| Background:Serum cystatin C is an inhibitor of cysteine protease. More attentions have been paid to cystatin C as a new sensitive indicator for the evaluation of renal functions. Recent studies have demonstrated that serum cystatin C is an early risk marker for the endpoints of coronary artery disease (CAD)(e.g., mortality, heart failure). However, the association of cystatin C with the severity and clinical classification of CAD in patients with normal renal function has not been fully investigated. Therefore, as clinical investigation part of the project which was supported by National Natural Science Foundation of China (30971409), Natural Science Foundation (ZR2009CZ009) and the international cooperation grant (2011) of Shandong Province of China, we explored the relationship between the level of serum Cystatin C and the severity of coronary lesions in suspected CAD patients who underwent coronary angiography. Subsequently, we excluded patients with renal dysfunctions associated with both cystatin C and CAD and focused on the level of serum Cystatin C in different clinical types of CAD and the correlation between Cystatin C and the severity of coronary lesions in CAD patients with normal estimate glomerular filtration rate (eGFR). This study would potentially provide clinical guidance for the diagnosis and treatment of CAD. Objective:1. To investigate the distribution of clinical parameters in patients who were diagnosed as CAD by coronary angiography and compare the serum levels of cystatin C between subjects with CAD and non-CAD;2. To investigate the distribution of serum cystatin C in CAD patients with Stable Angina Pectoris (SAP), Unstable Angina Pectoris (UAP) and Acute Myocardial Infarction (AMI);3. To explore the correlation between the serum cystatin C level and the number of coronary vessels with lesions;4. To investigate whether serum cystatin C level is an independent risk factor for multiple coronary lesions and discuss the potential value of serum cystatin C level in the diagnosis of CAD with multiple coronary lesions;Subjects and methods1. Study subjectsWe retrospectively recruited hospitalized patients who underwent coronary angiography in the Department of Cardiology and Emergency Medicine, Qilu Hospital of Shandong University from March2010to March2012. The patients were enrolled in the study according to the inclusion and exclusion criteria and then divided into CAD group (577cases) and non-CAD group (133cases) according to the results of coronary angiography. Clinical parameters between these two groups were compared. Quartile method was used to divide the patients into4groups based on the serum cystatin C level. Clinical parameters and Gensini scores were compared among these4groups with different levels of serum cystatin C. From the710patients described above, we selected460cases with normal eGFR (CAD group:370; non-CAD:90). The patients in the CAD group (with normal eGFR) were divided into three subgroups:stable angina pectoris (SAP), unstable angina pectoris (UAP) and acute myocardial infarction (AMI). The level of serum cystatin C in the non-CAD group was compared with that in these three subgroups. We also divided460cases (with normal eGFR) into four subgroups:No lesion; lesion in single coronary vessel; lesion in two coronary vessels and lesion in multiple coronary vessels. The level of serum cystatin C was compared among these4groups. Receiver operating characteristic curve (ROC curve) was used to evaluate the value of serum cystatin C in the diagnosis of multivessel coronary disease.2. Analysis of the clinical parametersGeneral information of the patients including gender, age, height, weight, smoking history, drinking history, history of hypertension and diabetes was recorded. Serum cystatin C level was determined by particle-enhanced turbidimetric assay (PETIA). Biochemical parameters including fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), fibrinogen (Fg), serum creatinine (sCr) and serum uric acid (UA) were also determined. Serum creatinine clearance was used to estimate glomerular filtration rate (GFR) according to the Cockcroft-Gault formula. Severity of the coronary artery disease was estimated by the reference Gensini score.3. Statistical analysisNormal distribution of the data was confirmed by Kolmogorov-Smirnov test. Data that do not conform to normal distribution were log converted to correct the skewed distribution. The mean of two samples was compared using t test. One-way ANOVA followed by a multiple-comparison test for subgroups by least significance difference(LSD) was used to compare the mean among multiple groups. Chi-square test was used for quantitative data. Binary logistic regression analysis was used for risk factors of multivessel coronary diseases. ROC curve was used to determine the cystatin C threshold of multivessel coronary disease.Results1. Distribution of clinical parameters and comparison of the serum levels of cystatin C between subjects with CAD and non-CAD;The percentage of male patients and patients with a history of smoking, drinking and diabetes in CAD group was higher than that in the non-CAD group. Compared with non-CAD groups, subjects with CAD had significantly higher SCr, Fg, FPG and significantly lower HDL-c (p<0.001). The level of cystatin C in CAD group was significantly higher than that in the non-CAD group (0.84±0.15vs.0.93±0.20, p<0.01). 