| BackgroundCoronary heart disease(CHD)has the highest morbidity of cardiovascular disease all over the world.In China,due to the prevalence of the risk factors such as smoking,obesity,hypertension,hyperlipidemia,diabetes,the morbidity of coronary heart disease is rising rapidly during the recent decades.The pathogenesis of coronary heart disease is very complex,but inflammation and oxidative stress reaction induced by various kinds of pathological factors are paid masses of medical attention.Acute coronary syndrome(ACS)is a emergency clinical type of coronary heart disease.Coronary atherosclerotic plaque rupture,erosion,ulcer complicated with thrombosis,vasoconstriction,vascular embolism leading to all or part of the artery obstruction is considered to be the main cause of acute coronary syndrome.The obstruction often can cause a series of serious consequences such as myocardial infarction,heart failure,fatal arrhythmia and even death.And in patients with acute coronary syndrome,the incidence caused by coronary plaque rupture of mild atherosclerosis without obvious stenosis is 10 times or more than that caused by severe stenosis.In western society.ACS is the leading cause of sudden cardiac death in the people over the age of 65.In all the heart related death,almost half were not expected.Pathological studies of sudden cardiac death have shown that acute coronary syndrome occurs primarily due to the rupture of coronary vulnerable plaque,which can cause thromboembolism in different time and different level.Therefore,it is very important to find out the patients of coronary artery disease with unstable plaque in the early time.How to recognise and treat the patients before the plaque rupture has become a major challenge we face.Although the identification of vulnerable plaques remains a challenge,it has been reported that plaque vulnerability,such as plaque rupture,plaque hemorrhage,or thrombus formation,can be obtained from angiographically complex lesions.However,as coronary angiography is an invasive procedure requiring catheterization,scientists and doctors hope to develop noninvasive alternatives such as blood biomarkers to detect vulnerable plaques even in asymptomatic patients with CHD.Various studies have confirmed the strong correlation between inflammation and the development of vulnerable plaque.Therefore,the investigators believe that inflammatory markers represent the potential predictors for vulnerable plaque.Macrophage migration inhibitory factor(MIF)is a proinflammatory cytokine,and the glucocorticoidinduced immunomodulator mainly produced by macrophages in response to a variety of inflammatory stimuli.Previous studies have revealed that MIF is involved in the pathogenesis of sepsis,inflammatory and autoimmune diseases,and atherosclerosis.Previous studies have demonstrated that serum MIF levels were increased in ACS patients and correlated with signs of plaque instability in patients with carotid atherosclerosis.However,the relationship between serum MIF levels and vulnerable plaque in CHD patients has never been fully elucidated.The relationship between the serum MIF levels and coronary angiography imaging findings remains unclear.ObjectivesThe aim of this study was to determine the levels of serum MIF in patients with CHD,and to study the correlation between the serum levels of MIF and the complex coronary artery lesions confirmed by angiography.In order to further explore the relationship between serum MIF and coronary atherosclerosis vulnerable plaque.Methods1.Study populationWe performed a single-centerl study.Patients enrolled in this study were patients who underwent diagnostic conventional coronary angiography for suspected CHD in the Provincial Hospital Affiliated to Shandong University between May 2013 and January 2015.A total of 232 consecutive CHD patients were recruited.CHD patients were subdivided according to the presence of ACS(n = 134)or stable angina pectoris(SAP)(n = 98).Besides,we also recruited 76 age-and sex-matched patients without coronary heart disease confirmed by coronary angiography showing no significant stenosis of the coronary artery in our hospital during the same period as healthy controls.Patients with heart failure,cardiomyopathy,infective diseases,active inflammatory disease,renal failure,severe liver complications,cancer,peripheral artery diseases,or hematological disorders were excluded from the study.Acute myocardial infarction(AMI)and unstable angina pectoris(UAP)were included in the ACS group.We defined AMI as chest pain that persisted for>30 min,arrival at hospital within 28d of the onset of chest pain,new