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Standardized Review of Atrial Anatomy for Cardiac Electrophysiologists

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Damián Sánchez-Quintana, Gonzalo Pizarro, José Ramón López-Mínguez, Siew Yen Ho & José Angel Cabrera

Journal of Cardiovascular Translational Research

ISSN 1937-5387 Volume 6 Number 2

J. of Cardiovasc. Trans. Res. (2013) 6:124-144 DOI 10.1007/s12265-013-9447-2

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J. of Cardiovasc. Trans. Res. (2013) 6:124–144 DOI 10.1007/s12265-013-9447-2

Standardized Review of Atrial Anatomy for Cardiac Electrophysiologists

Damián Sánchez-Quintana & Gonzalo Pizarro & José Ramón López-Mínguez & Siew Yen Ho & José Angel Cabrera

Received: 23 October 2012 /Accepted: 22 January 2013 /Published online: 7 February 2013 # Springer Science+Business Media New York 2013

Abstract Catheter ablation of cardiac arrhythmias has rap- relationship to other structures. This article is part of a JCTR idly evolved from a highly experimental procedure to a special issue on Cardiac Anatomy. standard form of therapy for various tachyarrhythmias. The advances in this field have included, first, the develop- Keywords Morphological substrate . Atrial fibrillation . ment of techniques of catheter ablation that often requires Atrial flutter . Pulmonary vein . Myoarchitecture the precise destruction of minute amounts of arrhythmo- genic tissues and, second, techniques of resynchronization therapy that require pacing different parts of the ventricles. Introduction A detailed prepocedural knowledge of cardiac anatomy can improve the safety of the procedure and its rate success. It The adoption of percutaneous interventional procedures for helps the electrophysiologist to choose the appropiate region the treatment of both structural heart defects and tachyarrhyth- for ablation, shortening the procedural time. The atrial anat- mias in humans has increased the interest in cardiac anatomy. omy structures are usually localized before ablation by Although new diagnostic techniques are now permitting the different imaging techniques such as fluoroscopy, electro- shape of the atrial cavities to be reconstructed with exquisite anatomic mapping, intracardiac echocardiography or multi- accuracy, and are revealing remarkably variable arrangements detector computed tomography. In this review, we describe of structures such as the pulmonary veins, it is helpful if the the normal anatomy of the atria, highlighting the landmarks interventional cardiologist can comprehend the morphologic of interest to intervencional cardiologist, stressing their and architectural features of the atrial chambers as seen in the autopsied heart. In addition, a new investigational wave has D. Sánchez-Quintana (*) emerged leading to revisitation of anatomic topics within the Departamento de Anatomía y Biología Celular, heart for which the information was incomplete or simply Facultad de Medicina, Universidad de Extremadura, wrong. As a result, recent studies have unraveled anatomic Avenida de Elvas s/n, 06071 Badajoz, Spain features, architectural aspects, and histological details of cer- e-mail: [email protected] tain components of the heart that are of fundamental impor- tance to those seeking to understand the substrates of D. Sánchez-Quintana tachycardias and their ablation [1–3]. It is also necessary to e-mail: [email protected] understand the arrangement of the cardiomyocytes aggregated : G. Pizarro J. A. Cabrera together to form the atrial walls, since this information can Hospital Universitario Quirón-Madrid, provide us with a better understanding of the preferential European University of Madrid, Madrid, Spain routes of conduction from one part of the atrium to the other J. R. López-Mínguez [4]. At the same time, it is important to know how the Servicio de Cardiología, Sección de Hemodinámica, myocardial walls of the two atrial chambers are joined togeth- Hospital Infanta Cristina, Badajoz, Spain er, and to recognize the location of the sinus node, the initiator of atrial activation. Our current purpose, therefore, is to review S. Y. Ho Cardiac Morphology Unit, Royal Brompton Hospital, the gross morphological and structural details of the right and Imperial College, London, UK left atria, concentrating of features such as the terminal crest, Author's personal copy

J. of Cardiovasc. Trans. Res. (2013) 6:124–144 125 the cavotricuspid isthmus, Koch’s triangle and its content, the sagittal plane. Instead, it is orientated obliquely from ante- Eustachian ridge and valve, the pulmonary venous orifices riorly to posteriorly rightward at an angle of around 65° to and their neighboring left atrial landmarks, and the architec- the sagittal plane [5]. Owing to the obliquity of this septal ture of the venoatrial junctions. We also discuss the anatom- plane and the difference between the levels of the mitral and ical features of important structures in the neighborhood of the tricuspid valvar orifices, the left atrial chamber is situated atria and the pulmonary veins, such as the esophagus and more posteriorly and superiorly than its right-sided counter- phrenic nerves. part. The pulmonary veins enter the posterior part of the left atrium, with the left veins located more superiorly than the right veins. The orifices of the right pulmonary veins are Location of the Atria directly adjacent to the plane of the atrial septum. The transverse pericardial sinus lies anterior to the left atrium, Both the right and left atrial chambers lie to the right of their and in front of this sinus is the root of the aorta. The tracheal respective ventricular chambers. Viewed from the front, the bifurcation, the esophagus, and descending thoracic aorta cavity of the right atrium is rightward and anterior, while are immediately behind the pericardium, being directly re- that of the left atrium is mainly positioned posteriorly lated to the posterior wall of the left atrium (Fig. 1). Further (Fig. 1). The plane of the atrial septum does not run in the behind is the vertebral column.

Fig. 1 a This picture of an endocast from a normal heart photographed tilted right superior and left perspectives, respectively, to show the in attitudinally appropriate position, with the so-called “right heart” in courses of the esophagus (Eso) and descending aorta relative to the blue and the “left heart” in red. As can be seen, the right atrium lies left atrium. CS coronary sinus, ICV inferior caval vein, LAA left atrial anterior to its alleged left-sided counterpart. Note the arrangement of appendage, LIPV left inferior pulmonary vein, LPA left pulmonary the terminal crest (white broken line). b External appearance of the artery, LSPV left superior pulmonary vein, OF oval fossa, RAA right right and left atriums viewed from superior view. Note the location of atrial appendage, RIPV right inferior pulmonary vein, RPA right the transverse sinus (yellow dotted line) and its relationship to the aorta, pulmonary artery, RS right superior pulmonary vein, SCV superior pulmonary trunk (PT) and atrial walls. c, d Specimens viewed from the caval vein Author's personal copy

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Spatial Location of the Atrial Chambers (Fig. 2), an inconstant and rudimentary valve seen as a During an Electrophysiological Study crescentic fold. The left atrium has an obvious smooth-walled body Two or more fluoroscopic views are usually needed to (Figs. 1 and 2), interposed between the vestibular and pul- define the anatomic position in the heart and to estimate monary venous components, with the pulmonary veins en- more accurately the location of the exploring electrode. The tering at the four corners of the venous part, enclosing a frontal view is used to introduce and position catheters in the prominent atrial dome (Fig. 1). Typically, two veins, posi- apex and outflow tract of the right ventricle, in the right tioned superiorly and inferiorly, drain into either side of the atrial appendage or the lateral aspect of the right atrium, and venous component. The endocardium of the chamber is in the region of the His bundle. The left anterior oblique smooth, with no muscular structure seen which is compara- (LAO) projection is generally used to catheterize the coro- ble to the right atrial terminal crest. Pectinate muscles are nary sinus independently of the type of venous approach. present in the left atrial appendage (Fig. 2), which arises From an attitudinal point of view, the right anterior oblique from the superolateral aspect of the body, and projects (RAO) projection defines what is anterior, posterior, supe- anteriorly over the proximal left circumflex artery, running rior, and inferior. The LAO defines superior, inferior, ante- alongside the pulmonary trunk. It is more tubular than the rior, and posterior locations for both the right and left normally pyramidal right appendage, and has a narrower atrioventricular (AV) grooves, which are almost parallel to base [7](Fig.2). The left side of the atrial septum is the plane of the image intensifier in this projection. smooth, but may contain a central shallow area, corresponding to the oval fossa (Fig. 2). Its anatomic feature is its two horns, which anchor it on the left side Components of the Atrial Chambers of the anterior interatrial groove.

