Wenhui Peng

Association between left atrial size and atrial fibrillation recurrence after single circumferential pulmonary vein isolation: a systematic review and meta-analysis of observational studies

AIMS Left atrial (LA) enlargement is associated with atrial fibrillation (AF). However, it is controversial whether dilated atrium can predict post-ablation AF recurrence. We undertook a systematic review and meta-analysis to analyse the association between LA diameter and AF recurrence after single circumferential pulmonary vein isolation (CPVI) and explore the potential mechanism. METHODS AND RESULTS Electronic databases and bibliographies of retrieved studies were searched. The anteroposterior diameters of LA were available in all included studies, which were measured at end-systole by M-mode transthoracic echocardiography. Subgroup analysis was conducted based on the duration of follow-up. Weighted mean difference (WMD) and 95% confidence interval (CI) were calculated using random-effect or fixed-effect model, depending on statistical heterogeneity. Twenty-two studies with a total of 3750 individuals met the inclusion criteria. The summary WMD of LA diameter between patients with and without recurrence was 1.87 mm (95% CI 1.26-2.48, P< 0.001). Meta-regression analysis of the 22 studies indicated that study design, duration of follow-up, and measurement of asymptomatic recurrences were significant sources of heterogeneity. Sensitivity analysis suggested that the difference in LA diameter between patients with and without recurrences persisted regardless of the duration of follow-up. CONCLUSION Dilated LA significantly increases the risk of AF recurrence after single CPVI. This is especially applicable to the patients with long-term follow-up.

Methylation of p15INK4b and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease

Background Genome-wide association studies have identified that multiple single nucleiotide polymorphisms on chromosome 9p21 are tightly associated with coronary artery disease (CAD). However, the mechanism linking this risk locus to CAD remains unclear. Methodology/Principal Findings The methylation status of six candidate genes (BAX, BCL-2, TIMP3, p14ARF, p15INK4b and p16INK4a) in 205 patients and controls who underwent coronary angiography were analyzed by quantitative MethyLight assay. Rs10757274 was genotyped and expression of INK4/ARF and antisense non-coding RNA in the INK4 locus (ANRIL) was determined by real-time RT-PCR. Compared with controls, DNA methylation levels at p15INK4b significantly increased in CAD patients (p = 0.006). To validate and dissect the methylation percentage of each target CpG site at p15INK4b, pyrosequencing was performed, finding CpG +314 and +332 remarkably hypermethylated in CAD patients. Further investigation determined that p15INK4b hypermethylation prevalently emerged in lymphocytes of CAD patients (p = 0.013). The rs10757274 genotype was significantly associated with CAD (p = 0.003) and GG genotype carriers had a higher level of ANRIL exon 1–5 expression compared among three genotypes (p = 0.009). There was a stepwise increase in p15INK4b and p16INK4a methylation as ANRIL exon 1–5 expression elevated (r = 0.23, p = 0.001 and r = 0.24, p = 0.001, respectively), although neither of two loci methylation was directly linked to rs10757274 genotype. Conclusions/Significance p15INK4b methylation is associated with CAD and ANRIL expression. The epigenetic changes in p15INK4b methylation and ANRIL expression may involve in the mechanisms of chromosome 9p21 on CAD development.

ROCK inhibitor fasudil attenuated high glucose-induced MCP-1 and VCAM-1 expression and monocyte-endothelial cell adhesion

