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Due to advances in medical treatments, a substantial proportion of heart failure (HF) patients with reduced left ventricular ejection fraction (EF, HFrEF) have experienced partial or complete recovery of EF, termed HFrecEF, and markedly improved clinical outcomes. In the present study, we sought to investigate the relationship between glycemic control and the incidence of HFrecEF in hospitalized HFrEF patients with type 2 diabetes mellitus (T2DM).A total of 463 hospitalized T2DM patients with HFrEF were consecutively enrolled. Follow-up echocardiogram was performed after around 12 months. Patients who had an absolute EF improvement ≥10% and a second EF 40% were classified into HFrecEF, and those who did not meet these criteria were defined as persistent HFrEF.During the 12-month follow-up, 44.5% of T2DM patients developed HFrecEF. Patients with HFrecEF had significantly lower HbA1c level than those with persistent HFrEF (6.5% [IQR 5.8% ∼ 7.2%] vs. 6.7% [IQR 6.1% ∼ 7.8%], P = 0.003), especially in HF of an ischemic etiology. HbA1c levels were inversely correlated with changes in EF during follow-up. After multivariate adjustment, every 1% increase in HbA1c conferred a 17.4% (OR: 0.826 [95% CI 0.701-0.968]) lower likelihood of HFrecEF. Compared to patients with good glycemic control (HbA1c ≤ 6.2%), those with poor glycemic control (HbA1c 7.1%) had a 52.0% (OR: 0.480 [95% CI 0.281-0.811] decreased likelihood of HFrecEF.This study demonstrates that uncontrolled HbA1c level is associated with compromised development of HFrecEF in T2DM patients with HF, especially in those with an ischemic etiology.

Background Because of advances in medical treatments, a substantial proportion of patients with heart failure (HF) have experienced recovery of ejection fraction (EF), termed HF with recovered EF (HFrecEF). Insulin resistance (IR) is prevalent in HF and tightly related with prognosis. This study investigates the relationship between IR and the incidence of HFrecEF in patients who are nondiabetic. Methods and Results A total of 262 patients with HF with reduced EF (HFrEF) who were nondiabetic were consecutively enrolled. Patients were classified into HFrecEF (follow‐up EF>40% and ≥10% absolute increase) or otherwise persistent HFrEF based on repeat echocardiograms after 12 months. IR was estimated by an updated homeostasis model assessment for IR (HOMA2‐IR). The median HOMA2‐IR level was 1.05 (interquartile range [IQR], 0.67–1.63) in our cohort of patients with HF who were nondiabetic. During follow‐up, 121 (odds ratio [OR], 46.2% [95% CI 40.2–52.2]) patients developed HFrecEF. Compared with patients with HFrEF, patients with HFrecEF had significantly lower HOMA2‐IR levels (0.92 [IQR, 0.61–1.37] versus 1.14 [IQR, 0.75–1.78], P =0.007), especially in nonischemic HF. Log 2 ‐transformed HOMA2‐IR was inversely correlated to improvements in EF (Pearson's r =−0.25, P Conclusions This study reveals that IR is independently associated with compromised development of HFrecEF in patients who are nondiabetic.

Background The optimal strategy of percutaneous coronary intervention (PCI) for isolated left anterior descending (LAD) ostial lesions remains debatable. This study aimed to compare clinical outcomes of patients with isolated LAD ostial stenosis treated by single-stent crossover versus accurate ostial stenting. Methods A total of 216 eligible consecutive patients with isolated de novo LAD ostial stenosis were enrolled, and were stratified according to the stenting techniques. Clinical follow-up was performed by review of medical charts or telephone contact with the patients, and repeat angiography was made at 9-12 months after the procedure. Major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, non-fatal stroke and target vessel revascularization (TVR) were recorded. Results Single-stent crossover and accurate ostial stenting were applied to 78 (36%) and 138 (64%) patients, respectively. During a mean of 13 ± 4.1 months of follow-up, the rate of composite MACE (19.6 vs. 8.9%; P = 0.040) was higher in LAD ostial stenosis patients treated with accurate ostial stenting than those treated with single-stent crossover technique, mainly driven by more frequent TVR (17.4 vs. 7.7%; P = 0.048). PCI strategy was an independent predictor of MACE (hazard ratio 2.561; 95% CI, 1.041-6.299; P = 0.021) in the multivariable Cox regression analysis. Conclusions Our retrospective study suggests that the single-stent crossover technique is associated with a better 1-year clinical outcome compared with accurate ostial stenting in patients with isolated LAD ostial stenosis.

Background. Left ventricular (LV) diastolic dysfunction (LVDD) is the defining feature of heart failure with preserved ejection fraction (HFpEF) and predicts subsequent incident heart failure (HF) and all-cause mortality. Mounting evidence reveals that cardiometabolic risk factors play critical roles in the development of LVDD. In this study, we sought to investigate the relation between serum uric acid (SUA) level and the progression of LVDD in apparently healthy patients. Methods. A total of 1082 apparently healthy subjects without diagnosed cardiovascular disease and LVDD were consecutively enrolled. SUA levels were measured, and repeat echocardiography and tissue Doppler imaging (TDI) were performed at baseline and during 1-year follow-up. Results. By dividing the study population based on quartiles of SUA, we found subjects in higher quartiles had greater increases in TDI-derived early diastolic velocity (e ′ ) and E (peak LV filling velocity)/e ′ ratios during 1-year follow-up. After multivariate adjustment, high SUA persisted to be an independent predictor for the subsequent worsening of LVDD (odds ratio: 1.351 [95% CI 1.125~1.625], per 100 μmol/L SUA). Subgroup analysis suggested that the association between SUA and LVDD development was more pronounced in subjects without other cardiometabolic risk factors involved. Factor analysis demonstrated that high SUA was the major cardiometabolic attribute in patients with LVDD progression. Conclusion. Our findings suggest that high SUA is an independent cardiometabolic risk factor for the progression of LVDD in apparently healthy subjects.

High-density lipoprotein (HDL) confers protection against cardiovascular disease partly attributable to its robust anti-oxidant activities, which is largely impaired in diabetic conditions. In this study, we analyzed the anti-oxidant activity of HDL, as represented by the arylesterase activity of paraoxonase 1 (PON1) in HDL particles, in 216 consecutive HF patients with (n = 79) or without (n = 137) type 2 diabetes, and age- and gender-matched 112 diabetic and 189 non-diabetic non-HF controls. We found arylesterase activity was significantly decreased in patients with than without HF, and was further decreased when comorbid with diabetes. After adjusting for conventional risk factors and apolipoprotein A-I levels, arylesterase activity remained correlated positively with left ventricular ejection fraction in diabetic (r = 0.325, P = 0.020) but not non-diabetic patients (r = 0.089, P = 0.415), and negatively with NT-proBNP and NYHA functional class in both subgroups. In regression analyses, a higher risk of HF was observed in diabetic than non-diabetic patients when having low arylesterase activities. In conclusion, our data demonstrate that impaired serum arylesterase activity in patients with HF is further reduced when comorbid with diabetes. The relationship of impaired arylesterase activity to HF is especially enhanced in diabetic patients.

