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Ligament of Marshall arrhythmogenesis and vein of Marshall ethanol: A problem with a solution

  • Miguel Valderrábano
    Correspondence
    Address reprint requests and correspondence: Dr Miguel Valderrábano, Division of Cardiac Electrophysiology, Department of Cardiology, Houston Methodist DeBakey Heart and Vascular Center, 6550 Fannin St, Suite 1901, Houston, TX 77030.
    Affiliations
    Department of Cardiology, Houston Methodist DeBakey Heart and Vascular Center and Research Institute, Houston, Texas
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Published:September 13, 2017DOI:https://doi.org/10.1016/j.hrthm.2017.09.013
      The ligament of Marshall (LOM) and vein of Marshall (VOM) have fascinated cardiac electrophysiologists for decades. Initially described by the British surgeon John Marshall in 1850
      • 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.
      as the normal involution of the left cardinal vein, the role of the LOM in electrophysiology was first unveiled by Benjamin Scherlag, PhD, in 1972,
      • Scherlag B.J.
      • Yeh B.K.
      • Robinson M.J.
      Inferior interatrial pathway in the dog.
      who showed evidence indicating the existence of functional atrial muscle within the ligament of Marshall that formed part of an “interatrial conduction pathway.” More interestingly, Scherlag showed that stimulation of the left cardiac sympathetic nerves led to the induction of an ectopic atrial rhythm arising from the LOM, thus providing a first proof of the LOM’s arrhythmogenic potential of neurogenic origin. Decades later, work in Peng-Sheng Chen’s laboratory confirmed the LOM’s role in adrenergic atrial tachycardia,
      • Doshi R.N.
      • Wu T.J.
      • Yashima M.
      • Kim Y.H.
      • Ong J.J.
      • Cao J.M.
      • Hwang C.
      • Yashar P.
      • Fishbein M.C.
      • Karagueuzian H.S.
      • Chen P.S.
      Relation between ligament of Marshall and adrenergic atrial tachyarrhythmia.
      delineated its myocardial architecture,
      • Kim D.T.
      • Lai A.C.
      • Hwang C.
      • Fan L.T.
      • Karagueuzian H.S.
      • Chen P.S.
      • Fishbein M.C.
      The ligament of Marshall: a structural analysis in human hearts with implications for atrial arrhythmias.
      • Chou C.C.
      • Kim D.T.
      • Fishbein M.C.
      • Chen P.S.
      Marshall bundle and the valve of vieussens.
      demonstrated the role of LOM-pulmonary vein (PV) connections in complex activation patterns in atrial fibrillation (AF),
      • Tan A.Y.
      • Chou C.C.
      • Zhou S.
      • Nihei M.
      • Hwang C.
      • Peter C.T.
      • Fishbein M.C.
      • Chen P.S.
      Electrical connections between left superior pulmonary vein, left atrium, and ligament of Marshall: implications for mechanisms of atrial fibrillation.
      and showed LOM triggers in certain cases of paroxysmal AF.
      • Hwang C.
      • Karagueuzian H.S.
      • Chen P.S.
      Idiopathic paroxysmal atrial fibrillation induced by a focal discharge mechanism in the left superior pulmonary vein: possible roles of the ligament of Marshall.
      As a source of ectopic beats that could initiate AF
      • Hwang C.
      • Wu T.J.
      • Doshi R.N.
      • Peter C.T.
      • Chen P.S.
      Vein of Marshall cannulation for the analysis of electrical activity in patients with focal atrial fibrillation.
      and of dual sympathetic
      • Kim D.T.
      • Lai A.C.
      • Hwang C.
      • Fan L.T.
      • Karagueuzian H.S.
      • Chen P.S.
      • Fishbein M.C.
      The ligament of Marshall: a structural analysis in human hearts with implications for atrial arrhythmias.
      and parasympathetic
      • Ulphani J.S.
      • Arora R.
      • Cain J.H.
      • Villuendas R.
      • Shen S.
      • Gordon D.
      • Inderyas F.
      • Harvey L.A.
      • Morris A.
      • Goldberger J.J.
      • Kadish A.H.
      The ligament of Marshall as a parasympathetic conduit.
      innervation of arrhythmogenic potential, these data suggested that the LOM could become a therapeutic target in its own right. In addition, the VOM anatomical location—connecting the coronary sinus with the PVs—coincides with the typical location of the mitral isthmus, commonly ablated to treat perimitral flutter. The LOM/VOM arrhythmogenic mechanisms are summarized in Figure 1.
