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Objectives This study sought to determine whether ablation of hidden substrate unmasked by right ventricular extrastimulation (RVE) improves ablation outcome of post-myocardial infarction (MI) ventricular tachycardia (VT). Background In patients with small or nontransmural scars after MI, part of the VT substrate may be functional and, in addition, masked by high-voltage far-field signals arising from adjacent normal myocardium. Methods In 60 consecutive patients, systematic analysis of electrograms recorded from the presumed infarct area was performed during sinus rhythm, RV pacing at 500 ms, and during a short-coupled RV extrastimulus. Sites showing low-voltage, near-field potentials with evoked conduction delay in response to RVE were targeted. Results In 37 (62%) patients, ablation target sites located in areas with normal voltage during sinus rhythm were unmasked by RVE (hidden substrate group). These patients had better left ventricular function (36 ± 11% vs. 26 ± 12%; p = 0.003), smaller electroanatomical scars ( 2 vs. 82 and 44 cm 2 ; p = 0.044 and p = 0.003) than did those in whom no hidden substrate was identified (overt substrate group). During a median follow-up of 16 months, 13 (22%) patients had VT recurrence. Patients with hidden substrate had a lower incidence of VT recurrence (12-month VT-free survival 89% vs. 50% in patients with overt substrate; p = 0.005). Compared with a historical cohort of 90 post-MI patients matched for left ventricular function and electroanatomical scar area, in whom no RVE was performed, patients in the hidden substrate group had a higher 1-year VT-free survival (89% vs. 73%; p = 0.039). Conclusions Hidden substrate ablation unmasked by RVE improves ablation outcome in post-MI patients with small or nontransmural scars.

Background The effect of right ventricular (RV) septal pacing as opposed to RV apical pacing on prognosis in patients undergoing pacemaker implantation remains controversial. This study was performed to examine the clinical efficacy of RV septal pacing in a large cohort with medium-term follow-up and propensity-matched analysis. Methods A total of 982 consecutive patients with first pacemaker implantation between 2008 and 2013 at two centers in Japan (51.4% male, age 76.1±10.6years, 64.3% septal pacing, 94% preserved ejection fraction [EF]) were enrolled. Propensity matching successfully matched 446 patients into RV septal and apical pacing groups. The primary endpoint, a combination of all-cause death and hospitalization due to heart failure, was compared between the two groups. Results In the propensity-matched cohort, the primary endpoint was observed in 61 patients (13.7%) over a median follow-up period of 2.1years (interquartile range, 1.1–3.5years). The effects of septal pacing on prognosis were not statistically significant (hazard ratio [HR]=1.10, 95% confidence interval [CI]=0.60–2.04, P=0.752). No significant benefit of septal pacing was observed on all-cause death (HR=1.86, 95%CI=0.74–4.66, P=0.187) and heart failure hospitalization (HR=0.93, 95%CI=0.44–1.98, P=0.847) when assessed separately. Conclusion Septal pacing did not show medium-term advantages in prognosis in this large-scale retrospective cohort study with propensity matching of patients with predominantly preserved EF.

The presented data were obtained from 982 consecutive patients receiving their first pacemaker implantation with right ventricular (RV) lead placement between January 2008 and December 2013 at two centers in Japan. Patients were divided into RV apical and septal pacing groups. Data of Kaplan–Meier survival analysis and Cox regression analysis are presented. Refer to the research article “Implications of right ventricular septal pacing for medium-term prognosis: propensity-matched analysis” (Mizukami et al., in press) [1] for further interpretation and discussion. Keywords: RV septal pacing, RV non-apical pacing, Prognosis, Heart failure, Mortality, Data

The present case report describes a 53-year-old man with drug-resistant heart failure. Electrocardiogram showed complete right-bundle branch block and left anterior fascicular block. A cardiac resynchronization therapy (CRT) device was implanted in him because echocardiography showed obvious left ventricular dyssynchrony between septal and lateral walls. After CRT implantation, dyssynchrony was improved and ejection fraction was increased. Evaluation of coexisting left hemiblock and left ventricular dyssynchrony may be needed in patients with atypical indications for CRT.

