Figure 3. Forest plot for the best-fitting conditional logistic regression.
Discussion:
Widely used scores predicting CES risk in NVAF have emphasized clinical characteristics including age and comorbidities. Few studies have explored the contribution of LAA structural characteristics to thrombotic risk. Clarifying the relationships between LAA anatomy, physiology, and thrombotic risk may refine CES risk estimates and impact anticoagulation or other stroke mitigation procedure decisions for NVAF patients.
Previous examinations of LAA morphologic determinants of CES risk relied on qualitative classifications of LAA shape, distinguishing between appendages that resemble a Chicken-Wing, Windsock, Cactus, and Cauliflower7. Several studies have demonstrated a lower risk of stroke and transient ischemic attack, and a higher LAA emptying flow velocities with Chicken-Wing type LAAs compared to other LAA morphologic types7-9. The variable appearance of LAA morphology in different TEE imaging planes, as well as LAA anatomic complexity and heterogeneity, may limit the reproducibility and utility of such morphologic criteria. Wu et al. examined inter-observer agreements categorizing qualitative descriptions of LAA morphology by CT in 2264 AF patients and found that all 3 reviewers came to consensus in only 28.9% of scans10. Thus, LAA anatomic and physiologic measurements that are objective and reproducible could be valuable in predicting thrombus formation and thromboembolic risk in NVAF.
Lower LAA emptying velocities are known to confer higher risk of thrombogenesis8. The presence of AF during TEE and persistent AF has predicted lower maximal LAA emptying flow velocities. Petersen et al. observed higher flow velocities in patients with AF who had Chicken-Wing LAA morphology, but interestingly only when patients were in sinus rhythm at the time of TEE11. After controlling for sinus rhythm at the time of TEE, we observed lower LAA exit velocities in the LAA thrombus cohort, consistent with prior publications.
The relationship between the LAA orifice area, a simple and reproducible measurement on TEE and cardiac CT, and thromboembolic risk in NVAF is unclear as previously published findings are conflicting. Khurram et al. studied 678 patients undergoing AF ablation with pre-procedure cardiac CT imaging, reporting an association of smaller LAA orifice size with thromboembolic events in univariate analyses12. In contrast, Lee JM et al. found that NVAF patients with stroke had larger LAA orifice area and larger LA volume13. Similarly, Lee Y et al. demonstrated larger LAA orifice diameters in patients with CES14. These conflicting reports describing the relationship of LAA orifice size and CES risk highlight the importance of further investigation.
In contrast to prior work examining the relationship between LAA structural characteristics and clinical thromboembolic event risk in AF, our study examines the structure and function of the LAA in AF patients with documented LAA thrombus. This difference in outcome of interest compared to previous studies that used clinical history of stroke and TIA as a surrogate for intracardiac thrombus formation represents a unique aspect of our study insulating our results from the variability associated with accurately diagnosing stroke or TIA. While most ischemic strokes in patients with NVAF are cardioembolic, at least 24% may have a non-cardioembolic etiology15. It may therefore be advantageous to directly study patients with documented LAA thrombus when characterizing LAA measurements that potentially predict thrombus formation in NVAF. We observed a lower LAA peak exit velocity in the thrombus group as compared to the control group (24.7 ± 1.6 cm/s vs. 37.9 ± 2.6 cm/s, p <0.0001). Additionally, we found that patients in the thrombus group had smaller LAA OA at 0 and 90 degrees (231.7 ± 13.0 mm2 vs. 328.6 ± 12.9 mm2, p<0.001), smaller LAA OA at 45 and 135 degrees (229.3 ± 12.6 mm2 vs. 336.4 ± 14.1 mm2, p<0.0001), smaller OA at the largest diameter (239.0 ± 12.1 mm2 vs. 356.3 ± 13.5 mm2, p<0.0001), smaller aggregate OA (223.3 ± 11.0 mm2 vs. 334.2 ± 12.4 mm2, p<0.0001), and smaller maximum LAA depth (26.7 ± 0.7 mm vs. 29.4 ± 0.7 mm, p=0.0088) as compared to patients in the control group. Our primary novel finding, smaller LAA ostial area as an independent risk factor for LAA thrombus in NVAF, may help refine current CES risk estimation models. In particular, incorporating physiologic and anatomic measurements in clinical thromboembolic risk models may be useful to identify truly low-risk AF patients.
There were several limitations to this study. In this case-control study, we identified patients with NVAF that were placed into the thrombus and control groups from different populations of NVAF patients undergoing TEE. This permitted identification of a larger number of patients for the thrombus group but introduced selection bias into the study. We undertook propensity matching in order to reduce the possibility of confounding from differences in baseline characteristics between the groups including age, LVEF, anticoagulation status at time of TEE, and sinus rhythm at time of TEE. Despite the propensity matching, a significant difference in the baseline characteristic of LVEF persisted with the thrombus group having a lower LVEF compared to the control group (45.1 ± 1.8% vs. 50.4 ± 1.5%, p=0.0285). However, this association did not persist after best-fitting conditional regression model analysis was performed (p=0.2161). Given the retrospective identification of patients, LAA ostial diameter measurements via TEE at all four mid-esophageal planes (0° and 90°, as well as 45°and 135°) were not universally available. Aggregate OA was calculated in order to incorporate maximal available measured LAA ostial data. Aggregate OA was found to be significantly smaller in the thrombus cohort as were all other OA evaluations including OA at 0° and 90°, OA at 45°and 135° and OA at largest diameter adding validity to these significant findings. Finally, the calculation of the OA used an ellipse formula that does not factor in the irregular shape of the LAA ostium. This limitation likely has less significance as both groups were evaluated with the same formulaic assumptions.