Although the atria differ markedly in their shape (Figs. 1 and 2), they possess the same basic components. Thus, each Structural Features of the Right Atrium atrium is made up of a venous component, an appendage, and a vestibule, with the chambers separated one from the The Terminal Crest and the Area of the Sinus Node other by the septum. These various components themselves are supported by the bodies of the atria [6]. The body is much The right atrium is the anatomic gateway to its left-sided more obvious in the left than in the right atrium. The body of counterpart, and a thorough understanding of its anatomy the right atrium is the part of the chamber between the site of and anatomic variants is essential. The terminal crest marks the left venous valve and the septum. In the postnatal heart, it the division between the ridge-lined atrial appendage and is not usually possible to recognize the site of the left venous the smooth venous part [2, 8]. The crest extends from the valve. Hence, it is difficult to distinguish the body of the right anteromedial wall on the left side of the entrance of the atrium from the systemic venous sinus. superior caval vein (Fig. 1). It passes to the right and in front From the outside, the anterolateral portion of the right of the venous orifice before descending laterally, curving to atrium is dominated by its appendage, a roughly triangular- the right of the entrance of the inferior caval vein, to con- shaped offshoot whose apex generally points upwards, over- tinue as an array of finer bundles that enter the region of the lapping the aortic root (Fig. 1). Its inferior margin is adjacent atrial wall well described as the inferior, or cavotricuspid, to the right atrioventricular groove, which contains the right isthmus (Fig. 3). A series of muscle bundles known as coronary artery. When inspected from its cavity, the right pectinate muscles arise from the lateral margin of the crest. atrial appendage is large, and contains multiple pectinate They fan out from the crest and run toward the vestibular muscles (Fig. 2). The junction between the appendage and portion (Figs. 2 and 3). The mean length of the crest was the systemic venous sinus is marked internally by the ex- measured at 51±9 mm [8] and its thickness from epicardium tensive and prominent terminal crest (Figs. 1 and 2), which to endocardium at the junction of the superior cava vein corresponds externally to the terminal groove, an obvious with the posterior atrial wall was 5.5±1.3 mm [2]. One of landmark extends vertically from the superior to the inferior the anterosuperior bundles is usually more prominent. This caval vein. The smooth-walled vestibule supports the hinge structure continues into the tip of the appendage and it is lines of the leaflets of the tricuspid valve, and is surrounded usually described as the septum spurium (Fig. 3). It is a by the pectinate muscles of the appendage. The caval veins, convenient landmark for dividing the appendage into ante- along with the coronary sinus, drain into this extensive romedial and posterolateral components. Other authors have venous component. The orifice of the superior caval vein described how in some hearts, one fifth of those examined, usually has no valve, while the orifice of the inferior the pectinate muscles medial to the crest end in a discrete caval vein is flanked anteriorly by the Eustachian valve ridge, which was nominated as a second crest [9] (Fig. 2). If Author's personal copy

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Fig. 2 a Opened right atrium in simulated right anterior oblique view the crescentic edge of the oval fossa (OF) valve. d This section taken to show the terminal crest (TC). The crest arches anterior to the orifice through the short axis of the heart shows the thin flap valve (open of the superior caval vein (SCV) and extends to the area of the anterior arrow) and the muscular rim of the fossa (small arrows). Note the interatrial groove, breaking up into a series of pectinate muscles which different shape and size of the atrial appendages. CSO coronary sinus do not reach to the vestibule. b Four-chamber section through the heart orifice, ICV inferior caval vein, IS interventricular septum, LAA left showing the atrial septum in profile. The floor of the oval fossa (open atrial appendage, LCx left circumflex artery, LIPV left inferior pulmo- arrow) is the true septum. Stars mark the levels of attachments of the nary vein, LLR left lateral ridge, LSPV left superior pulmonary vein, tricuspid and mitral valves at the septum. The inferior pyramidal space MV mitral valve, PT pulmonary trunk, RAA right atrial appendage, (small arrow) is covered by the vestibule of the right atrium. c Longi- RCA right coronary artery, RIPV right inferior pulmonary vein, RS right tudinal section through the left atrium and left ventricle, showing the superior pulmonary vein, RVOT right ventricular outflow tract, TV smooth endocardial aspect of the left atrium. The black arrow indicates tricuspid valve present, this anatomical feature may produce difficulties fibrosis, often encountered in the crest (Fig. 3), are micro- during the ablation of the cavotricuspid isthmus. scars of ischemic events. At all events, the crest acts as a The cardiomyocytes making up the crest are aligned natural barrier to conduction [11]. It may provide a substrate mainly in longitudinal fashion along its long axis [2], thus that is suitable for possible re-entrant mechanisms, which favoring preferential conduction (Fig. 3). By contrast, at the could potentially promote profibrillatory remodeling [12]. margins of both subepicardial and subendocardial sides of It was Keith and Flack [13], in 1907, who first described the crest, the cardiomyocytes are irregularly oriented, inter- the location of the sinus node. The sinus node is the source mingling horizontal with oblique or longitudinal myocytes, of the cardiac impulse [13]. It can be identified at the and extending subsequently to reach the pectinate muscles superior cavoatrial junction as a spindle-shaped structure or the wall of the intercaval region [2]. Other morphological within the epicardial surface of the terminal groove, its tail studies [10] suggest that small patches of replacement extending toward the inferior caval vein (Fig. 3). The nodal Author's personal copy

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Fig. 3 a Opened right atrium to show the most important landmarks and its four components. Note the OF and the TC which is a thick C- shaped muscular trabecula that distally ramifies to form the pectinate muscles. b Endocardial aspect of the right atrium. The “septum spurium” (SS) is the most prominent anterior pectinate muscle arising from the terminal crest. c Scanning electron micrograph of nonmacerated cross section through the body of the terminal crest shows mainly longitudinal myocytes (open arrow) with intermingling oblique or lateral (stars) myocytes. Bar 35 μm. d Scanning electron micrograph of nonmacerated cross-section of the body of the terminal crest which are encased in dense and coarse connective tissue matrix (stars) in a specimen from a 75 year old. Bar 90 μm. e Histological section of the sinus node (black dotted line delineates the nodal boundaries) within a dense matrix of connective tissue (green) and showing nodal extensions to superior caval vein (SCV) and epicardium. f Histological section of the nodal body (van Gieson’s stain). Note the irregular contour of the node towards the neighboring myocardium (arrows). CSO coronary sinus orifice, ICV inferior caval vein, RAA right atrial appendage, TV tricuspid valve

cells were described histologically as “striated, fusiform, discrete area, composed of loosely packed myocytes, which with well-marked elongated nuclei, plexiform in arrange- has now been named as the paranodal area [15] (Fig. 3). The ment, and embedded in densely packed connective tissue” node itself varies in position and length along the terminal [13, 14] (Fig. 3). Sections through the node also showed a groove. It has been observed that the tail of the node was Author's personal copy

