Mild ischemic stroke accounts for more than a half of all ischemic stroke patients (Reeves et al., 2013). However, patients who initially present with mild symptoms may eventually develop severe disability, and recent evidence suggests that early neurological deterioration (END) is one of the major predictors of poor prognosis (Seners et al., 2014; Mazya et al., 2018; Saleem et al., 2020). Although the effectiveness and safety of intravenous thrombolytic therapy in patients with mild neurological symptoms of ischemic stroke remains controversial, in clinical practice, 40–50.5% of patients receive intravenous thrombolytic therapy (Duan et al., 2020; Saber et al., 2020; Wang et al., 2021). Moreover, within a 4.5-h window of stroke onset, international guidelines recommend intravenous thrombolysis for disabling ischemic mild stroke (Powers et al., 2018; Berge et al., 2021). Recently, several multicenter studies of mild stroke have reported that END may occur in 10–30% of patients, and the majority are associated with recanalization occlusion (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995; Boulenoir et al., 2021; Seners et al., 2021). Some studies have aimed to detect predictors of END in all patients with ischemic stroke, which may help in early identification of patients at a risk of progression after stroke onset. But few studies have focused on patients with mild stroke. Therefore, it is of great importance to identify factors associated with END in patients with acute mild stroke.

Previous research found that diabetes was an independent predictor of END in minor strokes (Ferrari et al., 2010). Poor glucose control is associated with poor functional outcomes after stroke, suggesting that long-term impaired glucose metabolism is associated with the functional prognosis of ischemic stroke patients (Lattanzi et al., 2016). Merlino et al. (2021) found that stress hyperglycemia was associated with poor outcomes after intravenous thrombolysis in 414 patients with acute ischemic stroke, regardless of diabetic status. High blood glucose is associated with brain–blood barrier breakdown, brain edema, and increased apoptosis (Song et al., 2003; Chiu et al., 2013). In addition, hyperglycemia accelerates damage to neurons in hypoxic brain tissue (Luitse et al., 2012). Nevertheless, recently, the effect of hyperglycemia on END in patients with acute ischemic stroke has been considered controversial, it may be a contributing factor rather than a direct cause (Seners et al., 2015). Although hyperglycemia on admission may reflect abnormal glucose metabolism already present before the onset of stroke, it may also be the result of acute stress and inflammatory response after acute ischemic stroke. Hence, to more accurately assess the impact of pre-stroke hyperglycemic status on acute ischemic stroke, prior to the stroke, blood glucose levels must be monitored for an extended length of time. Chronic hyperglycemia, also known as pre-stroke glycemic control, is usually assessed by glycated hemoglobin (HbA1c), which is a reliable indicator of average blood glucose levels over a 2–3 month period (American Diabetes, 2014).

The predictive value of HbA1c for the incidence of END and functional outcomes at 90 days in mild stroke patients remains unclear. In this study, we aimed to evaluate the impact of chronic hyperglycemic status on END and clinical outcomes at 90 days in acute mild ischemic stroke patients treated with intravenous recombinant tissue-type plasminogen activator (rt-PA).

In the present study, we showed that high HbA1c levels were independently associated with END in patients with mild stroke after intravenous thrombolysis. ROC analysis revealed that the optimal predictive value of HbA1c was 7.75% for END. These results suggest that END is more likely to occur after stroke if blood glucose levels are poorly controlled prior to the stroke. In other words, greater HbA1c levels increase the odds of the develop the END in mild stroke patients. To the best of our knowledge, this is the first study examining the relationship between HbA1c and END in patients with acute mild ischemic stroke. This may help identify high-risk groups for END in specific patient populations.

Mechanistically, the hyperglycemic condition before reperfusion may function as a fibrinolytic inhibitor, reducing the efficiency of rt-PA (Alvarez-Sabin et al., 2003). Second, prolonged hyperglycemia may impair neurological recovery following ischemia damage in individuals receiving intravenous rt-PA (Masrur et al., 2015). Endothelial dysfunction, free radical generation, and impairment of the brain’s autoregulatory system may all contribute to reperfusion damage after successful recanalization in patients receiving intravenous thrombolysis (Martini and Kent, 2007; Suh et al., 2008; Choi et al., 2018; Diprose et al., 2020). It is also likely that persistent hyperglycemia causes microvascular remodeling, which impairs collateral circulation (Hou et al., 2013). Moreover, the chronic hyperglycemic state may be a condition in which the vessel walls become weak and alter the blood–brain barrier permeability, thereby increasing the risk of brain edema or reperfusion injury (Dua et al., 2010; Desilles et al., 2017; Shukla et al., 2017).