Background Patients with type 2 diabetes mellitus (T2DM) are predisposed to poor cardiovascular outcomes after ST-segment elevation myocardial infarction (STEMI). Left ventricular adverse remodeling (LVAR) triggered upon myocardial infarction is recognized as the predominant pathological process in the development of heart failure. In the present study, we sought to investigate whether visit-to-visit fasting plasma glucose (FPG) variability is a potential predictor of LVAR in T2DM patients after STEMI. Methods From January 2014 to December 2018 in Ruijin Hospital, T2DM patients with STEMI who underwent primary percutaneous coronary intervention were consecutively enrolled and followed up for ~ 12 months. The changes in left ventricular geometric and functional parameters between baseline and 12-month follow-up were assessed by echocardiography. The incidence of LVAR, defined as 20% increase in indexed left ventricular end-diastolic volume (LVEDV), and its relationship with visit-to-visit FPG variability were analyzed. Multivariate regression models were constructed to test the predictive value of FPG variability for post-infarction LVAR. Results A total of 437 patients with type 2 diabetes and STEMI were included in the final analysis. During a mean follow-up of 12.4 ± 1.1 months, the incidence of LVAR was 20.6% and mean enlargement of indexed LVEDV was 3.31 ± 14.4 mL/m2, which was significantly increased in patients with higher coefficient variance (CV) of FPG (P = 0.002) irrespective of baseline glycemic levels. In multivariate analysis, FPG variability was independently associated with incidence of post-infarction LVAR after adjustment for traditional risk factors, baseline HbA1c as well as mean FPG during follow-up (OR: 3.021 [95% CI 1.081–8.764] for highest vs. lowest tertile of CV of FPG). Assessing FPG variability by other two measures, including standard deviation (SD) and variability independent of the mean (VIM), yielded similar findings. Conclusions This study suggests that visit-to-visit FPG variability is an independent predictor of incidence of LVAR in T2DM patients with STEMI. Trial registration Trials number, NCT02089360; registered on March 17,2014.

Background To assess the prognostic role of coronary collaterals in patients with type 2 diabetes mellitus (T2DM) after successful percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). Methods Coronary collateralization was graded according to Rentrop scoring system in 198 type 2 diabetic patients and 335 non-diabetics with stable angina undergoing PCI for at least one CTO lesion. Left ventricular ejection fraction (LVEF) was determined and major adverse cardio-cerebral events (MACCE) were recorded during follow-up. Results Poor collateralization was more common in patients with T2DM than in non-diabetics (40% vs 29%, p = 0.008). At 13.5 ± 4.1 months, the rate of composite MACCE (17.3% vs 27.6%, p = 0.034) and repeat revascularization (15.2% vs 25.5%, p = 0.026) was lower and the increase in LVEF (3.10% vs 1.80%, p = 0.024) was greater in patients with good collaterals than in those with poor collaterals for non-diabetic group. The associations were in the same direction for T2DM group (35% vs 44%; 30% vs 36%; 2.14% vs 1.65%, respectively) with a higher all-cause mortality in diabetic patients with poor collaterals (p = 0.034). Multivariable Cox proportional hazards analysis showed that coronary collateralization was an independent factor for time to MACCE (HR 2.155,95% CI 1.290–3.599, p = 0.003) and repeat revascularization (HR 2.326, 95% CI 1.357–3.986, p = 0.002) in non-diabetic patients, but did not enter the model in those with T2DM. Conclusions T2DM is associated with reduced coronary collateralization. The effects of the status of coronary collateralization on long-term clinical outcomes and left ventricular function appear to be similar in size in type 2 diabetic patients and non-diabetics after successful recanalization of CTO.

Background Patients with type 2 diabetes are under substantially higher risk of in-stent restenosis (ISR) after coronary stent implantation. We sought to investigate whether visit-to-visit HbA1c variability is a potential predictor of ISR in diabetic patients after stent implantation. Methods We consecutively enrolled type 2 diabetic patients who underwent successful elective percutaneous coronary intervention and performed follow-up coronary angiography after around 12 months. The incidence of ISR and its relationship with visit-to-visit HbA1c variability, expressed as coefficient of variation (CV), standard deviation (SD) and variability independent of the mean (VIM), were studied. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of HbA1c variability for ISR. Results From September 2014 to July 2018 in Ruijin Hospital, a total of 420 diabetic patients (688 lesions) after stent implantation were included in the final analysis. During a mean follow-up of 12.8 ± 1.3 months, the incidence of ISR was 8.6%, which was significantly increased in patients with higher CV of HbA1c (P = 0.001). The mean diameter stenosis (DS), net luminal loss and net luminal gain were 22.9 ± 16.8%, 0.42 ± 0.88 mm and 1.66 ± 0.83 mm, respectively. Greater DS was observed in subjects with higher tertiles of CV of HbA1c (P

Background Controversies exist regarding the optimal blood pressure (BP) level that is safe and provides cardiovascular protection in patients with type 2 diabetes mellitus (T2DM) and coexistent coronary artery disease. Several new glucose-lowering agents have been found to lower BP as well, making the interaction between BP and T2DM even more complex. Methods With the reference to recent literature, this review article describes the potential mechanisms of increased risk of hypertension in T2DM and outlines the possible optimal BP levels based upon recommendations on the management of hypertension by the current guidelines, in combination with our research findings, for type 2 diabetic patients with coronary artery disease. Results The development of hypertension in T2DM involves multiple processes, including enhanced sympathetic output, inappropriate activation of renin-angiotensin- aldosterone system, endothelial dysfunction induced through insulin resistance, and abnormal sodium handling by the kidney. Both AGE-RAGE axis and adipokine dysregulation activate intracellular signaling pathways, increase oxidative stress, and aggravate vascular inflammation. Pancreatic β-cell specific microRNAs are implicated in gene expression and diabetic complications. Non-pharmacological intervention with lifestyle changes improves BP control, and anti-hypertensive medications with ACEI/ARB, calcium antagonists, β-blockers, diuretics and new hypoglycemic agent SGLT2 inhibitors are effective to decrease mortality and prevent major adverse cardiovascular events. For hypertensive patients with T2DM and stable coronary artery disease, control of BP Conclusions Hypertension and T2DM share certain similar aspects of pathophysiology, and BP control should be individualized to minimize adverse events and maximize benefits especially for patients with T2DM and coronary artery disease.

Background Adverse cardiac remodeling after ST-segment elevation myocardial infarction (STEMI) is a major cause for poor cardiovascular outcomes such as heart failure. The predisposing factors and underlying mechanisms remain not fully understood. This study investigates the association of insulin resistance and dysglycemia with left ventricular (LV) remodeling after STEMI in non-diabetic patients. Methods A total of 485 non-diabetic subjects with STEMI who underwent primary percutaneous coronary intervention were consecutively enrolled and followed up for 12 months. Relation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and glucose levels to changes in echocardiography parameters was studied. Results Left ventricular dilation was detected in 49.1% of subjects at 12-month follow-up after STEMI, and was more severe in subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and high HOMA-IR levels. HOMA-IR remained correlated to changes in LV dimensions after adjusting for confounding risk factors. Multivariate regression analysis demonstrated that higher HOMA-IR was independently associated with greater LV dilation after STEMI. A significant interaction term was present between HOMA-IR and IGT in the model (P = 0.001). Conclusions Our study reveals that insulin resistance and dysglycemia are prevalent in non-diabetic patients with STEMI and are predictors of the post-infarction LV dilation. Trial registration Trials number, NCT02089360; registered on March 17, 2014

Background We investigated whether or to what extent the interaction of lipoprotein (a) [Lp(a)] with cholesterol-containing lipids was associated with angiographic coronary collateralization in type 2 diabetic patients with chronic total occlusion. Methods Serum levels of Lp(a), total cholesterol, low-density lipoprotein–cholesterol (LDL-C), high-density lipoprotein–cholesterol (HDL-C), and triglyceride were determined and non-HDL-C was calculated in 706 type 2 diabetic and 578 non-diabetic patients with stable coronary artery disease and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3). Results For diabetic and non-diabetic patients, Lp(a), total cholesterol, LDL-C, and non-HDL-C levels were higher in patients with poor coronary collateralization than in those with good collateralization, whereas HDL-C and triglyceride levels were similar. After adjustment for potential confounding factors, tertiles of Lp(a), total cholesterol, LDL-C and non-HDL-C remained independent determinants for poor collateralization. A significant interaction between Lp(a) and total cholesterol, LDL-C or non-HDL-C was observed in diabetic patients (all P interaction

