Background
Acute coronary syndrome (ACS) refers to a severe subtype of coronary artery disease (CAD) that is characterized by the acute rupture of vulnerable atherosclerotic plaques in the coronary arteries and subsequent complete or incomplete obstruction of coronary blood flow due to thrombosis formation [
1,
2]. Patients with ACS often suffer from acute symptoms of chest pain or dyspnea, which are mainly caused by acute myocardial ischemia [
3,
4]. Currently, ACS can be classified as ST-segment elevation myocardial infarction (STEMI) and non ST-segment elevation ACS (NSTE-ACS) according to the dynamic changes in the ST segment on electrocardiography (ECG) [
5‐
7]. Although substantial advancements have been achieved in the diagnosis and treatment of ACS in recent decades, including percutaneous coronary intervention (PCI), patients with ACS remain at great risk for the development of adverse outcomes, including malignant arrhythmia, cardiac shock, heart rupture, and death [
8]. Therefore, studies of the key molecular pathways involved in the pathogenesis and progression of ACS are still of fundamental clinical importance for improving risk stratification and targeted treatment in these patients [
9].
Accumulating evidence suggests that both genetic factors and environmental factors contribute to the pathogenesis of ACS [
10]. Interactions between genetic and environmental factors may change various metabolic pathways during atherosclerosis development, leading to changes in the level of metabolites of the myocardium [
10]. Therefore, detection of some metabolites may be helpful for clarifying the pathophysiological mechanism of the disease [
11]. N-acetylneuraminic acid (Neu5Ac) is one of the commonly distributed natural carbohydrates, and it is also a basic component of many glycoproteins, including glycopeptides and glycolipids, with a wide range of biological functions [
12]. Moreover, the biochemical derivatives of Neu5Ac are also commonly used in the synthesis of medications [
12]. Recent studies showed that Neu5Ac may participate in the pathogenesis of atherosclerosis by promoting immune inflammatory response [
13,
14], regulating lipoprotein metabolism [
15], enhancing insulin resistance [
16], accelerating thrombosis formation [
17], and stimulating vascular smooth muscle cell proliferation and apoptosis [
18]. Moreover, inhibition of Neu5Ac via pharmacological inhibition of neuraminidase was associated with relieved myocardial injury in hypoxic cardiomyocytes and in an in vivo model of myocardial infarction (MI), which strongly demonstrates that Neu5Ac may be a novel target for improving myocardial ischemia [
19]. However, the changes in serum Neu5Ac in patients with various subtypes of ACS, the association between serum Neu5Ac and coronary lesion characteristics, risk stratification, and the relationship between serum Neu5Ac and prognosis of ACS, to the best of our knowledge, have not been fully explored. Therefore, the aim our study was to investigate the role of serum Neu5Ac in a real-world ACS patient cohort.
Discussion
In this prospective cohort study, by analyzing a real-world cohort of patients with suspected ACS who underwent CAG, we found that the serum Neu5Ac concentration was significantly higher in ACS patients than in controls with no CAD. Moreover, the serum level of Neu5Ac was even higher in patients with MI compared with that in patients with UAP, and the ROC curve analysis showed that an elevated serum Neu5Ac level is capable of predicting a diagnosis of MI. Moreover, an increased serum Neu5Ac level was closely correlated with conventional risk factors for CAD, including aging, hypertension, renal insufficiency, and low HDL-C. Importantly, a higher serum Neu5Ac level was correlated with more severe coronary lesions, high-risk on GRACE risk stratification, and poor prognosis in ACS patients. Taken together, the results of this pilot study demonstrated that serum Neu5Ac is associated with myocardial injury in ACS patients and may reflect the severity of coronary lesions and predict a poor prognosis in these patients. Future studies are needed to determine the molecular pathways mediating the role of Neu5Ac in acute myocardial ischemia and to clarify whether Neu5Ac is a biomarker only or a potential therapeutic target for myocardial injury caused by acute ischemia.
In recent years, the roles of metabolites in cardiovascular disease have attracted great attention. Comprehensive quantitative and qualitative analyses of various small molecule substances in patients with cardiovascular disease, such as CAD, have been confirmed to be helpful in elucidating the changes in endogenous metabolic substances within organisms after determination from the internal and external environment, helpful in identifying metabolic marker groups related to diseases, and useful for advancing the early diagnosis and treatment of the disease [
27‐
30]. Neu5Ac, also known as sialic acid, is a naturally occurring amino glucosamine. It was originally isolated from bovine submandibular gland mucins. It belongs to the monosaccharide family with a 9-carbon main chain and a high degree of structural diversity. Recently, Neu5Ac has been proposed to have multiple biological functions. As a viral receptor, it is closely related to malignant transformation, cancer metastasis, invasion, loss of contact inhibition, cell adhesion reduction and antigenicity [
31‐
33]. However, the mechanism of its role in CAD has not been fully understood. At present, it is suggested that plasma Neu5Ac may promote the formation of atherosclerosis through enhancing the inflammatory reaction, disrupting iron metabolism, promoting platelet thrombosis and other mechanisms [
34,
35]. Moreover, the level of plasma Neu5Ac may be related to the severity of CHD, and the release of a large amount of intracellular and cell surface Neu5Ac into the blood at the early stage of MI is considered to be the main cause of the increased serum Neu5Ac level in these patients [
19]. However, the relationships between serum Neu5Ac and the severity and prognosis of ACS have been rarely investigated.
