tbuckley/cabot-search huggingface dataset:
Abstract 5586: Catestatin Induces Therapeutic Neovascularization by Induction of Angiogenesis and Incorporation of Endothelial Progenitor Cells
Authors: Markus Theurl, Wilfried Schgoer, Karin Albrecht, Arno Beer, Margot Egger, Danijela Vasiljevic, Ivan Tancevski, Peter Schratzberger, Josef Patsch, Sushil Mahata, Rudolf Kirchmair
Journal: Circulation (2009)

Introduction Catestatin (Cat), a biologically active fragment of Chromogranin A was described as a nicotinic antagonist inhibiting catecholamine release. Recently, also other biological effects for this peptide were described like release of histamine or activation during cutaneous wounds. We found that Cat induces chemotaxis on a variety of cells including endothelial cells (EC) and therefore hypothesized that Cat might act as a novel angiogenic cytokine. Results To investigate the effect of Cat on EC differentiation into vascular structures in vitro , we performed a matrigel tube formation assay using different concentrations of Cat. Cat at 10 −9 M was most effective in promoting tube formation (rel. tube form. 1.77+/−0.08 vs. ctr.; n=4, P&lt;0.01). This effect could be blocked by a Cat antibody (Ab) (0.87 +/−0.1 vs. ctr; n=4, P&lt;0.01 vs. Cat). Additionally, Cat dose-dependently induced chemotaxis of EC (rel. chemotact. index 10 −9 M: 1.67+/−0.03 vs. ctr; n=6, P&lt;0.01) and promoted EC proliferation as measured by cell numbers of starved EC (rel. cell number 10 −9 M: 1.86 +/−0.13 vs. ctr., n=4, P&lt;0.01; Cat-Ab 0.97+/−0.06 vs. ctr; n=4, P&lt;0.05 vs. Cat). Western blot analysis revealed stimulation of ERK and AKT by 10 −9 M Cat indicating activation of these signal transduction pathways. We also tested for angiogenic effects in vivo by using 3 different mouse models. In the mouse cornea neovascularization model Cat induced significant growth of new blood vessels. In the unilateral limb ischemia model injection of Cat (10 μ g every other day for 2 weeks) into adductor muscles increased capillary (475+/−31 vs. 303+/−28/mm 2 ; n=7, P=0.003) and arteriole (10.1+/−0.8 vs. 5.2+/−1.0/mm 2 ; n=7, P=0.001) density, and accelerated perfusion recovery as shown by LDPI (LDPI ratio ischemic/control leg after 28 days of ischemia) 0.94 vs. 0.74; n=10, P=0.009. Moreover, Cat treated mice showed more incorporated EPC in ischemic limbs using the actin-GFP bone marrow transplant model (21.7+/−2.2 vs. 9.6+/−2.1; n=6, P&lt;0.001). Conclusion In summary our observations demonstrate that Cat therapy induces angiogenesis, arteriogenesis and vasculogenesis in the hind-limb ischemia model suggesting that Cat might be a promising agent for therapeutic angiogenesis in peripheral arterial disease.
