| BackgroudCoronary artery disease (CAD) is the leading cause of morbidity and mortality indeveloped countries. An early and correct diagnosis may warrant immediate initiationof therapy to potentially reduce the mortality rate. Biomarkers used to establish adiagnosis in patients with CAD, have emerged largely from targeted analyses ofknown myocardial proteins and become more and more important for diagnosis ofCAD. Some biomarkers are currently considered as the ‘gold standard’ for CADdiagnosis. However, the exploration of new biomarkers with high sensitivity andspecificity in early diagnosis of CAD never stop.Heart failure (HF), or the inability ofthe heart to meet hemodynamic demands, represents the end-stage of various forms ofcardiac disease. Coronary artery disease (CAD) topped the major pathological causeof heart failure and one of the hallmarks of HF is myocardial remodeling,characterized by cardiomyocyte hypertrophy, excitation-contraction coupling,increased myocyte loss, and myocardial fibrosis. Therefore, research to blockventricular remodeling after CAD have considerable significance for the preventionand treatment of HF. Aberrant expression profiles of circulating microRNAs(miRNAs) have been described in various diseases and provide high sensitivity andspecificity. MicroRNAs (miRNAs) are small (22-nucleotide) noncoding RNAsregulating gene expression on the posttranscriptional level by binding to the targetmRNA, leading either to degradation or to translational repression. MiRNAs controldevelopment and are critically involved in many biological processes in health anddisease including cardiovascular diseases. MiRNAs were considered to act asintracellular RNAs to control gene expression on a posttranscriptional level. In theheart, they have a crucial role in physiological development, hypertrophy,ischemia/reperfusion injury, angiogenesis, atherosclerosis, apoptosis, and fibrosis. Recently, the possibility that circulating miRNAs may be biomarkers ofcardiovascular disease has been raised. However, whether CAD is accompanied by aspecific circulating miRNA signature is still not well known. We thus aimed tocharacterize three circulating miRNAs profile of CAD, evaluating miRNAs directlyinvolved in angiogenesis (miR-100), fibrosis (miR-21), heart failure (miR-423-5P).Moreover, we assessed the correlation with the parameters of left ventricularremoldeling, as evaluated by transthoracic echocardiography.ObjectiveThe purpose of this study was to evaluate whether the expression of circulatingmiR-21, miR-100and miR-423-5p, were differentially expressed in the blood of CADpatients, and whether circulating miRNAs correlated with the parameters of leftventricular remoldeling.MethodsTwo hundred and sixty-eight unrelated patients diagnosed with coronay artery disease(CAD) were recruited at the Department of Cardiology, Guangzhou First People’sHospital Affiliated to Guangzhou Medical University. In addition,50healthy age-andsex-matched subjects received regular physical examination were enrolled in thestudy to serve as controls. All subjects underwent physical examination,electrocardiogram (ECG), transthoracic echocardiography, and blood collected forlaboratory test. Among268CAD patients,42were with stable angina (SA group),127with unstable angina (UA group), and99with acute myocardial infarction (AMIgroup). According to the transthoracic echocardiography parameters (includingLVEDV, LVESV, LVEF, LVMI), among268CAD patients,119patients wereassigned with left ventricular remoldeling group (LV remoldeling group),149patientswere defined with non-left ventricular remoldeling group (none-LV remoldelinggroup)*.Plasma levels of miR-21, miR-100and miR-423-5p were assessed byquantitative real-time polymerase chain reaction (Q-PCR) and were compared withlevels in different groups. Associations between miRNAs and the parameters of LVremoldeling had been analyzed. Receiver operating characteristic curve (ROC) wasapplied to evaluate the diagnositic value of circulating miR-21, miR-100andmiR-423-5p in LV remoldeling of CAD patients. Multivariate logistic regressionmodels were used to analyzing relationship between confusing variables and LV remoldeling.*Classification parameters defining LV remoldeling status were those established bythe American Society of Echocardiography and chambers of heart guidelines by ESC,or from the study form Fertin etc.[2,3]One or more index fulfilled were assigned toLV remoldeling.