| Acute coronary syndrome(ACS)is a cardiovascular emergency.In recent years,the diagnosis and treatment of ACS has made significant progress.However,due to its sudden onset and non-renewability after myocardial damage,ACS still leads to poor prognosis.It is an important reason,and it shows a trend of continuous rise and younger generation.The mechanism of ACS is relatively complicated.Research over the years has shown that changes in the body’s own metabolic processes and pathways are closely related to the pathogenesis of ACS.Among them,under the combined effects of the external environment and the individual’s own genetic background,the changes in related metabolic activities and pathways,Leading to changes in the level of metabolites in the body.With the advancement of technology,we can detect more metabolites.Through the analysis of these metabolites,it may be more helpful for us to understand the pathogenesis of ACS and provide possible targets for its diagnosis and treatment.N-acetyl-neuraminic acid(Neu5Ac)is a monosaccharide widely distributed in nature,especially in carbohydrates.As a basic component,it participates in the formation of many glycoproteins,glycopeptides and glycolipids,and has a wide range of biological functions.Due to the important role of Neu5Ac,its derivatives are star molecules of drug intervention targets.Basic clinical studies have shown that Neu5Ac may lead to atherosclerosis through the following mechanisms:1)activation of inflammatory response leads to atherosclerosis;2)Stimulate platelet aggregation in the circulatory system to form thrombosis and promote the formation of arteriosclerosis;3)Interference with iron metabolism;4)affect lipid metabolism and promote the formation of atherosclerotic plaques;5)Changes in microcirculation and intravascular microenvironment lead to local hypoxic necrosis of cells and promote the progression of disease;6)Involve in the proliferation and apoptosis of arterial smooth muscle cells.Animal experiments show that glucose-induced cardiomyocyte injury under hypoxic condition and ligation/isoprenaline-induced myocardial ischemic injury in rats can be improved by inhibiting neuraminidase 1(NEU1),an enzyme responsible for the regulation of Neu5Ac.Medications designed to treat and prevent influenza,e.g.,oseltamivir and zanamivir,are expected to prevent myocardial ischemic injury because on the pharmacological level,they protect myocardial cells and the heart from myocardial injury as neuraminidase inhibitors.Despite all this,the correlations between Neu5Ac and coronary heart disease(CHD)are rarely reported in domestic and foreign real-world studies.This article presents a real-world study that observed the plasma Neu5Ac levels in ACS patients and analyzed the correlations between the plasma Neu5Ac level and relevant biochemical and metabolic indicators,clinical risk stratification,and clinical prognosis,aiming to provide a theoretical basis for early diagnosis and evaluation ofACS,and development of new drugs and personalized treatment plans.[Objectives]:1.To discuss the diagnostic value of the plasma Neu5 Ac level for ACS management.2.To investigate possible correlations between the plasma Neu5Ac level in ACS and risk stratification using the thrombolysis in myocardial infarction(TIMI)and the Global Registry of Acute Coronary Events(GRACE)risk scores.3.To explore possible correlations between the plasma Neu5Ac level and the long-term clinical prognosis of ACS patients.