tbuckley/cabot-search huggingface dataset:
Abstract 19535: Constitutive Expression of a Dominant Negative TGF-β Type-II Receptor in the Posterior Left Atrium Attenuates NADPH Oxidase and Mitochondrial Superoxide Production and Decreases Atrial Fibrosis (Resulting in Decreased AF)
Authors: Aaron Kunamalla, Jason Ng, David Gordon, Suzanne Browne, Brandon Smeltzer, Bradley Knight, Rod Passman, Jeffrey Goldberger, Gary L Aistrup, Rishi Arora
Journal: Circulation (2012)

Background: Oxidative stress is an important mechanism in the creation of AF substrate, especially in the setting of heart failure (HF). This is in part through reactive oxygen species (ROS) leading to activation of TGF-β signaling, which results in creation of atrial fibrosis. ROS are also an important downstream mediator of TGF-β signaling. We therefore hypothesized that in a canine model of HF induced by ventricular tachypacing, decreasing TGF-β signaling via atria-targeted dominant-negative type II TGF-β receptor expression will attenuate both oxidative stress and atrial fibrosis, thereby leading to decreased AF. Methods: 17 dogs underwent injection + electroporation in the posterior left atrium (PLA) of either a plasmid expressing a dominant negative TGF-β type II receptor (pUBC-TGFβdnRII) (N=8) or control vector (p-UBC- LacZ ) (N=7), followed by 3-4 weeks of right ventricular tachypacing (240 bpm). A terminal study was performed to assess for AF inducibility. Tissue was assayed for changes in fibrosis (Trichrome staining) and oxidative stress (superoxide quantification via lucigenin chemiluminescence). Results: Downregulation of TGF-β signaling by TGFβdnRII significantly decreased fibrosis ( Figure 1a , blue staining), attenuated NADPH- and mitochondrial-generated superoxide ( Figure 1b ) and significantly decreased AF duration ( Figure 1c ), as compared to control animals. Conclusions: Targeted non-viral gene-therapy approaches aimed at reducing TGF-β signaling in the left atrium results in a decrease in AF substrate, in part through the reduction of oxidative stress and the development of fibrosis. Further optimization of this gene therapy approach may translate into effective AF therapies.
Abstract 19509: Cardiomyocyte-Specific Overexpression of the E3 Ubiquitin Ligase Wwp1 Causes Altered Connexin 43 and 45 Expression Leading to Arrhythmias and Sudden Cardiac Death
Authors: Wassim Basheer, Brett S Harris, Lydia E Matesic
Journal: Circulation (2012)

Rationale: The electrical coupling between adjacent cardiomyocytes is tightly regulated by gap junctions (GJ) to ensure proper electrical conduction in the myocardium. We have recently shown that the ubiquitin ligase Wwp1 can interact with and ubiquitylate the GJ protein connexin 43 (Cx43) causing its degradation. All mice ubiquitously overexpressing Wwp1 develop left ventricular hypertrophy (LVH), a 90% decrease in Cx43 protein, and die from sudden cardiac death (SCD) around 8 weeks of age. Hypothesis: We hypothesize that the effects of Wwp1 overexpression are cell autonomous to cardiomyocytes and that some degree of compensation exists until 8 weeks of age in mice. Methods: Cardiomyocyte-specific overexpression of Wwp1 was achieved using a tamoxifen-inducible cre transgenic mouse line driven by the α-MHC promoter. LVH was assessed in animals overexpressing cardiac Wwp1 (n=8) relative to their wild type littermates (n=8) using echocardiography. Cx43 and Cx45 protein levels and localization within myocardial tissue was determined via Western blotting and multi-immunofluorescence staining in conjunction with laser scanning confocal microscopy. Susceptibility to arrhythmias was ascertained using ventricular burst pacing monitored by ECG. Results: Induction of cardiomyocyte-specific Wwp1overexpression at 4 weeks of age resulted in decreased Cx43 expression, ECG abnormalities, and inducible ventricular arrhythmias as early as 48h following induction. In contrast, protein levels of Cx45 were unaltered but showed mislocalization. Unpaced Wwp1 overexpressers (n=12) displayed progressive LVH and SCD at 8 weeks of age. Interestingly, induction of cardiac Wwp1 overexpression at 8 weeks of age or later resulted in similar Cx43 and Cx45 changes and associated ECG abnormalities. Spontaneous or induced ventricular arrhythmias were observed as early as 48h following induction with no associated LVH. Conclusions: Wwp1 exerts its effects on cardiac structure and function in a cell autonomous manner. There is some plasticity in the myocardium which provides protection against spontaneous arrhythmias up until 8 weeks of age in mice. This mechanistic insight highlights the potential for novel anti-arrhythmia therapeutics targeting Wwp1.
Abstract 19523: Catheter-Based Renal Denervation for the Treatment of Patients with Drug-Resistant Hypertension: EnligHTN I: Three-Month Data of a First in Man Study Using a Multi-Electrode Radiofrequency Ablation Catheter
Authors: Vasilios Papademetriou, Stephen G Worthley, Costas Tsioufis, Matthew Worthley, Derek Chew, Ajay Sinhal, Ian Meredith, Yuvaraj Malaiapan
Journal: Circulation (2012)

