血清胱抑素C在冠心病诊断及冠脉病变评估的作用
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摘要
研究背景：
血清胱抑素C(Cys C)是半胱氨酸蛋白酶抑制蛋白,作为新的肾功能评价的敏感指标,Cys C被越来越多的研究所关注。近年多项研究报道血清Cys C也是冠心病(CAD)终点事件(死亡率、心力衰竭等)的早期危险标志之一,而对于肾脏功能正常的患者,Cys C与冠状动脉病变程度特别是与CAD不同临床类型的相关性研究却鲜见报道。本研究以拟诊为CAD行冠状动脉造影的患者为研究对象,初步分析血清Cys C水平与冠状动脉病变程度的关系。并排除与Cys C及CAD有关的混杂因素肾功能异常,探讨肾小球滤过率(eGFR)正常的CAD患者中,Cys C在不同临床类型中的分布特点及Cys C水平与冠脉病变支数之间的相关性。评价Cys C对冠状动脉多支病变的诊断价值,为CAD的诊断和治疗提供全面的临床指导。
目的：
1.观察经冠状动脉造影确诊为CAD患者的血清Cys C及临床指标的分布特点。
2.研究血清Cys C水平在eGFR正常的稳定型心绞痛(SAP)、不稳定型心绞痛(UAP)、心肌梗死(AMI)患者中的差异。
3.探讨血清Cys C水平与冠状动脉病变支数之间的相关性。
4评价血清Cys C水平对CAD多支病变的诊断价值。
研究对象与方法：
1.研究对象：
(1)收集山东大学齐鲁医院心内科及急诊内科2010年3月至2012年3月期间住院并行冠状动脉造影的患者。按照纳入排除标准入选患者后,根据冠状动脉造影结果分为CAD组(577例)和非CAD组(133例),比较两组间临床指标的差异。按照患者血清Cys C水平以四分位法分为四组,组间比较不同CysC水平的CAD患者临床指标及gensini评分在各组分布情况；
(2)从上述710病例中,筛选出eGFR正常者460例,其中非CAD组90例,CAD组370例,将CAD组根据临床类型分为稳定型心绞痛(SAP)、不稳定型心绞痛(UAP)、急性心肌梗死(AMI)三个亚组,比较非CAD组及以上三个亚组间血清Cys C水平差异；
(3)根据冠状动脉病变血管支数分为单支、双支、多支病变三个亚组,比较非CAD组及三亚组间血清Cys C水平差异。应用受试者工作特征曲线(ROC curve)评价血清Cys C对冠状动脉多支病变的诊断价值。
2.分析指标
记录患者性别、年龄、身高、体重、吸烟史、饮酒史、既往高血压病史及糖尿病病史等一般资料,血清Cys C水平采用乳胶颗粒增强免疫透射比浊法(PETIA)测定,同时测定空腹血糖(FPG)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-c)、高密度脂蛋白胆固醇(HDL-c)、纤维蛋白原(Fg)、血肌酐(SCr)血尿酸(UA)等各项生化指标。根据Cockcroft-Gault公式计算血肌酐清除率估计eGFR,冠状动脉病变严重程度评分参照gensini评分标准。
3.统计分析
数据正态性分析应用Kolmogorov-Smirnov检验,不服从正态分布的数据进行log转换。两样本均数间的比较采用t检验,多组间差异比较采用单因素方差分析；计数资料分析采用卡方检验。采用二分类logistic回归分析确定冠状动脉多支病变的危险因素,ROC曲线确定冠状动脉多支病变的Cys C临界值。
结果：
1.CAD组与非CAD组临床资料的分布及差异
CAD组与非CAD组相比,男性患者、具有吸烟史、饮酒史者所占比例较高；与非CAD组相比,CAD组FPG、Fg、SCr水平显著升高(p≤0.001), HDL-c水平降低(p<0.001),CAD组血清Cys C水平明显高于非CAD组(0.84±0.15vs.0.93±0.20, p<0.001)
2.以血清Cys C水平四分位间距分组后患者的临床资料分布特点
白血清Cys C水平下四分位至上四分位(Q1为133例,Q2为128例,Q3为160例,Q4为153例),患者年龄分布呈现逐渐增高的趋势,合并高血压病史、糖尿病病史者所占比例更高,随着血清Cys C水平的升高,患者SCr、 UA、FPG、Fg、SBP增高,组间差异有统计学意义(p<0.05), HDL-c水平降低(p<0.05),冠状动脉病变严重程度gensini评分分值自Q1至Q4组逐渐增加,差异有统计学意义(36.66+21.20vs.41.61±21.71vs.42.29±24.75vs.45.84±22.72, p<0.01).
