tbuckley/cabot-search huggingface dataset:
Abstract 19344: Evaluation of the Effects of Diabetes, Insulin Resistance, and Inflammation on Coronary Endothelial Function Assessed by Cardiac Perfusion MRI with Cold Pressor Test
Authors: Wanda Marfori, Jacqueline L Hollada, Alessia Tognolini, James W Sayre, Eric H Yang, Stefan Ruehm
Journal: Circulation (2012)

OBJECTIVE: To evaluate the effects of diabetes, insulin resistance (IR) and inflammation on coronary endothelial function assessed by cardiac stress perfusion MRI (CMRI) w/ cold pressor test (CPT). METHODS: 20 subjects (14 men, 6 women; mean age: 53.5 - Range: 39-62) w/ T2DM (5-15 years) and 20 healthy controls (age/sex matched) were enrolled in a prospective IRB-approved HIPAA compliant study. Medical history for risk factors was obtained. Subjects w/ known CAD were excluded. Fasting plasma glucose (FPG), insulin, C-peptide, HbA1c, eGFR, lipids and UA/Cr ratio; inflammatory markers: IL-6, TNF-α, hs-CRP and PAI-1 were obtained. 2-hour OGTT was performed on healthy subjects to confirm absence of pre-DM/T2DM. BMI, W/H ratio and HOMA-IR were calculated. To assess vascular tone and myocardial blood flow (MBF) responses to CPT, CMRI w/ CPT was performed w/ gadolinium (Multihance, Bracco) on a 3.0T scanner. Signal slope, myocardial perfusion reserve index (MPRI ), and RPP were calculated. RESULTS: Comparison of MPRI between T2DM ( 1.39 ± 0.10) vs. healthy (2.52 ± 0.36) showed significantly decreased endothelium-dependent change in MBF to CPT in diabetics (p=0.003). Univariate analysis showed that age (p=0.001); HbA1c (p=0.001); FPG (p=0.005); HOMA-IR (p=0.04); IL-6 (p=0.05) and TNF-α (p=0.004) showed significant association w/ MPRI in T2DM. Multivariate analysis, age (p=0.017); FPG (p=0.05); UA/Cr ratio (p=0.001); insulin (p=0.046) and C-peptide (p=0.036) remain statistically significant independent predictors of changes in MBF. Correlative studies showed an inverse relationship w/ MPRI and the following: BMI, W/H ratio, FPG, HOMA-IR, LDL, Triglycerides, PAI-1, IL-6, TNF-α and Hs-CRP as well as a direct relationship w/ HDL and eGFR. CONCLUSIONS: Our results demonstrate that the diabetic state characterized by IR and chronic inflammation is significantly associated w/ low or decreased MPRI that reflects impaired endothelium-related coronary vasomotion, CMRI w/ CPT provides a non-invasive, analytical tool for early detection of endothelial dysfunction. Large scale clinical trials using CMRI w/ CPT for detection of endothelial dysfunction in at-risk populations w/ long term follow-ups, after therapeutic and lifestyle intervention, is warranted.
Abstract 19437: Concomitant Overexpression of FGF2 and TGFbeta1 in Mesenchymal Stem Cells Improves Both Autocrine and Paracrine Properties Through Activation of Akt, ERK1/2 and SMAD2 Pathways and Upregulation of Soluble Factors
Authors: Manuela Mura, Federica Pisano, Giuseppe Malpasso, Patrizia Danieli, Elisabetta Cervio, Massimiliano Gnecchi
Journal: Circulation (2012)

