tbuckley/cabot-search huggingface dataset:
Abstract 18671: Exercise Training Associated With Testosterone Replacement Decreases Muscle Sympathetic Nerve Activity in Heart Failure Patients With Hypogonadism
Authors: Marcelo R dos Santos, Ana Luiza C Sayegh, Marco A Arap, Antonio Carlos P Barretto, Holly Middlekauff, Carlos E Negrço, Maria-Janieire d Alves
Journal: Circulation (2013)

Purpose: Heart failure (HF) is characterized by increase in muscle sympathetic nerve activity (MSNA). Advanced HF can be associated to testosterone deficiency. Study with HF patients and testosterone therapy showed improvement in VO2 and baroreflex sensitivity. The role of exercise with or without testosterone is unknown. Therefore, the aim of the study was to investigate if aerobic exercise with or without testosterone replacement decreases MSNA. Methods: 24 HF patients (52±2 yr) with low testosterone, FC III (NYHA) and LVEF 26±2%, were divided: Exercise Training (ET,n=9) Testosterone (Testo,n=8) and Exercise Training+Testosterone (ET+Testo,n=7). Total (TT) and free (FT) testosterone and SHBG were measured. Testosterone deficiency was characterized as TT &lt;350 ng/dL and FT &lt;131 pmol/L. Cardiopulmonary exercise was performed on bike. MSNA was measured by microneurography. Both groups Testo and ET+Testo were treated with undecilate of testosterone (intramuscular) at the beginning of the protocol and were monitored monthly. The exercise consisted in three 40-minutes sessions per week on an ergometer bike. Exercise intensity was between anaerobic threshold and respiratory compensation point. Results: After 4 months, TT and FT were restored in ET (307±40 to 429±93 ng/dL; p&lt;.001 and 160±26 to 246±50 pmol/L; p&lt;.001), Testo (279±33 to 575±66 ng/dL; p&lt;.001 and 137±18 to 381±55 pmol/L; p&lt;.001) and ET+Testo (223±18 to 497±82 ng/dL; p&lt;.001 and 135±22 to 353±49 pmol/L; p&lt;.001) groups. Peak VO2 increased in ET (14.76±1.60 to 18.06±2.26 ml/kg/min; p=.01), Testo (19.33±1.87 to 20.34±2.08 ml/kg/min; p=.01) and ET+Testo (17.61±1.37 to 20.63±2.72 ml/kg/min; p=.01). Maximal power (watts) was increased only within ET+Testo (75±8 to 129±21 watts; p&lt;.001). MSNA decreased in ET (49±4 to 34±1 bursts/min; p=.02) and ET+Testo (61±4 to 32±2 bursts/min; p&lt;.001) but was not different within Testo (39±4 to 34±3 bursts/min; p=.89). Conclusion: Functional capacity increased in all groups, but only ET+Testo improved muscle strength. Interestingly, exercise alone was able to restore testosterone. In addition, ET and ET+Testo reduced MSNA. These findings emphasize that ET and testosterone together should be included in the treatment of HF patients with hypogonadism.
Abstract 9817: The Changing Practice of Coronary Revascularization of Dialysis Patients in the US, 2004-2009
Authors: Charles A Herzog, Craig A Solid
Journal: Circulation (2012)

