Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) effectively improves functional outcomes in patients with acute ischemic stroke (AIS) (Emberson et al., 2014). However, thrombolytic therapy may cause hemorrhagic transformation (HT) (Yaghi et al., 2017), which can lead to early deterioration of neurological function, early death and poor prognosis (Mori et al., 2012; Yeo et al., 2013; Seners et al., 2015). Thus, a more objective and easily obtainable predictor is needed to identify high-risk patients of HT and conduct their individualized treatment.

Inflammation plays a pivotal role in vascular injury. Post-ischemic inflammatory responses that disrupt the blood–brain barrier may be responsible for hemorrhagic transformation, which then further worsens the prognosis of patients with acute ischemic stroke (Jickling et al., 2014). C-reactive protein, of which levels increase rapidly with inflammation or infection, has direct proinflammatory effects (Pasceri et al., 2000; Calabro et al., 2003) and has emerged as a strong independent risk factor for future cardiovascular events (Ridker, 2003). Serum albumin is a negative acute-phase protein, of which levels are linked to the intensity of the infection-triggered inflammatory response (Ritchie et al., 1999), and can directly protect vascular endothelium (Goldwasser and Feldman, 1997). Here we explored the combination of C-reactive protein and albumin, as an early serum biomarker, for predicting neurological outcomes in patients with acute ischemic stroke after thrombolysis. Indeed, the relationship between the ratio of C-reactive protein to albumin (CAR) and the prognosis of critically ill and cancer patients has been widely studied (Fairclough et al., 2009; Ranzani et al., 2013; Kinoshita et al., 2015), and CAR has already shown prognostic value in different types of cardiovascular diseases (Kinoshita et al., 2015; Yavuz et al., 2018; Mehmet and Kadriye, 2021), peripheral artery disease (Muhammed et al., 2022) and acute stroke (Jang et al., 2022).

The present study investigated whether the ratio of C-reactive protein to albumin might be associated with HT as well as poor functional outcomes in acute ischemic stroke patients after thrombolysis.

To our knowledge, this is one of the few studies to investigate an association between CAR before thrombolysis and post-thrombolysis early neurological outcomes. In this study, we found that higher CAR was associated with a greater risk of HT and worse prognosis in patients with acute ischemic stroke after thrombolysis, which may help to identify high-risk patients and conduct their individualized treatment.

Our study identifies CAR as an independent factor for predicting prognosis in acute ischemic stroke patients after thrombolysis and explores the possibility of CAR application in various clinical diseases. CAR has been proven to be a predictor of infection burdens in many infectious diseases (Ranzani et al., 2013; Oh et al., 2018; Bai et al., 2019). Previous studies have shown that elevated CAR is related to major adverse cardiac events or cardiovascular mortality among patients with coronary artery disease (Yavuz et al., 2018; Mehmet and Kadriye, 2021; Sabanoglu and Inanc, 2022) as well as all-cause mortality among patients with peripheral artery disease (Muhammed et al., 2022). Several recent studies also provided compelling evidence that early CAR determination may help to predict the in-hospital mortality of patients with spontaneous intracerebral hemorrhage (Bender et al., 2020) and patients with acute stroke (Jang et al., 2022).