ST-T wave changes or a new left bundle branch block on a 12-lead electrocardiogram,and elevated cardiac markers(creatine kinase-myocardial bound or troponin I).We defined UAP as angina at rest,accelerated angina,or new-onset angina without elevation of cardiac markers.We defined SAP as no change in the frequency,duration,or intensity of angina symptoms within 1-3 months before admission.2.Angiographic analysesCoronary angiography was carried out through the right radial artery or the femoral artery approach by conventional multiposition projection in the catheterization of our hospital.Angiograms were analyzed by two experienced interventional interventional cardiologists unaware of the laboratory values.Coronary stenosis was assessed morphologically according to the Ambrose classification and was classified as either simple or complex.Briefly,complex lesions were defined according to the presence of at least one of the following features:irregular morphology or scalloped borders,or both;overhanging or abrupt edges perpendicular to the vessel wall:plaque ulceration:the presence of filling defects consistent with intracoronary thrombus.Coronary lesions with no complex features were classified as simple lesions.3.Blood collection and biochemical analysesBlood samples were taken under fasting conditions directly before coronary angiography.Venous blood was drawn from the antecubital vein with minimal tourniquet pressure into serum separator tubes.Samples were allowed to clot for 30 min and stored at-80? until analysis.Serum fasting blood glucose(FBG),triglyceride,total cholesterol(TC),low-density lipoprotein cholesterol(LDL-c),and highdensity lipoprotein cholesterol(HDL-c)were measured on a Hitachi 7600 Automatic Biochemical Analyzer(Hitachi Co.,Tokyo,Japan)using the standard laboratory protocol.Quantitative determination of MIF levels in the serum was performed using the commercial immunosorbent assay(enzymelinked immunosorbent assay)kits with an intra-and interassay coefficient of variation of both<10%according to the manufacturers' protocols(R&D Systems,Minneapolis,MN).4.Statistical analysisData were analyzed using SPSS 16.0 for windows(SPSS,Inc.,Chicago,IL),results for normally distributed continuous variables are expressed as the mean±standard deviation,and continuous variables with non-normal distribution normality were expressed as the median value(interquartile range).MIF and coronary lesion complexity,comparisons between two groups were performed using the unpaired t-test,Mann-Whitney U test,or the chi-square test,as indicated.Comparisons of three or more groups were performed by the one-way analysis of variance,Kruskal-Wallis test,or chi-square test,when appropriate.Bonferronicorrected post hoc test was employed to adjust the observed significant level for multiple comparisons if the null hypothesis was rejected.Multivariate logistic regression was performed to assess the presence of complex lesion in patients with SAP.Values of P<0.05 were considered significant.Results1.Baseline characteristicsThe baseline clinical and laboratory characteristics of the subjects are depicted.With a mean age of 61 years and 63%males,the study population reflects a relatively typical population of patients with CHD.Compared with healthy controls,CHD patients had significantly higher blood pressure,FBG,TC,and LDL-c levels.CHD patients also had significantly lower HDL-c levels compared to healthy controls.In CHD patients,ACS patients had significantly higher LDL-c levels compared with SAP patients.2.Serum MIF levels in subjectsSAP patients had significantly higher serum MIF levels compared with healthy controls(1.35[0.88-3.05]VS.0.18[0.14-0.33]ng/mL,P<0.05).In CHD patients,ACS patients had significantly higher serum MIF levels compared with SAP patients(3.06[1.97-5.20]VS.1.35[0.88-3.05]ng/mL,P<0.05).3.Serum MIF levels in SAP patientsPatients with SAP were divided into the following two groups:simple lesion(n=50)and complex lesion(n=48)according to the presence or absence of angiographically complex coronary lesions.SAP patients with a complex lesion had significantly higher serum MIF levels compared to those with a simple lesion(1.98[1.02-4.01]VS.0.98[0.67-2.23]ng/mL,P<0.05).Multivariate logistic regression demonstrated that serum MIF levels were independently associated with the presence of complex coronary lesion in SAP patients(OR:1.46.95%CI:1.13-1.88;P =0.004).4.Serum MIF levels in ACS patientsACS patients were divided into the following three groups:no complex lesion(n= 12).one complex lesion(n =71),and multicomplex lesion(n =51)according to the number of angiographically