3.血清Cys C水平在不同临床类型CAD患者间的差异
与非CAD组(90例)相比,SAP(107例)、UAP(144例)、AMI(119例)三个亚组具有吸烟史、饮酒史者所占比例增高,Fg、FPG、SCr、UA、SBP、gensini评分增高,组间差异有统计学意义(p<0.05)；血清Cys C水平AMI>UAP>SAP>非CAD,差异有统计学意义(0.92±0.15vs.0.85±0.16vs.0.79±0.16vs.0.77±0.11, p<0.01)。
4.血清Cys C与冠状动脉病变支数之间的关系
在eGFR正常的CAD患者中按照冠状动脉病变分为单支、双支、多支病变三个亚组,血清Cys C水平分别为0.77±0.16,0.87±0.14,0.91±0.17mg/L,血清Cys C水平随冠脉病变支数的增加而增高,组间比较有统计学意义(p<0.01)。冠状动脉单支病变组与非CAD组相比,差异无统计学意义,冠状动脉双支病变组与多支病变组相比,差异无统计学意义。
5.CAD患者发生冠状动脉多支病变的危险因素分析
以CAD冠状动脉多支病变为因变量,应用二分类Logistic回归分析显示：血清Cys C、LDL-c、FPG是冠状动脉多支病变的独立危险因素,其中血清Cys C对eGFR正常的CAD患者发生冠状动脉多支病变的危险度为1.738(p<0.01)。
6.血清CysC对冠状动脉多支病变的诊断价值
应用ROC曲线分析血清Cys C对冠状动脉多支病变的诊断价值,结果显示其曲线下面积(AUC)为0.738(95%CI：0.692-0.785,p<0.001),选取0.815mg/L为诊断界点时,灵敏度为72.2%,特异度为71.1%.
结论：1.eGFR正常的CAD患者,血清CysC水平与CAD的临床类型相关,其在急性冠状动脉综合征(ACS)患者中水平明显高于SAP患者；
2.血清CysC水平与冠状动脉病变支数相关,是冠脉多支病变的危险因素；3.血清CysC对于GFR正常的CAD患者冠状动脉多支病变具有诊断价值。
研究背景：
代谢综合征(MetS)患者是冠状动脉粥样硬化的高危人群,其组成成分如向心性肥胖、高血糖、血脂异常、高血压是CAD重要的独立危险因素,隐匿型CAD是CAD的重要临床类型,由于缺乏典型的临床症状,常被临床医师漏诊甚至误诊,从而延误治疗,预后较差,目前缺乏简便无创的诊断方法。及早在MetS患者中进行大血管病变的危险因素筛查,对预测未来心血管疾病的发生、发展乃至预后至关重要。以往研究发现血清Cys C水平的升高与心血管病的不良事件及预后有关,近年来,亦有研究证实血清Cys C与MetS密切相关,而对于eGFR正常的MetS患者,血清Cys C对无症状型CAD的诊断预测价值未见报道。
目的：
本研究旨在通过测定eGFR正常的MetS患者血清Cys C水平,分析其与新诊断无症状CAD发生及冠脉病变严重程度的关系,探讨血清Cys C水平对MetS患者发生新诊断无症状CAD的预测价值,同时探讨血清Cys C与CAD危险因素间的相关性。
研究对象与方法：
1.研究对象：
回顾性收集山东大学齐鲁医院心内科2010年3月至2012年3期间就诊的无CAD临床症状eGFR正常的MetS患者,所有患者既往无CAD病史,入选患者因拟诊CAD行冠状动脉造影,按照纳入排除标准入选患者后,根据冠状动脉造影结果分为CAD组(136例)和非CAD组(75例),比较两组间临床指标的差别,采用二分类Logistic回归分析评价血清Cys C水平与无症状CAD的相关性及相关程度。采用受试者工作特征曲线(ROC curve)评价血清Cys C对无症状CAD的诊断价值,根据冠状动脉病变血管支数分为单支、双支、多支病变三个亚组,分别比较三亚组间血清Cys C水平差异。多元线性回归分析血清Cys C水平与冠状动脉病变严重程度评分(gensini score)的相关性,Cys C与冠状动脉危险因素的相关性采用双变量相关分析。
2.分析指标