Introduction: Renal denervation has emerged as a novel approach for the treatment of patients with drug-resistant hypertension. To-date studies in humans have been done using a single-tip electrode radiofrequency ablation catheter to achieve circumferential sympathetic fiber interruption through the renal artery wall. We investigated the safety and efficacy of a multi-electrode catheter ablation system developed by St Jude Medical (EnligHTN). Methods and results: The EnligHTN catheter has 4 electrodes attached on a basket mounted at the tip of the catheter. The basket is collapsed and can be expanded via an external mechanism once the catheter is placed in the desired location of the renal artery. The electrodes can then be activated sequentially to achieve the desired lesion pattern. In preclinical studies, in large animal models we found that using a predetermined algorithm, transmural lesions can be placed strategically in the renal artery so to achieve optimal renal denervation. In the present study we assessed the efficacy and safety of the EnligHTN catheter in 46 patients with drug resistant hypertension (av. age 60±10years, 33% women, BMI 32kg/m², 20% with CAD, 59% with hyperlipidemia , 33% with type II DM and 30% with sleep apnea). Patients were on an avg. of 4±0.6 antihypertensive medications at baseline. Bilateral renal nerve ablation was done using the femoral percutaneous approach. On av. 7.7±0.8 lesions were created in the right renal artery and 7.4±1.4 lesions in the left renal artery. The median procedure time was 34 minutes. At one month there was a 28/10 mmHg (n=46) reduction in BP (p&lt;0.001) and at three months a 35/14mmHg (n=24) reduction (baseline BP of 176±16). There was no significant change in serum creatinine or eGFR. There were no significant procedure related complications. Small hematomas were noted in 4 patients, vasovagal reaction in 3 and transient bradycardia in 1. Conclusions: In conclusion this data indicates that the EnligHTN ablation system is safe and effective. Sympathetic renal denervation can substantially improve BP control in patients with drug resistant hypertension.
Abstract 19494: PGC-1α Mediates Anti-Remodeling Impact of cGMP-PDE5 Inhibitor in Failing Hearts
Authors: Guangshuo Zhu, Manling Zhang, Nina Kaludercic, Djahida Bedja, Dong I Lee, Hideyuki Sasaki, Taro Kariya, Nazareno Paolocci, Kathleen Gabrielson, David Kass, Eiki Takimoto
Journal: Circulation (2012)

Background: The transcriptional coactivator peroxisome proliferator-activated receptor- coactivator 1 (PGC-1α) is a master regulator of mitochondrial biology, regulating cardiac mitochondrial metabolism and oxidative stress, and its down-regulation has been implicated to play a key role in pathogenesis of heart failure. NO-cGMP signal reportedly up-regulates PGC-1α in adipose tissue. We hypothesize that cGMP signal activation by sildenafil (SIL) up-regulates PGC-1α in cardiac myocytes and ameliorates cardiac failure remodeling. Methods and Results: Neonatal rat ventricular myocytes (NRVM) exposed to phenylephrine (20µM 96hr) revealed ∼40% down-regulation of PGC1α and impaired mitochondrial respiration (65% decrease in respiratory control ratio, RCR), both of which were normalized by SIL (1µM). Direct cGMP-PKG activation by adenoviral PKG overexpression in NRVM up-regulated PGC1α, and increased mitochondrial respiration (120% with glutamate/malate substrate), whereas enhanced mitochondrial respiratory function was abrogated when PGC1α was silenced. These suggest cGMP-PKG up-regulates PGC1α and modulate mitochondrial respiration in cardiac myocytes. We next tested in vivo role of this regulation using animals lacking in PGC1α (KO). In wild type controls (WT), pressure-overload (TAC) induced dilating remodeling at 1-2 wk, which further develops failure over 7wks, associated with ∼50% down-regulation of PGC-1α, reduced mitochondrial biogenesis and respiratory function (RCR), and increased oxidative stress. SIL treatment (100mg/kg/day 6wk) up-regulates PGC1a, and improves all of these features, including RCR for all three substrates. In contrast, KO hearts developed significantly worse remodeling after 3wk of pressure-overload induction (%FS, WT-TAC: 41.08±7.50 vs. KO -TAC: 32.90 ± 12.08 at 3wk, WT-TAC: 34.30±7.51 vs. KO-TAC:19.90 ± 1.84 at 7wk). Importantly, 6wk Sil treatment did not have any impact on this late remodeling progression or mitochondrial respiratory function in KO hearts. Conclusion: Sildenafil reverses cardiac failure remodeling process via a PGC-1α dependent mechanism. This highlights the beneficial actions of sildenafil for the treatment of heart failure.
Abstract 19560: Etv2 Regulates Endothelial Development via Activation of Sox7
Authors: Claudia Zierold, Ann N Behrens, Yi Ren, Naoko Koyano-Nakagawa, Daniel J Garry, Cindy M Martin
Journal: Circulation (2012)

