Li Jin Pu

Value of serum glycated albumin and high-sensitivity C-reactive protein levels in the prediction of presence of coronary artery disease in patients with type 2 diabetes

BackgroundCoronary artery disease (CAD) is a major vascular complication of diabetes mellitus and reveals high mortality. Up to 30% of diabetic patients with myocardial ischemia remain asymptomatic and are associated with worse prognosis compared to non-diabetic counterpart, which warrants routine screening for CAD in diabetic population. The purpose of this study was to evaluate the clinical value of serum glycated albumin and high-sensitivity C-reactive protein (hs-CRP) levels in predicting the presence of CAD in patients with type 2 diabetes.MethodsThree hundred and twenty-four patients with type 2 diabetes were divided into two groups based on presence (CAD group, n = 241) or absence (control group, n = 83) of angiographically-documented CAD (lumen diameter narrowing ≥70%). Serum levels of glycated albumin and hs-CRP as well as serum concentrations of glucose, lipids, creatinine, blood urea nitrogen and uric acid were measured in both groups. Predictors of CAD were determined using multivariate logistic regression model and receiver-operating characteristic (ROC) curves.ResultsSerum glycated albumin and hs-CRP levels were significantly increased in diabetic patients with CAD. Multivariate regression analysis revealed that male gender, age, serum levels of glycated albumin, hs-CRP, creatinine and lipoprotein (a) were independent predictors for CAD. Areas under the curve of glycated albumin and hs-CRP and for regression model were 0.654 (95%CI 0.579–0.730, P < 0.001), 0.721 (95%CI 0.658–0.785, P < 0.001) and 0.824 (95% CI 0.768–0.879, P < 0.001), respectively. The optimal values of cut-off point were 18.7% (sensitivity 67.9%, specificity 60.0%) for glycated albumin and 5.2 mg/l (sensitivity 72.2%, specificity 60.0%) for hs-CRP to predict CAD. Logistic regression model was defined as: P/(1-P) = EXP(-1.5 + 1.265 gender + 0.812 age + 1.24 glycated albumin + 0.953 hs-CRP + 0.902 lipoprotein(a) + 1.918 creatinine). The optimal probability value for predicting CAD in type 2 diabetic patients was 0.648 (sensitivity 82.3%, specificity 68.6%).ConclusionSerum glycated albumin and hs-CRP levels were significantly elevated in patients with type 2 diabetes and CAD. The logistic regression model incorporating with glycated albumin, hs-CRP and other major risk factors of atherosclerosis may be useful for screening CAD in patients with type 2 diabetes.

Increased glycated albumin and decreased esRAGE levels are related to angiographic severity and extent of coronary artery disease in patients with type 2 diabetes

OBJECTIVE This cross-sectional study aimed at evaluating the possible association of serum levels of glycated albumin (GA) and endogenous secretory RAGE (esRAGE) with angiographically significant coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM) and non-diabetic patients. METHODS Serum levels of GA, esRAGE, and inflammatory markers were measured in 1320 patients undergoing coronary angiography from three large districts in Shanghai. Patients were divided into four groups based on the presence/absence of T2DM and of significant CAD (diameter stenosis >or=70%). RESULTS Serum levels of GA, high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were significantly higher and, in contrast, serum esRAGE levels were lower in patients with both T2DM and significant CAD than in all other groups (all P<0.01), whereas there were no significant differences in GA and esRAGE levels between non-diabetic patients with CAD and those without. Serum GA and esRAGE levels correlated with angiographic CAD severity (P=0.031 and P=0.001), extent (both P<0.001) and number of diseased coronary arteries (both P<0.001) in diabetic CAD patients. At multivariable regression analysis, male gender, age, hypertension, cigarette smoking, HDL-C, lipoprotein (a), GA, esRAGE, hsCRP and TNF-alpha were all independent determinants of significant CAD in diabetic patients. Moreover, male gender, age, hypertension, lipoprotein (a), GA and esRAGE remained independently associated with three-vessel disease. CONCLUSION Patients with T2DM and CAD feature elevated serum GA and decreased serum esRAGE levels. Here serum GA and esRAGE levels are associated with angiographic extent and severity of CAD.

Increased glycated albumin and decreased esRAGE concentrations are associated with in-stent restenosis in Chinese diabetic patients.