Background: mesenchymal stem cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. However, donor age negatively influences paracrine properties of bone marrow MSC (BM-MSC). We have shown that in BM-MSC from elderly patients both TGFβ1 (T) and FGF2 (F) expression is decreased. We hypothesized that overexpression of these two factors involved in cytoprotection and angiogenesis may improve MSC repair capacity. Methods: rat BM-MSC were transduced with control (GFP-MSC) or with a bicistronic (TF-MSC) lentivirus. Cytoprotection was evaluated in MSC (autocrine) or in H9c2 (paracrine) cells exposed to 24 hrs of hypoxia in the presence of either unconditioned (CTRL-M) or conditioned medium (GFP-CM or TF-CM). Viability was measured by MTS assay and apoptosis by caspase-3 activation. Angiogenesis was assessed by evaluating HUVEC tube formation on Matrigel. Transcriptional levels of the pro-survival gene Bcl2 and genes encoding soluble factors were measured by RT-PCR. Activation of the three main TF-related pathways (ERK1/2, Akt and SMAD2) was tested by western blot. Results: TF-MSC showed a marked reduction of apoptosis rate (-27% p&lt;0.001) compared with GFP-MSC after 24 hrs of hypoxia. Furthermore, TF-CM increased H9c2 viability compared with CTRL-M (+46.3% p&lt;0.001). Caspase-3 activation in H9C2 was reduced by 60.3% in the presence of TF-CM vs CTRL-M (p&lt;0.001) and by 44.7% vs GFP-CM (p&lt;0.05). HUVEC tube formation was significantly enhanced by TF-CM compared to both CTRL-M (+57.5%; p&lt;0.001) and GFP-CM (+45.2%; p&lt;0.001). Both in TF-MSC and TF-CM treated-H9c2 we observed a strong activation of Akt, ERK1/2 and SMAD2 pathways and enhanced expression of Bcl2. Finally, in TF-MSC the transcriptional levels of soluble factors such as PDGF-β, VEGF, Ang1, IGF1, BMP2, and IL11 was upregulated. Conclusions: TF overexpression increases both autocrine and paracrine properties of MSC through upregulation of several soluble factors and activation of pathways known to be involved in cytoprotection and angiogenesis. These results pave the way for further research on modification of MSC as effective strategy to improve efficacy of stem cell therapy.
Abstract 19478: The Protective Effect of Beta3-Adrenergic Signaling Occurs via Differential Phosphorylation of nNOS in Cardiac Myocytes
Authors: Vabren L Watts, Fernando M Sepulveda, Oscar H Cingolani, Alice S Ho, Xiaolin Niu, Rosa Kim, Karen L Miller, Konrad Vandegaer, Djahida Bedja, Kathleen L Gabrielson, Brian O'Rourke, David A Kass, Lili A Barouch
Journal: Circulation (2012)

Rationale: Stimulation of β3-adrenoreceptor (β3-AR) signaling improves left ventricular function via a nNOS/NO-dependent manner in hypertrophied and failing animal hearts. nNOS, which is expressed in cardiac myocytes, is regulated by modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, how differential phosphorylation of these residues contribute to cardiomyocyte β3-AR-mediated NOS activation and signaling has yet to be explored. Objective: The aim of this study is to identify the molecular mechanisms involved in β3-AR-dependent regulation of nNOS activation and its downstream signaling in cardiomyocytes in the setting of hypertrophy. Methods and Results: In neonatal rat ventricular cardiomyocytes isolated from 4 day old pups, 48 hours of ET-1or 72 hours of norepinephrine lead to increased cell size and β3-AR mRNA. In hypertrophied cells, specific β3-AR agonist BRL-37433 induced NOS activity, nNOS phosphorylation at site Ser1412, dephosphorylation of site Ser847, and ROS suppression. BRL-dependent NOS activity and ROS suppression were attenuated by the nNOS inhibitor L-VNIO. NOS activity was also attenuated in phosphomimetic mutants Ser1412A (constitutively dephosphorylated) and Ser847D (constitutively phosphorylated). However, BRL failed to reduce ROS in the presence of Ser847D. In addition, Akt inhibition decreased BRL-induced Ser1412 phosphorylation and NOS activity, while Gi/o blockade altered BRL-regulation of both phosphorylation sites, NOS activity, and ROS reduction. In vivo, BRL administration completely dephosphorylated Ser847 and moderately increased Ser1412 phosphorylation in mice hearts under pressure overload. Conclusion: Our data suggest that β3-AR regulates myocardial NOS activity and ROS via alterations in nNOS phosphorylation in hypertrophied myocytes and failing hearts. This is the first study to demonstrate a role for nNOS phosphorylation as a key factor in cardiomyocyte and β3-AR signaling. These results contribute significantly to our understanding the protective properties of β3-AR signaling during cardiac sympathetic overdrive, and will ultimately aid in drug discoveries that target molecular mechanisms to treat heart failure.
Abstract 19236: Mapping the Role of the Mitochondrial Phosphate Carrier in Cardiomyocyte Life and Death
Authors: Manuel Gutierrez-Aguilar, Christopher P Baines
Journal: Circulation (2012)