Etv2 has recently been shown to be an important factor for the specification of the endocardial/endothelial and hematopoietic lineages. Transgenic embryos lacking Etv2 die between E9.0 and E9.5 due to absence of the endocardial/endothelial lineage and significant disruption of hematopoietic lineages. Sox 7, Sox 17 and Sox 18 comprise the Sox-F family which has been shown to be important in the regulation of hematopoietic cells and cardiovascular development. Therefore, we examined the hypothesis that the Sox family members were downstream targets of Etv2. Sox 7, Sox 17 and Sox 18 were found to be significantly downregulated in the Etv2 null mice compared to wildtype (WT) littermates at two developmental stages. WT embryoid body (EB) developmental expression profiles supported that Sox 7 and Sox 17, but not Sox 18, were direct downstream targets of Etv2. Studies performed using ES cells generated from the Etv2 null and WT littermate blastocysts confirmed the lack of the endothelial and hemogenic endothelium lineages in the absence of Etv2. The expression of all Sox F family members was also markedly altered in the Etv2 null EB system with a virtual absence of both Sox 7 and Sox18 expression in all developmental timepoints in the Etv2 null EBs when compared to WT controls. We utilized an array of molecular biological techniques to demonstrate that Etv2 is a direct upstream regulator of the Sox 7 gene. We also generated an inducible Sox7 overexpressing embryonic stem (ES) cell line and overexpression of Sox7 resulted in an induction of the endothelial molecular program with an increase in the percentage of Flk-1/Cdh5 double positive endothelial progenitor cells and increased expression of Pecam1 and Cdh5 in Sox7 overexpressing Day6 EBs. Collectively, these studies support the conclusion that Etv2 is essential for the endocardial/endothelial lineage including the hemogenic endothelium and Sox7 is an important factor in this developmental pathway. To further verify the role of Sox 7, we are undertaking rescue experiments of the Etv2 null ES cells by expressing Sox 7 under the control of an inducible lentivirus system. We anticipate that the induction of Sox 7 in Etv2 null EBs will reestablish expression of the endothelial and hemogenic endothelial molecular programs.
Abstract 19517: Pro-Angiogenic MicroRNA-27b Retards EPC Apoptosis and Accelerates Wound Healing in Type 2 Diabetes via Suppressing p53 and Bax/Bcl-2 Ratio
Authors: Jie-Mei Wang, Jing-Jing Cai, Hong Yuan, Alex F Chen
Journal: Circulation (2012)

