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STATE-OF-THE-ART REVIEW

Left Atrial Appendage

Embryology, Anatomy, Physiology, Arrhythmia andTherapeutic Intervention

Niyada Naksuk, MD,a Deepak Padmanabhan, MBBS,a Vidhushei Yogeswaran, BA,b Samuel J. Asirvatham, MDa,c

ABSTRACT

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Known for the pathological connection to atrial fibrillation (AF), the left atrial appendage (LAA) is the most common

source of thromboembolism in patients with AF and may be an arrhythmogenic source for the maintenance of AF.

Potential interventions of the LAA for stroke prevention have recently been developed through better understanding its

anatomy and physiology. Occlusion of the LAA is an alternative to the use of life-long anticoagulation in selected

nonvalvular AF cases. The PROTECT-AF (The WATCHMAN LAA Closure Device for Embolic PROTECTion in Patients with

Atrial Fibrillation) and PREVAIL (Randomized Trial of LAA Closure vs. Warfarin for Stroke/Thromboembolic Prevention in

Patients with Non-valvular Atrial Fibrillation) randomized controlled trials demonstrated that LAA exclusion using the

Watchman percutaneous device is not inferior to warfarin. However, the appendage is structurally complex and has

considerable morphological variations among individuals, and it can be challenging to generalize the device for all

patients. Continued technological developments including occlusion/ligation through epicardial, endocardial, or surgical

approaches, as well as operator expertise regarding LAA anatomy, physiology, and pathophysiology, should improve

interventional outcomes. Furthermore, the optimal strategy for re-entrant tachyarrhythmias arising from LAA remains

unknown. Whereas an observational study suggested that LAA isolation was more effective than focal ablation, LAA

isolation may be associated with significant impairments in LAA contractility, predisposing individuals to a risk of

thrombosis. (J Am Coll Cardiol EP 2016;2:403–12) © 2016 by the American College of Cardiology Foundation.

T he left atrial appendage (LAA) is a derivativeof the atrial primordium that has anatomicaland physiologic variations from the left

atrium (LA), which is an extension of the embryolog-ical pulmonary vein (PV) bud. As the major source ofthromboemboli in patients with atrial fibrillation(AF), our current understanding of the LAA anatomyand function has extended to the development ofLAA closure devices for stroke prevention. This reviewfocuses on the background of the LAA anatomy andphysiology and provides an overview of closure tech-niques, in particular, the Watchman device (MedStar,

m the aDivision of Cardiovascular Diseases, Department of Medicine,

ool, Mayo Clinic College of Medicine, Rochester, Minnesota; and the cDivi

d Adolescent Medicine, Mayo Clinic, Rochester, Minnesota. Dr. Asirvath

iccure, Biotronik, Biosense Webster, Boston Scientific, Medtonic, Medt

wer, Elsevier, and Zoll; and is a patent holder with Aegis, Access Point T

er authors have reported that they have no relationships relevant to the

nuscript received March 8, 2016; revised manuscript received May 11, 20

Washington, District of Columbia), which has beenrecently approved by the U.S. Food and Drug Admin-istration (FDA) for clinical use. Excellent reviewfor currently available LAA closure devices and indevelopment has been provided elsewhere (1,2).

EMBRYOGENESIS

The LAA is the only cardiac structure in the LA derivedfrom the primitive atrium; the rest are a part of PVs andare characterized by a smooth endocardium (OnlineVideo 1, Online Figure 1) (3). At week 4 of gestation,

Mayo Clinic, Rochester, Minnesota; bMayo Medical

sion of Pediatric Cardiology, Department of Pediatric

am is an uncompensated consultant for Abiomed,

elligence, St Jude Medical, Sanofi Aventis, Wolters

echnologies, Nevro, Sanovas, and Sorin Medical. All

contents of this paper to disclose.

16, accepted June 24, 2016.