根据病历记录收集患者性别、年龄、身高、体重等一般资料,用台式汞柱式血压计测量收缩压(SBP)与舒张压(DBP),给予静息及运动负荷后心电图(ECG)检查,收集患者既往高血压病史、糖尿病病史、吸烟史,测定患者空腹静脉血中血糖(FPG)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-c)、高密度脂蛋白胆固醇(HDL-c)、纤维蛋白原(Fg)、血肌酐(SCr)血尿酸(UA)等各项生化检测指标,乳胶颗粒增强免疫透射比浊法(PETIA)测定血清Cys C水平。根据Cockcroft-Gault公式计算血肌酐清除率估计eGFR,冠状动脉病变严重程度评分参照gensini评分标准。
3.统计分析
应用Kolmogorov-Smirnov检验进行变量正态性分析,不服从正态分布的变量进行log转换。两组间的计量资料比较采用独立样本t检验。计数资料分析采用卡方检验。计量资料多组间差异比较采用单因素方差分析,多重比较用LSD法。Cys C与新诊断无症状CAD危险因素的相关性采用pearson相关分析及多元逐步回归分析,逐步法多元线性回归分析各变量与gensini评分之间的相关性,计算各变量对gensini评分的回归系数。ROC曲线评价血清Cys C水平对新诊断无症状CAD的诊断价值,将是否患无症状CAD分组进行二分类Logistic回归分析变量后,计算各变量对无症状CAD发生的危险度。
结果：
1. eGFR正常的MetS患者中新诊断无症状CAD组与非CAD组临床资料的分布及差异
新诊断无症状CAD组患者年龄高于非CAD组,具有吸烟史、高血压病史、糖尿病史者在新诊断无症状CAD组所占比例较高,新诊断无症状CAD组与非CAD组相比FPG、Fg升高,差别有统计学意义(p<0.05)。血清Cys C水平在新诊断无症状CAD组明显高于非CAD组,差异有统计学意义(0.93±0.18xs.0.86±0.16,p=0.004)。
2.血清Cys C与CAD危险因素间的相关性
Pearson'相关分析显示：血清Cys C与年龄、SCr、UA、Fg呈正相关,血清Cys C与eGFR呈负相关,经校正年龄、性别、eGFR后,血清Cys C与UA、Fg、 TG、BMI呈正相关(p=0.031,p<0.001,)。多元逐步回归显示：血清Cys C与UA、Fg、BMI、TG呈线性正相关(标准化回归系数分别为为0.233.0.176、0.117、0.187, p<0.001、p=0.002、p=0.03、p=0.001),血清Cys C与eGFR呈负相关(标准化回归系数分别为-0.455,p<0.001)。
3.血清Cys C与冠状动脉病变严重程度间的相关性
(1)Spearman相关显示血清Cys C与gensini评分呈正相关(r=0.188,p=0.006),多元逐步回归显示：gensini评分与血清Cys C呈线性正相关(标准化回归系数为0.183,p=0.007)。
(2)将入选病例按照冠状动脉病变支数分为N=0,1,2,3四个亚组,结果显示血清Cys C水平随冠脉病变支数的增加而逐渐增高,组间比较有统计学意义(0.86±0.17vs.0.90±0.16vs.0.92±0.17vs.0.97±0.19, p=0.005)冠状动脉单支病变组血清Cys C水平与非CAD组相比,差异无统计学意义。冠状动脉三支病变组血清Cys C水平与单支病变组相比,组间比较有统计学意义(p=0.045)。
4. eGFR正常的MetS患者发生新诊断无症状CAD的危险因素分析
以新诊断无症状CAD为因变量,应用二分类Logistic回归分析显示：血清Cys C、吸烟史、Fg、FPG是新诊断无症状CAD的独立危险因素,其中血清Cys C对eGFR正常的MetS患者发生新诊断无症状CAD的危险度为1.326(p<0.01)。
5.血清Cys C水平对eGFR正常的MetS患者发生新诊断无症状CAD的诊断价值
应用ROC曲线分析血清Cys C对新诊断无症状CAD的诊断价值,结果显示其曲线下面积为0.622(95%CI：0543-0.701,p=0.003),选取0.825mg/L为诊断界点时,灵敏度为71.3%,特异度为54.7%.
结论：
1.在eGFR正常的MetS患者中,血清Cys C是发生无症状CAD的独立危险因素；
2.血清Cys C水平与冠状动脉病变严重程度呈正相关；
3.在eGFR正常的MetS患者中,与传统的CAD危险因素相比,血清Cys C是诊断无症状型CAD效力更优的血清标志物。
