Modulation of miR-10a-mediated TGF-ß1/Smads signaling affects atrial fibrillation-induced cardiac fibrosis and cardiac fibroblast proliferation.

Atrial fibrillation (AF) rat models and rat cardiac fibroblasts (CFs) with overexpressed or inhibited miR-10a were used to investigate the possible role of miR-10a-mediated transforming growth factor-ß (TGF-ß1)/Smads signaling in cardiac fibrosis and fibroblast proliferation in rats with AF. Gene ontology and pathway enrichment analyses were used to identify the possible function of miR-10a in cardiac fibrosis. The results showed that overexpressed miR-10a significantly prolonged the duration of AF, further elevated the collagen volume fraction (CVF), and increased the viability of CFs in AF rats; these findings were in contrast with the findings for rats with inhibition of miR-10a (all P<0.05). Moreover, miR-10a overexpression could promote miR-10a, collagen-I, collagen III, α-SMA, and TGF-ß1 protein expression and increase the levels of hydroxyproline but reduced Smad7 protein expression in atrial tissues and CFs in AF rats. Not surprisingly, inhibiting miR-10a led to completely contrasting results (all P<0.05). Moreover, TGF-ß1 treatment could reverse the inhibitory effect of miR-10a down-regulation on cardiac fibrosis in CFs. Bioinformatics analysis and luciferase reporter assay results demonstrated that miR-10a bound directly to the 3'-UTR of BCL6, which is involved in cell growth and proliferation. Thus, our study indicate that down-regulation of miR-10a may inhibit collagen formation, reduce atrial structure remodeling, and decrease proliferation of CFs, eventually suppressing cardiac fibrosis in AF rats via inhibition of the TGF-ß1/Smads signaling pathway.

Usefulness of upright T wave in lead aVR for predicting short-term prognosis of patients with ischemic stroke.

BACKGROUND: Upright T wave in lead aVR (TaVR) has recently been reported to be associated with cardiovascular death and mortality in general population and in patients with prior cardiovascular disease (CVD). However, the evidence for the predictive ability of TaVR in patients with ischemic stroke (IS) is lacking. METHODS: A total of 625 consecutive patients with IS (mean age: 66 ± 12 years; 379 male) were enrolled in this study between January 2013 and December 2014. Patients were divided into upright TaVR (≥0 mV; n = 201) and negative TaVR (<0 mV; n = 424) groups. All patients were evaluated with respect to clinical features and in-hospital clinical results. RESULTS: Overall, the prevalence of upright TaVR was 32.2% at baseline. Patients with an upright TaVR were older, had a higher percentage of CVD and hypertension, higher level of MB isoenzyme of creatine kinase (CKMB), faster heart rate, higher rate of QT prolongation > 450 ms, higher rate of negative T in lead II, higher rate of negative T in lead V6, higher rate of ST depression, and longer QTc duration. During the mean follow-up period of 20.0 ± 5.8 months, 29 (4.6%) patients experienced all-cause death and 12 (1.9%) patients experienced cardiovascular death, the primary end point. Concomitantly, 94 (15%) patients experienced recurrence of IS, the secondary end point. After adjusting for clinical covariates, upright TaVR was independently associated with all-cause death [hazard ratio (HR): 2.88, 95% confidence intervals (CI): 1.07-7.73], cardiovascular death (HR: 3.04, 95% CI: 1.07-8.64), and IS recurrence (HR: 1.86, 95% CI: 1.08-3.20). CONCLUSIONS: Upright TaVR in patients with IS is associated with increased mortality and recurrence of IS.

Usefulness of Red Blood Cell Distribution Width to Predict Heart Failure Hospitalization in Patients with Hypertrophic Cardiomyopathy.

