach was employed, integrating activation mapping, overdrive entrainment, and substrate mapping to delineate the reentrant circuit and the critical isthmus, which was targeted for RFA ablation. In cases of PMF, EIVOM was preferentially used as a first step when no clear endocardial electrograms were detectable, followed by RFA inside the CS to achieve AFL termination and reblock of posterior mitral isthmus line.

Statistical Analysis

Continuous variables were expressed as mean ± SD for normally distributed data and compared using the independent Student’s t-test. For non-normally distributed data, variables were presented as median (interquartile range) and analysed using the nonparametric Mann–Whitney U-test. Categorical variables were described as frequencies (percentages) and compared using the chi-square test or Fisher’s exact test, as appropriate. Post hoc pairwise comparisons for multiple categorical variables were performed using Fisher’s exact test with Bonferroni correction.

To identify potential predictors of mitral isthmus conduction recovery, variables with p<0.1 in the univariate analysis were included in the multivariate analysis. Multivariate binary logistic regression analysis was subsequently performed to determine independent predictors of mitral isthmus conduction recovery, with results reported as OR and corresponding 95% CI. A two-tailed p-value <0.05 was considered statistically significant. All data processing and statistical analyses were conducted using SPSS version 27.0 software (IBM Corporation).

Results

Patient Baseline Characteristics

A total of 1,426 non-PAF patients underwent index ablation in three tertiary hospitals, of whom 1,321 had EIVOM during this procedure, while the other 105 patients hadn’t received EIVOM procedure. Recurrent arrhythmias outside the blanking period occurred in 224 patients, of whom 91 underwent redo ablation, including 41 patients in the EIVOM cohort and the 50 non-EIVOM cohort. There was no significant difference in baseline characteristics between two cohorts except for LA dimension. In the index procedure, LPV isolation time in the EIVOM cohort was significantly shorter than that in the non-EIVOM cohort. An average balloon size of 2.0 mm, ethanol 7.0 ml and infusion duration 459 seconds were applied for EIVOM. There was a significantly higher prevalence of first-pass mitral isthmus block in the EIVOM cohort than in the non-EIVOM cohort (p<0.001). Acute mitral isthmus block was achieved in all subjects during the index ablation procedure, with 46 CGs closed in the EIVOM cohort and 83 CGs closed in the non-EIVOM cohort, respectively (p<0.001; Table 1 ).

Table 1: Baseline Characteristics and Procedural Parameters in the Index Procedure

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Chronic Pulmonary Vein and Mitral Isthmus Conduction Recovery in Reablation

Pulmonary Vein Reconnection

Reablation procedures were performed after a median of 14 (IQR 4–39) months following the index ablation. Sustained isolation of all pulmonary veins was achieved in 24 patients (58.5%) in the EIVOM cohort and 29 patients (58.0%) in the non-EIVOM cohort (p=1.00). The prevalence of chronic LPV reconnection did not differ significantly between the two cohorts (39% in the EIVOM cohort versus 28% in the non-EIVOM cohort; p=0.27; Table 2). RPV reconnection rates were also comparable. A total of 25 gaps were observed in the EIVOM cohort (18 for the LPV, seven for RPV), compared with 25 gaps in the non-EIVOM cohort (14 for the LPV, 11 for RPV). Notably, LPV-CGs in EIVOM cohort were more frequently localised at the inferior antrum of the left inferior pulmonary vein than in non-EIVOM cohort (9/18 versus 1/14; p=0.02; Figure 2).

Table 2: Procedural Parameters in Reablation Procedure

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Mitral Isthmus Conduction Recovery

The rate of mitral isthmus conduction recovery was significantly lower in EIVOM cohort compared with non-EIVOM cohort (19 [46.3%] versus 40 [80%]; p=0.002; Table 2). Multivariate binary logistic regression analysis identified two independent predictors of chronic mitral isthmus conduction recovery: the absence of EIVOM use (OR 3.611; 95% CI [1.377–9.465]; p=0.009) and longer AF duration (OR 1.012; 95% CI [1.002–1.023]; p=0.021; Supplementary Table 1 ).