Abstract 5544: ED-B Fibronectin Spect Imaging Detects Aortic Plaque Formation in vivo
Authors: Thore Dietrich, Dietmar Berndorff, Elisaveta Stepina, Peter Hauff, Lutger Dinkelborg, Marleen Neumann, Kirstin Atrott, Riad Bouayrou, Eckart Fleck, Kristof Graf
Journal: Circulation (2009)

The extracellular matrix protein ED-B fibronectin (ED-B) is upregulated in inflammatory atherosclerotic lesions and is associated with local macrophage accumulation. In the present study we evaluated whether a conjugate of 99mTc with the single chain antibody against ED-B (99mTC-anti-ED-B) can be used for in vivo detection of atherosclerotic plaque lesions in apolipoprotein E- deficient mice (apoE −/− ) compared to wildtype control mice (apoE +/+ ). Methods: 12 month old apoE −/− and apoE +/+ mice were studied by SPECT 4 hours after injection of 148 MBq of 99mTC-anti-ED-B. Finally mice were sacrificed and analyzed by autoradiography, histology, immunohistochemistry (IHC) and morphometry. Results: In vivo SPECT imaging of apoE −/− mice demonstrated a significant signal activity in the thoracic area which colocalizes with the aortic arch and the supraaortic arteries. The activity corresponded to aortic lesion formation was 52.2±40.6 (1/1*ccm). Low activity was observed in apoE +/+ 9.4±4.9 (1/1*ccm), which had no significant lesion formation. The strongest signals were detected in the aortic root, the aortic arch and along the abdominal part of the aorta from apoE −/− . No vascular signal activity was seen in apoE +/+ after injection of 99mTC-anti-ED-B. The autoradiographic analysis of aortas from apoE −/− and apoE +/+ , confirmed the in-vivo observation and demonstrated signal localization in typical plaque lesions, which significantly correlated with ED-B immunoreactivity, plaque lesion (r = 0.82, P&lt;0.01) and local macrophage accumulation (IHC with Mac3 r = 0.89, P&lt;0.01). There was a significant correlation between ED-B-radioactivity and macrophages (r= 0.93, P&lt;0.01). Conclusion: SPECT imaging using a 99mTc labelled antibody against ED-B fibronectin is a robust method to detect and assess inflammatory plaque lesion formation in-vivo and correlates with local macrophage accumulation.
Abstract 5479: Endothelial Cell TFPI Regulates Murine Arterial Thrombosis but Not Hemostasis or Development
Authors: Thomas A White, Tyra A Witt, Tucker F Johnson, Shuchong Pan, Gurpreet S Sandu, Cheri S Mueske, Laurel S Kleppe, Eric W Holroyd, Robert D Simari
Journal: Circulation (2009)

Background: Tissue factor pathway inhibitor (TFPI) is a key regulator of the tissue factor/factor VIIa complex. Systemic genetic disruption of TFPI exon 4 results in intrauterine lethality in mice. As such, the ability to study the biologic and tissue specific effects of TFPI deficiency has been limited. To define the tissue specific roles of TFPI we utilized a Cre-lox strategy and generated mice with flanking loxP sites surrounding exon 4 (encodes for the K1 domain). Homozygous floxed mice (TFPI Flox ) were crossed with the Tie2 Cre + or LysM Cre + mice and subsequently inbred to create homozygously floxed mice expressing Cre (TFPI Tie2 or TFPI LysM ). Methods and Results: The presence and efficiency of the deleted mRNA product was determined by RT-PCR. TFPI Tie2 and TFPI LysM mice were phenotypically similar to TFPI Flox littermates including weight, blood counts, and prothrombin and activated partial thromboplastin times. TFPI Tie2 mice have complete deletion in endothelial cells, blood cells and bone marrow cells. TFPI LysM mice show partial deletion in blood cells and complete deletion in macrophages. TFPI Tie2 mice had a 60% reduction (P &lt; 0.0001) in circulating TFPI activity compared to TFPI Flox littermate controls. TFPI LysM mice did not have a significant reduction in circulating TFPI activity levels compared to their TFPI Flox counterparts. Neither TFPI Tie2 nor TFPI LysM mice had significant changes in hemostasis compared to TFPI Flox mice as determined by a tail bleeding assay. In an ADP-induced model of thromboembolism there were no significant changes in mortality between the TFPI Tie2 or TFPI LysM and their TFPI Flox littermates. In a ferric chloride model of arterial thrombosis, TFPI Tie2 mice had a significant reduction (P &lt; 0.05) in time to occlusion while TFPI LysM mice did not differ compared to TFPI Flox mice. Conclusions: Deletion of TFPI from cells expressing Tie2 or LysM is consistent with normal development and hemostasis. TFPI Tie2 mice have decreased circulating levels of TFPI and an enhanced thrombotic response to ferric chloride. These data support an important regulatory role for EC TFPI in arterial thrombosis.
