Circular RNA FUNDC1 for Prediction of Acute Phase Outcome and Long-Term Survival of Acute Ischemic Stroke

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Circular RNA FUNDC1 for Prediction of Acute Phase Outcome and Long-Term Survival of Acute Ischemic Stroke

Juan Zu¹, Lei Zuo¹, Lin Zhang¹, Zan Wang¹, Yachen Shi¹, Lihua Gu¹ and Zhijun Zhang^1,2*

• ¹Department of Neurology, Key Laboratory of Developmental Genes and Human Disease, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
• ²Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

Circular RNAs (CircRNAs) have shown promising potential in the diagnosis and the prediction of outcomes of stroke. This study aimed to explore the potential value of circRNAs for identifying acute neurological deterioration and estimating long-term survival for acute ischemic stroke (AIS). One hundred healthy controls and 200 patients with AIS within 72 h were recruited, 140 of whom were admitted within 24 h after onset. CircRNA levels in peripheral blood were measured by quantitative polymerase chain reaction (qPCR). Compared to the controls, the levels of three circRNAs were significantly increased in three subgroups of patients, including large artery atherosclerosis (LAA) stroke, small artery occlusion (SAO) stroke, and cardioembolism (CE) stroke (all P < 0.001). Among, LAA stroke patients had higher levels of circular RNA FUNDC1 (circFUNDC1) compared to SAO stroke patients (P = 0.015). CircFUNDC1 levels were positively correlated with National Institutes of Health Stroke Scale (NIHSS) scores on the 7th day only in LAA patients (P = 0.048, r = 0.226). It should be noted that the levels of circFUNDC1 in patients with early neurological deterioration (END), admitted within 24 h after onset, were significantly higher than those without END (P = 0.013). In addition, circFUNDC1 levels positively correlated with baseline NIHSS scores (P = 0.016, r = 0.203) or the 7th day NIHSS scores (P = 0.001, r = 0.289) in patients within 24 h after onset. Importantly, after 18 months of follow-up, a significant difference was observed on survival Kaplan-Meier curves (P = 0.042) between AIS patients with low (below cut-off) or high circFUNDC1 levels (above cut-off). Circulating circFUNDC1 could be a potential biomarker for predicting acute-phase outcome and long-term survival in AIS.

Introduction

Stroke is a common cause of mortality and disability worldwide. Although age-standardised stroke mortality has declined, the absolute numbers of stroke cases, disability, and death per year are increasing, with ischemic stroke accounting for about 85% (1, 2). Neurological deterioration after stroke is a severe clinical condition, resulting in poor long-term outcome and increased mortality. Therefore, early identification of neurological deterioration can assist in monitoring and individualised treatment of stroke when interventions are most effective. Neuroimaging is widely used in the diagnosis and assessment of stroke, and diffusion weighted imaging (DWI) of magnetic resonance imaging (MRI) enables the early and accurate diagnosis of ischemic stroke (2, 3). Diffusion tensor imaging (DTI) technique is more accurate at predicting the prognosis of motor injury when stroke directly damages the corticospinal tract (4). However, the pathologic mechanisms of ischemic stroke are complex, and it is currently recognised that the mechanisms of its occurrence and development include metabolic disorders, inflammation, penumbral depolarization, oxidative stress, calcium overload, and apoptosis (5). Thus, new peripheral blood biomarkers are also being actively explored for the long-term efficacy evaluation after the onset in order to provide clues for the mechanism of post-stroke reperfusion injury and explore new intervention targets for neuroprotective treatment.

At present, the diagnosis and assessment of stroke mainly rely on clinical evaluation and neuroimaging, so more convenient, rapid, and accurate haematological markers are helpful to improve or speed up the diagnosis process of stroke so as to facilitate the earlier intervention treatment (6). Non-coding RNAs (ncRNAs), the products of eukaryotic transcription, mainly consist of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) (7). As a member of non-coding RNA family, circRNAs are generated by head-to-tail splicing and form a closed-loop structure, making them more stable and conserved (8, 9). Accumulated evidence indicated that circRNAs regulate gene expression through several approaches including miRNA sponges (10), RNA-binding proteins sponges (11), transcriptional activators (12), and translation into proteins (13). Compared with miRNA and lncRNA, circRNAs are more stable and not easy to degrade in peripheral blood, and their potential role in regulating synaptic function and neuroplasticity makes them a hot research spot in the field of stroke in recent years (14).

Our previous study found that the expression of three circRNAs [circular RNA FUNDC1 (circFUNDC1), circular RNA PDS5B (circPDS5B), and circular RNA CDC14A (circCDC14A)] was higher in acute ischemic stroke (AIS) patients than controls, and the levels of three circRNAs could predict stroke outcomes, which demonstrated that these three circRNAs could be served as potential biomarkers for the diagnosis and prognosis of AIS (15). Thus, the present study aimed to figure out the relationship between circRNAs and acute neurological deterioration and long-term survival, which could be helpful to guide the therapy and secondary prevention of acute ischemic stroke.

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