Surgical clip closure of the left atrial appendage

Abstract Atrial fibrillation (AF) is the most common atrial arrhythmia, but it is not a benign disease. AF is an important risk factor for thromboembolic events, causing significant morbidity and mortality. The left atrial appendage (LAA) plays an important role in thrombus formation, but the ideal management of the LAA remains a topic of debate. The increasing popularity of surgical epicardial ablation and hybrid endoepicardial ablation approaches, especially in patients with a more advanced diseased substrate, has increased interest in epicardial LAA management. Minimally invasive treatment options for the LAA offer a unique opportunity to close the LAA with a clip device. This review highlights morphologic, electrophysiologic, and surgical aspects of the LAA with regard to AF surgery, and aims to illustrate the importance of surgical clip closure of the LAA.


| INTRODUCTION
Atrial fibrillation (AF) is the most common atrial arrhythmia. It should not be considered a benign disease, in addition to symptom burden, loss of atrial and potentially ventricular function, AF is an important risk factor for cerebral stoke. This causes significant morbidity and mortality, especially in the aging populations of the developed countries. The left atrial appendage (LAA) plays an important role in thrombus formation. Data suggest that approximately 90% of atrial thrombi in nonrheumatic AF are found within the LAA. 1 Although oral anticoagulants (OACs) offer an important reduction in stroke risk, they also increase bleeding risk.
Benefits of rhythm control for more persistent forms of AF are becoming clearer, but results of catheter ablation remain far from ideal. 2 This led to a growing interest in minimally invasive AF surgery, [3][4][5][6] especially for patients who are refractory to medical and transcatheter therapy. 4,7,8 To date, transcatheter closure of the LAA shows no significant benefit compared to OAC. During thoracoscopic AF ablation, the surgeon has the unique opportunity to manage the LAA. In the past, complete LAA exclusion has proven challenging, while incomplete closure or amputation may increase thrombo-embolic risk. 9,10 However, clip occlusion devices have simplified surgical LAA management with consistent exclusion and, importantly, electrical isolation of the LAA. 11,12 Since the introduction of epicardial LAA management, over 250,000 clip occlusions have been performed in patients worldwide.
A recent large randomized controlled trial showed a significant reduction in ischemic stroke when LAA amputation or closure was performed as a concomitant procedure, in AF patient undergoing cardiac surgery, 13  exclusion. This review highlights morphologic, electrophysiologic, and surgical aspects of the LAA with regard to AF surgery, and aims to illustrate the practical implications for surgical rhythm management.

| LAA MANAGEMENT AND EFFECT ON LA AND LV MECHANICAL FUNCTION
Historically considered a useless embryonic remnant, 14 the importance of the LAA is increasingly being recognized. Not merely its role as "the most lethal human attachment" 15 due to its role in cardiac embolisms in AF patients, but also the important role in plays for both LA and LV functions. The LAA can act as a complementary reservoir that refills during left ventricular early systole when the mitral valve is closed and the LA is passively filled. The LAA has been shown to have greater compliance than the LA, particularly in diseases causing volume overload. Therefore, the LAA can play an important role in cardiac pressure-volume regulation. 1 However, decreased LA reservoir function is noted after LAA exclusion without affecting intrinsic LA contractility. 16 During early diastole, the LAA should be considered a compliance chamber that passively fills the LA and LV once the mitral valve is open, while during late diastole, the LAA acts as booster pump due to its intrinsic contractile function, thus contributing to stroke volume. 17,18 The LAA is calculated to contribute to up to 10% of the total LA volume. 19 However, contemporary series seem to exclude significant echocardiographic variation in LV stroke volume or LVEF in patients in sinus rhythm undergoing LAA occlusion. 16 These data have been confirmed in patients with reduced LVEF (<35%), [20][21][22] Despite a global increase in LA reservoir volume, a moderate improvement in conduit and booster pump function may be expected based on the Frank-Starling mechanism. It has to be noted that these findings were from endocardial LAA occlusion; little is known about hemodynamic effects of epicardial LAA occlusion.