Abstract 5526: Maternal Smoking and Smoking Cessation in Early Pregnancy and Endothelium-Dependent Bradykinin-Mediated Relaxation of Uterine Small Arteries
Authors: Malene R Andersen, Niels Uldbjerg, Steen Stender, Puk Sandager, Christian Aalkjćr
Journal: Circulation (2009)

Background - Impaired endothelium-dependent vasodilatation in pregnant smokers may reduce the uterine blood flow to the fetus and result in retarded fetal growth. The present study aimed at investigating endothelium-dependent bradykinin-mediated vasodilation in uterine small arteries from pregnant non-smokers, smokers, and ex-smokers who quitted smoking early in pregnancy. Methods and Results - Of 29 healthy, singleton pregnancies scheduled for elective cesarean section; 12 were non-smokers, 9 were smokers, and 8 were ex-smokers. Serum cotinine verified self-reported smoking. Newborns of smokers were shorter and had a smaller head circumference compared to those of non-smokers (P&lt;0.05), but newborns of ex-smokers were similar to those of smokers and non-smokers. Uterine arteries were dissected from myometrial biopsies and vascular function was assessed on a small vessel myograph for isometric recordings. Preconstricted arteries from non-smokers had a better bradykinin-induced relaxation than arteries from smokers and ex-smokers (P&lt;0.05). In the presence of L-N G -nitroarginine (nitric oxide (NO) synthase inhibitor), arteries from smokers and ex-smokers did not relax to bradykinin, while arteries from non-smokers relaxed at high bradykinin concentrations (P&lt;0.05). In the presence of L-N G -nitroarginine and indomethacin (cyclooxygenase inhibitor) arteries from non-smokers no longer responded to bradykinin. Relaxations to sodium nitroprusside (NO donor) were similar in arteries from non-smokers and smokers, but were better in arteries from ex-smokers (P&lt;0.05). Conclusions - The findings suggest that maternal smoking reduces endothelium-dependent bradykinin-mediated relaxation in uterine small arteries contributing to retarded fetal growth, and suggest that smoking cessation early in pregnancy does not abolish this effect, but improves smooth muscle sensitivity to NO.
Abstract 5481: Heparanase Regulates the Thrombotic Potential of Vascular Injury and Stent Placement
Authors: Aaron Baker, William Gibson, Vijaya B Kolachalama, Mordachai Golumb, Laura Indolfi, Elazer R Edelman
Journal: Circulation (2009)

Background: Heparanase cleaves heparan sulfate proteoglycans (HSPGs), key components of the extracellular matrix and critical endothelial mediators of hemostasis. Methods: Mice transgenic for human heparanase were used to evaluate the influence of heparanase overexpression on thrombosis in an ex-vivo and in-vivo model. To evaluate thrombotic potential, a laser induced thrombosis model was used. Arterial injury was also performed prior to measuring thrombosis to examine the effects of light and heavy injury on thrombosis in the heparanase transgenic mice. A novel ex-vivo murine assay of stent thrombosis was performed in which mouse aortas were stented into a flow loop perfused with mouse blood. Results: In the absence of injury there was no difference in the time for formation of thrombosis in the wildtype (WT) and heparanase transgenic (HPA Tg) mice. However, in the presence of light injury or heavy injury thrombosis in HPA Tg mice occurred significantly faster than in WT mice (63.0 minutes vs. 41.8 minutes, p=.034). The prothrombotic phenotype of HPA Tg mice was masked when heparin was administered prior to injury (68.5 minutes vs. 69.2 minutes p=NS). Blood from HPA Tg mice increased stent thrombosis threefold versus WT in flow loops as measured by optical density (2.81 vs. 1.0 optical density, p=.023) and increased adherent platelets were found in electron microscopy. Conclusions: Increased arterial expression of heparanase leads to increased thrombosis in the injured artery. In particular, endovascular stenting induces injury and flow disturbance that exacerbated the thrombotic potential of blood with increased heparanase levels. Figure 1. Electron microscopy of stents exposed to WT and HPA Tg blood.