      Figure thumbnail gr1
      Figure 1Ligament and vein of Marshall (LOM/VOM) arrhythmogenesis. A: Schematic of the VOM arrhythmogenic mechanisms: (1) sympathetic and parasympathetic innervation, which can generate a profibrillatory substrate and ectopic beats; (2) myocardial bundles, which can lead to epicardial connections with the pulmonary veins (PVs) and atrial tissue and can bypass ablation lesions created in the mitral isthmus (shaded gray area). B: Histology of the coronary sinus (CS) and VOM takeoff, showing the CS myocardial sleeve ending at the valve of Vieussens (VV) and the great cardiac vein (GCV) without myocardial sleeve. C: Sympathetic innervation (tyrosine hydroxylase staining, arrow) and adjacent myocardial tract in the LOM. D: Parasympathetic innervation bundles (acetylcholinesterase staining) adjacent to the VOM. E: Myocardial connections (arrow) between the LOM and the atrial myocardium. LA = left atrium.
      The LOM’s mechanistic role in clinical arrhythmias beyond animal studies has been more elusive. Hwang et al
      • Hwang C.
      • Wu T.J.
      • Doshi R.N.
      • Peter C.T.
      • Chen P.S.
      Vein of Marshall cannulation for the analysis of electrical activity in patients with focal atrial fibrillation.
      were the first to cannulate the VOM with a microelectrode catheter to record LOM electrograms in humans and showed the first convincing evidence that AF could have LOM triggers. Using a similar technique, Dave et al
      • Dave A.S.
      • Baez-Escudero J.L.
      • Sasaridis C.
      • Hong T.E.
      • Rami T.
      • Valderrabano M.
      Role of the vein of Marshall in atrial fibrillation recurrences after catheter ablation: therapeutic effect of ethanol infusion.
      studied systematically 54 patients with recurrent AF after prior PV isolation. Of note, all 54 patients had robust VOM electrograms, even those with prior extensive endocardial ablation. Direct VOM electrogram recordings and differential pacing for the first time demonstrated that VOM-mediated connections with the left inferior PV could bypass previous PV isolation lesions, as predicted by animal studies.
      • Tan A.Y.
      • Chou C.C.
      • Zhou S.
      • Nihei M.
      • Hwang C.
      • Peter C.T.
      • Fishbein M.C.
      • Chen P.S.
      Electrical connections between left superior pulmonary vein, left atrium, and ligament of Marshall: implications for mechanisms of atrial fibrillation.
      These were, however, rare—present in 5 of 32 patients with left inferior PV reconnection. VOM focal activity was rare.
      Therapeutic targeting of VOM electrical activity was limited to radiofrequency (RF) delivery in its neighborhood, either endocardially or epicardially, which lacked therapeutic specificity. VOM ethanol infusion allowed for specific ablation of the VOM, its intrinsic electrical activity,
      • Valderrabano M.
      • Chen H.R.
      • Sidhu J.
      • Rao L.
      • Ling Y.
      • Khoury D.S.
      Retrograde ethanol infusion in the vein of Marshall: regional left atrial ablation, vagal denervation and feasibility in humans.
      • Valderrabano M.
      • Liu X.
      • Sasaridis C.
      • Sidhu J.
      • Little S.
      • Khoury D.S.
      Ethanol infusion in the vein of Marshall: adjunctive effects during ablation of atrial fibrillation.
      the neighboring myocardium and associated PV connections,
      • Dave A.S.
      • Baez-Escudero J.L.
      • Sasaridis C.
      • Hong T.E.
      • Rami T.
      • Valderrabano M.
      Role of the vein of Marshall in atrial fibrillation recurrences after catheter ablation: therapeutic effect of ethanol infusion.
      the mitral isthmus,
      • Baez-Escudero J.L.
      • Morales P.F.
      • Dave A.S.
      • Sasaridis C.M.
      • Kim Y.H.
      • Okishige K.
      • Valderrabano M.
      Ethanol infusion in the vein of Marshall facilitates mitral isthmus ablation.
      and the associated parasympathetic innervation.
      • Baez-Escudero J.L.
      • Keida T.
      • Dave A.S.
      • Okishige K.
      • Valderrabano M.
      Ethanol infusion in the vein of Marshall leads to parasympathetic denervation of the human left atrium: implications for atrial fibrillation.
      Although these data had been confirmed in anecdotal case reports by other groups beyond its original proponents,
      • Keida T.
      • Fujita M.
      • Okishige K.
      • Takami M.
      Elimination of non-pulmonary vein ectopy by ethanol infusion in the vein of Marshall.
      • Yoshitani K.
      • Kujira K.
      • Okishige K.
      Simultaneous re-isolation of the left pulmonary veins and termination of peri-mitral flutter with only an ethanol infusion in the vein of Marshall: killing two birds with one stone.
      the therapeutic value of VOM ethanol needed validation.
      In this issue of HeartRhythm, Chugh et al
      • Chugh A.
      • Gurm H.S.
      • Krishnasamy K.
      • et al.
