Shulin Wu

Prospective Randomized Study to Assess the Efficacy of Site and Rate of Atrial Pacing on Long-Term Progression of Atrial Fibrillation in Sick Sinus Syndrome

Background— Atrial-based pacing is associated with lower risk of atrial fibrillation (AF) in sick sinus syndrome compared with ventricular pacing; nevertheless, the impact of site and rate of atrial pacing on progression of AF remains unclear. We evaluated whether long-term atrial pacing at the right atrial (RA) appendage versus the low RA septum with (ON) or without (OFF) a continuous atrial overdrive pacing algorithm can prevent the development of persistent AF. Methods and Results— We randomized 385 patients with paroxysmal AF and sick sinus syndrome in whom a pacemaker was indicated to pacing at RA appendage ON (n=98), RA appendage OFF (n=99), RA septum ON (n=92), or RA septum OFF (n=96). The primary outcome was the occurrence of persistent AF (AF documented at least 7 days apart or need for cardioversion). Demographic data were homogeneous across both pacing site (RA appendage/RA septum) and atrial overdrive pacing (ON/OFF). After a mean follow-up of 3.1 years, persistent AF occurred in 99 patients (25.8%; annual rate of persistent AF, 8.3%). Alternative site pacing at the RA septum versus conventional RA appendage (hazard ratio=1.18; 95% confidence interval, 0.79–1.75; P=0.65) or continuous atrial overdrive pacing ON versus OFF (hazard ratio=1.17; 95% confidence interval, 0.79–1.74; P=0.69) did not prevent the development of persistent AF. Conclusions— In patients with paroxysmal AF and sick sinus syndrome requiring pacemaker implantation, an alternative atrial pacing site at the RA septum or continuous atrial overdrive pacing did not prevent the development of persistent AF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00419640.

Prospective Randomized Study to Assess the Efficacy of Site and Rate of Atrial Pacing on Long-term Progression of Atrial Fibrillation in Sick Sinus Syndrome: Septal Pacing for Atrial Fibrillation Suppression Evaluation (SAFE) Study

Background— Atrial-based pacing is associated with lower risk of atrial fibrillation (AF) in sick sinus syndrome compared with ventricular pacing; nevertheless, the impact of site and rate of atrial pacing on progression of AF remains unclear. We evaluated whether long-term atrial pacing at the right atrial (RA) appendage versus the low RA septum with (ON) or without (OFF) a continuous atrial overdrive pacing algorithm can prevent the development of persistent AF. Methods and Results— We randomized 385 patients with paroxysmal AF and sick sinus syndrome in whom a pacemaker was indicated to pacing at RA appendage ON (n=98), RA appendage OFF (n=99), RA septum ON (n=92), or RA septum OFF (n=96). The primary outcome was the occurrence of persistent AF (AF documented at least 7 days apart or need for cardioversion). Demographic data were homogeneous across both pacing site (RA appendage/RA septum) and atrial overdrive pacing (ON/OFF). After a mean follow-up of 3.1 years, persistent AF occurred in 99 patients (25.8%; annual rate of persistent AF, 8.3%). Alternative site pacing at the RA septum versus conventional RA appendage (hazard ratio=1.18; 95% confidence interval, 0.79–1.75; P=0.65) or continuous atrial overdrive pacing ON versus OFF (hazard ratio=1.17; 95% confidence interval, 0.79–1.74; P=0.69) did not prevent the development of persistent AF. Conclusions— In patients with paroxysmal AF and sick sinus syndrome requiring pacemaker implantation, an alternative atrial pacing site at the RA septum or continuous atrial overdrive pacing did not prevent the development of persistent AF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00419640.