（1）Left Ventricular Mass index（LVMI）≥124g/m2（Male），LVMI≥110g/m2（Female）；（2）Left Ventricular Ejection Fraction（LVEF）<50%；（3）Left ventricular end diastolic volume（LVEDV）≥120ml（Male），LVEDV≥103ml（Female）；（4）Left ventricular end systolic volume（LVESV）≥58ml（Male），LVESV≥49ml（Female）.Results1. The average expression levels of miR-21, miR-100, and miR-423-5p wereroughly stable across age-groups and sex-divided groups. Patients ratio of leftventricular remoldeling and LVMI tended to increasing with ages, and LVEFdeclined with ages.2. Ratios of LV remoldeling were not different between male and female group,either between SA group and ACS group.3. Significant results of LV remoldeling ratios were obtained among miR-21,miR-423-5p quartiled groups, in which ratio rised with higher miR-21,miR-423-5p levels ((P<0.001or P=0.018)). LV remoldeling ratios increasedamong the first, second and third percentile of miR-100levels(P<0.001), but nosignificant diference observed between the third and the fouth percentile group（P=0.866）.4. After stratified by age, no significant difference for BMI, TC, HDL-c,hyperlipidemia ratio, beta-blocker usage, ACEI/ARB usage, CCB usage ornitrates usage were observed among age-group. Moreover, course of CAD, blooduric acid, BNP, NT-proBNP, HsCRP, hyperuricemia ratio, hypertention ratio anddiabetes mellitus ratio increased slowly with ages, which was consistent with theregular development pattern of disease, although not statistically significant. On the other hand, in the group in which age was less than60, male ratio, smokingratio, TG and LDL-c were significantly elevated. Furthermore, creatinine bloodlevel, heart failure ratio, digoxin usage and diuretics usage tended to be increasedwith age. Group in which age was more than80had higher ratio of digoxin usageand diuretics usage. Lipid-lowering drugs and asipirin usage were differentsignificantly among age-groups.5. Circulating miR-21, miR-423-5p levels in UA group and AMI group weresignificant higher than SA group and control group (all P<0.05). But thedifference of the miR-21, miR-423-5p between SA group and control group hadno statistic significance (all P>0.05). No statistical difference between UA groupand AMI group were obtained. Circulating miR-100level in UA group waselevated when compared with control group (P=0.003), but no significantdifferences were observed for the other groups (all P>0.05).6. We found significantly positive correlation coefficients for miR-21and serumcreatinine, uric acid, BNP, NT-proBNP, HsCRP, LVEDD, IVST, LVEDV, LVESV,LVM and LVMI(r=0.133,0.159,0.146,0.214,0.168,0.218,0.155,0.219,0.232,0.153, respectively，all p<0.05). Circulating miR-21was inversely correlated withHDL-c, LVEF (r=-0.146,-0.239, p<0.05or p<0.001). Moreover, negativelycorrelation between circulating miR-423-5p and LVEF were also observed.Circulating miR-423-5p levels were positively correlated with BNP, NT-proBNP,HsCRP, LVEDD, IVST, LVEDV, LVESV, LVM, LVMI（r=0.166,0.180,0.241,0.207,0.272,0.240,0.171, respectively, all p<0.05）.However, no correlation withany variables was found for miR-100(all p>0.05）.7. Circulating miR-21, miR-423-5p relative expression levels in LV remoldelinggroup were significant higher than non-LV remoldeling group and control group(all P<0.05). Circulating miR-21, miR-423-5p level in non-LV remoldeling groupwas significantly increased when compared with control group (P=0.026,P<0.001, respectively), but no significant differences were found among groupsfor miR-100(all P>0.05).8. According to independent variables of defining LV remoldeling, circulatingmiR-21in LV remoldeling groups assigned by values of LVMI, LVEF andLVESV respectively increased remarkably when compared with non-LVremoldeling groups(P=0.005，<0.001，or=0.018, respectively), but no significant difference was observed between LVEDV-defined groups(P=0.07). In addition,any significant differences were not found between groups for miR-100(allP>0.05). Moreover, circulating miR-423-5p were different markedly betweengroups defined by LVEF、LVESVand LVEDV values (P=0.001，0.003，0.01,respectively), but no remarkable statistic were found between LVMI-definedgroups(P=0.094).9. ROC curves for each of the miRNAs analyzed were generated; miR-21andmiR-423-5p had an optimal area value under the curve for estimating LVremoldeling (0.717,0.709, respectively). MiR-100had no optimal value injudging LV remoldeling (AUCROC=0.588).10. Multifactor logistic regression analysis indicated circulating miR-21, miR-423-5p,along with BNP, NT-proBNP, hypertention, taking digoxin were directlycorrelated with LV remoldeling(p<0.05).Conclusions1. Circulating miR-21and miR-423-5p might be useful in distinguishing patientswith acute coronary syndrome from patients with stable coronary heart disease,indicating that these two miRNAs play important roles in the pathogenesis ofcoronary artery disease, especially in acute coronary syndrome.2. Circulating miR-21and miR-423-5p may act as powerful regulators in thebiological processes of left ventricular remolding. However, there are noassessing values for miR-100in the pathologies of left ventricular remolding.3. Multifactor logistic regression analysis shows that circulating miR-21,miR-423-5p, along with BNP, NT-proBNP, hypertention, taking digoxin aredirectly correlated with LV remoldeling, suggesting that miR-21, miR-423-5p,BNP, NT-proBNP, hypertention may be independent risk factors for LVremodeling, and digoxin may be protective factor for LV remodeling. |
PDF Full Text Request