J. of Cardiovasc. Trans. Res. (2013) 6:124–144 129 located nearer to the endocardial surface of the crest than the of the atrium immediately anterior to it (Fig. 4). This part of head or body of the node in just over one quarter of speci- the vestibule, confined between the orifice of the coronary mens [16]. With age, the amount of connective tissue sinus and the attachment of the septal leaflet of the tricuspid increases with respect to the area occupied by the nodal valve, is the septal isthmus. It is often the target area for cells [17]. At the periphery of the node, the histologically ablation of the slow pathway into the atrioventricular node specialized cardiomyocytes are mixed with those of the [20] (Fig. 5a). It is also the target for ablation of isthmus- working myocardium (Fig. 3). In addition, multiple radia- dependent atrial flutter. The dimensions of Koch’s triangle tions or extensions interdigitating with the working atrial vary from one individual to another. This is clinically rele- myocardium have been described. These penetrate intra- vant in the case of catheter ablation procedures, which are myocardially into the crest, and toward the epicardium and largely guided by anatomic landmarks. In the 45° RAO the myocardium of the superior caval vein [16]. Sleeve-like projection, the plane of the triangle of Koch is parallel to extensions of right atrial myocardium that connect to the that of the image intensifier. To establish whether the cath- right atrium are usually found at the proximal level of the eter is on the triangle of Koch, the RAO and LAO views caval venous orifice (Fig. 3). Thus, atrial excitation from the must be combined. The LAO projection differentiates para- node can propagate directly into the musculature of the septal locations from inferior, anteroinferior, and anterior superior caval vein. These cardiomyocytes were found to positions of the probing electrode. The region of the His have pacemaker activity, with the enhanced automaticity bundle is superior, whereas the orifice of the coronary sinus suggested to play a role in the arrhythmogenic activity of is inferior. Right atrial angiography in the RAO projection the superior caval vein, potentially establishing ectopic trig- not only displays the limits and variable dimensions of the gers that could initiate paroxysmal atrial fibrillation [18] triangle of Koch but also identifies the exact position of the Table 1. catheter used for ablation in relation to the anterosuperior and posteroinferior limits of the tricuspid valve. This applies Koch’s Triangle, the Anatomic Location to ablative procedures in patients with AV nodal reentry of the Atrioventricular Node tachycardia; in patients with inferior paraseptal, septal, and superior paraseptal accessory pathways; and in patients with Another area of the right atrium of significance to interven- certain forms of atrial tachycardia arising from the triangle tional cardiologists is the triangle of Koch. This triangle is of Koch. The dimensions of the triangle of Koch may warn bordered posteriorly by a fibrous extension from the Eusta- the interventional electrophysiologist about the potential chian valve called the tendon of Todaro [19] (Fig. 4). The dangers of inducing unwanted damage over the atrioventric- anterior border is demarcated by the attachment of the septal ular node (Fig. 5b). leaflet of the tricuspid valve. The apex of this triangle The atrioventricular node itself is found at the apex of corresponds to the central fibrous body of the heart and is Koch’s triangle. It consists of a compact portion and areas of the site of penetration of the bundle of His. The so-called transitional cardiomyocytes [21]. The compact portion lies fast pathway of atrioventricular nodal reentry tachycardia, over the atrial surface of the central fibrous body (Fig. 4). It the most common type of reentrant supraventricular tachy- possesses rightward and leftward inferior extensions, with cardia, corresponds to the area of musculature close to the the right extension running close to the tricuspid annulus apex of the triangle of Koch (Fig. 1d). The base of the [22] (Fig. 4). The node was found to be displaced toward the triangle is the orifice of the coronary sinus and the vestibule base of the triangle in three quarters of specimens with

Table 1 Points of interest for ablation of tachycardias whose 1°—The sinus node varies in position and length along the terminal crest anatomical substrate were locat- 2°—Thickness of the terminal crest ed in the region of the sinus 3°—Atrial myocardial extensions into superior caval vein node, Koch’s triangle, and cav- — otricuspid isthmus 4° Risk of right phrenic nerve injury 5°—The dimensions of Koch’s triangle vary from one individual to another 6°—The atrioventricular node is found generally at the apex of Koch’s triangle 7°—Close anatomic proximity of AV nodal artery to endocardial surface at the base of Koch’s triangle 8°—His bundle surrounded and isolated by connective tissue which confers a better protection against ablation energy 9°—Length of the cavotricuspid isthmus: shorter ‘central isthmus’ 10°—A large Eustachian ridge/valve may lead to longer and more difficult ablative sessions 11°—The presence of a large sub-Thebesian recess is associated with a difficult ablation Author's personal copy

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Fig. 4 a, b Transillumination. Endocardial views of the right atrium to show the landmarks of the triangle of Koch. The vestibule of the right atrium and the coronary sinus orifice (CSO) form the lower limit. The apex of the triangle is the membranous septum. c Basal view showing macroscopically the course of the AV nodal artery across the inferior pyramidal space. At the base of the triangle, the artery runs inferior to the mouth of the coronary sinus and follows a course close to the septal attachment of the tricuspid valve (TV). d–f Sagittal sections stained with elastic van Gieson through the inferior extensions of the AV node (d), compact part of the AV node (black dotted line delineates the nodal boundaries) in e, and penetrating bundle of His (f) embedded in fibrous tissue. g Sagittal section through the mouth of the coronary sinus (CS) showing the proximity of the artery to the endocardium at the base of the triangle of Koch. ICV inferior caval vein, MV mitral valve, RAA right atrial appendage, SCV superior caval vein, STR sub-Thebesian recess, TC terminal crest, TT tendon of Todaro

Ebstein’s malformation, in which the inferior extensions conduction to the ventricles [21]. The artery supplying the reached the level of the cavotricuspid isthmus [23]. The node originates from the apex of the U turn of the distal right transitional cardiomyocytes are intermediate in size between coronary artery, and penetrates into the base of the inferior those of the compact node and the atrial working cardio- pyramidal space at the level of crux of the heart in around myocytes. They are surrounded by a greater quantity of nine tenths of patients [24] (Fig. 4). In the remaining one connective tissue matrix than that covering the working tenth of patients, it originates from the terminal portion of myocytes, but they are not insulated from the adjacent the circumflex artery or, uncommonly, is a dual structure, myocardium. Instead, they form a kind of bridge between arising from both the right and circumflex arteries. The the working and nodal myocardium and collect electrical artery provides branches to the inferior pyramidal space, information from the atrial walls, transmitting it to the interatrial septum, compact node, and penetrating bundle compact node, which continues distally as the His bundle. of His. In our postmortem study, we found that the mean This penetrating part of the atrioventricular conduction axis distance of the artery to the endocardial surface at the base can readily be distinguished from the compact node at the of Koch’s triangle was 3.5±1.5 mm [24] (Fig. 4). This may point where the axis itself becomes completely surrounded explain the possible risk of coagulating the artery during by the insulating tissues of the central fibrous body (Fig. 4). radiofrequency ablation in the region of the slow pathway. The bundle, of course, is the only pathway for electrical Complete atrioventricular block, when encountered, is Author's personal copy

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Fig. 5 a This is a human heart, note that the AV node and bundle of with replacement of muscle by granulation tissue at perimeter of the His (overlay in yellow) are located within the triangle of Koch. Abla- lesion and coagulative necrosis (asterisks) of underlying myocardium. tion in this area is avoided in order to prevent heart block. An injury Radiofrequency histological sections (Masson’s trichrome stain) in a from radiofrequency catheter ablation, however, is present in the base pig heart 1 day after application at the level of c central isthmus and d of the Koch’s triangle (dotted line). Ablation of the base of the triangle right inferior pulmonary vein. Note in c the subepicardial and endo- or paraseptal isthmus is commonly the target for ablation of the slow cardial bleedings and the disruption of the endocardium at sub-Thebe- pathway in AV nodal reentrant tachycardia. b Cryolesions histological sian recess (asterisk). Note in d the shape of the lesion (dotted blue characteristics at the AV node level in a pig heart 1 week after a single line) with coagulative necrosis of underlying myocardium and subepi- cryoenergy application. Note shape of the lesion resembling a prolate cardial bleeding. STV septal tricuspid valve, CSO coronary sinus ori- hemisphere (dotted yellow line) and the homogeneous nature of cry- fice, FO fossa oval, CFB central fibrous body, IVS interventricular olesion, with a smooth and sharp demarcation from intact myocardium, septum ventricular septum commonly a direct result of tissue injury to the compact lead to longer and more difficult ablative sessions [29] node itself after ablation of the fast pathway [25] (Table 1). (Figs. 5c and 6). We have divided the isthmus into three parallel levels [28]. With the heart in attitudinal orientation, The Inferior or Cavotricuspid, Isthmus, and Atrial Flutter we identified and measured its length at three different levels, namely paraseptal at 24±4 mm, inferior at 19±4 mm, and The commonest type of atrial flutter is the so-called isthmus- inferolateral at 30±3 mm (Fig. 6). The paraseptal isthmus dependent variant, in which the reentrant circuit is confined to forms the base of Koch’s triangle. The inferior isthmus, also the tricuspid vestibule, with the wave-front progressing in a known as the central isthmus owing to its location between the counterclockwise direction across the area between the orifice other two components, represents the optimal target for abla- of the inferior caval vein and the tricuspid valve (Fig. 6). This tion, since this is the site where the orifice of the inferior caval area, the cavotricuspid isthmus, is the target of catheter- vein is closest to the insertion of the septal leaflet of the directed ablation procedures, which are the treatment of choice tricuspid valve (Fig. 6). It is also shown that most diameters for cure of atrial flutter [26]. Autopsies, angiographic, and are larger in patients with flutter when compared to control echocardiographic studies have all shown that the anatomy of group [30]. The enlarged right atrium including the cavotricus- this structure is highly variable [27, 28]. Patients with short and pid isthmus may provide the pathophysiologic basis to sustain straight isthmuses require fewer ablation procedures and atrial flutter within an otherwise universally existing anatomic shorter exposure to radiation. Obstacles, such as a large Eusta- substrate. Fluoroscopically, these three levels of the isthmus chian ridge or valve, or a deep sub-Thebesian recess, may also cannot be visualized without angiographic techniques. In the Author's personal copy

