Introduction

The left atrial appendage (LAA) is a unique structure within the pericardium, close to the free wall of the left ventricle. It has unique developmental, structural, and physiological characteristics that separate it from the left atrium proper.[1] In normal cardiac physiology, the LAA plays an essential role in regulating intravascular volume by releasing natriuretic peptides in response to hemodynamic changes. The LAA also plays a vital role in the pathogenesis of transient ischemic attack (TIA) and stroke in patients with atrial fibrillation (AF).[2] 

Structure and Function

The left atrial appendage is often described as a small ear-shaped outpouching of the muscular wall of the left atrium. It lies anteriorly in the atrioventricular sulcus, close to the left circumflex artery, phrenic nerve, and pulmonary veins.[3][4] It is adjacent to the free wall of the left ventricle and, thus, is closely associated with left ventricular function. Although several physiological variants exist, in most individuals, the LAA is a unilobar structure lying parallel to the left superior pulmonary vein. A structural analysis of the LAA using computerized tomography (CT) in 612 individuals suggested that, on average, the appendage is 46 mm long and has a volume of approximately 9 mL.[2] The most common general topology of the LAA is for it to project anterosuperiorly to lie over the superior-most part of the left ventricle or the pulmonary trunk. In a small number of cases, it may be pointed behind the pulmonary trunk directly in the transverse cardiac sinus.[5] The interior surface of the LAA is muscular and marked with muscular ridges, in contrast to the rest of the left atrial interior surface, which is smooth, a difference that can be explained by their embryological origins, as described later.

In normal cardiac physiology, the LAA is an essential modulator of intravascular volume. In response to increased myocyte stretch, the LAA releases atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) into the coronary sinus. From here, these peptides enter the general circulation and regulate blood pressure and volume via their diuretic, natriuretic, and vasodilatory effects.[6] The action of ANP in response to increased myocyte stretch includes changes in both renal and systemic vasculature function. ANP promotes acute increased glomerular filtration and thus renal excretion of sodium and water.[7] Furthermore, its effect on the vasculature includes vascular smooth muscle relaxation and increased microvasculature permeability, which promotes protein movement into the interstitial space, effectively decreasing circulating intravascular volume. BNP is stored in a significantly lower concentration in the LAA compared to ANP and is found in greater concentration in the cardiac ventricles.[8][9] Nevertheless, it is also released from the LAA in response to cardiac overload. It is a sensitive biomarker for heart failure, as its levels rise markedly in response to congestive heart failure. BNP's half-life is around 20 minutes, significantly longer than that of ANP, which is approximately only 2 minutes.[10]

Embryology

The left atrial appendage develops during the fourth week of embryonic development as a remnant of the embryonic left atrium (LA), which forms during the third week of gestation.[1][11] This development contrasts with the rest of the LA cavity, which develops as an outgrowth of the pulmonary veins.[12] For this reason, the LAA is marked with muscular ridges in contrast to the rest of the left atrium, which is smooth-walled.

Nerves

The left atrial appendage does not have significant nervous innervation.

Muscles

The left atrial appendage does not perfuse any muscles.

Physiologic Variants

There are several well-described left atrial appendage morphologies. The LAA classification system has its basis on the shape, the relationship of the LAA to the left superior pulmonary vein, length from the ostium to apex, number of lobes, angle of the fist bend formed by the primary lobe, and the distance from the first bend to the LAA orifice. Based on these features, Wang et. described four classical structural morphologies accounting for the majority of anatomical variants seen.[2]

The “chicken wing” morphology describes an LAA with an obvious bend in the proximal or middle part of the dominant lobe and is the most common variant found in one study of 932 patients to be present in 40%.[3] The “cactus” LAA has a dominant central lobe with secondary lobes extending from the central lobe in both superior and inferior directions and was found in 30% of patients. The “windsock” morphology describes an LAA in which one dominant lobe of sufficient length is the primary structure, found in 19% of patients. Finally, the “cauliflower” LAA’s main characteristic is an LAA that has limited overall length with complex internal features, present in just 3% of patients.

Surgical Considerations

In open cardiac procedures, such as coronary artery bypass grafts (CABG), the left atrial appendage is often isolated or ligated. This process is especially important in patients with a history of AF, as isolation and catheter ablation correlates with a decrease in AF recurrence and a reduction in stroke risk.[13] The 2021 Left Atrial Appendage Occlusion Study (LAAOS III) was a randomized control trial treating patients undergoing cardiac surgery who had atrial fibrillation and a stroke risk score (CHA2DS2-VASC) of two or more with either standard of care or LAA occlusion at the time of their cardiac surgery.[14][15][14] The rationale behind this was that these patients are at increased risk of ischemic stroke as implied by their CHA2DS2-VASc score, and given the significant morbidity and mortality from ischaemic stroke, the known pathogenic site of LAA, and the relatively simple procedure for occlusion during concomitant cardiac surgery for other pathology, this may provide a good opportunity to administer prophylactic intervention in this patient group. The results of this trial, which included 4811 patients, demonstrated that in the intervention group undergoing concomitant LAA occlusion at the time of cardiac surgery, there was a 33% reduced risk of ischaemic stroke compared to the group undergoing cardiac surgery only.[16] 