Objective This study aimed to evaluate the relationship between coronary collateralization and in-stent restenosis (ISR) in stable coronary artery disease patients with chronic total occlusion (CTO) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation. Methods The degree of coronary collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded according to Rentrop classification in 216 patients with stable angina undergoing successful DES based PCI for CTO. Univariable and multivariable logistic regression analyses were performed to assess the potential factors related to angiographic ISR during follow-up. Results Despite similar number of diseased coronary arteries, good collateralization (Rentrop score 2 or 3) was more frequently associated with right coronary artery occlusion (60%), whereas poor collaterals (Rentrop score 0 or 1) occurred more often in left anterior descending artery occlusion (40%). Despite similar number of CTO intervened, stent length was longer in patients with good collateralization (59±27mm vs 47±23mm, p =0.001). At mean 18months, the rate of ISR did not significantly differ between patients with good collateralization and those with poor collateralization (12.7% vs 20.2%, p =0.148). At multivariable analysis, age (OR 1.058, 95%CI 1.015–1.104, p =0.008), history of diabetes mellitus (OR 2.382, 95%CI 1.109–5.116, p =0.026) and reference CTO vessel diameter (OR 0.219, 95% CI 0.051–0.951, p =0.043) were independent risk factors for ISR while Rentrop collateral grade (OR 0.795, 95% CI 0.365–1.732, p =0.414) was not associated with ISR. Conclusions The occurrence of ISR after successful DES based PCI for CTO may be not influenced by coronary collateralization.

Mimecan/osteoglycin is identified as an emerging biomarker of coronary atherosclerosis. We investigated whether and to what extent serum mimecan reflects angiographic coronary collateralization in patients with stable coronary artery disease and chronic total occlusion.Serum levels of mimecan were determined in 559 consecutive patients with stable angina and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3).Serum mimecan was significantly higher in patients with poor collateralization than in those with good collateralization, and correlated inversely with Rentrop score (adjusted Spearmen's r = -0.443, p 0.001). The prevalence of poor coronary collaterals increased stepwise from the lowest to the highest quartile of serum mimecan (OR 2.140, 95% CI 1.793-2.555; p for trend 0.001). After adjusting for age, gender, traditional risk factors for coronary artery disease, history of myocardial infarction, severity of coronary artery disease, renal function and C-reactive protein, serum mimecan (per SD) remained an independent determinant for poor collateralization (OR 2.674, 95% CI 2.057-3.475, p 0.001). The diagnostic value of mimecan (per SD) for detecting poor collateralization was consistent when the patients were specified by gender, age, body mass index, presence or absence of hypertension and diabetes, and status of renal function (OR 2.075-6.932, p interaction ≥ 0.059).Increased serum mimecan is associated with poor angiographic coronary collateralization in patients with chronic total occlusion.

It is thought that carbamylated modification plays a crucial role in the development and progression of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). However, information on the biological effects of carbamylated high-density lipoprotein (C-HDL) in ESRD is poor. The present study investigated the carbamylation level of HDL in ESRD and the effects of C-HDL on endothelial repair properties. HDL was isolated from healthy control subjects ( n = 22) and patients with ESRD ( n = 30). The carbamylation level of HDL was detected using ELISA. Isolated C-HDL for use in tissue culture experiments was carbamylated in vitro to a similar extent to that observed in ESRD. Human arterial endothelial cells were treated with C-HDL or native HDL to assess their migration, proliferation, and angiogenesis properties. HDL-associated paraoxonase 1 activity was also determined by spectrophotometry assay. Compared with healthy control subjects, the carbamylation level of HDL in ESRD patients was increased and positively correlated with blood urea concentration. In vitro, C-HDL significantly inhibited migration, angiogenesis, and proliferation in endothelial cells. Mechanistic studies revealed that HDL-associated paraoxonase 1 activity was decreased and negatively correlated with the carbamylation level of HDL in ESRD patients. In addition, C-HDL suppressed the expression of VEGF receptor 2 and scavenger receptor class B type I signaling pathways in endothelial cells. In conclusion, the present study identified a significantly increased carbamylation level of HDL in ESRD. Furthermore, C-HDL inhibited endothelial cell repair functions.

The present study aimed to investigate the relationship between serum levels of secretory vimentin and coronary artery disease (CAD). The biological effect of secretory vimentin was ascertained by experiments.We analysed serum levels of secretory vimentin in CAD patients (n = 288) and non-CAD controls (n = 195) by ELISA. To evaluate the pro-inflammatory effects of secreted vimentin, the human aortic endothelial cells (HAECs) and human peripheral blood mononuclear cells (PBMCs) were treated with recombinant vimentin or saline. Intraperitoneal injection of vimentin (1 μg/each) or saline was performed every other day for 12 weeks in ApoESerum levels of secretory vimentin were significantly increased in CAD patients than in health controls (p 0.05), and correlated with the number of diseased coronary arteries, Syntax and Gensini score (for all comparison, p 0.01). Logistic regression analysis showed that vimentin level is an independent determinant of CAD. In experiments, recombinant vimentin protein enhanced the expression of adhesion molecules and inflammatory cytokines in both endothelial cells and macrophages. This protein also promoted macrophage-endothelial cells adhesion in vitro and the recruitment of leukocytes to mesenteric venules in C57BL/6 mice. Compared with saline, intraperitoneal injection of recombinant vimentin (1 μg/each) every other day induced atherogenesis in ApoESerum vimentin levels are associated with the presence and the severity of CAD. Vimentin protein promotes atherogenesis in ApoE

Background Negative coronary artery remodeling is frequent in patients with diabetes, but its mechanism remains unclear. We here evaluated the association of serum levels of glycated albumin (GA) and endogenous secretory receptor for advanced glycation end products (esRAGE) with coronary artery remodeling in type 2 diabetic patients. Methods Serum levels of GA and esRAGE were measured and intravascular ultrasound was performed in 136 consecutive diabetic patients with 143 coronary intermediate lesions. The remodeling index (RI) was calculated as the ratio between external elastic membrane (EEM) area at the lesion site and EEM area at the reference segment. Negative remodeling (NR) was defined as an RI

Increased transcytosis of low-density lipoprotein (LDL) across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined.Expression of CTRP5 was analyzed in sera and atherosclerotic plaques of patients with coronary artery disease (CAD). The role of CTRP5 in atherogenesis was investigated in vitro and in vivo.We found CTRP5 serum levels were higher in patients with than without CAD (247.26 ± 61.71 vs. 167.81 ± 68.08 ng/mL, p 0.001), and were positively correlated with the number of diseased vessels (Spearman's r = 0.611, p 0.001). Increased expression of CTRP5 was detected in human coronary endarterectomy specimens as compared to non-atherosclerotic arteries. Immunofluorescence further showed that CTRP5 was predominantly localized in the endothelium, infiltrated macrophages and smooth muscle cells in the neointima. In vivo and in vitro experiments demonstrated that CTRP5 promoted transcytosis of LDL across endothelial monolayers, as well as the oxidative modification of LDL in endothelial cells. Mechanistically, we found that CTRP5 up-regulated 12/15-lipoxygenase (LOX), a key enzyme in mediating LDL trafficking and oxidation, through STAT6 signaling. Genetic or pharmacological inhibition of 12/15-LOX dramatically attenuated the deposition of oxidized LDL in the subendothelial space and the development of atherosclerosis.These data indicate that CTRP5 is a novel pro-atherogenic cytokine and promotes transcytosis and oxidation of LDL in endothelial cells via up-regulation of 12/15-LOX.