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Fig. 6 a Opened right atrium in simulated right anterior oblique view lateral ridge (LLR) between the left atrial appendage (LAA) and the left showing the position of the ablation catheter at the site (central isthmus) PVs. e, f Histological sections (Masson’s trichrome stain) at the level of of application of radiofrequency. b, c Transillumination. The endocardial the central (e) and paraseptal (f) isthmus illustrating its different myocar- surface of the right atrial isthmus is displayed to show the three levels dial thickness. g Transillumination of the right atrial isthmus. Note the (inferolateral, central or inferior, and paraseptal). Note the pouch (sub- large sub-Thebesian recess (STR) in this specimen. CSO coronary sinus Thebesian recess or STR) at the central isthmus and the distal branching orifice, ICV inferior caval vein, LI left inferior pulmonary vein, LS left of the terminal crest (TC) that feed into the inferolateral isthmus. d Short superior pulmonary vein, PT pulmonary trunk, RAA right atrial append- axis through the interatrial septum (green arrow). Note by transillumina- age, RVOT right ventricular outflow tract, SC supraventricular crest, SCV tion the oval fossa (OF), the membranous septum and the so-called left superior caval vein, TV tricuspid valve

LAO projection, three areas must also be distinguished: a Todaro, which runs in the musculature of the ridge (Fig. 6). paraseptal level (5 o’clock position), a central area (6 o’clock The Eustachian valve can be fluoroscopically visualized in position), and an inferolateral level (7 o’clock position). The the right anterior oblique projection only after injection of cardiac multidetector computed tomography (MDCT) can be contrast material into the inferior caval vein, close to the advantageous for noninvasively characterizing the cavotricus- right atrial junction. The Eustachian valve/ridge may be pid isthmus, including its size, depth, and anatomic relation- large and muscular in some cases, posing an obstacle to ship with the inferior caval vein, Eustachian ridge, and catheter passage. A large ridge is an anatomic barrier, and coronary sinus ostium. In addition, cardiac MDCT may also forms a line of fixed conduction block during typical flutter. depict deep pouch-like recesses, which are commonly present It has been demonstrated that in patients with large ridges, along the cavotricuspid isthmus, which can make the creation block of the paraseptal isthmus can be obtained only after of a complete ablation line to block the arrhythmia difficult. complete ablation of the enlarged ridge [31]. Cabrera et al. [28] observed that, in one quarter of their specimens, the The Eustachian Ridge or Valve ridge was thickened, with a mean thickness of 3.2±0.8 mm, and a range from 2.1 to 4.3 mm. A ridge thicker than 4 mm The Eustachian ridge is a rim between the oval foramen and is also seen in one quarter of the normal population studied the coronary sinus that is in continuation with the insertion with computed tomography [32]. The angiographic study of the Eustachian valve. The free border of the Eustachian carried out by Heidbüchel et al. [27] similarly revealed an valve continues in a subendocardial level as the tendon of enlarged ridge in one quarter of patients, with a consequent Author's personal copy

J. of Cardiovasc. Trans. Res. (2013) 6:124–144 133 increase in the number of pulse applications required for the threatening complications, particularly in patients with atyp- achievement of successful block (Table 1). ical anatomy or a small oval fossa. Given that a major portion of the atrial septation is formed by infolding right The Sub-Thebesian Recess or Sub-Thebesian Sinus and left atrial walls (interatrial groove), puncture outside the limited margins of the oval fossa during transseptal inter- This recess is an extension of the pouch-like isthmus found ventions will perforate the heart. Fluoroscopic angulations under the orifice of the coronary sinus (Fig. 6), never being used for transseptal punctures must be individualized be- found in the lateral third of the cavotricuspid isthmus. It is cause of the variability in the position of the heart in the often described as being sub-Eustachian, since when the heart thorax. Experienced operators may perform very efficiently is positioned on its apex, the recess lies directly beneath the the puncture of the oval fossa in the posteroanterior projec- fibrous flap that in many hearts is found adjacent to the orifice tion; others may prefer a very angulated LAO projection of the inferior caval vein. When viewed in attitudinally appro- (>45°). In the RAO projection, the oval fossa is posterior priate position, the recess is seen to be beneath the Thebesian and superior or at the same level as the site of recording of valve, which is the remnant of the valve of the embryonic the His bundle potential. By means of cardiac MDCT, venous sinus adjacent to the mouth of the coronary sinus technologies may be useful in planning transseptal interven- (Fig. 6). In autopsied specimens, this recess was found in tions by identifying the anatomy of the interatrial septum one sixth of the adult hearts [9]. The recess, on average, was and demonstrating the precise morphology of a possible 9.3±3.7 mm long and 6.1±1.9 mm deep. In the majority of patent foramen oval, as well as identifying the presence of specimens, the recess was membranous with scarce muscular an atrial septal defect, or also a lipomatous hypertrophy of fibers [28]. In one angiographic study, this recess was ob- the interatrial septum, which is characterized by accumula- served in almost half of the patients and had a mean depth of tion and deposition of fat in the interatrial septum and can 4.3±2.1 mm [27]. The dimensions vary from one individual to result in constriction of the fossa oval (Table 2). another, which is clinically relevant in the case of catheter ablation procedures in this area. The presence of a large recess, or deep pouches, is associated with significantly more appli- Structural Features of the Left Atrium cations of current as compared to those having a straight isthmus [28] (Table 1). Local delivery of current may be The Left Atrial Wall and its Thickness impaired by this structure because an area of limited blood flow results in delayed cooling of the catheter tip. The wall of the left atrium measures, on average, 3 mm in thickness. It is thicker than the walls of the right atrium when we exclude considerations of the terminal crest. Al- The Atrial Septum though the left atrium has relatively smooth walls (Figs. 2, 3, 4, 5, 6, and 7), it is by no means uniform in thickness or in Partitioning the atrial chambers, the true atrial septum is myoarchitecture. The walls can be described as being ante- limited to the floor of the oval fossa and its immediate rior, superior, left lateral, septal, and posterior. The anterior muscular rim at the anteroinferior part, this latter component wall is located behind the ascending aorta and the transverse being confluent with the apical part of Koch’striangle pericardial sinus (Fig. 7). From epicardium to endocardium, (Figs. 3 and 4). The entirety of the superior and posterior its width is 3.3±1.2 mm, with a range from 1.5 to 4.8 mm in rims of the fossa, along with much of the anterior rim, is no unselected postmortem hearts. This wall, nonetheless, can more than infoldings of the atrial walls (interatrial grove). become very thin at the area near the vestibule of the mitral The true septum is the flap valve, along with its point of annulus (Fig. 7), where it measures an average of 2 mm in anchorage antero-inferiorly. As indicated, this antero- thickness. The roof, or superior wall, is in close proximity to inferior rim becomes confluent with the floor of the triangle the right pulmonary artery. Its width ranges from 3.5 to of Koch, but much of the triangle is a sandwich rather than a 6.5 mm, with a mean thickness of 4.5±0.6 mm. The thick- septum, since the atrial wall overlaps the crest of the ven- ness of the lateral wall ranges between 2.5 and 4.9 mm, with tricular septum in this area, with an upward extension of the a mean of 3.9±0.7 mm [1]. The measurement of the mean inferior atrioventricular groove separating the atrial from the thickness of the atrial septum in normal hearts at the level of ventricular muscle masses. Although often described as the the anteroinferior portion of the muscular rim is 5.5± posterior septum, in reality this is the inferior pyramidal 2.3 mm, and the mean thickness of the flap valve is 1.5± space (Fig. 4). A transseptal approach is used if access to 0.6 mm [1]. These results agree with previously published the left side of the heart is mandated. In some cases, percu- studies performed by transesophageal echocardiography taneous puncture of the interatrial septum for the left heart [33]. The posterior wall is non-uniform [34] (Fig. 7), and catheterization can be difficult and may result in life- is a target of currently used ablative procedures in patients Author's personal copy