      Spectrum of atrial arrhythmias utilizing the ligament of Marshall in patients with atrial fibrillation.
      report on 56 patients in whom LOM was considered to be a legitimate therapeutic target on the basis of pacing data suggesting LOM-mediated left atrium–PV connections or mapping data suggesting LOM-mediated macroreentrant or focal tachycardias. The mechanistic involvement of the LOM was not confirmed with direct VOM recordings. In patients with LOM-mediated PV connections, the authors were able to use RF targeting the LOM to successfully achieve PV disconnection in 15 of 18 patients. The remaining 3 were successfully disconnected using VOM ethanol. A total of 13 patients had LOM-mediated tachycardia (9 macroreentrant and 4 focal). RF targeting the LOM was successful in all but 2 patients. In 31 patients with perimitral atrial flutter, venography showed a suitable VOM in 23, and 16 of them received VOM ethanol, which led to perimitral conduction block—with or without added RF—in 15 (94%).
      Their data are important because they represent a real-life account of clinical situations where VOM and its associated myocardium play a role in challenging ablation cases. Although the data supporting the VOM/LOM mechanistic involvement in clinical arrhythmias was purely inferential given the lack of VOM multipolar recordings or VOM pacing as reported by Dave et al,
      • Dave A.S.
      • Baez-Escudero J.L.
      • Sasaridis C.
      • Hong T.E.
      • Rami T.
      • Valderrabano M.
      Role of the vein of Marshall in atrial fibrillation recurrences after catheter ablation: therapeutic effect of ethanol infusion.
      most laboratories do not have or use microelectrode catheters in the VOM routinely and are limited to the same kind of inferential approaches. This may account for the lesser incidence of VOM-mediated PV connections reported in previous descriptions,
      • Dave A.S.
      • Baez-Escudero J.L.
      • Sasaridis C.
      • Hong T.E.
      • Rami T.
      • Valderrabano M.
      Role of the vein of Marshall in atrial fibrillation recurrences after catheter ablation: therapeutic effect of ethanol infusion.
      which included a highly selected research patient population. However, the rigor at attributing a mechanistic role of VOM/LOM connections seems of little practical value beyond that of academic pontification: what the clinician needs is a tool to solve the problem when standard RF fails. This article provides it.
      A second important contribution is the validation of the VOM ethanol injection approach. Although the technical success reported was lower than that reported by other operators (70% vs 89%
      • Rodriguez-Manero M.
      • Schurmann P.
      • Valderrabano M.
      Ligament and vein of Marshall: a therapeutic opportunity in atrial fibrillation.
      ), the overall effects confirm the previous reports and support the therapeutic utility of VOM ethanol for eliminating epicardial connections to the left PVs
      • Dave A.S.
      • Baez-Escudero J.L.
      • Sasaridis C.
      • Hong T.E.
      • Rami T.
      • Valderrabano M.
      Role of the vein of Marshall in atrial fibrillation recurrences after catheter ablation: therapeutic effect of ethanol infusion.
      and epicardial connections across the mitral isthmus.
      • Baez-Escudero J.L.
      • Morales P.F.
      • Dave A.S.
      • Sasaridis C.M.
      • Kim Y.H.
      • Okishige K.
      • Valderrabano M.
      Ethanol infusion in the vein of Marshall facilitates mitral isthmus ablation.
      In addition, the authors refrained from injecting ethanol in cases where the VOM appeared small or too richly collateralized. Our experience supports the safety of ethanol injections in such veins
      • Valderrabano M.
      • Morales P.F.
      • Rodríguez-Mañero M.
      • Lloves C.
      • Schurmann P.A.
      • Dave A.S.
      The human left atrial venous circulation as a vascular route for atrial pharmacological therapies: effects of ethanol infusion.
      since collaterals are obliterated by ethanol. Greater operator experience certainly increases technical success.
      RF remains the electrophysiologist’s workhorse. The use of chemical ethanol ablation via coronary veins is a niche approach limited to RF failures. Chugh et al
      • Chugh A.
      • Gurm H.S.
      • Krishnasamy K.
      • et al.
      Spectrum of atrial arrhythmias utilizing the ligament of Marshall in patients with atrial fibrillation.
      confirmed its clinical utility in the VOM. In addition, we have reported its value in other atrial veins
      • Valderrabano M.
      • Morales P.F.
      • Rodríguez-Mañero M.
      • Lloves C.
      • Schurmann P.A.
      • Dave A.S.
      The human left atrial venous circulation as a vascular route for atrial pharmacological therapies: effects of ethanol infusion.
      and in ventricular veins for refractory ventricular tachycardia.
      • Kreidieh B.
      • Rodriguez-Manero M.
      • Schurmann P.
      • Ibarra-Cortez S.H.
      • Dave A.S.
      • Valderrabano M.
      Retrograde coronary venous ethanol infusion for ablation of refractory ventricular tachycardia.
      As operators face increasingly complex arrhythmogenic substrates, familiarity with chemical ablation tools may become increasingly useful. Chugh et al’s experience is a step toward greater adoption of this technique.

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