| LAA MANAGEMENT AND NEUROENDOCRINE EFFECTS
The endocrine role of the LAA is related to the presence of intrinsic stretch-sensitive receptors able to release ANP. Experimental analysis has demonstrated the presence of so-called "ANP densely granulated cells" with the highest concentration in the LAA. [23][24][25] F I G U R E 1 Wang's classification for LAA morphologies. LAA length was measured from the orifice area (dashed orange line) to the farthest point of the LAA via the center of the main lobe. The bend angle was measured with an imaginary vertical line (red dashed line) and a line between the main lobe and the farthest point of the LAA. Cactus has a dominant central lobe, one or more secondary lobes, and total length <4 cm. ChickenWing has only one lobe, total length more than 4 cm, and a bend angle less than 100°. WindSock has one dominant lobe with several secondary, or even tertiary lobes, total length more than 4 cm, and a bend angle of over 100°. CauliFlower has a total length less than 4 cm and complex internal structures. LAA, left atrial appendage Fluid infusion at the level of the LAA increases blood ANP levels, leading to increased heart rate, natriuresis and diuresis, resulting in reduction of volume load, vasodilatation, and blood pressure decrease. 26 Several studies demonstrated significant downregulation and inhibition of the natriuresis pathway when the LAA is excluded surgically. Furthermore, noradrenaline, adrenaline, renin, and aldosterone are significantly downregulated in patients treated with epicardial LAA exclusion. [27][28][29] The appendage is richly innervated by sympathetic and parasympathetic nerves in strict relation to stretch receptors, and interconnected with the angiotensin system activated by ANP release. Turagam et al. 30

| LAA MORPHOLOGY
Increased interest in ablation techniques and management of the LAA, combined with improved imaging modalities, have led to classification systems for LAA morphology. The most commonly used Wang classification assigns the LAA to "Cactus," "Chicken wing," "Windsock," or "Cauliflower" (Figure 1) 32 morphologies. Such classifications system may assist both in planning interventions and the identification of "dangerous" appendages that require intervention. 33 Large LAAs and LAAs with single lobe morphology are more frequently present in patients who suffer from stroke. However, AF-induced elevated pressure and subsequently increased LAA volume may alter LAA morphology. The number of LAA lobes is reduced due to the remarkably thin (+/−1 mm) wall, combined with the lack of supporting tissue around the appendage. Additionally, bending of the LAA may occur due to dilatation, creating turbulence and eventually increasing thrombo-embolic risk.
This knowledge may guide patient selection for LAA management, 34 although more studies on this subject are required. For procedural planning, other imaging modalities such as contrast enhanced cardiac computerized tomography (CT) can be utilized, although the static nature of CT means differentiation between thrombus and sluggish flow can be difficult, as images are captured a few seconds after contrast reaches the left heart (LA/LAA). Cardiac magnetic resonance imaging is a promising modality for reliable assessment of LAA shape and dimensions/volume. At times, CCT and CMR can be challenging since irregular heart rate and tachycardia significantly reduce image quality (with an ideal heart rate <65 beats/ min). Transesophageal echocardiography (TOE) is used to assess the preprocedural presence of thrombus in the LAA.