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Table 2 Points of interest for ablation of tachycardias whose anatomical substrate were located in the left atrium and coronary sinus

1°—Puncture outside the limited margins of the oval fossa during transseptal interventions will perforate the heart 2°—Cardiac CT technologies may be useful in planning transseptal interventions (patent foramen oval, atrial septal defect, lipomatous hypertrophy) 3°—Non-uniform myocardial thickness of the left atrial wall 4°—Marked variability in pulmonary veins anatomy 5°—Thickness non-uniform of the myocardial sleeves of the pulmonary veins 6°—Autonomic nervous system on the epicardial surfaces of both the right and left superior veins 7°—Endocardial ridge: the left lateral ridge between the entrance of the left pulmonary veins and the mouth of the left atrial appendage 8°—Variability in the morphology of the left atrial appendage orifice 9°—Extra-appendicular pectinate muscles (mitral isthmus and vestibule) 10°—Marked variability in the dimensions of the mitral isthmus and its relationships (coronary sinus and circumflex artery) 11°—Changes in the musculature of Bachmann’s bundle and arrhythmias 12°—The coronary sinus is an important channel for mapping and for reaching accessory atrioventricular pathways around the mitral valve 13°—The coronary sinus is used as a conduit for left ventricular pacing during cardiac resynchronizarion therapy 14°—Close proximity of the left atrium to the esophagus, vagus nerve and left phrenic nerve with atrial fibrillation. Its thickness is greatest inferiorly, at annulus. By contrast, it is thinnest, at 2.2±0.3 mm, with a 6.5±2.5 mm, when measured immediately superior to the range from 1.2 to 4.5 mm, at the level of the right or left coronary sinus and between 6 and 15 mm from the mitral venoatrial junctions [35] (Table 2).

Fig. 7 a, b Longitudinal sections of two hearts illustrating endings of isthmus (blue dotted line). c, d Two heart specimens sectioned tran- the pulmonary veins into the left atrium. In a, the specimen showing a versally with the roof of the left atrium removed and viewed from short vestibule or funnel-like common vein for both left PVs. Note in b above to shows the entrance of the pulmonary veins. Note that in c, the that an individualized ending of the left superior PV (LS) and the left arrangement of four individualized ending of the PVs into the left inferior PV (LI) into the left atrium. The left PVs lie superior and atrium. In d, there are four PVs. However, the left PVs show a posterior to the mouth of the LAA, both separated by a muscular fold vestibule or funnel-like common vein before opening into the left so-called LLR. The anterior wall behind the ascending aorta can be- atrium (blue arrow). CS coronary sinus, LAA left atrial appendage, LI come very thin at the area near the vestibule of the mitral valve left inferior pulmonary vein, LLR left lateral ridge, LS left superior (asterisk). The line connecting the inferior margin of the ostium of pulmonary vein, MV mitral valve, RI right inferior pulmonary vein, RS the left inferior PV to the mitral annulus is the so-called the left atrial right superior pulmonary vein Author's personal copy

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Pulmonary Veins triggers for atrial fibrillation are located in this pulmonary venous myocardium. In recent times, various non-invasive imaging techniques, such as magnetic resonance imaging and multidetector com- Morphological Studies [42] puted tomography, have shown marked variability in pulmo- nary venous anatomy. This is well demonstrated in the number It was the early work by Nathan and Eliakim that established of venous orifices, with some patients having five distinct the presence of the muscular sleeves, revealing a mean extent openings, while others have common trunks. A common of 13 mm and a maximal extent of 25 mm. These sleeves were unilateral orifice is seen in one quarter of patients [36, 37], shown to be better developed in the upper than in the lower being more frequent on the left than on the right. The existence veins. Histological studies [1, 43] showed that the venous of extra veins, most commonly with a separate right vein walls were composed of a thin endothelium, a media of draining the middle lobe of the right lung, is another common smooth muscle, and a thick outer fibrous adventitia (Fig. 8). finding [38], and is also present in up to one quarter of patients The transition from atrial to venous walls was gradual as the [39]. Our anatomical study on a series of 35 heart specimens myocardial sleeves of ordinary atrial myocardium from the found the classic arrangement of four orifices in three quarters, left atrium overlapped with the smooth muscle of the venous with three tenths of these in the setting of a short vestibule or wall. The myocardial sleeves lay external to the venous media, funnel-like common vein (Fig. 7). We found five venous and internal to the epicardium and adventitia. They were orifices in 17 %, while the remaining 9 % had a common vein thickest at the venoatrial junction, with a mean of 1.1 mm, on the left or right side [40]. As well established by the group and thinned out distally. Their thickness was far from uniform, of Haïssaguerre [41], the left atrium is electrically connected with the inferior walls of the superior veins, and the superior to the veins by muscular sleeves. Four fifths of the focal walls of the inferior veins, having the thicker sleeves (Fig. 8).

Fig. 8 a Longitudinal histological section in Masson’s trichrome stain shows the thicker atrial wall becoming thinner at the entrances of the left PVs to form the muscular sleeves, which taper toward the lungs. b Cross- histological sections (Masson’s trichrome stain) through the left PVs showing variations in circumferential thickness of the myocardial sleeves (arrows). c Muscle bridges (arrows) between the superior and inferior pulmonary veins connect obliquely superior inferiorly. d, e Cross-histological sections illustrating in d the presence of gaps of connective tissue bridges between the myocardial fibers (red arrows) and note in e asmall area of myocardial degeneration with fibrous replacement (arrows). f Transillumination of the roof and posterior view of the left atrium of a 58-year-old man showing the acetylcholinesterase- stained epicardial ganglionated nerves (red arrows) extending to the superior surface of the left veno-atrial junctions. LI left inferior pulmonary vein, LS left superior pulmonary vein, RI right inferior pulmonary vein, RS right superior pulmonary vein Author's personal copy

