Multi-centre, prospective randomized comparison of three different substrate ablation strategies for persistent atrial fibrillation.

AIMS: The optimal strategy for persistent atrial fibrillation (PerAF) is poorly defined. We conducted a multicentre, randomized, prospective trial to compare the outcomes of different ablation strategies for PerAF. METHODS AND RESULTS: We enrolled 450 patients and randomly assigned them in a 1:1:1 ratio to undergo pulmonary vein isolation and subsequently undergo the following three different ablation strategies: anatomical guided ablation (ANAT group, n = 150), electrogram guided ablation (EGM group, n = 150), and extensive electro-anatomical guided ablation (EXT group, n = 150). The primary endpoint was freedom from atrial fibrillation (AF) lasting longer than 30 s at 12 months after a single ablation procedure. After 12 months of follow-up, 72% (108) of patients in the EXT group were free from AF recurrence, as compared with the 64% (96) in the EGM group (P = 0.116), and 54% (81) in the ANAT group (P = 0.002). The EXT group showed less AF/atrial tachycardia recurrence than the EGM group (60% vs. 50%, P = 0.064) and the ANAT group (60% vs. 37.3%, P < 0.001). The EXT group showed the highest rate of AF termination (66.7%), followed by 56.7% in the EGM group, and 20.7% in the ANAT group. The AF termination signified less AF recurrence at 12 months compared to patients without AF termination (30.1% vs. 42.7%, P = 0.008). Safety endpoints did not differ significantly between the three groups (P = 0.924). CONCLUSIONS: Electro-anatomical guided ablation achieved the most favourable outcomes among the three ablation strategies. The AF termination is a reliable ablation endpoint.

Inhibition of TRAF3 expression alleviates cardiac ischemia reperfusion (IR) injury: A mechanism involving in apoptosis, inflammation and oxidative stress.

Ischemia reperfusion (IR) injury is known as a major issue in cardiac transplantation and various pathogenesis are involved in myocardial IR injury. Here, we show that tumor necrosis factor receptor-associated factor 3 (TRAF3) was increased in hearts of mice with cardiac IR injury and in cardiomyocytes incubated with lipopolysaccharide (LPS) and H2O2. Reducing TRAF3 expression in vivo markedly reduced the infacrted area, attenuated the histological changes, improved cardiac dysfunction and injury in mice subjected to IR injury. Functional study further indicated that TRAF3 knockdown inhibited apoptosis in murine hearts of mice with cardiac IR injury and in LPS and H2O2-cotreated cardiomyocytes, as evidenced by the decreased expression of cleaved Caspase-3 and poly (ADP-ribose) polymerases (PARP). In addition, inflammatory response and oxidative stress observed in hearts of mice with IR operation were significantly alleviated by TRAF3 knockdown through inhibiting nuclear factor-κB (NF-κB) and xanthine oxidase (XO) signaling pathways, and similar results were detected in LPS and H2O2-cotreated cardiomyocytes in vitro. Moreover, the loss of TRAF3 also restrained the phosphorylated c-Jun N-terminal protein kinase (JNK) activation following cardiac IR injury. Importantly, blocking JNK activation, as TRAF3 knockdown, greatly reduced apoptosis, inflammation and reactive oxygen species (ROS) production in LPS and H2O2-cotreated cardiomyocytes. In contrast, TRAF3 knockdown-reduced apoptosis, inflammatory response and oxidative stress were significantly rescued by promoting JNK activity in LPS and H2O2-cotreated cardiomyocytes. In summary, the results of our study indicated that repressing TRAF3 expression could be served as essential therapeutic target for protection against cardiac IR injury through restraining JNK-meditated apoptosis, inflammation and the production of ROS.

Role of miR-128 in hypertension-induced myocardial injury.

