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\begin{document}

\title{The Coronary Sinus Marshall Structure: from an Anatomical Ligament to an
Arrhythmogenic Vein}



\author[1]{Thomas Rostock}%
\author[2]{Raphael Spittler}%
\affil[1]{Univ Hospital Mainz, II. Medical Department}%
\affil[2]{University Medical Center Mainz}%


\vspace{-1em}



  
  \date{June 12, 2024}


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\textbf{The Coronary Sinus Marshall Structure:}

\textbf{from an Anatomical Ligament to an Arrhythmogenic Vein}

Thomas Rostock, MD and Raphael Spittler, MD

From the University Hospital Mainz, Center for Cardiology,

Department of Cardiology II / Electrophysiology, Mainz, Germany

Word count: 1516

Disclosure: none

Funding: none

\textbf{Correspondence to:}

Thomas Rostock, MD

University Hospital Mainz

Center for Cardiology

Cardiology II / Electrophysiology

Langenbeckstr. 1

55131 Mainz, Germany

Email: throstock@gmail.com

Keywords: vein of Marshall, atrial fibrillation, catheter ablation

The original Marshall Plan was a foreign aid program of the United
States to prevent the economic deterioration of Western European
countries after the second world war, with a particular focus on Western
Germany. The Marshall plan was launched in an historical speech by the
Secretary of State, General George C. Marshall, on June 5, 1947 at
Harvard University (1). Almost a century earlier, in 1850, the English
surgeon John Marshall provided the description of a vestigial fold of
connective tissue in the vicinity of the anterior coronary sinus venous
system (2). While the postwar plan for foreign aid by George C. Marshall
almost instantaneously achieved historical significance, the role of the
invention by John Marshall took more than 150 years to become relevant
in the clinical setting of cardiac arrhythmias. After experimental and
clinical studies identified the arrhythmogenic potential of the
ligament/vein of Marshall in different atrial arrhythmias (3-5),
Valderrabano and co-workers first introduced in 2009 a systematic
approach to target the vein of Marshall (VOM) with ethanol infusion in
order to induce a transmural necrosis in its neighboring, venous drained
tissue (6). The Bordeaux Marshall plan for persistent atrial
fibrillation (AF), implemented by Derval et al (7), provided an ablation
approach consisting of VOM ethanol infusion combined with radiofrequency
ablation for pulmonary vein isolation (PVI) and linear ablation at the
mitral isthmus (including the coronary sinus, CS), left atrial (LA) roof
and cavotricuspid isthmus. This strategy, based on systematically
targeting anatomical structures rather than arrhythmia-related
endpoints, achieved an impressive outcome with 89\% of patients being
free of arrhythmia recurrences after 1 year and up to 2 ablation
procedures. However, the data need to be considered in the context that
they derived from a single-center, single-cohort study (without a
control group) performed by extremely experienced operators. It is again
the credit of Valderrabano et al. (8) to provide high-quality data on
VOM ethanol infusion in the setting of persistent AF: in a prospective,
single-blinded, multi-center, randomized trial, the authors evaluated
the effect of persistent AF ablation in conjunction with VOM ethanol
infusion (VENUS trial). A large population of almost 350 patients with
persistent AF (more than half of them with long-standing persistent AF)
was randomized to undergo PVI plus atrial substrate ablation in
conjunction with or without VOM ethanol infusion. Since a 15\% failure
rate at cannulating the VOM was expected, a 15\% excess of patients
randomized to the VOM group was designed per protocol. In contrast to
the Bordeaux Marshall-Plan approach where a standardized AF ablation
protocol was used, the strategy of persistent AF ablation beyond VOM
ethanol infusion was left at the discretion of the operator including
posterior wall isolation, mitral isthmus ablation and ablation of
complex fractionated atrial electrograms. However, all patients
underwent PVI. Freedom from atrial arrhythmias was higher in the VOM
group (65\% vs. 54\% after multiple procedures).