2. Distribution of clinical parameters among the four groups with different serum level of Cystatin CThe age, the percentage of smoking and hypertension history had an increasing trend in the group of patients with higher serum cystatin C level. The level of SCr, UA, FPG and SBP in the group with higher serum cystatin C level was significantly higher than that in the group with lower serum cystatin C level (p<0.05). Gensini score, which indicates the severity of the coronary lesions, in the group with higher serum cystatin C level was significantly higher than that in the group with lower serum cystatin C level (p<0.01).3. Comparison of serum cystatin C level in different clinical types of CAD patientsThe percentage of patients with history of smoking or drinking in the SAP, UAP or AMI subgroups was significantly higher than that in the non-CAD group. In addition, Fg, FPG, SCr, UA, SBP and Gensini score in the SAP, UAP or AMI subgroups were significantly higher than those in the non-CAD group (p<0.01). The serum level of Cystatin C increased accordingly in the in the SAP, UAP or AMI subgroups.4. Correlation between the serum level of cystatin C and the number of vessels with lesionsWe divided370CAD patients into four subgroups:lesion in single coronary vessel, lesion in two coronary vessels and lesion in multiple coronary vessels, and the serum level of cystatin C was0.77±0.16,0.87±0.14,0.91±0.17mg/L, respectively. The serum level of cystatin C significantly increased as the number of vessels with lesions was increased (p<0.01). In the non-CAD group, the serum level of cystatin C was not significantly different from that in the patients with lesion in single coronary vessel. Furthermore, the serum level of cystatin C in multiple coronary vessels was not significantly different from that in the patients with lesion in two coronary vessels.5. Analysis of independent risk factors for predicting the risk of multiple coronary vessels with stenosis of CADLogistic regression analysis showed that serum cystatin C, LDL-c and FPG levels are significant independent risk factors for predicting the risk of multiple coronary vessels with lesions of CAD. In addition, serum cystatin C level was positively associated with the risk (OR:1.738; p<0.01).6. The predictive value of serum cystatin C level in the diagnosis of patients with multiple coronary vessel stenosisROC curve analysis was used to analyze the predictive value of serum level of cystatin C in the diagnosis of multiple vessel stenosis. The results showed that the area under the curve was0.738(95%CI:0.692-0.785, p<0.001). When0.815mg/L was selected as the diagnostic threshold, the sensitivity was72.2%and specificity was71.1%.Conclusions:1. For the CAD patients with normal eGFR, serum level of cystatin C is correlated with the clinical types of CAD. Serum level of cystatin C in patients with acute coronary syndrome (ACS) was significantly higher than that in SAP patients.2. The serum level of cystatin C is an independent risk factor for predicting the risk of multiple coronary vessels with lesions of CAD.3. The serum level cystatin C could serve as a marker with a powerful predictive value for the presence of multiple coronary vessels with lesions of CAD. Background:Patients with metabolic syndrome (MetS) are high-risk populations of coronary atherosclerosis. All the components including central obesity, hyperglycemia, dyslipidemia and hypertension are important independent risk factors of CAD. asymptomatic CAD is an important clinical type of CAD. Due to lack of typical clinical symptoms, asymptomatic CAD is frequently missed or even misdiagnosed, leading to the delayed treatment and poor prognosis. Currently, simple and non-invasive diagnostic methods are not available. Therefore, early screening for risk factors of macrovascular disease in MetS patients is essential for the prediction of occurrence, development and prognosis of cardiovascular disease. Previous studies have shown that elevation of serum cystatin C level is correlated with the occurrence and prognosis of cardiovascular disease. Recent studies have also shown that serum cystatin C is closely correlated with MetS. However, the value of serum Cystatin C in the diagnosis of asymptomatic CAD in MetS patients with normal eGFR has not been reported.Objective:1. To investigate the association of serum cystatin C level with the presence and severity of newly diagnosed asymptomatic CAD;2. To explore the predictive value of serum cystatin C level to distinguish MetS patients with asymptomatic CAD from those without CAD;3. To investigate the correlation between serum cystatin C and the risk factors of CAD.Subjects and methods1. Study subjectsWe retrospectively recruted asymptomatic MetS patients without prior diagnosed CAD and with normal eGFR who presented for a annual medical evaluation at QiLu Hospital of Shandong University from March2010to March2012. All patients had no CAD history and underwent coronary angiography for suspected CAD. Patients were divided into CAD (n=136) and non-CAD groups (n=75) according to the results of coronary angiography. Clinical parameters were compared between the two groups. Binary logistic regression analysis was used to determine the correlation between serum Cystatin C level and asymptomatic CAD. ROC curve was used to assess the value of serum cystatin C in the diagnosis of asymptomatic CAD. We divided the patients into three subgroups:lesion in single coronary vessel; lesion in two coronary vessels and lesion in multiple coronary vessels. The serum cystatin C level was compared among these three subgroups. Multiple linear regression analysis was used to determine the correlation between serum cystatin C levels and coronary lesion severity (Gensini score). The correlation between cystatin C and coronary risk factors was also investigated.2. Analysis of the clinical parametersDemographic characteristics of the patients including gender, age, height weight were obtained from medical records, Systolic bold pressure (SBP) and diastolic blood pressure(DBP) was