The present study aimed to investigate the role and mechanism of micro RNA (miR)-128 in hypertension-induced myocardial injury. The peripheral blood of patients with hypertension was collected and the expression of miR-128 was detected using fluorescence reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Primary myocardial cells isolated from rat in vitro were cultured under conditions of hypoxia and glucose deprivation, and miR-128 expression was measured by RT-qPCR. The expression of c-Met protein was measured using western blot analysis and the apoptosis of transfected cells was measured by flow cytometry in rat myocardial cells following transfection with miR-128 mimics or c-Met siRNA. A luciferase assay was applied to assess the binding of miR-128 to c-Met mRNA. miR-128 expression was significantly higher in hypertension patients compared with controls (P<0.05). miR-128 expression was higher in patients with stage III/IV hypertension compared with patients with stage II hypertension. Similarly, miR-128 expression in primary cardiomyocytes cultured under deprivation of oxygen and glucose increased with the culture time and reached a peak at 12 h. c-Met expression decreased significantly (P<0.05) and the ratio of apoptotic cells increased significantly (P<0.05), following transfection of miR-128 mimics. The number of apoptotic cells also increased when c-Met expression was knocked down by siRNA. The dual luciferase assay indicated that fluorescence intensity decreased significantly in miR-128 mimics and wild type c-Met group (P<0.05), indicating that miR-128 can directly target c-Met. Therefore, the results of the current study suggest that miR-128 may promote myocardial cell injury by regulating c-Met expression.

Role of microRNA-130a in myocardial hypoxia/reoxygenation injury.

The aim of this study was to investigate the role of microRNA (miR)-130a in the pathogenesis of myocardial hypoxia/reoxygenation (H/R) injury. Primary rat cardiomyocytes were cultured and subjected to H/R treatment. Reverse transcription-quantitative polymerase chain reaction was performed to detect the levels of miR-130a, western blot analysis was used to determine the expression of various proteins, and CCK-8 assay was performed to determine cell viability. In addition, flow cytometry was used to assess apoptosis. The cell viability was significantly decreased and the apoptosis rate was significantly increased in H/R-treated primary cardiomyocytes, and the expression level of miR-130a was also elevated in these model cells. Transfection with miR-130a inhibitor significantly elevated the cell viability and reduced the apoptosis rate in H/R-treated cardiomyocytes. Bioinformatics analysis indicated that autophagy-related gene 14 (ATG14) is the target for miR-130a, which was confirmed by dual-luciferase reporter assay and western blot analysis. When the H/R model cells were co-transfected with miR-130a inhibitor and small interfering RNA against ATG14, the cell viability was significantly reduced and the apoptosis rate was significantly elevated, compared with that of cells transfected with miR-130a inhibitor alone. miR-130a inhibitor transfection significantly elevated the levels of ATG14 and phosphorylated (p-)Beclin 1, increased the LC3II/LC3I ratio, and decreased the expression levels of P62 and cleaved caspase-3, while the co-transfection of miR-130a inhibitor and siR-ATG14 attenuated these effects in H/R-induced primary cardiomyocytes. These results indicate that miR-130a is involved in H/R-induced injuries in primary cardiomyocytes, and that the inhibition of miR-130a increases the levels of ATG14 and p-Beclin 1, thereby increasing autophagy and inhibiting apoptosis in these cells.

Correlation between vascular endothelial growth factor and long-term prognosis in patients with acute myocardial infarction.

The aim of the present study was to investigate the correlation between plasma the levels of vascular endothelial growth factor (VEGF) and major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). A total of 124 patients with AMI undergoing emergency percutaneous coronary intervention (PCI) were selected, and plasma VEGF levels were measured 7 days after the onset of AMI using an enzyme-linked immunosorbent assay. The patients were divided into the L (≤190 pg/ml VEGF) and H (>190 pg/ml VEGF) groups, and were followed up every 2 months for an average of 12 months. MACE were recorded during follow-up. On the basis of these results, the patients were further divided into the MACE and non-MACE (N-MACE) groups, and the serum VEGF concentration was compared between the two groups. At the 6-month follow-up, the incidence of MACE in the H group was found to be significantly reduced compared with the L group. The serum VEGF concentration in the N-MACE group was significantly higher compared with the MACE group. Multinomial logistic regression revealed that reduced VEGF levels (ß=1.243; 95% CI, 1.018-1.326; P=0.026) were independent risk factors for MACE. In conclusion, high plasma VEGF levels at 7 days after AMI onset facilitate the long-term prognosis in the same infarct zone in patients with AMI, while low plasma VEGF levels are independent risk factors for MACE.

Association of VEGFR-2 Gene Polymorphisms With Clopidogrel Resistance in Patients With Coronary Heart Disease.