[Methods and Results]:Part One Diagnostic Value of Plasma Neu5Ac Level for ACS Management[Methods]:1.This is a monocentric,prospective,observational study that included 700 patients who were admitted by our hospital and received coronary angiography(CAG)between October 2018 and July 2019.According to their medical histories,CAG findings,and clinical/biochemical test results,these patients were divided into an ACS group(N=591)and a control group(N=109).The ACS group was further divided into two subgroups:the unstable angina pectoris(UAP)subgroup(N=494),and the acute myocardial infarction(AMI)subgroup(N=97).Inclusion criteria:ACS includes unstable angina pectoris(UAP),ST-segment elevation myocardial infarction(STEMI),and non-ST segment elevation myocardial infarction(NSTEMI).Control group criteria:The control group included patients who received CAG at our department during a given period and were found to be free of coronary-artery lesions.Exclusion criteria:Patients were rendered ineligible for the study if they were diagnosed with severe heart failure,hepatic and renal insufficiency,hematological disorder,infectious diseases,cancer or any other wasting diseases.2.On the next morning following the admission day,whole blood samples(5 mL each)were collected from the patients’ ulnar veins and sent to the Cardio-Pulmonary Laboratory.Blood serum was separated from each whole blood sample within 30 min and placed in a-80℃ deep freezer.After that,all blood serum samples were thawed and centrifuged to collect the supernatant,respectively.Then,each patient’s plasma Neu5 Ac level was measured with liquid chromatography-mass spectrometry(LC-MS)for intergroup comparison.3.CAG was performed on all patients to calculate the number of coronary artery branches with lesions and the Gensini scores.4.A binary logistic regression model was established to analyze ACS risk factors.5.The bivariate correlation was employed to analyze the correlations between the plasma Neu5 Ac level and relevant ACS risk factors and metabolic indicators.6.A receiver operating characteristic(ROC)curve was plotted to determine the diagnostic value of the plasma Neu5Ac level for ACS management and calculate the critical value.[Results]:1.This study involved 700 patients,including 390 males and 310 females,with an average age of(63.8±10.6).In the ACS group,the proportion of male patients,the average age,the proportions of patients with the smoking habit,complicated hypertension,and diabetes,and the levels of blood uric acid(UA),fasting blood glucose(FBG),serum creatinine(SCr),C-reactive protein(CRP),and D-dimer were significantly higher compared to the control group(P<0.05).On the other hand,the ACS group had a high-density lipoprotein(HDL)level significantly lower than the control group(P<0.05).2.The plasma Neu5Ac level in the ACS group was significantly higher than in the control group:252.00(124.75;325.00)VS 180.49(105.36;252.00)ng/mL(P<0.05).3.The correlation analysis showed that the plasma Neu5Ac level was positively correlated with age,complicated hypertension,and the levels of UA,SCr,lipoprotein(a)(Lp(a)),CRP,and D-dimer(P<0.05),but negatively correlated with the HDL cholesterol(HDL-C)level(P<0.05).4.The binary logistic regression analysis revealed that plasma Neu5Ac,SCr,and FBGwere three independent risk factors for ACS(P<0.05).5.ROC curve analysis indicated that the plasma Neu5Ac level could assist in the diagnosis of ACS(AUC=(0.680(0.631-0.729));sensitivity=38.1%;specificity=92.7%;critical value=288.50 ng/mL).When the SCr and GLU levels were taken into consideration,the AUC value and the sensitivity level were both elevated(AUC=(0.743(0.698-0.78 8));sensitivity=54.2%;specificity=84.4%).6.The ACS group was further divided into the UAP and AMI subgroups.On this basis,it was discovered that the plasma Neu5Ac level in the AMI subgroup was significantly higher than in the UAP subgroup,while that in the UAP subgroup was significantly higher than the control group:279.50(165.83.25;349.50)VS 248.00(122.53;318.2)VS 180.49(105.36;252.00)ng/mL(P<0.05).7.The ROC curve demonstrated the clinical value of plasma Neu5 Ac for the diagnosis of AMI(AUC=(0.640(0.582-0.698));sensitivity=38.1%;specificity=83.5%;critical value=330.50 ng/mL).8.The AMI subgroup was divided into the STEMI(n=76)and NSTEMI(n=21)subgroups,and the plasma Neu5Ac levels in these subgroups had no significant difference(289.00(178.73;350.25)VS 251.00(140.06;346.50))ng/mL(P>0.05).