Comparison of Mitral Isthmus Conduction Gaps during the Reablation Procedure

During reablation, mitral isthmus CGs were most commonly observed at the lateral ridge, endocardial MA and CS distal in the EIVOM cohort; in the non-EIVOM cohort, they were predominantly localised at the lateral ridge, vein of Marshall-related epicardial region and CS medium (Figure 1 ). The lateral ridge demonstrated a similarly high prevalence of CGs in both cohorts (30.4% in the EIVOM versus 40% in the non-EIVOM cohorts; p>0.05), suggesting it is a common site for mitral isthmus CGs regardless of the cohort. However, significant differences were noted in other regions: endocardial MA CGs were more frequent in the EIVOM cohort, while vein of Marshall-related epicardial CGs were more prevalent in the non-EIVOM cohort (Table 3 ).

Table 3: Comparison of Mitral Isthmus Conduction Gaps in the Reablation Procedure

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Procedural Parameters in Reablation

In the EIVOM cohort, 25 (61%) patients presented with 31 AFLs, including 19 PMF, nine CTI-dependent AFL, two LA anterior localised circuits and one atypical LPV gap-related PMF. The remaining 16 patients had AF recurrence (Supplementary Table 2). The LPV gap-related PMF case featured an atypical PMF circuit in which two LPV gaps formed the critical isthmus in the absence of mitral isthmus CGs (Supplementary Figure 3 ). EIVOM could be repeated in no cases due to the invisibility of vein of Marshall on CS venography. RFA successfully terminated AFL in all patients. In 16 patients undergoing AF reablation, mitral isthmus reblocking was achieved in all cases. Additional ablation strategies included LA posterior wall BOX isolation (successful in 10 of 15 attempts), anterior ablation (number of successes=11) and SVC isolation (number of successes=3).

In the non-EIVOM cohort, 35 (70%) patients presented with 42 AFLs, including 30 PMF, five LA-roof dependent re-entry, four CTI-dependent flutter and three LA anterior localised re-entry. EIVOM was performed in 15 of 30 PMF patients and directly terminated PMF in 12. The remaining AFL subtypes were successfully ablated by RFA. Additionally, the remaining 15 patients underwent recurrent AF ablation, with EIVOM performed in six. Supplementary ablation strategies included LA posterior wall BOX isolation (successful in three of five attempts), LA anterior wall ablation (n=7) and SVC isolation (n=7).

At the end of the redo procedures, mitral isthmus block was achieved in all 41 patients in the EIVOM cohort and in 49 of 50 patients in the non-EIVOM cohort (p=1.00). No major peri-operative complications, such as clinically significant pericardial effusion/cardiac tamponade, thromboembolic events or oesophageal injury were detected in any participants.

Discussion

This study had three primary findings. First, the combined EIVOM-RFA approach did not significantly improve long-term durability of LPV isolation compared with RFA alone. Second, the combined EIVOM-RFA approach significantly reduced long-term mitral isthmus conduction recovery compared with RFA alone. Third, distinct anatomical distributions of CGs were observed in both cohorts. LPV-CGs were more frequently localised at the inferior antrum in the EIVOM cohort than in the non-EIVOM cohort. Mitral isthmus CGs were predominantly clustered at the lateral ridge in both cohorts. However, endocardial MA-related CGs were more common in the EIVOM cohort and vein of Marshall-related epicardial CGs were more prevalent in the non-EIVOM cohort.

Together, these results provide important insights into the long-term efficacy and limitations of EIVOM as an adjunct to RFA in non-PAF ablation. These findings, their clinical implications and potential mechanisms are discussed in detail below.

Evidence for the ‘Vein of Marshall Ethanol Infusion First Followed by Radiofrequency Ablation’ Strategy and Potential Issues

The combined approach adopted for the index procedure in our study was ‘EIVOM first followed by RFA’. This was supported in several aspects. Anatomically, the vein of Marshall runs epicardially between the LPV and the LAA, ultimately draining into the CS.36 EIVOM typically generates a LVA averaging 4.7–13.2 cm², covering a median LA surface of 3.6%, predominantly localised along the lateral ridge between the LPV and LAA.27,37,38 This LVA usually extends to the upper mitral isthmus region and frequently involves the posteroinferior antrum of the LPV.39 By modifying the substrate in these critical areas, EIVOM may facilitate both posterior mitral isthmus line ablation and LPV isolation.