BACKGROUND We investigated the impact of glycated albumin (GA) and endogenous secretory receptor for advanced glycation end products (esRAGE) and RAGE polymorphisms on occurrence of in-stent restenosis (ISR) in Chinese patients with type 2 diabetes. METHODS Four hundred nineteen patients with diabetes were divided, based upon the presence or absence of coronary artery disease (CAD) and ISR, into Group I (205 patients without CAD), Group II (128 patients with CAD but without ISR) and Group III (86 patients with ISR). One hundred fifty-two normal subjects were served as controls. Serum concentrations of GA and esRAGE were measured, and RAGE polymorphisms (-374T>A, -429T>C and G82S) were analyzed. RESULTS Serum GA concentration was higher and, in contrast, esRAGE concentration was lower in Group III than in the other groups (P<0.05). These two protein concentrations correlated closely with loss index (all P<0.01), and were independent risk factors for ISR in diabetic patients (P=0.01 and P=0.025, respectively). However, there were no differences in the allele and genotype frequencies in the 3 polymorphisms of RAGE gene between groups. CONCLUSIONS Increased GA and decreased esRAGE concentrations, but not -374T>A, -429T>C and Gly82Ser polymorphisms of RAGE gene, are associated with ISR in Chinese patients with type 2 diabetes.

C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis

AIMS We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1. METHODS AND RESULTS We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 μg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-α expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-α-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP(-/-) mice than in those from C57BL/6 mice. CONCLUSION C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice.

Glycated albumin is superior to hemoglobin A1c for evaluating the presence and severity of coronary artery disease in type 2 diabetic patients.

Objectives: This study aimed to compare the value of serum glycated albumin (GA) level versus glycated hemoglobin A1c (HbA1c) for evaluating the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). Methods: Serum GA and blood HbA1c levels were measured in 829 consecutive T2DM patients with or without angiographically documented significant CAD (≥70% diameter stenosis). Results: Serum GA levels were higher in diabetic patients with significant CAD than in those without (20.57 ± 4.23 vs. 19.00 ± 4.48%; p < 0.001), but HbA1c was similar in the two groups (7.74 ± 1.34 vs. 7.51 ± 1.37% p > 0.05). Compared to HbA1c, GA correlated more closely with the sum of significant stenotic lesions (r = 0.275, p < 0.001 and r = 0.092, p = 0.019) and the extent index (r = 0.375, p < 0.001 and r = 0.091, p = 0.019). The area under the curve of GA was larger than that of HbA1c for detecting the presence of significant CAD (0.637 vs. 0.568; p = 0.046) and 3-vessel disease (0.620 vs. 0.536; p = 0.039). GA, but not HbA1c, was independently associated with significant CAD. Conclusions: Serum GA level is a better indicator than HbA1c for evaluating the presence and severity of CAD and predicting major adverse cardiac events in patients with T2DM.

Glycation of Apoprotein A-I Is Associated With Coronary Artery Plaque Progression in Type 2 Diabetic Patients

OBJECTIVE To investigate whether glycation level of apoprotein (apo)A-I is associated with coronary artery disease (CAD) and plaque progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Among 375 consecutive type 2 diabetic patients undergoing quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS), 82 patients with nonsignificant stenosis (luminal diameter narrowing <30% [group I]) and 190 patients with significant CAD (luminal diameter stenosis ≥70% [group II]) were included for analysis of apoA-I glycation level and serum activity of lecithin: cholesterol acyltransferase (LCAT). The control group had 136 healthy subjects. At the 1-year follow-up, angiography and IVUS were repeated mainly in group II patients for plaque progression assessment. RESULTS Relative intensity of apoA-I glycation by densitometry was increased, and serum LCAT activity was decreased stepwise across groups control, I, and II. These two measurements were associated with the number of diseased coronary arteries and extent index in group II. During 1-year follow-up, QCA detected 45 patients with plaque progression in 159 subjects, and IVUS found 38 patients with plaque progression in 127 subjects. Baseline relative intensity of apoA-I glycation was significantly increased in patients with plaque progression compared with those without, with values associated with changes in QCA and IVUS measurements. Multivariable regression analysis revealed that baseline relative intensity of apoA-I glycation was an independent determinant of CAD and plaque progression in type 2 diabetic patients. CONCLUSIONS ApoA-I glycation level is associated with the severity of CAD and coronary artery plaque progression in type 2 diabetic patients.

