Jianhui Zhuang

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.

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.

Association of Serum Vaspin and Adiponectin Levels with Renal Function in Patients with or without Type 2 Diabetes Mellitus

Vaspin and adiponectin are two adipocytokines with antidiabetic effects. Some studies reported that levels of adiponectin and vaspin were correlated with decreased glomerular filtration rate (FGR) and increased albuminuria. We therefore evaluated the vaspin and adiponectin levels in renal insufficiency (RI) patients with or without T2DM. Serum vaspin, adiponectin levels were measured in 416 subjects with or without T2DM. Analysis was made between groups divided by these subjects presence or absence of RI. We found that serum adiponectin level was significantly higher in nondiabetic patients with RI than in nondiabetic subjects without RI; however, there were no statistical differences between the diabetic patients with RI and without RI. In all the subjects, the serum adiponectin level was also higher in 50 individuals with RI than that in 366 subjects without RI. The serum vaspin levels showed no significant differences between the diabetic patients or nondiabetics subjects with RI and without RI. Contrary to adiponectin, the serum vaspin level was lower in 169 patients with T2DM than in 247 individuals without T2DM. Our data suggested that both of T2DM and renal insufficiency were correlated with the serum level of adiponectin. However, the serum vaspin levels showed no significant difference between the individuals with renal insufficiency and without renal insufficiency.

Insights into the clinical implications of carbohydrate antigen 125 as a biomarker of heart failure: a meta-analysis and systematic review of published studies.

Aims An increasing number of clinical studies have explored the possibility of using tumor biomarker carbohydrate antigen 125 (CA 125) in the management of patients with heart failure. This systematic review and meta-analysis was performed to comprehensively summarize the available evidence and evaluate the applicability of CA 125 in heart failure. Methods We searched PubMed, Embase, and Cochrane Central Register of controlled trials. Of the 253 studies identified, 23 studies investigating the application of CA 125 in the clinical management of heart failure were included for meta-analyses and systematic review. Results The serum levels of CA 125 increased significantly in heart failure patients compared with healthy controls (standardized mean difference of 1.49 U/ml, P < 0.001). The fluctuation of CA 125 was closely associated with echocardiographic parameters. Likewise, the CA 125 levels were positively correlated with brain natriuretic peptide and N-terminal pro-BNP. Further investigation found that CA 125 levels increased accordingly as cardiac function declined from the New York Heart Association class I/II to class III and further from class III to IV [1.58, 95% confidence interval (0.75–2.41) and 1.37, 95% confidence interval (0.76–1.98) U/ml, respectively]. Heart failure patients with poor outcomes showed higher CA 125 level relative to those without adverse effects in short-term or long-term follow-up. Conclusion CA 125 is a promising biomarker in the diagnosis, stratification, and outcome evaluation of heart failure patients. CA 125 may be regarded as a surrogate marker of echocardiographic variables, N-terminal pro-BNP and brain natriuretic peptide.

Vaspin attenuates the progression of atherosclerosis by inhibiting ER stress‑induced macrophage apoptosis in apoE‑/‑ mice

Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a novel adipokine with potential insulin-sensitizing properties, which was initially detected in the visceral adipose tissue of genetically obese rats. Previous studies have demonstrated that vaspin exerts a protective effect on arteries undergoing atherosclerosis in vitro, and it has been shown to exert anti-inflammatory and antimigratory effects on vascular smooth muscle cells. Vaspin promotes proliferation and inhibits apoptosis in endothelial cells, and decreases proliferation of the arterial intima under diabetic conditions. In addition, macrophage apoptosis is an important characteristic of atherosclerotic plaque development. In vivo experiments were performed by histological analysis, including Oil Red O, hematoxylin and eosin and Massons trichrome staining. Mice were injected with lentivirus via the tail vein and tissues were obtained for histological analysis. Cell apoptosis was determined by flow cytometry of Annexin-V/propidium iodide dual staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Total proteins were extracted and protein expression levels were detected by western blot analysis. The present study aimed to investigate whether vaspin was able to protect against atherosclerotic development in vivo, and to explore the underlying mechanisms of the potential antiatherogenic effects. The results of the current study indicated that vaspin inhibited the progression of atherosclerotic plaques in apoE−/− mice by inhibiting endoplasmic reticulum stress-induced macrophage apoptosis.