Catheter ablation restores decreased plasma miR-409-3p and miR-432 in atrial fibrillation patients

AIMS Despite numerous studies identifying specific microRNA (miRNA) expression profiles associated with atrial fibrillation (AF), changes in plasma miRNA expression in pre- and post-operative AF patients who have received catheter ablation, remain poorly characterized. This study aimed to reveal disease-related biomarkers by detecting plasma miRNA expression in AF patients, and examining the levels of AF-specific miRNAs in patients after catheter ablation, in order to help gauge therapeutic effects and assess prognosis. METHODS AND RESULTS A total of 100 Han Chinese patients with AF who had received catheter ablation, and 100 healthy individuals, were sequentially recruited to the study. Atrial fibrillation-specific plasma miRNAs were detected by Solexa sequencing and quantitative reverse transcription polymerase chain reaction. The expression levels of AF-specific miRNAs were also investigated in 40 post-operative patients (24-48 h) and 20 patients followed up (58.52 ± 36.00 days) after catheter ablation, to explore changes in miRNA expression. The expressions of miR-409-3p and miR-432 in the plasma of AF patients were lower than healthy individuals. In binary logistic regression analyses, reduced miR-409-3p and miR-432 levels were independently associated with AF (95% confidence interval: 1.02-2.22 and 1.09-2.43, P = 0.040 and 0.018, respectively). The levels of miR-409-3p and miR-432 showed no significant difference between post-operative patients and healthy individuals (P = 0.411 and 0.681, respectively), or between followed-up patients and healthy individuals (P = 0.720 and 0.073, respectively). CONCLUSION We suggest that plasma miR-409-3p and miR-432 are potential markers of AF, and catheter ablation restores their decreased levels in AF patients.

Incidence and outcomes of cerebrovascular events complicating catheter ablation for atrial fibrillation

AIMS Cerebrovascular complications are relatively uncommon, but severe adverse events are associated with catheter ablation of atrial fibrillation (AF). This study aimed to investigate the incidence, risk factors, and hospital outcomes of cerebrovascular events complicating AF ablation. METHODS AND RESULTS Cerebrovascular complications occurring during the procedure or hospitalization after AF ablation were assessed. Cerebrovascular events occurred in 9 of 1946 consecutive procedures (0.46%). Seven patients (0.36% per procedure) were diagnosed with ischaemic stroke and two patients (0.1% per procedure) with intracranial haemorrhage (ICH). Six events (6/9, 66.7%) occurred during the ablation and the remainders within 24 h after the ablation. Multivariable analysis revealed that previous ischaemic stroke [odds ratio (OR) 10.549; 95% confidence interval (CI) 2.551-43.625, P = 0.001] and mechanical valve replacement (OR 3.261; 95% CI 1.337-7.953, P = 0.009) were independent predictors. In a separate model, CHA2DS2-VASc score ≥3 (OR 7.992; 95% CI 2.046-31.215, P = 0.003) and mechanical valve replacement (OR 4.104; 95% CI 1.644-10.245, P = 0.002) were significantly associated with cerebrovascular complications. All patients survived to discharge except the two cases with ICH. CONCLUSION Cerebrovascular complications related to catheter ablation of AF are relatively infrequent and typically occur early either during the procedure or within the first 24 h after AF ablation. Previous ischaemic stroke, mechanical valve replacement, and CHA2DS2-VASc score ≥3 are independent predictors of such complications. The majority of these events are ischaemic stroke with a benign clinical outcome, while ICH may correlate with poor prognosis.

Effect of ranolazine on rat intrarenal arteries in vitro.