measured twice with a desk-models phygmomanometer. The rest and exercise stress ECG were assessed.smoking history, drinking history, history of hypertension and diabetes was recorded. Serum cystatin C level was determined by particle-enhanced turbidimetric assay (PETIA). Biochemical parameters including fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), fibrinogen (Fg), serum creatinine (sCr) and serum uric acid (UA) were also determined. Serum creatinine clearance was used to estimate glomerular filtration rate (GFR) according to the Cockcroft-Gault formula. Severity of the coronary artery disease was estimated by the reference Gensini score.3. Statistical analysisNormal distribution of the data was confirmed by Kolmogorov-Smirnov test. Data that do not conform to normal distribution were log converted to correct the skewed distribution. An unpaired student’s t test was used for normally distributed variables. The chi-square test was used to compare the categorical variables of subjects with and without CAD. One-way ANOVA followed by a multiple-comparison test for subgroups by least significance difference (LSD) was used to compare the mean among multiple groups. Pearson and partial correlation analysis were applied to determine factors that correlated with cystatin C. To determine the independent parameters correlated with cystatin C and the Gensini score, the parameters that correlated significantly in the univariate analysis and other parameters that were biologically relevant to cystatin C and the Gensini score were tested using multiple stepwise regression analysis. A logistic regression analysis was performed to assess the association between the presence of CAD and cystatin C levels. In addition, the receiver operating characteristics (ROC) curve was used to determine the cystatin C cut-off for predicting asymptomatic CAD.Results1. Distribution of clinical parameters and comparison of the serum levels of cystatin C between MetS patients with newly diagnosed asymptomatic CAD and non-CAD;patients with asymptomatic CAD were older than those without CAD.The rates of hypertension, smoking and diabetes mellitus in patients with asymptomatic CAD were higher than in patients without CAD, and asymptomatic CAD patients showed an increase of FPG (p<0.05). The fibrinogen concentrations were significantly higher in patients with asymptomatic CAD than in those without CAD Among the patients with MetS, those with asymptomatic CAD had significantly higher serum cystatin C levels than those without CAD (0.93±0.18vs.0.86±0.16, p=0.004).2. Correlation between serum cystatin C and the clinical biochemical parametersThe Pearson correlation analysis demonstrated that serum cystatin C was positively correlated with age, UA, SCr, and fibrinogen and negatively correlated with eGFR (p<0.01). After further adjustment for age, sex and eGFR, the positive correlation remained significant between cystatin C and UA, fibrinogen (p<0.001,p=0.001, respectively). A positive correlation was also observed between cystatin C and TG and BMI (p=0.031, p<0.001, respectively, Table3). Furthermore, multivariate stepwise regression analysis was performed to evaluate the independent factors of cystatin C. The analysis demonstrated that UA (standardized β=0.233, p<0.001), BMI (standardized β=0.176, p=0.002), TG (standardized β=0.117, p=0.03), eGFR (standardized β=-0.455, p<0.001), and fibrinogen (standardized β=0.187, p=0.001) were independently associated with serum cystatin C.3. Correlation between serum cystatin C and CAD severity(1) Spearman correlation analysis showed that serum cystatin C (r=0.188, p=0.006) was positively correlated with the Gensini score. We further performed a multivariate stepwise regression analysis to evaluate the association between serum cystatin C levels and the Gensini score.Serum cystatin C was the independent factor that significantly influenced the Gensini score (standardized β=0.183, p=0.007).(2) All of the subjects were further divided into four groups according to the number of disease vessels (N=0,1,2,3). The serum levels of cystatin C increased as the number of stenotic vessels increased (p=0.005). No significance was found for cystatin C levels in the N=0and N=1groups. Moreover, the serum cystatin C levels were significantly higher in the N=3group than in the N=1group (p=0.045).4. Analysis of independent risk factors for predicting the risk for the newly diagnosed asymptomatic CAD in MetS patients with normal GFR.Logistic regression analysis showed that serum Cystatin C, smoking history, fibrinogen, fasting plasma glucose are independent risk factors for newly diagnosed asymptomatic CAD, Serum cystatin C level was a risk factor (OR:1.326;p<0.01) for the newly diagnosed asymptomatic CAD in MetS patients with normal GFR.5. The predictive value of serum cystatin C level in distinguish MetS patients with asymptomatic CAD from those without CADThe ability of serum cystatin C level to distinguish MetS patients with asymptomatic CAD from those without CAD was assessed using ROC curve analysis. The ROC curves for asymptomatic CAD diagnosis had an area under the curve (AUC) of0.622(95%CI:0543-0.701, p=0.003). A serum cystatin C level of>0.825mg/L predicted the presence of CAD with a sensitivity of71.3%and specificity of54.7%.Conclusions:1. Serum cystatin C is an independent risk factor for the occurrence of newly diagnosed asymptomatic CAD In MetS patients with normal eGFR,;2. Serum cystatin C level was positively correlated with the severity of CAD;3. Serum cystatin C might be a more efficient marker than traditional CAD risk factors for early diagnosis of asymptomatic CAD in MetS patients with normal GFR,... |
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