Under pathologic conditions, mitochondria from cardiomyocytes experience a change in the highly selective transport of ions and metabolites to a non-selective permeability state. The Mitochondrial Permeability Transition Pore (MPTP) is a voltage-sensitive unselective channel thought to initiate such changes resulting in necrotic cell death during heart disease. While the biochemical behavior of the MPTP has been characterized in extenso , its molecular identity has remained an open question. Previous evidence suggesting Voltage Dependent Anion Channels and Adenine Nucleotide Translocators as putative components of this pore has been casted in doubt as genetic models lacking such proteins still exhibit an MPTP. So far, the mitochondrial Cyclophilin D (CypD) is the only widely accepted MPTP regulator. CypD is known to bind to proteins in the mitochondria such as the F 0 F 1 -ATP synthase lateral stalk and the Mitochondrial Phosphate Carrier (PiC) among others. Here we demonstrate that an N-terminal segment of CypD binds the C-terminus of the PiC by using pulldown assays and molecular docking simulations. In addition, we have generated three different transgenic mouse lines overexpressing the PiC at a medium and high level and a double transgenic line co-expressing PiC and CypD. Our results show that cardiac-specific PiC overexpression at the high level results in an MPTP with lesser sensitivity to Ca 2+ , possibly due the ability of Pi to buffer matrix Ca 2+ . These results suggest CypD binds to the PiC thus contributing to MPTP regulation.
Abstract 8401: Switching of Hif-α Isoforms is Critical in the Resolution of Inflammation
Authors: Norihiko Takeda, Hajime Abe, Hiroaki Senba, Randall Johnson, Ichiro Manabe, Ryozo Nagai
Journal: Circulation (2011)

Hypoxia is a pathological condition in which the tissue is deprived of adequate oxygen supply. It occurs in myocardial ischemia, cardiac hypertrophy and atherosclerosis, and accelerates the inflammatory processes in cardiac tissues. Each cell exerts its own responses to hypoxia, and most of them are mediated through a pair of transcription factors, hypoxia inducible factors- 1α (HIF- 1α) and HIF- 2α. Macrophages, key mediators of inflammation, are activated and accumulate in hypoxic area. Macrophages are currently classified into M1 (pro-inflammatory) and M2 (anti-inflammatory). However, the molecular mechanisms of M1 and M2-specific activations remain elusive. Here we revealed M1 and M2 specific functions of HIF-1α and HIF-2α, which play essential roles in the initiation and resolution of inflammation. HIF-1α was acutely induced in M1 activation, whereas HIF-2α was exclusively expressed in M2, but not in M1 macrophages. Th1 cytokines such as IFNγ induced HIF-1α, but strongly suppressed HIF-2α. In contrast, Th2 cytokine, including IL-4 increased HIF-2α level. We identified inducible NO synthase (iNOS, a M1 marker gene) as a HIF-1α target, and arginase1 (arg1, a M2 marker gene) as a HIF-2α target gene, respectively. These two enzymes compete for the common substrate, l-arginine, and inhibit each other's function. HIF-1α elicits NO production in M1, however, HIF-2α suppresses NO production through arginase1 induction in M2 macrophages. The balance between HIF-1α and HIF-2α determine that of iNOS/arg1, resulting in the regulation of NO production. To verify the roles of HIF-α in vivo, we generated macrophage specific HIF-1α knockout mice (mHIF-1α KO) and HIF-2α knockout (mHIF-2α KO). Intraperitoneal injection of lipopolysaccaride (LPS) induces plasma NO rises acutely (6hr), and it normalizes within 24 hours. In mHIF-1α KO mice, peak NO rise was attenuated. In contrast, mHIF-2α KO mice exhibited delayed recovery of NO level after LPS injection. Those results implied the essential role of HIF-1α in initiating NO production, whereas HIF-2α is critically important in the resolution. The switching of HIF-α isoforms could account for the functional diversity between M1 and M2, and contribute to the initiation and resolution of the inflammation.
Abstract 317: The Los Angeles Cardiac Arrest Network: Hypothermia Experience in Nonshockable Rhythm
Authors: Gene Y Sung, Dave Shavelle, William French, Marc Eckstein, James Niemann, Nichole Bosson, Deidre Gorospe, Paula Rashi, Richard Tadeo, William Koenig, Jay Thoma
Journal: Circulation (2012)