As for HbA1c levels did not affect functional prognosis, a possible explanation is that poor glycemic status may be a marker of stroke severity rather than a predictor of subsequent functional recovery, that is, a high HbA1c level may lead to END rather than directly affect functional outcomes. It may be related to the tolerance mechanism in patients with chronic hyperglycemia, which offsets adverse metabolic effects. Similar findings were observed in the stress hyperglycemia research, which found that stroke patients with stress hyperglycemia had a greater likelihood of experiencing an END but not a higher risk of poor outcome (Wang et al., 2022). As the END is strongly associated with poor functional prognosis (Seners et al., 2014; Mazya et al., 2018; Saleem et al., 2020), rigid blood glucose management before a stroke may have a beneficial effect on clinical outcomes. In addition, an interesting finding in our study was the relatively large number of diabetic patients in the unfavorable functional outcomes group. It is similar to previous studies that reported poorer neurological recovery and more severe disability in diabetic patients compared to non-diabetic patients (Megherbi et al., 2003; Roquer et al., 2014). Accordingly, current guidelines recommend a target HbA1c <7.0% to reduce vascular complications of diabetes (Kleindorfer et al., 2021). Despite this, it has been shown that increased HbA1c levels are an independent predictor of unfavorable clinical outcomes in patients with ischemic stroke (Lei et al., 2015), which might be owing to the distinct research group, as our study only included patients with mild stroke.

It is a worthwhile question to think about how glucose management should be performed in patients with mild stroke in the acute phase. In a large health system-based cohort study, lower HbA1c and higher HbA1c levels were found to be associated with a higher risk of stroke, forming a U-shaped curve. Intensive glucose reduction and poor glycemic control may be associated with an increased risk of stroke in patients with diabetes (Shen et al., 2020). Another multicenter randomized clinical trial showed that intensive glycemic control in acute ischemic stroke patients with hyperglycemia did not improve their functional outcomes significantly. This may be attributed to the higher incidence of hypoglycemia in the intensive treatment group (Johnston et al., 2019). As a result, in order to minimize the occurrence of END events, it is crucial to focus on stroke patients with high HbA1c and to administer modest glucose-lowering medication in the acute period. In contrast, it is critical to check for glucose metabolic status before a stroke starts in order to give rigorous glycemic control by lifestyle modifications and medication, which may prevent stroke occurrences and react better to reperfusion treatment in the acute phase of stroke.

Consistent with previous reports, the probability of haemorrhagic transformation after intravenous thrombolysis is low in mild stroke patients, this may suggest that END was more ischemic in origin (Mazya et al., 2018; Seners et al., 2021). Additionally, the low incidence of SICH indicates that intravenous rt-PA therapy may be safe and effective in patients with mild stroke (Xiong et al., 2021). Therefore, the difference between the higher rate of END and the lower risk of intracranial hemorrhage in mild stroke patients receiving intravenous thrombolysis, especially those with high HbA1c levels, requires that we treat these patients more actively. For example, lowering blood sugar properly (Wang et al., 2022) and early anti-platelet therapy (Li et al., 2022).

This study has several limitations. First, our statistical power is relatively limited due to the rather small number of patients who developed END in mild stroke patients treated with intravenous thrombolysis. Second, this is a single-center, retrospective study, and this study may be subject to recruitment bias. Third, we did not further compare with mild stroke patients who did not receive intravenous thrombolytic therapy. Because of these limitations, the results of our study should be interpreted with caution. Further prospective and randomized studies are needed to confirm our results.

In conclusion, our study suggests that higher HbA1c levels are an independent predictor of END in mild stroke patients treated with intravenous thrombolysis, whereas there is no effect on functional outcome at 90 days. According to our findings, the risk of END is particularly significant when HbA1c exceeds 7.75%, which requires aggressive glucose-lowering therapy, and it seems reasonable to maintain HbA1c levels below 7%.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of the First Hospital Affiliated to Soochow University (No. 2022403). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

QF and DW conceived and designed the research. DD analyzed the data. LH drafted the manuscript. LH, ZH, MM, and DW collected the data and performed the research. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

This study was supported by the National Natural Science Foundation of China (Nos. 82071300 to QF and 82001219 to DD) and the Natural Science Foundation of Jiangsu Province (BK20190183).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnagi.2022.1073267/full#supplementary-material