Background We investigated whether and to what extent stenosis of predominant collateral donor artery (PCDA) affects coronary collateral flow in relation to blood pressure (BP) in type 2 diabetic patients with chronic total occlusion (CTO). Methods Collateral flow index (CFI) as derived from intracoronary pressure distal to occluded segment and mean aortic pressure in 220 type 2 diabetic patients and 220 propensity score matched non-diabetic controls undergoing percutaneous coronary intervention for CTO. The severity of PCDA stenosis was graded according to lumen diameter narrowing. Results CFI decreased stepwise from mild to severe stenosis of the PCDA and was lower in diabetic patients with moderate or severe PCDA stenosis than in non-diabetic controls (0.36 ± 0.10 vs. 0.45 ± 0.08, P

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 (GA) and the endogenous secretory receptor for advanced glycation endproducts (esRAGE) may modulate risk related to atherosclerosis. We tested the hypothesis that elevated GA and reduced esRAGE in serum are associated with adverse clinical outcomes in patients with type 2 diabetes and stable coronary artery disease (CAD).We determined GA and esRAGE serum levels in 576 consecutive patients with type 2 diabetes and stable CAD undergoing sirolimus-eluting stent (SES)-PCI. The primary endpoint was the incidence of major adverse cardio-cerebral events (MACCE) including cardiac death, non-fatal myocardial infarction, and non-fatal stroke during a 2-year follow-up. The secondary endpoint was the occurrence of clinically driven repeat revascularization during a 2-year follow-up. The prognostic value of GA and esRAGE was determined with the Cox-proportional hazard model after adjustment for covariates.A total 40 patients (6.9%) experienced MACCE, and 108 (18.8%) patients underwent repeat coronary revascularization during the follow-up. Serum GA (HR=1.22, 95% CI 1.16-1.28; HR=1.15, 95% CI 1.11-1.19, respectively; for both p0.001) and esRAGE (HR=0.60, 95% CI 0.40-0.87; HR=0.75, 95% CI 0.61-0.92, respectively; for both p0.01) levels remained independent predictors of the primary and secondary endpoints after adjustment for possible confounders.Serum GA and esRAGE are novel predictors of long-term clinical outcomes in patients with type 2 diabetes and stable CAD. Increased serum GA and decreased esRAGE are associated with a poor prognosis in such patients.

As one of the members of the PLC family, the phosphoinositide-specific phospholipase Ce (PLCe) has been shown to play pivotal roles in multiple signal pathways and control a variety of cellular functions. A number of studies have shown that aberrant regulation of PLCe was involved in various types of animal and human cancer. However, the role of PLCe in cancer remains elusive. In this review, we provide an overview of the PLCe, especially its roles in multiple signal pathways, and summarize the recent findings that highlight the roles of PLCe in carcinogenesis and cancer progression, making an avenue to provide a novel therapeutic strategy for the treatment of cancer. A literature search mainly paying attention to the network of PLCe involved in tumorigenesis and development was performed in electronic databases. PLCe plays a key role in medicating the development and progression of human cancers with highest potency to be a target of cancer prevention and treatment.

Stanniocalcin (STC), first isolated from the corpuscles of stannius of teleost fishes, was originally known for its regulation on calcium/phosphate transport. Increasing evidence demonstrates that STCs display the important function in some physiological and pathological behaviors such as calcium regulation, oxidative stress, anti-inflammation, angiogenesis, ischemia reperfusion, nerve diseases, etc. Moreover, STCs are implicated in the development and progression of multiple malignancies through promoting cell growth, proliferation, invasion, metastasis, and apoptotic escape. Some studies have shown that NF-κB upregulates STC expression, thereby activating the downstream HIF-1/ERK1/2 signaling pathway, enhancing the transcriptional activity of tumor-related factors (MMP-2/9, cyclinD1, Bcl-2, N-cadherin, etc) and contributing to tumorigenesis. Here, this brief review describes recent progress of STCs in mammalians, focused mainly on their critical functions in cancer.

Background The extent of coronary collateral formation is a primary determinant of the severity of myocardial damage and mortality after coronary artery occlusion. Type 2 diabetes mellitus (T2DM) represents an important risk factor for impaired collateral vessel growth. However, the mechanism of reduced coronary collateralization in type 2 diabetic patients remains unclear. Methods With the reference to the recent researches, this review article describes the pathogenic effects of T2DM on collateral development and outlines possible clinical and biochemical markers associated with reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion (CTO). Results Diffuse coronary atherosclerosis in T2DM reduces pressure gradient between collateral donor artery and collateral recipient one, limiting collateral vessel growth and function. An interaction between advanced glycation end-products and their receptor activates several intracellular signaling pathways, enhances oxidative stress and aggravates inflammatory process. Diabetic condition decreases pro-angiogenic factors especially vascular endothelial growth factor and other collateral vessel growth related parameters. Numerous clinical and biochemical factors that could possibly attenuate the development of coronary collaterals have been reported. Increased serum levels of glycated albumin, cystatin C, and adipokine C1q tumor necrosis factor related protein 1 were associated with poor coronary collateralization in type 2 diabetic patients with stable coronary artery disease and CTO. Diastolic blood pressure and stenosis severity of the predominant collateral donor artery also play a role in coronary collateral formation. Conclusions T2DM impairs collateral vessel growth through multiple mechanisms involving arteriogenesis and angiogenesis, and coronary collateral formation in patients with T2DM and CTO is influenced by various clinical, biochemical and angiographic factors. This information provides insights into the understanding of coronary pathophysiology and searching for potential new therapeutic targets in T2DM.

Aims Impaired anti-inflammatory ability of high-density lipoprotein (HDL) has been demonstrated in patients with type-2 diabetes mellitus (T2DM). However, whether HDL from patients with diabetic nephropathy (DN) suffers additional damage remains unknown. This study compared the anti-inflammatory capacities of HDL from healthy controls, T2DM patients with normal renal function, and T2DM patients with DN. Materials and methods HDL was isolated from healthy controls (n=33) and T2DM patients with normal renal function (n=21), chronic kidney disease (CKD) (n=27), and end-stage renal disease (ESRD) (n=27). Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers were pretreated with HDL (100μg/mL) for 1h, then incubated with lipopolysaccharide (LPS) (50ng/mL) for 24h. The anti-inflammatory ability of HDL was measured as the secretion of TNF-α in LPS-activated monocytes. Results The anti-inflammatory ability of HDL was gradually impaired as kidney function declined. Serum amyloid A (SAA) concentration in HDL DN significantly increased and was positively correlated with the impaired anti-inflammatory ability of HDL (Pearson r=0.315, P=0.006). Furthermore, HDL supplemented with SAA significantly increased TNF-α release from PBMCs compared with that from control HDL. Conclusions These findings identified an impaired anti-inflammatory capacity of HDL from DN patients, which might be attributable to SAA enrichment.

Background Nonenzymatic glycation of apolipoproteins plays a role in the pathogenesis of the vascular complications of diabetes. Objectives This study investigated whether apolipoprotein (apo) A-IV was glycated in patients with type 2 diabetes mellitus (T2DM) and whether apoA-IV glycation was related to coronary artery disease (CAD). The study also determined the biological effects of glycated apoA-IV. Methods The authors consecutively enrolled 204 patients with T2DM without CAD (Group I), 515 patients with T2DM with CAD (Group II), and 176 healthy subjects (control group) in this study. ApoA-IV was precipitated from ultracentrifugally isolated high-density lipoprotein, and its glycation level was determined based on Western blotting densitometry (relative intensity of apoA-IV glycation). ApoA-IV NƐ-(carboxylmethyl) lysine (CML) modification sites were identified by mass spectrometry in 37 control subjects, 63 patients in Group I, and 138 patients in Group II. Saline or glycated apoA-IV (g-apoA-IV) generated by glyoxal culture was injected into apoE –/– mice to evaluate atherogenesis, and was also used for the cell experiments. Results The relative intensity and the abundance of apoA-IV glycation were associated with the presence and severity of CAD in patients with T2DM (all p –/– mice through the nuclear receptor NR4A3. G-apoA-IV with mutations (K-A) at high-frequency glycation sites exhibited more weakened proinflammatory and atherogenic effects than did g-apoA-IV both in vitro and in vivo. Conclusions ApoA-IV glycation is associated with CAD severity in patients with T2DM, and g-apoA-IV induces atherogenesis through NR4A3 in apoE –/– mice.

