Abstract
Background:
Elevated CHA2DS2-VASc scores are considered to be predictors of left atrial appendage (LAA) thrombus (LAAT); however, individuals with low scores remain at risk. Studies have indicated that aortic atherosclerosis (AA) is associated with increased stroke risk. AA on transoesophageal echocardiography (TOE) has been overlooked as a ‘vascular’ variable in the CHA2DS2-VASc score.
Aims:
Determine the prevalence of LAAT in patients with low thromboembolic risk and the correlation of AA with LAAT.
Methods:
We performed a retrospective review of all TOEs performed for patients who underwent electrophysiology procedures at the McGill University Health Centre from 2012 to 2017 and collected pertinent clinical and echocardiography variables. We reviewed all TOEs to evaluate the presence and severity of AA using the Katz score, American Society of Echocardiography (ASE) grade and the Ferrari score. In patients with a CHADS2 of 0 and CHA2DS2-VASc score of ≤1, logistical regression and receiver operating characteristic curves were used to identify predictors for LAAT.
Results:
592 patients underwent a pre-procedure TOE and were included in the analysis. Among 249 patients with CHA2DS2-VASc scores ≤1, 7.5% had LAA. AA burden by Katz score was an independent predictor of LAAT (area under the curve (AUC) 0.76 95% CI [0.60–0.92]) for CHA2DS2-VASc ≤1.
Conclusion:
AA visualised on TOE was significantly associated with an increased risk of LAAT development in patients with low CHA2DS2-VASc scores. Incorporating AA assessment into risk stratification may enhance clinical decision-making for the use of anticoagulation for patients with AF. Future studies are warranted to evaluate the use of other imaging modalities for AA detection.
Keywords: Atrial fibrillation, left atrial appendage thrombus, transoesophageal echocardiography
The left atrial appendage (LAA) is the most common site for thrombus formation in patients with AF due to reduced velocity of the blood flow in the LAA.1–11 Previous investigators have reported the prevalence of LAA thrombus as 0.3–4.4% on pre-ablation transoesophageal echocardiography (TOE).1–9 Despite a low prevalence of periprocedural thromboembolism, this risk is not negligible.1–3,5,12 TOE has a high sensitivity and specificity for the diagnosis of LAA thrombus and is considered to be the gold standard test.12–16 As such, pre-ablation and pre-cardioversion TOEs are commonly performed. A recent survey of AF ablation experts revealed that more than 50% of them would still perform a TOE preablation to screen for LAA thrombus regardless of a patient’s risk profile.12 Initiation of anticoagulation in patients with AF/AFL is typically guided by CHA2DS2-VASc scores. High scores are strongly associated with an increased risk of LAA thrombus (LAAT) with LA enlargement and persistent AFalso independent risk factors.3–6,8,16,17 In contrast, in patients with low-risk scores, both LAAT and spontaneous echocardiographic contrast are uncommon and are only detected in 0.3–1% of patients.5,7,9
Another notable risk factor for stroke is the presence of aortic atherosclerosis (AA), which is associated with a 3- to 4-fold increase in the risk of ischaemic stroke.10,18–20 The role of AA in thromboembolic risk stratification for patients with AF remains poorly understood. While pre-ablation TOE provides valuable information on AA, it is often underused for this purpose. The objective of this study was to determine the prevalence of LAAT and the association of AA burden with LAAT in patients with AF or atrial flutter and a low risk of stroke.
Methods
Study Population
We conducted a retrospective review of patients who had a planned electrophysiology procedure (AF ablation, atrial flutter ablation and electrical cardioversion) between March 2012 and August 2017 at the McGill University Health Centre in Montreal, Canada. All patients who underwent TOE prior to their procedure were included. During this time period, all patients who were scheduled for an AF ablation had a TOE regardless of baseline rhythm or risk score. If patients scheduled for atrial flutter ablation were in atrial flutter the morning of the procedure, a TOE was performed regardless of their risk score. If the patient was in sinus rhythm, then no TOE was performed. The study was approved by the McGill University Institutional Review Board.