The additional effect of VOM ablation can be explained by an enhanced
atrial denervation, eradication of arrhythmogenic triggers, a higher
rate of acute conduction block and lower rate of conduction recovery of
the mitral isthmus (3, 8). However, the volume of atrial tissue (or even
atrial mass, considering the transmurality of the lesion) and the
distinct distribution of VOM ablation induced atrial low voltage areas
may further beneficially impact long-term outcomes.

In the current issue of the journal, Kamakura and co-workers (9) provide
a comprehensive analysis of the amount and distribution of low voltage
atrial tissue induced exclusively by VOM ethanol infusion. In a total
number of 114 patients undergoing de-novo ablation for persistent AF, a
high-density CARTO map obtained by a multi-polar catheter (Pentaray,
Biosense Webster) was created before and after the VOM procedure with a
mean of more than 1.000 points. In all patients, VOM ethanol infusion
was the first step of the procedure before any other ablation was
performed. After the second map, the procedure was continued according
to the Bordeaux Marshall plan approach with PVI, roof line,
mitral-isthmus- and cavotricuspid isthmus ablation. With the aim to
systematically describe the anatomical distribution of LOM ablation
induced low voltage areas, the authors defined five different LA regions
of which four were further subdivided, resulting in a total of 11
different segments mainly confined to the lateral and posterior LA.
Interestingly, VOM ethanol infusion induced low voltage in almost all
patients in two regions: the upper part of the mitral isthmus (PV site)
and the anterior carina of the left PVs, thereby providing a distinct
fingerprint of VOM ablation. However, an arborization with anastomosis
to branches of posterior and roof veins was frequently observed,
resulting in an expansion of low voltage into the respective areas in
some but not all patients. Of note, the present study only comprised
patients in whom a venous branch of the coronary sinus, angiographically
considered to represent the VOM, was successfully cannulated. Of them,
the LA appendage vein was actually treated inadvertently in three
patients, however not resulting in LA appendage isolation in any of
them. It is one of the most important findings of this study that
successful VOM ethanol infusion in conjunction with radiofrequency
ablation within the CS (in all patients) was able to achieve
bidirectional block of the mitral isthmus in 97\%, a result that
virtually promise a guarantee of bidirectional block of the most
challenging linear lesion in the human atria.

The strength of the presented study by Kamakura et al (9) is that it
provides important new data on the distribution of lesion sets
specifically induced by VOM ethanol infusion in a large cohort of
patients with persistent AF. Moreover, the authors identified a distinct
fingerprint lesion pattern of VOM ethanol infusion that is observed in
almost all patients undergoing successful VOM ethanol infusion. Thus, it
is important to know what ``ablation effect'' on arrhythmias can
actually be anticipated with this procedure since it adds another step
of technical challenge to the complexity of persistent AF ablation.
Nevertheless, whenever this fingerprint region needs to be treated in
order to eliminate arrhythmogenic substrates of either AF or atrial
tachycardias, successful VOM ethanol infusion obviously creates
transmural lesions, evidenced by the highest rate of mitral isthmus
block achievement ever reported. Furthermore, a higher long-term
endurance of mitral isthmus block can be expected with VOM ablation
since the most common part of mitral isthmus recovery was found to be
located at the upper part of the line close to the LIPV (11), which
represents the fingerprint area of VOM ethanol infusion.