[Conclusions]:1.ACS patients experience a significant increase in the plasma Neu5Ac level,which shows positive correlations with age,complicated hypertension,and the levels of BUA,SCr,Lp(a),CRP,and D-dimer but a negative correlation with the HDL-C level.Therefore,the plasma Neu5Ac level may serve as an indicator that reflects the metabolic condition of an ACS patient.2.Plasma Neu5Ac,SCr,and GLU are three independent risk factors for ACS.When the plasma Neu5Ac level reaches 288.50 ng/ml and above,the diagnostic sensitivity is 38.1%,while the specificity is up to 92.7%.In combination with the SCr and GLU levels,the diagnostic sensitivity can be as high as 54.2%.3.Plasma Neu5Ac may facilitate the diagnosis of AMI.When the plasma Neu5Ac level is at or above 330.50 ng/mL,the diagnostic sensitivity reaches 38.1%,and the specificity is 83.5%.4.Plasma Neu5Ac is a promising metabolic marker for clinical diagnosis of ACS.Part Two Correlations of Plasma Neu5Ac Level with TIMI and GRACE Risk Scores[Methods]:1.The TIMI risk score was used for risk stratification in the ACS group,with different scoring criteria being applied to the UAP/NSTEMI and STEMI subgroups.The ACS patients were divided into three groups by their TIMI scores:high-risk,moderate-risk,and low-risk TIMI groups,for intergroup comparison of plasma Neu5Ac levels.2.The GRACE risk score was used for risk stratification in the non-ST segment elevation ACS(NSTE-ACS)group,with the patients being classified as high-risk,moderate-risk,and low-risk GRACE groups for intergroup comparison of plasma Neu5Ac levels.3.The ROC curve analysis was carried out to determine the diagnostic value of the plasma Neu5Ac level for risk stratification using the TIMI and GRACE risk scores and calculate the critical values.[Results]:1.Patients in the ACS group were divided into high-risk(n=102),moderate-risk(n=412)and low-risk(n=77)TIMI groups based on risk stratification using the TIMI risk score.Moreover,the plasma Neu5Ac level in the high-risk TIMI group was significantly higher than in the low-risk TIMI group(265.50(137.49;333.50)VS 228.00(116.88;289.50))ng/mL(P<0.05).2.The Gensini score system was applied to assess the severity of coronary-artery lesions in the three TIMI groups.The analytical results showed that the high-risk TIMI group scored significantly higher than the low-risk TIMI group(30.00(11.50;52.00)VS 10.00(5.00;40.5))(P<0.05);in the high-risk and moderate-risk TIMI groups,patients having three coronary artery branches with lesions significantly outnumbered those in the low-risk TIMI group,whereas the low-risk TIMI group had more patients having a single coronary artery branch with lesions compared to the high-risk and moderate-risk TIMI groups(P<0.05);no significant difference was observed in the number of patients having two coronary artery branches with lesions(P>0.05).3.The median of the Gensini score was 27.00.Patients who scored above 27.00 had a plasma Neu5Ac level significantly higher than those with a score ≤27.00(259.50(126.52;340.00)VS 245.00(122.91;299.50))ng/mL(P<0.05).4.The NSTE-ACS group was divided into high-risk(n=30),moderate-risk(n=228),and low-risk(n=257)GRACE groups based on risk stratification using the GRACE risk score.It was noted that the plasma Neu5Ac level in the high-risk GRACE group was significantly higher than the low-risk GRACE group(272.00(144.45;436.00)VS 234.00(117.72;303.00))ng/mL,(P<0.05).5.In the GRACE risk stratification setting,the three groups had no significant difference in the number of coronary artery branches with lesions and the Gensini score(P>0.05).6.The ROC curve showed that plasma Neu5Ac had diagnostic value for those in the moderate-and high-risk GRACE groups,with AUC=(0.636(0.535-0.737)),sensitivity=33.3%,specificity=80.0%,and critical value=390.00 ng/mL.For the high-risk TIMI group,however,there was no significant difference in the diagnosis of ACS(P>0.05).