Baseline Characteristics and Transoesophageal Echocardiography
We reviewed hospital charts to obtain baseline demographic and clinical information. Baseline transthoracic echocardiography data included left ventricular ejection fraction (LVEF), presence of valvular disease and LA diameter in the parasternal long axis view. Reports of TOE studies were reviewed and TOE images analysed to determine the presence of LAAT. TOE images were further reviewed to determine AA grade using the Katz score, the American Society of Echocardiography (ASE) grading system and the Ferrari score.21–23 The burden of atherosclerosis in the aorta was classified as diffuse or localised based on the parts involved on the imaged aorta. Aortic valve thickening and calcification were also included. TOE images were reviewed by authors SA and JJ.
Using the Katz score, we classified the burden of AA into five grades: grade I for normal to mild intimal thickness (IT); grade II for severe IT; grade III for protruding atheroma <5 mm; grade IV for protruding atheroma ≥5 mm; and grade V for any thickness with a mobile component.21,22
We further evaluated the AA using the ASE grading system and the Ferrari score.22–24 We classified the burden of AA using the ASE grading system as normal or grade 1 for IT <2 mm; mild or grade 2 for IT of 2–3 mm; moderate or grade 3 for IT of 3–5 mm; severe or grade 4 for an atheroma >5 mm; and grade 5 for the presence of a complex lesion in the presence of a mobile or ulcerated component.
Using the Ferrari score, we divided aortic atherosclerosis into three grades: I for IT of 1–3.9 mm, II for IT >4 mm and III for any plaque with a mobile component. To reduce inter-observer bias, all images were initially assessed by reviewer 1 (SA). If there was a disagreement with the reported grade, a second reviewer (JJ) independently re-evaluated the study. In cases where the Katz score was not originally documented, both reviewers assessed the images and discrepancies were resolved with a discussion to achieve consensus. Formal inter- and intra-observer reproducibility analyses were not performed, which is acknowledged as a study limitation.
Statistical Analyses
Data analysis was performed using IBM SPSS V-23. The continuous variables (age, LA size, haemoglobin level, creatinine and international normalised ratio) were expressed as medians and interquartile ranges (IQR). We used a non-parametric median test to investigate any difference in LAAT for continuous variables. A chi-square test was used to examine the association between categorical variables. A non-parametric median test was employed to investigate any difference in LAAT for continuous variables. Multivariate logistic regression was used to determine the significant predictors of LAAT (these variables were included in the analysis: KATZ grade, ASE atherosclerosis grade, Ferrari score, age group, sex, hypertension, heart failure, stroke, diabetes, vascular disease, arrhythmia proceeding electrophysiology study (EPS), valvular disease, CHADS2 and CHA2DS2-VASc score). Receiver operating characteristic (ROC) curves were created for the prediction of LAAT and aortic atherosclerosis score. A p-value of less than 5% was considered statistically significant.
Results
Study Population
Among 859 patients referred for electrical cardioversion or ablation of AF or atrial flutter, 592 had TOE and were included in the analysis (Figure 1). Baseline characteristics are summarised in Table 1. The median age was 65 years (IQR 56–72) and 24.8% were women. The most common arrhythmia was paroxysmal AF, which was found in 49% of the group. The median CHADS2 score was 1 (IQR 0–2) and the median CHA2DS2-VASc score was 2 (IQR 1–3). The median LA diameter was 43 mm (IQR 39–48 mm) and LVEF was 58% (IQR 45–60%). Of the patients included, 65% were on a direct oral anticoagulant. A total of 33 patients had a prosthetic or rheumatic mitral valve. A subgroup of patients with CHA2DS2-VASc ≤1 was analysed separately (Supplementary Table 1). Among these, only five had either mitral rheumatic heart disease or a mechanical valve.
Figure 1: Flow Diagram of Patient Population Selection.