INTRODUCTION: The optimal method of coronary artery revascularization in dialysis pts is controversial. In-stent restenosis complicates the use of bare metal stents (BMS), prolonged dual anti-platelet therapy (and attendant hemorrhagic risk, including in transplant waitlisted pts) is problematic for drug-eluting stents (DES), and coronary artery bypass surgery (CAB) has markedly increased in-hospital mortality, but superior long-term survival. There are few published data comparing recent trends in selection of coronary revascularization procedures in dialysis pts. METHODS: We searched the records of the United States Renal Data System database to identify 23,038 dialysis pts having coronary artery bypass surgery (CAB), BMS or DES in 2004-2009. One year survival was estimated by Kaplan-Meier method. RESULTS: During the study period, the total number of revascularization procedures decreased from 4,347 in 2004 to 3,344 in 2009. CAB procedures typically accounted for 25% to 30% of all procedures. From 2004-2006, DES accounted for 59% of procedures and BMS 15%. However, from 2007-2009 those percentages were 43% and 31%, respectively. From 2006 to 2007 alone, the number of DES pts dropped from 2,495 to 1,462 (a 41% reduction) while the number of BMS pts increased from 607 to 1,121 (an 85% increase). Survival for CAB and DES pts, but not BMS improved for 2009 vs 2004 pts (p= .002, p= .015, p= ns, respectively by log rank test). CONCLUSION: Our data suggest a recent shift in interventional practice patterns in US dialysis pts, with a reduction in the use of DES. Despite prior reports of superior long-term survival after CAB, only 25% of coronary revascularization was CAB in 2009. Unadjusted survival after DES and CAB improved from 2004 to 2009.
Abstract 18652: Identification of Novel, Potentially Deleterious Variants in the ADAMTS7 Gene via Combined Exome and Sanger Sequence Analysis
Authors: Robert C Bauer, Chenyi Xue, Xuan Zhang, Ron Do, Daniel H Kiss, Sekar Kathiresan, Daniel J Rader, Muredach P Reilly
Journal: Circulation (2013)

The ADAMTS7 locus has been identified in multiple recent genome-wide association studies as being associated with coronary artery disease (CAD) in humans. Based on these associations, we hypothesized that functional rare variants in the gene may be causal risk alleles for CAD in humans. In order to identify rare variants in the human ADAMTS7 gene, we used data from the NHLBI Exome Sequencing Project (ESP) of 6503 participants, which, as per Exome Variant Server (data release ESP6500SI-V2), identified 404 variants in the entire genic sequence of ADAMTS7, of which 169 were missense variants and 2 were nonsense variants. We acquired BAM files for the ADAMTS7 region in 5438 ESP samples and performed in-house realignment, filtering and variant calling for the ADAMTS7 gene using the following criteria; sequences needed ≥90% alignment to the reference sequence, as well as ≥2% better alignment to the actual ADAMTS7 gene vs. pseudogenes or else they were excluded from analysis. In these custom analyses we identified 103 missense and 2 nonsense variants. In addition, we performed Sanger sequencing of 200 PennCath patients (100 MI cases, 100 controls) using primer design that accounted for pseudogenes. For variant calling we only used data with 2X coverage in &gt;50% of samples tested (19/28 amplicons). The Sanger sequence data revealed 27 missense and zero nonsense variants. Comparison of the custom analysis of ESP data and independent Sanger sequencing provided high-confidence calls for 12 coding variants (including the S214P variant, a lead SNP in the GWAS association) in the ADAMTS7 gene. In summary, several variants in the ADAMTS7 gene included in the Exome Variant Server appear to arise from pseudogenes, while a number of high-confidence ADAMTS7 variants are not included on the exome chip. By combining multiple sequencing technologies from multiple studies, we identified 12 variants located in the actual coding sequence of ADAMTS7 for future functional studies. In summary, pseuodogenes present a unique challenge to identifying coding variants in the age of exome and whole genome sequencing and require a customized strategy for sequence alignment and variant calling. ADAMTS7 provides a cautionary example and we present one approach to overcome these challenges.
Abstract 18534: TAT-Protein Blockade of PTEN After Cardiac Ischemia is Highly Protective
Authors: Xiangdong Zhu, Zuohui Shao, Huashan Wang, Jing Li, Angelo Meliton, Sy-Jou Chen, Changqing Li, Alan R Leff, Terry L Vanden Hoek
Journal: Circulation (2013)