FIGUR

The po

(LIPV),

artery

crosse

ostium

atrial a

ABBR EV I A T I ON S

AND ACRONYMS

AF = atrial fibrillation

CT = computed tomography

LAA = left atrial appendage

LA = left atrium

LOM = ligament of Marshall

LSPV = left superior

pulmonary vein

LV = left ventricle

PA = pulmonary artery

PV = pulmonary vein

TEE = transesophageal

echocardiography

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the primitive atrium undergoes a right-handed looping toward its ultimate location.The subsequent cellular protrusion phase so-lidifies the basal mesodermal layer and formsthe trabeculae/pectinate muscles that lead tothe rough endocardium characteristic of theLAA (3,4). When the lungs develop, anoutgrowth of the primordial PV buds connectsto the primitive atrium and completes thedevelopment of LA at approximately day 50 ofthe embryologic life (3).

DEVELOPMENTAL ANOMALIES. Very fewdevelopmental abnormalities of the LAAhave been reported. Isomerism of the LAA is

associated with fatal congenital syndromes (5). Itis important to distinguish the congenital absenceof the LAA from the LAA membrane, found inciden-tally, from complete or flush thrombotic occlusion (6).Congenital LAA aneurysms are associated withpectinate muscle dysplasia, predisposing to throm-bus formation, supraventricular arrhythmias, andrupture. Therefore, aneurysmectomy is generallyrecommended (7). The congenital absence of thepericardium may be associated with appendage her-niation that could result in difficulties in a pericardialintervention of the LAA (2).

E 1 LAA and its Adjacent Organs

sterior aspect of the left atrial appendage (LAA) lies close to the

and ligament of Marshall (LOM). (A, B) The superior aspect is re

(LCX), the great cardiac vein (GCV), and the left ventricle (LV) lie

s posterolaterally. On the endocardial aspect (C), the left lateral r

from the LSPV. There are several pits or diverticula around the in

ppendage.

ANATOMY

Fixed in the front part of the pericardial space, theLAA is within close proximity to several vital organs.Projecting to a various curve, the body of the LAA isanterior to the LA and parallel to the left PVs (8). Itstip points to the pulmonary artery (PA), right ven-tricular outflow tract, and left ventricular (LV) freewall (Figures 1 and 2) (9). The PA and left PA thencourse superoposteriorly and are separated by thetransverse sinus. The inferior aspect and ostium areclosely related to the left circumflex artery and thegreat cardiac vein that course along the atrioventric-ular groove and the mitral valve. The left phrenicnerve also courses posterolaterally. An indentation ofthe ligament of Marshall (LOM), or a remnant of leftsuperior vena cava, serves as an epicardial landmarkbetween the left lateral aspect and left superior PV(LSPV). Slightly lateral to the ligament, there isBachmann’s bundle encircling the LAA neck (2).

Albeit heavily trabeculated endocardium, the LAAwall is remarkably thin (w1 mm) (2). Its ostium has anincomplete boundary and a prominent ridge from theLOM (also known as the left lateral ridge, or “Q-tip”sign on echocardiography), posterosuperiorly sepa-rating LAA and LSPV. The anterior and inferior as-pects are indistinct from the LA.

left superior pulmonary vein (LSPV), the left inferior pulmonary vein

lated to the pulmonary artery (PA) and left PA. The left circumflex

in close proximity to the inferior aspect. The left phrenic nerve (LPN)

idge (LLL) at the corresponding area of the LOM separates the LAA

distinct border of the ostium (*). Also see Online Video 1. LAA ¼ left

FIGURE 2 Cardiac CT Illustrates the Relationship Between the LCX Anteroinferior to the LAA

(A) Note the persistent left-sided superior vena cava (SVC) sits between the left atrial appendage (LAA) and left superior pulmonary vein

(LSPV). There are left pulmonary artery superiorly and free wall LV inferiorly (B). Computed tomography (CT) demonstrates the four most

common LAA morphologies: (C1) “Cactus” has a dominant central lobe with extending secondary lobes. (C2) “Windsock” has a dominant

lobe larger than the distal portions of the LAA. (C3) “Cauliflower” has no dominant lobe, but has more complex characteristics than other

morphologies. (C4) “Chicken-wing” presents an obvious bend in the proximal or middle part of the dominant lobe, or folding back on itself

which can be a secondary lobe or twig. Abbreviations as in Figure 1. (C1 to C4) Reprinted with permission from Romero et al. LAA morphology

and physiology: the missing piece in the puzzle. J Cardiovasc Electrophysiol 2015;23:928–33.