Abstract 5536: Strain-dependent Susceptibility for Hypertension in Mice Resides in the Natural Killer Gene Complex
Authors: Zhila Taherzadeh, Ed VanBavel, Judith de Vos, Hanke Matlung, Gert van Montfrans, Lizzy Brewster, Leonard Seghers, Paul H.A. Quax, Erik N.T.P. Bakker
Journal: Circulation (2009)

Hypertension is accompanied by vascular remodeling and inflammation. We tested the hypothesis that the sensitivity to develop hypertension and vascular remodeling depends on the immunological background. Methods: Blood pressure, vascular remodeling and expression of inflammatory cytokines were determined in mice with a genetically determined difference in immune background: C57BL/6 mice and BALB/c mice; and additionally BALB.B6-Cmv1r mice, a congenic strain where the natural killer (NK) gene complex of C57BL/6 mice is introduced in BALB/c background. Mice were treated for 4 weeks with L-NAME (NG-nitro-L-arginine methyl ester). Systemic and local inflammatory responses were quantified in spleen and mesenteric arteries respectively. Results: L-NAME treatment induced a significant increase in mean arterial blood pressure in C57BL/6 mice, from 101±4 mmHg (n=7) to 154±5 mmHg (n=5, P&lt;0.001). This was accompanied by a highly significant increase in vessel wall-to-lumen ratio, from 0.104±0.002 (n= 6) to 0.126±0.003 in L-NAME treated mice (n=6, P&lt;0.001). In BALB/c mice the blood pressure (117±3 mmHg for untreated vs. 126±6 mmHg for L-NAME treated mice) and wall to lumen ratio (0.104±0.003 in untreated vs. 0.113±0.003 in L-NAME treated mice) were not altered after 4 weeks of L-NAME treatment. The congenic BALB.B6-Cmv1r mice showed a similar sensitivity to develop hypertension and vascular remodeling as C57Bl/6 mice: blood pressure increased from 111±11 mmHg to 155±7 mmHg (P&lt;0.01). The wall to lumen ratio increased from 0.107±0.003 to 0.125±0.008 (P&lt;0.05). Expression of inflammatory markers such as IFN γ , IL1, IL10 and CD68 (macrophages) was similar in C57BL/6 and BALB/c, with exception of CD11b, which increased in vessels of C57BL/6 mice only. Confocal microscopy showed that CD11b co-localized with NK1.1, and reflected the recruitment of natural killer cells in C57BL/6 mice. Conclusions: These data show that vascular remodeling and hypertension are strain dependent. We have identified the NK gene complex as important determinant in the genetically determined sensitivity to develop hypertension in mice.
Abstract 5487: Randomized Comparison of Prehospital Initiated Facilitated PCI versus Primary PCI in Acute Myocardial Infarction With &lt; 3 h After Symptom Onset
Authors: Holger Thiele, Ingo Eitel, Claudia Meinberg, Gerd Plock, Dietrich Pfeiffer, Andreas Hartmann, Gerhard Schuler
Journal: Circulation (2009)

Background: Facilitated PCI with fibrinolysis did not show a benefit in comparison to primary PCI in recently published trials. However, a subgroup of patients with high-risk STEMI presenting early after symptom onset, treated with optimal antiplatelet co-medication, and with long transfer times might benefit from a fibrinolytic-based facilitated PCI. Aim of this multicenter trial was therefore to assess the merits of facilitated PCI versus primary PCI in a STEMI network with long transfer distances. Methods: Patients with STEMI (&lt; 3 h after symptom onset) were randomized to either prehospital initiated facilitated PCI using tenecteplase (group A; n=80) or primary PCI (group B; n=80). Optimal prehospital co-medication consisted of 600 mg clopidogrel loading-dose plus aspirin. Glycoprotein IIb/IIIa-inhibitors were given liberally during PCI. The primary endpoint was infarct size assessed by MRI. Secondary endpoints were microvascular obstruction and myocardial salvage assessed by MRI, ST-segment resolution at 90 min, and a composite of death, re-MI, and congestive heart failure at 30 day follow-up. Safety was assessed by major bleeding and any stroke. Results: The median time from symptom-onset to randomization was 64 min (IQR 42; 103) in group A versus 55 min in group B (IQR 27; 91; p=0.26). The median symptom-onset to balloon time was 157 min (IQR 121; 224) versus 131 min (IQR 108; 177; p=0.03). Despite better preinterventional TIMI-flow in group A (76% versus 28% TIMI 2/3; p&lt;0.001) the infarct size was similar in group A versus group B (14.1% of left ventricle [IQR 5.3; 26.7] versus 15.1% [IQR 7.5; 23.3]; p=0.75). There was also no difference in microvascular obstruction, myocardial salvage (p=0.65 and 0.71) and ST-segment resolution (p=0.42). For the combined clinical endpoint there was trend towards higher event rates in group A (18.9% versus 8.1%; p=0.09, relative risk 2.33, 95% confidence interval, 0.98–5.63) without a difference in major bleeding and stroke (8.2% versus 5.5%; p=0.74) Conclusion: In patients with STEMI presenting early after symptom onset a fibrinolytic-based facilitated PCI approach with optimal antiplatelet comedication does not offer a benefit over primary PCI with respect to infarct size and tissue perfusion.
