Mechanisms of Vein of Marshall-Related Tachyarrhythmias & Ethanol Infusion — Comprehensive Notes

Introduction

  • Historical discovery & nomenclature
    • 1850: John Marshall first describes a ligamentous structure between the superior & inferior left pulmonary veins (PVs)
    • Later termed “Ligament of Marshall (LOM)”
  • Composition & embryology
    • Remnant of embryonic sinus venosus + left cardinal vein
    • Tissue constituents: fat, fibrous tissue, blood vessels, multiple myocardial bundles, autonomic nerve fibres, ganglia
  • Early electrophysiology
    • 1972 Scherlag BJ et al.: demonstrated LOM as a terminal, insulated tract activated via an inferior inter-atrial pathway, without reconnection to atrial musculature
    • 2000 Kim DT et al.: gross & microscopic study on 7 human hearts ➔ showed:
    • Sympathetic innervation
    • Greater complexity vs canine LOM (ganglia, multiple sympathetic fibres, myocardial bundles, vessels)
    • Multiple insertions into coronary sinus (CS) & LA free wall, insulated by fibro-fatty tissue
  • Clinical significance
    • Unique properties provide substrate for:
    • Focal automaticity / triggered activity (AF/AT triggers)
    • Micro- & macro-reentry circuits (drivers, rotors, epicardial bypass)
    • Difficulties with pure endocardial ablation due to:
    • Thicker & longer mitral isthmus (MI)
    • Epicardial structures (CS, VOM, circumflex artery) shielding energy
    • Fibro-fatty insulation
    • Ethanol infusion into the Vein of Marshall (EI-VOM) emerges as adjunctive, effective, relatively safe therapy

Gross Anatomy & Musculature

  • Segmental division (Makino / Han classification)
    • Proximal LOM: joins CS muscle sleeve directly
    • Mid-portion: connects to left lateral ridge & left PVs
    • Distal LOM: may extend beyond PVs into LA free wall
  • Prevalence & variants (autopsy / surgical series)
    • Multiple / broad LA connections in ≈33%\approx 33\%
    • Complete epicardial attachment w/o discrete ligament in some hearts
    • Distal insertion sites: LSPV ostium, ridge, LA roof, etc.
  • Vein of Marshall (VOM)
    • One of largest LA veins; embedded within LOM
    • Courses obliquely inferiorly toward CS; ostium lies proximal to Vieussens valve
    • Visualised in >90\% of cases on CS venography

Neural Composition

  • Immunohistochemistry
    • Dense autonomic innervation: sympathetic fibres (tyrosine-hydroxylase positive) + parasympathetic ganglia
  • Spatial gradient (Makino 2006)
    • Distal LOM rich in sympathetic nerves
    • Proximal (near CS) rich in parasympathetic ganglia
  • Functional study (Yu 2018, canine)
    • Rapid atrial pacing (20 Hz, 2×2\times threshold, 6 h) ➔ shortening of ERP, ↑ dispersion, ↑ AF inducibility
    • Selective distal LOM ablation:
    • ↓ serum norepinephrine, ↓ sympathetic HRV indices
    • Prevented pacing-induced ERP shortening & AF maintenance
    • Implication: distal LOM modulates global atrial sympatho-vagal balance

Mechanistic Roles (Overview)

  • Four arrhythmogenic facets (Fig-3 concept)
    1. Trigger source – focal ectopy
    2. Driver / micro-reentry – high-frequency rotors
    3. Macro-reentry path – part of perimitral or bi-atrial circuits
    4. Autonomic storm – local sympathetic / parasympathetic discharge

LOM as Focus (Trigger) for AF

  • Experimental
    • Sympathetic stimulation of left cardiac nerves in dogs ➔ ectopy from LOM
  • Human studies / statistics
    • Hwang 2000: recorded double potentials in VOM; ablation at insertion terminated AF in 4/6 pts
    • Katritsis 2001: abolition of Marshall potentials reduced adrenergic AF burden
    • Lin 2003 (240 PAF pts, 358 foci): 20% non-PV; of these LOM =8.2%= 8.2\% (6 pts / 73 foci)
    • Liu 2019 (254 non-PAF pts): among 102 non-PV foci, LOM =19.6%=19.6\%
  • Topography of ectopy
    • AF triggers: predominantly distal LOM
    • Ectopic AT: more often proximal LOM / near CS

LOM as Substrate for AF (Epicardial Connections)