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 methods
1. Study subjects
We 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 parameters
General 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 analysis
Normal 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.
Results
1. 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 C
The 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 patients
The 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 lesions
We 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 CAD
Logistic 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 stenosis
ROC 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 methods
1. Study subjects
We 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 parameters
Demographic 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 analysis
Normal 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.
Results
1. 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 parameters
The 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 CAD
The 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,
血清胱抑素C(Cys C)是半胱氨酸蛋白酶抑制蛋白,作为新的肾功能评价的敏感指标,Cys C被越来越多的研究所关注。近年多项研究报道血清Cys C也是冠心病(CAD)终点事件(死亡率、心力衰竭等)的早期危险标志之一,而对于肾脏功能正常的患者,Cys C与冠状动脉病变程度特别是与CAD不同临床类型的相关性研究却鲜见报道。本研究以拟诊为CAD行冠状动脉造影的患者为研究对象,初步分析血清Cys C水平与冠状动脉病变程度的关系。并排除与Cys C及CAD有关的混杂因素肾功能异常,探讨肾小球滤过率(eGFR)正常的CAD患者中,Cys C在不同临床类型中的分布特点及Cys C水平与冠脉病变支数之间的相关性。评价Cys C对冠状动脉多支病变的诊断价值,为CAD的诊断和治疗提供全面的临床指导。
目的：
1.观察经冠状动脉造影确诊为CAD患者的血清Cys C及临床指标的分布特点。
2.研究血清Cys C水平在eGFR正常的稳定型心绞痛(SAP)、不稳定型心绞痛(UAP)、心肌梗死(AMI)患者中的差异。
3.探讨血清Cys C水平与冠状动脉病变支数之间的相关性。
4评价血清Cys C水平对CAD多支病变的诊断价值。
研究对象与方法：
1.研究对象：
(1)收集山东大学齐鲁医院心内科及急诊内科2010年3月至2012年3月期间住院并行冠状动脉造影的患者。按照纳入排除标准入选患者后,根据冠状动脉造影结果分为CAD组(577例)和非CAD组(133例),比较两组间临床指标的差异。按照患者血清Cys C水平以四分位法分为四组,组间比较不同CysC水平的CAD患者临床指标及gensini评分在各组分布情况；