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In particular, we were able to show two structural features in pulmonary vein stenosis or complete pulmonary vein occlu- specimens without heart disease. First, throughout the vein, sion may be symptomatic. Patients with symptomatic and and even at the venoatrial junction, there were gaps in the severe pulmonary vein stenosis will require therapeutic pro- myocardial sleeves that were mainly composed of fibrous cedures, such as stenting and balloon angioplasty. Thus, tissue [43]. These gaps create discontinuities between groups follow-up imaging postablation (Fig. 5d) is crucial for the of myocytes (Fig. 8). Second, interpulmonary myocardial early detection and prompt treatment of PV stenosis. connections are common, occurring in 15 of the 18 hearts examined (Fig. 8)[44]. Bridges of atrial myocardium, and The Left Lateral Ridge crossing strands, have been observed connecting superior and inferior veins, occurring more frequently between the left The left atrium does not have a terminal crest, but it has a so- veins than the right veins. They are located in the subendocar- called ridge, which was already described in 1907 by Keith dium in just over half, in the subepicardium in just over one [47]astheleft tænia terminalis [48]orterminalbandorstrip, quarter, and in both aspects in one fifth [44]. The arrangement and later by Papez [48] as the left posterior crest [49]. This left of the bundles of cardiomyocytes within the sleeves is rather lateral ridge interposes between the entrance of the left pulmo- complex. In contrast to previous reports [42], our findings nary veins and the mouth of the left atrial appendage (Fig. 9). revealed a mesh-like arrangement of muscular fascicles, made This is no more than an infolding of the atrial wall. It is, up of circular-orientated bundles that interconnected with nonetheless, the most relevant structural prominence to be seen bundles that ran in a longitudinal orientation [43]. We have in the endocardial surface of the left atrium (Fig. 9). The shape suggested that such an arrangement leads to anisotropic con- and size of this ridge is of relevance during attempted catheter duction between the bundles, which can act in itself as a focal ablation of atrial fibrillation, when the operator encircles the trigger, or provide the substrate for micro re-entry. Patchy orifices of the left pulmonary veins, or attempts to ablate areas of fibrosis (Fig. 8), which were also detected, may take extrapulmonary venous triggers arising around or inside the an active part in the role of the pulmonary venous muscular appendage. A three-dimensional study based on resonance sleeves in initiating atrial fibrillation [43]. Interestingly, no imaging showed that the ridge was pointed in shape, and correlation was seen between the age of the patients and the narrower than 5 mm in the majority of patients, thus determin- histological findings. Another important anatomical feature is ing the possibility of obtaining stable positions for the catheter that these myocardial connections may be the anatomical in this region [50]. Our anatomical study showed that the ridge substrate for electrical links between different pulmonary is a fold of the atrial wall, having a mean width that is narrower veins. This may have clinical implications for local discon- superiorly than inferiorly, and possessing thicker myocardium nection of the veins when attempting radiofrequency catheter at the anterosuperior level than postero-inferiorly [3]. The vein ablation [44]. Other studies have suggested that the triggers or ligament of Marshall is located at the epicardial aspect of the and drivers for fibrillation to be found in the muscular sleeves, ridge (Fig. 9), in close proximity to the endocardial surface, at a and in the posterior left atrial wall, are at least partially modu- distance of 3 mm at the superior level of the ridge in almost lated by the autonomic nervous system [45]. Vaitkevicius et al. three quarters of the specimens [3]. The oblique vein of Mar- [46] carefully examined the morphologic pattern of nerves shall, a remnant of the left superior caval vein, descends along and ganglia supplying the human pulmonary veins. They the lateral and posterior walls of the left atrium, extending observed the richest areas containing epicardial ganglia, from between the appendage and the left pulmonary veins (Fig. 9). which intrinsic nerves extend to the veins, concentrated at the It is present in around nine tenths of the population [51]. It joins inferior and superior surfaces of both the right and left superior the cardiac venous system at the junction of the great cardiac veins (Fig. 8). No ganglia were identified beneath the venous vein and the coronary sinus, approximately 3 cm away from the endothelium. These locations, therefore, might be considered right atrial opening of the sinus (Fig. 9)[51]. The vein is short, as potential targets for focal ablation in patients with atrial no more than 2–3 cm in length, and its superior part can be fibrillation (Table 2). obliterated by fibrosis. Complete fibrosis or obliteration in the The incidence of pulmonary vein stenosis caused by atrial form of a cord or ligament is seen in up to one eighth of cases fibrillation ablation was reported as 3–42 %, but had de- [52]. The average diameter is 1 mm, and the angle made with creased to <1 % due to improved techniques. These improve- the sinus varies between 25° and 50° [53]. In clinical studies, ments include changing the ablation site from inside the electrical activity originating from the vein or ligament can be pulmonary veins to outside the orifice of the pulmonary veins, recorded from the endocardial aspect of the left atrium, in or reducing the target temperature and amount of radiofrequency around the orifices of the left pulmonary veins [54]. Postmor- energy delivery, and using a 3D mapping system to guide the tem human studies demonstrated multiple connections by myo- catheter [47]. Symptoms such as cough, chest pain, dyspnea, cytic bundles that crossed the oblique vein of Marshall to hemoptysis, or recurrent lung infection, are more likely seen connect with different structures, such as the left lateral ridge, with severe stenosis (>70 %). However, even severe the free wall of the left atrium, the muscular sleeve of the Author's personal copy

J. of Cardiovasc. Trans. Res. (2013) 6:124–144 137

Fig. 9 a Endocardial visualization of the left posterolateral wall. muscle sleeve. c, d Macroscopical and histological section (Mas- Note the prominent left LLR between the LAA and both LS and LI son’s trichrome stain) of a specimen showing a pointed profile of pulmonary veins. In this specimen, extrapectinate muscle trabecu- the endocardial left lateral ridge extending to the inferior margin lations extending inferiorly from the appendage to the vestibule of of the LS pulmonary vein. The vestibule overlies the LCx and the mitral valve (MV; arrows). b Dissection to show the myocyte GCV. e This histological section in similar orientation shows a arrangement in the subepicardium of the left lateral ridge. Note flattened profile of the fold that forms the ridge. There is a small the multiple myocyte connections (asterisks) between the vein of artery (arrow)inthefold.RIPV right inferior pulmonary vein, RS Marshall (VOM) with the lateral ridge and the coronary sinus (CS) right superior pulmonary vein coronary sinus, and the atrial junctions of the left pulmonary (Fig. 4), or pointing posteriorly, or even toward the back of the veins [3]. Additionally, abundant ganglia and fibers of the aorta (Fig. 10). The circumflex artery runs epicardially in the autonomic nervous system are present in the environs of the fat-filled atrioventricular groove, related to the smooth anterior vein or ligament of Marshall, and its adjacent epicardium, vestibule and in close proximity to the inferior border of the contains, with a higher neural density also observed that the orifice of the appendage (Fig. 10). The shortest distance from epicardial aspect of the ridge, particularly at its superior level the mouth of the appendage to the circumflex artery was less where it is relation with the opening of the left superior pulmo- than 5 mm in four fifths of our unselected human postmortem nary vein [3]. Other authors have raised the possibility that the hearts. In computed tomographic studies, the artery was found intrinsic cardiac nerves, notably the superior left ganglionated within 2 mm of the mouth of the appendage in three quarters of plexus, can activate and contribute to atrial fibrillation [55]. cases, an anatomic detail to be considered when ablating inside or around its mouth [57]. The appendage has crenellations, or The Left Atrial Appendage lobes, that are potential sites for deposition of thrombus, but are challenging to image adequately [56]. Most intracardiac In human hearts, the left appendage is characteristically a small thrombus originates in the left atrial appendage during and finger-like extension of the atrium, with a multilobulated ap- after atrial fibrillation causing stroke, infarction, and emboli. pearance in four fifths of hearts [56](Fig.10). The tip of the Despite the advances in treatments with the new oral anti- appendage can be in a variety of positions, lying over the coagulants, approximately one third of patients are considered pulmonary trunk, or left anterior descending coronary artery at high risk of bleeding. Therefore, the interventional treatment Author's personal copy

