Yinglong Hou

The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials

Current evidence suggests that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have emerged as novel drugs for preventing the development of atrial fibrillation (AF). A meta‐analysis was performed of 26 randomized controlled clinical trials evaluating the effect of ACEIs or ARBs on the prevention of AF. Overall, ACEIs and ARBs revealed statistically significant preventive effects on AF (odds ratio (OR), 0.65; 95% confidence interval (CI), 0.55–0.76). The preventive effect was similar in the two classes of drugs (ACEI: OR, 0.68; ARB: OR, 0.69). ACEIs and ARBs showed greater preventive effects on recurrent AF (OR, 0.45; 95% CI, 0.31–0.65) than on new‐onset AF (OR, 0.80; 95% CI, 0.70–0.92). Prevention was greatest in patients with AF who were receiving amiodarone as a basic treatment drug (OR, 0.35; 95% CI, 0.26–0.48). In patients with heart failure, there appeared to be a large effect (OR, 0.497), but the credible interval (CrI) limits were wide (95% CrI, 0.187–1.161).

MicroRNA-1 Accelerates the Shortening of Atrial Effective Refractory Period by Regulating KCNE1 and KCNB2 Expression: An Atrial Tachypacing Rabbit Model

Background The potential mechanisms of microRNA-1 (miR-1) in the electrical remodeling of atrial fibrillation remain unclear. The purpose of this study was to evaluate the effects of miR-1 on the atrial effective refractory period (AERP) in a right atrial tachypacing model and to elucidate the potential mechanisms. Methods and Results QRT-PCR and western blot were used to detect the expression of the miR-1, KCNE1, and KCNB2 genes after 1-week of right atrial tachypacing in New Zealand white rabbits. The AERP was measured using a programmable multichannel stimulator, and atrial fibrillation was induced by burst stimulation in vivo. The slowly activating delayed rectifier potassium current (IKs) and AERP in atrial cells were measured by whole cell patch clamp in vitro. Right atrial tachypacing upregulated miR-1 expression and downregulated KCNE1 and KCNB2 in this study, while the AERP was decreased and the atrial IKs increased. The downregulation of KCNE1 and KCNB2 levels was greater when miR-1 was further upregulated through in vivo lentiviral infection. Electrophysiological tests indicated a shorter AERP, a great increase in the IKs and a higher atrial fibrillation inducibility. In addition, similar results were found when the levels of KCNE1 and KCNB2 were downregulated by small interfering RNA while keeping miR-1 level unaltered. Conversely, knockdown of miR-1 by anti-miR-1 inhibitor oligonucleotides alleviated the downregulation of KCNE1 and KCNB2, the shortening of AERP, and the increase in the IKs. KCNE1 and KCNB2 as the target genes for miR-1 were confirmed by luciferase activity assay. Conclusions These results indicate that miR-1 accelerates right atrial tachypacing-induced AERP shortening by targeting potassium channel genes, which further suggests that miR-1 plays an important role in the electrical remodeling of atrial fibrillation and exhibits significant clinical relevance as a potential therapeutic target for atrial fibrillation.

MicroRNA Profiling of Atrial Fibrillation in Canines: MiR-206 Modulates Intrinsic Cardiac Autonomic Nerve Remodeling by Regulating SOD1

Background A critical mechanism in atrial fibrillation (AF) is cardiac autonomic nerve remodeling (ANR). MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Numerous miRNAs are involved in diseases of the nervous and cardiovascular systems. Objective We aimed to assess the underlying role of miRNAs in regulating cardiac ANR in AF by right atrial tachypacing (A-TP) in canines. Methods and Results Following 4-week A-TP, the superior left ganglionated plexuses (SLGPs), which are embedded in the fat pads of the left atrium, were subjected to miRNA expression profiling to screen preferentially expressed miRNAs. Sixteen miRNAs showed significantly differential expression between the control and A-TP groups, including miR-206, miR-203, miR-224 and miR-137. In particular, we focused on miR-206, which was elevated ~10-fold in A-TP dogs. Forced expression of miR-206 through lentiviral infection based on A-TP in vivo significantly shortened the atrial effective refractory period (AERP) (81 ± 7 vs. 98 ± 7 ms, P < 0.05). Immunohistochemical analysis showed that the regeneration of nerves increased more than 2-fold by miR-206 overexpression (P < 0.01). The expression of superoxide dismutase 1 (SOD1) was repressed by miR-206 overexpression by Western blot and luciferase assay, indicative of SOD1 as a direct target of miR-206. Overexpression of miR-206 increased reactive oxygen species (ROS) levels in vitro and in vivo, whereas miR-206 silencing attenuated irradiation- or A-TP-induced ROS. Knockdown of SOD1 effectively abolished ROS reduction caused by miR-206 silencing. Conclusions Our results found the differential expression of miRNAs in response to ANR in AF and elucidated the important role of miR-206 by targeting SOD1. The study illustrated the novel molecular mechanism of ANR and indicated a potential therapeutic target for AF.