complex coronary lesions.A significant positive correlation was found between increments in serum MIF levels and number of complex lesions(1.89[0.66-2.30]ng/mL in the no complex lesion group,2.68[1.97-4.76]ng/mL in the one complex lesion group,and 3.94[2.35-5.36]ng/mL in the multicomplex lesion group,P<0.05)in ACS patients.ConclusionsOur findings support a link between MIF activation and the complex coronary artery lesions confirmed by angiography in CHD patients.In SAP patients,serum MIF levels were independently associated with the presence of complex coronary lesion.MIF holds the potential to be explored as a biomarker for complex lesions due to its pathophysiological role in the formation of vulnerable plaque and the relationship between angiographically complex coronary lesions and plaque vulnerability.We revealed that serum MIF levels elevated with the increment of complex lesions in ACS patients.Serum MIF levels are a potential biomarker for reflecting the presence and severity of angiographically complex coronary lesion in CHD patients.The number of complex lesions may have prognostic importance because multiple complex lesions correlate with adverse clinical outcomes in ACS patients.Therefore,our results suggested that MIF in serum might also be a prognostic marker of disease progression in ACS patients.BackgroundAngina is the clinical syndrome with the main features of chest pain due to the temporary myocardial ischemia,stable angina pectoris refers to the angina that the degree,the frequency,nature and predisposing factors had no significant change in the past 1-3 months.The typical symptoms of angina have an important value for the diagnosis of patients with stable angina pectoris,but there is about 40%patients with stable angina pectoris have no angina symptoms induced by myocardial ischemia.there is no direct relationship between the clinical symptoms and the prognosis of patients with stable angina pectoris.In the past few decades,because of the new diagnosis technology,the effective drugs for the treatment and revascularization techniques.a lot of patients with stable angina pectoris of coronary heart disease have received timely and effective treatment,but there is still a high mortality.Coronary atherosclerosis is the main reason of stable angina pectoris.The mechanism and clinical outcome of stable angina pectoris are deeply recognized,including the instability of plaque and the relationship of coronary flow and myocardial ischemia.At present,the prevention of acute coronary syndrome,the improvement of ischemic symptoms and the improvement of the quality of life of patients are mainly the target of the stable angina pectoris treatment.It is particularly important to prevent the occurrence of acute coronary syndrome.So we need risk stratification for stable angina pectoris,including clinical manifestations,the load test response,left ventricular function,coronary artery angiography.Coronary angiography is undoubtedly the "gold standard" for the diagnosis of coronary heart disease,according which we can make a better therapy strategy.With the development of medical technology,the rate of severe complications caused by coronary angiography was still about 0.1%-0.3%.In addition to,angiography is an invasive examination.In practical work,doctors should first conduct a non-invasive examination,including ECG,echocardiography and myocardial perfusion scan.These tests can evaluate light,moderate symptoms of the patients,and help to guide the risk stratification and the treatment of the future.But there are many defaults of these noninvasive assessment by means of the low sensitivity and the high costs.People look forward to find a new approach to risk stratification and prognosis of patients which is more economical and accurate for patients with stable angina pectoris.Macrophage migration inhibitory factor(MIF)is a proinflammatory cytokine.According to the research on human,the increase of serum MIF expression in cardiovascular disease have been reported.There is a close relationship between MIF and atherosclerosis.MIF are expressed in different stages of atherosclerosis.The vascular endothelial cells,smooth muscle cells,lymphocytes and macrophages can secrete MIF,once released.MIF then combined with its receptors CD74/CD44 or CXCR2/4,after the combination.MIF can not only induce macrophage cell adhesion,migration and transformation into foam cells,it also affect atherosclerotic plaque instability,cell structure in atherosclerotic plaque.By means of inducing the vulnerability and rupture of the atherosclerotic plaque which eventually lead to