  • Pulmonary vein reconnection via LOM epicardial fibres
    • Dave 2012: left PV reconnection through VOM in subset post-PVI
    • Barrio-Lopez 2020: epicardial connections in 13.5% (72/534); half were PV–LOM; ↓ acute PVI success (86.1% vs 99.1%); ↑ arrhythmia recurrence (HR =1.7=1.7)
  • Persistent Left Superior Vena Cava (PLSVC)
    • Failure of left cardinal vein regression; may share pathway with LOM; can act as trigger; isolation reduces recurrence
  • Post-mortem diversity (Makino)
    • Close CS junction connections in 64%64\%; distant ridge/PV in 72%72\%; continuous wide extensions in 36%36\%
  • Electrophysiology (Han 2010, 64 pts)
    • Single CS connection 17.2%17.2\%; double CS+LA 35.9%35.9\%; multiple 46.9%46.9\% (rapid, fractionated activity during AF)
  • Dominant frequency gradient
    • Canine chronic pacing: LOM cycle length 84±584\pm5 ms (freq ≈12 Hz\approx 12\,Hz) vs LA free wall 96±596\pm5 ms
    • Human persistent AF: VOM CL 140±31140\pm31 ms; dominant freq 9.7±1.59.7\pm1.5 Hz – faster than any other atrial site

LOM in Atrial Tachycardia (AT) Circuits

  • Types (Takigawa / Vlachos 2019)
    1. LOM-related perimitral flutter (PMF)
    2. LOM-related localized reentry (pseudo-focal)
  • Incidence after extensive ablation
    • Among 199 scar-related ATs: 60 (30%) LOM-related
    • Hayashi 2016: up to 11%11\% of PMFs post-PVI/valve surgery due to MB epicardial connection
  • Recurrence patterns (Takigawa 2020)
    • Perimitral & roof flutters recur with similar circuits in 57.7%57.7\% and 44.4%44.4\%
    • Epicardial structures involved in 51.2%51.2\% redo ATs; CS/VOM in 75%75\% of PMF recurrences
  • Mapping clues (Fig-4)
    • Centrifugal breakout at LA ridge, LAA ostium, mid-ridge, or near LIPV ➔ suspect epicardial LOM bypass

Endocardial / Epicardial RF Ablation Strategies

  • Endocardial with VOM catheter guidance (Hwang 2000)
    • 1.5–2.7 Fr catheter in VOM via CS records double potentials (LA then LOM)
    • RF at LA ridge (esp. inferior to LIPV) to delete LOM potentials
  • Epicardial percutaneous approach (Sosa technique)
    • Useful when VOM un-cannulatable; transthoracic access; invasive, limited to experienced centers
  • Limitations
    • MI block success rates 31–92%31–92\%; CS RF needed 59–91%59–91\%
    • Risk of pseudo-block (20–30%): residual epicardial conduction via LOM despite endocardial block
    • Alternative anterior / anteroseptal lines reduce MI challenges but increase bi-atrial tachycardias

Ethanol Infusion into VOM (EI-VOM)

Mechanistic Benefits

  • Chemical ablation of LOM musculature + autonomic denervation
  • Creates deep, transmural lesion set across posterior MI without heat-related complications

Impact on Mitral Isthmus (MI) Ablation

  • Combined EI-VOM + RF achieves MI block 98–100%98–100\% (vs 63–92%63–92\% with RF alone)
  • Key studies
    • Takigawa 2020 (PMF, n = 103):
    • Tachy termination by EI-VOM alone =68.6%=68.6\%
    • RF time for conversion: median 00 s vs 312312 s (RF-only)
    • RF time to MI block: 246246 s vs 900900 s
    • 1-yr recurrence: 18.8%18.8\% vs 40.8%40.8\% (HR =0.35=0.35)
    • Nakashima 2020 (first-time MI line): acute block 98.7%98.7\% vs 63.6%63.6\%; shorter RF (5 vs 19 min); durable block at redo 62.9%62.9\% vs 32.6%32.6\%
    • Meta-analysis (1322 pts, 10 studies): EI-VOM ↑ bidirectional MI block rate significantly

Impact on Persistent AF Ablation

  • VENUS-AF RCT (n = 343):
    • Recurrence-free (single procedure, no AAD) 49.2%49.2\% (EI-VOM) vs 38.0%38.0\% (control)
    • Benefit greater when MI block achieved
  • Marshall-PLAN (Derval 2021):
    • Complete lesion set in 91%91\%; 12-mo arrhythmia-free 79%79\%
  • Upgraded 2C3L strategy (Lai 2021): better 12-mo outcome vs RF 2C3L alone
  • Conflicting MARS trial (repeat ablation cohort, n = 80): no statistical difference ➔ benefits may depend on population & lesion set

