In the present study, 7.6% patients with ESUS were diagnosed to have AF during follow-up. Implanting ILR increased the detection rate of AF by 6.5 times compared with routine follow-up of EKG or Holter monitoring. The prevalence of new AF detection after ILR was similar to that reported in previous studies.18,19 The lesion pattern of a confluent plus additional lesions in a single vascular territory and biomarkers of left atrial cardiopathy including LAE and NSAT were independently associated with newly diagnosed AF in ESUS patients. The sensitivity of diagnosing new AF in ESUS patients with LAE, NSAT, or a confluent plus additional lesions pattern was 91.7%, suggesting that such patients may be the potential target for ILR implantation. The positive predictive value of diagnosing new AF in ESUS patients with LAE, NSAT, and a confluent plus additional lesions pattern was 40.0%. These patients might particularly benefit from ILR implantation.
Most of the existing scoring systems for identifying potential ILR recipients focused on conventional risk factors or cardiac markers.20–22 However, a more comprehensive approach regarding the culprit (i.e., markers of left atrial cardiopathy) and its result (i.e., ischemic lesions in the brain) may be needed. Ischemic lesion patterns well represent the stroke mechanism, and a recent study showed that a large territorial infarction in a single vascular territory pattern was associated with AF detection in ESUS patients receiving ILR.23 Paroxysmal AF related-strokes showed larger lesions and higher NIHSS scores than aortic arch atheroma or PFO related strokes, explained by the large fibrin containing clot formed from the left atrium.24 In comparison to stoke related to PFO, strokes related to AF showed confluent lesion with additional small lesions, as PFOs may work as filters, allowing only smaller emboli to pass through the shunt.11 Previous study reported that aortic arch atheroma related-stroke group had smaller lesions in multiple vascular territories than AF related stroke group.24 An autopsy study revealed that emboli containing cholesterol crystals such as emboli from aortic arch or large artery atherosclerosis frequently result in small borderzone infarction.25 In line with these findings, we found that the sensitivity and positive predictive value of detecting AF among ESUS patients was maximized when the imaging pattern of a confluent plus additional lesions in a single vascular territory was used together with left atrial cardiopathy markers (i.e., LAE and NSAT).
Enlarged left atrium, a structural marker of left atrial cardiopathy, is associated with the risk of stroke. 26 It is possible that, LAE itself promotes blood stasis, thereby leading to the risk of stroke. 27 On the other hand, LAE may increase the risk of the development of AF, considering that LAE was associated with AF detection in patients with ESUS.7,28 Structural changes in the left atrium may have led to electrophysiological abnormalities such as AF. While the detection of NSAT from Holter monitoring is a potentially useful electrophysiological biomarker for left atrial cardiopathy, there are controversies on whether NSAT itself can cause stroke or increase the risk of stroke by reflecting the presence of hidden paroxysmal AF. While the previous studies mostly focused on the structural changes of the left atrium or their functions, electrophysiological changes with frequent APCs or NSAT may more directly reflect the risk of paroxysmal AF.29 Accordingly, ischemic stroke patients with NSAT show similar characteristics to those with cardioembolic stroke.30
Though the use of ILR increased the detection of AF, it failed to translate to a significant reduction in recurrent stroke.31 This may be explained by the poor correlation between newly detected AF and recurrent stroke. However, the effect of anticoagulation may be more efficient in patients with markers of left atrial cardiopathy and a newly diagnosed AF. A subgroup analysis of the NAVIGATE ESUS trial showed that the use of NOAC reduced the risk of recurrent stroke in those with LAE.32In another observation study, ESUS patients with severe LAE showed benefit from anticoagulation treatment.33 The results of ongoing trials focusing on the effect of anticoagulation in ESUS patients with left atrial cardiopathy may therefore be of interest. In addition, specific lesion patterns may also be considered in future clinical trials.
Our study has several limitations. First, as this study was performed at a single center, its results have limitations regarding generalizability. However, as all patients received cardiac evaluation under a standardized center protocol, the heterogeneity could be minimized. Second, the data were collected retrospectively and ILR was performed only in selected patients. A well-designed prospective study focusing on the efficacy of long-term monitoring in those with left atrial cardiopathy or specific imaging patterns may be helpful. Lastly, we did not compare our results with the previous scoring systems as the purpose of our study was not to develop or validate a new scoring system. Rather, we tried to identify ESUS patients who may particularly benefit from ILR implantation, and the factors identified in our multivariable analysis had acceptable sensitivity and positive predictive value for detecting AF.
Despite these limitations, our study showed that the chance of missing hidden AF during follow-up was particularly low in ESUS patients with LAE, NSAT, or the imaging pattern of confluent plus additional lesions in a single vascular territory. In ESUS patients with LAE, NSAT, or the imaging pattern of confluent plus additional lesions in a single vascular territory, the chance of detecting newly diagnosed AF during follow-up was particularly high. Implanting ILR in this population may maximize the sensitivity and positive predictive value for AF detection.