Background Sirolimus-eluting stents (SES) with a biodegradable polymer coating have demonstrated promising results but have not been compared to SES with a durable polymer in high-risk patients. We compared the efficacy of these 2 stent types in patients with acute myocardial infarction (STEMI). Methods One thousand one hundred ninety-two STEMI patients were randomized to receive SES coated with biodegradable (n = 596) or durable polymer (n = 596). The study end-point was the composite of major adverse cardiac events (MACE) including all-cause death, recurrent myocardial infarction (MI), or target lesion revascularization (TLR) at 1-year follow-up. Secondary end-points included individual components of primary end-point and stent thrombosis. Results Compared with durable polymer SES, the noninferiority of SES with biodegradable polymer coating was established by an absolute risk difference of 0.9% in the primary end-point (12.4% vs. 13.3%, P = 0.67) and an upper limit of one-sided 95% confidence interval (CI) of 2.96% (P for noninferiority = 0.001). Rate of death, recurrent MI, and TLR were 7.9% and 8.6% (HR: 0.92; 95% CI: 0.61–1.38, P = 0.67), 2.9% and 3.5% (HR: 0.80; 95% CI: 0.42–1.54, P = 0.51), and 2.0% and 3.2% (HR: 0.62; 95% CI: 0.30–1.30, P = 0.20) in the biodegradable polymer SES and durable polymer SES group at 1-year clinical follow-up, respectively. Despite similar rates of 30-day ARC definite/probable stent thrombosis, late stent thrombosis (stent thrombosis occurring beyond 30 days) was lower with biodegradable polymer SES (0.7% vs. 2.2%, P = 0.028). Conclusions In patients undergoing primary PCI for STEMI, the use of biodegradable polymer SES was associated with noninferior 1-year rates of MACE compared with durable polymer SES. (J Interven Cardiol 2014;27:131–141)

BACKGROUND The present study investigated whether serum levels of soluble vascular endothelial growth factor receptor (sVEGFR)-1, -2 and -3 are related to poor coronary collateralization in patients with stable coronary artery disease (CAD). METHODS AND RESULTS Serum levels of sVEGFR-1, -2, -3, VEGF, and placental growth factor (PLGF) were determined in 403 consecutive patients with angiographic total or subtotal occlusion of at least 1 major coronary artery. The degree of collateralization was graded according to the Rentrop scoring system. Low (Rentrop score of 0 or 1) and high (Rentrop score of 2 or 3) coronary collateralization occurred in 161 and 242 patients, respectively. Serum levels of sVEGFR-1 and -2 were significantly elevated, in contrast, VEGF and PLGF levels were remarkably decreased in patients with low collateralization than in those with high collateralization (all P

Background Glycated albumin (GA) has been shown to be a better indicator than glycosylated hemoglobin A1c (HbA1c) in terms of severity of renal impairment in patients with type 2 diabetes mellitus (T2DM). This study aimed to determine whether elevated serum GA levels are associated with an increased risk for contrast-induced acute kidney injury (CI-AKI) and worse clinical outcome in patients with T2DM and at least moderate renal insufficiency (RI) undergoing coronary angiography. Methods Serum levels of fasting blood glucose (FBG), HbA1c and GA were measured in 1030 patients with T2DM and moderate to severe RI (eGFR 15–59mL/min/1.73m 2 ). CI-AKI was defined as ≥25% increase in serum creatinine within 72h after the procedure. Receiver-operating characteristic curve was constructed to assess the predictive value of GA, HbA1c and FBG for CI-AKI. Multivariable logistic regression model was developed to identify risk factors for CI-AKI, and Kaplan–Meier curve analysis was used to compare the rates of dialysis and major adverse cardiac events (MACE) during one-year follow-up. Results The overall rate of CI-AKI was 11.1%. GA was significantly higher in patients with CI-AKI than in those without, and correlated positively with changes of renal function after the procedure. After adjusting for age, sex, left ventricular ejection fraction, multi-vessel disease, type and volume of contrast media, FBG, and HbA1c, GA remained an independent risk factor for CI-AKI. GA≥21% was associated with increased rates of dialysis and MACE during one-year follow-up in patients with or without CI-AKI. Conclusions Increased GA level serves as a valuable risk factor for CI-AKI and indicates poor one-year clinical outcome in patients with T2DM and moderate to severe RI.

Background We investigated whether an additional intracoronary tirofiban bolus administration following upstream intravenous treatment could further improve myocardial reperfusion and clinical outcome in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods A total of 453 eligible STEMI patients were randomly allocated to intracoronary bolus administration of tirofiban (10μg/kg; n=229) or saline (10mL; n=224) during primary PCI, followed by intravenous tirofiban infusion (0.15μg/kg/min) for 24–36h. Serum levels of P-selectin, vWF, CD40L and serum amyloid A (SAA) in the coronary sinus were measured before and after intracoronary bolus administration. The primary endpoint was ST-segment resolution (STR) at 90min after the procedure. Second endpoints included corrected TIMI frame count (cTFC), left ventricular volumes and ejection fraction (EF), and major adverse cardiac events (MACE) at 30-day and 6-month follow-up. Results Intracoronary tirofiban administration resulted in a higher rate of completed STR (59.0% vs. 44.6%, P=0.002), lower cTFC (21.6±5.4 vs. 23.7±7.8, P=0.048), and significantly reduced coronary sinus levels of P-selectin, vWF, CD40L and SAA. Patients treated with intracoronary tirofiban had a trend toward less MACE at 30days (3.1% vs. 6.7%, P=0.072). At 6months, left ventricular end-systolic volume was smaller, EF was higher and MACE-free survival was improved (96.1% vs. 90.6%, P=0.020) in the intracoronary tirofiban group. Conclusions An additional intracoronary tirofiban bolus administration following upstream intravenous treatment reduces coronary circulatory platelet activation and inflammatory process, and significantly improves myocardial reperfusion and left ventricular function as well as 6-month MACE-free survival for STEMI patients undergoing primary PCI.

The study sought to evaluate the safety and efficacy of FIREHAWK, a novel abluminal groove-filled biodegradable polymer sirolimus-eluting stent (SES) for treating patients with single de novo coronary lesions compared with the durable polymer everolimus-eluting stent (EES) XIENCE V.A total of 458 patients with single de novo native coronary lesions ≤24 mm in length and a coronary artery ≥2.25 to ≤4.0 mm in diameter were enrolled in the TARGET I study, a prospective, randomised, non-inferiority trial. The primary endpoint was in-stent late lumen loss (LLL) at nine-month follow-up. The secondary endpoint, target lesion failure (TLF), was defined as the composite of cardiac death, target vessel myocardial infarction (TVMI), or ischaemia-driven target lesion revascularisation (iTLR). Patients were centrally randomised to treatment with either biodegradable polymer SES (n=227) or durable polymer EES (n=231). The nine-month in-stent LLL of the biodegradable polymer SES was comparable to the EES group (0.13 ± 0.24 mm vs. 0.13 ± 0.18 mm, p=0.94; difference and 95% confidence interval 0.00 [-0.04, 0.04] mm; p for non-inferiority0.0001). Cardiac death (0.4% vs. 0.0%), TVMI (1.3% vs. 1.7%), iTLR (0.4% vs. 0.4%) and TLF (2.2% vs. 2.2%) were similar between the biodegradable polymer SES and durable polymer EES groups at 12-month follow-up (all p0.05). No definite/probable stent thrombosis was observed in both of these groups.In the multicentre TARGET I trial, the novel abluminal groove-filled biodegradable polymer SES FIREHAWK was non-inferior to the durable polymer EES XIENCE V with respect to the primary endpoint of in-stent LLL at nine months for treating patients with single de novo coronary lesions. The incidences of clinical endpoints were low in both of the stents at 12-month follow-up. (ClinicalTrials.gov identifier: NCT01196819).