Furthermore, the addition of LAA occlusion added no significant extra time to heart bypass during the concomitant procedure being performed. Despite removing the proposed source of embolic stroke from circulation, the authors did not recommend ceasing therapeutic anticoagulation following LAA occlusion, given the lack of evidence comparing LAA occlusion alone versus anticoagulation for stroke prevention. Interestingly, despite a hypothesized increase in heart failure one might observe in patients following LAA occlusion owing to the physiologically impaired ability to excrete sodium and water in volume overload from reduced atrial natriuretic peptide production, there was no statistical difference in the incidence of heart failure between the groups in LAAOS III, either immediately post-operatively or at long-term follow-up.[17][14]

Although providing solid evidence for the use of LAA in the cardiac surgery setting for patients with atrial fibrillation, there remains a question as to the best way to manage ischaemic stroke risk in patients with atrial fibrillation who do not have cardiac surgery planned. Any surgical intervention carries risk, and randomized control trials are needed to interrogate the relative benefit of continuing anticoagulation alone or undertaking LAA occlusion in patients with atrial fibrillation with no cardiac surgery planned.[16] Of note, although studies such as the PROTECT-AF and PREVAIL clinical trials have compared the use of the Watchman LAA closure device with anticoagulation with warfarin only, the recent ascent of the use of direct-acting oral anticoagulants (DOACs) for a broad range of indications including atrial fibrillation means that these trials need to be updated with a direct comparison of these new drugs (e.g., apixaban, rivaroxaban, dabigatran) in order to be relevant to the current population.[18][19][18][20] However, existing evidence regarding the risk of left atrial appendage occlusion devices shows there are several known associated complications, including hematoma associated with vascular access, air embolism related to device-delivery sheaths, and pericardial effusion associated with the transseptal puncture approach for device implantation, and the relative risk of these must be examined in the context of the anticoagulated atrial fibrillation patient group.[21]

Clinical Significance

The LAA is implicated in the pathogenesis of several conditions, including AF and hypertension.

It is well established that the LAA is the primary site of thrombi formation in patients with nonvalvular AF.[2] Researchers postulate that the LAA is the source of thromboembolism in up to 90% of these patients[22]. In normal sinus rhythm, there is good blood flow within the LAA and thus no thrombus formation in normal cardiac function. However, in atrial fibrillation there is reduced contractility, flow stasis, and this consequently causes the LAA to act more as a static pouch in which thombi can easily form[5]. Therefore, anticoagulation therapy and/or LAA occlusion systems are often used prophylactically to reduce stroke risk in these patients. Until recently, there has been little published data on the impact that LAA isolation has on the release of ANP. Several animal models demonstrated an immediate reduction in the immediate levels of ANP secretion following an atrial appendectomy.[6] However, these studies did not explore the long-term effects on ANP levels associated with the isolation of the LAA.

The 2018 LAA HOMEOSTASIS study was one of the first studies which examined the impact of epicardial and endocardial LAA occlusion techniques on neurohormonal modulation in humans. This study, consisting of 77 patients, found that after epicardial LAA closure, ANP and BNP levels decrease significantly immediately post-procedure, began to rise at 24 hours, and normalized at three months. In patients undergoing endocardial LAA device implantations, the ANP/BNP levels significantly increased post-procedure and normalized by three months. Of note, epicardial LAA devices were associated with a down-regulation of the adrenergic system and RAAS, resulting in a significant decrease in systolic blood pressure. No such effect was noted in endocardial device implantations.[23] Further studies are required to determine what effect, if any, these changes in neurohormonal regulation may have on outcomes or patient management.

LAA morphology has demonstrated a correlation with the risk of stroke in patients with atrial fibrillation. Following large imaging cohorts of patients, four main LAA morphologies have been classified: chicken wing, cactus, windsock, and califlower - the former of these four being the most prevelant found in 48% of patients and the other found in 30%, 19%, and 3%, respectively[24]. A multicenter study found that in patients with AF, the cauliflower morphology was associated with the highest risk of stroke, while those with the chicken wing morphology had the lowest risk of stroke.[3] This consideration may be a valuable consideration when developing a more sophisticated risk assessment for the chronic management of individuals with AF.

There have also been reports of tears in the LAA associated with blunt chest wall trauma from motor vehicle accidents. Despite being a rare complication, these injuries correlate with high morbidity and mortality. Approximately 10% of blunt trauma to the chest involves the LAA, and mortality estimates range between 50% to 80%.[25] There are multiple causes for cardiac rupture, ranging from simple blows to severe directional forces. The heart is particularly vulnerable as it hangs freely in the mediastinum, suspended by the great vessels between the sternum and thoracic vertebrae.[26] All chambers of the heart are susceptible to injury, but the LAA is particularly vulnerable due to its relative thinness. The presence of an intact pericardium is a protective factor in these injuries—restricting the effects of tamponade, thereby preventing fatal exsanguination and allowing for patients to survive the journey to the hospital.[25]