Clinical studies (such as VENOUS, Marshall-Plan, PROMPT-AF, etc.) have demonstrated that the ‘EIVOM first followed by RFA’ strategy has a shorter ablation time and yields a higher rate of mitral isthmus block and a lower rate of acute mitral isthmus conduction recovery compared with RFA alone, the results of which align with our previous study.18–25,30 Notably, emerging evidence suggests EIVOM may also improve LPV isolation efficacy. Recent studies reported enhanced first-pass LPV isolation rate and decreased acute pulmonary vein reconnections with adjunctive EIVOM therapy.26,27 Similar to these studies, LPV RF application time reduction was observed in EIVOM cohort compared with the non-EIVOM cohort (Table 1 ). Under certain extreme circumstances, if the EIVOM-related LVA is sufficiently extensive, LPV isolation may be achieved through EIVOM only.40

Besides being time-saving and highly efficient in mitral isthmus block and PVI isolation, another issue for the strategy was the higher success rate of vein of Marshall visualisation. A recent study demonstrated that a ‘RFA first followed by EIVOM’ strategy would lead to inadvertent occlusion of the ostium of the vein of Marshall, resulting in a 30% visualisation failure rate.31 Similarly, previous ablation in the CS was identified as the only predictor for vein of Marshall nonidentification.41 For this reason, an EIVOM-first strategy would serve as a better choice.

While the acute benefits of this combined ‘EIVOM first followed by RFA’ approach are well-documented, data on its long-term durability – particularly regarding sustained LPV isolation and mitral isthmus block beyond 3 months post-ablation – remain limited and contradictory. This study provides valuable new evidence that enhances our knowledge of this critical issue.

Rationale of Radiofrequency Ablation Adjustment in Vein of Marshall Ethanol Infusion-Induced Low-voltage Areas

As previously described, EIVOM-induced LVAs primarily localise to the lateral ridge and the inferior/posteroinferior LPV antral regions. This anatomical distribution suggests that maintaining conventional RFA power settings in these areas may increase the risk of tissue perforation and oesophageal injury. Of particular concern, emerging clinical evidence demonstrates an unusually high incidence of atrio–oesophageal fistula formation (two of 158 subjects) with the combined EIVOM-RFA approach.34 The safety considerations strongly support either reduction of target AI parameters or complete avoidance of RF energy delivery in these vulnerable regions.

Divergent Impact of Vein of Marshall Ethanol Infusion on Durable Left Pulmonary Vein Isolation and Mitral Isthmus Block

Our study reveals that the combined EIVOM-RFA strategy does not improve the long-term durability of LPV isolation. This outcome may be attributed to the markedly higher prevalence of pulmonary vein CGs at the inferior antrum of the LPV in the EIVOM cohort compared with the non-EIVOM cohort. This finding is further corroborated by a representative case demonstrating that pulmonary vein CGs at previously unablated EIVOM-induced LVAs served as the arrhythmogenic substrate for PMF recurrence (Supplementary Figure 3). These observations suggest that EIVOM-induced LVAs may represent transient electrophysiological alterations prone to late recovery. Consequently, our findings underscore the necessity for future research to optimise RFA parameters capable of achieving durable pulmonary vein isolation while maintaining procedural safety.

Conversely, our study demonstrates that the combined EIVOM-RFA approach significantly enhances the long-term durability of mitral isthmus block, even after adjusting RF energy delivery in the low-voltage upper region of the posterior mitral isthmus line. This effect may be attributed to several key factors. First, repeated RFA for consolidation can be performed within LVAs located at a safe distance from the oesophagus. Second, touch-up ablation of conduction breakthroughs at a remote distance from the posterior mitral isthmus line (typically in normal voltage areas) can be applied if a single posterior mitral isthmus line fails to achieve block, using standard RFA settings. Third, epicardial ablation within the CS serves as a viable adjunct when endocardial ablation alone is insufficient for achieving mitral isthmus block.

Localisation of Mitral Isthmus Conduction Gaps in the Index and Redo Procedures

Our study provides the first detailed characterisation of chronic CGs along the posterior mitral isthmus line to date to our knowledge. During the index ablation, the EIVOM-RFA approach significantly reduced CGs at the lateral ridge, facilitating mitral isthmus block by overcoming the inherent challenges of creating transmural lesions in this anatomically thick region. However, during reablation procedures, lateral ridge-associated CGs remained prevalent in both cohorts. This observation suggests that EIVOM-induced LVAs at the lateral ridge may also represent transient electrophysiological modifications rather than permanent transmural lesions, mirroring the pattern of pulmonary vein CG observed in EIVOM-induced LVAs at the LPV inferior antrum.