Several studies have demonstrated a relation between the rennin-angiotensin-aldosterone system and atrial fibrillation (AF), but there are no reports on the effect of eplerenone, a selective aldosterone blocker, on the prevention of AF recurrence after radiofrequency catheter ablation (RFCA). The aim of this study was to evaluate the effects of eplerenone on clinical outcomes after RFCA in patients with long-standing persistent AF. A total of 161 consecutive patients with long-standing persistent AF (sustained AF duration 1 to 20 years, mean 3.4 ± 3.8) who underwent RFCA were investigated. Eplerenone was used in 55 patients and not used in the remaining 106 patients. Other conventional pharmacologic agents, including angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers, were used equally in the 2 groups. After 24 months of follow-up, 47% of the patients were free from AF recurrence. The rate of freedom from AF recurrence was significantly greater in the eplerenone group (60%) than in the noneplerenone group (40%) (p = 0.011). By univariate analysis, the duration of sustained AF (p0.001), left atrial diameter (p = 0.010), left atrial volume index (p = 0.017), and early AF recurrence (p0.001) were significantly associated with AF recurrence, and the use of eplerenone was associated with maintenance of sinus rhythm after RFCA (p = 0.022). Multivariate Cox regression analysis showed that longer duration of sustained AF (3 years) (p0.001) and early AF recurrence (p0.001) were significantly associated with AF recurrence, and only eplerenone therapy significantly improved maintenance of sinus rhythm (p = 0.017). In conclusion, eplerenone significantly improved maintenance of sinus rhythm after RFCA in patients with long-standing persistent AF.

The full-length cDNA clone of a novel GRP78-binding protein (GBP) was isolated from rat brain using PCR-selected cDNA subtraction. GBP was predominantly expressed in neuronal cells among various brain tissues. GBP mRNA was already detected in the E12 brain and then gradually increased to reach a peak within P0-2 weeks after birth. GBP expression in the brain decreased age-dependently to approximately 30% of the postnatal level at 12 months. GBP encoded 1021 amino acids and was predicted to have two transmembrane regions and glutamic acid- and proline-rich regions. Because the sequence of GBP offered few clues to the possible function, we performed a GST-tagged GBP pull-down assay in PC12 lysates and identified GRP78, one of the heat shock proteins, as a counterpart. Observation of COS7 cells expressing green fluorescent protein- or Myc-tagged GBP showed that GBP was localized in the endoplasmic reticulum-Golgi domain where BODIPY 558/568 (4,4-difluro-5-(2-thienyl)-4-bora-3alpha,4alpha-diaza-S-indacene)-labeled brefeldin A accumulated. To investigate a biological role for GBP, we established Neuro2a cells stably expressing Myc-tagged GBP. Overexpression of GBP did not affect cell growth or morphological features but attenuated the time-dependent decrease in cell viability caused by serum deprivation compared with control cells. After 48 h of serum starvation, Neuro2a cells overexpressing GBP were resistant to the cell death induced by serum withdrawal. These results suggest that GBP would have a relevant functional role in embryonic and postnatal development of the brain.

Neural-restrictive silencer element (NRSE)/repressor element-1 (RE1) regulates neuron-specific gene expression by binding the transcriptional factor REST/NRSF which functions as a silencer in nonneuronal cells. In neuronal cells, a truncated, neuronal-specific REST/NRSF isoform, REST4, has been found but little is known about its function. To address this, we investigated the effect of REST/NRSF and REST4 on the activity-dependent activation of BDNF gene promoter I (BDNFp-I) using cultured rat cortical neurons. REST/NRSF markedly repressed the transcriptional activation of BDNFp-I, whereas the effect of REST4 was weak, depending upon the NRSE/RE1 sequence. In addition, REST4 enhanced the basal transcriptional activity of BDNFp-I. Coexpression of REST4 with REST/NRSF competitively inhibited the silencing effect of REST/NRSF on the activation of BDNFp-I. Although REST4 itself has a weak repressive effect on activation of the BDNF gene via NRSE/RE1, it can compete the silencing effect of REST/NRSF, suggesting a primary role for REST4 in preventing the neuron-specific gene from being inactivated by REST/NRSF and allowing gene activation in response to a variety of neuronal stimuli.

Neural-restrictive silencer (NRS) has been identified in at least twenty neuron-specific genes, and its nuclear DNA-binding factor, NRSF (also known as RE1-silencing transcription factor (REST)), has been cloned from human and rat, and was shown to repress transcription by recruiting corepressors mSin3 and/or CoREST via its N- and C-terminal domains, leading to chromatin reorganization by mSin3-associated histone deacetylase, HDAC. However, it is largely unknown how NRSF gene expression is regulated. To elucidate the mechanisms for gene expression of NRSF, we isolated the transcriptional unit of the NRSF gene from mouse and human, identified three 5′-non-coding exons in addition to three coding exons, determined transcription start sites, and identified two basal promoter activities in the upstream of the first two non-coding exons. Both promoters functioned equally in neuronal and non-neuronal cells, suggesting that levels of initial transcripts of NRSF gene are similar in neuronal and non-neuronal cells. These results suggest that the level of NRSF gene expression is not determined by transcription per se, and rather is modulated at the post-transcriptional level, e.g. splicing, mRNA stability, and/or post-translational modifications, in a cell-specific manner. Consistent with this idea, NRSF protein was apparently present even in neuronal cells and tissues, but was unable to bind to the NRS element, suggesting that NRSF is regulated at least in part post-translationally.