Red cell distribution width (RDW) has been associated with heart failure (HF) hospitalization in the general population, but the correlation to HF hospitalization in patients with hypertrophic cardiomyopathy (HCM) is unclear.Ninety-eight HCM patients without a history of HF were enrolled and RDW was assessed as a predictor.During a 16.8 ± 9.0 month follow-up period, 17 subjects were hospitalized due to HF. HF hospitalization patients had higher RDW than non-HF patients (14.7 ± 1.4% versus 13.0 ± 0.9%, P < 0.001). The cut-off value of RDW for predicting HF hospitalization was 14% with a sensitivity of 83.2% and a specificity of 82.7%. Multivariate analysis demonstrated that brain natriuretic protein (BNP) (HR 1.028, 95% CI 1.011-1.045, P = 0.001) and RDW (HR 1.711, 95% CI 1.042-2.809, P = 0.034) were predictors of HF hospitalization.High RDW is an independent predictor of HF hospitalization and might be useful for predicting the prognosis in HCM patients.

Sigma-1 Receptor Stimulation with PRE-084 Ameliorates Myocardial Ischemia-Reperfusion Injury in Rats.

BACKGROUND: The sigma receptors are a relatively novel receptor group with respect to knowledge of their effect on health. Although the sigma-1 receptor agonist PRE-084 exhibits a cardioprotective effect in some studies, the benefits in cases of myocardial ischemia/reperfusion (I/R) are not clear. The aim of this study was to explore the mechanism of action and assess the effect of PRE-084 on myocardial I/R injury in rats. METHODS: In this study, rats were assigned randomly to three groups with computer (n = 14 for each group): a sham group, an I/R group, and a PRE-084 group. In the PRE-084 group, rats were administered PRE-084 1 h before operation. In the myocardial I/R model, the left anterior descending branch of rats was ligated and opened half an hour later. Cardiac function was assessed, and the apoptosis index was evaluated. The mechanisms of the cardioprotective effects of PRE-084 were explored. RESULTS: PRE-084 pretreatment preserved cardiac function and reduced myocardial apoptosis (F = 86.0, P < 0.01) with Western blotting analysis, showing significantly reduced expression of Bax (F = 75.7, P < 0.01) and cleaved-caspase 3 (F = 44.7, P < 0.01), along with increased expression of the Bcl-2 protein (P < 0.01) and phosphorylated protein kinase B (p-Akt) (P < 0.01) and phosphorylated-endothelial nitric oxide synthase (p-eNOS; P < 0.01). CONCLUSION: PRE-084 preserved cardiac function and reduced myocardial apoptosis through the activation of Akt and eNOS.

Neural substrate of posterior left atrium: A novel modulation for inducibility and remodeling of atrial fibrillation in canine.

BACKGROUND: The neural mechanism of posterior left atrium (PLA) for genesis of atrial fibrillation has not been completely elucidated. We sought to assess the contribution of PLA denervation on atrial fibrillation (AF) inducibility and atrial remodeling. METHODS AND RESULTS: After left thoracotomy in anesthetized dogs (n = 32), electrode catheters were attached to the PLA, left atrial roof, left pulmonary vein and left atrial appendage. Experiment 1 (n = 16): Vagal stimulation (VS group, n = 8) led to more pronounced ERP shortening in PLA than in other sites (CTL:71±7 ms vs VS: 52±6 ms, P<0.05;). Compared with control group (CTL group, n = 8), atropine alone or with propranolol applied to PLA greatly inhibited VS-induced ERP shortening, ERP dispersion increase, and AF inducibility in the left atrium (P<0.05); but ERP was not significantly different between atropine alone and DB conditions (Atro:85±8 ms vs DB:90±9ms, P>0.05). In addition, domain frequency (DF) of VS-induced AF waveform was not affected by atropine alone, while selective double autonomic blockade at PLA significantly decreased DF at all sites (P<0.05). Experiment 2 (n = 16): In group 1 (n = 8), ERP was markedly shortened in the first 2 hours (11-19% decrease) and then stabilized; however, WOV was progressively widened throughout the 6 hours rapid atrial pacing (BS: 51±9ms vs 6th hour: 161±30ms, P<0.05). After drug application, ERP was increased in all sites of atria, the ERP dispersion was significantly decreased (Atro: 2.36±0.02 vs 6th hour: 5.09±0.07, P<0.05) and AF could be induced in only 1 of 8 dogs. In group 2 (n = 8), 6 hours rapid atrial pacing failed to shorten the ERP and increased ERP dispersion, and only 2 episodes of AF could be induced (WOV = 0). CONCLUSION: Local denervation of PLA, as predominant atrial autonomic profile, greatly inhibits AF inducibility and atrial remodeling.