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Fig. 10 a Internal view of the LAA showing the long and short diam- finger (f) and stump-like (g). h Histological section (Masson’strichrome eters of the ostium of the appendage (double arrows). Note the extrap- stain) showed the internal structure of the LAA and its close proximity to ectinate muscle trabeculations (arrow). b–e Images demonstrating adjacent structures. Note the thin wall of the appendage in between the significant interindividual variation in left atrial appendage morphology. pectinate muscles. i In this specimen, the epicardium has been removed to Note in d that the tip of the LAA oriented inferiorly and in e the tip is show the arrangement of the LCx painted in red. Note the relationship oriented superiorly and located between PT and the left atrial body (red between the LAA and the artery. CS coronary sinus, LCA left coronary arrow). f, g Silicone casts that show the morphological appearance of the artery, LI left inferior pulmonary vein, LV left ventricle, LS left superior LAA, which may be classified into two types: slender like a crooked pulmonary vein, MV mitral valve, VOM vein of Marshall for left atrial appendage closure represents a complementary less well-defined. The orifice of the appendage is not round, and effective treatment for this group of patients. Given the being oval in shape, with a mean long diameter of 17.4±4 mm variability of the left atrial appendage orifice morphology, a and short diameter of 10.9±4.2 mm [7]. While the rim of the detailed knowledge of its anatomical characteristics could be orifice is smooth, a complicated whorl-like network of pecti- very useful when planning the intervention. Owing to tubular nate muscles lines the endocardial surface of the appendage shape of the left atrial appendage, the junction with the atrium [58](Figs.9 and 10). In between the muscle bundles, the wall is narrow, often defined as a waist. On the endocardial aspect, is paper thin. In just over a quarter of specimens, muscular the superior and posterior borders of the orifice of the append- trabeculations can be found extending inferiorly from the age are well demarcated by the ridge separating the mouth appendage to the vestibule of the mitral valve (Fig. 9). These from the orifices of the left superior pulmonary veins (Figs. 7, extra-appendicular myocardial bands correspond to the small 8,and9) Lacking a ridge, the anterior and inferior borders are posterior set of pectinate muscles originating from the Author's personal copy

J. of Cardiovasc. Trans. Res. (2013) 6:124–144 139 myocardial bundles to embrace the appendage [3]. In those the thickest atrial wall was midway between the mitral annu- hearts with extra-appendicular posterior pectinate muscles, the lus and the left inferior vein, with tapering at either end of the areas in between the muscular trabeculae and the atrial wall isthmus [61]. On the other hand, Wittkampf et al. [61]have become exceptionally thin, no more than 0.5 mm, increasing suggested that the muscular sleeve around the coronary sinus, the risk of cardiac perforation during ablative procedure [3] and the close anatomic proximity with the circumflex artery, (Table 2). are the two major anatomic determinants for the creation of conduction block across the isthmus (Fig. 11). The coronary The Left Atrial Isthmus or Mitral Isthmus sinus is always a close neighbor of the circumflex artery, which crosses the venous structure in the majority of speci- Although the posteroinferior area of the lateral wall between mens. The local cooling mediated by atrial arteries and veins the orifice of the left inferior pulmonary vein and the mitral may protect the surrounding left atrial myocardium, prevent- annulus (Fig. 11)cannotbeconsideredananatomicentity,itis ing the formation of transmural lesions by applications of now termed by electrophysiologists as the left atrial isthmus, energy, and consequently making it difficult or impossible to or mitral, isthmus. Linear ablations connecting the inferior create conduction block across the isthmus. Also, relevant is margin of the ostium of the left inferior pulmonary vein and the unpredictable content of atrial myocardium due to the the mitral annulus, particularly when complete linear block is existence of extrapectinate muscles extending inferiorly from achieved, appear to increase the success rate of catheter abla- the appendage in the area of the isthmus, which may cause tion in patients with atrial fibrillation, and prevent macro- entrapping of the tip of the ablation catheter (Figs. 9, 10,and reentry around the mitral annulus or the left veins [59]. The 11), potentially leading to excessive tissue heating, isthmus creation of such lesions by catheter ablation, nonetheless, may perforation, and tamponade [3]. These anatomic observations be associated with significant complications. can be explained by the regional differences in thickness of the The isthmus showed a marked variability in its dimensions, left atrial wall at the level of the isthmus (Table 2). with considerable differences in thickness of the myocardium at various levels and among different hearts [60]. The mean distance between the left inferior vein and the mitral annulus The Myoarchitecture of the Left Atrial Walls ranged between 17 and 51 mm, with a mean of 34.6 mm. The and Interatrial Muscular Connections wall thickness midway between the veins and the mitral annulus was 2.8 mm, with a range from 1.2 to 4.4 mm. In Detailed transmural dissections of the atrial wall have shown a contrast, a more recent histological examination revealed that complex architecture of overlapping cardiomyocytes, with

Fig. 11 a Sagittal section through the left atrium and esophagus (Eso) the space between the pectinate muscles where the left atrial wall showing the ostium of the LAA, the orifices of the left pulmonary veins becomes thinner (double red arrows). Note also in b and c that a muscular and the mitral isthmus (double-headed arrow). b–d Longitudinal histo- continuity (stars) between the sleeve of the coronary sinus and left atrial logical sections (Masson’s trichrome stain) through the mitral isthmus to wall. Ao aorta, LI left inferior pulmonary vein, LS left superior pulmonary illustrate its anatomic relations with the CS or GCV and LCx. Note in b vein, MV mitral valve, PT pulmonary trunk, VOM vein of Marshall Author's personal copy

140 J. of Cardiovasc. Trans. Res. (2013) 6:124–144 different orientations giving the false impression of layers, as fashion relative to the plane of the atrioventricular junction these are not separated by sheaths of insulating fibrous tissue (Fig. 12). Bachmann’s bundle extends rightward to the junc- [4, 48, 62]. There are individual variations from heart to heart tion between the right atrium and the superior caval vein. but, in general, the myoarchitecture conforms to the pattern Changes in the musculature of Bachmann’s bundle could first shown so elegantly in human hearts by Papez in 1920 block or prolong interatrial conduction, resulting in abnormal [49]. From the epicardial aspect, it is common to find a broad atrial excitability, atrial dysfunction, atrial fibrillation, and muscular bundle that runs along the anterior atrial wall. other arrhythmias. Although Bachmann’s bundle and its vas- Known as Bachmann’s bundle, or the interatrial band, it is cular supply can easily be detected by 64 cardiac MDCT, composed of cardiomyocytes that are aligned in parallel Bachmann’s bundle is less visible in patients with severe

Fig. 12 Serial dissections to display the atrial myoarchitecture in a deeper dissection showing the myoarchitecture in the subendocardium. normal human heart. Broken lines highlight the major orientations. a, b The septoatrial bundle (red broken lines), arises from the anterior septal Cross-histological section, Masson’s trichrome stain. Show the Bach- raphe underneath Bachmann’s bundle and its myocytes run obliquely in mann’s bundle crossing the anterior interatrial groove and branching three directions: across the dome of the left atrium, also pass leftward into toward the atrial appendages. c Bachmann’s bundle combines with the the lateral wall, and others continue into the fine ridges lining the cavity of superficial circular fibers passing to the left lateral wall (yellow broken the LAA. h Cross-histological section (Masson’s trichrome stain) shows lines). d–f Shows the longitudinal fibers of the septopulmonary bundle the Bachmann bundle and its rightward extensions (arrow) toward the (yellow broken lines), which arises from the interatrial groove underneath sinus node. i Cross-histological section (Masson’s trichrome stain) show- Bachmann’s bundle, fanning out to line the pulmonary veins and to pass ing a muscular bridge (arrow) across the anterior interatrial groove. ICV longitudinally over the dome (d), in the posterior wall of the left atrium inferior caval vein, LA left atrium, LAA left atrial appendage, LI left and the superficial circular fibers in the inferior wall (e and f). Note in e inferior pulmonary vein, LS left superior pulmonary vein, LV left ventri- and f muscular bridges (arrow) across the posterior interatrial groove (e) cle, OF oval fossa, RAA right atrial appendage, RI right inferior pulmo- and inferior interatrial connections (arrow) through the CS. g Show a nary vein, RS right superior pulmonary vein, SCV superior caval vein Author's personal copy