Vascular endothelial growth factor receptor 2 (VEGFR-2) plays a central role in atherogenesis. We investigated the correlation between VEGFR-2 polymorphisms and the risk of clopidogrel resistance (CR) in patients with coronary heart disease (CHD). The study involved 275 patients with CHD undergoing percutaneous coronary intervention and on antiplatelet clopidogrel therapy. The participants were divided into CR group (n = 59) and non-CR group (NCR, n = 216) based on maximum platelet aggregation measurements. VEGFR-2 gene polymorphisms, +1192C>T (rs2305948), +1416T>A (rs1870377), and -271A>G (rs7667298), were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Enzyme-linked immunosorbent assay was used to measure serum transforming growth factor, beta receptor 2 levels. CR was found in 59 patients (20.45%). A significantly higher proportion of patients in the CR group had a history of diabetes mellitus compared with the NCR group (P < 0.05). Genotype and allele frequency of VEGFR-2 +1192C>T (rs2305948) was significantly higher in the CR group than in the NCR group (all P < 0.01). In the VEGFR-2 +1192C>T (rs2305948), the angina pectoris, recurrent myocardial infarction, and combined end point events were significantly more prevalent in the TT carriers than in the CC + CT carriers. In VEGFR-2 -271A>G (rs7667298), the GG carriers had a lower proportion of target lesion revascularization and angina pectoris in contrast to the AA + AG carriers (all P < 0.05). Based on our results, VEGFR-2 +1192C>T (rs2305948) polymorphism is strongly associated with increased CR and main adverse cardiovascular event incidence in patients with CHD undergoing percutaneous coronary intervention. Additionally, patients with CHD with diabetes mellitus history were more likely to develop CR. The associations of +1416T>A (rs1870377) and -271A>G (rs7667298) polymorphisms with CR were inconclusive and will need to be examined further.

Serum VEGF Predicts Worse Clinical Outcome of Patients with Coronary Heart Disease After Percutaneous Coronary Intervention Therapy.

BACKGROUND: Percutaneous coronary intervention (PCI) is an effective treatment for coronary heart disease (CHD) patients. However, patients after PCI treatment often have ischemic events that result in poor prognosis. Our study aimed to investigate the effects of vascular endothelial growth factor (VEGF) level on the prognosis of CHD patients. MATERIAL AND METHODS: We enrolled 114 CHD patients in the study. Serum VEGF level was measured by enzyme-linked immunosorbent assay (ELISA). Total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and Hs-CRP were also tested in patients. The patients were divided into 2 groups according to the level of VEGF. Kaplan-Meier curve was used to observe the differences in survival situation of patients of the 2 groups. Cox regression analysis was conducted to judge whether VEGF was an independent biomarker for prognosis in CHD. RESULTS: We included 104 patients for survival analysis. VEGF level in CHD patients was significantly lower than that of healthy individuals (P<0.05). In the analysis of basic information, we found differences in sex distribution and hypertension between groups (P<0.05 for both). Kaplan-Meier curve indicated that patients with low expression of VEGF presented with poor prognosis. The mortality rate of the low-expression group was 37.71%, higher than that of the high-expression group (14.3%). Cox analysis suggested that VEGF could serve as a biomarker for prognosis in CHD (HR: 3.014, P: 0.019). CONCLUSIONS: Low level of VEGF may predict poor clinical outcome of CHD patients after PCI treatment.

Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility.

AIM: Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. METHODS: 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. RESULTS: The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). CONCLUSION: we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.

Association between phosphatase related gene variants and coronary artery disease: case-control study and meta-analysis.

Recent studies showed that the serum alkaline phosphatase is an independent predictor of the coronary artery disease (CAD). In this work, we aimed to summarize the association between three phosphatase related single nucleotide polymorphisms (rs12526453, rs11066301 and rs3828329) and the risk of CAD in Han Chinese. Our results showed that the rs3828329 of the ACP1 gene was closely related to the risk of CAD in Han Chinese (OR = 1.45, p = 0.0006). This significant association of rs3828329 with CAD was only found in the females (Additive model: OR = 1.80, p = 0.001; dominant model: OR = 1.69, p = 0.03; recessive model: OR = 1.96, p = 0.0008). Moreover, rs3828329 was likely to exert its effect in females aged 65 years and older (OR = 2.27, p = 0.001). Further meta-analyses showed that the rs12526453 of PHACTR11 gene (OR = 1.14, p < 0.0001, random-effect method) and the rs11066301 of PTPN11 gene (OR = 1.15, p < 0.0001, fixed-effects method) were associated with CAD risk in multiple populations. Our results showed that the polymorphisms rs12526453 and rs11066301 are significantly associated with the CAD risk in multiple populations. The rs3828329 of ACP1 gene is also a risk factor of CAD in Han Chinese females aged 65 years and older.