Technical Approaches to EI-VOM

  • Right Internal Jugular (superior) approach
    1. 7 Fr CS sheath (Rapido) ➔ CS
    2. CS occlusive balloon venogram to locate VOM ostium
    3. Sub-selective catheter (LIMA or JR) + 0.014" wire ➔ engage VOM
    4. 2 mm × 8 mm angioplasty balloon inflated; selective venogram
    5. 2×12 \times 1 mL 100% ethanol over 2 min each
    6. Optional mapping catheter in VOM records Marshall potentials
  • Right Femoral (inferior) approach (Agilis steerable sheath)
    1. Agilis into CS; 5 Fr LIMA/JR within sheath
    2. Contrast puffs or CS balloon occlusion to visualise VOM
    3. 1.5–2.5 mm × 6–15 mm balloon; total ethanol 6–12 mL (0.5–3 mL aliquots)
  • Success & failure rates
    • Overall cannulation success ≈88–92%\approx 88–92\%
    • Failure reasons: absent VOM, tiny calibre, dissection, wrong vein, CS anomalies (PLSVC)
  • Novel tools
    • Lumen BeeAT multipolar catheter with internal cardioversion + VOM access via 2.7 Fr EP-star FIX AIV

Venous Anatomy Variability

  • Valderrábano classification of LA veins (septal, inferior, VOM, LAA veins, anterior roof)
  • Distal branching patterns
    • True main tract with posterior branch (Fig-6A)
    • Plexus-like short VOM (6B)
    • Roof branch from distal tract (6C)
    • Stump with two branches at ostium (6D)
  • Quantitative data (Takigawa):
    • CS-to-VOM ostium distance 4.25±2.574.25\pm2.57 cm
    • Main tract length 2.99±1.822.99\pm1.82 cm
    • Reach to LIPV in 72.8%72.8\%; to LSPV in 9.6%9.6\%; shorter in 17.6%17.6\%
    • Communication with PVs seen in 37.7%37.7\%
  • Post-EI-VOM low-voltage map (Kamakura 2022)
    • Inferior ridge affected in 82.5%82.5\%; PV-side MI in 92.1%92.1\%
    • Annular-side gaps common residual site
    • Posterior wall impact (near oesophagus) in 19.3%19.3\% ➔ potential option when RF limited by temperature rise
  • Pre-procedural CT protocol (Takagi 2022)
    • 50 mL iodine @5 mL/s + 40 mL @3 mL/s + 20 mL saline; 20 s delay after LA 100 HU
    • Sublingual nitroglycerin to enhance venous opacification
    • Detection rate of VOM 63%63\% vs 35%35\% (standard)

Complications & Safety

  • Largest cohort (Kamakura 2021, n = 713)
    • Success: 88.9%88.9\% (634 pts)
    • VOM perforation 2.8%2.8\% (contrast into pericardium)
    • Pericarditis 1.8%1.8\%
    • Major complications 2.0%2.0\% :
    • Cardiac tamponade 1.0%1.0\% (57% delayed; median 7–106 d)
    • Stroke 0.6%0.6\%
    • Anaphylaxis, AV block, inadvertent LAA isolation 0.1%0.1\% each
    • VOM perforation ↑ tamponade risk (10% vs 0.7%)
  • Delayed tamponade vs standard RF
    • General AF ablation delayed tamponade rate 0.16%0.16\% (Cappato 2011) vs ≈3%\approx 3\% after EI-VOM in some series
    • Mechanism: inflammatory pericarditis vs sealed perforation
  • Localised contrast staining (~30% cases) not linked to worse outcome or higher complications

Conclusions

  • LOM = complex epicardial neuro-myocardial bundle ⇒ triggers + substrate (AF/AT)
  • Its epicardial location & insulation limit effectiveness of endocardial RF alone, especially at MI
  • EI-VOM provides:
    • Deep, durable lesion of LOM & adjacent MI
    • Autonomic denervation
    • Significant reduction in RF time, ↑ acute block, ↑ long-term freedom from AF/AT
  • Procedural success >90\% with both jugular & femoral approaches; complication profile acceptable but vigilance for delayed tamponade required
  • Future directions: refine imaging-guided selection, combine with tailored lesion sets (Marshall-PLAN, upgraded 2C3L) & evaluate long-term outcomes across diverse AF populations