Main air pollutants and ventricular arrhythmias in patients with implantable cardioverter-defibrillators: A systematic review and meta-analysis.

OBJECTIVE: Previous studies of ambient air pollutants and ventricular arrhythmias in patients with implantable cardioverter-defibrillator (ICD) have yielded mixed results, and the association between air pollution and ventricular arrhythmias in these patients remains unclear. This study aimed to assess and quantify the association between exposure to major air pollutants [CO, inhalable particles (PM10), SO2, fine particulate matter (PM2.5), O3, and NO2] and the presence of ventricular arrhythmia in patients with ICD. METHODS: The Medline, PubMed, Web of Science, Global Health Library, Virtual Health Library, Population Information Online (POPLINE), and New York Academy of Medicine Grey Literature Report databases were searched to identify studies analyzing the association between ventricular arrhythmias in patients with ICD and the abovementioned main air pollutants. Pooled estimates were generated using a random-effects model or fixed-effects model, according to the value of heterogeneity. Heterogeneity within studies was assessed using Cochran's Q and I2 statistics. Funnel plots, Egger's regression test, and Begg's rank correlation method were used to evaluate publication bias. Sensitivity analyses were also conducted to evaluate the potential sources of heterogeneity. RESULTS: After a detailed screening of 167 studies, seven separate studies were identified. Ventricular arrhythmias in patients with ICD were found to be positively, but not significantly, associated with CO, PM10, SO2, PM2.5, and NO2, with a pooled estimate [odds ratio (OR) associated with each 10 µg/m3 increase in pollutant concentration, except for CO, which was associated with each 1 mg/m3 increase in concentration] of 1.03 [95% confidence interval (CI): 0.92-1.17, P = 0.59] for CO, 1.01 (95%CI: 0.97-1.05, P = 0.55) for PM10, 1.09 (95%CI: 0.95-1.24, P = 0.22) for SO2, 1.07 (95%CI: 0.95-1.21, P = 0.25) for PM2.5, and 1.06 (95%CI: 0.98-1.14, P = 0.16) for NO2. No increased risk of ventricular arrhythmias in patients with ICD was found to be associated with O3 (OR = 1.00; 95%CI: 0.98-1.01, P = 0.56). CONCLUSIONS: The results of this study provide little evidence that ambient air pollutants affect the risk of ICD discharges for treating ventricular arrhythmias.

Effects of Dantrolene Treatment on Ventricular Electrophysiology and Arrhythmogenesis in Rats With Chronic ß-Adrenergic Receptor Activation.

Dantrolene, which is primarily used to treat malignant hyperthermia, has recently been suggested for the prevention of arrhythmogenesis in various animal models. In this study, the effects of dantrolene treatment on electrophysiological properties and ventricular arrhythmias (VAs) in rats with chronic ß-adrenergic receptor (ß-AR) activation were investigated. Rats were randomized to treatment with saline (control group), isoproterenol (ISO; ISO group), or ISO + dantrolene (ID group) for 2 weeks. An electrophysiological study was performed to assess action potential duration restitution (APDR) and induce action potential duration (APD) alternans or VA in vitro. The protein levels of Cav1.2, sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a), and ryanodine receptor 2 (RyR2) were detected by Western blot. Compared with the control group, chronic administration of ISO significantly increased APD, the maximum slope (Smax) of APDR curve, and the spatial dispersions of Smax and APD (all P < .01), and all effects were attenuated by dantrolene treatment (all P < .05). Additionally, chronic ISO administration significantly reduced the protein levels of SERCA2 and RyR2, but increased the Cav1.2 protein expression (all P < .05). However, compared with the ISO group, dantrolene treatment preserved SERCA2a and RyR2 protein levels and decreased Cav1.2 protein levels in the ID group (all P < .05). The intracellular Ca(2+) ([Ca(2+)]i) levels measured by incubating isolated cardiomyocytes with Fluo-3/alveolar macrophages were significantly increased in the ISO group compared with the control group (P < .01). Dantrolene treatment markedly reduced the rise of [Ca(2+)]i levels caused by chronic administration of ISO (P < .05). Dantrolene treatment also prevented the reductions in the APD alternans and VA thresholds induced by chronic ISO stimulation (all P < .05). These data suggest that dantrolene stabilizes ventricular electrophysiological characteristics and increases the expression of key sarcoplasmic reticulum calcium cycling proteins to reduce vulnerability to VA in rats with chronic ß-AR activation.