| THE ROLE OF LAA CLIP OCCLUSION IN THROMBOEMBOLIC STROKE RISK REDUCTION
In general, the LAA is the most common site for cardiac thrombi in patients, both in AF and in SR. 35 LA enlargement promotes stasis and thus thromboembolic risk. 36 An additional stroke risk is the presence of a heavily trabeculated LAA endocardium. 33 Although there is a strong relationship between AF and stroke, the causal relationship between stroke and thrombus formation within the LAA is not undisputed. It has been demonstrated that in AF patient population, 91% of all thrombi were formed within the LAA. 37 In another prospective study, TEE examination show that of 230 patients with AF for >2 days, 33 out of 34 cardiac thrombi were located in the LAA. 38 As a part of the original Cox-Maze procedure, the atrial appendices were routinely amputated, and his group has published extensively on rhythm outcome but also stroke reduction benefit after Maze surgery. 39 The recent LAAOS III trial, randomizing AF patients undergoing cardiac surgery to concomitant LAA closure or not, demonstrated that LAA closure results in a relative stroke risk reduction of 33% at 3.8 years follow-up. 13 42 Electrical exclusion of the LAA therefore provides an antiarrhythmogenic benefit. Di Biase et al. 43 reported that 27% of their AF ablation patient population had foci in the LAA, while the LAA was the only mapped trigger in 8.7% of cases. In transcatheter ablations studies in AF, arrhythmia-free survival was better in patients who undergo additional LAA isolation compared to pulmonary vein isolation alone; Heeger et al. 44 showed 49% arrhythmia free survival compared to 37% in the control group (p = 0.02). Similar results were achieved in the BELIEF Trial. 45 Nevertheless, there is concern about potential excess stroke risk after electrical isolation of the LAA via catheter ablation, since the procedure creates an akinetic cul-de-sac in communication with the left atrium, which has proven to be highly thrombogenic. 45 Epicardial LAA clip exclusion offers a potential solution to this problem. Using the clip to occlude the LAA, complete electrical isolation of the LAA has been demonstrated, excluding potential AF onset triggers. 46 In the long term, the  In patients with a history of previous uncontrolled life-threatening bleeding, LAA occlusion followed by discontinuation of OAC/NOAC may be a reasonable approach, but requires a careful, tailored approach.

| SPECIAL CONSIDERATIONS
Due to the complete extracardiac nature of the procedure, no anticoagulation regimen is required. Therefore, LAA clip occlusion is highly suitable for those patients with relative and absolute contraindication to anticoagulant drugs, like those with ongoing bleeding complications.
Since the standard device ( Figure 2) has a closed structure, positioning requires it to be placed around the LAA from its distal end, | 2869 over the body, to the base of the structure, where it is closed and released. During this process, fresh thrombus within the LAA may be dislodged and embolize. Therefore, LAA thrombosis is a contraindication for LAA epicardial exclusion. Nevertheless, latest generation devices with a V shaped closing mechanism ( Figure 2) may provide potential for LAA closure in those patients with refractory LAA thrombosis that is limited to the distal end of the appendage. 40 In general, thoracoscopic LAA epicardial exclusion with an Atriclip device is a very safe and swift procedure. 59 To maintain this very low risk threshold, we strongly recommend careful assessment of patients using imaging techniques as previously described (TOE, CT scan, and/or magnetic resonance imaging). From a surgical standpoint, we suggest staying >1 cm from the phrenic nerve, to avoid permanent or transient paralysis of the hemidiaphragm. It is very important to manage the LAA gently, avoiding grabbing the LAA as this tissue can be damaged easily. The device can be positioned very easily by pushing it open on top of the LAA while a-traumatically "caressing" the LAA into the device frame with a peanut device.
Finally, it is very important to understand how this procedure can be also performed in patients with different degree of cardiovascular abnormalities by experienced surgeons. Our experience shows how a complete LAA exclusion was obtained without additional risks in patients with a persistent left superior vena cava ( Figure 5) and also in patients with dextrocardia with situs inversus (Figure 6). There are several important clinical and theoretical advantages of epicardial LAA clip occlusion, including stroke risk reduction and improved rhythm outcome. Epicardial clip occlusion is reported to be feasible, safe, and very effective, however its role as a standalone procedure remains to be established. Currently, isolated epicardial LAA clip closure is reserved for patients with a relative or strict contraindication for anticoagulation and/or antiplatelet therapy, and for those rare case of refractory automatic arrhythmias originating in the LAA. As a concomitant procedure, there is strong evidence that LAA closure can prevent stroke, although further research is needed and current guidelines do not include this recommendation yet.
Understanding of LAA morphology and pathology may help with planning epicardial LAA management.
Adding epicardial LAA clip to the technical armamentarium and openly discussing individual cases within an AF Heart Team is pivotal to developing a personalized approach and identifying the most appropriate LAA treatment for each individual patient.