The Bordeaux group again provides important new data and adds another
piece to the puzzle elucidating the impact of VOM ethanol infusion on
persistent AF ablation. However, the widespread clinical application of
this procedure is still limited, not only because of its technical
complexity. Therefore, some few aspects of the consequences of VOM
ethanol infusion in the context of persistent AF ablation should be
considered. First, the fingerprint area of VOM, or in other words, the
upper mitral isthmus area anterior from the LIPV and posterior to the LA
appendage, usually do not exhibit spontaneous or AF-induced low voltage
areas (11). In contrast, the anterior LA is far more frequently affected
by fibrotic alterations in persistent AF patients with the potential to
represent an arrhythmogenic substrate of both, AF and atrial
tachycardias (11). Thus, treating the anterior LA for arrhythmias in the
presence of a complete mitral isthmus line after VOM ethanol infusion
has a high risk to result in inadvertent LAA isolation, particularly in
the presence of a complete roof block. Second, VOM ethanol infusion does
not provide the avoidance of CS ablation with all its inherent risks. In
the present study, all patients with bidirectional block required
additional CS ablation since the VOM ethanol ablation area obviously not
includes the musculature network of the CS itself. Third, the radiation
exposure to the patient, especially when an additional CT scan is
performed prior to the procedure in order to visualize the VOM, is
markedly increased in a VOM procedure (8, 12). In our own clinical
routine work, a persistent AF ablation procedure consisting of PVI and
linear ablation at the LA anterior wall and roof habitually requires a
mean of 2-3 minutes of fluoroscopy time (without pre-procedural
imaging). And finally, VOM ethanol infusion is best performed as a
four-hand procedure, especially in centers without high-volume
experience in this approach. Again, the VOM ethanol infusion procedure
is anything but a technically undemanding part of AF ablation, requiring
experience in CS arborization variants as well as manual skills with a
steerable sheath, angiography catheters, coronary guidewires and
vascular balloon dilatation techniques.

Although VOM ethanol infusion appears to offer an attractive strategy to
achieve transmural lesions at least in its fingerprint region, the
above-mentioned aspects associated with the procedure claim appropriate
consideration. Not surprisingly, persistent AF ablation yet remains a
challenge to the clinical electrophysiologist, even in the aspect of
selecting the most beneficial ablation procedure for the individual
patient. However, having a fingerprint lesion pattern of VOM ethanol
infusion, this new information can help to guide the decision to either
start persistent AF substrate ablation with the ethanol syringe or a RF
ablation catheter.

\textbf{References}

1. https://en.wikisource.org/wiki/The\_Marhall\_Plan-Speech

2. Marshall J. On the development of the great anterior veins in man and
mammalia: including an account of certain remnants of foetal structure
found in the adult, a comparative view of these great veins in the
different mammalia, and an analysis of their occasional peculiarities in
the human subject. Phil Trans R Soc Lond. 1850;140:1324-1327.

3. Scherlag BJ, Yeh BK, Robinson MJ. Inferior interatrial pathway in the
cog. Circ Res. 1972;31:18-35.

4. Hwang C, Karagueuzian HS, Chen PS. Idiopathic paroxysmal atrial
fibrillation induced by a focal discharge mechanism in the left superior
pulmonary vein: possible roles of the ligament of Marshall. J Cardiovasc
Electrophysiol. 1999;10:636-648.

5. Katritsis D, Joannidis JP, Anagnoustopoulos CE, Sarris GE,
Giazitzoglou E, Korovesis S, Camm AJ. Identification and catheter
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6. Valderrabano M, Chen HR, Sdhu J, Rao L, Ling Y, Khoury DS. Retrograde
ethanol infusion in the vein of Marshall: regional left atrial ablation,
vagal denervation and feasibility in humans. Circ Arrhyhtm
Electrophysiol. 2009;2:50-56.

7. Derval N, Duchateau J, Denis A, Ramirez FD, Mahida S, Andre C, Krisai
P, Nakatani Y, Kitamura T, Takigawa M, Chauvel R, Tixier R, Pillois X,
Sacher F, Hocini M, Haissaguerre M, Jais P, Pambrun T. Marshall bundle
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8. Valderrabano M, Peterson LE, Swarup V, Schurmann PA, Makkar A, Doshi
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10. Rostock T, O'Neill MD, Sanders P, Rotter M, Jais P, Hocini M,
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11. Chen J, Arentz T, Cochet H, Müller-Edenborn B, Kim S,
Moreno-Weidmann Z, Minners J, Kohl P, Lehrmann H, Allgeier J, Trenk D,
Hocini M, Jais P, Haissaguerre M, Jadidi A. Extent and spatial
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12. Takagi T, Derval N, Pambrun T, Nakatani Y, Andre C, Ramirez FD,
Nakashima T, Krisai P, Kamakura T, Pineau X, Tixier R, Chauvel R,
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