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 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.

Background Cyanate has recently gained attention for its role in the pathogenesis of vascular injury. Nonetheless, the effect of cyanate on angiogenesis remains unclear. Methods and Results In this study, we demonstrated that oral administration of cyanate impaired blood perfusion recovery in a mouse hind‐limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of cyanate‐treated mice. Likewise, there were fewer capillaries in the ischemic hind‐limb tissue of cyanate‐exposed mice. Our in vitro study showed that cyanate, together with its carbamylated products, inhibited the migration, proliferation, and tube‐formation abilities of endothelial cells. Further research revealed that cyanate regulated angiogenesis partly by interrupting the vascular endothelial growth factor receptor 2/phosphatidylinositol 3‐kinase/Akt pathway. The serum concentrations of homocitrulline, a marker of cyanate exposure, were determined in 117 patients with stable angina and chronic total occlusion. Consistent with the antiangiogenic role of cyanate, homocitrulline levels were increased in patients with poor coronary collateralization (n=58) compared with those with high collateralization (n=59; 21.09±13.08 versus 15.54±9.02 ng/mL, P =0.009). In addition, elevated homocitrulline concentration was a strong predictor of poor coronary collateral growth. Conclusions Impaired angiogenesis induced by cyanate might contribute to poor coronary collateral growth.

Objective— In a previous study, we established diabetic and nondiabetic minipig models with coronary artery in-stent restenosis (ISR). Mass spectrometry showed that high-mobility group box (HMGB) 2 level was higher in ISR than in non-ISR tissue from diabetic minipigs. We here investigated whether serum HMGB2 levels were related to ISR in coronary artery disease patients. The effect of HMGB2 was evaluated in mice with femoral artery wire injury and in human aortic smooth muscle cells. Approach and Results— From 2513 patients undergoing coronary artery intervention and follow-up angiography at ≈1 year, 262 patients were diagnosed with ISR, and 298 patients with no ISR were randomly included as controls. Serum HMGB2 levels were significantly higher in patients with ISR than in those without ISR and were associated with ISR severity. Multivariable logistic regression analysis showed that HMGB2 level was independently associated with ISR. In experiments, HMGB2 expression was increased in vascular tissue after injury. Perivascular HMGB2 administration promoted injury-induced neointimal hyperplasia in C57Bl/6 mice compared with in the control, whereas such pathophysiological features were attenuated in Hmgb2 –/– mice. Mechanistically, HMGB2 enhanced neointimal hyperplasia in mice and proliferation and migration in human aortic smooth muscle cells by inducing reactive oxygen species through increased p47phox phosphorylation. Knocking down p47phox, however, inhibited HMGB2-induced effects in human aortic smooth muscle cells. Finally, HMGB2-induced effects were significantly declined in receptor of advanced glycation end products knockdown or deficient cells, but not in Toll-like receptor 4 knockdown or deficient cells. Conclusions— Serum HMGB2 levels were associated with ISR in patients. HMGB2 promoted neointimal hyperplasia in mice with arterial wire injury through reactive oxygen species activation.

Although high-density lipoprotein (HDL) can exhibit anti-inflammatory properties, these potent activities can become deficient and even transform into proinflammatory effects under various pathophysiological states. We investigated the effect of diabetic HDL on the inflammatory response in human monocytes and its relation to the existence of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM). HDL was isolated from DM patients with (n = 61) or without (n = 31) CAD (diameter stenosis ≥50%) and healthy controls (n = 40). Human peripheral blood mononuclear cells were incubated with HDL and the proinflammatory ability of HDL was determined by tumor necrosis factor-α (TNF-α) secretion in peripheral blood mononuclear cells. Secretion of TNF-α in human monocytes in response to diabetic HDL was significantly increased compared with that of the control HDL. Of note, HDL from DM patients with CAD stimulated the release of TNF-α in monocytes to a greater extent than that of HDL from those without CAD. Multiple linear regression analysis showed that the proinflammatory ability of HDL was independently associated with diabetes duration, hemoglobin A1c, serum levels of high-sensitivity C-reactive protein (hs-CRP) and reduced glomerular filtration rate (GFR). Furthermore, the proinflammatory ability of HDL was a significant predictor for the presence of CAD in patients with DM.

We investigated whether serum vasostatin-2 level is related to chronic heart failure (CHF) in patients with previous myocardial infarction (MI) and MACE in 3-year follow-up. The biological effect of vasostatin-2 on ischemic HF was evaluated in animal experiments.After exclusion of the subjects not eligible, this study included 450 patients with CHF and previous MI, and 149 healthy controls. Serum vasostatin-2 level was analyzed. CHF patients were followed up for three years and major adverse cardiac events (MACE) were recorded, defined as reinfarction, target-vessel revascularization, cardiovascular death and refractory HF requiring hospitalizations.Notably, serum vasostatin-2 level was decreased in CHF patients than in controls, and significant difference was observed between CHF patients with MACE and those without (both P0.05). Vasostatin-2 level was correlated with HF stages (Spearman's r=-0.288, P0.05), LVEF (r=0.377, P0.05) and pro-BNP level (r=-0.294, P0.05). Multivariable logistic regression analysis suggested that vasostatin-2, conventional risk factors, severity of HF stages and LVEF were independently associated with MACE in CHF patients. Vasostatin-2 (100μg) or PBS was injected intraperitoneally every other day in MI rats, follow by echocardiography, hemodynamic analysis after 2months. Compared with PBS, vasostatin-2 treatment prevented ischemic HF in MI rats, accompanied with reduction of infarct size, remodeling, fibrosis and inflammation, mainly through inhibition of Rho, Wnt and TLR-4 pathways and modulation of renin-angiotensin system.Decreased serum vasostatin-2 level is associated with ischemic CHF and with MACE in three-year follow-up. Intraperitoneal injection of vasostatin-2 protects against ischemic HF in MI rats.

We investigated whether serum level of C1q/TNF-related protein (CTRP) 5 is associated with in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation, and assessed the biological effects of CTRP5 in human aortic smooth muscle cells (hASMCs).Serum CTRP5 levels were assayed in 306 patients with and 306 patients without angiographic ISR at approximately one year after DES-based PCI. Multivariate logistic regression analysis was performed to determine risk factors for ISR. Notably, serum CTRP5 levels were higher in ISR patients than in non-ISR counterparts (197±84ng/mL vs. 150±74ng/mL, P0.001). Compared with the lowest tertile (125ng/mL) of CTRP5, patients with the mid (125-200ng/mL) and the highest tertile (200ng/mL) of CTRP5 had a more than 1.6-fold (adjusted OR=1.670-2.127, P≤0.039) and 7.4-fold (adjusted OR=7.478-11.264, all P0.001) increased risk of ISR (all P for trend0.001), respectively, after adjustment for potential clinical, biochemical and angiographic characteristics. To assess the biological effects of CTRP5, we stimulated hASMCs with this protein. CTRP5 concentration-dependently induced the expression of MMP-2, cyclin D1 and TNF-α in hASMCs, with activation of Notch1, TGF-β and hedgehog signaling pathways. Consistently, this protein promoted migration and proliferation of hASMCs in wound-healing, Boyden chamber and Brdu incorporation assay.Increased serum CTRP5 level is associated with ISR after PCI with DES implantation. CTRP5 promotes proliferation, inflammation and migration in vascular smooth muscle cells through activation of multiple pathways.