AVN = atrioventricular note ablation; EP = electrophysiology; TOE = transoesophageal echocardiography
Table 1: Baseline Characteristics of the Study Population.
| Variables | Total (n=592), n (%) | LAA Thrombus (n=62), n (%) | No LAA Thrombus (n=530), n (%) | p-value |
|---|---|---|---|---|
| Age (years), median (IQR) | 65 (56–72) | 69.50 (59.50–76.50) | 65 (56–72) | 0.027 |
|
308 (52.02) | 24 (38.7) | 284 (53.6) | 0.028 |
|
179 (30.2) | 21 (33.9) | 158 (29.8) | 0.510 |
|
105 (17.8) | 17 (27.4) | 88 (16.6) | 0.035 |
| Sex | 0.851 | |||
|
445 (75.2) | 46 (74.2) | 399 (75.3) | |
|
147 (24.8) | 16 (25.8) | 131 (24.2) | |
| Spontaneous echo contrast | 206 (36.3) | 49 (79) | 157 (31) | <0.001 |
| Electrophysiological procedure | ||||
| AFL ablation | 192 (32.4) | 19 (30.6) | 174 (32.8) | 0.728 |
| AF ablation cardioversion | 310 (52.4) | 28 (45.2) | 285 (53.8) | 0.199 |
| 90 (15.2) | 15 (24.2) | 71 (13.4) | 0.022 | |
| Baseline rhythm | ||||
|
202 (34.3) | 22 (36.2) | 180 (34.1) | 0.834 |
|
290 (49.2) | 24 (39.3) | 266 (50.4) | 0.141 |
|
97 (16.5) | 15 (24.6) | 82 (15.5) | 0.087 |
| Rhythm on day of TOE | ||||
| Sinus rhythm | 115 (25.2) | 02 (3.7) | 113 (28) | <0.001 |
| AFL | 161 (35.2) | 18 (33.3) | 143 (35.5) | 0.756 |
| AF | 181 (39.6) | 34 (63) | 147 (36.5) | <0.001 |
| Katz21 grade ≥2 | 423 (71.5) | 50 (80.6) | 373 (70.4) | 0.090 |
| ASE21 atherosclerosis grade ≥2 | 417 (70.4) | 49 (79.0) | 368 (69.4) | 0.117 |
| Ferrari et al.22 score ≥2 | 120 (20.3) | 17 (27.4) | 103 (19.4) | 0.138 |
| Hypertension | 192 (37.4) | 23 (42.6) | 169 (36.7) | 0.400 |
| Diabetes | 112 (19.8) | 20 (35.1) | 92 (20.2) | 0.002 |
| Heart failure | 165 (28.9) | 35 (60.3) | 130 (25.4) | <0.001 |
| History of stroke/transient ischaemic attack | 47 (8.3) | 11 (19.3) | 36 (7.0) | 0.001 |
| Vascular disease | 118 (20.7) | 17 (29.3) | 101 (19.7) | 0.008 |
| Valvular disease* | 34 (7.7) | 12 (26.7) | 22 (5.5) | <0.001 |
| CHADS | <0.001 | |||
|
218 (36.8) | 10 (16.1) | 208 (39.2) | |
|
374 (63.2%) | 52 (83.9%) | 322 (60.8%) | |
| CHADS -VASc score | 0.002 | |||
|
118 (19.6) | 3 (4.8) | 113 (21.2) | |
|
476 (80.4) | 59 (95.2) | 417 (78.7) | |
| LVEF | 0.001 | |||
|
164 (33.7) | 29 (53.7) | 135 (31.2) | |
|
323 (66.3) | 25 (46.3) | 298 (68.8) | |
| Anticoagulant/antiplatelet | ||||
|
154 (27.1) | 35 (60.3) | 119 (21.3) | <0.001 |
|
2 (0.30) | 0 | 2 (0.30) | NA |
|
140 (24.6) | 8 (13.8) | 132 (25.8) | 0.044 |
|
116 (20.4) | 7 (12.1) | 109 (21.3) | 0.097 |
|
113 (19.9) | 3 (5.2) | 110 (21.5) | 0.003 |
|
44 (7.7) | 5 (8.6) | 39 (7.6) | 0.789 |
| LA size, median (IQR) | 43 (39–48.25) | 50 (43.25–54) | 43 (38–48) | <0.001 |
*Missing values 149 (25%). AFL = atrial flutter; IQR = interquartile range; LA = left atrial; LAA = left atrial appendage; LVEF = left ventricular ejection fraction; TOE = transoesophageal echocardiography.
