Changes of Metabolites in Acute Ischemic Stroke and Its Subtypes

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Changes of Metabolites in Acute Ischemic Stroke and Its Subtypes

Xin Wang^1,2, Luyang Zhang^1,2, Wenxian Sun^1,2, Lu-lu Pei^1,2, Mengke Tian^1,2, Jing Liang^1,2, Xinjing Liu^1,2, Rui Zhang^1,2, Hui Fang^1,2, Jun Wu^1,2, Shilei Sun^1,2, Yuming Xu^1,2*, Jian-Sheng Kang^1* and Bo Song^1,2*

• ¹Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
• ²Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou, China

Existing techniques have many limitations in the diagnosis and classification of ischemic stroke (IS). Considering this, we used metabolomics to screen for potential biomarkers of IS and its subtypes and to explore the underlying related pathophysiological mechanisms. Serum samples from 99 patients with acute ischemic stroke (AIS) [the AIS subtypes included 49 patients with large artery atherosclerosis (LAA) and 50 patients with small artery occlusion (SAO)] and 50 matched healthy controls (HCs) were analyzed by non-targeted metabolomics based on liquid chromatography–mass spectrometry. A multivariate statistical analysis was performed to identify potential biomarkers. There were 18 significantly different metabolites, such as oleic acid, linoleic acid, arachidonic acid, L-glutamine, L-arginine, and L-proline, between patients with AIS and HCs. These different metabolites are closely related to many metabolic pathways, such as fatty acid metabolism and amino acid metabolism. There were also differences in metabolic profiling between the LAA and SAO groups. There were eight different metabolites, including L-pipecolic acid, 1-Methylhistidine, PE, LysoPE, and LysoPC, which affected glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, histidine metabolism, and lysine degradation. Our study effectively identified the metabolic profiles of IS and its subtypes. The different metabolites between LAA and SAO may be potential biomarkers in the context of clinical diagnosis. These results highlight the potential of metabolomics to reveal new pathways for IS subtypes and provide a new avenue to explore the pathophysiological mechanisms underlying IS and its subtypes.

Introduction

Stroke is one of the main causes of human death and disability (Wang et al., 2014) and is associated with a high rate of disability and recurrence. According to population-based studies (Benjamin et al., 2017), ischemic stroke (IS) accounts for more than 80% of all strokes. According to its etiology and imaging, IS can be categorized into five subtypes (Adams et al., 1993; Chen et al., 2012), including large artery atherosclerosis (LAA), small artery occlusion (SAO), cardioembolism, stroke of other determined cause, and stroke of undetermined cause. The classification of IS can help with the early treatment and prevention of long-term recurrence in patients (Montaner et al., 2008). However, the diagnosis and classification of IS mainly rely on neuroimaging techniques, which are scarce, expensive, and time-consuming (Latchaw et al., 2009). Therefore, new biomarkers for the rapid and accurate prediction, diagnosis, and classification of IS might play a positive role in clarifying the pathophysiological mechanism of IS and promoting the secondary prevention and management of patients with IS.

It is difficult to release macromolecules from the brain into the blood due to the presence of the blood–brain barrier (Jickling and Sharp, 2015). Some conventional detection methods make it difficult to detect specific sensitive different metabolites in patients with IS. However, with the development of the emerging science of metabolomics, it may be possible to identify specific small molecular biomarkers in patients with IS and determine the underlying etiology. Metabolomics is an effective method to reveal biomolecules’ phenotypes. This method enables the identification of changes in small molecular metabolites in various diseases, which can greatly help in understanding and diagnosing diseases. Many studies using metabolomics have revealed the differences in metabolites between patients with acute ischemic stroke (AIS) and healthy controls (HCs) (Jung et al., 2011; Kimberly et al., 2013). To date, few studies have explored the differences in metabolites between the LAA and SAO subtypes of IS. In this study, non-targeted metabolites based on liquid chromatography–mass spectrometry (LC–MS) were used to study the different metabolites between patients with AIS and the HCs and between patients with the LAA and SAO subtypes of IS. The proposed method offers important advantages over traditional alternatives, ensuring that it is feasible to screen potential biomarkers and further explore the relevant underlying pathophysiological mechanisms.