Introduction: Endothelial progenitor cells (EPCs) are promising candidates for autologous cell therapy of diabetic wound repair because of their high angiogenic potentials. However, increased EPC apoptosis in diabetes directly limits its clinical success. MicroRNAs are endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level, but their roles in EPC-mediated angiogenesis in diabetes are incompletely understood. We hypothesized that the pro-angiogenic miR-27b inhibits EPC apoptosis and improves wound healing in type 2 diabetes. Methods and Results: Bone marrow-derived EPCs from adult male type 2 diabetic db/db mice and their normal littermates db/+ mice were used. MiR-27b expression (real-time PCR) in EPCs was decreased by &gt;66% in db/db vs. db/+ mice (n=4, p&lt;0.05). The impaired EPC angiogenesis of &gt;70% (Matrigel tube formation, n=4, vs. db/+) and increased EPC apoptosis (TUNEL staining, n=3, p&lt;0.05 vs. db/+) in diabetes were rescued following miR-27b mimic transfection (n=3, p&lt;0.05 vs. db/db + scramble). p53 and Bax/Bcl-2 ratio in EPCs (Western blot analyses) were significantly higher in db/db mice (by 23% and 58%, respectively, vs. db/+), which were suppressed by miR-27b mimic (n=3, p&lt;0.05 vs. db/db + scramble). Excisional wound (6-mm diameter) closure was markedly delayed in db/db vs. db/+ mice (n=5, p&lt;0.05), accompanied by poorer wound angiogenesis (Laser Doppler detection, n=5, p&lt;0.05) and elevated expression of p53 (&gt; 72%) and Bax/Bcl-2 ratio (&gt; 55%) (both n=5 vs. db/+). Local delivery of miR-27b mimic or cell therapy using diabetic EPCs (10 6 ) with miR-27b mimic transfection significantly accelerated wound closure rates (n=5, p&lt;0.05), with a concomitant augmentation of wound perfusion in db/db mice (n=5, p&lt;0.05). Conclusion: miR-27b retards EPC apoptosis and accelerates wound healing in type 2 diabetic mice, at least in part, via suppressing p53 and Bax/Bcl-2 ratio. These findings may provide a mechanistic basis for rescuing EPC dysfunction in diabetes for successful autologous cell therapy.
Abstract 19492: Adipose-Specific Gene Therapy Corrects Leptin Deficiency in vivo
Authors: Sean M O'Neill, Shu-Jen Chen, Arbansjit Sandhu, Christine Hinkle, Stephen Stephan, Julie Johnston, Muredach Reilly
Journal: Circulation (2012)

Objective: To develop an in vivo , systemic method of gene therapy specifically targeting adipose tissue. We assessed the hypothesis that adipose-specific gene therapy using adeno-associated viruses (AAV) can correct leptin deficiency in vivo . Background: Obesity is a major risk factor for developing coronary heart disease. Adipose is an endocrine organ critical for energy intake and expenditure. Available data on adipose is limited, in part, because of the difficulties in adapting experimental techniques to tissue with high lipid content. Few studies have investigated in vivo gene transfer in adipose tissue, and these studies used subcutaneous injections in obese mice. Method and Results: Tail vein iv delivery of genes to adipose tissue was assessed in healthy C57BL/6 mice injected with AAV serotype 8 (AAV8) containing the expression vector of interest. Mice were sacrificed 2-3 weeks after injection, and tissues were analyzed for transgene expression. Systemic delivery of a vector containing the GFP gene under control of a CMV promoter induced GFP transgene expression in most tissues, including all adipose depots tested. Replacing the CMV promoter with an adiponectin enhancer/promoter unit and incorporating liver specific micro-RNA-122 target sites into the vector restricted GFP expression to adipose tissue. The leptin gene was put into the adipose-targeted expression vector and delivered by AAV8 to 9-10 week old ob/ob mice. Phenotypic changes were then measured for 8 weeks. Expression of leptin gene was detectable in multiple adipose tissue beds at both RNA and protein levels in mice receiving AAV8 leptin vector, but absent in control mice. Mice receiving leptin gene ate less food and had lower insulin levels compared to control mice. At sacrifice, average weight of mice receiving leptin gene was 14 g less than control mice. Glucose tolerance tests demonstrated adipose-targeted leptin gene therapy increased insulin sensitivity in ob/ob mice. Conclusion: AAV8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and thus correct for leptin deficiency in ob/ob mice. This novel approach has therapeutic potential in obesity and downstream complications such as insulin resistance and diabetes.
Abstract 19508: Remote Supervised Reinforcement of Cardiopulmonary Resuscitation Skills by Telephone Improves One-Year Retention: A Randomized-Controlled Trial
Authors: Jia LI, Yimin Xu, Peng Yue, Yanling Wang, Fangqin Wu, Lin Zhou, Meng Yu, Ling Wang, Lijuan Xing, Shu Zhang, Ying Wu
Journal: Circulation (2012)