The present study confirms that CAR can be served as a useful indicator for reflecting systemic inflammatory state and predicting the prognosis among acute stroke patients (Bender et al., 2020; Jang et al., 2022). The effect of inflammation on the pathogenesis and progression of ischemic stroke has been more clearly understood in recent years (Anrather and Iadecola, 2016; Becker and Buckwalter, 2016; Chamorro et al., 2016; Shichita et al., 2017; Rust et al., 2018; Shi et al., 2019), and post-ischemic inflammatory responses can cause hemorrhagic transformation and neurological deterioration by inducing oxidative stress that further disrupt the blood–brain barrier (Jickling et al., 2014; Arba et al., 2020). The new parameter, CAR reflects the stability of albumin and C-reactive protein levels inside the body, which is thoughted to be a better indicator of the inflammatory status compared to C-reactive protein or albumin separately (Fairclough et al., 2009; Ranzani et al., 2013; Kinoshita et al., 2015). C-reactive protein, an important indicator of increased inflammation, of which elevation is common in patients with acute ischemic stroke, is produced by hepatocytes and regulated by proinflammatory cytokines (Iwata et al., 2006). During the onset of the inflammatory response, C-reactive protein promotes the release of tissue factor from peripheral blood monocytes as well as endothelial cells (Cermak et al., 1993; Napoleone et al., 2002) and induces the expression and activity of plasminogen activator inhibitor-1 in endothelial cells (Devaraj et al., 2003), which may contribute to the progression of cerebral tissue injury (Vila et al., 2000). It has been established that C-reactive protein levels can reflect the extent of cerebral infarction (Di Napoli et al., 2001), and elevated levels of C-reactive protein are associated with increased in-hospital mortality as well as long-term poor functional outcomes in patients with ischemic stroke (Lee et al., 2020). However, during persistent systemic inflammation, the production of albumin and prealbumin was inhibited (Heinrich et al., 1990; Reuben et al., 2002), indicating that lower levels of serum albumin may be associated with cytokine activation and ongoing inflammation (Ritchie et al., 1999). Serum albumin can also directly protect vascular endothelium. Higher albumin levels may exert antioxidant effects by triggering vasodilation, binding toxins, preventing platelets from aggregation, and protecting endothelial cells against apoptotic death thereby protecting the vascular endothelium from damage (Goldwasser and Feldman, 1997).

Another possible explanation is that the severity of index stroke could be a connector between CAR, HT, and poor functional outcomes. According to our research, the group of patients with CAR higher than the median value showed a higher initial NIHSS score and a decreased number of small vessel occlusion strokes. It is well known that stroke severity and large stroke volumes are strong predictors of HT and poor functional outcomes (Mori et al., 2012; Emberson et al., 2014; Seners et al., 2015). Therefore, the CAR may serve as a marker for patients with severe stroke who are vulnerable to HT and poor functional outcomes.

Similar to our findings, another sample of Asian patients observed that higher CAR was significantly associated with worse functional outcomes in patients with acute stroke (Jang et al., 2022). Differently, the populations they studied were patients with acute stroke including cerebral infarction, intracranial hemorrhage, and subarachnoid hemorrhage, while patients who received intravenous thrombolysis were not studied separately. Additionally, the relationship between CAR and the risk of HT was not analyzed in their study. We also did not find any relation between CAR and in-hospital mortality after thrombolysis, which could be explained by the small sample size and low clinical severity of ischemic stroke at admission. Future work is needed for a larger sample size to clarify the effects of CAR on mortality in patients with acute ischemic stroke after thrombolysis.

In the current study, HT was observed in 15.8% of our patients, which is consistent with the range of 10–43% reported in previous studies (Yaghi et al., 2017). As in other studies, we found that atrial fibrillation and higher NIHSS score were significantly associated with increased risk of HT and worse functional outcomes, confirming results from studies of reperfusion therapy (Yaghi et al., 2017).

Our findings should be interpreted with caution given some limitations. Our sample came from a single center, and we measured CAR only once during hospitalization, yet it can vary during treatment. The fact that we consecutively recruited patients treated by tissue plasminogen activator without restrictive inclusion or exclusion criteria implies that our findings can be extended to all stroke subtypes, but this should be confirmed in future work. Last, the effects of vascular obstruction sites and patients which received endovascular treatment should be considered before generalizing our results to the clinical field.

Our study identifies CAR as an independent predictor of HT and poor functional outcomes among acute ischemic stroke patients after intravenous thrombolysis. Thus, CAR may be an objective and easily obtainable predictor to assist in identifying at-risk patients as well as optimizing treatment. CAR may also be a useful inclusion criterion in clinical trials involving thrombolysis. Our findings justify further investigation into the complex relationships between inflammation and HT and other complications.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Department of Neurology at The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China. Due to the retrospective nature of the study, the requirement for written informed consent was waived by the Second Affiliated Hospital of Wenzhou Medical University.

TX wrote the first draft of the article. All author contributed to the proposal and design of the study as well as the collection, analysis and interpretation of the data. All authors contributed to the article and approved the submitted version.

This study was funded by the National Natural Science Foundation of China (82271344) and Clinical Scientific Research Foundation of the Second Affiliated Hospital of Wenzhou Medical University (SAHoWMU-CR2017-01-212).

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.2023.1109144/full#supplementary-material