Association of elevated apoA-I glycation and reduced HDL-associated paraoxonase1, 3 activity, and their interaction with angiographic severity of coronary artery disease in patients with type 2 diabetes mellitus

ObjectiveTo investigate whether apolipoprotein A (apoA)-I glycation and paraoxonase (PON) activities are associated with the severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM).MethodsRelative intensity of apoA-I glycation and activities of high-density lipoprotein (HDL)-associated PON1 and PON3 were determined in 205 consecutive T2DM patients with stable angina with (n = 144) or without (n = 61) significant CAD (luminal diameter stenosis ≥ 70 %). The severity of CAD was expressed by number of diseased coronary arteries, extent index, and cumulative coronary stenosis score (CCSS).ResultsThe relative intensity of apoA-I glycation was higher but the activities of HDL-associated PON1 and PON3 were lower in diabetic patients with significant CAD than in those without. The relative intensity of apoA-I glycation increased but the activities of HDL-associated PON1 and PON3 decreased stepwise from 1 - to 3 - vessel disease patients (P for trend < 0.001). After adjusting for possible confounding variables, the relative intensity of apoA-I glycation correlated positively, while the activities of HDL-associated PON1 and PON3 negatively, with extent index and CCSS, respectively. At high level of apoA-I glycation (8.70 ~ 12.50 %), low tertile of HDL-associated PON1 (7.03 ~ 38.97U/mL) and PON3 activities (7.11 ~ 22.30U/mL) was associated with a 1.97− and 2.49− fold increase of extent index and 1.73− and 2.68− fold increase of CCSS compared with high tertile of HDL-associated PON1 (57.85 ~ 154.82U/mL) and PON3 activities (39.63 ~ 124.10U/mL), respectively (all P < 0.01).ConclusionsElevated apoA-I glycation and decreased activities of HDL-associated PON1 and PON3, and their interaction are associated with the presence and severity of CAD in patients with T2DM.

Two-Dimensional Fluorescence In-Gel Electrophoresis of Coronary Restenosis Tissues in Minipigs Increased Adipocyte Fatty Acid Binding Protein Induces Reactive Oxygen Species–Mediated Growth and Migration in Smooth Muscle Cells

Objective—We aimed to uncover the protein changes of coronary artery in-stent restenosis (ISR) tissue in minipigs with and without streptozotocin-induced diabetes mellitus by quantitative 2-dimensional fluorescence in-gel electrophoresis (2D-DIGE), and to investigate the influences of crucial proteins identified, particularly adipocyte fatty acid binding protein (AFABP), in human arterial smooth muscle cells. Methods and Results—Sirolimus-eluting stents were implanted in the coronary arteries of 15 diabetic and 26 nondiabetic minipigs, and angiography was repeated after 6 months. The intima tissue of significant ISR and non-ISR segments in both diabetic and nondiabetic minipigs was analyzed by 2D-DIGE and MALDI-TOF/TOF mass spectrometry. AFABP level was significantly increased in ISR tissue than in non-ISR tissue in both diabetic and nondiabetic minipigs, with level being higher in diabetic ISR than in nondiabetic ISR tissue. In human arterial smooth muscle cells, overexpression of AFABP significantly altered phenotype and promoted growth and migration, with effects more prominent in high-glucose than in low-glucose medium, whereas AFABP knockdown inhibited these effects. AFABP overexpression increased reactive oxygen species production by upregulating the expression of NADPH oxidase subunits Nox1, Nox4, and P22 through multiple pathways, with elevation of downstream gene cyclin D1, matrix metalloproteinase-2, and monocyte chemoattractant protein-1. However, AFABP-induced effects were inhibited by diphenyleneiodonium, pathway inhibitors, and small interfering RNA. In addition, the supernatant from AFABP-expressing human arterial smooth muscle cells and recombinant AFABP also promoted cellular growth and migration. Conclusion—This study has demonstrated that AFABP is significantly increased in coronary artery ISR segments of both diabetic and nondiabetic minipigs. Increased AFABP expression and secretory AFABP of human arterial smooth muscle cells promote growth and migration via reactive oxygen species-mediated activation.