(2)从上述710病例中,筛选出eGFR正常者460例,其中非CAD组90例,CAD组370例,将CAD组根据临床类型分为稳定型心绞痛(SAP)、不稳定型心绞痛(UAP)、急性心肌梗死(AMI)三个亚组,比较非CAD组及以上三个亚组间血清Cys C水平差异；
(3)根据冠状动脉病变血管支数分为单支、双支、多支病变三个亚组,比较非CAD组及三亚组间血清Cys C水平差异。应用受试者工作特征曲线(ROC curve)评价血清Cys C对冠状动脉多支病变的诊断价值。
2.分析指标
记录患者性别、年龄、身高、体重、吸烟史、饮酒史、既往高血压病史及糖尿病病史等一般资料,血清Cys C水平采用乳胶颗粒增强免疫透射比浊法(PETIA)测定,同时测定空腹血糖(FPG)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-c)、高密度脂蛋白胆固醇(HDL-c)、纤维蛋白原(Fg)、血肌酐(SCr)血尿酸(UA)等各项生化指标。根据Cockcroft-Gault公式计算血肌酐清除率估计eGFR,冠状动脉病变严重程度评分参照gensini评分标准。
3.统计分析
数据正态性分析应用Kolmogorov-Smirnov检验,不服从正态分布的数据进行log转换。两样本均数间的比较采用t检验,多组间差异比较采用单因素方差分析；计数资料分析采用卡方检验。采用二分类logistic回归分析确定冠状动脉多支病变的危险因素,ROC曲线确定冠状动脉多支病变的Cys C临界值。
结果：
1.CAD组与非CAD组临床资料的分布及差异
CAD组与非CAD组相比,男性患者、具有吸烟史、饮酒史者所占比例较高；与非CAD组相比,CAD组FPG、Fg、SCr水平显著升高(p≤0.001), HDL-c水平降低(p<0.001),CAD组血清Cys C水平明显高于非CAD组(0.84±0.15vs.0.93±0.20, p<0.001)
2.以血清Cys C水平四分位间距分组后患者的临床资料分布特点
白血清Cys C水平下四分位至上四分位(Q1为133例,Q2为128例,Q3为160例,Q4为153例),患者年龄分布呈现逐渐增高的趋势,合并高血压病史、糖尿病病史者所占比例更高,随着血清Cys C水平的升高,患者SCr、 UA、FPG、Fg、SBP增高,组间差异有统计学意义(p<0.05), HDL-c水平降低(p<0.05),冠状动脉病变严重程度gensini评分分值自Q1至Q4组逐渐增加,差异有统计学意义(36.66+21.20vs.41.61±21.71vs.42.29±24.75vs.45.84±22.72, p<0.01).
3.血清Cys C水平在不同临床类型CAD患者间的差异
与非CAD组(90例)相比,SAP(107例)、UAP(144例)、AMI(119例)三个亚组具有吸烟史、饮酒史者所占比例增高,Fg、FPG、SCr、UA、SBP、gensini评分增高,组间差异有统计学意义(p<0.05)；血清Cys C水平AMI>UAP>SAP>非CAD,差异有统计学意义(0.92±0.15vs.0.85±0.16vs.0.79±0.16vs.0.77±0.11, p<0.01)。
4.血清Cys C与冠状动脉病变支数之间的关系
在eGFR正常的CAD患者中按照冠状动脉病变分为单支、双支、多支病变三个亚组,血清Cys C水平分别为0.77±0.16,0.87±0.14,0.91±0.17mg/L,血清Cys C水平随冠脉病变支数的增加而增高,组间比较有统计学意义(p<0.01)。冠状动脉单支病变组与非CAD组相比,差异无统计学意义,冠状动脉双支病变组与多支病变组相比,差异无统计学意义。
5.CAD患者发生冠状动脉多支病变的危险因素分析
以CAD冠状动脉多支病变为因变量,应用二分类Logistic回归分析显示：血清Cys C、LDL-c、FPG是冠状动脉多支病变的独立危险因素,其中血清Cys C对eGFR正常的CAD患者发生冠状动脉多支病变的危险度为1.738(p<0.01)。
6.血清CysC对冠状动脉多支病变的诊断价值
应用ROC曲线分析血清Cys C对冠状动脉多支病变的诊断价值,结果显示其曲线下面积(AUC)为0.738(95%CI：0.692-0.785,p<0.001),选取0.815mg/L为诊断界点时,灵敏度为72.2%,特异度为71.1%.
