The present study found a significant interaction between IAB and low-risk PFO pertaining to CS risk. The results of the multiplicative interaction analysis and subgroup analysis indicated that isolated low-risk PFO was not associated with CS; however, when combined with IAB, low-risk PFO increased the risk of CS. The additive interaction results suggested that nearly 70% of the increased risk of CS associated with low-risk PFO was attributed to the interaction with IAB. Nevertheless, no significant multiplicative interaction between high-risk PFO and IAB was observed. Correspondingly, IAB was significantly associated with CS in patients with low-risk PFO, but not in those with high-risk PFO and without PFO.
PFO has been considered as an important risk factor for CS [1]. The prevalence of PFO is approximately 25% in the general population. Not all PFOs lead to stroke. Identifying high-risk PFOs is a crucial aspect of secondary prevention for patients with CS and may even serve as an important strategy for primary prevention. Currently, the diagnosis of PFO-associated strokes is primarily determined by clinical characteristics and the high-risk features of the PFO. In addition to clinical characteristics and the features of the PFO, the present study suggested that IAB was a neglected but important factor modifying the risk of PFO in CS and should be considered in clinical practice. There are several potential mechanisms underlying the interactions between PFO and IAB.
First, IAB may increase PFO-RLS, thereby raising the risk of paradoxical embolism associated with PFO. Although the mechanisms behind PFO-associated strokes are not fully understood, paradoxical embolism is considered a major contributing factor. PFO-RLS forms the basis of paradoxical embolism and stands as the most significant risk factor for PFO-associated strokes [1]. Factors leading to an increase in PFO-RLS, such as ASA, prominent Chiari network, and Eustachian valve, may increase CS risk [10]. Previously, researchers have focused primarily on the morphological factors of PFO that may lead to an increase in PFO-RLS. However, the impact of abnormal atrial electrical activity on PFO-RLS remains unclear. Normal atrial electrical activity originates from the sinoatrial node, and travels through the Bachmann bundle, interatrial septum, and coronary sinus to activate the left atrium. Therefore, the right atrium contracts earlier than the left atrium. When the right atrium contracts before the left, its pressure exceeds that of the left atrium, leading to PFO-RLS. Therefore, when IAB further delays the contraction of the left atrium, the risk of paradoxical embolism increases. A previous study reported that atrial mechanical dyssynchrony, a consequence of IAB, increased PFO-RLS [12]. Second, PFO may exacerbate the left atrial blood stasis caused by IAB. IAB itself is a risk factor for CS. The mechanisms underlying CS caused by IAB may be associated with left atrial blood stasis [5]. PFO-RLS may exert a significant effect on left atrial hemodynamics. A recent study reported that PFO-RLS may reduce stroke in the patients with AF by increasing left atrial appendage emptying velocity [13]. However, in a computational fluid dynamics study, PFO-RLS contributed to increased blood stasis in the left atrium [14]. Third, IAB may be associated with the risk of in situ thrombus formation in PFO. In addition to the paradoxical embolism, the PFO may also lead to in situ thrombus formation [3]. IAB may be associated with increased interatrial septal fat, a local marker of endothelial dysfunction and myocardial fibrosis [15, 16]. Therefore, IAB may be associated with the risk of in situ thrombus formation in PFO.Furthermore, IAB may also be associated with other risk factors of PFO-associated stroke, such as a hypermobile septum and left atrial enlargement [17, 18]. Overall, in theory, a complex interaction may exist between the IAB and PFO in the causation of CS. Future studies are warranted to explore the potential mechanisms underlying the interaction between PFO and IAB.
In the present case–control study, we demonstrated a significant interaction between IAB and PFO in the development of CS. Similar to previous studies, the present study did not observe a significant association between low-risk PFO and CS [1]. However, low-risk PFO increased the risk of CS approximately thrice in patients with IAB. This finding holds crucial clinical significance. Currently, the diagnosis of PFO-associated stroke is primarily based on clinical features and PFO morphology. In patients with low-risk PFO, the probability of PFO-associated stroke is usually considered low. However, based on our findings, we should not neglect the significance of low-risk PFO in patients with IAB. With regard to high-risk PFO, similar to previous studies, we confirmed the significant association between high-risk PFO and CS. However, it was interesting that no significant interaction between IAB and high-risk PFO was detected. It was speculated that the strong association between high-risk PFO and CS might overshadow the role of interaction between high-risk PFO and IAB negligible. For example, the large RLS of high-risk RLS would dilute the impact of IAB on PFO-RLS, as mentioned above. To further explore the mechanism underlying the interaction between IAB and PFO, we assessed the correlation between IAB and the high-risk features of PFO, including PFO-RLS, ASA, and hypermobile septum, but no significant association was detected. While we did not demonstrate that IAB increases the PFO-RLS, it may still extend the duration of PFO-RLS. Whether this may increase the probability of paradoxical embolism requires further investigation. Furthermore, these results suggest that the interaction between IAB and PFO may be independent of PFO-RLS.
This study had several limitations. First, as a single-center study, the findings should be interpreted with caution and require further validation through multi-center studies. Second, the retrospective design introduces significant bias, particularly selection bias, since the study included only patients who underwent cTEE at our center, potentially resulting in a higher incidence of PFO compared to the general population. However, due to the low incidence of CS, conducting a prospective cohort study would be challenging. Despite these limitations, the primary aim of this study was to investigate the interaction between PFO and IAB. We demonstrated that IAB is not associated with PFO or its characteristics, minimizing the impact of selection bias on the assessment of the interaction. Additionally, subgroup analyses further validated the interaction between PFO and IAB. Lastly, we did not provide evidence for the mechanism underlying PFO and IAB interaction, thus warranting further investigation.
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