J. of Cardiovasc. Trans. Res. (2013) 6:124–144 141 coronary artery disease, atrial fibrillation, and interatrial bundle can coexist with muscular bridges across the anterior conduction block. In the absence of Bachmann’s bundle, interatrial groove [1]. Another structure that allows connec- the area is replaced by fat. Thus, this suggests an tions between the atria is the coronary sinus. The sinus runs association between the above conditions and diseased along the posteroinferior wall of the left atrium, on the atrial Bachmann’s bundle fibers [63]. side of the true atrioventricular junction [64](Figs.11 and 12). Deep to Bachmann’s bundle, and inferior to it, are cardio- In all specimens examined, the venous wall of the sinus was myocytes arising from the anterior rim of the oval fossa. These surrounded by a sleeve of myocardium extending, in some blend into Bachmann’s bundle, and pass leftward to the lateral cases, almost 5 cm from the right atrial orifice [65]. Myocar- wall of the left atrium, passing to either side of the neck of the dial connections of varying in number and morphology left left appendage, and then reuniting as a broad band that runs this muscular sleeve and connected to the wall of the left circumferentially around the inferior wall to enter the posterior atrium (Figs. 11 and 12). The right atrial orifice of the sinus septal raphe (Fig. 12). Another important bundle, composed abuts the superior margin of the right atrioventricular junction of longitudinally to obliquely arranged cardiomyocytes, arises and the inferior paraseptal mitral annulus in the pyramidal from the anterosuperior septal raphe, and passes beneath space (Figs. 4, 5,and6). The inferior interatrial connections Bachmann’s bundle onto the surface of the atrial roof. These through the walls of the sinus may explain the need for cardiomyocytes were described by Papez as the septopulmo- additional ablation in and on the venous channel so as to cure nary bundle [49]. They fan out to pass in front, between, and atrial fibrillation [65]. In addition, from the perspective of behind the insertions of the pulmonary veins, joining with the ablationists, the coronary sinus is an important channel for venous muscular sleeves (Fig. 12). On the posterior wall, the mapping and for reaching accessory atrioventricular pathways septopulmonary bundle often has two diverging branches that around the mitral valve and those traversing the inferior pyra- fuse with, and become indistinguishable from, the circumfer- midal space (the inferior paraseptal pathways). The orifice of ential cardiomyocytes coming from the lateral wall. the coronary sinus may be accessed also for ablating the slow Deeper than the septopulmonary bundle and forming the pathway in patients with atrioventricular nodal re-entrant subendocardium is the septoatrial bundle described by tachycardia. The coronary sinus is used as a conduit for Papez [49] (Fig. 12). This bundle arises from the anterior catheter treatment of arrhythmias as well as left ventricular septal raphe as an array of obliquely arranged cardiomyo- pacing during cardiac resynchronizarion therapy. To obtain cytes. These combine with the oblique cardiomyocytes from recordings of the left atrium and left ventricle, a catheter is the anterior vestibule, and those from the septopulmonary guided into the coronary sinus. Because of the sharp angle of bundle to the atrial roof, continuing between the orifices of the coronary sinus with the left atrium, catheterization of this the left and right pulmonary veins on the posterior wall of structure is easier via the superior caval vein (Table 2). the left atrium (Fig. 12). It is common to find extensions from the septoatrial bundle forming loops around the area of the venoatrial junctions, and often these can be traced to the Important Structures in the Neighborhood of the Atria circular cardiomyocytes of the venous sleeves. In some cases, however, the subendocardial cardiomyocytes are lon- Relationship between the Esophagus and Left Atrium gitudinal, running along the long axis of the vein, while the subepicardial cardiomyocytes encircle the veins. Branches Due to the close proximity of the esophagus to the posterior from the septoatrial bundle also pass leftward into the lateral wall of the left atrium [35] (Fig. 13), ablative procedures wall. Some of the cardiomyocytes encircle the mouth of the involving this region of the atrium may cause esophageal left appendage, while others continue into the fine ridges damage, resulting some times in the formation of an atrialeso- lining the cavity of the appendage. phageal fistula [66]. Computed tomography is a valuable tool Apart from muscular continuity at the margins and the floor for showing the relationship between the atrial wall and the of the oval fossa, there are other muscular bundles that permit esophagus or the descending aorta prior to undertaking the conduction between the atria. In the majority of hearts, the ablation procedure [67]. Peristalsis, however, and dynamic most obvious muscular interatrial bridge is Bachmann’sbun- movement of the esophagus during the procedure, can result dle. Its rightward and leftward communications fan out to in discordance between the preprocedural and intraprocedural blend into musculature of the atrial walls. Its rightward com- anatomy. In an anatomical study, we found that the length of munications, nonetheless, are mainly on the epicardial side of the esophagus in contact with the posterior left atrium ranged the terminal crest anterior to the mouth of the superior caval from 30 to 53 mm, with a mean of 42±7 mm. The esophagus vein and close to the site of the sinus node (Fig. 12). It is the was within 5 mm of the endocardium of the posterior left atrial proximity of Bachman’s bundle to the crest, and the site of the wall in two fifths of the specimens [35]. Behind the posterior node, which makes this the most significant electrical intera- wall is a layer of fibrous pericardium, along with fibro-fatty trial connection. Additionally, in some hearts, Bachmann’s tissue of irregular thickness that contains esophageal arteries Author's personal copy

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Fig. 13 a Left atrium view from the back after removal of the the course of the right phrenic nerve. e Histological sections (Masson’s descending thoracic aorta to show the course of the Eso in situ and trichrome stain) through the right superior pulmonary vein (RS) and its relationship to the vagus nerves. b An overview of a transthoracic right venoatrial junction. The right phrenic nerve is adherent to the section through the mediastinum showing the locations of the esoph- fibrous pericardium. Note the short distance between the endocardium agus and descending aorta relative to the right pulmonary veins and left of the RS and the right phrenic nerve. f Left lateral view of the heart atrium. c Cross-histological section (Masson’s trichrome stain) show- showing the close anatomic relation of the left phrenic nerve with the ing the proximity of the esophagus to middle of the posterior wall of LAA and the lateral wall of the LV to penetrate into the left part of the the left atrium. d This dissection shows an anterior view of the heart diaphragm. LI left inferior pulmonary vein, LS left superior pulmonary with the fibrous pericardium around it. The lungs were removed. Note vein, PT pulmonary trunk, RI right inferior pulmonary vein and the plexus formed by the vagus nerve (Fig. 13). These of 0.3±0.5 mm, while the minimal distance to the right anatomic structures may be affected by ablative procedures. superior pulmonary vein is 2.1±0.4 mm (Fig. 13). In one The vagus nerves pass behind the root of the lungs, and form third of human heart specimens, the anterior wall of the right right and left posterior pulmonary plexuses. From the caudal superior pulmonary vein was within 2 mm of the nerve [69]. part of the left pulmonary plexus, two branches descend on the Consequently, catheter ablation aimed at modifying the anterior surface of the esophagus (Fig. 13) joining with a function of the sinus node at the lateral right atrium, and branch from the right pulmonary plexus to form the anterior catheter ablation for atrial fibrillation at the orifice and esophageal plexus. The posterior and anterior esophageal plex- adjacent area of the right superior pulmonary vein, carry a uses enter the abdomen through the esophageal diaphragmatic certain risk of damaging the right phrenic nerve [70]. opening, reuniting to become the posterior and anterior vagal The left phrenic nerve descends on the fibrous pericardium, trunks that innervate the stomach and pyloric canal, along with taking one of three courses. It runs over the anterior surface of the digestive tract as far as the proximal part of the colon. Our the left ventricle in one fifth of the population, over the lateral observations on postmortem hearts revealed a mean distance margin of the left ventricle in three fifths, and in a poster- between the bundles of the anterior esophageal plexus and oinferior direction in the remainder [71]. Computed tomo- posterior left atrial endocardium, or veno-atrial junctions, of graphic angiography can demonstrate the left phrenic 4.1±1.4 mm with a range from 2.5 to 6.5 mm [68]. neurovascular bundle as it passes over the pericardium cover- ing the left ventricle in three quarters of the studies [72]. It is Relationship between the Phrenic Nerves and the Atria difficult to image the right phrenic nerve, but high output pacing causing diaphragmatic contractions can be used to The phrenic nerves lie along the lateral mediastinum, and mark its course. During electrophysiologic interventions, the run from the thoracic inlet to the diaphragm [69]. The right left nerve is especially at risk when procedures are performed phrenic nerve has a close anatomical relationship with the in the vicinity of the left atrial appendage (Fig. 13). In a study superior caval vein, with a minimal distance between them of cadavers, the endocardium of the roof of the left appendage Author's personal copy

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