BackgroundPrevious studies suggested that the RhoA/ROCK pathway may contribute to vascular complications in diabetes. The present study was designed to investigate whether ROCK inhibitor fasudil could prevent high glucose-induced monocyte-endothelial cells adhesion, and whether this was related to fasudil effects on vascular endothelial cell expression of chemotactic factors, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1).MethodsHUVECs were stimulated with high glucose (HG) or HG + fasudil in different concentration or different time. Monocyte-endothelial cell adhesion was determined using fluorescence-labeled monocytes. The mRNA and protein expression of VCAM-1 and MCP-1 were measured using real-time PCR and western blot. The protein levels of RhoA, ROCKI and p-MYPT were determined using western blot analysis. ELISA was employed to measure the expression of soluble VCAM-1 and MCP-1 in cell supernatants and human serum samples.ResultsFasudil significantly suppressed HG-induced adhesion of THP-1 to HUVECs. Fasudil reduced Rho/ROCK activity (as indicated by lower p-MYPT/MYPT ratio), and prevented HG induced increases in VCAM-1 and MCP-1 mRNA and protein levels. Fasudil also decreased MCP-1 concentration in HUVEC supernatants, but increased sVCAM-1 shedding into the media. In human diabetic subjects, 2 weeks of fasudil treatment significantly decreased serum MCP-1 level from 27.9 ± 10.6 pg/ml to 13.8 ± 7.0 pg/ml (P < 0.05), while sVCAM-1 increased from 23.2 ± 7.5 ng/ml to 39.7 ± 5.6 ng/ml after fasudil treatment (P < 0.05).ConclusionsTreatment with the Rho/ROCK pathway inhibitor fasudil attenuated HG-induced monocyte-endothelial cell adhesion, possibly by reducing endothelial expression of VCAM-1 and MCP-1. These results suggest inhibition of Rho/ROCK signaling may have therapeutic potential in preventing diabetes associated vascular inflammation and atherogenesis.

Role of Serum Vaspin in Progression of Type 2 Diabetes: A 2-Year Cohort Study

Vaspin is a novel adipocytokine that has potential insulin-sensitizing effects. The aim of this study is to explore the role of vaspin in the progression of type 2 diabetes mellitus (T2DM) in humans through a longitudinal process. This was a 2-year follow-up study that included 132 patients with T2DM and 170 non-diabetic subjects. The serum vaspin and adiponectin levels were determined with ELISA. Anthropometric measurements, circulating glucose, hemoglobin A1c, insulin level, liver function, kidney function, and lipid profile were measured for each participant. The new onset of T2DM was counted in non-diabetic subjects and the glycemic control was analyzed in T2DM patients at follow-up. At enrollment, the serum vaspin and adiponectin levels were lower in T2DM patients compared with non-diabetic subjects. Significant positive correlation between serum vaspin and HDL-C levels (r = 0.23, P = 0.006) was observed in non-diabetic controls. The serum vaspin concentration was also significantly correlated with body mass index (BMI) (r = 0.19, P = 0.028), waist-hip ratio (WHR) (r = 0.17, P = 0.035) and homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.14, P = 0.029) in T2DM patients. In cohort analyses, it was found that lower serum vaspin [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.10–0.87, P = 0.015] and adiponectin (OR = 0.35, 95% CI: 0.20–0.72, P = 0.015) levels at baseline were risk factors for new onset of T2DM at follow-up. The percentage of insulin treatment in T2DM patients was higher in the sub-group with lower serum vaspin level than that in the sub-group with higher vaspin level at follow-up (55.3% vs. 44.7%, P = 0.020). Our study indicates that low serum concentration of vaspin is a risk factor for the progression of T2DM.

Inhibitory Effects of Vinpocetine on the Progression of Atherosclerosis Are Mediated by Akt/NF-κB Dependent Mechanisms in apoE-/- Mice

Background Recent studies have found additional roles for vinpocetine, a potent phosphodiesterase type I inhibitor, in anti-proliferation and anti-inflammation of vascular smooth muscle cells and cancer cells via different mechanisms. In this study, we attempted to investigate whether vinpocetine protected against atherosclerotic development in apoE-/- mice and explore the underlying anti-atherogenic mechanisms in macrophages. Methodology/Principal Findings Vinpocetine markedly decreased atherosclerotic lesion size in apoE-/- mice measured by oil red O. Masson’s trichrome staining and immunohistochemical analyses revealed that vinpocetine significantly increased the thickness of fibrous cap, reduced the size of lipid-rich necrotic core and attenuated inflammation. In vitro experiments exhibited a significant decrease in monocyte adhesion treated with vinpocetine. Further, active TNF-α, IL-6, monocyte chemoattractant protein-1and matrix metalloproteinase-9 expression induced by ox-LDL were attenuated by vinpocetine in a dose-dependent manner. Similarly, ox-LDL-induced reactive oxygen species were significantly repressed by vinpocetine. Both western blot and luciferase activity assay showed that vinpocetine inhibited the enhanced Akt, IKKα/β, IκBα phosphorylation and NF-κB activity induced by ox-LDL, and the inhibition of NF-κB activity was partly caused by Akt dephosphorylation. However, knockdown of PDE1B did not affect Akt, IKKα/β and IκBα phosphorylation. Conclusions These results suggest that vinpocetine exerts anti-atherogenic effects through inhibition of monocyte adhesion, oxidative stress and inflammatory response, which are mediated by Akt/NF-κB dependent pathway but independent of PDE1 blockade in macrophages.