Cadmium induces vascular permeability via activation of the p38 MAPK pathway

The vasculature of various organs is a targeted by the environmental toxin, cadmium (Cd). However, mechanisms leading to pathological conditions are poorly understood. In the present study, we examined the effect of cadmium chloride (CdCl2) on human umbilical vein endothelial cells (HUVECs). At 4 μM, CdCl2 induced a hyper-permeability defect in HUVECs, but not the inhibition of cell growth up to 24h. This effect of CdCl2 was dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. The p38 MAPK inhibitor SB203850 suppressed the CdCl2-induced alteration in trans-endothelial electrical resistance in HUVEC monolayers, a model measurement of vascular endothelial barrier integrity. SB203850 also inhibited the Cd-induced membrane dissociation of vascular endothelial (VE) cadherin and β-catenin, the important components of the adherens junctional complex. In addition, SB203850 reduces the Cd-induced expression and secretion of tumor necrosis factor α (TNF-α). Taken together, our findings suggest that Cd induces vascular hyper-permeability and disruption of endothelial barrier integrity through stimulation of p38 MAPK signaling.

Statin Therapy for the Prevention of Atrial Fibrillation: A Meta-analysis of Randomized Controlled Trials

Study Objectives. To assess the efficacy of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) for primary and secondary prevention of atrial fibrillation, and to evaluate the efficacy of individual statins and their dosages.

The safety and efficacy of antithrombotic therapy in patients undergoing cardiac rhythm device implantation: a meta-analysis

AIMS The meta-analysis was to assess the safety and efficacy of periprocedural antithrombotic therapy and to evaluate the risk factors potentially associated with bleeding among patients undergoing cardiac implantable electronic devices implantations. METHODS AND RESULTS A systematic literature search of PubMed, EMBASE, and Cochrane Controlled Trials Register was performed. Anticoagulation and antiplatelet therapies were assessed separately. Uninterrupted anticoagulation was associated with significant lower bleeding risk compared with heparin bridging strategy [odds ratio (OR) = 0.31, 95% confidence interval (CI) 0.18-0.53, and P < 0.0001], but there was no significant difference in thromboembolic risk between these two strategies (OR = 0.82, 95% CI 0.32-2.09, and P = 0.65). The haematoma rate was significantly increased in dual antiplatelet therapy group (OR = 6.84, 95% CI 4.16-11.25, and P < 0.00001), but not in single antiplatelet therapy (OR = 1.52, 95% CI 0.93-2.46, and P = 0.09). Clopidogrel increased the risk of haematoma vs. aspirin (OR = 2.91, 95% CI 1.27-6.69, and P = 0.01). Otherwise, a lower risk of haematoma was observed in pacemaker group vs. cardiac resynchronization therapy and/or implantable cardioverter defibrillator group (OR = 0.64, 95% CI 0.50-0.82, and P = 0.0004). CONCLUSION This meta-analysis suggested that uninterrupted oral anticoagulation seems to be the better strategy, associated with a lower risk of bleeding complications rather than heparin bridging, and dual antiplatelet therapy carried a significant risk of bleeding whereas single antiplatelet therapy was relatively safe among patients undergoing cardiac implantable electronic devices implantations. Meanwhile, cardiac resynchronization therapy and/or implantable cardioverter defibrillator implantations increase the bleeding.

Dihydroartemisinin inhibits vascular endothelial growth factor-induced endothelial cell migration by a p38 mitogen-activated protein kinase-independent pathway.

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has been demonstrated to possess a strong antiangiogenic activity. However, the molecular mechanisms underlying this effect remain unclear. Endothelial cell (EC) migration is an essential component of angiogenesis, and the p38 mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in the regulation of migration induced by vascular endothelial growth factor (VEGF). The aim of the present study was to investigate the effects of DHA on EC migration and the p38 MAPK signaling pathway. Human umbilical vein ECs (HUVECs) were treated with DHA and VEGF-induced migration was analyzed. The activation of p38 MAPK was detected by western blot analysis, and the migration assays were performed with a p38-specific inhibitor, SB203850. It was revealed that 20 μM DHA significantly reduced EC migration in the transwell migration assay, wound healing assay and electrical cell-substrate impedance sensing real-time analysis. However, DHA did not affect p38 MAPK phosphorylation or expression. In the absence or presence of SB203850, DHA induced a similar proportional reduction of EC migration in the three migration assays. Therefore, the present study demonstrated that DHA inhibits VEGF-induced EC migration via a p38 MAPK-independent pathway.

