Transradial catheter ablation of left accessory pathway in patient with severe chest deformity.

A 45-year-old woman with severe chest deformity and great vessel tortuosity successfully underwent left accessory pathway ablation of atrioventricular reentrant tachycardia via right transradial arterial access. Transradial catheter ablation of left accessory pathway was safe and efficacious without complications. When transfemoral or transseptal access was impossible, transradial access was a good alternative route.

Transcatheter closure of large atrial septal defects in 18 patients.

PURPOSE: This study was designed to evaluate the efficacy and safety of transcatheter closure of large atrial septal defects (ASD). METHODS: Eighteen patients diagnosed as ostium secundum defect with a diameter of 30-40 mm were enrolled in this study. With the guidance of echocardiography and fluoroscopy, the Amplazter occlusion devices were implanted percutaneously through the femoral vein. RESULTS: A small residual left-to-right shunt was detected with echocardiography immediately postprocedure but resolved after 1 week. The occlusion devices remained in proper position, and there was no residual shunt at 1- and 29-month follow-ups. Cardiac function and atrial sizes improved significantly as compared with the preclosure states. CONCLUSIONS: Transcatheter closure of large atrial septal defects with the Amplazter occlusion device is feasible, safe and effective.

Loss of redox factor 1 decreases NF-kappaB activity and increases susceptibility of endothelial cells to apoptosis.

OBJECTIVE: The aim of this project was to test the hypothesis that redox factor 1 (Ref-1) was a critical upstream determinant of NF-kappaB-dependent survival signaling pathways in the vessel wall. METHODS AND RESULTS: Aortas from hemizygous transgenic mice harboring a single allele of Ref-1 exhibited a significant loss in NF-kappaB DNA binding activity. The NF-kappaB-dependent survival gene A20 was significantly downregulated in aortas of hemizygous Ref-1 mice, whereas IAP-2 was unchanged. Overexpression of A20 rescued cells from tumor necrosis factor (TNF)-induced apoptosis, suggesting that the loss of A20 in Ref-1 hemizygotes may be a rate-determining step in endothelial cell fate. Deletion of the previously defined redox-sensitive or the AP endonuclease domains of Ref-1 significantly decreased NF-kappaB transcriptional activation and endothelial cell survival. Furthermore, TNF-induced apoptosis was significantly potentiated in endothelial cells after delivery of Morpholino antisense oligodeoxynucleotides targeted to Ref-1. Loss of the redox-sensitive domain blocked the ability of Ref-1 to reduce p50; however, loss of the endonuclease domain did not effect p50 reduction, suggesting alternative mechanisms of action of Ref-1 on NF-kappaB activity. CONCLUSIONS: These findings establish a role for Ref-1 as an upstream determinant of NF-kappaB and A20-dependent signaling and endothelial survival in the vessel wall.

The role of [beta]-transducin repeat-containing protein ([beta]-TrCP) in the regulation of NF-[kappa]B in vascular smooth muscle cells.

OBJECTIVE: Degradation of IkappaB is an essential step in nuclear factor (NF)-kappaB activation. However, the determinants regulating this process have not been defined in vascular smooth muscle cells (VSMCs). We hypothesized that the E3-ligase, beta-transducin repeat-containing protein 1 (beta-TrCP1), was a rate-determining mediator that regulates the ubiquitin-mediated degradation of IkappaBalpha (in VSMC). METHODS AND RESULTS: Upregulation of beta-TrCP1 accelerated the rate of IkappaBalpha degradation, leading to increased NF-kappaB activity. In contrast, VSMCs harboring a dominant-negative beta-TrCP1 transgene lacking the F-box domain exhibited a reduction in serum-stimulated NF-kB activity but no alteration in response to tumor necrosis factor (TNF). These findings suggest that beta-TrCP1 increases the rate of NF-kappaB activation but is not rate-limiting in response to TNF in VSMCs. Endogenous beta-TrCP1 expression was regulated through the conserved Wnt cascade. Upregulation of Wnt1 resulted in beta-catenin-mediated activation of Tcf-4, leading to increased beta-TrCP1 expression and NF-kappaB activity. Furthermore, VSMCs harboring a Tcf-4 mutant lacking a beta-catenin binding domain exhibited a significant reduction in beta-TrCP1 expression along with abolishment of NF-kappaB activity. CONCLUSIONS: We provide the first evidence of crosstalk between the Wnt cascade and NF-kappaB signaling in VSMCs. This crosstalk is mediated through the E3-ligase, beta-TrCP1.

Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks.

Mechanical unloading of the heart with a left ventricular assist device (LVAD) significantly decreases mortality in patients with heart failure. Moreover, it provides a human model to define the critical regulatory genes governing myocardial remodeling in response to significant reductions in wall stress. Statistical analysis of a gene expression library of 19 paired human heart samples harvested at the time of LVAD implant and again at explant revealed a set of 22 genes that were downregulated and 85 genes that were upregulated in response to mechanical unloading with a false discovery rate of less than 1%. The analysis revealed a high percentage of genes involved in the regulation of vascular networks including neuropilin-1 (a VEGF receptor), FGF9, Sprouty1, stromal-derived factor 1, and endomucin. Taken together these findings suggest that mechanical unloading alters the regulation of vascular organization and migration in the heart. In addition to vascular signaling networks, GATA-4 binding protein, a critical mediator of myocyte hypertrophy, was significantly downregulated following mechanical unloading. In summary, these findings may have important implications for defining the role of mechanical stretch and load on autocrine/paracrine signals directing vascular organization in the failing human heart and the role of GATA-4 in orchestrating reverse myocardial remodeling. This unbiased gene discovery approach in paired human heart samples has the potential to provide critical clues to the next generation of therapeutic treatments aimed at heart failure.

Oxidative stress and apoptosis in cardiomyocyte induced by high-dose alcohol.

Binge drinking of alcohol causes cardiac dysfunction in some people. The mechanism remains unclear. This study was designed to investigate high doses of alcohol-induced oxidative stress and apoptosis in cardiomyocytes and protective effects of antioxidants. Cardiomyocytes isolated from 1- to 2-day-old Sprague-Dawley rats were treated with ethanol at doses of 0 mM, 50 mM, 100 mM, and 200 mM for 24 hours. Vitamin E (1 mM) and vitamin C (0.2 mM) were added to medium 1 hour before addition of ethanol. Results showed typical apoptosis: chromatin condensation, membrane blebbing, shrinkage, and cytoplasm condensation. Apoptosis is concentration-dependent in the range of 0 to 100 mM ethanol (apoptosis rates were respectively 0.68%, 2.03%, and 9.66% at ethanol concentration of 0 mM, 50 mM, and 100 mM). Necrotic cells became greatly increased in the 200 mM ethanol-treated group. Intracellular production of reactive oxygen intermediates increased as mitochondrial membrane potential decreased after ethanol treatment. Cytochrome c was found to be greater in the cytosol of the ethanol-treated groups. Activity of caspase-3 was higher in ethanol-treated groups (P < 0.05). Both vitamin E and vitamin C inhibited oxidative stress and myocyte apoptosis in ethanol-treated groups (P < 0.05). In conclusion, our data indicated that acute high-dose ethanol treatment primarily induces cardiomyocyte apoptosis at concentration up to 100 mM while necrosis is predominate at 200 mM. The underlying mechanism appears to involve mitochondrial damage via an increase in oxidative stress and releasing cytochrome c, which activates caspases that initiate chromatin fragmentation and apoptosis. Antioxidants, to a large extent, inhibit oxidative stress and apoptosis induced by ethanol.