Introduction: Cooling protects against cardiac ischemia/reperfusion (I/R) injury by enhancing PI3K/Akt/NOS signaling. PI3K/Akt signaling depends on binding by its regulatory subunit p85 to the catalytic subunit p110 or the inhibitory phosphatase PTEN. We studied novel TAT-p85 fusion proteins that selectively inhibit these competing p85 interactions. We hypothesized that TAT fused p85 lacking the PTEN binding site (TAT-ΔPTEN p85) would enhance Akt phosphorylation to afford cardioprotection in a heart cell model of I/R. Conversely, TAT fused p85 lacking the p110 binding site (TAT-Δp110p85) would abrogate protection. To further test TAT fusion proteins for the I/R injury of mouse cardiac arrest (CA), we studied whether a TAT-fused PTEN C-terminal 9 amino acid (TAT-PTEN9c) PTEN inhibitor would activate Akt in critical organs and improve survival. Methods: A TAT-Δp110 p85 plasmid was constructed with nucleotide deletions at amino acids 478-513. The TAT-ΔPTEN p85 plasmid deleted amino acids 1-313. TAT-PTEN9c was synthesized by Anaspec. Cardiomyocytes were isolated from 1-2-day old C57BL6/J mice and exposed to up to 90 min ischemic arrest with 3 h reperfusion (I/R). Cell viability was evaluated by propidium iodide uptake and p-Akt was measured by Western blot. C57BL6 mice were subjected to an established potassium-induced CA protocol. TAT-PTEN9c (7.8 mg/kg) was given IV after return of spontaneous circulation (ROSC) (n=10) and the 2nd dose for another 5 mice was given at 60 min after ROSC. Results: TAT-Δp110 p85 increased cell death from 44.6 +/- 2.7% to 92.5 +/- 3.4%, while TAT-ΔPTEN p85 decreased cell death caused by I/R from 47.8 +/- 1.4% to 11.9 +/- 5.3%. 30 mice were randomized to either saline or TAT-PTEN9c post-ROSC. TAT fusion proteins could be seen within heart and brain tissues within 2 minutes of IV infusion. The survival rate was significantly increased in TAT-PTEN9c treated mice compared with that of saline treated mice at 2 hrs (14/15, 93% vs. 9/15, 60%, P &lt; 0.05) and at 4 hrs (10/15, 67% vs. 6/15, 40%, P &lt; 0.05) after ROSC. Conclusions: TAT fusion protein inhibition of PTEN during cardiac I/R and after cardiac arrest appear to be promising strategies for enhancing Akt activation and survival.
Abstract 18310: Therapeutic Use of Encapsulated Genetically Engineered Mesenchymal Stem Cells for Vascular Regeneration
Authors: Kiyoko Takemiya, Jane S Titterington, Giji Joseph, Daiana Weiss, Alicia N Lyle, Christa Caesar, Susan A Safely, Collin J Weber, Jacques Galipeau, W. Robert Taylor
Journal: Circulation (2013)

Background: We have previously shown that encapsulation of mesenchymal stem cells (MSCs) in alginate improves cell retention and efficacy of stem cell therapies in the hind limb model of vascular insufficiency. Erythropoietin (EPO), a hematopoietic cytokine, is also known as an angiogenic factor. The purpose of this study is to evaluate the efficacy of encapsulated, gene transfected MSCs as therapeutic strategy for enhancing collateral formation in hind limb ischemia model by using EPO transfected MSCs (MSC-EPO). Methods and Results: MSCs and MSCs-EPO were encapsulated into alginate microcapsules. Hind limb ischemia was induced by ligating and excising both the super facial femoral artery and vein in the left leg. The mice were implanted with either empty capsules, encapsulated 1 X 10 6 MSCs (MSC group), encapsulated 0.9 X 10 6 MSCs + 0.1 X 10 6 MSCs-EPO (low EPO group), or encapsulated 0.5 X 10 6 of MSC + 0.5 X 10 6 of MSCs-EPO (high EPO group). Blood analysis was performed on post-operative day (POD) 14 and 28 and histological evaluation with immunohistochemistry was performed on POD 14 (n=4/group). To evaluate the functional recovery, a spontaneous running wheel test was performed between POD 14 to POD 21. On POD 14, there was no significant change in hematocrit in 4 groups. On POD 28, the hematocrit in the high EPO group was significantly increased (57.2±4.6%) Histological evaluation revealed that the density of collateral vessels was increased in both the low and high EPO groups. (0.7±0.04, 0.84±005, 0.98±0.05 and 1.06±0.06 respectively) Although the high EPO group had a much higher density of collateral vessels, the running distance was significantly reduced to two third of the other groups.(6507±208.3, 6223±294.0, 6067±510.5 and 3952±322.1m/day, respectively) Conclusion: The use of alginate encapsulation of MSCs is a viable strategy for site directed gene therapy. Our data show that EPO can be effectively delivered resulting in an improvement in collateral vessel formation. However, chronic over-expression of EPO may cause adverse effects likley as a result of increased blood viscosity.
Abstract 9755: Bleeding Complications During Long-term Dual Antiplatelet Treatment In Diabetic Patients Treated With 1 <sup>St</sup> Generation Drug Eluting Stent Implantation
Authors: Vassilis Voudris, Panagiotis Karyofillis, Constantinos Doulaptsis, Ioannis Moukas, Sophia Thomopoulou, Dennis V Cokkinos
Journal: Circulation (2012)