Reduced serum levels of vasostatin-2, an anti-inflammatory peptide derived from chromogranin A, are associated with the presence and severity of coronary artery disease

AIMS We here investigated the endothelial effects of the chromogranin A-derived peptide vasostatin-2 and its relation to coronary artery disease (CAD). METHODS AND RESULTS We assessed the impact of recombinant vasostatin-1 and vasostatin-2 on tumour necrosis factor-alpha (TNFα)-, angiotensin II-, and oxidized low-density lipoprotein (oxLDL)-induced expression of adhesion molecules in human arterial endothelial cells. Vasostatin-1 and vasostatin-2 levels were examined in coronary endarterectomy specimens (n= 23), atherosclerotic aortas (n= 16), non-significant-atherosclerotic internal mammary arteries (n= 30), and non-atherosclerotic aortas (n= 10), as well as in peripheral blood mononuclear cells (PBMCs) from severe CAD patients (n= 50) and healthy volunteers (n= 21). Serum levels of vasostatin-2 were analysed in 968 consecutive patients undergoing coronary angiography. Vasostatin-1 and vasostatin-2 concentration-dependently inhibited TNFα-, angiotensin II-, and oxLDL-induced expression of adhesion molecules; and attenuated TNFα-induced adhesion of U937 monocytes to endothelial cells. Vasostatin-2 levels were significantly decreased in endarterectomy samples and atherosclerotic aortas compared with non-atherosclerotic internal mammary arteries and aortas, as well as in PBMCs of severe CAD patients compared with healthy controls (all P< 0.05). Serum vasostatin-2 levels were significantly lower in CAD patients (diameter stenosis ≥ 50%, n= 554) than in controls (normal arteries or diameter stenosis <30%, n= 281) (P< 0.001). Its concentrations correlated with the number of diseased coronary arteries and Syntax score in CAD patients (all P< 0.05). At multivariable regression analysis, decreased vasostatin-2 levels remained associated with CAD when other variables were taken into account. CONCLUSION Vasostatin-2 has anti-inflammatory properties and is decreased in atherosclerotic plaque specimens and in PBMC of CAD patients. Decreased serum vasostatin-2 levels are associated with the presence and severity of CAD.

Dysregulation of matrix metalloproteinases and their tissue inhibitors is related to abnormality of left ventricular geometry and function in streptozotocin‐induced diabetic minipigs

This study aimed to characterize matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in relation to changes in left ventricle (LV) geometry and function in a porcine model with streptozotocin (STZ)‐induced diabetes. In 15 Chinese Guizhou minipigs with STZ‐induced diabetes (diabetic group) and 15 age‐matched normal controls (control group), Doppler tissue imaging was performed at 6 months of diabetes. Serum MMP‐2, ‐9, TIMP‐1, ‐4 and B‐type natriuretic peptide (BNP) were determined. Expression of MMPs, TIMPs, urokinase type‐plasminogen activator (uPA), its receptor (uPAR) and plasminogen activator inhibitor‐1 (PAI‐1) in aortic intima and LV myocardium was evaluated, with gelatinolytic activities of tissue MMP‐2, ‐9 accessed by zymography. Left ventricle end‐diastolic septum thickness (P < 0.05) and mass (P < 0.05) were increased, whereas peak systolic mitral annulus velocity (Sm, P < 0.001), LV systolic (P = 0.01) and diastolic strain (P < 0.001) were significantly decreased in diabetic group than in controls. Diabetic group showed higher expression of TIMP‐1, ‐4 in aortic intima and LV myocardium (P < 0.01 or P < 0.05), with increased collagen content and elevated serum BNP level (P = 0.004) and lower gelatinolytic activities of tissue MMP‐2, ‐9 (all P < 0.05). Semi‐quantitative RT‐PCR of those diabetic tissues revealed elevated mRNA levels of major TIMPs, uPA, uPAR and PAI‐1. Reduction of serum MMP‐2 and ‐9 levels was observed in diabetic group vs. control group (both P < 0.05). This study features elevated levels of TIMP‐1, ‐4, uPA, uPAR and PAI‐1, and decreased activities of MMP‐2, ‐9 in aorta and myocardium in STZ‐induced diabetic minipigs, indicating that MMP–TIMP dysregulation is associated with LV hypertrophy, cardiac dysfunction and increased cardiovascular fibrosis in diabetes.