Jiangrong Wang

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.

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.

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.

An altered expression of genes involved in the regulation of ion channels in atrial myocytes is correlated with the risk of atrial fibrillation in patients with heart failure

The aim of this study was to investigate the correlation between the altered expression of genes involved in the regulation of ion channels in atrial myocytes and the risk of atrial fibrillation (AF) in patients with heart failure (HF). Right atrial appendages were obtained from 18 HF patients and 18 patients with normal cardiac functions who had undergone surgery. The mRNA expression levels of Kv4.3α, KvLQT1, Kv1.5, L-Caα1c and NCX were measured by reverse transcription-PCR (RT-PCR). Protein expression levels were also detected by western blotting. In comparison with the control group exhibiting normal cardiac functions, the mRNA and protein expression levels of Kv4.3α, KvLQT1 and L-Caα1c were significantly reduced in HF patients. By contrast, the mRNA and protein expression levels of NCX were significantly increased in HF patients compared with the control group (P<0.01). The mRNA expression levels of Kv1.5 were not evidently altered. We demonstrated that increased levels of Kv4.3α, KvLQT1 and L-Caα1c and decreased levels of NCX are correlated with the risk of AF in HF patients. Changes in the gene expression of ion channel-related proteins may therefore be used as biological markers of AF occurring in HF patients in future studies.

Altered long non-coding RNA expression profile in rabbit atria with atrial fibrillation: TCONS_00075467 modulates atrial electrical remodeling by sponging miR-328 to regulate CACNA1C

Electrical remodeling has been reported to play a major role in the initiation and maintenance of atrial fibrillation (AF). Long non-coding RNAs (lncRNAs) have been increasingly recognized as contributors to the pathology of heart diseases. However, the roles and mechanisms of lncRNAs in electrical remodeling during AF remain unknown. In this study, the lncRNA expression profiles of right atria were investigated in AF and non-AF rabbit models by using RNA sequencing technique and validated using quantitative real-time polymerase chain reaction (qRT-PCR). A total of 99,843 putative new lncRNAs were identified, in which 1220 differentially expressed transcripts exhibited >2-fold change. Bioinformatics analysis was conducted to predict the functions and interactions of the aberrantly expressed genes. On the basis of a series of filtering pipelines, one lncRNA, TCONS_00075467, was selected to explore its effects and mechanisms on electrical remodeling. The atrial effective refractory period was shortened in vivo and the L-type calcium current and action potential duration were decreased in vitro by silencing of TCONS_00075467 with lentiviruses. Besides, the expression of miRNA-328 was negatively correlated with TCONS_00075467. We further demonstrated that TCONS_00075467 could sponge miRNA-328 in vitro and in vivo to regulate the downstream protein coding gene CACNA1C. In addition, miRNA-328 could partly reverse the effects of TCONS_00075467 on electrical remodeling. In summary, dysregulated lncRNAs may play important roles in modulating electrical remodeling during AF. Our study may facilitate the mechanism studies of lncRNAs in AF pathogenesis and provide potential therapeutic targets for AF.

Combination Use of Clopidogrel and Proton Pump Inhibitors Increases Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease: A Meta-Analysis.

Background: Published data indicated that combination use of clopidogrel and proton pump inhibitors (PPIs) may increase the incidence of major adverse cardiovascular events (MACEs). This has been a highly controversial topic for years. Design: The present study was performed to evaluate whether combination therapy of clopidogrel and PPIs is associated with increased risk of MACEs than with clopidogrel alone in patients with coronary artery disease. Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Library was conducted for studies recording the occurrence of MACEs in patients with exposure to concomitant use of clopidogrel and PPIs up to February 2015. Odds ratios (ORs) were combined using a random-effects model. Results: Patients receiving combination therapy with PPIs and clopidogrel were at significantly increased risk of MACEs (OR: 1.42; 95% confidence interval [CI]: 1.30-1.55). Adding a PPI to clopidogrel treatment was associated with a higher rate of MACE occurrence in rapid metabolizers (RMs, *1/*1) of CYP2C19 (OR: 1.42; 95% CI: 1.12-1.81), but there was no obviously increased rate (OR: 1.43; 95% CI: 0.89-2.28) in decreased metabolizers (with 1 or 2 loss-of-function allele). The increased risk of MACEs was similar in 4 classes of PPIs (omeprazole, lansoprazole, esomeprazole, and pantoprazole), but rabeprazole (OR: 1.03; 95% CI: 0.55-1.95) wasn’t. Conclusion: The combination use of clopidogrel and certain types of PPIs (omeprazole, lansoprazole, esomeprazole, pantoprazole) increases the risk of MACE in patients with coronary artery disease. Only in the RMs of CYP2C19, PPIs were associated with significantly increased MACE in patients coadministered with clopidogrel.