Background: Dual antiplatelet treatment (DAPLT) for at least 12 months is recommended after drug-eluting stent (DES) implantation. We investigate the frequency, correlates, and clinical significance of bleeding complications in diabetic patients (pts) on long-term DAPLT (5 years) after 1 st generation DES implantation. Methods: We assessed 610 consecutive diabetes mellitus (DM) pts (male 80%, mean age 65±9 years) after 1 st generation DES implantation (sirolimus 80%, paclitaxel 10%, combination 10%). Five years clinical follow-up (FU), obtained in 587/610 (96%) of them; at the end of FU, 211(36%) pts were on single APLT (SAPLT) and 376 (64%) on DAPLT. Bleeding complications were defined according to PLATO and TIMI definitions. Hard end-point (HEP) was considered the combination of death, non-fatal myocardial infarction, and cerebrovascular accident; stent thrombosis (ST) is assessed according to ARC definition. Results: There was no difference in the incidence of ST and HEP in pts treated with DAPLT vs. SAPLT. The incidence of bleeding was higher on DAPLT pts (14.6% vs 3.8%, p &lt; 0.0001). Minor bleeding according to PLATO occurred in 1.9% of pts on SAPLT and 11.7% on DAPLT (p&lt;0.0001) and according to TIMI in 2.4% vs. 13.6% respectively (p&lt; 0.0001). Major bleeding according to PLATO presented the 1.9% of pts on SAPLT and 2.9% on DAPLT (p: NS); according to TIMI the incidence of major bleeding was 1.4% and 1.1% respectively (p: NS). The incidence of cardiovascular adverse events was similar between pts with bleeding as compared with those without bleeding. In a multivariable analysis, smoking was an independent predictor for overall as well as major bleeding according to PLATO (HR 6.2, 95% CI 1.2-30.4, p=0.024), whereas DAPLT was an independent predictor for overall and minor bleeding (HR 6.2, 95% CI 2.2-17.3, p&lt;0.0001) Conclusions: Long-term DAPLT in DM pts treated with 1 st generation DES is associated with higher risk of overall and minor but not major bleeding. Smoking was an independent predictor for overall and major bleeding according to PLATO definitions.
Abstract 14534: Sarcoplasmic Reticulum Ca2+ Release via Ryanodine Receptor Type-2 Promotes Maintenance to Chronic Atrial Fibrillation
Authors: Na Li, David Y Chiang, Sameer Ather, Wilhelm Schmitz, Frank U Müller, Dobromir Dobrev, Dobromir Dobrev, Xander H Wehrens
Journal: Circulation (2012)

Na Li, 2012 Finalist and Presenting Author
Abstract 17232: Amiodarone Inhibits Small Conductance Ca <sup>2+</sup> -Activated K <sup>+</sup> (SK2) Channel Expressed in HEK-293 Cells
Authors: Isik Turker, Po-Cheng Chang, Zhenhui Chen, Peng-Sheng Chen, Tomohiko Ai
Journal: Circulation (2011)