Therapeutic hypothermia after resuscitation from a non-shockable cardiac arrest rhythm: Outcomes in a regionalized cardiac arrest system Introduction: Therapeutic hypothermia (TH) improves neurologic outcome (CPC 1-2) in patients resuscitated from VF. Its effect on neurologic outcome following resuscitation from non-shockable arrest rhythms remains uncertain. Of equal importance is the possibility that TH will improve survival in this group but not neurologic outcome (CPC 3-4). The purpose of this study was to evaluate neurologic outcome in patient resuscitated from a non-shockable out-of-hospital cardiac arrest rhythm. Methods: This is a retrospective cohort study of data reported to a single registry from EMS systems serving a population of approximately 10 million and collected between April 1 and Dec 31, 2011. All patients achieving ROSC in the field are transported to designated hospitals with TH protocols and PCI capabilities. The registry includes current Utstein data cells. Patients with an initial non-shockable rhythm were identified. Patients were excluded if they were awake and responsive in the ED. The survival rate and neurologic outcome of those receiving TH were compared to those that did not receive TH. The decision to initiate or withhold TH was determined by the treating physician. Results: Outcomes are shown in the table. The OR for a CPC 1 or 2 with TH was 2.4 (95%CI 1.1-5.5)(p=0.01) compared to patients not receiving TH. The proportion of patients with CPC 3 or 4 was not different between groups, unpaired t-test (p=0.6). Conclusion: TH improves neurologic outcome in patients resuscitated from initial non-shockable rhythms in a regionalized system for post-resuscitation care. Additionally, the number of surviving but severely neurologically impaired patients is not increased.
Abstract 9665: PKA / CREB Pathway Initiates Endothelial And Hematopoietic Cell Differentiation Via Etv2 Induction
Authors: Kohei Yamamizu, Taichi Matsunaga, Shiori Katayama, Jun K. Yamashita
Journal: Circulation (2011)

Ets-family protein Etv2 (also called ER71 or Etsrp) is a key factor for vascular and blood development from mesodermal cells. However, regulatory mechanisms and a triggering signal for Etv2 expression have been largely unknown. We previously established an ES cell differentiation system that reproduces early vascular development using vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2)-positive cells as common vascular progenitors. Recently, we revealed that cAMP/protein kinase A (PKA) signaling enhanced differentiation of vascular progenitors into endothelial cells (ECs) and hematopoietic cells (HPCs) using this system. Here we show that PKA activation induces Etv2 expression, which can trigger EC/HPC differentiation. We found that Etv2 was markedly upregulated by PKA activation preceding EC and HPC differentiation. Inhibition of Etv2 using siRNA completely abolished PKA-elicited EC and HPC differentiation from ES cells. We identified two cAMP response element (CRE) sequences in Etv2 promoter region, and confirmed that CRE-binding protein (CREB) directly binds to the CRE sites. Furthermore, PKA activated Etv2 promoter activity in luciferase assay, which was disappeared in CRE-mutant Etv2 promoters. Expression of dominant negative form of CREB completely inhibited PKA-elicited Etv2 expression and induction of EC/HPCs from ES cells. PKA/CREB pathway is, thus, a critical regulator for the initiation of EC/HPC differentiation through Etv2 transcription. This early stage molecular linkage between a triggering signal and transcriptional cascades for differentiation would provide novel insights in vascular and blood development and novel molecular targets for vascular and blood regeneration medicine.
Abstract 88: Delayed Administration of Argon Reduces Ischemic Brain Damage and Preserves Functional Recovery After Cardiac Arrest in Rats
Authors: Anne Brücken, Christian Bleilevens, Matthias Derwall, Kay Nolte, Joachim Weis, Rolf Rosaint, Michael Fries
Journal: Circulation (2012)

Introduction: Argon is neuroprotective when given 1 hour after cardiac arrest (CA) in rats. Here, we investigated if a delayed administration of argon would also reduce neurologic dysfunction. Material and Methods: 18 male Sprague-Dawley rats were subjected to 7 mins of CA and 3 mins of cardiopulmonary resuscitation (CPR). Three hours after successful CPR, animals were randomized to ventilation with 70% argon for 1h in comparison to untreated controls receiving 70% nitrogen. A neurologic deficit score (NDS) was calculated on seven days following the experiment before the animals were killed and the brains harvested for histopathological analyses. Neuronal damage was semiquantitatively assessed by determining the proportion of neuronal cells showing shrunken and/or hypereosinophilic cytoplasm (HE staining) in combination with a loss of nuclear NeuN-immunoreactivity. Results: All animals survived. Untreated controls exhibited severe neurologic dysfunction while animals from the argon group showed significant improvements in the NDS at all points in time (Fig.1). This was paralleled by a significant reduction in the degree of ischemic brain damage in the neocortex, the basal ganglia and the hippocampal CA 3/4 region (Fig.2). Conclusions: Our study demonstrates that a one hour application of 70% argon, even when treatment was delayed for 3 hours after CA, provided a significant reduction in histopathological damage of the neocortex, basal ganglia and hippocampus which was associated with a marked improvement in functional neurologic recovery.
Abstract 19495: Extraction of St. Jude Riata Leads: Clinical Experience and Outcomes at a High Volume Extraction Center
Authors: Solomon J Sager, Roger G Carrillo
Journal: Circulation (2012)