coronary thrombosis.MIF has played a very important role.Recent studies have found that people with hypertension,diabetes,obesity and other metabolic syndrome have significantly high level of MIF.Through recent researches,we believe that MIF is an important factor in the development of atherosclerosis,but whether MIF is an independent risk factor of coronary heart disease remains controversial.There is still no final conclusion about MIF and prognosis of' coronary heart disease,the related researches at home and abroad are less.Hypertension is an important risk factor of coronary heart disease,this point is an indisputable fact,regardless of race or region,the relationship between blood pressure and risk of cardiovascular events is consistent,persistent and independent of other risk factors.A considerable part of the coronary heart disease patients have hypertension at the same time.Compared with patients without hypertension,patients with hypertension have earlier onset of coronary heart disease,and the coronary heart disease progress faster and have bad prognosis.The early and appropriate treatment in clinical examination will undoubtedly have a greater benefit for such patients.ObjectivesThe aim of this study was to determine the level of serum MIF in patients with stable angina pectoris and primary hypertension,and to study the correlation between the serum levels of MIF and the prognosis of patients with stable angina pectoris and primary hypertension.Methods1.Study populationWe performed a single-center,prospective cross-sectional study.Patients enrolled in this study were patients with stable angina pectoris who underwent diagnostic conventional coronary angiography for suspected coronary heart disease in the Provincial Hospital Affiliated to Shandong University between October 2014 and October 2015.A total of 196 stable angina pectoris patients were recruited.According to the presence of hypertension,stable angina pectoris patients were subdivided to stable angina with hypertension(n ?101)and stable angina pectoris without hypertension(n =95).Besides,we also recruited 50 age-and sex-matched patients without coronary heart disease confirmed by coronary angiography showing no significant stenosis of the coronary artery in our hospital during the same period as healthy controls.Patients with heart failure.1-diabetes mellitus.secondary hypertension,cardiomyopathy,infective diseases,active inflammatory disease,renal failure,severe liver complications,cancer,peripheral artery diseases,or hematological disorders were excluded from the study.We defined stable angina pectoris as no change in the frequency,duration,or intensity of angina symptoms within 1-3 months before admission.2.Angiographic analysesCoronary angiography was carried out through the right radial artery or the femoral artery approach by conventional multiposition projection in the catheterization of our hospital.Angiograms were analyzed by two experienced interventional cardiologists unawared of the laboratory values.3.Blood collection and biochemical analysesBlood samples were taken in the second day after admissiom directly before coronary angiography.Venous blood was drawn from the antecubital vein with minimal tourniquet pressure into serum separator tubes.Samples were allowed to clot for 30 min and stored at-80? until analysis.Serum low-density lipoprotein cholesterol(LDL-c),high-density lipoprotein cholesterol(HDL-c)and C-reactive protein(CRP)were measured on a Hitachi 7600 Automatic Biochemical Analyzer(Hitachi Co.,Tokyo.Japan)using the standard laboratory protocol.Quantitative determination of MIF levels in the serum was performed using the commercial immunosorbent assay(enzymelinked immunosorbent assay)kits with an intra-and interassay coefficient of variation of both<10%according to the manufacturers'protocols(R&D Systems,Minneapolis,MN).4.Follow-up studyAll the patients were follow up every 90 days,by means of outpatient visits,telephone follow-up,or access to hospital records,until the end of follow-up time of 365 days or less than 365 days but the incidence of major adverse cardiovascular events(MACE),the MACE is defined as cardiac death,nonfatal acute myocardial infarction,unstable angina,coronary revascularization,heart failure due to coronary heart disease and other complications and readmission.The relationship between MIF levels and MACE occurred within 365 days were compared.5.Statistical analysisData were analyzed using SPSS 16.0 for windows(SPSS,Inc.,Chicago,IL),results for normally distributed continuous variables are expressed as the mean±standard deviation,and continuous