High-mobility group box (HMGB) family is related to inflammatory diseases. We investigated whether serum HMGB2 levels are related to myocardial infarction (MI) severity and major adverse cardiac events (MACE) during MI. We included 432 consecutive patients with ST-segment elevation myocardial infarction and 312 controls. Serum HMGB2 levels were significantly higher in MI patients than in controls. Increased HMGB2 levels were associated with MACE and negatively with ejection fraction in MI patients. HMGB2 was an independent determinant of MACE in logistic regression analysis. HMGB2 protein (10 μg) or saline was injected intramyocardially in MI rats, with or without coadministration of the NADPH oxidase inhibitor apocynin. After 72 h, pathological, echocardiographic, and hemodynamic examinations showed that HMGB2 increased infarct size and worsened cardiac function in MI rats. Moreover, HMGB2 administration enhanced reactive oxygen species (ROS) production, cell apoptosis, inflammation, and autophagosome clearance impairment, which were attenuated by coadministration of apocynin or knock down of receptor for advanced glycation end products (RAGE). In conclusion, increased serum HMGB2 levels are associated with MI severity and MACE at 1 mo. HMGB2 promotes myocardial ischemic injury in rats and hypoxic H9C2 cell damage via ROS provoked by RAGE.NEW & NOTEWORTHY We demonstrate that serum high-mobility group box 2 is associated with major adverse cardiac events at 1 mo in myocardial infarction patients. Mechanistically, high-mobility group box 2 promotes reactive oxygen species production via receptor for advanced glycation end products signaling in ischemic myocardium, thereby aggravating cell apoptosis, inflammation, and autophagosome clearance impairment. This study reveals that high-mobility group box 2 is a novel factor enhancing ischemic injury in myocardial infarction.

This study investigated the impact of elevated glycated albumin (GA) and reduced soluble receptor for advanced glycation end-products (sRAGE) and endogenous secretory receptor for advanced glycation end-products (esRAGE) levels in serum on the severity of albuminuria, occurrence of contrast-induced acute kidney injury (CI-AKI) and 1-year clinical outcome in type 2 diabetic patients undergoing sirolimus-eluting stent-based percutaneous coronary intervention.We compared serum levels of GA, sRAGE, esRAGE, and glycosylated hemoglobin (HbA1c), occurrence of CI-AKI, and major adverse cardiac events at 1-year clinical follow-up in 3 groups of type 2 diabetes based on 24-hour urinary albumin excretion: I = normoalbuminuria (30 mg; n = 190); II = microalbuminuria (30-300 mg; n = 102); and III = macroalbuminuria (≥ 300 mg; n = 86).Serum levels of GA and HbA1c increased step-wise from group I to III, and serum levels of sRAGE and esRAGE were decreased in the groups with albuminuria, with the lowest values in those with microalbuminuria. GA (Pearson's r = 0.264; P0.001), sRAGE (Pearson's r = -0.210; P0.001), esRAGE (Pearson's r = -0.145; P = 0.04), and HbA1c (Pearson's r = 0.214; P0.001) correlated significantly with urinary albumin excretion. After adjusting for confounding factors, GA, sRAGE, esRAGE, and albuminuria status remained independently associated with both CI-AKI and 1-year major adverse cardiac events.Elevated GA and reduced sRAGE and esRAGE levels in serum are associated with severity of albuminuria and postprocedural CI-AKI, and exert a negative impact on 1-year clinical outcome in patients with type 2 diabetes undergoing percutaneous coronary intervention with sirolimus-eluting stent implantation.

We aim to check if serum levels of receptor for advanced glycation endproduct (RAGE) ligands S100B, S100A6 and S100P were related to myocardial injury in acute coronary syndrome (ACS).Serum levels of S100B, S100A6, S100P, and soluble RAGE (sRAGE) were analyzed in 882 patients. Based upon clinical and laboratory findings, they were assigned into control (n=251), stable angina (n=211), and ACS (n=420). To verify clinical data of ACS, forty Sprague-Dawley rats were subjected to cardiac ischemia-reperfusion (I/R) injury by occluding proximal (large infarct size; n=20) or distal (small infarct size; n=20) left anterior descending coronary artery, and another 20 rats were in sham-operation group. The expressions of S100B, S100A6, S100P and RAGE in the myocardium were analyzed.Serum levels of S100B, S100A6 and S100P were higher in ACS group than in stable angina and control groups, and sRAGE levels were higher in ACS patients versus controls (all p0.01). S100B and S100P levels correlated significantly with CK-MB and troponin I levels in ACS group (all p0.05). In multivariable regression analysis, S100B, S100A6, S100P and conventional risk factors were independently associated with ACS. In animal models, the expressions of S100B, S100A6 and S100P were closely related to infarct size (all p0.05).This study indicates that serum levels of S100B, S100A6 and S100P are associated with ACS, and serum levels and myocardial expression of these proteins are related to infarct size.

Background— Traditional reperfusion options for patients with acute ST-segment elevation myocardial infarction (STEMI) presenting to non-primary percutaneous coronary intervention (PPCI)-capable hospitals generally include onsite fibrinolytics or emergency transfer for PPCI. A third option, involving interventionalist transfer, was examined in the REVERSE-STEMI study. Methods and Results— A total of 334 patients with acute STEMI who presented to 5 referral hospitals with angiographic facilities but without interventionalists qualified for PPCI were randomized to receive PPCI with either an interventionalist- (n=165) or a patient-transfer (n=169) strategy. The primary end point of door-to-balloon (D2B) time and secondary end points of left ventricular ejection fraction and major adverse cardiac events (MACE) at 1-year clinical follow-up were compared between the 2 groups. Compared with the patient-transfer strategy, the interventionalist-transfer strategy resulted in a significantly shortened D2B time (median, 92 minutes versus 141 minutes; P P P P =0.019). Multivariate Cox proportional hazards modeling revealed that the interventionalist-transfer strategy was an independent factor for reduced risk of composite MACE (hazard ratio, 0.63; 95% CI, 0.45 to 0.88; P =0.003). Conclusions— The interventionalist-transfer strategy for PPCI may be effective in improving the care of patients with STEMI presenting to a non-PPCI-capable hospital, particularly in a congested cosmopolitan region where patient transfers could be prolonged. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00713557.

We sought to examine if polymorphisms in the promoter region of YKL-40 gene (CHI3L1) are associated with serum YKL-40 levels and coronary artery disease (CAD) in Chinese patients.Three single nucleotide polymorphisms (SNPs) (-329GA, rs10399931; -247CT, rs10399805; -131GC, rs4950928) in the CHI3L1 promoter were determined in 213 consecutive patients with angiographically documented CAD (luminal diameter stenosis ≥50%) and 248 normal controls. Coronary cumulative obstruction score and number of diseased vessels represent the severity of CAD. Serum YKL-40 levels were assessed using an ELISA kit.Patients with CAD had remarkably higher serum YKL-40 levels compared to controls (p0.001). There was no difference in the allele, genotype and haplotype distribution of these three SNPs between controls and CAD patients. The minor alleles of CHI3L1-329GA and -131GC were significantly associated with decreased serum YKL-40 levels in both controls (p = 0.001 and p0.001, respectively) and CAD patients (p = 0.007 and p0.001, respectively), whereas CHI3L1-247CT had no appreciable effect. None of these genetic variants and haplotypes was associated with severity of angiographic CAD.CHI3L1-329GA and -131GC polymorphisms are associated with serum YKL-40 levels, but not with the prevalence or severity of CAD.