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There are several variations in size, number oflobes, shape, ostium, and dimension of the LAA(Table 1) (2,10). The LAA morphology is generallydivided into 4 types, including “chicken wing,”“cauliflower,” “cactus,” and “windsock” (Figure 2).Recognition of these morphologic variations is help-ful in planning interventions. For instance, the“chicken wing” morphology with its several sharpbends and an extremely superior LAA orientation isdeemed unsuitable for some epicardial closuredevices (11). After LAA occlusion, there is a residualrisk of pits or diverticula, petite structures which arelocated around the proximal ostium that could not becompletely occluded by the device’s deployment andmay cause catheter entrapment (Figure 1C) (12).

PHYSIOLOGY

LAA is a contractile reservoir and decompressionchamber that acts as a suction during ventricularsystole and as a conduit during diastole (13). Thisunique function can be evaluated through trans-esophageal echocardiography (TEE). An organized

quadriphasic flow is found in normally functioningLAA (14), although this pattern is less prominent inmyopathic LAA (Figure 3).

Functioning as an endocrine organ, the LAA, whenstretched, produces w30% of atrial natriuretic pep-tides (15). An animal study suggests that the LAA mayalso mediate thirst in a hypovolemic state (16).

Hypothetically, LAA excision may have severaldownstream effects. Animal studies suggested thatLAA exclusion resulted in decreased pulmonaryvenous flow, increased diastolic transmittal flow (17),and a 50% decrease in cardiac output (18). However,no data to date have demonstrated the long-termconsequences of elimination or manipulation of theLAA on human physiology (10).

The role of the LAA as a reservoir of cardiac pro-genitor cells was elegantly suggested through animalmodels (19). These cells were cultured and formed amature cardiomyocyte-like appearance proposed forpreserving cardiac function after an infarct (20).Albeit these were preliminary results, the role ofthese cells as cardiac stem cells merits furtherinvestigation.

TABLE 1 Variations of the Left Atrial Appendage Morphology

LAA Variations

Morphology “Cactus” (30%), “chicken wing” (48%), “windsock” (19%), and“cauliflower” (3%). The “cactus” has a central lobe with secondarylobes extending above and below. The “windsock” has one mainlobe and other smaller lobes arising within the main lobe. The“cauliflower” has a shorter length than the others and a moreirregular internal shape. The “chicken wing” folds back on itselfafter the ostium (31,53).

Lobes A single lobe (20%–70%), 2 lobes (16%–54%), up to 4 lobes in theremaining (53).

Ostium location There is variation in the orientation of the ostium related to the LSPV. In60%–65% of individuals, it is at the same level as the LSPV butsuperior in 25%–30% and inferior in the rest (2).

Ostium shape Many variations have been reported regarding the shape of the ostium.These shapes include elliptical (or oval), round, triangular,water–drop-like, and foot-like. Elliptical shapes are the mostcommon (69%).

Ostium width 21.9 � 4.1 mm (range: 12.1–38.8 mm) (4).

Ostium length 49.4 � 9.1 mm (range: 24.9–85.7 mm) (4).

Ostium depth Range: 16–51 mm (14).

Pits There are several pits surrounding the ostium that may contribute toclot formation. Typical pits range from 0.5 to 10.3 mm (54).

Body The LAA has a narrow base with a hook-like apex that points inferiorly.A wide body and narrow neck are typical (14).

Curvature Curvilinear bending course at 90� � 20� after the initial 14 � 4 mm(75%) (2).

Direction of the tip The tip of the LAA is directed mostly anteriorly and cephalad,overlapping with the pulmonary trunk but may face otherdirections (4).

Wall thickness A study reported the mean atrial wall thickness was only 1 mm(0.4–1.5 mm) (54).

LAA ¼ left atrial appendage; LSPV ¼ left superior pulmonary vein.