variables with non-normal distribution normality were expressed as the median value(interquartile range).Comparisons of normally variables between two groups were performed using the unpaired t-test,comparisons between multiple groups were performed using using one-way ANOVA.The non-normal distribution data using rank sum test.Count data expressed by percentage were compared by ?2 test.Correlation analysis using Pearson correlation test.Logistic regression analysis was used in multivariate analysis.The Kaplan-Meier curve and Log-Rank test were used to compare the survival rate of non-correction of MACE occurred between the two groups.By multivariate Cox regression analysis,independent risk factors of MACE were tested.P<0.05 was statistically significant.Results1.Baseline characteristicsThere are no significant differences in age,gender,HDL-c.left ventricular ejection fraction between the three groups(P>0.05).Compared with the control group,the research group of stable angina pectoris of coronary heart disease with hypertension significantly increased in systolic blood pressure(138.55±19.46 VS.118.68±11.55mmHg,P<0.05),CRP(5.10±2.40 VS.4.32±1.98mg/L,<0.05),LDL-c(3.41±0.57 VS.2.44±0.58 mmol/L,P<0.05),the number of smokers(52.9%VS.42.0%.P<0.05)and the number of patients with type 2 diabetes(46.1%VS.0,P<0.05)have significant difference.The number of patients with type 2 diabetes in stable angina pectoris of coronary heart disease complicated with hypertension group was significantly higher than that in stable angina pectoris patients without hypertension(46.1%VS.28.6%,P<0.05).2.Serum MIF levels in subjectsStable angina pectoris with hypertension patients had significantly higher serum MIF levels compared with healthy controls(2.53[1.95-3.14]VS.0.16[0.14-0.23]ng/mL,P<0.05).Stable angina pectoris without hypertension patients had significantly higher serum MIF levels compared with healthy controls(1.94[0.94-2.34]VS.0.16[0.14-0.23]ng/mL.P<0.05).Stable angina pectoris with hypertension patients had significantly higher serum MIF levels compared with stable angina pectoris without hypertension patients(2.53[1.95-3.14]VS.1.94[0.94-2.34]ng/mL.P<0.05).3.The occurrence of MACEA total of 196 stable angina pectoris patients completed follow-up,MACE occurred in 32(31.7%)patients with stable angina and hypertension,the number of nonfatal myocardial infarction patients was 2.unstable angina in 25 people.revascularization in 5 patients without the occurrence of acute coronary syndrome coronary;MACE occurred in 14(14.7%)patients with stable angina patients without hypertension,unstable angina in 12 people,revascularization in 2 patients without the occurrence of acute coronary syndrome coronary;In stable angina pectoris with hypertension group.MIF levels in patients with MACE were significantly higher than those of the event did not occur(3.22[3.06-3.34]VS.2.18[1.41-2.64]ng/mL,P<0.05);In stable angina pectoris patients without hypertension.MIF levels in patients with MACE were not significantly higher than those of the event did not occur(2.37[0.98-2.85]VS.1.73[0.93-2.20]ng/mL,P>0.05).Kaplan-Meier analysis found that higher levels of MIF resulted in a significantly higher probability of MACE than lower leves of MIF in patients with stable angina and hypertension,but MIF levels had no significant correlation with the MACE occurance in stable angina pectoris patients without hypertension.4.Relationship between MIF levels and prognosisIn patients with stable angina pectoris and hypertensive,single factor COX regression analysis showed that serum MIF levels(risk ratio 1.62.95%Cl 1.23-2.13.P =0.001),type 2 diabetes(risk ratio 1.86.95%CI 1.25-2.76,P =0.002).LDL-c(risk coefficient 1.43,95%Cl 0.98-2.10,P =0.043)was significantly correlated with the incidence of MACE,the risk factors,including smoking.type 2 diabetes.CRP.LDL-c.MIF.whose P value was less than 0.3 in the single factor COX regression analysis were tested with multiple COX regression analysis.Multiple COX regression analysis showed that there was significant correlation between the occurrence MACE and MIF levels(risk ratio 1.55.95%CI 1.15-2.08,P=0.004).MIF levels have significantly independent predictive value on the occurrence of MACE.ConclusionsOur results showed that serum MIF levels in patients with stable angina and hypertension were significantly increased,and the higher the MIF levels the highter the MACE rate,therefore,our results suggest that serum MIF levels are significantly independent predictors for patients with stable angina pectoris and hypertension in MACE. |
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