Abstract: Introduction: Our recent study showed that apamin-sensitive K+ currents (IKAS), mainly carried by SK2 channel, is upregulated in failing ventricles. IKAS upregulation predisposes heart failure patients to recurrent ventricular fibrillation (electrical storm) by shortening of the action potential duration after initial successful defibrillation. Amiodarone is the drug of choice for the treatment of electrical storms. Hypothesis: Amiodarone can inhibit SK2 currents at therapeutic concentrations. Methods: The pCMV6 plasmids containing human KCNN2, the gene encoding SK2 channel (transcript variant 1: NM_021614 ), were cotransfected with the pcDNA3 plasmids containing GFP into HEK-293 cells using Lipofectamine 2000. Effects of amiodarone were studied using whole-cell and inside-out mode of patch-clamp methods at 36°C. SK2 currents were induced with voltage-pulse protocols and various concentrations of intracellular Ca2+. Results: The whole-cell SK2 currents showed Ca2+-dependency (IKAS at +40 mV: 25.5 ± 9.7 pA/pF with 250 nM [Ca2+]i, n = 5; 60.4 ± 24.9 pA/pF with 500 nM [Ca2+]i, n = 5; 180.0 ± 16.9 pA/pF with 1 µM [Ca2+]i, n = 15). Amiodarone inhibited the SK2 currents activated with 1 µM intrapipette Ca2+ in a dose-dependent manner (IC50, 1.73 ± 0.01 µM, Hill coefficient, 1.28 ± 0.01, total n = 15), and the block was not voltage-dependent. The maximal inhibition was observed with 50 µM amiodarone, and 70.0 ± 7.2% of IKAS was inhibited with 1 µM intrapipette Ca2+ (n = 15). The inhibitory effects of amiodarone on the IKAS with 500 nM intrapipette Ca2+ was similar (66.0 ± 8.6% at 40 mV, n = 5). However, we did not observe any inhibition of the IKAS with 250 nM intrapipette Ca2+ (n = 5). Interestingly, amiodarone did not inhibit the inside-out SK2 currents (n = 3). Conclusions: Amiodarone inhibits SK2 channel at therapeutic concentrations. The SK2 blocking effects may explain the efficacy of amiodarone in treating electrical storm.
Abstract 184: Inhibition of Nitric Oxide Synthase Attenuate Hemorrhage Induced Inflammatory Response and Protect Against Multiple Organ Injury in a Rat Model
Authors: Mona Soliman, Maha Arafah
Journal: Circulation (2013)

Hemorrhagic shock activates inflammatory pathways and results in upregulation of cytokine synthesis. Nitric oxide has been implicated in the pathophysiology of hemorrhagic shock. Objectives: We have investigated the protective effects of inhibition of inducible nitric oxide synthase (iNOS) using N G - nitro-L-arginine methyl ester (L-NAME) on preventing organ injury in a rat model of hemorrhagic shock and resuscitation. Methods: Male Sprague Dawley rats (300-350 gm) were assigned to 3 experimental groups (n= 6 per group): 1) Normotensive rats (N), 2) Hemorrhagic shock rats (HS) and 3) Hemorrhagic shock rats treated with L-NAME (HS-L-NAME). Rats were hemorrhaged over 60 min to reach a mean arterial blood pressure of 40 mmHg. Rats were treated with 1 ml of 8 mg/Kg L-NAME intra-arterially after 60 min hemorrhagic shock. Resuscitation was performed in vivo by the reinfusion of the shed blood for 30 min to restore normo-tension. Arterial blood samples were collected from all groups at the end of the experimental period for measurement of tumor necrosis factor α (TNF-α). Biopsy samples were taken for light microscopy. Histological examination of hemorrhagic shocked untreated rats revealed structural damage. Less histological damage was observed in multiple organs in L-NAME- treated rats. L-NAME-treatment decreased the number of inflammatory cells and mitochondrial swollen in myocardial cells. Treatment with L-NAME decreased the inflammatory response to hemorrhagic shock by lowering the levels of TNF-α. L-NAME treatment reduced microscopic damage and injury in multiple organs and reduced the inflammatory response to hemorrhagic shock by inhibiting iNOS in a hemorrhagic shock model in rats.
Abstract 18345: Coronary Artery Disease With Acute Myocardial Infarction, but Not Without, is an Independent Risk Factors for Incident Heart Failure Among Community-Dwelling Older Adults
Authors: Taimoor Hashim, Shereen Elbaz, Gregg C Fonarow, Sumanth D Prabhu, Kanan Patel, Charity J Morgan, Wilbert S Aronow, Ali Ahmed
Journal: Circulation (2013)