结论：1.eGFR正常的CAD患者,血清CysC水平与CAD的临床类型相关,其在急性冠状动脉综合征(ACS)患者中水平明显高于SAP患者；
2.血清CysC水平与冠状动脉病变支数相关,是冠脉多支病变的危险因素；3.血清CysC对于GFR正常的CAD患者冠状动脉多支病变具有诊断价值。
研究背景：
代谢综合征(MetS)患者是冠状动脉粥样硬化的高危人群,其组成成分如向心性肥胖、高血糖、血脂异常、高血压是CAD重要的独立危险因素,隐匿型CAD是CAD的重要临床类型,由于缺乏典型的临床症状,常被临床医师漏诊甚至误诊,从而延误治疗,预后较差,目前缺乏简便无创的诊断方法。及早在MetS患者中进行大血管病变的危险因素筛查,对预测未来心血管疾病的发生、发展乃至预后至关重要。以往研究发现血清Cys C水平的升高与心血管病的不良事件及预后有关,近年来,亦有研究证实血清Cys C与MetS密切相关,而对于eGFR正常的MetS患者,血清Cys C对无症状型CAD的诊断预测价值未见报道。
目的：
本研究旨在通过测定eGFR正常的MetS患者血清Cys C水平,分析其与新诊断无症状CAD发生及冠脉病变严重程度的关系,探讨血清Cys C水平对MetS患者发生新诊断无症状CAD的预测价值,同时探讨血清Cys C与CAD危险因素间的相关性。
研究对象与方法：
1.研究对象：
回顾性收集山东大学齐鲁医院心内科2010年3月至2012年3期间就诊的无CAD临床症状eGFR正常的MetS患者,所有患者既往无CAD病史,入选患者因拟诊CAD行冠状动脉造影,按照纳入排除标准入选患者后,根据冠状动脉造影结果分为CAD组(136例)和非CAD组(75例),比较两组间临床指标的差别,采用二分类Logistic回归分析评价血清Cys C水平与无症状CAD的相关性及相关程度。采用受试者工作特征曲线(ROC curve)评价血清Cys C对无症状CAD的诊断价值,根据冠状动脉病变血管支数分为单支、双支、多支病变三个亚组,分别比较三亚组间血清Cys C水平差异。多元线性回归分析血清Cys C水平与冠状动脉病变严重程度评分(gensini score)的相关性,Cys C与冠状动脉危险因素的相关性采用双变量相关分析。
2.分析指标
根据病历记录收集患者性别、年龄、身高、体重等一般资料,用台式汞柱式血压计测量收缩压(SBP)与舒张压(DBP),给予静息及运动负荷后心电图(ECG)检查,收集患者既往高血压病史、糖尿病病史、吸烟史,测定患者空腹静脉血中血糖(FPG)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-c)、高密度脂蛋白胆固醇(HDL-c)、纤维蛋白原(Fg)、血肌酐(SCr)血尿酸(UA)等各项生化检测指标,乳胶颗粒增强免疫透射比浊法(PETIA)测定血清Cys C水平。根据Cockcroft-Gault公式计算血肌酐清除率估计eGFR,冠状动脉病变严重程度评分参照gensini评分标准。
3.统计分析
应用Kolmogorov-Smirnov检验进行变量正态性分析,不服从正态分布的变量进行log转换。两组间的计量资料比较采用独立样本t检验。计数资料分析采用卡方检验。计量资料多组间差异比较采用单因素方差分析,多重比较用LSD法。Cys C与新诊断无症状CAD危险因素的相关性采用pearson相关分析及多元逐步回归分析,逐步法多元线性回归分析各变量与gensini评分之间的相关性,计算各变量对gensini评分的回归系数。ROC曲线评价血清Cys C水平对新诊断无症状CAD的诊断价值,将是否患无症状CAD分组进行二分类Logistic回归分析变量后,计算各变量对无症状CAD发生的危险度。
结果：
1. eGFR正常的MetS患者中新诊断无症状CAD组与非CAD组临床资料的分布及差异
新诊断无症状CAD组患者年龄高于非CAD组,具有吸烟史、高血压病史、糖尿病史者在新诊断无症状CAD组所占比例较高,新诊断无症状CAD组与非CAD组相比FPG、Fg升高,差别有统计学意义(p<0.05)。血清Cys C水平在新诊断无症状CAD组明显高于非CAD组,差异有统计学意义(0.93±0.18xs.0.86±0.16,p=0.004)。
2.血清Cys C与CAD危险因素间的相关性
Pearson'相关分析显示：血清Cys C与年龄、SCr、UA、Fg呈正相关,血清Cys C与eGFR呈负相关,经校正年龄、性别、eGFR后,血清Cys C与UA、Fg、 TG、BMI呈正相关(p=0.031,p<0.001,)。多元逐步回归显示：血清Cys C与UA、Fg、BMI、TG呈线性正相关(标准化回归系数分别为为0.233.0.176、0.117、0.187, p<0.001、p=0.002、p=0.03、p=0.001),血清Cys C与eGFR呈负相关(标准化回归系数分别为-0.455,p<0.001)。