FIGURE 3 A Quadriphasic Flow Pattern of Normal LAA During Sinus Rhythm

1, Forward flow during late diastole, known as the peak velocity associated with increased

risk of stroke; 2, retrograde LAA filling; 3 and 4, systolic reflection phase with positive and

negative components from ventricular relaxation and LAA elasticity. Abbreviations as in

Figure 1.

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PATHOPHYSIOLOGY

The LAA accounts for 91% of the thrombus sourcesin nonvalvular AF and 15% to 38% in non-AFpatients with a cardiomyopathy who have developedstroke (21,22). Stroke secondary to LAA emboli pre-sents with worse disability and mortality than carotiddisease (23). The interplay between AF (leading toreduced LAA velocity, increase blood stasis, andcoagulability) and the LAA (the heavily trabeculatedchamber) underlies the pathophysiology of thrombusformation (Central Illustration). As such, decreases inLAA contraction and velocity as measured by TEE areone of the strongest predictors of stroke (24). Analysisof stroke prevention in the AF III trial proposed thatpeak anterograde LAA velocity <20 cm/s wasindependently associated with LAA thrombus (25).Furthermore, autopsy studies found that LAA remod-eling in the setting of longstanding AF was character-ized by chamber dilatation and hypotrophy of thepectinate muscle (26,27). Clinically, cardiac magneticresonance has made it possible to identify scar inde-pendently linked to LAA thrombus formation (28).

Conflicting data implicate a link between LAAmorphology and stroke risk. Among proposedanatomical features, including orifice size, neckdimension, volume, multiple lobes, degree of trabe-culations, position of the LAA, and fibrosis, the spe-cific four LAA morphologies have been the mostinvestigated topic. Although previous retrospectivestudies proposed the “cauliflower” and “non-chickenwing” morphology were linked to risk of thrombusformation (29,30), the largest meta-analysis to dateopposed the notion that the “chicken wing” LAA wasassociated with the highest thromboembolic risk (31).

The mechanism of thrombotic formation in LAAamong non-AF patients may involve a connectionbetween the deterioration of the LAA flow and anelevated filling pressure in the setting of cardiomy-opathy. As the LAA is confined to a fixed pericardialspace superior to the free wall LV, diastolic LVdistention may contribute to a reduction inappendage function (32).

ARRHYTHMIA

The LAA has been implicated as the focal point ofatrial tachycardia or a maintenance circuit in 2% to27% of patients with recurrent AF after ablation(33,34). There is some uncertainty about the optimaltime (at index vs. repeat ablation procedures) andstrategy (focal ablation vs. electrical isolation) forablating these LAA arrhythmias, given that currentdata were based on small observational studies

CENTRAL ILLUSTRATION Underlying Mechanism of LAA Thrombus Formation

Naksuk, N. et al. J Am Coll Cardiol EP. 2016;2(4):403–12.

The LAA with prominent pectinate muscles becomes remodeled as a result of long-standing AF. The changes involving chamber dilatation,

scarring, endocardial dysfunction and low emptying velocity predispose for thrombus formation. AF ¼ atrial fibrillation; LAA ¼ left atrial

appendage.

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during short-term follow-up. Focal LAA ablation tar-geting the scar site with fragmented and mid-diastolicelectrocardiograms in persistent AF was associatedwith an 87% rate of maintaining sinus rhythm (33).Electrical isolation appears to be attractive, with asignificant decrease in AF recurrence after 1 yearfollow-up. A study of 86 patients with the LAA as thesource of recurrent AF proposed that LAA isolation bycircular catheter delivery at the LAA ostium achieved

a lower recurrent AF than ablation targeting theearliest electrical activation (34). Furthermore, LAAclosure can achieve electrical isolation (by inductionof necrosis), presenting a potential for simultaneoustreatment of AF and prevention of stroke. A smallstudy of 15 patients supported that finding by usingthe Lariat suture delivery system (Sentreheart,Redwood City, California) produced a shorter P-waveduration and an increase in P-wave amplitude,

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suggesting a reversal of the electrical remodeling andan improvement in LA function (35).

The LAA can also be a source of arrhythmia inyoung adults without a structural heart disease. Datafound w3% of arrhythmias secondary to abnormalautomaticity rise from LAA (36,37). Furthermore, aleft-sided accessory pathway connection between theLAA and LV has been reported (38). Radiofrequencyablation is generally successful and withoutcomplications.