Background: Coronary artery disease (CAD) is a major risk factor for heart failure (HF) in older adults. Whether this risk varies by the presence of prior acute myocardial infarction (AMI) remains unclear. We examined the independent of association of non-AMI CAD and AMI with incident HF. Methods: Of the 5521 participants in the Cardiovascular Health Study (CHS) without baseline HF, 4558 were free of baseline CAD. Using these no-CAD participants as reference, we assembled two pre-match cohorts including (1) 519 with non-AMI CAD (n=5077) and (2) 444 with AMI (n=5002). We then assembled two propensity-matched cohorts of 379 pairs (non-AMI CAD vs. no-CAD) and 325 pairs (AMI vs. no-CAD) of participants, both balanced on 65 baseline characteristics (mean age, 74 (±6) years in both). Results: During 13 years of follow-up, incident HF occurred in 24% and 28% of matched participants with no CAD and non-AMI CAD, respectively (hazard ratio {HR}, 1.21; 95% CI, 0.91-1.60; P=0.190), and in 27% and 38% of matched no-CAD and AMI participants, respectively (HR, 1.70; 95% CI, 1.29-2.24; P&lt;0.001; Figure ). Conclusions: Among community-dwelling older adults, compared to no CAD, those with AMI but those with non-AMI CAD, had independent association with incident HF. These findings suggest that the presence of AMI may be used to risk stratify older adults at higher risk for HF for preventative efforts. ""
Abstract 18366: Disruption of Histone Deacetylase 4 Sumoylation Promotes Hypoxia-Induced Injury in Cardiomyocytes
Authors: Jian Feng Du, Ting C Zhao
Journal: Circulation (2013)

Background: Histone deacetylase (HDAC) inhibition has been shown to play an important role in eliciting cardioprotection. However, molecular mechanism(s) of HDAC modification that mediate the survival of myocytes remains unknown. Objectives: The goal of this study is to test whether disruption of HDAC4 sumoylation abolishes HDAC inhibitor-induced protective effects in H9c2 cardiomyocytes exposed to hypoxia/reoxygenation, and whether HDAC inhibitor leads HDAC4 sumoylation, which cause subsequent HDAC4 ubiquitination. Methods: Rat H9c2 cardiomyocytes were cultured and then subjected to hypoxia for 48 hours followed by 2 hours of re-oxygenation. Cardiomyocytes were preconditioned with trichostatin A, a selective HDAC inhibitor that blocks HDAC activity. To further examine the function of HDAC4 sumyolation in the regulation of HDAC inhibition-induced protective effects, stable cardiomyocyte lines expressing wild type HDAC4 and dead HDAC4 sumoylation (HDAC4K559R) were established, respectively. Cell cytotoxicities were estimated by the measurement of lactate dehydrogenase (LDH) leakages. The cell viabilities were assessed by MTT assay. Western blot and immunoprecipitation were employed to detect HDAC4 protein sumoylation following HDAC inhibition. Results: Inhibition of HDAC increased the resistance of cardiomyocytes against hypoxia-reoxygenation, as indicated by the reduction in LDH leakage and the increase in cell viabilities. As compared with wild type HDAC4 over-expressing of cardiomyocytes, disruption of HDAC4 sumoylation at lysine 559 increases the susceptibility of cardiomyocytes to hypoxia-reoxygenation injury. Western blot and co-immunoprecipitation assay demonstrated that HDAC inhibition-mediated HDAC4 sumoylation was associated with ubiquitination of HDAC4. Conclusion: Our study demonstrated that HDAC inhibition produces protective effects in cardiomyocytes, which is modulated by specific HDAC4 sumoylation.