3.血清Cys C与冠状动脉病变严重程度间的相关性
(1)Spearman相关显示血清Cys C与gensini评分呈正相关(r=0.188,p=0.006),多元逐步回归显示：gensini评分与血清Cys C呈线性正相关(标准化回归系数为0.183,p=0.007)。
(2)将入选病例按照冠状动脉病变支数分为N=0,1,2,3四个亚组,结果显示血清Cys C水平随冠脉病变支数的增加而逐渐增高,组间比较有统计学意义(0.86±0.17vs.0.90±0.16vs.0.92±0.17vs.0.97±0.19, p=0.005)冠状动脉单支病变组血清Cys C水平与非CAD组相比,差异无统计学意义。冠状动脉三支病变组血清Cys C水平与单支病变组相比,组间比较有统计学意义(p=0.045)。
4. eGFR正常的MetS患者发生新诊断无症状CAD的危险因素分析
以新诊断无症状CAD为因变量,应用二分类Logistic回归分析显示：血清Cys C、吸烟史、Fg、FPG是新诊断无症状CAD的独立危险因素,其中血清Cys C对eGFR正常的MetS患者发生新诊断无症状CAD的危险度为1.326(p<0.01)。
5.血清Cys C水平对eGFR正常的MetS患者发生新诊断无症状CAD的诊断价值
应用ROC曲线分析血清Cys C对新诊断无症状CAD的诊断价值,结果显示其曲线下面积为0.622(95%CI：0543-0.701,p=0.003),选取0.825mg/L为诊断界点时,灵敏度为71.3%,特异度为54.7%.
结论：
1.在eGFR正常的MetS患者中,血清Cys C是发生无症状CAD的独立危险因素；
2.血清Cys C水平与冠状动脉病变严重程度呈正相关；
3.在eGFR正常的MetS患者中,与传统的CAD危险因素相比,血清Cys C是诊断无症状型CAD效力更优的血清标志物。
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 methods
1. Study subjects
We 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 parameters
General 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 analysis
Normal 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.
Results
1. 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 C
The 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 patients
The 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 lesions
We 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 CAD
Logistic 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 stenosis
ROC 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 methods
1. Study subjects
We 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 parameters
Demographic 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 analysis
Normal 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.
Results
1. 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 parameters
The 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 CAD
The 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,
引文
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