Abstract 5527: Double-Stranded RNA Causes Leakage in Human Pulmonary Artery Endothelial Cell Monolayer
Authors: Zoltán Bálint, Diana Zabini, Gergely A Végh, György Váró, Imola Wilhelm, István A Krizbai, Viktória Kónya, Ákos Heinemann, Horst Olschewski, Andrea Olschewski
Journal: Circulation (2009)

Proper function of endothelial cells is necessary to maintain vessel integrity and to regulate the uptake of circulating substances. Increased levels of circulating RNA may result from excessive cell damage or cancer. We investigated the effect of double-stranded RNA (dsRNA) on monolayer permeability, mechanical properties and intercellular junctions of primary human pulmonary artery endothelial cells (hPAECs). Primary hPAECs were used to investigate shape and mechanical changes caused by Poly I:C (synthetic dsRNA) and dsRNA incubation by means of in situ atomic force microscopy in time. To assess junctional changes, vascular endothelial cadherin staining was performed on control and 24h Poly I:C or dsRNA treated hPAECs. For visualizing cytoskeletal rearrangements, the F-actin network was stained with phalloidin. The cellular barrier properties of hPAECs, as a read-out for cell function, were assessed by measuring changes in the trans-endothelial electric resistance. The in situ atomic force microscopy topographies show a remarkable cell shape change after 2 hours of incubation with Poly I:C. The cell height is increased and they become more elongated. Furthermore, after 6 hours the cell-cell contacts are disrupted and the surface of the culturing dish appeared on the topographies. The local force measurements showed a time dependent stiffening of hPAECs under Poly I:C incubation. Parallel to this effect a 2-fold increase in the Young moduli of the cells was observable, which was further raised to 5-fold increase compared to the initial state, at 24 hours of incubation. The 24h Poly I:C incubated cells presented a decrease in VE-cadherin staining, pointing to loosened cell-cell contacts. The phalloidin staining showed an increased signal at the cell boundaries, confirming the cytoskeletal rearrangement. The electrical resistance of the monolayer was decreased by 50% after 24h Poly I:C or dsRNA treatment, whereas the first, significant drop in the resistance was already observed after 2 hours. In conclusion, our data suggest that double-stranded RNA causes endothelial leakage in human pulmonary endothelial cell monolayer and contributes to barrier disruption as well as endothelial dysfunction.
Abstract 5633: Endothelial Progenitor Cells - A Troian Horse in Systemic Endothelial Damage in Patients With Cardiac Parvovirus B19?
