The Left Atrial Appendage in Humans: Structure, Physiology, and Pathogenesis

Nabeela Karim; Siew Yen Ho; Edward Nicol; Wei Li; Filip Zemrak; Vias Markides; Vivek Reddy; Tom Wong


Europace. 2020;22(1):5-18. 

In This Article

Left Atrial Appendage and Thrombogenesis

The LAA is thought to be the source of 90% of the thrombi in non-valvular AF (NVAF) and 57% in valvular AF.[46] Left atrial appendage anatomy, function and its's dysfunction plays a key role (Figure 4).

Figure 4.

Role of the LAA in thrombogenesis. The green arrows signify the variables that affect the corresponding LAA characteristic. The blue boxes represent LAA characteristics. The gradients in colour from yellow to red represent LAA morphology (yellow), LAA mechanical function (light orange), LAA dimensions (dark orange) and LAA tissue characteristic (red). AF, atrial fibrillation; LAA, left atrial appendage; LVEF, left ventricular ejection fraction; MS, mitral stenosis; os, ostium.

Left Atrial Appendage Anatomy and Thrombogenesis

Left atrial appendage orifice size is independently associated with thromboembolic risk in AF patients.[47] An orifice area >4.5 cm2 ± 1.5 is associated with an increased incidence of stroke.[48] In other studies, LAA casts from post-mortem hearts were more likely to have thrombus detected if the LAA body and ostium were enlarged.[49] Systemic embolism in the presence of mitral stenosis was over three times more likely to occur in those with a larger LAA.[50] In cryptogenic stroke/transient ischaemic attack (TIA) cohorts, LAA volume (measured by CT scan during mid-diastole) was larger compared with age- and gender-matched controls.[51,52] In addition, the combination of large orifice area and low flow velocity is significantly associated with stroke risk, including in those with CHA2DS2-VASC scores 0–1.[48,53] Left atrial appendage flow velocity <40 cm/s combined with an orifice area of >4 cm2, has been shown to be associated with a high odds ratio for stroke.[54]

In a retrospective study of an AF ablation cohort who had undergone CT scanning, a high burden of LAA trabeculation, was shown to be independently associated with stroke risk,[47] whilst in another study, increased LAA fibrosis, as analysed by late gadolinium enhancement magnetic resonance imaging, was associated with reduced LAA flow.[55]

Left Atrial Appendage Flow Velocities and Thrombogenesis

A number of studies have demonstrated increased thromboembolic risk with reduced LAA flow velocity, regardless of rhythm or systolic function.[53,56–58] Values less than 37 cm/s[48] to 55 cm/s,[57] are associated with increased risk of spontaneous echo contrast and thrombus formation. A reduction in LAA contraction is also significantly related to increased embolic events after catheter ablation for paroxysmal AF[59] with one study recommending LAA evaluation prior to invasive interventions, when velocities are <40 cm/s.[12] The effects of LAA flow velocity on thromboembolic risk has been considered a potential variable.[57,58]

Left Atrial Appendage Endothelial Dysfunction and Thrombogenesis

Structural remodelling in the LA due to AF or other pathological process; either due to cardiomyopathy or clinical factors such as diabetes and ageing, can lead to modulation of LAA endothelium[60,61] resulting in increased expression of prothrombogenic factors, such as von Willebrand factor, vascular cell adhesion molecule-1, and p-selectin.[62–65] Increased expression of von Willebrand factor has been shown to contribute to local thrombus formation in the LAA independent of AF,[66] which may explain why thrombogenesis can occur in the context of episodes of sinus rhythm.[65]

Left Atrial Appendage Morphology and Thrombogenesis

The chicken wing morphological subtype is associated with lower prevalence of stroke/TIA and the cauliflower subtype with the highest.[13,53,67] This has also been confirmed in a meta-analysis which combined eight studies with a total of 2596 patients.[68] Silent cerebral ischaemia has also been shown to correlate with non-chicken wing morphology, particularly the cauliflower subtype[69] Importantly, it has also been demonstrated that low stroke risk patients (CHADS2 0–1), have a 10-fold increase in prior stroke/TIA when they have a non-chicken wing LAA subtype.[13] Additionally, increased number of LAA lobes has been implicated in stroke risk, independent of clinical risk and blood stasis.[70]

Mechanism Behind Left Atrial Appendage Morphology and Thrombogenesis

The higher incidence of stroke in non-chicken wing subtype could be due to a combination of many factors already mentioned. Firstly, their increased morphological complexity is thought to promote local blood stasis.[69] Secondly, these subtypes demonstrate extensive trabeculations compared with the chicken-wing subtype.[14] Thirdly, studies have shown that LAA morphology is a significant determinant of LAA flow velocity, with the chicken wing subtype positively associated[71] and non-chicken wing subtype negatively associated.[72] In one study, the cauliflower subtype's association with increased thromboembolic risk was in part explained by a larger orifice and having a low flow velocity.[73] This was analysed further in another study, which concluded that LAA morphology was no longer an associated variable when flow velocity and orifice size were adjusted for.[53]

Atrial Fibrillation Rhythm, Left Atrial Appendage, and Thrombogenesis

Atrial fibrillation impacts the LAA in many ways to promote its thrombogenic predisposition. The characteristic contractility seen in sinus rhythm is reduced and a decrease in flow velocity ensues.[1,4,25] Atrial fibrillation also contributes to remodelling of the LA which leads to LAA dilation, including of the orifice.[74] Endothelial dysfunction also manifests during AF.[69]