PERCUTANEOUS LAA CLOSURE TECHNIQUES

There are many techniques of LAA occlusion availablein clinical practice and in development (OnlineTable 1) (1,2). The Amplatzer family (AGA MedicalCorporation, Golden Valley, Minnesota) developedfrom the atrial and ventricular septal defect occludersare available for use in Europe (39–41). The Lariatsystem, with the concept of delivering pre-formedsutures through an endocardial-epicardial approachis now under review by the FDA (42,43). The systemoffers the unique advantage of avoiding anti-coagulation/antiplatelet therapy after the procedure,given an absence of an intracardiac foreign body.Despite missing long-term safety data, the prospec-tive AMAZE (Left Atrial Appendage Ligation with theLARIAT Suture Delivery System as Adjunctive Ther-apy to Pulmonary Vein Isolation for Persistent orLongstanding Persistent Atrial Fibrillation) study(NCT02513797) will test the Lariat system as anadjunct to catheter ablation in patients with long-standing AF (44,45).

FIGURE 4 Watchman Device Resembles an Umbrella With the Dome

(A) The hooks used to anchor to the trabeculations in concert with the n

device position retention. Reprinted with permission from Yu et al. (1).

Dr. David J. Holmes, Jr.

WATCHMAN DEVICE. Among 3 types of percuta-neous LAA closures, the Watchman device is the onlyFDA-approved LAA occluder for nonvalvular AF pa-tients who are suitable for long-term warfarin ther-apy. Recently, the device has been approved forreimbursement by the Centers for Medicare andMedicaid, which has extended the device as an optionfor the patients who are not candidates for long-termanticoagulation (but could still tolerate short-termwarfarin). The Watchman is the only LAA occlusiondevice that was evaluated through randomizedstudies. In the PROTECT-AF trial, the Watchman wasnoninferior to warfarin therapy but had lower hem-orrhagic stroke and cardiovascular death (46). How-ever, the FDA cited the high rates of periproceduralcomplications as worrisome factors. These short-comings led to the institution of the PREVAIL trial,which defined the primary and late outcomes sepa-rately to differentiate among the mechanisms ofaction of stroke prevention (47). Although the re-sults were initially promising, with decreased ratesof complications, the additional follow-up yielded ahigher number of ischemic strokes in the Watchmangroup. Conclusively, the Watchman failed todemonstrate noninferiority to warfarin. Overall, inboth of the trials and in the real-world setting, therate of adverse events was 1.5% to 4.4%, with theleading contributors of periprocedural complicationslisted as pericardial effusion and procedure-relatedischemic stroke (42,46,47).

The Watchman atrial framework is made of nitinolcovered by a polyethylene terephthalate membranethat promotes endothelialization and is permeable to

Toward the LA

egative traction were applied at the time of deployment to enhance

(B) Watchman device is placed in the LAA ostium. Figure courtesy of

FIGURE 5 Role of TEE and CT in Determining Suitability of Endovascular LAA Occlusion

(A) Multiplanar 3D TEE images to measure the size of LAA orifice. (B) 3D TEE demonstrates large thrombus (arrows). (C, D) Pre-procedural CT for the LAA dimensions

using orthogonal views of the appendage and (E) finally calculating the most effective dimensions of the LAA. CT ¼ computed tomography; TEE ¼ transesophageal

echocardiography; other abbreviations as in Figure 1. (A, B) Reprinted with permission Yu et al. (1). (C) Reprinted with permission from Siobhan et al. Imaging the LAA

prior to, during, and after occlusion. J Am Coll Cardiol Img 2011;4:303–6. (C, D, E) Figure courtesy of Dr. Mohammad Sarraf, Mayo Clinic.

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blood but not thrombotic particles (Figure 4) (12,48).A 10% to 15% oversizing of the device relative to theLAA ostium helps reduce peri-device leaks, but thetrade-off is a greater risk of damage to the sur-rounding structures (8,49). Dedicated TEE (preferably3D TEE) and cardiac computed tomography (CT) canbe used to characterize LAA morphological details,and assess the ostium size and relationship to nearbystructure, which are important in selecting eligiblepatients (Figure 5, Table 2) (1,8,50,51).