Objectives: St. Jude Riata leads were recalled December 2011. We sought to compare our procedural experience and outcomes extracting the Riata defibrillator lead with extraction of non-Riata leads. Methods: Data was obtained from 2008-2012 from a prospective lead extraction registry established at a single tertiary referral high volume extraction center. The experience with Riata extraction was analyzed and compared with extractions performed on non-Riata leads in a cohort of patients matched for comorbidities using the Charlson comorbidity index. Results: A total of seventy-two patients had Riata lead extractions, 35 for electrical malfunction and 37 for infections. There were 53 males (73.6%) and 19 females (26.4%). Flouroscopy before extraction revealed exteriorized cables on 15 patients (20.8%). Of patients with infections, 20 (54.1%) had vegetations ranging in size from 3-32 mm. Average age for Riata lead was 60 years old, and average ejection fraction (EF) was 42% +/- 8%. All leads were successfully extracted with no major complications. One patient developed a minor complication of arm swelling that resolved at two weeks. Rate of complications in the matched cohort of seventy two patients with extraction of non-Riata leads was .1%. There was no statistically significant difference in complication rates. Conclusion: Riata lead extraction is a safe procedure. Current techniques allow successful extraction in a majority of cases.
Abstract 8266: Double Jeopardy: The Influence of Excessive Daytime Sleepiness and Impaired Cognition on Quality of Life in Adults with Heart Failure
Authors: Barbara Riegel, Steven Sayers, William Weintraub, Sarah J Ratcliffe
Journal: Circulation (2011)

Poor health-related quality of life (HRQL) is pervasive in adults with heart failure (HF). Others have shown that cognitive impairment (CI) is associated with poor HRQL, but the contribution of EDS to HRQL has not been described in HF. Methods: Adults with a confirmed diagnosis of stage C chronic HF were enrolled into a prospective cohort comparison study. Those with dementia, recent drug or alcohol abuse, and night shift workers were excluded. Data were obtained from 280 subjects enrolled from 3 sites in the northeastern US, 242 of whom completed the 6-month follow-up. At baseline we identified a cohort with EDS and a control group without EDS using the Epworth Sleepiness Scale (score ≥6 = EDS). Each EDS group was further subdivided into those with and without CI using a battery of 5 neuropsychological tests (score &gt; 1.5 SD on ≥2 tests). Two disease-specific measures, Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Functional Outcomes of Sleep Questionnaire (FOSQ), were used to measure HRQL; higher scores indicate better HRQL. General linear modeling of square-transformed variables was used to test the hypothesis that cohort membership was a significant predictor of HRQL summary scores after adjusting for enrollment site, age, gender, race, income, NYHA functional class, depressive symptoms, and perceived health. Results: At 6-months the remaining sample was 62.5 (SD 12) years old, mostly male (63%), white (65%), and functionally compromised (72% NYHA class III/IV). Cognitive impairment and EDS were unique constructs (r=0.05, p=0.44). The cohort with EDS+ and CI+ had the lowest overall KCCQ score (KCCQ: 62.1±22.3) compared to the cohort without EDS or CI (79.1±18.3, p=&lt;.001). A similar effect was seen on the FOSQ (FOSQ: 16.7±2.7) compared to the cohort without EDS or CI (18.7±1.8, p=&lt;.001). The cohort with CI but without EDS was not significantly different in HRQL from the cohort without EDS or CI (KCCQ: p=0.39, FOSQ: p=0.20). Conclusion: Daytime sleepiness combined with CI is a significant predictor of HRQL in adults with HF. Cognitive impairment is challenging to influence but interventions designed to influence EDS may improve HRQL in this population.