Prevalence of Left Atrial Appendage Thrombus
LAAT was detected in 62 of the 592 patients (10.5%). LAAT was significantly associated with heart failure, higher CHADS2 and CHA2DS2-VASc scores (Supplementary Figure 1) and larger LA diameter. Aortic valve calcification was also more prevalent among those with LAAT. Among low-risk patients, LAAT was present in four out of 218 (1.8%) people with a CHADS2 score of 0, and 13 of 249 (5.2%) patients with CHA2DS2-VASc ≤1.
Aortic Atherosclerosis and Left Atrial Appendage Thrombus
Aortic atherosclerosis was significantly associated with LAAT. Approximately 80% of patients with LAAT had a Katz score ≥2 (Table 1, Supplementary Figure 2). In univariate analysis, the Katz score was significantly associated with an increased risk of LAAT in unadjusted bivariate analysis (OR 1.39, 95% CI [1.06–1.80]) but this association did not maintain significance after multivariate analysis adjusted (Katz grade, ASE score, Ferrari score, age, gender, hypertension, heart failure, stroke, diabetes, vascular disease, arrhythmia proceeding EPS, valvular disease, CHADS2 and CHA2DS2-VASc score) (Supplementary Table 2). In addition, the Katz score demonstrated limited discriminative ability for predicting LAA thrombus, with an AUC of 0.585 (95% CI [0.510–0.660]; SE=0.038; p=0.029) in the full cohort (Supplementary Figure 3).
The prevalence of LAAT in patients with CHA2DS2-VASc ≤1 was 7.5%. Multivariate logistic regression with backward selection was performed. Each of the three scores were included in the models separately. Katz grade, ASE and Ferrari scores showed significant association with LAAT in both unadjusted and adjusted OR (Table 2). Katz, ASE and Ferrari scores were significant predictors of LAAT in both unadjusted and adjusted multivariate models (Table 2). Adjusted OR were Katz 2.17 (95% CI [1.33–3.54]; p=0.002), ASE 1.71 (95% CI [1.05–2.79], p=0.032), and Ferrari 3.00 ([1.21–7.44], p=0.018). However, after exclusion of patients with rheumatic mitral heart disease or mechanical valve, these associations were attenuated and no longer significant.
Table 2: Aortic Plaque and Left Atrial Appendage Thrombus in CHA2DS2-VASc ≤1.
ROC analysis in the low-risk cohort (CHA2DS2-VASc ≤1), Katz score showed good discriminative performance for predicting LAAT, with an AUC of 0.745 (95% CI [0.593–0.897]; SE=0.077; p=0.002). The optimal cut-off of ≥2.5 yielded a sensitivity of 61.5% and specificity of 80.1% (1 specificity = 0.199; Figure 2).
Figure 2: ROC Curve of Katz Score as Predictor of LAA in CHA2DS2-VASc ≤1 Patients.
ROC = receiver operating characteristic
Discussion
In patients undergoing TOE before EP procedures, the prevalence of detected LAAT was 7% in patients with CHA2DS2-VASc ≤1. The presence of aortic atherosclerosis on TOE was associated with an increased risk of LAAT and the severity of AA assessed using the Katz score emerged as an independent significant predictor for LAAT in patients with a CHA2DS2-VASc score of ≤1.
The risk of LAAT among low-risk patients remains non-negligible despite adequate anticoagulation. The national Danish validation cohort reported 1.4% 10-year risk of thromboembolic events in AF patients with vascular disease.25 Frenkel et al. observed LAAT in 29% of patients with AF and a CHA2DS2-VASc score of <2, while other studies reported LAAT prevalence of 0.3% and 6.0% in patients with CHADS2 <2 or receiving oral anticoagulation.5,7
AA is not uncommon among patients with AF.26 In our study, AA (Katz ≥2) was identified in 63% of patients with CHA2DS2-VASc 1. Complex AA has long been associated with thromboembolic stroke.25,27–30 Aortic plaque thickness of 4 mm or more has been shown to strongly correlate with cerebral thromboembolism in AF, reinforcing the clinical usefulness of assessing AA severity via Katz score.11,26,31 Our findings suggest that the Katz score can enhance risk stratification in otherwise low-risk patients. Notably, a Katz score >2 identified patients with a significant likelihood of LAAT, despite having a CHA2DS2-VASc ≤1. Yet aortic plaque grading is not routinely reported when TOE is used solely to exclude LAAT.
