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Circulation research [journal]
- Selected CD133+ Progenitor Cells to Promote Angiogenesis in Patients with Refractory Angina: The Final Results of the PROGENITOR Randomized Trial. [JOURNAL ARTICLE]
- Circ Res 2014 Sep 17.
Rationale: Refractory angina (RA) constitutes a clinical problem. Objective: The aim of this study was to assess the safety and the feasibility of transendocardial injection of CD133+cells to foster angiogenesis in patients with RA. Methods and Results: in this randomized, double-blinded, multicenter controlled trial, eligible patients were treated with granulocyte-colony-stimulating factor, underwent an apheresis and NOGA mapping and were randomized to receive treatment with CD133+cells or no treatment. The primary endpoint was the safety of transendocardial injection of CD133+cells, as measured by the occurrence of major adverse cardiac and cerebrovascular event at 6-month. Secondary endpoints analyzed the efficacy. Twenty-eight patients were included (n=19 treatment; n=9 control). At 6-month, 1 patient in each group suffered ventricular fibrillation and 1 patient in each group died. One patient (treatment group) had a cardiac tamponade during mapping. There were no significant differences between groups with respect to efficacy parameters, however, the comparison within groups showed: a significant improvement in the number of angina episodes/per month (median-absolute difference (mAD):-8.5(95%CI, -15.0;-4-0) and in angina functional class in the treatment arm but not in the control group. At 6-months, only one SPECT parameter: Summed Score improved significantly in the treatment group: at rest and at stress:(mAD:-1.0(95%CI,-1.9;-0.1) but not in the control arm. Conclusions: Our findings support feasibility and safety of transendocardial injection of CD133+cells in patients with RA. The promising clinical results and favorable data observed in SPECT summed score may set up the basis to test the efficacy of cell therapy in a larger randomized trial.
- Phosphorylation of Nox1 Regulates Association with NoxA1 Activation Domain. [JOURNAL ARTICLE]
- Circ Res 2014 Sep 16.
Rationale: Activation of Nox1 initiates redox-dependent signaling events crucial in the pathogenesis of vascular disease. Selective targeting of Nox1 is an attractive potential therapy but requires a better understanding of the molecular modifications controlling its activation. Objective: To determine the whether posttranslational modifications of Nox1 regulate its activity in vascular cells. Methods and Results: We first found evidence that Nox1 is phosphorylated in multiple models of vascular disease. Next, studies using mass spectroscopy and a pharmacological inhibitor demonstrated that protein kinase C-beta1 (PKC-βI) mediates phosphorylation of Nox1 in response to tumor necrosis factor-α (TNF-α). siRNA-mediated silencing of PKC-βI abolished TNF-α-mediated reactive oxygen species (ROS) production and vascular smooth muscle cell (VSMC) migration. Site-directed mutagenesis and isothermal titration calorimetry indicated that PKC-βI phosphorylates Nox1 at T429. Moreover, Nox1 T429 phosphorylation facilitated the association of Nox1 with the NoxA1 activation domain and was necessary for NADPH oxidase complex assembly, ROS production, and VSMC migration. Conclusions: We conclude that PKC-βI phosphorylation of T429 regulates activation of Nox1 NADPH oxidase.
- Actin Binding GFP Allows 4D In Vivo Imaging of Myofilament Dynamics in the Zebrafish Heart and the Identification of Erbb2 Signaling as a Remodeling Factor of Myofibril Architecture. [JOURNAL ARTICLE]
- Circ Res 2014 Sep 16.
Rationale: Dilated cardiomyopathy is a leading cause of congestive heart failure and a debilitating complication of anti-neoplastic therapies. Despite disparate causes for dilated cardiomyopathy, maladaptive cardiac remodeling and decreased systolic function are common clinical consequences, begging an investigation of in vivo contractile dynamics in development and disease, one that has been impossible to date. Objective: Imaging in vivo myocardial contractile filament dynamics and assess potential causes of dilated cardiomyopathy in anti-neoplastic therapies targeting Erbb2. Methods and Results: We generated a transgenic zebrafish line expressing an actin-binding GFP in cardiomyocytes, allowing in vivo imaging of myofilaments. Analysis of this line revealed architectural differences in myofibrils of the distinct cardiomyocyte subtypes. We used this model to investigate the effects of Erbb2 signaling on myofibrillar organization, since drugs targeting ERBB2 (HER2/NEU) signaling, a mainstay of breast cancer chemotherapy, cause dilated cardiomyopathy in many patients. High-resolution in vivo imaging revealed that Erbb2 signaling regulates a switch between a dense apical network of filamentous myofibrils and the assembly of basally localized myofibrils in ventricular cardiomyocytes. Conclusions: Using this novel line, we compiled a reference for myofibrillar microarchitecture among myocardial subtypes in vivo and at different developmental stages, establishing this model as a tool to analyze in vivo cardiomyocyte contractility and remodeling for a broad range of cardiovascular questions. Further, we applied this model to study Erbb2 signaling in cardiomyopathy. We show a direct link between Erbb2 activity and remodeling of myofibrils, revealing an unexpected mechanism with potentially important implications for prevention and treatment of cardiomyopathy.
- Response to letter regarding article, "renal denervation for the treatment of cardiovascular high risk-hypertension or beyond?". [Letter]
- Circ Res 2014 Sep 12; 115(7):e19-20.
- Letter by wang regarding article, "renal denervation for the treatment of cardiovascular high risk-hypertension or beyond?". [Letter]
- Circ Res 2014 Sep 12; 115(7):e18.
- Recent developments in cardiovascular genetics and genomics. [Journal Article]
- Circ Res 2014 Sep 12; 115(7):e11-7.
- Prior Publication Productivity, Grant Percentile Ranking, and Topic-Normalized Citation Impact of NHLBI Cardiovascular R01 Grants. [Journal Article]
- Circ Res 2014 Sep 12; 115(7):617-24.
We previously demonstrated absence of association between peer-review-derived percentile ranking and raw citation impact in a large cohort of National Heart, Lung, and Blood Institute cardiovascular R01 grants, but we did not consider pregrant investigator publication productivity. We also did not normalize citation counts for scientific field, type of article, and year of publication.To determine whether measures of investigator prior productivity predict a grant's subsequent scientific impact as measured by normalized citation metrics.We identified 1492 investigator-initiated de novo National Heart, Lung, and Blood Institute R01 grant applications funded between 2001 and 2008 and linked the publications from these grants to their InCites (Thompson Reuters) citation record. InCites provides a normalized citation count for each publication stratifying by year of publication, type of publication, and field of science. The coprimary end points for this analysis were the normalized citation impact per million dollars allocated and the number of publications per grant that has normalized citation rate in the top decile per million dollars allocated (top 10% articles). Prior productivity measures included the number of National Heart, Lung, and Blood Institute-supported publications each principal investigator published in the 5 years before grant review and the corresponding prior normalized citation impact score. After accounting for potential confounders, there was no association between peer-review percentile ranking and bibliometric end points (all adjusted P>0.5). However, prior productivity was predictive (P<0.0001).Even after normalizing citation counts, we confirmed a lack of association between peer-review grant percentile ranking and grant citation impact. However, prior investigator publication productivity was predictive of grant-specific citation impact.
- Mark sussman: programming heart cells to heal. [Journal Article]
- Circ Res 2014 Sep 12; 115(7):613-6.
- miR-25 in Heart Failure. [Journal Article]
- Circ Res 2014 Sep 12; 115(7):610-2.
- "Going Long": Long Non-Coding RNAs as Biomarkers. [Editorial]
- Circ Res 2014 Sep 12; 115(7):607-9.