Authors: Caroline Schmidt-Lucke, Sophie Van Linthout, Felicitas Escher, Thomas Zobel, Dirk Lassner, Frank Spillmann, Heinz-Peter Schultheiss, Carsten Tschope
Journal: Circulation (2009)

Detection of the vasculotropic parvovirus B19 (B19V) in endomyocardial biopsies (EMB) is strongly associated with endothelial dysfunction and coronary vasospasms mimicking acute myocardial infarction. B19V replicates primarily in erythroblasts in bone marrow (BM). Endothelial progenitors (EPC) mobilised from BM participate in endothelial cell (EC) regeneration. We, therefore, tested the hypothesis of a systemic EC damage with a direct influence of B19V on EPC and endothelial regeneration. Circulating apoptotic mature endothelial cells (CMAEC; CD45 − CD146 + vWF + Ann + ) and CD45 dim CD34 + KDR + -EPC were quantified from blood by FACS analysis. In 12 patients with B19V (&gt;500 copies/ μ g DNA) in EMB, numbers of CMAEC (27±12.8/ μ l) were 6fold higher compared to 9 healthy controls (p&lt;0.05). There were no transcoronary gradients (TCG) of CMAEC, in contrast (p&lt;0.05) to patients with troponin T negative acute coronary syndromes (n=11; +150%; p&lt;0.05), pointing to a systemically induced EC damage. EPC were significantly higher in patients with B19V compared to controls (0.24±0.1%/PMNC vs. 0.008±0.001%/PMNC; p&lt;0.05). In contrast, EPC-function (CFU-Hill) was reduced in these patients (p&lt;0.05). There was a strong trend towards a negative TCG (−33%±40%, p=0.051) of EPC. Intracardiac SDF-1 α mRNA was 4.6-fold (p&lt;0.05) and CXCR4 mRNA was twofold (p&lt;0.05) increased in B19V+-patients compared to controls, further supporting the hypothesis of a continuous homing. In a second study, CD34 + KDR + -EPC of these patients (n=7) were magnetically separated from BM and blood and B19V DNA with qPCR compared to 5 controls. Compared to controls, only patients had B19V DNA in BM and blood (21399±10378 vs. 16±12 copies/ug DNA in CD34 − , p&lt;0.05) and documenting replication intermediates of B19V, mRNA was detected in CD34 + KDR + -EPC (4 – 1435 copies cDNA/ μ g DNA) in BM and blood. Indeed, in one patient with highest copy numbers of B19V mRNA in CD34 + KDR + in blood, B19V mRNA was detected in EMB. Thus, for the first time we present a virally-induced systemic endothelial damage and B19V infection in EPC with replication intermediates. Continuous circulation of BM-derived, B19V-infected EPC could contribute to impaired endothelial regeneration.
Abstract 5498: The Cumulative Risk of Stroke and Death From Carotid Endarterectomy Followed by Coronary Artery Bypass Surgery in Patients With Concomitant Critical Coronary and Carotid Stenosis
Authors: Zeshan A Rana, Saif Tahsin, Nowwar Mustafa, William S Weintraub, Ehsanur Rahman
Journal: Circulation (2009)

Background: Coexisting critical coronary artery disease (CAD) requiring coronary artery bypass grafting (CABG) and critical carotid stenosis requiring carotid endarterectomy (CEA) is becoming increasingly common. The reported incidence of stroke and death as perioperative complications of CABG range from 1.1 to 3.8% and 1 to 3%, respectively. The cumulative risk of stroke and death in patients undergoing a CEA followed by CABG in a high-risk subset, as described above, is not well defined. Objective: To determine the cumulative risk of in-hospital stroke and death when CEA precedes CABG, and also if a preceding history of transient ischemic attack (TIA)/cerebrovascular accident (CVA) increases the risk of in-hospital stroke and death. Methods: Using ICD-9 codes we identified 114 consecutive patients in our institution who were scheduled to undergo a staged CEA followed by CABG. Records of all patients were reviewed to identify comorbidities and confirm the incidence of all-cause mortality and stroke. The patients were further divided into two groups based on the presence or absence of a prior history of TIA/CVA. Results: Three patients died after CEA, 111 patients proceeded to CABG. Conclusion: Cumulative risk of stroke and death from both procedures should be considered in these patients. Despite CEA procedure aimed at reducing the risk of perioperative stroke from CABG, 3.6% of the patients in our study had a nonfatal CVA after CABG. Patients with a prior history of TIA/CVA did not show a significant increase in periprocedural risk of stroke and death. Table 1 Cumulative risk of nonfatal CVA and Death Table 2 Risk of nonfatal CVA and Death based on a history of TIA/CVA