Beyond being a marker of vascular disease, emerging evidence links atherosclerosis to systemic inflammation.32 Goldman et al. demonstrated a strong correlation between reduced LAA flow velocity in the presence of AA in patients with AF.11 Inflammation may be linked to the pathogenesis of AF and its associated phenotype of atrial myopathy, fibrosis and LA enlargement.33 Late gadolinium enhancement (LGE) on cardiac MRI has been used to identify areas of fibrosis in the left atrium, correlating with AF burden and stroke risk.33,34 Up to 48% of patients with CHADS2 < 2 and 20% of CHA2DS2VASc <2 show significant LA fibrosis by LGE.30,33,34 These findings implicate inflammation, possibly triggered by aortic plaque.35 Recent studies have expanded this concept by introducing haematological markers such as whole blood viscosity (WBV) into stroke risk assessment.
In this study, both low and high shear rate WBV were independently associated with LA thrombus detection on TOE. These findings align with our study’s proposition that vascular inflammation and atherosclerosis – whether systemic (via WBV) or local (via AA) – are crucial contributors to thromboembolic risk.
Importantly, subclinical vascular disease has been shown to affect clinical decisions. Wang et al. found that coronary calcification in AF patients with a CHA2DS2-VASc score of 1 altered anticoagulation plans in 50% of cases.36 Similarly, AA detection by TOE may inform decisions not only about initiating anticoagulation but also about its continuation after catheter ablation in low-risk patients.
While TOE remains the gold standard for detecting LAAT, its use for AA grading is underrecognised. Alternative imaging modalities such as CT or MRI may be valuable, although the Katz score has not yet been validated for these modalities. Further validation is needed to assess whether AA imaging can augment current clinical scoring systems to improve thromboembolic risk stratification.
Study Limitations
This is a retrospective cohort study design which has inherent limitations. Formal assessment of inter- and intra-observer variability in the grading of AA was not performed; however, discrepancies were resolved by consensus between two experienced reviewers to minimise potential bias. The presence of inter-observer variability in TOE reporting may have resulted in a difference in the description of the severity of AA.
Adherence to oral anticoagulation therapy and time in therapeutic range for patients on warfarin was not evaluated and if it had been under-therapeutic it may explain the presence of LAAT in these patients. Although certain LAA morphologies have been described as being associated with an increased risk for LAAT, this data was not collected in our study. There were missing values on valvular disease status and incident thromboembolic events were not identified as there was a lack of complete follow-up in many of these patients. Our results represent a single-centre experience with a relatively small sample. Validation of the results in a larger population would be necessary to demonstrate the impact of our findings.
Conclusion
The prevalence of LAAT and AA in patients with low CHA2DS2-VASc scores is not negligible. Our findings highlight the potential role of the diagnosis of complex AA on TOE to assist with risk stratification in patients with AF and low risk of stroke. Further studies are needed to evaluate other imaging methods for detection of AA.
Clinical Perspective
Aortic atherosclerosis or plaque detected on transoesophageal echocardiography has the potential to become a useful risk modifier for patients with AF and low thromboembolic risk.
The risk of left atrial appendage thrombus is predicted to be low in patients with low thromboembolic risk according to CHA2DS2-VASc score.
Future large trials involving patients with low thromboembolic risk are essential to assess the impact of aortic atherosclerosis and its role in dictating the benefits of oral anticoagulation after ablation.
Supplementary Material
Funding Statement
This work was supported by a Clinical Research Scholar Award to VE from Fonds de Recherche du Quebec-Santé (FRQS) and funding from Bayer.
Footnotes
Ethics: The study was approved by the McGill University Institutional Review Board. It was carried out according to the Code of Ethics of the World Medical Association (Declaration of Helsinki).
Consent: This is a retrospective chart review study and informed consent was not required.
Data availability:
The datasets generated and analysed during the current study are not publicly available due to patient confidentiality agreements and access is subject to institutional approval.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and analysed during the current study are not publicly available due to patient confidentiality agreements and access is subject to institutional approval.