[Conclusions]:1.The high-risk TIMI group has a plasma Neu5Ac level significantly higher than the low-risk TIMI group,and the plasma Neu5Ac level appears to be associated with the severity of angiostenosis.2.The plasma Neu5Ac level in the high-risk GRACE group is significantly higher than in the low-risk GRACE group.For high-risk patients with NSTE-ACS,when the plasma Neu5Ac level is at or above 390.00 ng/mL,the diagnostic specificity is up to 80%.3.Plasma Neu5Ac provides a basis for the clinical risk stratification of ACS.Part Three Correlations of Plasma Neu5Ac Level with Long-term Clinical Prognosis of ACS[Methods]:1.A follow-up questionnaire survey was designed to record the ACS group’s conditions after discharge.Regular telephone interviews(every three months)or an outpatient visit were required within average 21.5 months after discharge.During this period,all major adverse cardiac events(Maces)were recorded,including time and description of such events,and the ACS patients were divided into Maces and non-Maces groups to compare their plasma Neu5 Ac levels.2.Maces included recurrent angina pectoris,heart failure,recurrent myocardial infarction,cerebral apoplexy,cerebral hemorrhage,re-revascularization,stent thrombosis,stent restenosis,cardiac death,and death from all causes.3-Proportional risk regression model(Cox regression model)was used to analyze the correlation between plasma Neu5Ac level and Maces events.4.The subjects were divided into Neu5Ac>252.00ng/mL group and Neu5Ac ≤252.00ng/mL group according to the median of 252.00ng/mL of Neu5Ac in all ACS patients,and Kaplan-Meier method was used to draw the cumulative end point event occurrence curve.Long-term end point events in patients with different levels of Neu5Ac were assessed in the two groups.[Results]:1.Maces occurred in 83(14.04%)out of the 591 ACS patients;there were 15 patients(2.54%)who were lost to follow-up;the non-Maces group was formed by 493 patients(83.42%).2.To be specific,58 patients(9.81%)had recurrent angina pectoris;29(4.91%)had heart failure;21(3.5%)had recurrent myocardial infarction;2(0.34%)had cerebral apoplexy;12(2.03%)had cerebral hemorrhage;10(1.7%)underwent re-revascula?rization;no stent thrombosis occurred;1(0.17%)experienced stent restenosis;5(0.85%)had cardiac death;2(0.34%)died from all causes.3.Baseline data showed that in the Maces group,the patient age,the proportion of patients with diabetes,the levels of SCr,D-dimer,and CK-MB,and the Gensini score were significantly higher compared to the non-Maces group,(P<0.05).4.The plasma Neu5Ac level in the Maces group was significantly higher than in the non-Maces group(284.00(13.90;353.00)VS 250.00(124.14;319.00))ng/mL,(P<0.05).5.The Cox regression analysis showed that plasma Neu5Ac,age,and the Gensini score were three independent risk factors in Maces,(P<0.05).6.A total of 292 patients with ACS had Neu5Ac>252.00ng/mL,and 52 of them(17.8%)had an end point event during the follow-up;A total of 299 patients were enrolled in Neu5Ac≤252.00ng/ml group,among which 31 patients(10.4%)had an end point event during the follow-up.The incidence of Maces in the Neu5Ac>252.00ng/mL group was significantly higher than that in the Neu5Ac≤252.00ng/mL group.The mean number of days between the two groups was 567.51 days and 618.16 days,χ2=7.406,P<0.05 by log-rank test.[Conclusions]:1.Plasma Neu5Ac level,age and Gensini score were independent risk factors for the occurrence of Maces events.2.The proportion of end point events in the plasma Neu5Ac>252.00ng/mL group was higher than that in the plasma Neu5Ac≤252.00ng/mL group.3.The mean time of end point event in plasma Neu5Ac>252.00ng/mL group was earlier than that in plasma Neu5Ac ≤252.00ng/mL group.4.Plasma Neu5Ac has reference value for the long-term prognosis of ACS,and provides a new reference basis for the prognosis judgment of ACS and the clinical application of targeted prevention and treatment of coronary heart disease. |
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