Brief, stepwise procedures are illustrated inFigure 6. During 45 days post procedure, patientsreceive warfarin and aspirin therapy. Subsequent TEEis then performed to evaluate for residual device leaks.Warfarin can be discontinued in patients without sig-nificant leaks (i.e., a single jet <5 mm in diameter), butclopidogrel will be added. Long-term isolated aspirintherapy begins at 6 months post procedure.

TABLE 2 Suitable Morphology of the LAA for the

Watchman Device

LAA ostial diameter: 17–31 mm

Length of the LAA should be more than the LAA ostial diameter

Low angulation between the longitudinal axis of the LAA and theplane of the LAA orifice

No LAA thrombus

LAA ¼ left atrial appendage.

UNANSWERED QUESTIONS AND

FUTURE DIRECTIONS

A method to afford the patients who are ineligible foranticoagulation should be a primary research direc-tion. Results of the ASAP prospective registry, whichenrolled patients to dual antiplatelet therapy afterWatchman implant showed comparable strokerates to the PROTECT-AF trial (52). A prospectiverandomized trial to confirm these results is needed todirect the management of patients with absolutecontraindications to anticoagulation. The epicardialapproach using the Aegis system (Aegis Medical Sys-tem, Vancouver, Canada) may also help since it doesnot need concomitant anticoagulation or antiplatelettherapy. However, the absence of trials comparingeach LAA closure modality, as with the novel anti-coagulant therapy, makes it difficult to decide whichtherapy is superior for patients. Because each LAAocclusion technique offers unique benefits and risks,patient selection must be individualized. Anatomicalrecognition of the location of the LAA ostium,definition and management of device leaks, andmanagement of LAA with variant anatomy remainimportant topics to be addressed. Finally, evidencesuggests that the LAA itself may be a marker forstroke risk. However, the proposed functional mea-surements have not been tested against or as

FIGURE 6 Real-Time Imaging for Watchman Implantation

(A) 1, Left anterior oblique fluoroscopic view presents a pigtail catheter used to perform cine-angiograms. 2, Access sheath is then introduced

into the LAA over the wire. 3, After the position is secured, the “tug test” is performed to check for stability prior to release of the delivery

cable. (B) Intracardiac echocardiogram demonstrates a well-seated 27-mm Watchman at the ostium with appropriate device compression

(22 mm) (reduction of the device width by 20%). Color Doppler shows <5 mm jets, suggestive of adequate all-lobes exclusion. (B) Reprinted

with permission from Siobhan et al. Imaging the LAA prior to, during, and after occlusion. J Am Coll Cardiol Img 2011;4:303–6.

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additional stroke risk stratification to the existingCHA2DS2-VASc (congestive heart failure, hyperten-sion, age $75 years, diabetes mellitus, prior stroke,TIA, or thromboembolism, vascular disease, age65–74 years, sex category [female] score).

SUMMARY

The LAA is a unique organ with contractile capacity.When electrical, structural, or functional remodelingof the LAA occurs in the setting of AF, the LAA be-comes a primary source of thrombus formation. Thisunique pathogenesis has made the LAA a target fortherapeutic intervention.

ACKNOWLEDGMENTS The authors thank Jan H.Case, Margaret A. McKinney, and Ernest S. Hain forpreparing figures, video, and illustrations, and KristiJ. Simmons, Susan E. Bisco, and Shauna S. Otternessfor efforts in preparing the manuscript.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Samuel J. Asirvatham, Division of CardiovascularDiseases, Department of Internal Medicine, Divisionof Pediatric Cardiology, Department of Pediatrics andAdolescent Medicine, Mayo Clinic, 200 First StreetSW, Rochester, Minnesota 55905. E-mail: asirvatham.samuel@mayo.edu.

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KEY WORDS anatomy, closure, left atrialappendage, ligation, pathophysiology,physiology

APPENDIX For supplemental figures, atable, and a video, please see the online versionof this article.