Elsevier

Heart Rhythm

Volume 18, Issue 7, July 2021, Pages 1074-1082
Heart Rhythm

Contemporary Review
Vein of Marshall ethanol infusion in the treatment of atrial fibrillation: From concept to clinical practice

https://doi.org/10.1016/j.hrthm.2021.03.032Get rights and content

The vein of Marshall (VOM) contains innervation, myocardial connections, and arrhythmogenic foci that make it an attractive target in catheter ablation of atrial fibrillation (AF). Additionally, it co-localizes with the mitral isthmus, which is critical to sustain perimitral flutter, and is a true atrial vein that communicates with underlying myocardium. Retrograde balloon cannulation of the VOM from the coronary sinus is feasible and allows for ethanol delivery, which results in rapid ablation of neighboring myocardium and its innervation. Here we review the body of work performed over a span of 13 years, from the inception of the technique, to its preclinical validation, to demonstration of its ablative and denervation effects, and finally to completion of a randomized clinical trial demonstrating favorable outcomes, improving rhythm control in catheter ablation of persistent AF.

Section snippets

Anatomy and physiology of the vein of Marshall

Targeting the vein of Marshall (VOM) for antiarrhythmic purposes is based on its unique anatomic and functional characteristics (previously reviewed in detail1). Described in 1850, the VOM is the normal involution of the left anterior cardinal vein as the venous system transitions from bilateral symmetry to right dominance, turning the left superior vena cava into the ligament of Marshall (LOM).2 The left-to-right evolution of the developing heart is governed by the PITX2 gene and has

VOM ethanol preclinical validation: Tissue ablation and local denervation

Developing a new procedure requires preclinical validation in animal models. Canines have an atrial anatomy similar to that of humans. We were able to complete VOM retrograde balloon cannulation and ethanol infusion in 10 of 17 canines,26 demonstrating a local ablation in the expected area (Figure 1) from the mitral annulus to the LIPV. Additionally, we proved regional denervation effects. VOM ethanol abolished the local decrease in effective refractory period created by cervical vagal

First-in-man procedures: The VOM as a true atrial vein and not a vestigial fold

Navigating US regulatory hurdles to perform a new procedure required a Food and Drug Administration Investigational New Drug protocol as well as assuaging the Institutional Review Board’s safety concerns and inherent reluctance. In May 2008, we performed the first VOM ethanol infusion procedure in a patient undergoing persistent AF ablation.26 We sought to demonstrate that the VOM is not an embryologic vestige but a true atrial vein, draining venous return from atrial tissues. This was critical

Outcomes after VOM ethanol: The VENUS trial

From October 2013 through June 2018, we conducted the VENUS-AF (Vein of Marshall EthaNol in Untreated perSistent AF) trial (NCT01898221).37,38 We included patients with persistent AF undergoing their first ablation procedure and randomized them to either standard catheter ablation (CA; pulmonary vein isolation [PVI] plus additional lesions as deemed necessary by the treating physician) alone or in combination with VOM ethanol infusion (VOM-CA) in a 1:1.15 fashion, to include 15% more patients

Procedural steps for VOM ethanol infusion

With understanding of fluoroscopic anatomy and angioplasty tools, the VOM ethanol procedure technique is simple and successful in ∼90% of cases.39 Failures should be limited to patients without VOM. The equipment required includes (1) CS sheath: typically a CS sheath for left ventricular lead delivery if accessed from the right internal jugular or left subclavian vein (CPS Direct SL II, Abbott, St Paul, MN; or similar) or a long steerable sheath from the femoral vein (Preface, Biosense, Irvine,

Validation and reproducibility

Since our initial description, multiple groups have successfully reproduced the technique and its results, both short and long term,13,40, 41, 42, 43 and validated a routine femoral vein approach to minimize AF ablation workflow disruption.44 Two randomized clinical trials that may confirm the results of VENUS are under way: PROMPT-AF (Prospective randomized comparison between upgraded '2C3L' vs. PVI approach for catheter ablation of persistent atrial fibrillation)45 and MARSHALL-Plan (MARSHALL

Future directions

Unexplored therapeutic strategies capitalizing on the knowledge generated thus far remain. Examples include a practical right-sided only approach to PMF ablation using VOM ethanol plus CS ablation, ethanol ablation in all atrial veins to maximize epicardial ablation when extensive ablation is planned, and use of other chemicals46 or biologics.47

Conclusion

Due to its mechanistic involvement in AF and its co-localization with the mitral isthmus, the VOM is a valid therapeutic target during AF ablation. VOM ethanol infusion is feasible and safe, and achieves rapid ablation of left atrial tissue and local innervation, including the epicardial myocardium sustaining PMF. In the VENUS randomized clinical trial, adding VOM ethanol infusion to catheter ablation resulted in improved rhythm control of persistent AF. The technique is reproducible, and

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    Funding sources: This work was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) Grants R21HL097305 and R01 HL1150030; the Lois and Carl Davis Centennial Chair; and the Charles Burnett III endowments. Disclosures: The author has no conflicts of interest to disclose.

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