Ranolazine is mainly used to treat patients with chronic stable angina in clinical practice. However, ranolazine does not lower significantly systemic blood pressure. The direct effect of ranolazine on vascular tone remains unknown. In the present study, we investigated the vascular effects and mechanisms of action of ranolazine in isolated rat intrarenal arteries. Rings of intrarenal arteries were mounted in a small vessel myography using two stainless steel wires for the measurement of isometric tension. L-type Ca²⁺ currents were recorded in isolated single renal arterial smooth muscle cells using patch clamp techniques in whole-cell mode. Ranolazine induced concentration-dependent relaxations in rings contracted with phenylephrine, but ranolazine failed to cause any relaxation in rings pre-contracted by U46619, 5-HT or endothelin-1. Ranolazine also induced relaxations in norepinephrine pre-contracted rings. Yohimbine failed to induce relaxation in rings pre-contracted by norepinephrine. Propranolol did not affect ranolazine-induced relaxation but the relaxant effect of ranolazine was much less than that of prazosin. Ranolazine-induced relaxations were slight but significantly attenuated by endothelial denudation. Partial inhibition was observed in endothelium-intact arteries exposed to a combination of iberiotoxin and apamin. Ranolazine at higher concentration (>30 μM) inhibited Ca²⁺-induced contraction in a noncompetitive manner. Ranolazine reduced L-type Ca²⁺ currents at potentials between -30 and 50 mV in isolated renal artery myocytes. Therefore it can be said that ranolazine has significant α₁-adrenergic receptor and weak calcium channel antagonistic effects in rat intrarenal arteries.

Targeting EZH1 and EZH2 contributes to the suppression of fibrosis-associated genes by miR-214-3p in cardiac myofibroblasts

The role of microRNA-214-3p (miR-214-3p) in cardiac fibrosis was not well illustrated. The present study aimed to investigate the expression and potential target of miR-214-3p in angiotensin II (Ang-II)-induced cardiac fibrosis. MiR-214-3p was markedly decreased in the fibrotic myocardium of a mouse Ang-II infusion model, but was upregulated in Ang-II-treated mouse myofibroblasts. Cardiac fibrosis was shown attenuated in Ang-II-infused mice received tail vein injection of miR-214-3p agomir. Consistently, miR-214-3p inhibited the expression of Col1a1 and Col3a1 in mouse myofibroblasts in vitro. MiR-214-3p could bind the 3′-UTRs of enhancer of zeste homolog 1 (EZH1) and −2, and suppressed EZH1 and −2 expressions at the transcriptional level. Functionally, miR-214-3p mimic, in parallel to EZH1 siRNA and EZH2 siRNA, could enhance peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and inhibited the expression of Col1a1 and Col3a1 in myofibroblasts. In addition, enforced expression of EZH1 and −2, and knockdown of PPAR-γ resulted in the increase of Col1a1 and Col3a1 in myofibroblasts. Moreover, the NF-κB signal pathway was verified to mediate Ang-II-induced miR-214-3p expression in myofibroblasts. Taken together, our results revealed that EZH1 and −2 were novel targets of miR-214-3p, and miR-214-3p might be one potential miRNA for the prevention of cardiac fibrosis.

Macrophage migration inhibitory factor promotes expression of GLUT4 glucose transporter through MEF2 and Zac1 in cardiomyocytes

OBJECTIVE Evidence shows that both macrophage migration inhibitory factor (MIF) and GLUT4 glucose transporter are involved in diabetic cardiomyopathy (DCM), but it remains largely unknown whether and how MIF regulates GLUT4 expression in cardiomyocytes. The present study aims to investigate the mechanism underlying the modulation of GLUT4 by MIF in cardiomyocytes. MATERIAL AND METHODS Activations of AKT and AMPK signaling, and expressions of MIF, GLUT4 and the candidate GLUT4 regulation associated transcription factors in the diabetic mouse myocardium were determined. The screened transcription factors mediating MIF-promoted GLUT4 expression were verified by RNA interference (RNAi) and electrophoretic mobility shift assay (EMSA), respectively. RESULTS MIF was increased, but GLUT4 was decreased in the diabetic mouse myocardium. MIF could enhance glucose uptake and up-regulate GLUT4 expression in NMVCs. Expressions of transcription factor MEF2A, -2C, -2D and Zac1 were significantly up-regulated in MIF-treated neonatal mouse ventricular cardiomyocytes (NMVCs), and markedly reduced in the diabetic myocardium. Knockdown of MEF2A, -2C, -2D and Zac1 could significantly inhibit glucose uptake and GLUT4 expression in cardiomyocytes. Moreover, EMSA results revealed that transcriptional activities of MEF2 and Zac1 were significantly increased in MIF-treated NMVCs. AMPK signaling was activated in MIF-stimulated NMVCs, and AMPK activator AICAR could enhance MEF2A, -2C, -2D, Zac1 and GLUT4 expression. Additionally, MIF effects were inhibited by an AMPK inhibitor compound C and siRNA targeting MIF receptor CD74, suggesting the involvement of CD74-dependent AMPK activation. CONCLUSIONS Transcription factor MEF2 and Zac1 mediate MIF-induced GLUT4 expression through CD74-dependent AMPK activation in cardiomyocytes.