Influence of Body Mass Index on Recurrence and Quality of Life in Atrial Fibrillation Patients After Catheter Ablation: A Meta-Analysis and Systematic Review

Accumulating evidence has demonstrated that overweight and obesity, expressed as high body mass index (BMI), are associated with the development of atrial fibrillation (AF) and quality of life (QoL) in AF patients. However, the role of high BMI as a risk factor for prognosis and QoL in AF patients undergoing ablation remains controversial.

The Yin–Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling

Objective— DNA methylation plays an important role in chronic diseases such as atherosclerosis, yet the mechanisms are poorly understood. The objective of our study is to indicate the regulatory mechanisms of DNA methylation in vascular smooth muscle cells (VSMCs) and its roles in atherosclerosis. Approach and Results— In ApoE−/− mice fed a Western diet, DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, significantly attenuated atherosclerotic lesions (20.1±2.2% versus 30.8±7.5%; P=0.016) and suppressed DNA methyltransferase activity and concomitantly decreased global 5-methylcytosine content in atherosclerotic lesions of ApoE−/− mice. Using a carotid ligation model, we found that 5-aza-2′-deoxycytidine also dramatically inhibited neointimal formation (intimal area: 2.25±0.14×104 versus 4.07±0.22×104 &mgr;m2; P<0.01). Abnormal methylation status at the promoter of ten–eleven translocation 2, one of the key demethylation enzymes in mammals, was ameliorated after 5-aza-2′-deoxycytidine treatment, which in turn caused an increase in global DNA hydroxymethylation and 5-hydroxymethylcytosine enrichment at the promoter of Myocardin. In vitro, 5-aza-2′-deoxycytidine treatment or DNA methyltransferase 1 knockdown decreased global 5-methylcytosine content and restored Myocardin expression in VSMCs induced by platelet-derived growth factor, thus preventing excessive VSMCs dedifferentiation, proliferation, and migration. Furthermore, DNA methyltransferase 1 binds to ten–eleven translocation 2 promoter and is required for ten–eleven translocation 2 methylation in VSMCs. Conclusions— The inhibitory effects of DNA demethylation on global 5-methylcytosine content and ten–eleven translocation 2 hypermethylation in atherosclerotic aorta can recover 5-hydroxymethylcytosine enrichment at the Myocardin promoter and prevent VSMC dedifferentiation and vascular remodeling.

The Rho/Rho-associated protein kinase inhibitor fasudil in the protection of endothelial cells against advanced glycation end products through the nuclear factor κB pathway

Accumulating evidence has demonstrated that the Rho/Rho-associated protein kinase (Rho/ROCK) and nuclear factor κB (NF-κB) signaling pathways are involved in the pathogenesis of diabetic vascular injury. In this study, we investigated the beneficial effects of fasudil, a ROCK inhibitor, on vascular endothelial injury induced by advanced glycation end products (AGEs) in vitro. Human umbilical vein endothelial cells (HUVECs) were stimulated with AGEs and AGEs plus fasudil in various concentrations for different time periods. Monocyte-endothelial cell adhesion, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression, protein expression and activation of Rho/ROCK, activation of NF-κB and reactive oxygen species (ROS) production were evaluated. Fasudil suppressed AGE-induced monocyte-endothelial adhesion. Fasudil also reduced the mRNA and protein expression of VCAM-1 and MCP-1 in a concentration- and time-dependent manner. Moreover, increases in the protein levels of Rho/ROCK and ROCK activity mediated by AGEs were inhibited by the addition of fasudil. Additionally, fasudil attenuated AGE-induced NF-κB-dependent transcriptional activity and inhibition of NF-κB (IκB) phosphorylation. ROS production induced by AGEs was also reduced by fasudil in HUVECs. The results suggest that ROCK inhibition may protect the vascular endothelium against AGE-induced monocyte-endothelial adhesion in vitro through the reduction of ROS generation and the downregulation of NF-κB signaling. Thus, ROCK inhibition may be a novel therapeutic approach for the treatment of vascular complications in diabetes.