Objectives We investigated whether α2-adrenergic receptor (AR) polymorphisms (α2A-AR, α2B-AR and α2C-AR gene) affected silent myocardial ischemia (SMI) in patients with type 2 diabetes mellitus (T2DM). Design and methods Genetic polymorphisms were determined in 321 patients with T2DM and coronary artery disease (CAD). Among them, 129 patients experienced transient asymptomatic ST-depression during 24-hour ambulatory electrocardiogram (SMI group), and the remaining 192 patients who had ambulatory electrocardiogram-symptom matching angina were categorized as angina group. Results The genotype distribution and allele frequencies of α2B-AR gene polymorphism (insertion [I]/deletion[D]) exhibited significant difference between SMI group and angina group (both P

BACKGROUND: This study sought to examine whether circulatory levels of endothelial dysfunction biomarkers [vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1), sE-selectin, von Willebrand factor (vWF), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1)] are associated with occurrence of late or very late stent thrombosis (ST) after percutaneous coronary intervention with sirolimus-eluting stent implantation, and to assess the possible influence of genetic variants of these proteins on ST. METHODS: Serum levels of sVCAM-1, sICAM-1, sE-selectin, vWF, t-PA and PAI-1 were measured, and polymorphisms of vWF (-1234C/T, -1185A/G and -1051G/A), t-PA (insertion/deletion) and PAI-1 genes (4G/5G) were determined in 41 patients who experienced at least one episode of late or very late ST. Eighty-two patients without ST randomly selected from the same study period served as controls. RESULTS: Serum levels of vWF, sVCAM-1 and sICAM-1 were significantly increased in patients with ST than in controls (all P

OBJECTIVES This study aimed to evaluate the impact of angiographic and intravascular ultrasound (IVUS) features on clinical outcome in nondiabetic and type 2 diabetic patients after percutaneous coronary intervention (PCI) with sirolimus-eluting stent (SES) implantation. METHODS Repeat coronary angiography with IVUS imaging was performed after SES-based PCI for de-novo lesions in 128 diabetic and 327 nondiabetic patients (189 lesions and 504 lesions, respectively). The rate of major adverse cardiac events including cardiac death, non fatal myocardial infarction (MI), and target lesion revascularization during clinical follow-up was recorded. RESULTS In-stent and in-segment late loss, intimal hyperplasia volume, and percentage volumetric obstruction were similar, but stented external elastic membrane cross-sectional area and reference/stented segment ratio were lower in diabetic than in nondiabetic patients. Incomplete stent apposition (ISA) was less frequent, but occurrence of new coronary lesions was higher in diabetic than in nondiabetic patients. Despite similar target lesion revascularization, cumulative survival rates freedom from composite cardiac death and nonfatal MI or major adverse cardiac events were reduced in diabetic patients. Cox proportional hazards model identified diabetes, left ventricular ejection fraction, minimal stent CSA, maximal ISA area, atherosclerotic progression and lesion length as independent predictors of non fatal MI or mortality at follow-up. CONCLUSION In diabetic patients, PCI with SES implantation neutralizes the excess risk of intimal hyperplasia and decreases occurrence of ISA, but could not modify the propensity of increased adverse clinical outcomes at follow-up.

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.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 stenosisor=70%).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 P0.01), 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 P0.001) and number of diseased coronary arteries (both P0.001) 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.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.

Background We assessed the possible association of glycated albumin (GA) and circulatory adhesion molecules with diffuse coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). Methods Six hundred and two consecutive patients with CAD, based upon angiographic features and presence or absence of T2DM, were categorized as Group I (296 patients with non-diffuse CAD but no T2DM), Group II (138 patients with diffuse CAD but no T2DM), Group III (78 patients with non-diffuse CAD and T2DM) and Group IV (90 patients with diffuse CAD and T2DM). Serum levels of glycated albumin, adhesion molecules, endogenous secretory receptor of advanced glycation end products (esRAGE) and inflammatory factors were determined. Results Serum levels of GA, hsCRP, sVCAM-1, sICAM-1 and sE-selectin were increased, while esRAGE levels were decreased in diabetic patients than in non-diabetic patients (all P

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.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 (-374TA, -429TC and G82S) were analyzed.Serum GA concentration was higher and, in contrast, esRAGE concentration was lower in Group III than in the other groups (P0.05). These two protein concentrations correlated closely with loss index (all P0.01), 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.Increased GA and decreased esRAGE concentrations, but not -374TA, -429TC and Gly82Ser polymorphisms of RAGE gene, are associated with ISR in Chinese patients with type 2 diabetes.

Background Glycated albumin is the predominant circulating Amadori-type glycated protein in vivo and plays a major role in the development of diabetic vascular complications. The aim of this study was to assess the relationship between increased serum glycated albumin level and the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). Methods and Results In a total of 320 consecutive patients with T2DM, coronary angiography revealed normal coronary arteries in 83 patients (control group) and significant coronary stenosis (≥70% luminal diameter narrowing) in 237, of whom 51 patients had 1-vessel disease (Group I), 80 had 2-vessel disease (Group II), and 106 had 3-vessel disease (Group III). Serum glycated albumin, hemoglobin A1c (HbA1c) and tumor necrosis factor (TNF)-α levels, lipid profile, and renal function were measured. Logistic regression analysis was performed to determine the relative risk of serum glycated albumin level for the presence and severity of CAD. Multivariate stepwise linear regression analysis was done to identify independent determinants of the glycated albumin level. Serum glycated albumin (21.2±5.3% vs 19.4±4.3%, p=0.005) and TNF-α levels (123 ±115 pg/ml vs 65±59 pg/ml, p

Background and aims Macrophage is a major contributor to the development of atherosclerosis by taking up deposited lipoprotein and eliciting local inflammation. Previously, we and others have shown C1q/TNF-related proteins (CTRPs) play diverse roles in vascular functions. In this study, we sought to investigate the changes in CTRP expression levels during vital biological processes in macrophages and their relation to inflammatory responses. Methods Western blot and real-time PCR were performed to analyze CTRPs expression levels in human peripheral blood mononuclear cells, primary macrophages and lipid-laden foam cells. Mechanisms that regulate CTPR1 expression were further investigated by bioinformatic analysis and chromatin immunoprecipitation. Enzyme-linked immunosorbent assay was performed to measure the concentration of inflammatory cytokines. Results We found that almost all CTRPs were significantly increased in primary human macrophages after differentiation from peripheral blood mononuclear cells. In particular, CTRP1 was further up-regulated upon exposure to oxidized low-density lipoprotein (oxLDL) in a peroxisome proliferator-activated receptor (PPAR)-dependent manner. Chromatin immunoprecipitation also confirmed the presence of PPAR-γ in the CTRP1 promoter after oxLDL treatment. Stimulation of CTRP1 led to markedly enhanced secretion of pro-atherogenic factors, including MCP-1, TNF-α, IL-1β, and IL-6, whereas oxLDL-induced inflammatory cytokine production was significantly attenuated after the treatment with CTRP1 neutralizing antibody. Conclusions These data suggest an essential role of CTRP1 in linking dysregulation of lipid metabolism and inflammatory responses in macrophages.

Background: Our previous study suggested that heart-type fatty acid-binding protein (HFABP) levels were greatly elevated in the conditioned medium of explant culture of in-stent restenosis (ISR) tissue from diabetic minipigs compared with those of non-ISR tissue. We here verified this result in animal tissues and investigated the impact of HFABP overexpression in human aortic smooth muscle cells (hASMCs). Methods and Results: In Western blot and real-time RT-PCR, HFABP protein and mRNA levels were significantly higher in ISR than in non-ISR tissues from minipigs, and higher in the ISR tissue from diabetic minipigs than that from nondiabetic minipigs. The mRNA microarray and cellular effects of hASMC retroviral overexpression of HFABP and vector was analyzed. Compared with vector, HFABP transduction activates multiple signaling pathways (e.g. adipokine, TGF-β, Toll-like receptor, Wnt, Hedgehog, ErbB and Notch) and promotes inflammation, growth and migration in hASMCs whereas the knockdown of HFABP by small hairpin RNA attenuates these effects. Conclusion: HFABP expression is significantly higher in ISR tissue than in non-ISR tissue from diabetic and nondiabetic minipigs. Overexpression of HFABP induces multiple pathway-related promotion of inflammation, growth and migration in vascular SMCs, suggesting a potential role in coronary artery ISR.