Interleukin‑1β increases permeability and upregulates the expression of vascular endothelial‑cadherin in human renal glomerular endothelial cells

The renal glomerular capillary endothelium is part of the glomerular filtration barrier and is involved in acute and chronic inflammation of the glomerulus. Glomerular endothelial cells are a unique type of microvascular cell, which remain to be fully characterized. The aim of the present study was to examine the permeability of glomerular endothelial cells and their responses to interleukin (IL)‑1β, a pro‑inflammatory cytokine. Human glomerular endothelial cell (HRGEC) and human umbilical vein endothelial cell (HUVEC) monolayers were examined using a Transwell permeability assay, transendothelial electrical resistance (TEER) and by determining the expression of the adhesion molecule, vascular endothelial (VE)‑cadherin, in the absence or presence of 10 ng/ml IL‑1β. Compared with the HUVECs, the HRGECs demonstrated higher permeability, lower TEER and reduced expression of VE‑cadherin. IL‑1β induced an increase in the permeability and a decrease in the TEER of the HRGECs, however, to a lesser extent compared with the HUVECs. Following IL‑1β treatment, the expression of VE‑cadherin was increased in the HRGECs and decreased in the HUVECs. These results suggested that HRGECs have distinct biological properties and specific gene expression features in response to IL‑1β.

Association of killer cell immunoglobulin‐like receptor and human leucocyte antigen‐Cw gene combinations with systemic lupus erythematosus

Killer cell immunoglobulin‐like receptors (KIRs) are a diverse family of activating and inhibitory receptors expressed on natural killer (NK) cells and T cells, the genes of which show extreme polymorphism. Some KIRs bind to human leucocyte antigen (HLA) class I subgroups, and genetic interactions between KIR genes and their ligand HLA have been shown to be associated with several autoimmune diseases. The present study aimed to investigate whether the combinations of KIR genes and HLA‐Cw ligands associate with the susceptibility of systemic lupus erythematosus (SLE). Polymerase chain reaction using sequence‐specific primers was used to determine the genotypes of KIR genes and HLA‐Cw alleles. We found that the frequencies of HLA‐Cw07 were statistically significantly higher in the patient group than those in the control group (P = 0·009). KIR2DS1+HLA−CwLys was more common in subjects with SLE compared to control subjects (P = 0·015). In addition, the frequency of KIR2DS1 was increased in SLE when KIR2DL1/HLA‐Cw are absent, and the difference was significant (P = 0·001). KIR genotype and HLA ligand interaction may potentially influence the threshold for NK (and/or T) cell activation mediated through activating receptors, thereby contributing to the pathogenesis of SLE.

Renin-angiotensin system inhibitors prevent the recurrence of atrial fibrillation: a meta-analysis of randomized controlled trials.

Objective: This study was designed to assess whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could prevent the recurrence of atrial fibrillation (AF). Methods: A systemic literature search of PubMed, EMBASE, and Cochrane Controlled Trials Register till 2012 was performed to identify randomized controlled trials involving the prevention of recurrence of AF with renin–angiotensin system blockade therapy. Subgroup analysis and meta-regression were performed. Publication bias was checked through funnel plot and Eggers test. Results: Twenty-one randomized controlled trials including 13,184 patients with AF were identified. Overall, the recurrence of AF was significantly reduced in patients using ACEI/ARBs [odds ratio (OR), 0.43; 95% confidence interval (CI), 0.32−0.56; P < 0.00001], especially both in irbesartan subgroup (OR, 0.38; 95% CI, 0.21−0.68; P = 0.001) and in patients receiving antiarrhythmic drug (AAD) (OR, 0.37; 95% CI, 0.29−0.48; P < 0.00001), and there was no significant difference between ACEIs and ARBs (ACEIs: OR, 0.42; 95% CI, 0.31−0.57 and ARBs: OR, 0.42; 95% CI, 0.31−0.57). Moreover, it was found that the benefits of ACEI/ARBs revealed positive correlation to systolic blood pressure (regression coefficient: −0.0700257, P = 0.000) in no-AAD users. Conclusions: ACEI/ARBs are effective on the secondary prevention of AF, especially in patients receiving AAD and suffering from hypertension.