Vinpocetine Attenuates Neointimal Hyperplasia in Diabetic Rat Carotid Arteries after Balloon Injury

Background Diabetes exacerbates abnormal vascular smooth muscle cell (VSMC) accumulation in response to arterial wall injury. Vinpocetine has been shown to improve vascular remolding; however, little is known about the direct effects of vinpocetine on vascular complications mediated by diabetes. The objective of this study was to determine the effects of vinpocetine on hyperglycemia-facilitated neointimal hyperplasia and explore its possible mechanism. Materials and Methods Nondiabetic and diabetic rats were subjected to balloon injury of the carotid artery followed by 3-week treatment with either vinpocetine (10 mg/kg/day) or saline. Morphological analysis and proliferating cell nuclear antigen (PCNA) immunostaining were performed on day 21. Rat VSMCs proliferation was determined with 5-ethynyl-20-deoxyuridine cell proliferation assays. Chemokinesis was monitored with scratch assays, and production of reactive oxygen species (ROS) was assessed using a 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) flow cytometric assay. Apoptosis was detected by annexin V-FITC/PI flow cytometric assay. Cell signaling was assessed by immunblotting. Results Vinpocetine prevented intimal hyperplasia in carotid arteries in both normal (I/M ratio: 93.83 ± 26.45% versus 143.2 ± 38.18%, P<0.05) and diabetic animals (I/M ratio: 120.5 ± 42.55% versus 233.46 ± 33.98%, P<0.05) when compared to saline. The in vitro study demonstrated that vinpocetine significantly inhibited VSMCs proliferation and chemokinesis as well as ROS generation and apoptotic resistance, which was induced by high glucose (HG) treatment. Vinpocetine significantly abolished HG-induced phosphorylation of Akt and JNK1/2 without affecting their total levels. For downstream targets, HG-induced phosphorylation of IκBα was significantly inhibited by vinpocetine. Vinpocetine also attenuated HG-enhanced expression of PCNA, cyclin D1 and Bcl-2. Conclusions Vinpocetine attenuated neointimal formation in diabetic rats and inhibited HG-induced VSMCs proliferation, chemokinesis and apoptotic resistance by preventing ROS activation and affecting MAPK, PI3K/Akt, and NF-κB signaling.

A comparison of 2 devices for radial artery hemostasis after transradial coronary intervention.

Background and Objective:Transradial access is an attractive approach for angiography or percutaneous coronary intervention. Different devices have been used to apply pressure locally at the site of arterial entry for achieving hemostasis. The aim of this study was to evaluate the effect of 2 different hemostatic devices on radial artery outcomes after transradial coronary intervention. Subjects and Methods:This study included 600 patients who had undergone transradial coronary intervention who were randomized into 2 groups after the procedure: 300 were treated with a radial compression device (TR Band, Terumo Medical, Tokyo, Japan) (CD group) and the other 300 patients were treated using a chitosan-based pad (Anscare, Daxon, Taoyuan, Taiwan) (CS group). Compression time, major and minor access site bleeding complications, and incidence of radial artery occlusion were recorded. Results:There were no statistical differences in the baseline clinical characteristics of the patients between the 2 groups. Compression time in the CS group was significantly shorter than that in the CD group (P < .001). Although no major access site bleeding complications were observed in either group, 6 patients in each group experienced minor access site bleeding complications. At the same time, 61 patients in the CD group and 21 patients in the CS group experienced errhysis (20% vs 7%, respectively; P < .001). Early radial artery occlusion (24 hours) occurred in 11.7% of the patients in the CD group and 5.4% of the patients in the CS group (P < .05). Chronic radial artery occlusion (30 days) occurred in 10% of the patients in the CD group and 5% of the patients in the CS group (P < .05). Conclusion:The application of the chitosan-based pad showed better hemostatic efficacy and a lower incidence of radial artery occlusion after transradial coronary intervention compared with the compression device.