Transcriptome Analysis of Canine Cardiac Fat Pads: Involvement of Two Novel Long Non‐Coding RNAs in Atrial Fibrillation Neural Remodeling

Intrinsic cardiac autonomic neural remodeling (ANR) has been reported to be involved in the initiation and maintenance of atrial fibrillation (AF). Long non‐coding RNAs (lncRNAs) are important orchestrators of gene regulatory networks. However, little is known about the relationships between lncRNAs and cardiac ANR in AF. In this study, second‐generation RNA sequencing was performed to examine the transcriptomes of lncRNAs in AF and non‐AF canine cardiac fat pads. A total of 61,616 putative lncRNAs were yielded, in which 166 were downregulated and 410 were upregulated with more than twofold change. Bioinformatics analysis showed that the aberrantly expressed genes were associated with neural development, migration and neurodegenerative disorders. On the basis of a series of filtering pipelines, two new lncRNAs, namely, TCONS_00032546 and TCONS_00026102, were selected. Silencing of TCONS_00032546 or TCONS_00026102 with lentiviruses in vivo could significantly shorten or prolong the atrial effective refractory period thereby increasing or preventing AF inducibility by promoting or inhibiting the neurogenesis. Besides, the expression of CCND1‐FGF19‐FGF4‐FGF3 gene cluster and SLC25A4, the nearby genes of TCONS_00032546 and TCONS_00026102, were negatively correlated with that of lncRNAs. Furthermore, combining bioinformatics analysis with literature review, TCONS_00032546 and TCONS_00026102 may induce effects by increasing the CCND1‐FGF19‐FGF3‐FGF4 gene cluster and SLC25A4 via complex mechanisms during neural remodeling. Taken together, dysregulated lncRNAs may play regulatory roles in AF neural remodeling, which may further provide potential therapeutic targets for prophylaxis and treatment of AF. J. Cell. Biochem. 116: 809–821, 2015.

Benefits of laboratory personalized antiplatelet therapy in patients undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials

BACKGROUND The preventive effects of laboratory personalized antiplatelet therapy (PAPT) strategy in-cluding genetic detection and platelet function testing (PFT) on major adverse cardiac events (MACEs) and bleeding events in coronary artery disease (CAD) patients undergoing stenting has been extensively studied. Despite that, no clear conclusion can be drawn. In this study, a meta-analysis was performed to explore a more precise estimation of the benefits of laboratory PAPT. METHODS Randomized controlled trials were identified by the use of search databases such as PubMed, Embase, and Cochrane Controlled Trials Register up to May 2017, and the estimates were pooled. RESULTS Fourteen studies including 9497 patients met the inclusion criteria. The laboratory PAPT reduced MACEs risk (risk ratio [RR] 0.58, 95% confidence interval [CI] 0.42-0.80, p = 0.001), stent thrombosis (RR 0.60, 95% CI 0.41-0.87, p = 0.008) and myocardial infarctions (RR 0.43, 95% CI 0.21-0.88, p = 0.02) compared to the non-PAPT group. No statistically significant difference was observed between the two groups regarding cardiovascular death (RR 0.77, 95% CI 0.51-1.16, p = 0.21), bleeding events (RR 0.96, 95% CI 0.81-1.13, p = 0.59) and ischemic stroke (RR 0.81; 95% CI 0.39-1.66, p = 0.57). The preventive effect on MACEs was more significant in patients with high on-treatment platelet reactivity (RR 0.46; 95% CI 0.27-0.80, p = 0.006). CONCLUSIONS Coronary artery disease patients after stenting could obtain benefits from laboratory PAPT. (Cardiol J 2018; 25, 1: 128-141).