Objective: Bystander CPR is an effective way of improving the outcome of out of hospital cardiac arrest (OHCA). However, the survival rate of OHCA remains &lt; 10% due to rapid skill deterioration following CPR training. We explored the effect of two remote supervised review models (audio-visual [AV] and audio-visual-practice [AVP]) on CPR skill retention. Method: Family members of patients at high risk of sudden cardiac arrest (SCA) were recruited from communities in Beijing, China. All subjects received a 90-min CPR course, and a CPR instruction booklet for review at home as needed. At the end of the course, if the subjects passed the skill test, they were randomized into one of the 3 groups (AV, AVP, and control) using sealed envelopes. The AV group was provided with a CPR instruction video (CPR-V) and asked to watch it every 3 months. The AVP group was provided with a practice dummy (designed for the project) as well as a CPR-V, and asked to practice their skills on the dummy while watching the CPR-V every 3 months. Both groups were given telephone follow up every 3 months to encourage compliance. The controls were given a placebo video without follow up. CPR skills were re-assessed after 12 months using Resusci Anne recording manikins. The subjects, the instructors, and the evaluators were blinded to the group assignment. Results: Of the 262 family members who finished the study, the retention rates of overall, and key elements of CPR skills were significantly higher in the AVP and AV groups, compared to the control group. Skill retention was higher in the AVP group compared to the AV group. Conclusion: Both review models improved long-term CPR skill retention for family members of high-risk patients with SCA. The AVP model was more effective than the AV model especially for skills related to performing high quality chest compression.
Abstract 19522: Trends and Outcomes in Mechanical Circulatory Support Among Medicare Beneficiaries
Authors: Prateeti Khazanie, Brad G Hammill, Zubin J Eapen, Lesley H Curtis, Adrian F Hernandez
Journal: Circulation (2012)

Background: Mechanical circulatory support (MCS) has emerged as a growing technology for patients with advanced heart failure, but diffusion and temporal trends of outcomes of this technology across centers is poorly understood. Methods: Using 2006-2010 Medicare inpatient claims, we identified all fee-for-service beneficiaries who received an implantable MCS device. Patients were excluded if they had major cardiac surgery or non-implantable MCS device within 30d prior to implant. Outcomes of interest were in-hospital mortality and, among those discharged alive, 30d and 1yr post-discharge mortality, transplant, and readmission. We also calculated the cumulative number of readmissions and inpatient days following discharge. Death and transplant were treated as competing risks for each other and for all other post-discharge outcomes. Results: We identified 1835 patients who received an MCS device. Annual implant volume increased from 176 in 2006 to 661 in 2010. Demographic characteristics of those receiving a device were consistent over time--mean age 59 years, 81% men, and 72% white. Elective admissions for an MCS increased over time (26% to 40%). Volume of cases per center varied but overall increased over time (Figure). In-hospital mortality decreased over time (30% to 12%, p&lt;.001). There was a trend towards decreased 30-d readmissions with 32.5% in 2006 and 26.7% in 2010 (p=0.07). Among the 1549 patients discharged alive, observed post-discharge outcomes at 30d and 1yr were: post-discharge mortality 2.1%, 19.2%; heart transplant 2.3%, 29.5%; all-cause readmission 27.4%, 83.0%; cardiovascular readmission 11.4%, 48.8%; no. of all-cause readmissions 0.31, 1.98; and no. of inpatient days 3.2, 17.6, respectively. Conclusions: The volume overall of MCS and proportion of elective MCS implants has increased over time. Readmission and mortality outcomes have generally improved over time as implant volume has increased and the patient profiles have changed.
Abstract 8803: Bioprosthetic Tricuspid Valve Regurgitation Associated with Device Lead Implantation
Authors: Mackram F Eleid, Lori A Blauwet, Yong-Mei Cha, Heidi M Connolly, Peter A Brady, Joseph A Dearani, Raúl E Espinosa
Journal: Circulation (2011)

Background Little is known about the effects of permanent transvenous device leads on bioprosthetic tricuspid valve (BTV) function. Hypothesis The goal of this study was to test the hypothesis that transvalvular device leads promote clinically significant BTV regurgitation. Methods A retrospective review of 58 patients who underwent BTV implantation and subsequently required endocardial pacemaker (n=52) or defibrillator (n=6) lead implantation through the BTV was conducted. Patient and prosthesis characteristics, lead type, and clinical events were collected. The incidence and severity of prosthetic tricuspid regurgitation (TR), determined by Doppler echocardiography, was compared to 265 patients who underwent BTV implantation without undergoing subsequent transvalvular device lead implantation. Results Over a mean follow up of 25 months, 5 patients (9%) with a transvalvular lead developed ≥ moderate prosthetic TR compared to 12 patients (5%) in the control group (P = 0.20). Kaplan Meier survival analysis revealed no significant difference in the incidence of TR in BTV patients with and without transvalvular leads (p = 0.45). Clinically significant prosthetic TR in patients with and without a transvalvular lead more commonly occurred 2 years or later after lead implantation or BTV implantation (4/5, 80% and 10/12, 83%). Conclusions Compared to BTV controls, there was no significant difference in the incidence of ≥ moderate prosthetic TR in patients with a transvalvular pacemaker or defibrillator lead (p = 0.45). Transvalvular lead implantation appears to be an acceptable approach for patients with a BTV who require permanent pacemaker or defibrillator placement.