Additionally, endocardial MA-related CGs appear characteristic of EIVOM application, as this region is not drained by the vein of Marshall. Notably, CS distal-related CGs were not uncommon in the EIVOM cohort, which differ anatomically from vein of Marshall-related epicardial CGs, and represent a distinct subtype of epicardial connection bypassing the posterior mitral isthmus line.42 In contrast, vein of Marshall-related epicardial CGs accounted for 40% of mitral isthmus CGs in non-EIVOM cohort, highlighting their role as the primary epicardial connections in this cohort.

Mitral Isthmus Ablation Strategies in Persistent AF: Navigating the Post-Pulsed Field Ablation Era

Although pulsed field ablation (PFA) demonstrates high acute block rates (89–100%) and safety in persistent AF beyond PVI, mitral isthmus line durability remains concerning. While acute block rates reach 81.3–100%, long-term conduction recovery ranges from 22% to 100%.43,44 This heterogeneity stems from limited long-term PFA data, with most studies having small sample sizes (<100 patients). Nevertheless, a clear trend emerges: mitral isthmus lines exhibit the highest recurrence among extra-PVI ablation targets.45 Despite EIVOM improving mitral isthmus block durability with RFA in the PROMPT-AF and Marshall Plan trials, this benefit does not extend to PFA.46,47 Initial assumptions that PFA’s transmurality could replace EIVOM were challenged by a recent study, reporting 100% posterior mitral isthmus reconnection at 1 year with combined PFA and EIVOM.46 A randomised trial demonstrated that endocardial ablation time and RF applications for mitral isthmus block were significantly reduced in the vein of Marshall/RFA group versus PFA-only.47 In terms of safety, PFA near the mitral isthmus region carries a 7–12% risk of iatrogenic coronary arterial spasm due to proximity to the left circumflex artery as well as dosage-dependent haemolysis.48

In conclusion, RFA combined with EIVOM still remains the most effective way to get longtime mitral isthmus blockage, the suboptimal long-term mitral isthmus block durability of PFA and safety concern makes it a nonpreferred method in mitral isthmus blockage. The results of our study will still make sense in the PFA era.

Limitations

Some potential limitations of our study need to be addressed. First, despite achievement of PVI and mitral isthmus block in the first ablation procedure being prerequisite for patients’ enrolment, the baseline characteristics may not be completely balanced between the EIVOM and non-EIVOM cohorts due to the retrospective cohort design of this study.

Second, pulmonary vein and mitral isthmus conduction recovery is merely evaluated in patients undergoing reablation for treating recurrent atrial tachyarrhythmias, rather than all the patients undergoing AF ablation. Information on pulmonary vein and mitral isthmus conduction recovery in patients without reablation could not be acquired.

Third, one of the independent predictors of mitral isthmus conduction recovery, the duration of AF, was defined as the time duration from the date of the first medical record or electrocardiograph diagnosis until the date of enrolment in our study, rather than under continuous rhythm monitoring, meaning that the duration we recorded would be shorter than actual duration. However, this was an irreversible and uncontrollable parameter for physicians at the first medical contact with a patient and not the focus of our study; thus, the underestimation of the duration of AF had little effect on our conclusion.

Finally, the techniques of EIVOM regarding ethanol volume, injection time and segmental balloon positioning may vary among different electrophysiological labs and may impact significantly on LVA formation at the peri-mitral isthmus region. These limitations may influence the interpretation of the findings and the generalisability of the results. Therefore, caution is warranted in extrapolating the results of our study.

Conclusion

The ‘EIVOM-first followed by RFA’ approach significantly reduces chronic mitral isthmus conduction recovery, but does not improve long-term durability of LPV isolation compared with RFA alone. The CGs exhibited distinct anatomical distributions for both LPV and mitral isthmus conduction recovery, which may provide useful clues for refining ablation strategies in non-PAF ablation.

Click here to view Supplementary Material.

Clinical Perspective

  • This study highlights the efficacy of vein of Marshall ethanol infusion (EIVOM) in reducing chronic mitral isthmus conduction recovery in the absence of improvement of long-term durability of left pulmonary vein isolation in the setting of adjusted ablation index values for radiofrequency ablation at the EIVOM-affected region.
  • The distinct anatomical distribution of pulmonary vein and mitral isthmus conduction gaps provides valuable insights for the rapid localisation of conduction gaps and optimisation of ablation strategies.
  • These findings suggest that EIVOM may be a valuable adjunctive technique in achieving durable mitral isthmus block in patients with non-paroxysmal AF undergoing catheter ablation and warrant further research to refine pulmonary vein isolation approaches post-EIVOM.

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