| Backdrounds:Acute myocardial infarction(AMI)is the main cause of mortality and disability worldwide with an ongoing increase in incidence.In Europe,approximately three to four million people are estimated to suffer from AMI each year.Every sixth man and every seventh woman will die from AMI[4].Approximately every 25 seconds,an American will have a coronary event,and approximately every minute,someone will die of one[5]About 3 million people die from coronary artery disease(CAD)every year and now an estimated 2 million people have AMI in China[19].Rapid and correct diagnosis is of great importance to enable immediate and intensified treatment which consequently reduces mortality[1].If treatment of AMI is done within 1h(the golden hour)effectively,mortality can be reduced from 3%to 9%,if delay of 3-4 h,mortality could be five times higher[2].The 12-lead electrocardiogran(ECG)and cardiac troponin(cTn)are the diagnostic cornerstones of AMI and complement clinical assessments.The ECG by itself is often insufficient to diagnose acute myocardial ischaemia or infarction,since ST deviation may be observed in other conditions.Currently,according to the consensus guidelines from the American College of Cardiology(ACC)and the European Society of Cardiology(ESC),definitive diagnosis of AMI is mainly based on the elevated biomarkers of damaged cardiomyocytes,cardiac troponin T and I(cTnT and cTnI)or creatinine kinase-MB isoenzyme(CK-MB)[3].A major drawback of the contemporary cTn assays is their inadequate sensitivity during the first 3 to 6 hours after the onset of AMl,as they are released slowly from damaged cardiomyocytes[7]Newly developed hs-cTnT assays have led to an improved diagnosis of AMI as early as 3 h after the onset of symptoms[8-9].Nevertheless,guidelines still advise measuring cTn at presentation to the hospital and 3-6 h later[3]in order to see temporal changes in cTn concentrations,suggestive for AMI.The main disadvantage of hs-cTnT assays is that in a substantial part of the population,especially elderly,continuously elevated levels of cTn are measured due to heart failure or chronic kidney disease[10-11],resulting in false positive hs-cTnT assays[11].The disadvantage of CK-MB as a biomarker of MI is its lower tissue specificity compared to cTn[7]and its delayed elevation(7 h)after the onset of symptoms[13].Therefore the ideal biomarker for early,rapid and reliable diagnosis of AMI is still required.Recent studies have revealed that microRNAs(miRNAs)are involved in the regulation of cardiac development,physiologic,and pathologic processes via post-transcriptional control of gene expression.The tissue-or cell-specific distribution features of miRNAs and its remarkable stably existing in serum and plasma make them attractive biomarkers for AMI.Certain miRNA species that have been shown to be highly enriched either in cardiac and skeletal muscle in general(miR-1,-133a and-499-5p)or specifically in cardiomyocytes(miR-208a and-208b)are released into the circulation following myocardial infarction.Objectives:In the present study.we explored the diagnostic potential of myocardial-specific miR-208a and miR-208b in a patients with acute ST elevation myocardial infarction(acute STEMI)compared with cTnI and in addition to evaluate correlations with blood lipid profiles and left ventricular ejection fractions.Furthermore,we also evaluate correlations with recently investigated biomarkers h-FABP and hs-CRP.Patients and Methods:Twenty nine control subjects,thirty nine consecutive acute STEMI and twenty five unstable angina pectoris(UAP)patients were enrolled.The plasma samples from acute STEMI and UAP patients were obtained at admission and next morning after the admission to CCU.For the healthy control subjects,plasma sample were obtained once,at enrollment.The circulating miR-208a and miR-208b levels were analyzed using quantitative real-time PCR.Plasma cardiac Troponin I(cTnI),CK-MB,hs-CRP and h-FABP were measured by the ELISA methods according to the manufacturer’s protocol.LVEF were measured by 2D echocardiography.Results:The miR-208a and miR-208b levels in plasma from acute STEMI patients were markedly increased by 15.18-fold and 9.51-fold,respectively.compared to those in control subjects(P<0.001 in both).Receiver operating characteristic(ROC)curves of miR-208a and miR-208b strongly distinguished between acute STEMI and healthy controls groups,with an area under curve(AUC)of 0.955(95%confidence interval(CI)0.912-0.999),P=0.000 and 0.894(95%Cl,0.813-0.974),P=0.000,respectively.Both miRNAs also,were slightly elevated in patients with UAP compared to healthy controls(P=0.000 for miR-208a and P=0.009 for miR-208b).ROC curves of miR-208a and miR-208b were significantly distinguished between patients with UAP and healthy controls groups with an AUC of 0.825,P=0.000 and AUC of 0.705,P=0.015,respectively.There were statistically significant differences in the levels of miR-208b between the acute STEMI and UAP groups(P=0.047).In the differentiating between Acute STEMI and UAP patients,cTnI exhibited good accuracy(AUC=0.848,P=0.000).The AUCs for miR-208a and miR-208b were 0.659(P=0.040)and 0.695(P=0.012),respectively.The elevated circulating miR-208a and miR-208b levels were recovered to the control levels at 16.46±4.98 hours after acute STEMI(P<0.05).In acute STEMI patients who admitted less than 3 hours after the onset of chest pain,miR-208a was increased in all affected individuals 26/26,100%and miR-208b was increased in 23/26,88.46%of patients,while cTn I was positive only in 14/26,53.85%of patients.In addition,there was a correlation between circulating miR-208a levels and cTnI(P=0.027).The levels of h-FABP at presentation were significantly higher in patients with acute STEMI than healthy control,p=0.002 and compared with patients UAP group P= 0.600.h-FABP showed moderate performance in the distinction of AMI from healthy control AUC 0.749,P=0.002.There were a moderate but significant correlation of h-FABP with miR-208a and miR-208b(rho=0.289,P=0.009 and rho=0.320,P= 0.003,respectively).The plasma hs-CRP levels were higher in patients with acute STEMI than healthy controls(P=0.000)and UAP groups(P=0.033).UAP group had higher hs-CRP levels compare with healthy controls,P=0.000.We found positive,moderate correlation of hs-CRP with miR-208a and miR-208b(Spearman rho=0.287,P=0.013 and rho=0.346,P=0.002,respectively).In addition,we found,inverse correlations these two miRNAs with high density lipoprotein(HDL)and left ventricular ejection fraction(LVEF).Conclutions1.The miR-208a and miR-208b levels in plasma in acute STEMI patients were increased compared to those in control subjects.2.Circulating heart specific miR-208a and miR-208b might be potential biomarkers for the early diagnosis of AMI.3.Plasma levels of miR-208a and miR-208b correlated with inflammatory marker hs-CRP and marker of necrosis h-FABP.In addition,also correlated with LVEF and HDL.4.Circulating heart specific miR-208a and miR-208b might be prognostic biomarkers for the AMI.5.These miRNAs could be released into circulation from the living myocardium pointing towards a cardioprotective role for these miRNAs.6.Large-scale,appropriately designed standardized study will be required to definitively assess the potential of circulating miRNAs as diagnostic and prognostic biomarkers of AMI.7.Furthermore,really need investigate from which part of the myocardium or under what conditions miRNAs are released into circulating blood. |
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