Effects of endothelin-1 chronic stimulation on electrical restitution, beat-to-beat variability of repolarization, and ventricular arrhythmogenesis.

Chronically elevated levels of endothelin-1 (ET-1) have been detected in several cardiovascular diseases. In this study, we investigated the chronic effects of ET-1 on the electrophysiological characteristics expected to influence the genesis and maintenance of ventricular arrhythmia (VA). Rabbits were randomized to ET-1 (ET-1 group) or 0.9% saline (control group) for 2 weeks. The S1-S2 protocol and S1-S1 dynamic pacing were performed to assess the action potential duration restitution (APDR) and to induce APD alternans or VA in 4 sites of Langendorff-perfused rabbit hearts. The beat-to-beat variability of repolarization was quantified as short-term variability and long-term variability. Compared with the control group, chronic ET-1 administration significantly prolonged QT intervals, APD at 90% repolarization (APD90), and effective refractory period (ERP), steepened the maximum slopes of the APDR curve, decreased the ERP/APD90 ratio, and increased the spatial dispersions of APD90, ERP, and maximum slopes (P < 0.05 for all). Moreover, chronic ET-1 administration markedly increased the short-term variability and long-term variability (P < 0.01 for all). APD alternans occurred in both groups, but the threshold of APD alternans was decreased at all sites in the ET-1 group (P < 0.01 for all). We also observed that chronic ET-1 stimulation significantly increased the incidence and duration of the VA episodes. These results suggest that chronic stimulation with ET-1 facilitated VA by steepening the APDR curve and increasing the spatial dispersion of APDR and beat-to-beat variability of repolarization.

[Frequency and transcript variant analysis of gene fusions between TMPRSS2 and ETS transcription factor genes in prostate cancer].

OBJECTIVE: To investigate the frequencies and types of fusions between the transmembrane protease serine 2 (TMPRSS2), ETS-related gene (ERG), ETS variant-1 (ETV1), and ETS variant-4 (ETV4) genes in prostate cancer (PCa) and significance thereof. METHODS: Biopsy samples of prostate were obtained under transrectal ultrasound (TRUS) from 32 PCa patients, aged (74 +/- 8) and 34 patients with benign prostate hyperplasia (BPH). Nested RT-PCR and direct DNA sequencing were used to detect the fusion genes of TMPRSS2/ERG, TMPRSS2/ETV1, and TMPRSS2/ETV4. The association between the fusion-positive tumor rate and Gleason grading was analyzed. RESULTS: Of the 32 PCa patients, TMPRSS2/ERG fusion was detected in 17 cases (53.1%), including 5 variant fusion transcripts one of which was newly discovered with the GenBank accession number of EU090248. TMPRSS2/ETV1 fusion was detected in only 2 cases (6.3%), including one newly discovered variant fusion transcripts with the GenBank accession number of EU090249. TMPRSS2/ETV4 fusion was not detected. The positive rates of TMPRSS2/ERG and TMPRSS2/ETV1 fusions showed no statistical association with the Gleason grade (P = 0.169). No fusion between the TMPRSS2 and ETS transcription factor genes was detected in the 34 BPH samples. CONCLUSION: TMPRSS2/ERG and TMPRS22/ETV1 fusion genes with different subtypes exist in the tissues of PCa. TMPRSS2/ERG and TMPRSS2/ETV1 fusion genes may be used as diagnostic tools for PCa.