In this study, we found that the serum level of Neu5Ac in patients with MI was significantly higher than that in patients with UAP or that in controls. We also divided the AMI group into STEMI and NSTEMI groups, and no significant difference in the serum Neu5Ac level was found between these two groups. These results suggest that serum Neu5Ac may be a metabolic marker of myocardial injury and necrosis, independent of the type of MI. Via ROC curve analysis, we found that the level of Neu5Ac in serum can assist in the diagnosis of acute MI, with a cut-off value of 330.5 ng/ml. Moreover, correlation analyses showed that the serum level of Neu5Ac was positively correlated with age, hypertension, CKMB, Gensini score, UA and SCr, and negatively correlated with the level of HDL-C. All of these factors have been confirmed to be closely correlated with the degree of myocardial injury. Taken together, these findings demonstrate that the increased level of serum Neu5Ac in MI patients might reflect the degree of cardiac necrosis, metabolism and the severity of coronary artery disease. Therefore, measurement of serum Neu5Ac may be of significance for the early identification of patients at high risk for the development of MI.
In a previous study, Zhang et al. [
19] analyzed a large number of plasma samples using non-targeted metabolomics and found that Neu5Ac can activate the Rho/ROCK signaling pathway by combining RhoA and Cdc42 and thereby caused myocardial injury both in vitro and in vivo. Rho kinase has two isomers, Rock1 and Rock2, which are expressed in vascular smooth muscle and heart. Activation of the Rho/Rho kinase signaling pathway through different pathways leads to phosphorylation of myosin light chain (MLC) and aggregation of integrin, which results in increased permeability of endothelial cells. The subsequent molecular mechanisms for upregulation of Neu5Ac and activation of Rho/Rho kinase signaling may include monocyte/macrophage migration, transportation of oxidized low-density lipoprotein, endothelial dysfunction, as well as phenotype switch and proliferation of vascular smooth muscle cells, which all contribute to the pathogenesis of atherosclerosis.
Current diagnosis of ACS is based on CKMB and troponin combined with the symptoms, ECG, and coronary angiography findings of patients. However, it has been suggested that these parameters may not be adequate for the guidance of individualized treatment. Interestingly, clinical studies have shown that the recurrence rate of cardiovascular events in patients diagnosed with influenza and treated with oseltamivir or other anti-influenza drugs is significantly lower than that among patients not treated with anti-influenza drugs [
36,
37]. Notably, the active metabolites of oseltamivir play a role by inhibiting neuraminidase-1. Therefore, drugs that inhibit neuraminidase-1 may be useful for protecting myocardial cells and heart tissue from myocardial injury in the future, representing a new intervention for CAD treatment. These findings highlight the potential therapeutic significance of Neu5Ac metabolism as a novel target for the treatment of myocardial ischemia. In our study, during the follow-up (5–14 months) after discharge, we found that serum Neu5Ac levels in patients with MACEs were significantly higher than those in patients who did not experience MACEs, and our binary correlation analysis showed that the serum level of Neu5Ac was an independent risk factor for MACEs. These findings suggest that the serum level of Neu5Ac is related to the clinical prognosis of ACS patients, and therapeutics that reduce the serum Neu5Ac level may also reduce the incidence of MACEs in these patients. Whether pharmacological interventions to inhibit Neu5Ac can improve the prognosis of ACS patients will need to be determined in future clinical trials.
Despite of the potential strengths of our study as the first real-world study to elucidate the role of Neu5Ac in ACS patients, our study also has limitations. First, due to the limited sample size, we were unable to determine whether the significance and potential prognostic role of Neu5Ac change according to patient or study characteristics, such as age, gender, ethnicity, DM, or concurrent medications. Moreover, although some potential confounding factors were adjusted in the analysis of the association between elevated serum Neu5Ac and poor outcomes in ACS patients, we could not exclude the possibility that residual factors may confound the association, such as patients’ nutritional status and the administration of medications that influence Neu5Ac metabolism during follow-up. Finally, as an observational study, we were unable to determine whether the relationships between an elevated Neu5Ac level and the severity and prognosis of ACS are causative. In-depth experimental studies and randomized controlled trials are needed to further characterize these relationships.
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