CDK6 mediates the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy

MicroRNA-1 (miR-1) is approved involved in cardiac hypertrophy, but the underlying molecular mechanisms of miR-1 in cardiac hypertrophy are not well elucidated. The present study aimed to investigate the potential role of miR-1 in modulating CDKs-Rb pathway during cardiomyocyte hypertrophy. A rat model of hypertrophy was established with abdominal aortic constriction, and a cell model of hypertrophy was also achieved based on PE-promoted neonatal rat ventricular cardiomyocytes (NRVCs). We demonstrated that miR-1 expression was markedly decreased in hypertrophic myocardium and hypertrophic cardiomyocytes. Dual luciferase reporter assays revealed that miR-1 interacted with the 3′UTR of CDK6, and miR-1 was verified to inhibit CDK6 expression at the posttranscriptional level. CDK6 protein expression was observed increased in hypertrophic myocardium and hypertrophic cardiomyocytes. Morover, miR-1 mimic, in parallel to CDK6 siRNA, could inhibit PE-induced hypertrophy of NRVCs, with decreases in cell size, newly transcribed RNA, expressions of ANF and β-MHC, and the phosphorylated pRb. Taken together, our results reveal that derepression of CDK6 and activation of Rb pathway contributes to the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy.

Allitridi inhibits transient outward potassium currents in human atrial myocytes.

1. It has been reported that allitridi, an active compound extracted from garlic, has many cardiovascular effects. However, it remains unknown whether allitridi affects major repolarization currents, such as the transient outward K+ current (Ito), ultrarapid delayed rectifier K+ current (IKur) and the L‐type Ca2+current (ICa), in human atrial myocytes.

Long-Term Outcomes of Radio-Frequency Catheter Ablation on Ventricular Tachycardias Due to Arrhythmogenic Right Ventricular Cardiomyopathy: A Single Center Experience

Aims To summarize our experience of radiofrequency catheter ablation (RFCA) for recurrent drug-refractory ventricular tachycardias (VTs) due to arrhythmogenic right ventricular cardiomyopathy (ARVC) in our center over the past 11 years and its related factors. Methods and Results We reviewed 48 adults (mean age 39.9 ± 12.9 years, range: 14 to 65) who met the present ARVC diagnostic criteria and accepted RFCA for VTs from December 2004 to April 2016. The patients received a total of 70 procedures using two ablation approaches, the endocardial approach in 52 RFCAs, and the combined epicardial and endocardial approach (the combined approach) in 18 RFCAs. Kaplan-Meier survival analysis showed that the combined approach achieved better acute procedural success (p = 0.003) and better long-term outcomes (p = 0.028) than the endocardial approach. Patients who obtained acute procedural success with non-inducibility had better long-term outcomes (p < 0.001). COX regression of multivariate analysis showed that procedural success was the only factor that benefited long-term outcome, irrespective of the endocardial or the combined approach (p = 0.001). The rate of sudden cardiac death (SCD) in patients without procedural success was significantly higher than that in patients with procedural success (p = 0.005). All patients without implantable cardioverter defibrillator (ICD) implantation who had successful final RFCA survived. Conclusions The combined approach resulted in better procedural success and long-term VT-free survival compared with the endocardial approach in ARVC patients with recurrent VTs. Acute procedural success with non-inducibility was strongly related to better long-term VT-free survival and reduced SCD, irrespective of whether this was achieved by the endocardial approach or the combined approach.